Mental Health

THE CASE

John C* is a 57-year-old man with hypertension, hyperlipidemia, and schizophrenia who followed up with a psychiatrist monthly at the community mental health center (CMHC). He had no primary care doctor. His psychiatrist referred him to our new Integrated Behavioral Health (IBH) clinic, also located in the CMHC, to see a family physician for complaints of urinary frequency, blurred vision, thirst, and weight loss. An on-site fingerstick revealed his blood glucose to be 357 mg/dL. Given the presumptive diagnosis of diabetes, we checked his bloodwork, prescribed metformin, and referred him for diabetes education. That evening, his lab results showed a hemoglobin A1C > 17%, a basic metabolic panel with an anion gap, ketones in the urine, and a low C-peptide level. We were unable to reach Mr. C by phone for further management.

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

Coordination of behavioral health and primary care can take many forms, from simple synchronized care via referral, to co-located services, to fully integrated care.¹ Reverse integration, the subject of this article, is the provision of primary care in mental health or substance use disorder treatment settings. Published evidence to date regarding this model is minimal. This article describes our experience in developing a model of reverse integration in which family physicians and nurse practitioners are embedded in a CMHC with psychiatric providers, counselors, and social workers to jointly address physical and behavioral health care issues and address social determinants of health.

The rationale for reverse integration

Many individuals with serious mental illness (SMI), including schizophrenia and bipolar disorder, have rates of comorbid chronic physical health conditions that are higher than in the general population. These conditions include obesity, diabetes, metabolic syndrome, cardiovascular disease, chronic obstructive pulmonary disease, HIV, viral hepatitis, and tuberculosis.² Outcomes in the SMI group are also considerably worse than in the general population. People with SMI have a demonstrated loss of up to 32 years of potential life per patient compared with the general-­population average, primarily due to poor physical health.² Maladaptive health behaviors such as poor diet, lack of physical activity, tobacco use, and substance use contribute to this increased mortality.^2,3 Social determinants of poor health are more prevalent among individuals with SMI, and a relative inability to collaborate in one’s own health care due to psychiatric symptoms further exacerbates the challenges.

Patients at a community mental health center may grow tired of conversation or feel overwhelmed in completing multiple tasks. Visits may need to be shorter and more frequent.

Many individuals with SMI receive psychiatric care, case management, counseling, and psychosocial services in CMHCs. Their psychiatric caregiver may be their only regular health care provider. Family physicians—who receive residency training in behavioral health and social determinants of health in community settings—are distinctively capable of improving overall health care outcomes of patients with SMI.

THE ADVANTAGES OF A REVERSE-INTEGRATION PRACTICE MODEL

Delivering primary care in a CMHC with a behavioral health team can benefit patients with SMI and be a satisfying practice for family physicians. Specifically, family physicians

• find that caring for complex patients can be less stressful because they benefit from the knowledge and resources of the CMHC team. The CMHC team offers case management, counseling, employment services, and housing assistance, so the primary care provider and patient are well supported.
• see fewer patients per hour due to higher visit complexity (and coding). In our experience, team-based care and additional time with patients make complex patient care more enjoyable and less frustrating.
• benefit from a situation in which patients feel safe because the CMHC support staff knows them well.

Continue to: Other benefits

Other benefits. When primary care is delivered in a CMHC, there are “huddles” and warm handoffs that allow for bidirectional collaboration and care coordination between the primary care and behavioral health teams in real time. In addition, family medicine residents, medical students, and other learners can be successfully included in an IBH clinic for patients with SMI. The behavioral health team provides the mentorship, education, and modelling of skills needed to work with this population, including limit-setting, empathy, patience, and motivational interviewing.

For their part, learners self-report increased comfort and interest in working with underserved populations and improved awareness of the social determinants of health after these experiences.^4,5 Many patients at CMHCs are comfortable working with learners if continuity is maintained with a primary care provider.

Challenges we’ve faced, tips we can offer

For primary care providers, the unique workplace culture, terminology, and patient population encountered in a CMHC can be challenging. Also challenging can be the combining of things such as electronic medical records (EMRs).

Culture. The CMHC model focuses on team-based care spearheaded by case managers, in contrast to the traditional family medicine model wherein the physician coordinates services. Case managers provide assessments of client stability and readiness to be seen. They also attend primary care visits to support patient interactions, provide important psychosocial information, and assess adherence to care.

Terminology. It’s not always easy to shift to different terminology in this culture. Thus, orientation needs to address things such as the use of the word “patient,” rather than “client,” when charting.

Continue to: The complexities of the patient population

The complexities of the patient population. Many patients treated at a CMHC have a history of trauma, anxiety, and paranoia, requiring adjustments to exam practices such as using smaller speculums, providing more physical space, and offering to leave examination room doors open while patients are waiting.

In addition, individuals with SMI often have multiple health conditions, but they may become uncomfortable with physical closeness, grow tired of conversation, or feel overwhelmed when asked to complete multiple tasks in 1 visit. As a result, visits may need to be shorter and more frequent.

It’s also worth noting that, in our experience, CMHC patients may have a higher no-show rate than typical primary care clinics, requiring flexibility in scheduling. To fill vacant primary care time slots, our front desk staff uses strategies such as waiting lists and offering walk-in visits to patients who are on site for other services.

Ideally, IBH clinics use a single, fully integrated EMR, but this is not always possible. If the primary care and CMHC EMR systems do not connect, then record review and repeat documentation is needed, while care is taken to adhere to the confidentiality standards of a particular state.

Standards of care and state policies. Written standards of care, procedures, and accreditation in CMHCs rarely include provisions for common primary care practice, such as vaccines, in-clinic medications, and implements for simple procedures. To provide these services in our clinic, we ordered/stocked the needed supplies and instituted protocols that mirrored our other outpatient family medicine clinical sites.

Continue to: Some states may have...

Some states may have policies that prevent reimbursement for mental health and primary care services billed on the same day. Seeing a family physician and a psychiatry provider on the same day is convenient for patients and allows for collaboration between providers. But reimbursement rules can vary by state, so starting an IBH clinic like this requires research into local billing regulations.

WANT TO START AN INTEGRATED BEHAVIORAL HEALTH CLINIC?

Detailed instruction on starting a primary care clinic in a CMHC is beyond the scope of this article. However, the Substance Abuse and Mental Health Services Administration provides guidance on integrating primary care services into a local CMHC.⁶ Start by performing a baseline needs assessment of the CMHC and its patients to help guide clinic design. Leadership buy-in is key.

The community mental health center model focuses on team-based care spearheaded by case managers. This contrasts with the family medicine model, in which the physician coordinates services.

Leadership must provide adequate time and financial and technological support. This includes identifying appropriate space for primary care, offering training on using the EMR, and obtaining support from Finance to develop a realistic and competent business plan with an appropriate budgetary runway for start-up. (This may include securing grants in the beginning.)

We recommend starting small and expanding slowly. Once the clinic is operational, formal pathways for good communication are necessary. This includes holding regular team meetings to develop and revise clinic workflows—eg, patient enrollment, protocols, and administrative procedures such as managing medications and vaccinations—as well as addressing space, staffing, and training issues that arise. The IBH transitional leadership structure must include clinicians from both primary care and behavioral health, support staff, and the administration. Finally, you need the right staff—people who are passionate, flexible, and interested in trying something new.

THE CASE

The next day, an outreach was made to the CMHC nurse, who had the case manager go to Mr. C’s house and bring him to the CMHC for education on insulin injection, glucometer use, and diabetes nutrition. Mr. C was prescribed long-acting insulin at bedtime; his metformin was stopped and he was monitored closely.

Continue to: Mr. C now calls...

Mr. C now calls the CMHC nurse every few weeks to report his blood sugar levels, have his insulin dose adjusted, or just say “hello.” He continues to see his psychiatrist every month and his family physician every 4 months. The team collaborates as issues arise. His diabetes has been well controlled for more than 3 years.

The IBH clinic has grown in number of patients and family medicine providers, is self-sustaining, and has expanded services to include hepatitis C treatment. 

THE CASE

John C* is a 57-year-old man with hypertension, hyperlipidemia, and schizophrenia who followed up with a psychiatrist monthly at the community mental health center (CMHC). He had no primary care doctor. His psychiatrist referred him to our new Integrated Behavioral Health (IBH) clinic, also located in the CMHC, to see a family physician for complaints of urinary frequency, blurred vision, thirst, and weight loss. An on-site fingerstick revealed his blood glucose to be 357 mg/dL. Given the presumptive diagnosis of diabetes, we checked his bloodwork, prescribed metformin, and referred him for diabetes education. That evening, his lab results showed a hemoglobin A1C > 17%, a basic metabolic panel with an anion gap, ketones in the urine, and a low C-peptide level. We were unable to reach Mr. C by phone for further management.

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

Coordination of behavioral health and primary care can take many forms, from simple synchronized care via referral, to co-located services, to fully integrated care.¹ Reverse integration, the subject of this article, is the provision of primary care in mental health or substance use disorder treatment settings. Published evidence to date regarding this model is minimal. This article describes our experience in developing a model of reverse integration in which family physicians and nurse practitioners are embedded in a CMHC with psychiatric providers, counselors, and social workers to jointly address physical and behavioral health care issues and address social determinants of health.

The rationale for reverse integration

Many individuals with serious mental illness (SMI), including schizophrenia and bipolar disorder, have rates of comorbid chronic physical health conditions that are higher than in the general population. These conditions include obesity, diabetes, metabolic syndrome, cardiovascular disease, chronic obstructive pulmonary disease, HIV, viral hepatitis, and tuberculosis.² Outcomes in the SMI group are also considerably worse than in the general population. People with SMI have a demonstrated loss of up to 32 years of potential life per patient compared with the general-­population average, primarily due to poor physical health.² Maladaptive health behaviors such as poor diet, lack of physical activity, tobacco use, and substance use contribute to this increased mortality.^2,3 Social determinants of poor health are more prevalent among individuals with SMI, and a relative inability to collaborate in one’s own health care due to psychiatric symptoms further exacerbates the challenges.

Patients at a community mental health center may grow tired of conversation or feel overwhelmed in completing multiple tasks. Visits may need to be shorter and more frequent.

Many individuals with SMI receive psychiatric care, case management, counseling, and psychosocial services in CMHCs. Their psychiatric caregiver may be their only regular health care provider. Family physicians—who receive residency training in behavioral health and social determinants of health in community settings—are distinctively capable of improving overall health care outcomes of patients with SMI.

THE ADVANTAGES OF A REVERSE-INTEGRATION PRACTICE MODEL

Delivering primary care in a CMHC with a behavioral health team can benefit patients with SMI and be a satisfying practice for family physicians. Specifically, family physicians

• find that caring for complex patients can be less stressful because they benefit from the knowledge and resources of the CMHC team. The CMHC team offers case management, counseling, employment services, and housing assistance, so the primary care provider and patient are well supported.
• see fewer patients per hour due to higher visit complexity (and coding). In our experience, team-based care and additional time with patients make complex patient care more enjoyable and less frustrating.
• benefit from a situation in which patients feel safe because the CMHC support staff knows them well.

Continue to: Other benefits

Other benefits. When primary care is delivered in a CMHC, there are “huddles” and warm handoffs that allow for bidirectional collaboration and care coordination between the primary care and behavioral health teams in real time. In addition, family medicine residents, medical students, and other learners can be successfully included in an IBH clinic for patients with SMI. The behavioral health team provides the mentorship, education, and modelling of skills needed to work with this population, including limit-setting, empathy, patience, and motivational interviewing.

For their part, learners self-report increased comfort and interest in working with underserved populations and improved awareness of the social determinants of health after these experiences.^4,5 Many patients at CMHCs are comfortable working with learners if continuity is maintained with a primary care provider.

Challenges we’ve faced, tips we can offer

For primary care providers, the unique workplace culture, terminology, and patient population encountered in a CMHC can be challenging. Also challenging can be the combining of things such as electronic medical records (EMRs).

Culture. The CMHC model focuses on team-based care spearheaded by case managers, in contrast to the traditional family medicine model wherein the physician coordinates services. Case managers provide assessments of client stability and readiness to be seen. They also attend primary care visits to support patient interactions, provide important psychosocial information, and assess adherence to care.

Terminology. It’s not always easy to shift to different terminology in this culture. Thus, orientation needs to address things such as the use of the word “patient,” rather than “client,” when charting.

Continue to: The complexities of the patient population

The complexities of the patient population. Many patients treated at a CMHC have a history of trauma, anxiety, and paranoia, requiring adjustments to exam practices such as using smaller speculums, providing more physical space, and offering to leave examination room doors open while patients are waiting.

In addition, individuals with SMI often have multiple health conditions, but they may become uncomfortable with physical closeness, grow tired of conversation, or feel overwhelmed when asked to complete multiple tasks in 1 visit. As a result, visits may need to be shorter and more frequent.

It’s also worth noting that, in our experience, CMHC patients may have a higher no-show rate than typical primary care clinics, requiring flexibility in scheduling. To fill vacant primary care time slots, our front desk staff uses strategies such as waiting lists and offering walk-in visits to patients who are on site for other services.

Ideally, IBH clinics use a single, fully integrated EMR, but this is not always possible. If the primary care and CMHC EMR systems do not connect, then record review and repeat documentation is needed, while care is taken to adhere to the confidentiality standards of a particular state.

Standards of care and state policies. Written standards of care, procedures, and accreditation in CMHCs rarely include provisions for common primary care practice, such as vaccines, in-clinic medications, and implements for simple procedures. To provide these services in our clinic, we ordered/stocked the needed supplies and instituted protocols that mirrored our other outpatient family medicine clinical sites.

Continue to: Some states may have...

Some states may have policies that prevent reimbursement for mental health and primary care services billed on the same day. Seeing a family physician and a psychiatry provider on the same day is convenient for patients and allows for collaboration between providers. But reimbursement rules can vary by state, so starting an IBH clinic like this requires research into local billing regulations.

WANT TO START AN INTEGRATED BEHAVIORAL HEALTH CLINIC?

Detailed instruction on starting a primary care clinic in a CMHC is beyond the scope of this article. However, the Substance Abuse and Mental Health Services Administration provides guidance on integrating primary care services into a local CMHC.⁶ Start by performing a baseline needs assessment of the CMHC and its patients to help guide clinic design. Leadership buy-in is key.

The community mental health center model focuses on team-based care spearheaded by case managers. This contrasts with the family medicine model, in which the physician coordinates services.

Leadership must provide adequate time and financial and technological support. This includes identifying appropriate space for primary care, offering training on using the EMR, and obtaining support from Finance to develop a realistic and competent business plan with an appropriate budgetary runway for start-up. (This may include securing grants in the beginning.)

We recommend starting small and expanding slowly. Once the clinic is operational, formal pathways for good communication are necessary. This includes holding regular team meetings to develop and revise clinic workflows—eg, patient enrollment, protocols, and administrative procedures such as managing medications and vaccinations—as well as addressing space, staffing, and training issues that arise. The IBH transitional leadership structure must include clinicians from both primary care and behavioral health, support staff, and the administration. Finally, you need the right staff—people who are passionate, flexible, and interested in trying something new.

THE CASE

The next day, an outreach was made to the CMHC nurse, who had the case manager go to Mr. C’s house and bring him to the CMHC for education on insulin injection, glucometer use, and diabetes nutrition. Mr. C was prescribed long-acting insulin at bedtime; his metformin was stopped and he was monitored closely.

Continue to: Mr. C now calls...

Mr. C now calls the CMHC nurse every few weeks to report his blood sugar levels, have his insulin dose adjusted, or just say “hello.” He continues to see his psychiatrist every month and his family physician every 4 months. The team collaborates as issues arise. His diabetes has been well controlled for more than 3 years.

The IBH clinic has grown in number of patients and family medicine providers, is self-sustaining, and has expanded services to include hepatitis C treatment. 

THE CASE

John C* is a 57-year-old man with hypertension, hyperlipidemia, and schizophrenia who followed up with a psychiatrist monthly at the community mental health center (CMHC). He had no primary care doctor. His psychiatrist referred him to our new Integrated Behavioral Health (IBH) clinic, also located in the CMHC, to see a family physician for complaints of urinary frequency, blurred vision, thirst, and weight loss. An on-site fingerstick revealed his blood glucose to be 357 mg/dL. Given the presumptive diagnosis of diabetes, we checked his bloodwork, prescribed metformin, and referred him for diabetes education. That evening, his lab results showed a hemoglobin A1C > 17%, a basic metabolic panel with an anion gap, ketones in the urine, and a low C-peptide level. We were unable to reach Mr. C by phone for further management.

● How would you proceed with this patient?

* The patient’s name has been changed to protect his identity.

Coordination of behavioral health and primary care can take many forms, from simple synchronized care via referral, to co-located services, to fully integrated care.¹ Reverse integration, the subject of this article, is the provision of primary care in mental health or substance use disorder treatment settings. Published evidence to date regarding this model is minimal. This article describes our experience in developing a model of reverse integration in which family physicians and nurse practitioners are embedded in a CMHC with psychiatric providers, counselors, and social workers to jointly address physical and behavioral health care issues and address social determinants of health.

The rationale for reverse integration

Many individuals with serious mental illness (SMI), including schizophrenia and bipolar disorder, have rates of comorbid chronic physical health conditions that are higher than in the general population. These conditions include obesity, diabetes, metabolic syndrome, cardiovascular disease, chronic obstructive pulmonary disease, HIV, viral hepatitis, and tuberculosis.² Outcomes in the SMI group are also considerably worse than in the general population. People with SMI have a demonstrated loss of up to 32 years of potential life per patient compared with the general-­population average, primarily due to poor physical health.² Maladaptive health behaviors such as poor diet, lack of physical activity, tobacco use, and substance use contribute to this increased mortality.^2,3 Social determinants of poor health are more prevalent among individuals with SMI, and a relative inability to collaborate in one’s own health care due to psychiatric symptoms further exacerbates the challenges.

Patients at a community mental health center may grow tired of conversation or feel overwhelmed in completing multiple tasks. Visits may need to be shorter and more frequent.

Many individuals with SMI receive psychiatric care, case management, counseling, and psychosocial services in CMHCs. Their psychiatric caregiver may be their only regular health care provider. Family physicians—who receive residency training in behavioral health and social determinants of health in community settings—are distinctively capable of improving overall health care outcomes of patients with SMI.

THE ADVANTAGES OF A REVERSE-INTEGRATION PRACTICE MODEL

Delivering primary care in a CMHC with a behavioral health team can benefit patients with SMI and be a satisfying practice for family physicians. Specifically, family physicians

• find that caring for complex patients can be less stressful because they benefit from the knowledge and resources of the CMHC team. The CMHC team offers case management, counseling, employment services, and housing assistance, so the primary care provider and patient are well supported.
• see fewer patients per hour due to higher visit complexity (and coding). In our experience, team-based care and additional time with patients make complex patient care more enjoyable and less frustrating.
• benefit from a situation in which patients feel safe because the CMHC support staff knows them well.

Continue to: Other benefits

Other benefits. When primary care is delivered in a CMHC, there are “huddles” and warm handoffs that allow for bidirectional collaboration and care coordination between the primary care and behavioral health teams in real time. In addition, family medicine residents, medical students, and other learners can be successfully included in an IBH clinic for patients with SMI. The behavioral health team provides the mentorship, education, and modelling of skills needed to work with this population, including limit-setting, empathy, patience, and motivational interviewing.

For their part, learners self-report increased comfort and interest in working with underserved populations and improved awareness of the social determinants of health after these experiences.^4,5 Many patients at CMHCs are comfortable working with learners if continuity is maintained with a primary care provider.

Challenges we’ve faced, tips we can offer

For primary care providers, the unique workplace culture, terminology, and patient population encountered in a CMHC can be challenging. Also challenging can be the combining of things such as electronic medical records (EMRs).

Culture. The CMHC model focuses on team-based care spearheaded by case managers, in contrast to the traditional family medicine model wherein the physician coordinates services. Case managers provide assessments of client stability and readiness to be seen. They also attend primary care visits to support patient interactions, provide important psychosocial information, and assess adherence to care.

Terminology. It’s not always easy to shift to different terminology in this culture. Thus, orientation needs to address things such as the use of the word “patient,” rather than “client,” when charting.

Continue to: The complexities of the patient population

The complexities of the patient population. Many patients treated at a CMHC have a history of trauma, anxiety, and paranoia, requiring adjustments to exam practices such as using smaller speculums, providing more physical space, and offering to leave examination room doors open while patients are waiting.

In addition, individuals with SMI often have multiple health conditions, but they may become uncomfortable with physical closeness, grow tired of conversation, or feel overwhelmed when asked to complete multiple tasks in 1 visit. As a result, visits may need to be shorter and more frequent.

It’s also worth noting that, in our experience, CMHC patients may have a higher no-show rate than typical primary care clinics, requiring flexibility in scheduling. To fill vacant primary care time slots, our front desk staff uses strategies such as waiting lists and offering walk-in visits to patients who are on site for other services.

Ideally, IBH clinics use a single, fully integrated EMR, but this is not always possible. If the primary care and CMHC EMR systems do not connect, then record review and repeat documentation is needed, while care is taken to adhere to the confidentiality standards of a particular state.

Standards of care and state policies. Written standards of care, procedures, and accreditation in CMHCs rarely include provisions for common primary care practice, such as vaccines, in-clinic medications, and implements for simple procedures. To provide these services in our clinic, we ordered/stocked the needed supplies and instituted protocols that mirrored our other outpatient family medicine clinical sites.

Continue to: Some states may have...

Some states may have policies that prevent reimbursement for mental health and primary care services billed on the same day. Seeing a family physician and a psychiatry provider on the same day is convenient for patients and allows for collaboration between providers. But reimbursement rules can vary by state, so starting an IBH clinic like this requires research into local billing regulations.

WANT TO START AN INTEGRATED BEHAVIORAL HEALTH CLINIC?

Detailed instruction on starting a primary care clinic in a CMHC is beyond the scope of this article. However, the Substance Abuse and Mental Health Services Administration provides guidance on integrating primary care services into a local CMHC.⁶ Start by performing a baseline needs assessment of the CMHC and its patients to help guide clinic design. Leadership buy-in is key.

The community mental health center model focuses on team-based care spearheaded by case managers. This contrasts with the family medicine model, in which the physician coordinates services.

Leadership must provide adequate time and financial and technological support. This includes identifying appropriate space for primary care, offering training on using the EMR, and obtaining support from Finance to develop a realistic and competent business plan with an appropriate budgetary runway for start-up. (This may include securing grants in the beginning.)

We recommend starting small and expanding slowly. Once the clinic is operational, formal pathways for good communication are necessary. This includes holding regular team meetings to develop and revise clinic workflows—eg, patient enrollment, protocols, and administrative procedures such as managing medications and vaccinations—as well as addressing space, staffing, and training issues that arise. The IBH transitional leadership structure must include clinicians from both primary care and behavioral health, support staff, and the administration. Finally, you need the right staff—people who are passionate, flexible, and interested in trying something new.

THE CASE

The next day, an outreach was made to the CMHC nurse, who had the case manager go to Mr. C’s house and bring him to the CMHC for education on insulin injection, glucometer use, and diabetes nutrition. Mr. C was prescribed long-acting insulin at bedtime; his metformin was stopped and he was monitored closely.

Continue to: Mr. C now calls...

Mr. C now calls the CMHC nurse every few weeks to report his blood sugar levels, have his insulin dose adjusted, or just say “hello.” He continues to see his psychiatrist every month and his family physician every 4 months. The team collaborates as issues arise. His diabetes has been well controlled for more than 3 years.

The IBH clinic has grown in number of patients and family medicine providers, is self-sustaining, and has expanded services to include hepatitis C treatment. 

In 2015-2016, almost 40% of adults and 18.5% of children ages 2 to 19 years in the United States met the definition for obesity—a chronic, relapsing, multifactorial, neurobehavioral disease that results in adverse metabolic, biomechanical, and psychosocial health consequences.^1,2

Tremendous resources have been invested in research, policy development, and public education to try to prevent obesity and its related complications. Despite this, the obesity epidemic has worsened. Here, we explore how to evaluate and treat obese patients in a primary care setting based on the evidence and our experience seeing patients specifically for weight management in a family medicine residency teaching clinic. Pharmacotherapy and surgery, while often helpful, are outside the scope of this article.

It begins withan obesity-friendly office

Patients may have reservations about health care interactions specific to obesity, so it is important to invite them into a setting that facilitates trust and encourages collaboration. Actively engage patients with unhealthy weight by creating an environment where they feel comfortable. Offer wide chairs without armrests, which will easily accommodate patients of all sizes, and ensure that scales have a weight capacity > 400 lb. Communicate a message to patients, via waiting room materials and videos, that focuses on health rather than on weight or body mass index (BMI).

Understand the patient’s goals and challenges

Most (although not all) family physicians will see obese patients in the context of a visit for diabetes, hypertension, or another condition. However, we feel that having visits specifically to address weight in the initial stages of weight management is helpful. The focus of an initial visit should be getting to know how obesity has affected the patient and what his or her motive is in attempting to lose weight. Explore previous attempts at weight loss and establish what the patient’s highest weight has been, as this will impact weight-loss goals. For example, if a patient has weighed > 300 lb all her adult life, it will be extremely difficult to maintain a weight loss of 150 lb.

What else to ask about. Discuss stressors that may be causing increased food intake or poor food choices, including hunger, anger, loneliness, and sleep difficulties. Multidisciplinary care including a psychologist can aid in addressing these issues. Ask patients if they keep a food diary (and if not, recommend that they start), as food diaries are often helpful in elucidating eating and drinking patterns. Determine a patient’s current and past levels of physical activity, as this will guide the fitness goals you develop for him or her.

Screen for psychosocial disorders

As noted earlier, the physical component of obesity is commonly associated with mood disorders such as anxiety and depression.² This requires a multidisciplinary team effort to facilitate healing in the patient struggling with obesity.

Screening for depression and anxiety using standardized tools such as the Patient Health Questionnaire-9 or the Generalized Anxiety Disorder-7 is encouraged in patients who are overweight or obese. Positive screens should be addressed as part of the patient’s treatment plan, as untreated depression and anxiety can inhibit success with weight loss. Be mindful that many medications commonly used to treat these conditions can impair weight loss and even promote weight gain.

Continue to: Don't overlook binge-eating disorders

Don’t overlook binge-eating disorders. Screening specifically for binge-eating disorders is important, given the implications on treatment. The US Department of Veterans Affairs developed a single-item tool for this purpose, the VA Binge Eating Screener. The validated questionnaire asks, “On average, how often have you eaten extremely large amounts of food at one time and felt that your eating was out of control at that time?” Response options are: “Never,” “< 1 time/week,” “1 time/week,” “2-4 times/week,” and “5+ times/week.” A response of ≥ 2 times/week had a sensitivity of 88.9% and specificity of 83.2% for binge-eating disorder.³

For patients who prefer a vegan or vegetarian whole food diet, it is important to note that these diets are generally deficient in vitamin B12 and omega 3 fatty acids, so supplementing these should be considered.

Patients with positive screens should undergo psychotherapy and consider pharmacotherapy with lisdexamfetamine as part of their treatment plan. Caution should be used if recommending intermittent fasting for someone with binge-eating disorder.

Evaluate for underlying causes and assess for comorbidities

Review the patient’s current medication list and history. Many medications can cause weight gain, and weight loss can often be achieved by deprescribing such medications. When feasible, prescribe an alternative medication with a more favorable weight profile. A previous article in The Journal of Family Practice addresses this in more depth.⁴

Laboratory and other testing

Laboratory analysis should primarily be focused on determining treatment alterations specific to underlying pathophysiology. Tests to consider ordering are outlined in the Table. Identification of underlying causes and/or comorbid conditions through such testing can guide medication changes, treatment choices, and diet recommendations.

Diabetes and insulin resistance. The American Diabetes Association recommends screening patients who are overweight or obese and have an additional risk factor for diabetes.⁵ This can be done by obtaining a fasting glucose level, hemoglobin A1C, or a 2-hour oral glucose tolerance test.

Continue to: Since it is known that...

Since it is known that insulin resistance increases the risk for coronary heart disease⁶ and can be treated effectively,⁷ we recommend testing for insulin resistance in patients who do not already have impaired fasting glucose, prediabetes, type 2 diabetes, or impaired glucose tolerance. The homeostatic model assessment for insulin resistance (HOMA-IR)⁸ is a measure of insulin resistance and can be calculated from the fasting insulin and fasting glucose levels. This measure should not be done in isolation, but it can be a useful adjunct in identifying patients with insulin resistance and directing treatment.

If there is evidence of diabetes or insulin resistance, consider treatment with metformin ± initiation of a low-carbohydrate diet.

Hypothyroidism. Consider screening for thyroid dysfunction with a thyroid-stimulating hormone level, if it has not been checked previously.

Renal abnormalities. When serum creatinine levels and glomerular filtration rate indicate chronic kidney disease, consider recommending a protein-restricted diet and adjust medications according to renal dosing protocols, as indicated.

Liver abnormalities, including nonalcoholic fatty liver disease (NAFLD). Monitor aspartate aminotransferase and alanine aminotransferase for resolution of elevations as weight loss is achieved. If abnormalities persist, consider ordering a liver ultrasound. Traditionally, low-calorie diets have been prescribed to treat NAFLD, but evidence shows that low-carbohydrate diets can also be effective.⁹

Continue to: Hypertriglyceridemia and low high-density lipoprotein (HDL) levels

Hypertriglyceridemia and low high-density lipoprotein (HDL) levels. Obtain a lipid panel if one has not been completed within the past several years, as hypertriglyceridemia and low HDL can improve dramatically with specific dietary changes.⁷ Observe trends to assess for resolution of lipid abnormalities as weight loss is achieved.

Gout. Consider checking a uric acid level if you are thinking about recommending a low-carbohydrate diet, particularly in patients with a history of gout, as this may temporarily increase the risk of gout flare.

Hypovitaminosis D. If the patient’s vitamin D level is low, consider appropriate supplementation to support the patient’s overall health. While vitamin D deficiency is common in obesity, the role of supplementation in this population is unclear.

Cardiovascular disease. Consider ordering an electrocardiogram, particularly if you are thinking of prescribing medication therapy. Use caution with initiation of certain medications, such as phentermine or diethylproprion, in the presence of arrhythmias or active cardiovascular disease.

Obstructive sleep apnea. Sleep health is important to address, since obesity is one of the most significant risk factors for obstructive sleep apnea.¹⁰ If your patient is given a diagnosis of OSA following a sleep study, consider treatment with continuous positive airway pressure (CPAP), although there are conflicting studies regarding the effects of CPAP therapy in OSA on weight.^11,12

Continue to: Provide guidance on lifestyle changes

Provide guidance on lifestyle changes

Addressing obesity with patients can be challenging in a busy primary care clinic, but it is imperative to helping patients achieve overall health. Counseling on nutrition and physical activity is an important part of this process.

There is no one-size-fits-all approach to nutrition counseling. Focus on creating individualized plans through which patients can achieve success. Some guidance follows, but also beware of common pitfalls that we have observed in clinical practice which, when addressed, can enable significant weight loss (see “Common pitfalls inhibiting weight loss”).

Choose an approach that works for the patient. Commonly prescribed diets to address obesity include, but are not limited to, Atkins, Dietary Approaches to Stop Hypertension (DASH), Glycemic Index, Mediterranean, Ornish, Paleolithic, Zone, whole food plant-based, and ketogenic. We attempt to engage patients in making the decision on what food choices are appropriate for them considering their food availability, culture, and belief systems. For patients who prefer a vegan or vegetarian whole food diet, it is important to note that these diets are generally deficient in vitamin B12 and omega 3 fatty acids, so supplementing these should be considered.

We recommend that patients focus on eliminating sweetened beverages, such as soft drinks, sports drinks, energy drinks, vitamin water, sweet tea, chocolate milk, and Frappuccinos.

Rather than focus on a specific diet, which may not be sustainable long term, encourage healthy eating habits. Low-­carbohydrate diets have been shown to promote greater weight loss compared to low-fat diets.^13,14 Low-calorie diets can also be quite effective in promoting short-term weight loss. In our clinic, when weight loss is the primary goal, patients are typically encouraged to focus on either calorie or carbohydrate restriction in the initial stages of weight loss.

Eliminate sugar and refined carbohydrates. While rigorous mortality data are not available, more recent trials have demonstrated significant improvements in atherosclerotic cardiovascular disease risk markers, including weight reduction and diabetes reversal, when following a diet that markedly decreases carbohydrate intake, especially sugar and refined carbohydrates.^7,14-17

Continue to: We recommend that patients focus...

We recommend that patients focus on eliminating sweetened beverages, such as soft drinks, sports drinks, energy drinks, vitamin water, sweet tea, chocolate milk, and Frappuccinos. We also recommend substantially limiting or eliminating fruit juices and fruit smoothies due to their high sugar content. For example, 8 oz of orange juice contains 26 g of carbohydrates, which is almost as much as 8 oz of soda.

Compared with eating whole fruit, consuming fruit juice has demonstrated a small amount of weight gain in young children and adults.^18,19 It also has shown a higher insulin response compared with eating the same amount of carbohydrates in whole fruit.²⁰ Better options to drink include water, unsweetened tea, and black coffee. Also, avoid ultra-processed carbohydrates from foods such as breads, cereals, and pastries, as they have similar effects on blood glucose when compared to sugar.²¹

Greatly restrict highly processed foods. The evidence suggests that the availability of processed food is associated with increasing obesity.²² Simple advice to offer your patients is to encourage them to shop the perimeter of the grocery store, where fresh produce, meat, and dairy products are primarily located, and avoid the inner aisles, which contain primarily processed foods. Choosing food items with 5 or fewer ingredients is a starting point when teaching patients to read labels.

Consider limiting saturated fats. In 1977, the Dietary Guidelines for Americans recommended that Americans eat no more than 30% of total energy intake from fat and less than 10% of total energy intake from saturated fat; however, no randomized controlled trials had been done that supported this recommendation and epidemiologic data supporting it were weak.²³

The 2015 Dietary Guidelines continue to recommend limiting total energy intake from saturated fats.²⁴ While there may be a small decrease in cardiovascular risk with a reduction of saturated fat intake and replacement with unsaturated fats, no overall mortality benefit has been demonstrated.^24,25 More research is needed in this area to guide patients in decisions regarding consumption of saturated fats and what types of unsaturated fats are best for their health.

Continue to: Eat only 3 meals per day

Eat only 3 meals per day, but aim for fewer than that. The prescription of fasting is a modality that can be used for weight loss and improved health. Fasting has been a prescribed healing practice for thousands of years.²⁶ It is a practice that virtually every major religion in the world embraces. Studies have demonstrated fasting to be safe and effective in the setting of obesity without significant comorbidities, and it may promote weight loss and metabolic health.^26-29

There are multiple types of intermittent fasting. A practical way for patients to start is by restricting the number of hours in which they eat or drink calorie-containing beverages to 8 hours per day. In our experience, this regimen is easier for most patients to follow than alternate-day or other longer fasts. While there has been caution in the prescription of intermittent fasting due to concerns about causing eating disorders, a recent small study did not demonstrate increased risk of eating disorders with daily intermittent fasting.³⁰

Participate in healthy exercise. Nonpharmacologic office-based strategies for treating obesity have generally focused on increasing exercise and decreasing caloric intake.³¹ While exercise has significant health benefits, including preventing weight regain, evidence does not support monotherapy with exercise as an effective long-term weight-loss strategy.³² There are no studies available that adequately support prescribing an exact dose of exercise.³³ Generally, less than 150 minutes of exercise per week is not effective and more than that does have a dose-related response.³³

Follow up to help patients stay on target

There is no ideal interval for follow-up visits. However, frequent visits—anywhere from weekly to monthly—in the initial stages of weight loss increase the patient’s sense of accountability and, in our experience, seem to be helpful.

Patients may also choose to track their progress by weighing themselves regularly. A small study published in the International Journal of Obesity found that patients who weighed themselves daily had greater and more sustained weight loss than those who didn’t.³⁴ But the decision of whether to weigh one’s self at home should be individualized for each patient.

CORRESPONDENCE
Wesley Eichorn, DO, 1000 Oakland Drive, Kalamazoo, MI 49008; wesley.eichorn@med.wmich.edu

In 2015-2016, almost 40% of adults and 18.5% of children ages 2 to 19 years in the United States met the definition for obesity—a chronic, relapsing, multifactorial, neurobehavioral disease that results in adverse metabolic, biomechanical, and psychosocial health consequences.^1,2

Tremendous resources have been invested in research, policy development, and public education to try to prevent obesity and its related complications. Despite this, the obesity epidemic has worsened. Here, we explore how to evaluate and treat obese patients in a primary care setting based on the evidence and our experience seeing patients specifically for weight management in a family medicine residency teaching clinic. Pharmacotherapy and surgery, while often helpful, are outside the scope of this article.

It begins withan obesity-friendly office

Patients may have reservations about health care interactions specific to obesity, so it is important to invite them into a setting that facilitates trust and encourages collaboration. Actively engage patients with unhealthy weight by creating an environment where they feel comfortable. Offer wide chairs without armrests, which will easily accommodate patients of all sizes, and ensure that scales have a weight capacity > 400 lb. Communicate a message to patients, via waiting room materials and videos, that focuses on health rather than on weight or body mass index (BMI).

Understand the patient’s goals and challenges

Most (although not all) family physicians will see obese patients in the context of a visit for diabetes, hypertension, or another condition. However, we feel that having visits specifically to address weight in the initial stages of weight management is helpful. The focus of an initial visit should be getting to know how obesity has affected the patient and what his or her motive is in attempting to lose weight. Explore previous attempts at weight loss and establish what the patient’s highest weight has been, as this will impact weight-loss goals. For example, if a patient has weighed > 300 lb all her adult life, it will be extremely difficult to maintain a weight loss of 150 lb.

What else to ask about. Discuss stressors that may be causing increased food intake or poor food choices, including hunger, anger, loneliness, and sleep difficulties. Multidisciplinary care including a psychologist can aid in addressing these issues. Ask patients if they keep a food diary (and if not, recommend that they start), as food diaries are often helpful in elucidating eating and drinking patterns. Determine a patient’s current and past levels of physical activity, as this will guide the fitness goals you develop for him or her.

Screen for psychosocial disorders

As noted earlier, the physical component of obesity is commonly associated with mood disorders such as anxiety and depression.² This requires a multidisciplinary team effort to facilitate healing in the patient struggling with obesity.

Screening for depression and anxiety using standardized tools such as the Patient Health Questionnaire-9 or the Generalized Anxiety Disorder-7 is encouraged in patients who are overweight or obese. Positive screens should be addressed as part of the patient’s treatment plan, as untreated depression and anxiety can inhibit success with weight loss. Be mindful that many medications commonly used to treat these conditions can impair weight loss and even promote weight gain.

Continue to: Don't overlook binge-eating disorders

Don’t overlook binge-eating disorders. Screening specifically for binge-eating disorders is important, given the implications on treatment. The US Department of Veterans Affairs developed a single-item tool for this purpose, the VA Binge Eating Screener. The validated questionnaire asks, “On average, how often have you eaten extremely large amounts of food at one time and felt that your eating was out of control at that time?” Response options are: “Never,” “< 1 time/week,” “1 time/week,” “2-4 times/week,” and “5+ times/week.” A response of ≥ 2 times/week had a sensitivity of 88.9% and specificity of 83.2% for binge-eating disorder.³

For patients who prefer a vegan or vegetarian whole food diet, it is important to note that these diets are generally deficient in vitamin B12 and omega 3 fatty acids, so supplementing these should be considered.

Patients with positive screens should undergo psychotherapy and consider pharmacotherapy with lisdexamfetamine as part of their treatment plan. Caution should be used if recommending intermittent fasting for someone with binge-eating disorder.

Evaluate for underlying causes and assess for comorbidities

Review the patient’s current medication list and history. Many medications can cause weight gain, and weight loss can often be achieved by deprescribing such medications. When feasible, prescribe an alternative medication with a more favorable weight profile. A previous article in The Journal of Family Practice addresses this in more depth.⁴

Laboratory and other testing

Laboratory analysis should primarily be focused on determining treatment alterations specific to underlying pathophysiology. Tests to consider ordering are outlined in the Table. Identification of underlying causes and/or comorbid conditions through such testing can guide medication changes, treatment choices, and diet recommendations.

Diabetes and insulin resistance. The American Diabetes Association recommends screening patients who are overweight or obese and have an additional risk factor for diabetes.⁵ This can be done by obtaining a fasting glucose level, hemoglobin A1C, or a 2-hour oral glucose tolerance test.

Continue to: Since it is known that...

Since it is known that insulin resistance increases the risk for coronary heart disease⁶ and can be treated effectively,⁷ we recommend testing for insulin resistance in patients who do not already have impaired fasting glucose, prediabetes, type 2 diabetes, or impaired glucose tolerance. The homeostatic model assessment for insulin resistance (HOMA-IR)⁸ is a measure of insulin resistance and can be calculated from the fasting insulin and fasting glucose levels. This measure should not be done in isolation, but it can be a useful adjunct in identifying patients with insulin resistance and directing treatment.

If there is evidence of diabetes or insulin resistance, consider treatment with metformin ± initiation of a low-carbohydrate diet.

Hypothyroidism. Consider screening for thyroid dysfunction with a thyroid-stimulating hormone level, if it has not been checked previously.

Renal abnormalities. When serum creatinine levels and glomerular filtration rate indicate chronic kidney disease, consider recommending a protein-restricted diet and adjust medications according to renal dosing protocols, as indicated.

Liver abnormalities, including nonalcoholic fatty liver disease (NAFLD). Monitor aspartate aminotransferase and alanine aminotransferase for resolution of elevations as weight loss is achieved. If abnormalities persist, consider ordering a liver ultrasound. Traditionally, low-calorie diets have been prescribed to treat NAFLD, but evidence shows that low-carbohydrate diets can also be effective.⁹

Continue to: Hypertriglyceridemia and low high-density lipoprotein (HDL) levels

Hypertriglyceridemia and low high-density lipoprotein (HDL) levels. Obtain a lipid panel if one has not been completed within the past several years, as hypertriglyceridemia and low HDL can improve dramatically with specific dietary changes.⁷ Observe trends to assess for resolution of lipid abnormalities as weight loss is achieved.

Gout. Consider checking a uric acid level if you are thinking about recommending a low-carbohydrate diet, particularly in patients with a history of gout, as this may temporarily increase the risk of gout flare.

Hypovitaminosis D. If the patient’s vitamin D level is low, consider appropriate supplementation to support the patient’s overall health. While vitamin D deficiency is common in obesity, the role of supplementation in this population is unclear.

Cardiovascular disease. Consider ordering an electrocardiogram, particularly if you are thinking of prescribing medication therapy. Use caution with initiation of certain medications, such as phentermine or diethylproprion, in the presence of arrhythmias or active cardiovascular disease.

Obstructive sleep apnea. Sleep health is important to address, since obesity is one of the most significant risk factors for obstructive sleep apnea.¹⁰ If your patient is given a diagnosis of OSA following a sleep study, consider treatment with continuous positive airway pressure (CPAP), although there are conflicting studies regarding the effects of CPAP therapy in OSA on weight.^11,12

Continue to: Provide guidance on lifestyle changes

Provide guidance on lifestyle changes

Addressing obesity with patients can be challenging in a busy primary care clinic, but it is imperative to helping patients achieve overall health. Counseling on nutrition and physical activity is an important part of this process.

There is no one-size-fits-all approach to nutrition counseling. Focus on creating individualized plans through which patients can achieve success. Some guidance follows, but also beware of common pitfalls that we have observed in clinical practice which, when addressed, can enable significant weight loss (see “Common pitfalls inhibiting weight loss”).

Choose an approach that works for the patient. Commonly prescribed diets to address obesity include, but are not limited to, Atkins, Dietary Approaches to Stop Hypertension (DASH), Glycemic Index, Mediterranean, Ornish, Paleolithic, Zone, whole food plant-based, and ketogenic. We attempt to engage patients in making the decision on what food choices are appropriate for them considering their food availability, culture, and belief systems. For patients who prefer a vegan or vegetarian whole food diet, it is important to note that these diets are generally deficient in vitamin B12 and omega 3 fatty acids, so supplementing these should be considered.

We recommend that patients focus on eliminating sweetened beverages, such as soft drinks, sports drinks, energy drinks, vitamin water, sweet tea, chocolate milk, and Frappuccinos.

Rather than focus on a specific diet, which may not be sustainable long term, encourage healthy eating habits. Low-­carbohydrate diets have been shown to promote greater weight loss compared to low-fat diets.^13,14 Low-calorie diets can also be quite effective in promoting short-term weight loss. In our clinic, when weight loss is the primary goal, patients are typically encouraged to focus on either calorie or carbohydrate restriction in the initial stages of weight loss.

Eliminate sugar and refined carbohydrates. While rigorous mortality data are not available, more recent trials have demonstrated significant improvements in atherosclerotic cardiovascular disease risk markers, including weight reduction and diabetes reversal, when following a diet that markedly decreases carbohydrate intake, especially sugar and refined carbohydrates.^7,14-17

Continue to: We recommend that patients focus...

We recommend that patients focus on eliminating sweetened beverages, such as soft drinks, sports drinks, energy drinks, vitamin water, sweet tea, chocolate milk, and Frappuccinos. We also recommend substantially limiting or eliminating fruit juices and fruit smoothies due to their high sugar content. For example, 8 oz of orange juice contains 26 g of carbohydrates, which is almost as much as 8 oz of soda.

Compared with eating whole fruit, consuming fruit juice has demonstrated a small amount of weight gain in young children and adults.^18,19 It also has shown a higher insulin response compared with eating the same amount of carbohydrates in whole fruit.²⁰ Better options to drink include water, unsweetened tea, and black coffee. Also, avoid ultra-processed carbohydrates from foods such as breads, cereals, and pastries, as they have similar effects on blood glucose when compared to sugar.²¹

Greatly restrict highly processed foods. The evidence suggests that the availability of processed food is associated with increasing obesity.²² Simple advice to offer your patients is to encourage them to shop the perimeter of the grocery store, where fresh produce, meat, and dairy products are primarily located, and avoid the inner aisles, which contain primarily processed foods. Choosing food items with 5 or fewer ingredients is a starting point when teaching patients to read labels.

Consider limiting saturated fats. In 1977, the Dietary Guidelines for Americans recommended that Americans eat no more than 30% of total energy intake from fat and less than 10% of total energy intake from saturated fat; however, no randomized controlled trials had been done that supported this recommendation and epidemiologic data supporting it were weak.²³

The 2015 Dietary Guidelines continue to recommend limiting total energy intake from saturated fats.²⁴ While there may be a small decrease in cardiovascular risk with a reduction of saturated fat intake and replacement with unsaturated fats, no overall mortality benefit has been demonstrated.^24,25 More research is needed in this area to guide patients in decisions regarding consumption of saturated fats and what types of unsaturated fats are best for their health.

Continue to: Eat only 3 meals per day

Eat only 3 meals per day, but aim for fewer than that. The prescription of fasting is a modality that can be used for weight loss and improved health. Fasting has been a prescribed healing practice for thousands of years.²⁶ It is a practice that virtually every major religion in the world embraces. Studies have demonstrated fasting to be safe and effective in the setting of obesity without significant comorbidities, and it may promote weight loss and metabolic health.^26-29

There are multiple types of intermittent fasting. A practical way for patients to start is by restricting the number of hours in which they eat or drink calorie-containing beverages to 8 hours per day. In our experience, this regimen is easier for most patients to follow than alternate-day or other longer fasts. While there has been caution in the prescription of intermittent fasting due to concerns about causing eating disorders, a recent small study did not demonstrate increased risk of eating disorders with daily intermittent fasting.³⁰

Participate in healthy exercise. Nonpharmacologic office-based strategies for treating obesity have generally focused on increasing exercise and decreasing caloric intake.³¹ While exercise has significant health benefits, including preventing weight regain, evidence does not support monotherapy with exercise as an effective long-term weight-loss strategy.³² There are no studies available that adequately support prescribing an exact dose of exercise.³³ Generally, less than 150 minutes of exercise per week is not effective and more than that does have a dose-related response.³³

Follow up to help patients stay on target

There is no ideal interval for follow-up visits. However, frequent visits—anywhere from weekly to monthly—in the initial stages of weight loss increase the patient’s sense of accountability and, in our experience, seem to be helpful.

Patients may also choose to track their progress by weighing themselves regularly. A small study published in the International Journal of Obesity found that patients who weighed themselves daily had greater and more sustained weight loss than those who didn’t.³⁴ But the decision of whether to weigh one’s self at home should be individualized for each patient.

CORRESPONDENCE
Wesley Eichorn, DO, 1000 Oakland Drive, Kalamazoo, MI 49008; wesley.eichorn@med.wmich.edu

In 2015-2016, almost 40% of adults and 18.5% of children ages 2 to 19 years in the United States met the definition for obesity—a chronic, relapsing, multifactorial, neurobehavioral disease that results in adverse metabolic, biomechanical, and psychosocial health consequences.^1,2

Tremendous resources have been invested in research, policy development, and public education to try to prevent obesity and its related complications. Despite this, the obesity epidemic has worsened. Here, we explore how to evaluate and treat obese patients in a primary care setting based on the evidence and our experience seeing patients specifically for weight management in a family medicine residency teaching clinic. Pharmacotherapy and surgery, while often helpful, are outside the scope of this article.

It begins withan obesity-friendly office

Patients may have reservations about health care interactions specific to obesity, so it is important to invite them into a setting that facilitates trust and encourages collaboration. Actively engage patients with unhealthy weight by creating an environment where they feel comfortable. Offer wide chairs without armrests, which will easily accommodate patients of all sizes, and ensure that scales have a weight capacity > 400 lb. Communicate a message to patients, via waiting room materials and videos, that focuses on health rather than on weight or body mass index (BMI).

Understand the patient’s goals and challenges

Most (although not all) family physicians will see obese patients in the context of a visit for diabetes, hypertension, or another condition. However, we feel that having visits specifically to address weight in the initial stages of weight management is helpful. The focus of an initial visit should be getting to know how obesity has affected the patient and what his or her motive is in attempting to lose weight. Explore previous attempts at weight loss and establish what the patient’s highest weight has been, as this will impact weight-loss goals. For example, if a patient has weighed > 300 lb all her adult life, it will be extremely difficult to maintain a weight loss of 150 lb.

What else to ask about. Discuss stressors that may be causing increased food intake or poor food choices, including hunger, anger, loneliness, and sleep difficulties. Multidisciplinary care including a psychologist can aid in addressing these issues. Ask patients if they keep a food diary (and if not, recommend that they start), as food diaries are often helpful in elucidating eating and drinking patterns. Determine a patient’s current and past levels of physical activity, as this will guide the fitness goals you develop for him or her.

Screen for psychosocial disorders

As noted earlier, the physical component of obesity is commonly associated with mood disorders such as anxiety and depression.² This requires a multidisciplinary team effort to facilitate healing in the patient struggling with obesity.

Screening for depression and anxiety using standardized tools such as the Patient Health Questionnaire-9 or the Generalized Anxiety Disorder-7 is encouraged in patients who are overweight or obese. Positive screens should be addressed as part of the patient’s treatment plan, as untreated depression and anxiety can inhibit success with weight loss. Be mindful that many medications commonly used to treat these conditions can impair weight loss and even promote weight gain.

Continue to: Don't overlook binge-eating disorders

Don’t overlook binge-eating disorders. Screening specifically for binge-eating disorders is important, given the implications on treatment. The US Department of Veterans Affairs developed a single-item tool for this purpose, the VA Binge Eating Screener. The validated questionnaire asks, “On average, how often have you eaten extremely large amounts of food at one time and felt that your eating was out of control at that time?” Response options are: “Never,” “< 1 time/week,” “1 time/week,” “2-4 times/week,” and “5+ times/week.” A response of ≥ 2 times/week had a sensitivity of 88.9% and specificity of 83.2% for binge-eating disorder.³

For patients who prefer a vegan or vegetarian whole food diet, it is important to note that these diets are generally deficient in vitamin B12 and omega 3 fatty acids, so supplementing these should be considered.

Patients with positive screens should undergo psychotherapy and consider pharmacotherapy with lisdexamfetamine as part of their treatment plan. Caution should be used if recommending intermittent fasting for someone with binge-eating disorder.

Evaluate for underlying causes and assess for comorbidities

Review the patient’s current medication list and history. Many medications can cause weight gain, and weight loss can often be achieved by deprescribing such medications. When feasible, prescribe an alternative medication with a more favorable weight profile. A previous article in The Journal of Family Practice addresses this in more depth.⁴

Laboratory and other testing

Laboratory analysis should primarily be focused on determining treatment alterations specific to underlying pathophysiology. Tests to consider ordering are outlined in the Table. Identification of underlying causes and/or comorbid conditions through such testing can guide medication changes, treatment choices, and diet recommendations.

Diabetes and insulin resistance. The American Diabetes Association recommends screening patients who are overweight or obese and have an additional risk factor for diabetes.⁵ This can be done by obtaining a fasting glucose level, hemoglobin A1C, or a 2-hour oral glucose tolerance test.

Continue to: Since it is known that...

Since it is known that insulin resistance increases the risk for coronary heart disease⁶ and can be treated effectively,⁷ we recommend testing for insulin resistance in patients who do not already have impaired fasting glucose, prediabetes, type 2 diabetes, or impaired glucose tolerance. The homeostatic model assessment for insulin resistance (HOMA-IR)⁸ is a measure of insulin resistance and can be calculated from the fasting insulin and fasting glucose levels. This measure should not be done in isolation, but it can be a useful adjunct in identifying patients with insulin resistance and directing treatment.

If there is evidence of diabetes or insulin resistance, consider treatment with metformin ± initiation of a low-carbohydrate diet.

Hypothyroidism. Consider screening for thyroid dysfunction with a thyroid-stimulating hormone level, if it has not been checked previously.

Renal abnormalities. When serum creatinine levels and glomerular filtration rate indicate chronic kidney disease, consider recommending a protein-restricted diet and adjust medications according to renal dosing protocols, as indicated.

Liver abnormalities, including nonalcoholic fatty liver disease (NAFLD). Monitor aspartate aminotransferase and alanine aminotransferase for resolution of elevations as weight loss is achieved. If abnormalities persist, consider ordering a liver ultrasound. Traditionally, low-calorie diets have been prescribed to treat NAFLD, but evidence shows that low-carbohydrate diets can also be effective.⁹

Continue to: Hypertriglyceridemia and low high-density lipoprotein (HDL) levels

Hypertriglyceridemia and low high-density lipoprotein (HDL) levels. Obtain a lipid panel if one has not been completed within the past several years, as hypertriglyceridemia and low HDL can improve dramatically with specific dietary changes.⁷ Observe trends to assess for resolution of lipid abnormalities as weight loss is achieved.

Gout. Consider checking a uric acid level if you are thinking about recommending a low-carbohydrate diet, particularly in patients with a history of gout, as this may temporarily increase the risk of gout flare.

Hypovitaminosis D. If the patient’s vitamin D level is low, consider appropriate supplementation to support the patient’s overall health. While vitamin D deficiency is common in obesity, the role of supplementation in this population is unclear.

Cardiovascular disease. Consider ordering an electrocardiogram, particularly if you are thinking of prescribing medication therapy. Use caution with initiation of certain medications, such as phentermine or diethylproprion, in the presence of arrhythmias or active cardiovascular disease.

Obstructive sleep apnea. Sleep health is important to address, since obesity is one of the most significant risk factors for obstructive sleep apnea.¹⁰ If your patient is given a diagnosis of OSA following a sleep study, consider treatment with continuous positive airway pressure (CPAP), although there are conflicting studies regarding the effects of CPAP therapy in OSA on weight.^11,12

Continue to: Provide guidance on lifestyle changes

Provide guidance on lifestyle changes

Addressing obesity with patients can be challenging in a busy primary care clinic, but it is imperative to helping patients achieve overall health. Counseling on nutrition and physical activity is an important part of this process.

There is no one-size-fits-all approach to nutrition counseling. Focus on creating individualized plans through which patients can achieve success. Some guidance follows, but also beware of common pitfalls that we have observed in clinical practice which, when addressed, can enable significant weight loss (see “Common pitfalls inhibiting weight loss”).

Choose an approach that works for the patient. Commonly prescribed diets to address obesity include, but are not limited to, Atkins, Dietary Approaches to Stop Hypertension (DASH), Glycemic Index, Mediterranean, Ornish, Paleolithic, Zone, whole food plant-based, and ketogenic. We attempt to engage patients in making the decision on what food choices are appropriate for them considering their food availability, culture, and belief systems. For patients who prefer a vegan or vegetarian whole food diet, it is important to note that these diets are generally deficient in vitamin B12 and omega 3 fatty acids, so supplementing these should be considered.

We recommend that patients focus on eliminating sweetened beverages, such as soft drinks, sports drinks, energy drinks, vitamin water, sweet tea, chocolate milk, and Frappuccinos.

Rather than focus on a specific diet, which may not be sustainable long term, encourage healthy eating habits. Low-­carbohydrate diets have been shown to promote greater weight loss compared to low-fat diets.^13,14 Low-calorie diets can also be quite effective in promoting short-term weight loss. In our clinic, when weight loss is the primary goal, patients are typically encouraged to focus on either calorie or carbohydrate restriction in the initial stages of weight loss.

Eliminate sugar and refined carbohydrates. While rigorous mortality data are not available, more recent trials have demonstrated significant improvements in atherosclerotic cardiovascular disease risk markers, including weight reduction and diabetes reversal, when following a diet that markedly decreases carbohydrate intake, especially sugar and refined carbohydrates.^7,14-17

Continue to: We recommend that patients focus...

We recommend that patients focus on eliminating sweetened beverages, such as soft drinks, sports drinks, energy drinks, vitamin water, sweet tea, chocolate milk, and Frappuccinos. We also recommend substantially limiting or eliminating fruit juices and fruit smoothies due to their high sugar content. For example, 8 oz of orange juice contains 26 g of carbohydrates, which is almost as much as 8 oz of soda.

Compared with eating whole fruit, consuming fruit juice has demonstrated a small amount of weight gain in young children and adults.^18,19 It also has shown a higher insulin response compared with eating the same amount of carbohydrates in whole fruit.²⁰ Better options to drink include water, unsweetened tea, and black coffee. Also, avoid ultra-processed carbohydrates from foods such as breads, cereals, and pastries, as they have similar effects on blood glucose when compared to sugar.²¹

Greatly restrict highly processed foods. The evidence suggests that the availability of processed food is associated with increasing obesity.²² Simple advice to offer your patients is to encourage them to shop the perimeter of the grocery store, where fresh produce, meat, and dairy products are primarily located, and avoid the inner aisles, which contain primarily processed foods. Choosing food items with 5 or fewer ingredients is a starting point when teaching patients to read labels.

Consider limiting saturated fats. In 1977, the Dietary Guidelines for Americans recommended that Americans eat no more than 30% of total energy intake from fat and less than 10% of total energy intake from saturated fat; however, no randomized controlled trials had been done that supported this recommendation and epidemiologic data supporting it were weak.²³

The 2015 Dietary Guidelines continue to recommend limiting total energy intake from saturated fats.²⁴ While there may be a small decrease in cardiovascular risk with a reduction of saturated fat intake and replacement with unsaturated fats, no overall mortality benefit has been demonstrated.^24,25 More research is needed in this area to guide patients in decisions regarding consumption of saturated fats and what types of unsaturated fats are best for their health.

Continue to: Eat only 3 meals per day

Eat only 3 meals per day, but aim for fewer than that. The prescription of fasting is a modality that can be used for weight loss and improved health. Fasting has been a prescribed healing practice for thousands of years.²⁶ It is a practice that virtually every major religion in the world embraces. Studies have demonstrated fasting to be safe and effective in the setting of obesity without significant comorbidities, and it may promote weight loss and metabolic health.^26-29

There are multiple types of intermittent fasting. A practical way for patients to start is by restricting the number of hours in which they eat or drink calorie-containing beverages to 8 hours per day. In our experience, this regimen is easier for most patients to follow than alternate-day or other longer fasts. While there has been caution in the prescription of intermittent fasting due to concerns about causing eating disorders, a recent small study did not demonstrate increased risk of eating disorders with daily intermittent fasting.³⁰

Participate in healthy exercise. Nonpharmacologic office-based strategies for treating obesity have generally focused on increasing exercise and decreasing caloric intake.³¹ While exercise has significant health benefits, including preventing weight regain, evidence does not support monotherapy with exercise as an effective long-term weight-loss strategy.³² There are no studies available that adequately support prescribing an exact dose of exercise.³³ Generally, less than 150 minutes of exercise per week is not effective and more than that does have a dose-related response.³³

Follow up to help patients stay on target

There is no ideal interval for follow-up visits. However, frequent visits—anywhere from weekly to monthly—in the initial stages of weight loss increase the patient’s sense of accountability and, in our experience, seem to be helpful.

Patients may also choose to track their progress by weighing themselves regularly. A small study published in the International Journal of Obesity found that patients who weighed themselves daily had greater and more sustained weight loss than those who didn’t.³⁴ But the decision of whether to weigh one’s self at home should be individualized for each patient.

CORRESPONDENCE
Wesley Eichorn, DO, 1000 Oakland Drive, Kalamazoo, MI 49008; wesley.eichorn@med.wmich.edu

An estimated 20 million patients in the United States have a substance use disorder (SUD), with hundreds of millions of prescriptions for controlled substances written annually. Consequently, urine drug screening (UDS) has become widely utilized to evaluate and treat patients with an SUD or on chronic opioid or benzodiazepine therapy.¹

Used appropriately, UDS can be a valuable tool; there is ample evidence, however, that it has been misused, by some physicians, to stigmatize patients who use drugs of abuse,² profile patients racially,² profit from excessive testing,³ and inappropriately discontinue treatment.⁴

A patient-centered approach. We have extensive clinical experience in the use and interpretation of urine toxicology, serving as clinical leads in busy family medicine residency practices that care for patients with SUDs, and are often consulted regarding patients on chronic opioid or benzodiazepine therapy. We have encountered countless situations in which the correct interpretation of UDS is critical to providing care.

Over time, and after considerable trial and error, we developed the patient-centered approach to urine toxicology described in this article. We believe that the medical evidence strongly supports our approach to the appropriate use and interpretation of urine toxicology in clinical practice. Our review here is intended as a resource when you consider implementing a UDS protocol or are struggling with the management of unexpected results.

Urine toxicology for therapeutic drug monitoring

Prescribing a controlled substance carries inherent risks, including diversion, nonmedical use, and development of an SUD. Prescribed medications, particularly opioids and benzodiazepines, have been linked to a large increase in overdose deaths over the past decade.⁵ Several strategies have been investigated to mitigate risk (see “How frequently should a patient be tested?,” later in the article).

Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed a substance use disorder—has been shown to be highly inaccurate.

Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed an SUD—has been shown to be highly inaccurate. Implicit racial bias might affect the physician’s judgment, leading to changes in testing and test interpretation. For example, Black patients were found to be 10% more likely to have drug screening ordered while being treated with long-term opioid therapy and 2 to 3 times more likely to have their medication discontinued as a result of a marijuana- or cocaine-positive test.²

Other studies have shown that testing patients for “bad behavior,” so to speak—reporting a prescription lost or stolen, consuming more than the prescribed dosage, visiting the office without an appointment, having multiple drug intolerances and allergies, and making frequent telephone calls to the practice—is ineffective.⁶ Patients with these behaviors were slightly more likely to unexpectedly test positive, or negative, on their UDS; however, many patients without suspect behavior also were found to have abnormal toxicology results.⁶ Data do not support therapeutic drug monitoring only of patients selected on the basis of aberrant behavior.⁶

Continue to: Questions and concerns about urine drug screening

 

 

Questions and concerns about urine drug screening

Why not just ask the patient? Studies have evaluated whether patient self-reporting of adherence is a feasible alternative to laboratory drug screening. Regrettably, patients have repeatedly been shown to underreport their use of both prescribed and illicit drugs.^7,8

That question leads to another: Why do patients lie to their physician? It is easy to assume malicious intent, but a variety of obstacles might dissuade a patient from being fully truthful with their physician:

• Monetary gain. A small, but real, percentage of medications are diverted by patients for this reason.⁹
• Addiction, pseudo-addiction due to tolerance, and self-medication for psychological symptoms are clinically treatable syndromes that can lead to underreporting of prescribed and nonprescribed drug and alcohol use.
• Shame. Addiction is a highly stigmatized disease, and patients might simply be ashamed to admit that they need treatment: 13% to 38% of patients receiving chronic opioid therapy in a pain management or primary care setting have a clinically diagnosable SUD.^10,11

Is consent needed to test or to share test results? Historically, UDS has been performed on patients without their consent or knowledge.¹² Patients give a urine specimen to their physician for a variety of reasons; it seems easy to “add on” UDS. Evidence is clear, however, that confronting a patient about an unexpected test result can make the clinical outcome worse—often resulting in irreparable damage to the patient–­physician relationship.^12,13 Unless the patient is experiencing a medical emergency, guidelines unanimously recommend obtaining consent prior to testing.^1,5,14

Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months.

Federal law requires written permission from the patient for the physician to disclose information about alcohol or substance use, unless the information is expressly needed to provide care during a medical emergency. Substance use is highly stigmatized, and patients might—legitimately—fear that sharing their history could undermine their care.^1,12,14

How frequently should a patient be tested? Experts recommend utilizing a risk-based strategy to determine the frequency of UDS.^1,5,15 Validated risk-assessment questionnaires include:

• Opioid Risk Tool for Opioid Use Disorder (ORT-OUD)^a
• Screener and Opioid Assessment for Patients With Pain–Revised (SOAPP-R)^b
• Diagnosis, Intractability, Risk and Efficacy (DIRE)^c
• Addiction Behaviors Checklist (ABC).^d

Continue to: Each of these tools...

Each of these tools takes less than 5 minutes to administer and can be used by a primary care physician to objectively quantify the risk of prescribing; there is no evidence for the use of 1 of these screeners over the others.¹⁵ It is recommended that you choose a questionnaire that works for you and incorporate the risk assessment into prescribing any high-risk medication.^1,5,15

Once you have completed an initial risk assessment, the frequency of UDS can be based on ongoing assessment that incorporates baseline testing, patient self-reporting, toxicology results, behavioral monitoring, and state database monitoring through a prescription drug monitoring program. Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months (FIGURE).¹⁵

Many state and federal agencies, health systems, employers, and insurers mandate the frequency of testing through guidelines or legislation. These regulations often are inconsistent with the newest medical evidence.¹⁵ Consult local guidelines and review the medical evidence and consensus recommendations on UDS.

What are the cost considerations in providing UDS? Insurers have been billed as much as $4000 for definitive chromatography testing (described later).³ This has led to insurance fraud, when drug-testing practices with a financial interest routinely use large and expensive test panels, test too frequently, or unnecessarily send for confirmatory or quantitative analysis of all positive tests.^3,14 Often, insurers refuse to pay for unnecessary testing, leaving patients with significant indebtedness.^3,14 Take time to review the evidence and consensus recommendations on UDS to avoid waste, potential accusations of fraud, and financial burden on your patients.

Urine toxicology for addiction treatment

UDS protocols in addiction settings are often different from those in which a controlled substance is being prescribed.

Continue to: Routine and random testing

Routine and random testing. Two common practices when treating addiction are to perform UDS on all patients, at every visit, or to test randomly.¹ These practices can be problematic, however. Routine testing at every visit can make urine-tampering more likely and is often unnecessary for stable patients. Random testing can reduce the risk of urine-tampering, but it is often difficult for primary care clinics to institute such a protocol. Some clinics have patients provide a urine specimen at every visit and then only send tests to the lab based on randomization.¹

Contingency management—a behavioral intervention in which a patient is rewarded, or their performance is reinforced, when they display evidence of positive change—is the most effective strategy used in addiction medicine to determine the frequency of patient visits and UDS.^14,16 High-risk patients with self-reported active substance use or UDS results consistent with substance use, or both, are seen more often; as their addiction behavior diminishes, visits and UDS become less frequent. If addiction behavior increases, the patient is seen more often. Keep in mind that addiction behavior decreases over months of treatment, not immediately upon initiation.^14,17 For contingency management to be successful, patient-centered interviewing and UDS will need to be employed frequently as the patient works toward meaningful change.¹⁴

The technology of urine drug screening

Two general techniques are used for UDS: immunoassay and chromatography. Each plays an important role in clinical practice; physicians must therefore maintain a basic understanding of the mechanism of each technique and their comparable advantages and disadvantages. Such an understanding allows for (1) matching the appropriate technique to the individual clinical scenario and (2) correctly interpreting results.

Immunoassay technology is used for point-of-care and rapid laboratory UDS, using antibodies to detect the drug or drug metabolite of interest. Antibodies utilized in immunoassays are designed to selectively bind a specific antigen—ie, a unique chemical structure within the drug of choice. Once bound, the antigen–antibody complex can be exploited for detection through various methods.

Chromatography–mass ­spectrometry is considered the gold standard for UDS, yielding confirmatory results. This is a 2-step process: Chromatography separates components within a specimen; mass spectrometry then identifies those components. Most laboratories employ liquid, rather than gas, chromatography. The specificity of the liquid chromatography–mass spectrometry method is such that a false-positive result is, essentially, impossible.¹⁸

Continue to: How is the appropriate tests elected for urine drug screening?

 

 

How is the appropriate tests elected for urine drug screening?

Variables that influence your choice of the proper test method include the clinical question at hand; cost; the urgency of obtaining results; and the stakes in that decision (ie, will the results be used to simply change the dosage of a medication or, of greater consequence, to determine fitness for employment or inform criminal justice decisions?). Each method of UDS has advantages that can be utilized and disadvantages that must be considered to obtain an accurate and useful result.

Immunoassay provides rapid results, is relatively easy to perform, and is, comparatively, inexpensive.^1,14 The speed of results makes this method particularly useful in settings such as the emergency department, where rapid results are crucial. Ease of use makes immunoassay ideal for the office, where non-laboratory staff can be trained to properly administer the test.

A major disadvantage of immunoassay technology, however, is interference resulting in both false-positive and false-negative results, which is discussed in detail in the next section. Immunoassay should be considered a screening test that yields presumptive results.

Liquid chromatography–mass spectrometry is exquisitely specific and provides confirmatory test results—major advantages of the method. However, specificity comes at a price: significantly increased cost and longer wait time for results (typically days, if specimens are sent out to a laboratory). These barriers can make it impractical to employ this method in routine practice.

Interpretation of results: Not so fast

Interpreting UDS results is not as simple as noting a positive or negative result. Physicians must understand the concept of interference, so that results can be appropriately interpreted and confirmed. This is crucial when results influence clinical decisions; inappropriate action, taken on the basis of presumptive results, can have severe consequences for the patient–provider relationship and the treatment plan.^1,14

Continue to: Interference falls into 2 categories...

Interference falls into 2 categories: variables inherent in the testing process and patient variables.

Obtain consent prior to performing urine drug screening, even if you are already collecting a specimen for other testing.

Antibody cross-reactivity. A major disadvantage of immunoassay technology is interference that results in false-positive and false-negative results.^19,20 The source of this interference is antibody cross-­reactivity—the degree to which an antibody binds to structurally similar compounds. Antibody–­antigen interactions are incredibly complex; although assay antibodies are engineered to specifically detect a drug class of interest, reactivity with other, structurally similar compounds is unavoidable.

Nevertheless, cross-reactivity is a useful phenomenon that allows broad testing for multiple drugs within a class. For example, most point-of-care tests for benzodiazepines reliably detect diazepam and chlordiazepoxide. Likewise, opiate tests reliably detect natural opiates, such as morphine and codeine. Cross-reactivity is not limitless, however; most benzodiazepine immunoassays have poor reactivity to clonazepam and lorazepam, making it possible that a patient taking clonazepam tests negative for benzodiazepine on an immunoassay.^14,20 Similarly, standard opioid tests have only moderate cross-reactivity for semisynthetic opioids, such as hydrocodone and hydromorphone; poor cross-r­eactivity for oxycodone and oxymorphone; and essentially no cross-­reactivity for full synthetics, such as fentanyl and methadone.¹⁴

It is the responsibility of the ordering physician to understand cross-reactivity to various drugs within a testing class.

Routine urine drug screening at every visit can make urine tampering more likely and is often unnecessary for stable patients.

Whereas weak cross-reactivity to drugs within a class can be a source of false-negative results, cross-reactivity to drugs outside the class of interest is a source of false-positive results. An extensive review of drugs that cause false-positive immunoassay screening tests is outside the scope of this article; commonly prescribed medications implicated in false-positive results are listed in TABLE 1.¹⁹

Continue to: In general...

In general, amphetamine immunoassays produce frequent false-positive results, whereas cocaine and cannabinoid assays are more specific.^1,18 Common over-the-counter medications, including nonsteroidal anti-inflammatory drugs, decongestants, and antacids, can yield false-positive results, highlighting the need to obtain a comprehensive medication list from patients, including over-the-counter and herbal medications, before ordering UDS. Because of the complexity of cross-reactivity, it might not be possible to identify the source of a false-positive result.¹⁴

Patient variables. Intentional effort to skew results is another source of interference. The frequency of this effort varies by setting and the potential consequences of results—eg, employment testing or substance use treatment—and a range of attempts have been reported in the literature.^21,22 Common practices are dilution, adulteration, and substitution.^20,23

• Dilution lowers the concentration of the drug of interest below the detection limit of the assay by directly adding water to the urine specimen, drinking copious amounts of fluid, taking a diuretic, or a combination of these practices.
• Adulteration involves adding a substance to urine that interferes with the testing mechanism: for example, bleach, household cleaners, eye drops, and even commercially available products expressly marketed to interfere with UDS.²⁴
• Substitution involves providing urine or a urine-like substance for testing that did not originate from the patient.

Methods to minimize patient-related interference include observed collection and specimen validity testing for pH, creatinine, and adulterants (TABLE 2).^1,15 Efforts to detect patient interference must be balanced against concerns about privacy, personnel resources, and the cost of expanded testing.^14,19,20

Additional aspects inherent to the testing process, such as cutoff concentrations and detection windows, can lead to interference. Laboratories must set reporting cutoffs, and specimens with a drug concentration present but below the cutoff value are reported as a negative result. Detection windows are complex and are influenced by inherent properties of the drug, including metabolic pathway and route and frequency of use.¹ A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported (TABLE 3^1,23).

Managing test results

Appropriate management of UDS results is built on the foundation of understanding the testing mechanism, selecting the correct test, and properly interpreting results. Drug testing is, ultimately, a therapeutic tool used to monitor treatment, provide reinforcement, and explore substance use behavior; results of testing should be employed to achieve those objectives.^1,4,14 A negative or expected UDS result can be utilized as positive reinforcement for a patient who is adherent to the treatment plan—much the way objective weight loss in an obese patient can provide encouragement to continue lifestyle changes.

Continue to: Test results should be presented...

Test results should be presented in an objective, nonconfrontational, and compassionate manner, not with stigmatizing language, such as “clean” or “dirty.”^1,13,14 Using stigmatizing terms such as “substance abuser” instead of “person with a substance use disorder” has been shown, even among highly trained health care professionals, to have a negative effect on patient care.¹³

A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported.

Inevitably, you will encounter an unexpected result, and therefore must develop a rational, systematic, and compassionate management approach. “Unexpected result” is a broad term that includes results that conflict with

• a patient’s self-report
• your understanding of what the patient is taking (using)
• prescribed medications
• a patient’s typical substance use pattern.

When faced with an unexpected test result, first, ensure that the result in question is reliable. If a screening test yields an unanticipated finding—especially if it conflicts with the patient’s self-reporting—make every effort to seek confirmation if you are going to be making a significant clinical decision because of the result.^1,14

Second, use your understanding of interference to consider the result in a broader context. If confirmatory results are inconsistent with a patient’s self-report, discuss whether there has been a break in the ­ph­ysician–patient relationship and emphasize that recurrent use or failure to adhere to a treatment plan has clear consequences.^1,14 Modify the treatment plan to address the inconsistent finding by escalating care, adjusting medications, and connecting the patient to additional resources.

Third, keep in mind that a positive urine test is not diagnostic of an SUD. Occasional drug use is extremely common¹⁷ and should not categorically lead to a change in the treatment plan. Addiction is, fundamentally, a disease of disordered reward, motivation, and behavior that is defined by the consequences of substance use, not substance use per se,²⁵ and an SUD diagnosis is complex, based on clinical history, physical examination, and laboratory testing. Similarly, a negative UDS result does not rule out an SUD.^4,10

Continue to: Fourth, patient dismissal...

Fourth, patient dismissal is rarely an appropriate initial response to UDS results. Regrettably, some physicians misinterpret urine toxicology results and inappropriately discharge patients on that basis.

In general, amphetamine immunoassays produce frequent falsepositive results, whereas cocaine and cannabinoid assays are more specific.

The Centers for Disease Control and Prevention guideline for prescribing opioids has increased utilization of UDS in primary care settings but does not provide the necessary education on proper use of the tool, which has resulted in a rise in misinterpretation and inappropriate discharge.^13,26

If recurrent aberrant behavior is detected (by history or urine toxicology), do not abruptly discontinue the patient’s medication(s). Inform the patient of your concern, taper medication, and refer the patient to addiction treatment. Abrupt discontinuation of an opioid or benzodiazepine can lead to significant harm.^1,14

CORRESPONDENCE
John Hayes, DO, Department of Family and Community Medicine, Medical College of Wisconsin, 1121 E North Avenue, Milwaukee, WI, 53212; jrhayes@mcw.edu

An estimated 20 million patients in the United States have a substance use disorder (SUD), with hundreds of millions of prescriptions for controlled substances written annually. Consequently, urine drug screening (UDS) has become widely utilized to evaluate and treat patients with an SUD or on chronic opioid or benzodiazepine therapy.¹

Used appropriately, UDS can be a valuable tool; there is ample evidence, however, that it has been misused, by some physicians, to stigmatize patients who use drugs of abuse,² profile patients racially,² profit from excessive testing,³ and inappropriately discontinue treatment.⁴

A patient-centered approach. We have extensive clinical experience in the use and interpretation of urine toxicology, serving as clinical leads in busy family medicine residency practices that care for patients with SUDs, and are often consulted regarding patients on chronic opioid or benzodiazepine therapy. We have encountered countless situations in which the correct interpretation of UDS is critical to providing care.

Over time, and after considerable trial and error, we developed the patient-centered approach to urine toxicology described in this article. We believe that the medical evidence strongly supports our approach to the appropriate use and interpretation of urine toxicology in clinical practice. Our review here is intended as a resource when you consider implementing a UDS protocol or are struggling with the management of unexpected results.

Urine toxicology for therapeutic drug monitoring

Prescribing a controlled substance carries inherent risks, including diversion, nonmedical use, and development of an SUD. Prescribed medications, particularly opioids and benzodiazepines, have been linked to a large increase in overdose deaths over the past decade.⁵ Several strategies have been investigated to mitigate risk (see “How frequently should a patient be tested?,” later in the article).

Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed a substance use disorder—has been shown to be highly inaccurate.

Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed an SUD—has been shown to be highly inaccurate. Implicit racial bias might affect the physician’s judgment, leading to changes in testing and test interpretation. For example, Black patients were found to be 10% more likely to have drug screening ordered while being treated with long-term opioid therapy and 2 to 3 times more likely to have their medication discontinued as a result of a marijuana- or cocaine-positive test.²

Other studies have shown that testing patients for “bad behavior,” so to speak—reporting a prescription lost or stolen, consuming more than the prescribed dosage, visiting the office without an appointment, having multiple drug intolerances and allergies, and making frequent telephone calls to the practice—is ineffective.⁶ Patients with these behaviors were slightly more likely to unexpectedly test positive, or negative, on their UDS; however, many patients without suspect behavior also were found to have abnormal toxicology results.⁶ Data do not support therapeutic drug monitoring only of patients selected on the basis of aberrant behavior.⁶

Continue to: Questions and concerns about urine drug screening

 

 

Questions and concerns about urine drug screening

Why not just ask the patient? Studies have evaluated whether patient self-reporting of adherence is a feasible alternative to laboratory drug screening. Regrettably, patients have repeatedly been shown to underreport their use of both prescribed and illicit drugs.^7,8

That question leads to another: Why do patients lie to their physician? It is easy to assume malicious intent, but a variety of obstacles might dissuade a patient from being fully truthful with their physician:

• Monetary gain. A small, but real, percentage of medications are diverted by patients for this reason.⁹
• Addiction, pseudo-addiction due to tolerance, and self-medication for psychological symptoms are clinically treatable syndromes that can lead to underreporting of prescribed and nonprescribed drug and alcohol use.
• Shame. Addiction is a highly stigmatized disease, and patients might simply be ashamed to admit that they need treatment: 13% to 38% of patients receiving chronic opioid therapy in a pain management or primary care setting have a clinically diagnosable SUD.^10,11

Is consent needed to test or to share test results? Historically, UDS has been performed on patients without their consent or knowledge.¹² Patients give a urine specimen to their physician for a variety of reasons; it seems easy to “add on” UDS. Evidence is clear, however, that confronting a patient about an unexpected test result can make the clinical outcome worse—often resulting in irreparable damage to the patient–­physician relationship.^12,13 Unless the patient is experiencing a medical emergency, guidelines unanimously recommend obtaining consent prior to testing.^1,5,14

Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months.

Federal law requires written permission from the patient for the physician to disclose information about alcohol or substance use, unless the information is expressly needed to provide care during a medical emergency. Substance use is highly stigmatized, and patients might—legitimately—fear that sharing their history could undermine their care.^1,12,14

How frequently should a patient be tested? Experts recommend utilizing a risk-based strategy to determine the frequency of UDS.^1,5,15 Validated risk-assessment questionnaires include:

• Opioid Risk Tool for Opioid Use Disorder (ORT-OUD)^a
• Screener and Opioid Assessment for Patients With Pain–Revised (SOAPP-R)^b
• Diagnosis, Intractability, Risk and Efficacy (DIRE)^c
• Addiction Behaviors Checklist (ABC).^d

Continue to: Each of these tools...

Each of these tools takes less than 5 minutes to administer and can be used by a primary care physician to objectively quantify the risk of prescribing; there is no evidence for the use of 1 of these screeners over the others.¹⁵ It is recommended that you choose a questionnaire that works for you and incorporate the risk assessment into prescribing any high-risk medication.^1,5,15

Once you have completed an initial risk assessment, the frequency of UDS can be based on ongoing assessment that incorporates baseline testing, patient self-reporting, toxicology results, behavioral monitoring, and state database monitoring through a prescription drug monitoring program. Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months (FIGURE).¹⁵

Many state and federal agencies, health systems, employers, and insurers mandate the frequency of testing through guidelines or legislation. These regulations often are inconsistent with the newest medical evidence.¹⁵ Consult local guidelines and review the medical evidence and consensus recommendations on UDS.

What are the cost considerations in providing UDS? Insurers have been billed as much as $4000 for definitive chromatography testing (described later).³ This has led to insurance fraud, when drug-testing practices with a financial interest routinely use large and expensive test panels, test too frequently, or unnecessarily send for confirmatory or quantitative analysis of all positive tests.^3,14 Often, insurers refuse to pay for unnecessary testing, leaving patients with significant indebtedness.^3,14 Take time to review the evidence and consensus recommendations on UDS to avoid waste, potential accusations of fraud, and financial burden on your patients.

Urine toxicology for addiction treatment

UDS protocols in addiction settings are often different from those in which a controlled substance is being prescribed.

Continue to: Routine and random testing

Routine and random testing. Two common practices when treating addiction are to perform UDS on all patients, at every visit, or to test randomly.¹ These practices can be problematic, however. Routine testing at every visit can make urine-tampering more likely and is often unnecessary for stable patients. Random testing can reduce the risk of urine-tampering, but it is often difficult for primary care clinics to institute such a protocol. Some clinics have patients provide a urine specimen at every visit and then only send tests to the lab based on randomization.¹

Contingency management—a behavioral intervention in which a patient is rewarded, or their performance is reinforced, when they display evidence of positive change—is the most effective strategy used in addiction medicine to determine the frequency of patient visits and UDS.^14,16 High-risk patients with self-reported active substance use or UDS results consistent with substance use, or both, are seen more often; as their addiction behavior diminishes, visits and UDS become less frequent. If addiction behavior increases, the patient is seen more often. Keep in mind that addiction behavior decreases over months of treatment, not immediately upon initiation.^14,17 For contingency management to be successful, patient-centered interviewing and UDS will need to be employed frequently as the patient works toward meaningful change.¹⁴

The technology of urine drug screening

Two general techniques are used for UDS: immunoassay and chromatography. Each plays an important role in clinical practice; physicians must therefore maintain a basic understanding of the mechanism of each technique and their comparable advantages and disadvantages. Such an understanding allows for (1) matching the appropriate technique to the individual clinical scenario and (2) correctly interpreting results.

Immunoassay technology is used for point-of-care and rapid laboratory UDS, using antibodies to detect the drug or drug metabolite of interest. Antibodies utilized in immunoassays are designed to selectively bind a specific antigen—ie, a unique chemical structure within the drug of choice. Once bound, the antigen–antibody complex can be exploited for detection through various methods.

Chromatography–mass ­spectrometry is considered the gold standard for UDS, yielding confirmatory results. This is a 2-step process: Chromatography separates components within a specimen; mass spectrometry then identifies those components. Most laboratories employ liquid, rather than gas, chromatography. The specificity of the liquid chromatography–mass spectrometry method is such that a false-positive result is, essentially, impossible.¹⁸

Continue to: How is the appropriate tests elected for urine drug screening?

 

 

How is the appropriate tests elected for urine drug screening?

Variables that influence your choice of the proper test method include the clinical question at hand; cost; the urgency of obtaining results; and the stakes in that decision (ie, will the results be used to simply change the dosage of a medication or, of greater consequence, to determine fitness for employment or inform criminal justice decisions?). Each method of UDS has advantages that can be utilized and disadvantages that must be considered to obtain an accurate and useful result.

Immunoassay provides rapid results, is relatively easy to perform, and is, comparatively, inexpensive.^1,14 The speed of results makes this method particularly useful in settings such as the emergency department, where rapid results are crucial. Ease of use makes immunoassay ideal for the office, where non-laboratory staff can be trained to properly administer the test.

A major disadvantage of immunoassay technology, however, is interference resulting in both false-positive and false-negative results, which is discussed in detail in the next section. Immunoassay should be considered a screening test that yields presumptive results.

Liquid chromatography–mass spectrometry is exquisitely specific and provides confirmatory test results—major advantages of the method. However, specificity comes at a price: significantly increased cost and longer wait time for results (typically days, if specimens are sent out to a laboratory). These barriers can make it impractical to employ this method in routine practice.

Interpretation of results: Not so fast

Interpreting UDS results is not as simple as noting a positive or negative result. Physicians must understand the concept of interference, so that results can be appropriately interpreted and confirmed. This is crucial when results influence clinical decisions; inappropriate action, taken on the basis of presumptive results, can have severe consequences for the patient–provider relationship and the treatment plan.^1,14

Continue to: Interference falls into 2 categories...

Interference falls into 2 categories: variables inherent in the testing process and patient variables.

Obtain consent prior to performing urine drug screening, even if you are already collecting a specimen for other testing.

Antibody cross-reactivity. A major disadvantage of immunoassay technology is interference that results in false-positive and false-negative results.^19,20 The source of this interference is antibody cross-­reactivity—the degree to which an antibody binds to structurally similar compounds. Antibody–­antigen interactions are incredibly complex; although assay antibodies are engineered to specifically detect a drug class of interest, reactivity with other, structurally similar compounds is unavoidable.

Nevertheless, cross-reactivity is a useful phenomenon that allows broad testing for multiple drugs within a class. For example, most point-of-care tests for benzodiazepines reliably detect diazepam and chlordiazepoxide. Likewise, opiate tests reliably detect natural opiates, such as morphine and codeine. Cross-reactivity is not limitless, however; most benzodiazepine immunoassays have poor reactivity to clonazepam and lorazepam, making it possible that a patient taking clonazepam tests negative for benzodiazepine on an immunoassay.^14,20 Similarly, standard opioid tests have only moderate cross-reactivity for semisynthetic opioids, such as hydrocodone and hydromorphone; poor cross-r­eactivity for oxycodone and oxymorphone; and essentially no cross-­reactivity for full synthetics, such as fentanyl and methadone.¹⁴

It is the responsibility of the ordering physician to understand cross-reactivity to various drugs within a testing class.

Routine urine drug screening at every visit can make urine tampering more likely and is often unnecessary for stable patients.

Whereas weak cross-reactivity to drugs within a class can be a source of false-negative results, cross-reactivity to drugs outside the class of interest is a source of false-positive results. An extensive review of drugs that cause false-positive immunoassay screening tests is outside the scope of this article; commonly prescribed medications implicated in false-positive results are listed in TABLE 1.¹⁹

Continue to: In general...

In general, amphetamine immunoassays produce frequent false-positive results, whereas cocaine and cannabinoid assays are more specific.^1,18 Common over-the-counter medications, including nonsteroidal anti-inflammatory drugs, decongestants, and antacids, can yield false-positive results, highlighting the need to obtain a comprehensive medication list from patients, including over-the-counter and herbal medications, before ordering UDS. Because of the complexity of cross-reactivity, it might not be possible to identify the source of a false-positive result.¹⁴

Patient variables. Intentional effort to skew results is another source of interference. The frequency of this effort varies by setting and the potential consequences of results—eg, employment testing or substance use treatment—and a range of attempts have been reported in the literature.^21,22 Common practices are dilution, adulteration, and substitution.^20,23

• Dilution lowers the concentration of the drug of interest below the detection limit of the assay by directly adding water to the urine specimen, drinking copious amounts of fluid, taking a diuretic, or a combination of these practices.
• Adulteration involves adding a substance to urine that interferes with the testing mechanism: for example, bleach, household cleaners, eye drops, and even commercially available products expressly marketed to interfere with UDS.²⁴
• Substitution involves providing urine or a urine-like substance for testing that did not originate from the patient.

Methods to minimize patient-related interference include observed collection and specimen validity testing for pH, creatinine, and adulterants (TABLE 2).^1,15 Efforts to detect patient interference must be balanced against concerns about privacy, personnel resources, and the cost of expanded testing.^14,19,20

Additional aspects inherent to the testing process, such as cutoff concentrations and detection windows, can lead to interference. Laboratories must set reporting cutoffs, and specimens with a drug concentration present but below the cutoff value are reported as a negative result. Detection windows are complex and are influenced by inherent properties of the drug, including metabolic pathway and route and frequency of use.¹ A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported (TABLE 3^1,23).

Managing test results

Appropriate management of UDS results is built on the foundation of understanding the testing mechanism, selecting the correct test, and properly interpreting results. Drug testing is, ultimately, a therapeutic tool used to monitor treatment, provide reinforcement, and explore substance use behavior; results of testing should be employed to achieve those objectives.^1,4,14 A negative or expected UDS result can be utilized as positive reinforcement for a patient who is adherent to the treatment plan—much the way objective weight loss in an obese patient can provide encouragement to continue lifestyle changes.

Continue to: Test results should be presented...

Test results should be presented in an objective, nonconfrontational, and compassionate manner, not with stigmatizing language, such as “clean” or “dirty.”^1,13,14 Using stigmatizing terms such as “substance abuser” instead of “person with a substance use disorder” has been shown, even among highly trained health care professionals, to have a negative effect on patient care.¹³

A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported.

Inevitably, you will encounter an unexpected result, and therefore must develop a rational, systematic, and compassionate management approach. “Unexpected result” is a broad term that includes results that conflict with

• a patient’s self-report
• your understanding of what the patient is taking (using)
• prescribed medications
• a patient’s typical substance use pattern.

When faced with an unexpected test result, first, ensure that the result in question is reliable. If a screening test yields an unanticipated finding—especially if it conflicts with the patient’s self-reporting—make every effort to seek confirmation if you are going to be making a significant clinical decision because of the result.^1,14

Second, use your understanding of interference to consider the result in a broader context. If confirmatory results are inconsistent with a patient’s self-report, discuss whether there has been a break in the ­ph­ysician–patient relationship and emphasize that recurrent use or failure to adhere to a treatment plan has clear consequences.^1,14 Modify the treatment plan to address the inconsistent finding by escalating care, adjusting medications, and connecting the patient to additional resources.

Third, keep in mind that a positive urine test is not diagnostic of an SUD. Occasional drug use is extremely common¹⁷ and should not categorically lead to a change in the treatment plan. Addiction is, fundamentally, a disease of disordered reward, motivation, and behavior that is defined by the consequences of substance use, not substance use per se,²⁵ and an SUD diagnosis is complex, based on clinical history, physical examination, and laboratory testing. Similarly, a negative UDS result does not rule out an SUD.^4,10

Continue to: Fourth, patient dismissal...

Fourth, patient dismissal is rarely an appropriate initial response to UDS results. Regrettably, some physicians misinterpret urine toxicology results and inappropriately discharge patients on that basis.

In general, amphetamine immunoassays produce frequent falsepositive results, whereas cocaine and cannabinoid assays are more specific.

The Centers for Disease Control and Prevention guideline for prescribing opioids has increased utilization of UDS in primary care settings but does not provide the necessary education on proper use of the tool, which has resulted in a rise in misinterpretation and inappropriate discharge.^13,26

If recurrent aberrant behavior is detected (by history or urine toxicology), do not abruptly discontinue the patient’s medication(s). Inform the patient of your concern, taper medication, and refer the patient to addiction treatment. Abrupt discontinuation of an opioid or benzodiazepine can lead to significant harm.^1,14

CORRESPONDENCE
John Hayes, DO, Department of Family and Community Medicine, Medical College of Wisconsin, 1121 E North Avenue, Milwaukee, WI, 53212; jrhayes@mcw.edu

An estimated 20 million patients in the United States have a substance use disorder (SUD), with hundreds of millions of prescriptions for controlled substances written annually. Consequently, urine drug screening (UDS) has become widely utilized to evaluate and treat patients with an SUD or on chronic opioid or benzodiazepine therapy.¹

Used appropriately, UDS can be a valuable tool; there is ample evidence, however, that it has been misused, by some physicians, to stigmatize patients who use drugs of abuse,² profile patients racially,² profit from excessive testing,³ and inappropriately discontinue treatment.⁴

A patient-centered approach. We have extensive clinical experience in the use and interpretation of urine toxicology, serving as clinical leads in busy family medicine residency practices that care for patients with SUDs, and are often consulted regarding patients on chronic opioid or benzodiazepine therapy. We have encountered countless situations in which the correct interpretation of UDS is critical to providing care.

Over time, and after considerable trial and error, we developed the patient-centered approach to urine toxicology described in this article. We believe that the medical evidence strongly supports our approach to the appropriate use and interpretation of urine toxicology in clinical practice. Our review here is intended as a resource when you consider implementing a UDS protocol or are struggling with the management of unexpected results.

Urine toxicology for therapeutic drug monitoring

Prescribing a controlled substance carries inherent risks, including diversion, nonmedical use, and development of an SUD. Prescribed medications, particularly opioids and benzodiazepines, have been linked to a large increase in overdose deaths over the past decade.⁵ Several strategies have been investigated to mitigate risk (see “How frequently should a patient be tested?,” later in the article).

Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed a substance use disorder—has been shown to be highly inaccurate.

Clinical judgment—ie, when a physician orders a drug test upon suspecting that a patient is diverting a prescribed drug or has developed an SUD—has been shown to be highly inaccurate. Implicit racial bias might affect the physician’s judgment, leading to changes in testing and test interpretation. For example, Black patients were found to be 10% more likely to have drug screening ordered while being treated with long-term opioid therapy and 2 to 3 times more likely to have their medication discontinued as a result of a marijuana- or cocaine-positive test.²

Other studies have shown that testing patients for “bad behavior,” so to speak—reporting a prescription lost or stolen, consuming more than the prescribed dosage, visiting the office without an appointment, having multiple drug intolerances and allergies, and making frequent telephone calls to the practice—is ineffective.⁶ Patients with these behaviors were slightly more likely to unexpectedly test positive, or negative, on their UDS; however, many patients without suspect behavior also were found to have abnormal toxicology results.⁶ Data do not support therapeutic drug monitoring only of patients selected on the basis of aberrant behavior.⁶

Continue to: Questions and concerns about urine drug screening

 

 

Questions and concerns about urine drug screening

Why not just ask the patient? Studies have evaluated whether patient self-reporting of adherence is a feasible alternative to laboratory drug screening. Regrettably, patients have repeatedly been shown to underreport their use of both prescribed and illicit drugs.^7,8

That question leads to another: Why do patients lie to their physician? It is easy to assume malicious intent, but a variety of obstacles might dissuade a patient from being fully truthful with their physician:

• Monetary gain. A small, but real, percentage of medications are diverted by patients for this reason.⁹
• Addiction, pseudo-addiction due to tolerance, and self-medication for psychological symptoms are clinically treatable syndromes that can lead to underreporting of prescribed and nonprescribed drug and alcohol use.
• Shame. Addiction is a highly stigmatized disease, and patients might simply be ashamed to admit that they need treatment: 13% to 38% of patients receiving chronic opioid therapy in a pain management or primary care setting have a clinically diagnosable SUD.^10,11

Is consent needed to test or to share test results? Historically, UDS has been performed on patients without their consent or knowledge.¹² Patients give a urine specimen to their physician for a variety of reasons; it seems easy to “add on” UDS. Evidence is clear, however, that confronting a patient about an unexpected test result can make the clinical outcome worse—often resulting in irreparable damage to the patient–­physician relationship.^12,13 Unless the patient is experiencing a medical emergency, guidelines unanimously recommend obtaining consent prior to testing.^1,5,14

Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months.

Federal law requires written permission from the patient for the physician to disclose information about alcohol or substance use, unless the information is expressly needed to provide care during a medical emergency. Substance use is highly stigmatized, and patients might—legitimately—fear that sharing their history could undermine their care.^1,12,14

How frequently should a patient be tested? Experts recommend utilizing a risk-based strategy to determine the frequency of UDS.^1,5,15 Validated risk-assessment questionnaires include:

• Opioid Risk Tool for Opioid Use Disorder (ORT-OUD)^a
• Screener and Opioid Assessment for Patients With Pain–Revised (SOAPP-R)^b
• Diagnosis, Intractability, Risk and Efficacy (DIRE)^c
• Addiction Behaviors Checklist (ABC).^d

Continue to: Each of these tools...

Each of these tools takes less than 5 minutes to administer and can be used by a primary care physician to objectively quantify the risk of prescribing; there is no evidence for the use of 1 of these screeners over the others.¹⁵ It is recommended that you choose a questionnaire that works for you and incorporate the risk assessment into prescribing any high-risk medication.^1,5,15

Once you have completed an initial risk assessment, the frequency of UDS can be based on ongoing assessment that incorporates baseline testing, patient self-reporting, toxicology results, behavioral monitoring, and state database monitoring through a prescription drug monitoring program. Annual screening is appropriate in low-risk patients; moderate-risk patients should be screened twice a year, and high-risk patients should be screened at least every 4 months (FIGURE).¹⁵

Many state and federal agencies, health systems, employers, and insurers mandate the frequency of testing through guidelines or legislation. These regulations often are inconsistent with the newest medical evidence.¹⁵ Consult local guidelines and review the medical evidence and consensus recommendations on UDS.

What are the cost considerations in providing UDS? Insurers have been billed as much as $4000 for definitive chromatography testing (described later).³ This has led to insurance fraud, when drug-testing practices with a financial interest routinely use large and expensive test panels, test too frequently, or unnecessarily send for confirmatory or quantitative analysis of all positive tests.^3,14 Often, insurers refuse to pay for unnecessary testing, leaving patients with significant indebtedness.^3,14 Take time to review the evidence and consensus recommendations on UDS to avoid waste, potential accusations of fraud, and financial burden on your patients.

Urine toxicology for addiction treatment

UDS protocols in addiction settings are often different from those in which a controlled substance is being prescribed.

Continue to: Routine and random testing

Routine and random testing. Two common practices when treating addiction are to perform UDS on all patients, at every visit, or to test randomly.¹ These practices can be problematic, however. Routine testing at every visit can make urine-tampering more likely and is often unnecessary for stable patients. Random testing can reduce the risk of urine-tampering, but it is often difficult for primary care clinics to institute such a protocol. Some clinics have patients provide a urine specimen at every visit and then only send tests to the lab based on randomization.¹

Contingency management—a behavioral intervention in which a patient is rewarded, or their performance is reinforced, when they display evidence of positive change—is the most effective strategy used in addiction medicine to determine the frequency of patient visits and UDS.^14,16 High-risk patients with self-reported active substance use or UDS results consistent with substance use, or both, are seen more often; as their addiction behavior diminishes, visits and UDS become less frequent. If addiction behavior increases, the patient is seen more often. Keep in mind that addiction behavior decreases over months of treatment, not immediately upon initiation.^14,17 For contingency management to be successful, patient-centered interviewing and UDS will need to be employed frequently as the patient works toward meaningful change.¹⁴

The technology of urine drug screening

Two general techniques are used for UDS: immunoassay and chromatography. Each plays an important role in clinical practice; physicians must therefore maintain a basic understanding of the mechanism of each technique and their comparable advantages and disadvantages. Such an understanding allows for (1) matching the appropriate technique to the individual clinical scenario and (2) correctly interpreting results.

Immunoassay technology is used for point-of-care and rapid laboratory UDS, using antibodies to detect the drug or drug metabolite of interest. Antibodies utilized in immunoassays are designed to selectively bind a specific antigen—ie, a unique chemical structure within the drug of choice. Once bound, the antigen–antibody complex can be exploited for detection through various methods.

Chromatography–mass ­spectrometry is considered the gold standard for UDS, yielding confirmatory results. This is a 2-step process: Chromatography separates components within a specimen; mass spectrometry then identifies those components. Most laboratories employ liquid, rather than gas, chromatography. The specificity of the liquid chromatography–mass spectrometry method is such that a false-positive result is, essentially, impossible.¹⁸

Continue to: How is the appropriate tests elected for urine drug screening?

 

 

How is the appropriate tests elected for urine drug screening?

Variables that influence your choice of the proper test method include the clinical question at hand; cost; the urgency of obtaining results; and the stakes in that decision (ie, will the results be used to simply change the dosage of a medication or, of greater consequence, to determine fitness for employment or inform criminal justice decisions?). Each method of UDS has advantages that can be utilized and disadvantages that must be considered to obtain an accurate and useful result.

Immunoassay provides rapid results, is relatively easy to perform, and is, comparatively, inexpensive.^1,14 The speed of results makes this method particularly useful in settings such as the emergency department, where rapid results are crucial. Ease of use makes immunoassay ideal for the office, where non-laboratory staff can be trained to properly administer the test.

A major disadvantage of immunoassay technology, however, is interference resulting in both false-positive and false-negative results, which is discussed in detail in the next section. Immunoassay should be considered a screening test that yields presumptive results.

Liquid chromatography–mass spectrometry is exquisitely specific and provides confirmatory test results—major advantages of the method. However, specificity comes at a price: significantly increased cost and longer wait time for results (typically days, if specimens are sent out to a laboratory). These barriers can make it impractical to employ this method in routine practice.

Interpretation of results: Not so fast

Interpreting UDS results is not as simple as noting a positive or negative result. Physicians must understand the concept of interference, so that results can be appropriately interpreted and confirmed. This is crucial when results influence clinical decisions; inappropriate action, taken on the basis of presumptive results, can have severe consequences for the patient–provider relationship and the treatment plan.^1,14

Continue to: Interference falls into 2 categories...

Interference falls into 2 categories: variables inherent in the testing process and patient variables.

Obtain consent prior to performing urine drug screening, even if you are already collecting a specimen for other testing.

Antibody cross-reactivity. A major disadvantage of immunoassay technology is interference that results in false-positive and false-negative results.^19,20 The source of this interference is antibody cross-­reactivity—the degree to which an antibody binds to structurally similar compounds. Antibody–­antigen interactions are incredibly complex; although assay antibodies are engineered to specifically detect a drug class of interest, reactivity with other, structurally similar compounds is unavoidable.

Nevertheless, cross-reactivity is a useful phenomenon that allows broad testing for multiple drugs within a class. For example, most point-of-care tests for benzodiazepines reliably detect diazepam and chlordiazepoxide. Likewise, opiate tests reliably detect natural opiates, such as morphine and codeine. Cross-reactivity is not limitless, however; most benzodiazepine immunoassays have poor reactivity to clonazepam and lorazepam, making it possible that a patient taking clonazepam tests negative for benzodiazepine on an immunoassay.^14,20 Similarly, standard opioid tests have only moderate cross-reactivity for semisynthetic opioids, such as hydrocodone and hydromorphone; poor cross-r­eactivity for oxycodone and oxymorphone; and essentially no cross-­reactivity for full synthetics, such as fentanyl and methadone.¹⁴

It is the responsibility of the ordering physician to understand cross-reactivity to various drugs within a testing class.

Routine urine drug screening at every visit can make urine tampering more likely and is often unnecessary for stable patients.

Whereas weak cross-reactivity to drugs within a class can be a source of false-negative results, cross-reactivity to drugs outside the class of interest is a source of false-positive results. An extensive review of drugs that cause false-positive immunoassay screening tests is outside the scope of this article; commonly prescribed medications implicated in false-positive results are listed in TABLE 1.¹⁹

Continue to: In general...

In general, amphetamine immunoassays produce frequent false-positive results, whereas cocaine and cannabinoid assays are more specific.^1,18 Common over-the-counter medications, including nonsteroidal anti-inflammatory drugs, decongestants, and antacids, can yield false-positive results, highlighting the need to obtain a comprehensive medication list from patients, including over-the-counter and herbal medications, before ordering UDS. Because of the complexity of cross-reactivity, it might not be possible to identify the source of a false-positive result.¹⁴

Patient variables. Intentional effort to skew results is another source of interference. The frequency of this effort varies by setting and the potential consequences of results—eg, employment testing or substance use treatment—and a range of attempts have been reported in the literature.^21,22 Common practices are dilution, adulteration, and substitution.^20,23

• Dilution lowers the concentration of the drug of interest below the detection limit of the assay by directly adding water to the urine specimen, drinking copious amounts of fluid, taking a diuretic, or a combination of these practices.
• Adulteration involves adding a substance to urine that interferes with the testing mechanism: for example, bleach, household cleaners, eye drops, and even commercially available products expressly marketed to interfere with UDS.²⁴
• Substitution involves providing urine or a urine-like substance for testing that did not originate from the patient.

Methods to minimize patient-related interference include observed collection and specimen validity testing for pH, creatinine, and adulterants (TABLE 2).^1,15 Efforts to detect patient interference must be balanced against concerns about privacy, personnel resources, and the cost of expanded testing.^14,19,20

Additional aspects inherent to the testing process, such as cutoff concentrations and detection windows, can lead to interference. Laboratories must set reporting cutoffs, and specimens with a drug concentration present but below the cutoff value are reported as a negative result. Detection windows are complex and are influenced by inherent properties of the drug, including metabolic pathway and route and frequency of use.¹ A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported (TABLE 3^1,23).

Managing test results

Appropriate management of UDS results is built on the foundation of understanding the testing mechanism, selecting the correct test, and properly interpreting results. Drug testing is, ultimately, a therapeutic tool used to monitor treatment, provide reinforcement, and explore substance use behavior; results of testing should be employed to achieve those objectives.^1,4,14 A negative or expected UDS result can be utilized as positive reinforcement for a patient who is adherent to the treatment plan—much the way objective weight loss in an obese patient can provide encouragement to continue lifestyle changes.

Continue to: Test results should be presented...

Test results should be presented in an objective, nonconfrontational, and compassionate manner, not with stigmatizing language, such as “clean” or “dirty.”^1,13,14 Using stigmatizing terms such as “substance abuser” instead of “person with a substance use disorder” has been shown, even among highly trained health care professionals, to have a negative effect on patient care.¹³

A given patient might well be using a substance, but if the specimen was obtained outside the detection window, a false-negative result might be reported.

Inevitably, you will encounter an unexpected result, and therefore must develop a rational, systematic, and compassionate management approach. “Unexpected result” is a broad term that includes results that conflict with

• a patient’s self-report
• your understanding of what the patient is taking (using)
• prescribed medications
• a patient’s typical substance use pattern.

When faced with an unexpected test result, first, ensure that the result in question is reliable. If a screening test yields an unanticipated finding—especially if it conflicts with the patient’s self-reporting—make every effort to seek confirmation if you are going to be making a significant clinical decision because of the result.^1,14

Second, use your understanding of interference to consider the result in a broader context. If confirmatory results are inconsistent with a patient’s self-report, discuss whether there has been a break in the ­ph­ysician–patient relationship and emphasize that recurrent use or failure to adhere to a treatment plan has clear consequences.^1,14 Modify the treatment plan to address the inconsistent finding by escalating care, adjusting medications, and connecting the patient to additional resources.

Third, keep in mind that a positive urine test is not diagnostic of an SUD. Occasional drug use is extremely common¹⁷ and should not categorically lead to a change in the treatment plan. Addiction is, fundamentally, a disease of disordered reward, motivation, and behavior that is defined by the consequences of substance use, not substance use per se,²⁵ and an SUD diagnosis is complex, based on clinical history, physical examination, and laboratory testing. Similarly, a negative UDS result does not rule out an SUD.^4,10

Continue to: Fourth, patient dismissal...

Fourth, patient dismissal is rarely an appropriate initial response to UDS results. Regrettably, some physicians misinterpret urine toxicology results and inappropriately discharge patients on that basis.

In general, amphetamine immunoassays produce frequent falsepositive results, whereas cocaine and cannabinoid assays are more specific.

The Centers for Disease Control and Prevention guideline for prescribing opioids has increased utilization of UDS in primary care settings but does not provide the necessary education on proper use of the tool, which has resulted in a rise in misinterpretation and inappropriate discharge.^13,26

If recurrent aberrant behavior is detected (by history or urine toxicology), do not abruptly discontinue the patient’s medication(s). Inform the patient of your concern, taper medication, and refer the patient to addiction treatment. Abrupt discontinuation of an opioid or benzodiazepine can lead to significant harm.^1,14

CORRESPONDENCE
John Hayes, DO, Department of Family and Community Medicine, Medical College of Wisconsin, 1121 E North Avenue, Milwaukee, WI, 53212; jrhayes@mcw.edu

It is often assumed that cognitive decline is an inevitable part of aging, but a new study of centenarians suggests otherwise.

Investigators found that despite the presence of neuropathologies associated with Alzheimer’s disease (AD), many centenarians maintained high levels of cognitive performance.

“Cognitive decline is not inevitable,” senior author Henne Holstege, PhD, assistant professor, Amsterdam Alzheimer Center and Clinical Genetics, Amsterdam University Medical Center, said in an interview.

“At 100 years or older, high levels of cognitive performance can be maintained for several years, even when individuals are exposed to risk factors associated with cognitive decline,” she said.

The study was published online Jan. 15 in JAMA Network Open.
 

Escaping cognitive decline

Dr. Holstege said her interest in researching aging and cognitive health was inspired by the “fascinating” story of Hendrikje van Andel-Schipper, who died at age 115 in 2015 “completely cognitively healthy.” Her mother, who died at age 100, also was cognitively intact at the end of her life.

“I wanted to know how it is possible that some people can completely escape all aspects of cognitive decline while reaching extreme ages,” Dr. Holstege said.

To discover the secret to cognitive health in the oldest old, Dr. Holstege initiated the 100-Plus Study, which involved a cohort of healthy centenarians.

The investigators conducted extensive neuropsychological testing and collected blood and fecal samples to examine “the myriad factors that influence physical health, including genetics, neuropathology, blood markers, and the gut microbiome, to explore the molecular and neuropsychologic constellations associated with the escape from cognitive decline.”

The goal of the research was to investigate “to what extent centenarians were able to maintain their cognitive health after study inclusion, and to what extent this was associated with genetic, physical, or neuropathological features,” she said.

The study included 330 centenarians who completed one or more neuropsychological assessments. Neuropathologic studies were available for 44 participants.

To assess baseline cognitive performance, the researchers administered a wide array of neurocognitive tests, as well as the Mini–Mental State Examination, from which mean z scores for cognitive domains were calculated.

Additional factors in the analysis included sex, age, APOE status, cognitive reserve, physical health, and whether participants lived independently.

At autopsy, amyloid-beta (A-beta) level, the level of intracellular accumulation of phosphorylated tau protein in neurofibrillary tangles (NFTs), and the neuritic plaque (NP) load were assessed.
 

Resilience and cognitive reserve

At baseline, the median age of the centenarians (n = 330, 72.4% women) was 100.5 years (interquartile range, 100.2-101.7). A little over half (56.7%) lived independently, and the majority had good vision (65%) and hearing (56.4%). Most (78.8%) were able to walk independently, and 37.9% had achieved the highest International Standard Classification of Education level of postsecondary education.

The researchers found “varying degrees of neuropathology” in the brains of the 44 donors, including A-beta, NFT, and NPs.

The duration of follow-up in analyzing cognitive trajectories ranged from 0 to 4 years (median, 1.6 years).

Assessments of all cognitive domains showed no decline, with the exception of a “slight” decrement in memory function (beta −.10 SD per year; 95% confidence interval, –.14 to –.05 SD; P < .001).

Cognitive performance was associated with factors of physical health or cognitive reserve, for example, greater independence in performing activities of daily living, as assessed by the Barthel index (beta .37 SD per year; 95% CI, .24-.49; P < .001), or higher educational level (beta .41 SD per year; 95% CI, .29-.53; P < .001).

Despite findings of neuropathologic “hallmarks” of AD post mortem in the brains of the centenarians, these were not associated with cognitive performance or rate of decline.

APOE epsilon-4 or an APOE epsilon-3 alleles also were not significantly associated with cognitive performance or decline, suggesting that the “effects of APOE alleles are exerted before the age of 100 years,” the authors noted.

“Our findings suggest that after reaching age 100 years, cognitive performance remains relatively stable during ensuing years. Therefore, these centenarians might be resilient or resistant against different risk factors of cognitive decline,” the authors wrote. They also speculate that resilience may be attributable to greater cognitive reserve.

“Our preliminary data indicate that approximately 60% of the chance to reach 100 years old is heritable. Therefore, to get a better understanding of which genetic factors associate with the prolonged maintenance of cognitive health, we are looking into which genetic variants occur more commonly in centenarians compared to younger individuals,” said Dr. Holstege.

“Of course, more research needs to be performed to get a better understanding of how such genetic elements might sustain brain health,” she added.
 

A ‘landmark study’

Commenting on the study in an interview, Thomas Perls, MD, MPH, professor of medicine, Boston University, called it a “landmark” study in research on exceptional longevity in humans.

Dr. Perls, the author of an accompanying editorial, noted that “one cannot absolutely assume a certain level or disability or risk for disease just because a person has achieved extreme age – in fact, if anything, their ability to achieve much older ages likely indicates that they have resistance or resilience to aging-related problems.”

Understanding the mechanism of the resilience could lead to treatment or prevention of AD, said Dr. Perls, who was not involved in the research.

“People have to be careful about ageist myths and attitudes and not have the ageist idea that the older you get, the sicker you get, because many individuals disprove that,” he cautioned.

The study was supported by Stichting Alzheimer Nederland and Stichting Vumc Fonds. Research from the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Dr. Holstege and Dr. Perls reported having no relevant financial relationships. The other authors’ disclosures are listed on the original article.

A version of this article first appeared on Medscape.com.

It is often assumed that cognitive decline is an inevitable part of aging, but a new study of centenarians suggests otherwise.

Investigators found that despite the presence of neuropathologies associated with Alzheimer’s disease (AD), many centenarians maintained high levels of cognitive performance.

“Cognitive decline is not inevitable,” senior author Henne Holstege, PhD, assistant professor, Amsterdam Alzheimer Center and Clinical Genetics, Amsterdam University Medical Center, said in an interview.

“At 100 years or older, high levels of cognitive performance can be maintained for several years, even when individuals are exposed to risk factors associated with cognitive decline,” she said.

The study was published online Jan. 15 in JAMA Network Open.
 

Escaping cognitive decline

Dr. Holstege said her interest in researching aging and cognitive health was inspired by the “fascinating” story of Hendrikje van Andel-Schipper, who died at age 115 in 2015 “completely cognitively healthy.” Her mother, who died at age 100, also was cognitively intact at the end of her life.

“I wanted to know how it is possible that some people can completely escape all aspects of cognitive decline while reaching extreme ages,” Dr. Holstege said.

To discover the secret to cognitive health in the oldest old, Dr. Holstege initiated the 100-Plus Study, which involved a cohort of healthy centenarians.

The investigators conducted extensive neuropsychological testing and collected blood and fecal samples to examine “the myriad factors that influence physical health, including genetics, neuropathology, blood markers, and the gut microbiome, to explore the molecular and neuropsychologic constellations associated with the escape from cognitive decline.”

The goal of the research was to investigate “to what extent centenarians were able to maintain their cognitive health after study inclusion, and to what extent this was associated with genetic, physical, or neuropathological features,” she said.

The study included 330 centenarians who completed one or more neuropsychological assessments. Neuropathologic studies were available for 44 participants.

To assess baseline cognitive performance, the researchers administered a wide array of neurocognitive tests, as well as the Mini–Mental State Examination, from which mean z scores for cognitive domains were calculated.

Additional factors in the analysis included sex, age, APOE status, cognitive reserve, physical health, and whether participants lived independently.

At autopsy, amyloid-beta (A-beta) level, the level of intracellular accumulation of phosphorylated tau protein in neurofibrillary tangles (NFTs), and the neuritic plaque (NP) load were assessed.
 

Resilience and cognitive reserve

At baseline, the median age of the centenarians (n = 330, 72.4% women) was 100.5 years (interquartile range, 100.2-101.7). A little over half (56.7%) lived independently, and the majority had good vision (65%) and hearing (56.4%). Most (78.8%) were able to walk independently, and 37.9% had achieved the highest International Standard Classification of Education level of postsecondary education.

The researchers found “varying degrees of neuropathology” in the brains of the 44 donors, including A-beta, NFT, and NPs.

The duration of follow-up in analyzing cognitive trajectories ranged from 0 to 4 years (median, 1.6 years).

Assessments of all cognitive domains showed no decline, with the exception of a “slight” decrement in memory function (beta −.10 SD per year; 95% confidence interval, –.14 to –.05 SD; P < .001).

Cognitive performance was associated with factors of physical health or cognitive reserve, for example, greater independence in performing activities of daily living, as assessed by the Barthel index (beta .37 SD per year; 95% CI, .24-.49; P < .001), or higher educational level (beta .41 SD per year; 95% CI, .29-.53; P < .001).

Despite findings of neuropathologic “hallmarks” of AD post mortem in the brains of the centenarians, these were not associated with cognitive performance or rate of decline.

APOE epsilon-4 or an APOE epsilon-3 alleles also were not significantly associated with cognitive performance or decline, suggesting that the “effects of APOE alleles are exerted before the age of 100 years,” the authors noted.

“Our findings suggest that after reaching age 100 years, cognitive performance remains relatively stable during ensuing years. Therefore, these centenarians might be resilient or resistant against different risk factors of cognitive decline,” the authors wrote. They also speculate that resilience may be attributable to greater cognitive reserve.

“Our preliminary data indicate that approximately 60% of the chance to reach 100 years old is heritable. Therefore, to get a better understanding of which genetic factors associate with the prolonged maintenance of cognitive health, we are looking into which genetic variants occur more commonly in centenarians compared to younger individuals,” said Dr. Holstege.

“Of course, more research needs to be performed to get a better understanding of how such genetic elements might sustain brain health,” she added.
 

A ‘landmark study’

Commenting on the study in an interview, Thomas Perls, MD, MPH, professor of medicine, Boston University, called it a “landmark” study in research on exceptional longevity in humans.

Dr. Perls, the author of an accompanying editorial, noted that “one cannot absolutely assume a certain level or disability or risk for disease just because a person has achieved extreme age – in fact, if anything, their ability to achieve much older ages likely indicates that they have resistance or resilience to aging-related problems.”

Understanding the mechanism of the resilience could lead to treatment or prevention of AD, said Dr. Perls, who was not involved in the research.

“People have to be careful about ageist myths and attitudes and not have the ageist idea that the older you get, the sicker you get, because many individuals disprove that,” he cautioned.

The study was supported by Stichting Alzheimer Nederland and Stichting Vumc Fonds. Research from the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Dr. Holstege and Dr. Perls reported having no relevant financial relationships. The other authors’ disclosures are listed on the original article.

A version of this article first appeared on Medscape.com.

It is often assumed that cognitive decline is an inevitable part of aging, but a new study of centenarians suggests otherwise.

Investigators found that despite the presence of neuropathologies associated with Alzheimer’s disease (AD), many centenarians maintained high levels of cognitive performance.

“Cognitive decline is not inevitable,” senior author Henne Holstege, PhD, assistant professor, Amsterdam Alzheimer Center and Clinical Genetics, Amsterdam University Medical Center, said in an interview.

“At 100 years or older, high levels of cognitive performance can be maintained for several years, even when individuals are exposed to risk factors associated with cognitive decline,” she said.

The study was published online Jan. 15 in JAMA Network Open.
 

Escaping cognitive decline

Dr. Holstege said her interest in researching aging and cognitive health was inspired by the “fascinating” story of Hendrikje van Andel-Schipper, who died at age 115 in 2015 “completely cognitively healthy.” Her mother, who died at age 100, also was cognitively intact at the end of her life.

“I wanted to know how it is possible that some people can completely escape all aspects of cognitive decline while reaching extreme ages,” Dr. Holstege said.

To discover the secret to cognitive health in the oldest old, Dr. Holstege initiated the 100-Plus Study, which involved a cohort of healthy centenarians.

The investigators conducted extensive neuropsychological testing and collected blood and fecal samples to examine “the myriad factors that influence physical health, including genetics, neuropathology, blood markers, and the gut microbiome, to explore the molecular and neuropsychologic constellations associated with the escape from cognitive decline.”

The goal of the research was to investigate “to what extent centenarians were able to maintain their cognitive health after study inclusion, and to what extent this was associated with genetic, physical, or neuropathological features,” she said.

The study included 330 centenarians who completed one or more neuropsychological assessments. Neuropathologic studies were available for 44 participants.

To assess baseline cognitive performance, the researchers administered a wide array of neurocognitive tests, as well as the Mini–Mental State Examination, from which mean z scores for cognitive domains were calculated.

Additional factors in the analysis included sex, age, APOE status, cognitive reserve, physical health, and whether participants lived independently.

At autopsy, amyloid-beta (A-beta) level, the level of intracellular accumulation of phosphorylated tau protein in neurofibrillary tangles (NFTs), and the neuritic plaque (NP) load were assessed.
 

Resilience and cognitive reserve

At baseline, the median age of the centenarians (n = 330, 72.4% women) was 100.5 years (interquartile range, 100.2-101.7). A little over half (56.7%) lived independently, and the majority had good vision (65%) and hearing (56.4%). Most (78.8%) were able to walk independently, and 37.9% had achieved the highest International Standard Classification of Education level of postsecondary education.

The researchers found “varying degrees of neuropathology” in the brains of the 44 donors, including A-beta, NFT, and NPs.

The duration of follow-up in analyzing cognitive trajectories ranged from 0 to 4 years (median, 1.6 years).

Assessments of all cognitive domains showed no decline, with the exception of a “slight” decrement in memory function (beta −.10 SD per year; 95% confidence interval, –.14 to –.05 SD; P < .001).

Cognitive performance was associated with factors of physical health or cognitive reserve, for example, greater independence in performing activities of daily living, as assessed by the Barthel index (beta .37 SD per year; 95% CI, .24-.49; P < .001), or higher educational level (beta .41 SD per year; 95% CI, .29-.53; P < .001).

Despite findings of neuropathologic “hallmarks” of AD post mortem in the brains of the centenarians, these were not associated with cognitive performance or rate of decline.

APOE epsilon-4 or an APOE epsilon-3 alleles also were not significantly associated with cognitive performance or decline, suggesting that the “effects of APOE alleles are exerted before the age of 100 years,” the authors noted.

“Our findings suggest that after reaching age 100 years, cognitive performance remains relatively stable during ensuing years. Therefore, these centenarians might be resilient or resistant against different risk factors of cognitive decline,” the authors wrote. They also speculate that resilience may be attributable to greater cognitive reserve.

“Our preliminary data indicate that approximately 60% of the chance to reach 100 years old is heritable. Therefore, to get a better understanding of which genetic factors associate with the prolonged maintenance of cognitive health, we are looking into which genetic variants occur more commonly in centenarians compared to younger individuals,” said Dr. Holstege.

“Of course, more research needs to be performed to get a better understanding of how such genetic elements might sustain brain health,” she added.
 

A ‘landmark study’

Commenting on the study in an interview, Thomas Perls, MD, MPH, professor of medicine, Boston University, called it a “landmark” study in research on exceptional longevity in humans.

Dr. Perls, the author of an accompanying editorial, noted that “one cannot absolutely assume a certain level or disability or risk for disease just because a person has achieved extreme age – in fact, if anything, their ability to achieve much older ages likely indicates that they have resistance or resilience to aging-related problems.”

Understanding the mechanism of the resilience could lead to treatment or prevention of AD, said Dr. Perls, who was not involved in the research.

“People have to be careful about ageist myths and attitudes and not have the ageist idea that the older you get, the sicker you get, because many individuals disprove that,” he cautioned.

The study was supported by Stichting Alzheimer Nederland and Stichting Vumc Fonds. Research from the Alzheimer Center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. Dr. Holstege and Dr. Perls reported having no relevant financial relationships. The other authors’ disclosures are listed on the original article.

A version of this article first appeared on Medscape.com.

Evidence Summary

Single-dose IV ketamine elicits a short-term response

A meta-analysis of RCTs evaluating a single dose of IV ketamine vs placebo for severe depression found that it increased the chance of a treatment response for up to 1 week afterward. Studies included patients with severe (N = 30), treatment-resistant (N = 40), and psychotic depression (N = 10), based on Diagnostic and Statistical Manual of Mental Disorders–Fifth Edition criteria.¹

The primary outcome was treatment response: either an improvement of > 50% on a standardized depression scale or a Clinical Global Impression–Improvement scale score of 1 or 2 (“very much” and “much” improved, respectively, as assessed by a clinician). Ketamine increased the likelihood of short-term response or improvement at 24 hours (3 RCTs; N = 56; odds ratio [OR] = 11; 95% CI, 2-58); at 72 hours (3 RCTs; N = 56; OR = 13; 95% CI, 2-66); and at 7 days (4 RCTs; N = 88; OR = 2.6; 95% CI, 1.1-6.2).¹ Response rates equaled placebo at 2 weeks. The authors rated the RCTs as low quality.

Another systematic review of single-dose IV ketamine vs placebo for major depression and bipolar disorder included 3 additional small, low-quality RCTs, 2 of which showed short-term response to ketamine. The authors used Hedge’s g statistic to standardize effect size (a score of magnitude 0.2 indicates a small effect; 0.6, moderate; 1.2, large; and 2, very large). One RCT (n = 26) found a very large 1-day response (effect size: –2; 95% CI, –2.8 to –1.3), and 2 RCTs found conflicting responses at 12 days (RCT with N = 18: effect size: –0.2; 95% CI, –0.4 to 0.02 [no significant response] vs RCT with N = 8: effect size: –1.5; 95% CI, –2.5 to –0.5).²

More frequent dosing of IV ketamine improves symptoms

An RCT (N = 67) evaluating twice- or thrice-weekly IV ketamine vs placebo in patients with recurrent depression (with at least 1 treatment failure) found that ketamine significantly improved standardized depression scores and response rates at 15 days. Patients with clinically significant suicidality were excluded.³

Researchers randomized patients to IV ketamine (0.05 mg/kg) twice or thrice weekly or to saline control and used the 60-point Montgomery-Asberg Depression Rating Scale (MADRS). A response was defined as a reduction of the MADRS score by 50%.

A single dose of IV ketamine increased the chance of a treatment response for up to 1 week, compared to placebo.

Both ketamine arms produced greater symptom improvement at 15 days, compared to placebo (twice weekly: −18.4 vs −5.7; P < 0.001; thrice weekly: −17.7 vs −3.1; P < 0.001) in addition to higher response rates (twice weekly: 69% vs 15%; P = .005; number needed to treat [NNT] = 2; and thrice-weekly: 54% vs 6%; P = .004; NNT = 2).³ There was no significant difference between twice- or thrice-weekly dosing. The study was flawed by dropouts (N = 57 at 15 days and N = 25 at 28 days), primarily attributed to ketamine adverse effects, that prevented assessment beyond 2 weeks.

Oral ketamine has a moderate effecton depression

A systematic review included 2 low-quality RCTs evaluating oral ketamine vs placebo as adjunctive treatment with sertraline, and oral ketamine vs diclofenac, and found improvement in patients with moderate depression.⁴ In the first RCT (n = 45), researchers found that oral ketamine (25 mg bid) plus sertraline (25 mg titrated up to 150 mg/d) produced more treatment responses (> 50% reduction on a standardized depression rating scale) than placebo plus sertraline (2 weeks: 85.4% vs 42.5%; P < .001; 6 weeks: 85.4% vs 57.5%; P = .005).⁴

In the second RCT (n = 23), researchers randomized patients with mild-to-moderate depression and comorbid chronic headaches to take oral ketamine (50 mg tid) or oral diclofenac (50 mg tid) and measured effect size on standardized depression scores at 3 weeks (no difference) and 6 weeks (Cohen d effect size = 0.79 [rated as a moderate effect]; P = .017).⁴

Nasal esketamine + oral antidepressants boosts treatment response rates

A meta-analysis with 4 RCTs (N = 708) evaluating intranasal esketamine vs placebo as an adjunct to oral antidepressants for patients with predominantly treatment-resistant major depression found that it boosted response rates by about 40%. Researchers randomized patients to intranasal esketamine (mostly 28-84 mg twice weekly for 28 days) or placebo spray as an adjunct to oral antidepressants (duloxetine, escitalopram, sertraline, venlafaxine).

The primary outcomes were treatment response (≥ 50% reduction in depression scores) or remission (a MADRS score < 12). Adjunctive intranasal esketamine produced greater rates of treatment response compared to placebo at 24 hours (21% vs 7%; relative risk [RR] = 8.4; 95% CI, 1.4 to 21.2; P < .02; NNT = 7) and at 28 days (59% vs 43%; RR = 1.4; 95% CI, 1.2 to 1.60; P < .0001; NNT = 6).⁵ Adjunctive intranasal esketamine also produced greater rates of remission at the end of the study (mostly at 28 days), compared with placebo (41% vs 25%; RR = 1.4; 95% CI, 1.2 to 1.7; P = .0004; NNT = 7).⁵ The authors rated study quality as moderate to high.

Adverse effects are common, may cause Tx discontinuation

Ketamine-produced adverse effects (AEs) included confusion (2 trials; N = 76; OR = 3.7; 95% CI, 1.1-12) and emotional blunting (1 trial; N = 30; OR = 23; 95% CI, 1.1-489).¹

A 2018 systematic review assessed the safety of ketamine in depression after single and repeated dose in 60 studies (N = 899; 20 RCTs, 17 open-label-trials, 20 case series, and 3 retrospective studies). The most common AEs reported were headache (35% of studies), dizziness (33%), dissociation (28%), elevated blood pressure (28%), and blurred vision (23%), with the majority reported to resolve shortly after administration. The most common psychiatric AE was anxiety (15%).⁶ Included studies varied greatly in design and dosage form, and no meta-analysis could be performed.

Nasal esketamine produced more AEs causing discontinuation than did placebo (5.8% vs 1.5%; RR = 3.5; 95% CI, 1.34-8.9; number needed to harm [NNH] = 23), including blurred vision, dizziness, sedation, nausea, and dysphoria.⁵A review (5 RCTs and 1 open-label trial; N = 1708) analyzing the cardiac safety profile of intranasal esketamine adjuvant therapy found that it produced transient and asymptomatic blood pressure elevations (OR = 3.2; 95% CI, 1.9-5.8; NNH = 13).⁷

Recommendations from others

A clinical practice guideline from the US Veterans Administration lists IV ketamine as 1 of the therapeutic options for patients with treatment-resistant depression and suicidal ideation.⁸ However, a Department of Veterans Affairs Panel restricted its use to a pre-approved case-by-case basis.⁸

Editor’s takeaway

Physicians with patients facing the all-too-common problem of treatment-resistant major depression will be wondering if ketamine, either by itself or as an augmentation therapy, can help. Unfortunately, the outcomes we report here are too short term to answer that question, and we must await the results of further studies. Augmentation with intranasal esketamine, at a cost of $370/month, might offer some promise.

Evidence Summary

Single-dose IV ketamine elicits a short-term response

A meta-analysis of RCTs evaluating a single dose of IV ketamine vs placebo for severe depression found that it increased the chance of a treatment response for up to 1 week afterward. Studies included patients with severe (N = 30), treatment-resistant (N = 40), and psychotic depression (N = 10), based on Diagnostic and Statistical Manual of Mental Disorders–Fifth Edition criteria.¹

The primary outcome was treatment response: either an improvement of > 50% on a standardized depression scale or a Clinical Global Impression–Improvement scale score of 1 or 2 (“very much” and “much” improved, respectively, as assessed by a clinician). Ketamine increased the likelihood of short-term response or improvement at 24 hours (3 RCTs; N = 56; odds ratio [OR] = 11; 95% CI, 2-58); at 72 hours (3 RCTs; N = 56; OR = 13; 95% CI, 2-66); and at 7 days (4 RCTs; N = 88; OR = 2.6; 95% CI, 1.1-6.2).¹ Response rates equaled placebo at 2 weeks. The authors rated the RCTs as low quality.

Another systematic review of single-dose IV ketamine vs placebo for major depression and bipolar disorder included 3 additional small, low-quality RCTs, 2 of which showed short-term response to ketamine. The authors used Hedge’s g statistic to standardize effect size (a score of magnitude 0.2 indicates a small effect; 0.6, moderate; 1.2, large; and 2, very large). One RCT (n = 26) found a very large 1-day response (effect size: –2; 95% CI, –2.8 to –1.3), and 2 RCTs found conflicting responses at 12 days (RCT with N = 18: effect size: –0.2; 95% CI, –0.4 to 0.02 [no significant response] vs RCT with N = 8: effect size: –1.5; 95% CI, –2.5 to –0.5).²

More frequent dosing of IV ketamine improves symptoms

An RCT (N = 67) evaluating twice- or thrice-weekly IV ketamine vs placebo in patients with recurrent depression (with at least 1 treatment failure) found that ketamine significantly improved standardized depression scores and response rates at 15 days. Patients with clinically significant suicidality were excluded.³

Researchers randomized patients to IV ketamine (0.05 mg/kg) twice or thrice weekly or to saline control and used the 60-point Montgomery-Asberg Depression Rating Scale (MADRS). A response was defined as a reduction of the MADRS score by 50%.

A single dose of IV ketamine increased the chance of a treatment response for up to 1 week, compared to placebo.

Both ketamine arms produced greater symptom improvement at 15 days, compared to placebo (twice weekly: −18.4 vs −5.7; P < 0.001; thrice weekly: −17.7 vs −3.1; P < 0.001) in addition to higher response rates (twice weekly: 69% vs 15%; P = .005; number needed to treat [NNT] = 2; and thrice-weekly: 54% vs 6%; P = .004; NNT = 2).³ There was no significant difference between twice- or thrice-weekly dosing. The study was flawed by dropouts (N = 57 at 15 days and N = 25 at 28 days), primarily attributed to ketamine adverse effects, that prevented assessment beyond 2 weeks.

Oral ketamine has a moderate effecton depression

A systematic review included 2 low-quality RCTs evaluating oral ketamine vs placebo as adjunctive treatment with sertraline, and oral ketamine vs diclofenac, and found improvement in patients with moderate depression.⁴ In the first RCT (n = 45), researchers found that oral ketamine (25 mg bid) plus sertraline (25 mg titrated up to 150 mg/d) produced more treatment responses (> 50% reduction on a standardized depression rating scale) than placebo plus sertraline (2 weeks: 85.4% vs 42.5%; P < .001; 6 weeks: 85.4% vs 57.5%; P = .005).⁴

In the second RCT (n = 23), researchers randomized patients with mild-to-moderate depression and comorbid chronic headaches to take oral ketamine (50 mg tid) or oral diclofenac (50 mg tid) and measured effect size on standardized depression scores at 3 weeks (no difference) and 6 weeks (Cohen d effect size = 0.79 [rated as a moderate effect]; P = .017).⁴

Nasal esketamine + oral antidepressants boosts treatment response rates

A meta-analysis with 4 RCTs (N = 708) evaluating intranasal esketamine vs placebo as an adjunct to oral antidepressants for patients with predominantly treatment-resistant major depression found that it boosted response rates by about 40%. Researchers randomized patients to intranasal esketamine (mostly 28-84 mg twice weekly for 28 days) or placebo spray as an adjunct to oral antidepressants (duloxetine, escitalopram, sertraline, venlafaxine).

The primary outcomes were treatment response (≥ 50% reduction in depression scores) or remission (a MADRS score < 12). Adjunctive intranasal esketamine produced greater rates of treatment response compared to placebo at 24 hours (21% vs 7%; relative risk [RR] = 8.4; 95% CI, 1.4 to 21.2; P < .02; NNT = 7) and at 28 days (59% vs 43%; RR = 1.4; 95% CI, 1.2 to 1.60; P < .0001; NNT = 6).⁵ Adjunctive intranasal esketamine also produced greater rates of remission at the end of the study (mostly at 28 days), compared with placebo (41% vs 25%; RR = 1.4; 95% CI, 1.2 to 1.7; P = .0004; NNT = 7).⁵ The authors rated study quality as moderate to high.

Adverse effects are common, may cause Tx discontinuation

Ketamine-produced adverse effects (AEs) included confusion (2 trials; N = 76; OR = 3.7; 95% CI, 1.1-12) and emotional blunting (1 trial; N = 30; OR = 23; 95% CI, 1.1-489).¹

A 2018 systematic review assessed the safety of ketamine in depression after single and repeated dose in 60 studies (N = 899; 20 RCTs, 17 open-label-trials, 20 case series, and 3 retrospective studies). The most common AEs reported were headache (35% of studies), dizziness (33%), dissociation (28%), elevated blood pressure (28%), and blurred vision (23%), with the majority reported to resolve shortly after administration. The most common psychiatric AE was anxiety (15%).⁶ Included studies varied greatly in design and dosage form, and no meta-analysis could be performed.

Nasal esketamine produced more AEs causing discontinuation than did placebo (5.8% vs 1.5%; RR = 3.5; 95% CI, 1.34-8.9; number needed to harm [NNH] = 23), including blurred vision, dizziness, sedation, nausea, and dysphoria.⁵A review (5 RCTs and 1 open-label trial; N = 1708) analyzing the cardiac safety profile of intranasal esketamine adjuvant therapy found that it produced transient and asymptomatic blood pressure elevations (OR = 3.2; 95% CI, 1.9-5.8; NNH = 13).⁷

Recommendations from others

A clinical practice guideline from the US Veterans Administration lists IV ketamine as 1 of the therapeutic options for patients with treatment-resistant depression and suicidal ideation.⁸ However, a Department of Veterans Affairs Panel restricted its use to a pre-approved case-by-case basis.⁸

Editor’s takeaway

Physicians with patients facing the all-too-common problem of treatment-resistant major depression will be wondering if ketamine, either by itself or as an augmentation therapy, can help. Unfortunately, the outcomes we report here are too short term to answer that question, and we must await the results of further studies. Augmentation with intranasal esketamine, at a cost of $370/month, might offer some promise.

Evidence Summary

Single-dose IV ketamine elicits a short-term response

A meta-analysis of RCTs evaluating a single dose of IV ketamine vs placebo for severe depression found that it increased the chance of a treatment response for up to 1 week afterward. Studies included patients with severe (N = 30), treatment-resistant (N = 40), and psychotic depression (N = 10), based on Diagnostic and Statistical Manual of Mental Disorders–Fifth Edition criteria.¹

The primary outcome was treatment response: either an improvement of > 50% on a standardized depression scale or a Clinical Global Impression–Improvement scale score of 1 or 2 (“very much” and “much” improved, respectively, as assessed by a clinician). Ketamine increased the likelihood of short-term response or improvement at 24 hours (3 RCTs; N = 56; odds ratio [OR] = 11; 95% CI, 2-58); at 72 hours (3 RCTs; N = 56; OR = 13; 95% CI, 2-66); and at 7 days (4 RCTs; N = 88; OR = 2.6; 95% CI, 1.1-6.2).¹ Response rates equaled placebo at 2 weeks. The authors rated the RCTs as low quality.

Another systematic review of single-dose IV ketamine vs placebo for major depression and bipolar disorder included 3 additional small, low-quality RCTs, 2 of which showed short-term response to ketamine. The authors used Hedge’s g statistic to standardize effect size (a score of magnitude 0.2 indicates a small effect; 0.6, moderate; 1.2, large; and 2, very large). One RCT (n = 26) found a very large 1-day response (effect size: –2; 95% CI, –2.8 to –1.3), and 2 RCTs found conflicting responses at 12 days (RCT with N = 18: effect size: –0.2; 95% CI, –0.4 to 0.02 [no significant response] vs RCT with N = 8: effect size: –1.5; 95% CI, –2.5 to –0.5).²

More frequent dosing of IV ketamine improves symptoms

An RCT (N = 67) evaluating twice- or thrice-weekly IV ketamine vs placebo in patients with recurrent depression (with at least 1 treatment failure) found that ketamine significantly improved standardized depression scores and response rates at 15 days. Patients with clinically significant suicidality were excluded.³

Researchers randomized patients to IV ketamine (0.05 mg/kg) twice or thrice weekly or to saline control and used the 60-point Montgomery-Asberg Depression Rating Scale (MADRS). A response was defined as a reduction of the MADRS score by 50%.

A single dose of IV ketamine increased the chance of a treatment response for up to 1 week, compared to placebo.

Both ketamine arms produced greater symptom improvement at 15 days, compared to placebo (twice weekly: −18.4 vs −5.7; P < 0.001; thrice weekly: −17.7 vs −3.1; P < 0.001) in addition to higher response rates (twice weekly: 69% vs 15%; P = .005; number needed to treat [NNT] = 2; and thrice-weekly: 54% vs 6%; P = .004; NNT = 2).³ There was no significant difference between twice- or thrice-weekly dosing. The study was flawed by dropouts (N = 57 at 15 days and N = 25 at 28 days), primarily attributed to ketamine adverse effects, that prevented assessment beyond 2 weeks.

Oral ketamine has a moderate effecton depression

A systematic review included 2 low-quality RCTs evaluating oral ketamine vs placebo as adjunctive treatment with sertraline, and oral ketamine vs diclofenac, and found improvement in patients with moderate depression.⁴ In the first RCT (n = 45), researchers found that oral ketamine (25 mg bid) plus sertraline (25 mg titrated up to 150 mg/d) produced more treatment responses (> 50% reduction on a standardized depression rating scale) than placebo plus sertraline (2 weeks: 85.4% vs 42.5%; P < .001; 6 weeks: 85.4% vs 57.5%; P = .005).⁴

In the second RCT (n = 23), researchers randomized patients with mild-to-moderate depression and comorbid chronic headaches to take oral ketamine (50 mg tid) or oral diclofenac (50 mg tid) and measured effect size on standardized depression scores at 3 weeks (no difference) and 6 weeks (Cohen d effect size = 0.79 [rated as a moderate effect]; P = .017).⁴

Nasal esketamine + oral antidepressants boosts treatment response rates

A meta-analysis with 4 RCTs (N = 708) evaluating intranasal esketamine vs placebo as an adjunct to oral antidepressants for patients with predominantly treatment-resistant major depression found that it boosted response rates by about 40%. Researchers randomized patients to intranasal esketamine (mostly 28-84 mg twice weekly for 28 days) or placebo spray as an adjunct to oral antidepressants (duloxetine, escitalopram, sertraline, venlafaxine).

The primary outcomes were treatment response (≥ 50% reduction in depression scores) or remission (a MADRS score < 12). Adjunctive intranasal esketamine produced greater rates of treatment response compared to placebo at 24 hours (21% vs 7%; relative risk [RR] = 8.4; 95% CI, 1.4 to 21.2; P < .02; NNT = 7) and at 28 days (59% vs 43%; RR = 1.4; 95% CI, 1.2 to 1.60; P < .0001; NNT = 6).⁵ Adjunctive intranasal esketamine also produced greater rates of remission at the end of the study (mostly at 28 days), compared with placebo (41% vs 25%; RR = 1.4; 95% CI, 1.2 to 1.7; P = .0004; NNT = 7).⁵ The authors rated study quality as moderate to high.

Adverse effects are common, may cause Tx discontinuation

Ketamine-produced adverse effects (AEs) included confusion (2 trials; N = 76; OR = 3.7; 95% CI, 1.1-12) and emotional blunting (1 trial; N = 30; OR = 23; 95% CI, 1.1-489).¹

A 2018 systematic review assessed the safety of ketamine in depression after single and repeated dose in 60 studies (N = 899; 20 RCTs, 17 open-label-trials, 20 case series, and 3 retrospective studies). The most common AEs reported were headache (35% of studies), dizziness (33%), dissociation (28%), elevated blood pressure (28%), and blurred vision (23%), with the majority reported to resolve shortly after administration. The most common psychiatric AE was anxiety (15%).⁶ Included studies varied greatly in design and dosage form, and no meta-analysis could be performed.

Nasal esketamine produced more AEs causing discontinuation than did placebo (5.8% vs 1.5%; RR = 3.5; 95% CI, 1.34-8.9; number needed to harm [NNH] = 23), including blurred vision, dizziness, sedation, nausea, and dysphoria.⁵A review (5 RCTs and 1 open-label trial; N = 1708) analyzing the cardiac safety profile of intranasal esketamine adjuvant therapy found that it produced transient and asymptomatic blood pressure elevations (OR = 3.2; 95% CI, 1.9-5.8; NNH = 13).⁷

Recommendations from others

A clinical practice guideline from the US Veterans Administration lists IV ketamine as 1 of the therapeutic options for patients with treatment-resistant depression and suicidal ideation.⁸ However, a Department of Veterans Affairs Panel restricted its use to a pre-approved case-by-case basis.⁸

Editor’s takeaway

Physicians with patients facing the all-too-common problem of treatment-resistant major depression will be wondering if ketamine, either by itself or as an augmentation therapy, can help. Unfortunately, the outcomes we report here are too short term to answer that question, and we must await the results of further studies. Augmentation with intranasal esketamine, at a cost of $370/month, might offer some promise.

The Food and Drug Administration has approved the nonstimulant medication viloxazine extended-release capsules (Qelbree, Supernus Pharmaceuticals) for the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6-17 years, the company has announced.

Viloxazine (formerly SPN-812) is a selective norepinephrine reuptake inhibitor. Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce, as needed.

The approval of viloxazine is supported by data from four phase 3 clinical trials involving more than 1,000 pediatric patients aged 6-17 years, the company said.

In one randomized, placebo-controlled phase 3 study that included more than 400 children, viloxazine reduced symptoms of ADHD as soon as 1 week after dosing and was well tolerated.

As reported by this news organization, the study was published last July in Clinical Therapeutics.

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical associate professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interview.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The prescribing label for viloxazine includes a boxed warning regarding the potential for suicidal thoughts and behaviors in some children with ADHD treated with the drug, especially within the first few months of treatment or when the dose is changed. 

In clinical trials, higher rates of suicidal thoughts and behavior were reported in pediatric patients treated with viloxazine than in patients treated with placebo. Patients taking viloxazine should be closely monitored for any new or sudden changes in mood, behavior, thoughts, and feelings.

Viloxazine has shown promise in a phase 3 trial involving adults with ADHD.

The company plans to submit a supplemental new drug application to the FDA for viloxazine in adults later this year.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved the nonstimulant medication viloxazine extended-release capsules (Qelbree, Supernus Pharmaceuticals) for the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6-17 years, the company has announced.

Viloxazine (formerly SPN-812) is a selective norepinephrine reuptake inhibitor. Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce, as needed.

The approval of viloxazine is supported by data from four phase 3 clinical trials involving more than 1,000 pediatric patients aged 6-17 years, the company said.

In one randomized, placebo-controlled phase 3 study that included more than 400 children, viloxazine reduced symptoms of ADHD as soon as 1 week after dosing and was well tolerated.

As reported by this news organization, the study was published last July in Clinical Therapeutics.

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical associate professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interview.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The prescribing label for viloxazine includes a boxed warning regarding the potential for suicidal thoughts and behaviors in some children with ADHD treated with the drug, especially within the first few months of treatment or when the dose is changed. 

In clinical trials, higher rates of suicidal thoughts and behavior were reported in pediatric patients treated with viloxazine than in patients treated with placebo. Patients taking viloxazine should be closely monitored for any new or sudden changes in mood, behavior, thoughts, and feelings.

Viloxazine has shown promise in a phase 3 trial involving adults with ADHD.

The company plans to submit a supplemental new drug application to the FDA for viloxazine in adults later this year.

A version of this article first appeared on Medscape.com.

The Food and Drug Administration has approved the nonstimulant medication viloxazine extended-release capsules (Qelbree, Supernus Pharmaceuticals) for the treatment of attention deficit hyperactivity disorder (ADHD) in children aged 6-17 years, the company has announced.

Viloxazine (formerly SPN-812) is a selective norepinephrine reuptake inhibitor. Capsules may be swallowed whole or opened and the entire contents sprinkled onto applesauce, as needed.

The approval of viloxazine is supported by data from four phase 3 clinical trials involving more than 1,000 pediatric patients aged 6-17 years, the company said.

In one randomized, placebo-controlled phase 3 study that included more than 400 children, viloxazine reduced symptoms of ADHD as soon as 1 week after dosing and was well tolerated.

As reported by this news organization, the study was published last July in Clinical Therapeutics.

In addition to its fast onset of action, the fact that it was effective for both inattentive and hyperactive/impulsive clusters of symptoms is “impressive,” study investigator Andrew Cutler, MD, clinical associate professor of psychiatry, SUNY Upstate Medical University, Syracuse, N.Y., said in an interview.

Also noteworthy was the improvement in measures of quality of life and function, “especially function in the areas of school, home life, family relations, and peer relationships, which can be really disrupted with ADHD,” Dr. Cutler said.

The prescribing label for viloxazine includes a boxed warning regarding the potential for suicidal thoughts and behaviors in some children with ADHD treated with the drug, especially within the first few months of treatment or when the dose is changed. 

In clinical trials, higher rates of suicidal thoughts and behavior were reported in pediatric patients treated with viloxazine than in patients treated with placebo. Patients taking viloxazine should be closely monitored for any new or sudden changes in mood, behavior, thoughts, and feelings.

Viloxazine has shown promise in a phase 3 trial involving adults with ADHD.

The company plans to submit a supplemental new drug application to the FDA for viloxazine in adults later this year.

A version of this article first appeared on Medscape.com.

Exhaustion, numbness, dissociation, and most notably, anger are my emotional response when viewing the video of George Floyd’s death. The homicide trial of former Minneapolis police officer Derek Chauvin activates the shared stress of those who experienced intergenerational trauma and the legacy of racism in the United States of America.

On May 25, 2020, Mr. Floyd died after Derek Chauvin used a lethal maneuver and placed his knee on Mr. Floyd’s neck for 9 minutes and 29 seconds. Mr. Floyd has died physically, but his death is replayed through high-definition social media daily, if not hourly, as I write this article and think of the generational legacy of trauma that African Americans must cope with on an everyday basis. I struggle daily to explain this legacy to my daughters, students, residents, and colleagues. I hope to share with you some of my perspectives on the current trial and give you some insight as to how my training and personal life experience have affected my views on police brutality and the use of lethal force toward African American men.

My earliest recollection of public video-recorded images of police brutality occurred when Rodney King was beaten and assaulted by the Los Angeles Police Department on March 3, 1991. At that time, I was a senior in high school, and the world was different. My clear expectation was that any attempt to resist police arrest would be met with overwhelming and potentially lethal force. This was simply a matter of my daily reality, so, while witnessing the assault of Mr. King, the 17-year-old child didn’t expect much, if any, real change to come about in regard to police brutality. At that time, my mother kept me focused on one singular goal – becoming a physician – and protected me as best she could from the effects of intergenerational trauma woven into the African American experience.

The issue of police brutality and police-involved deaths has been recognized as a significant public health concern for some time. Over the 3 decades since the assault on Mr. King, several researchers have examined these issues. A review of all the research is beyond the scope of this opinion piece. Still, I will highlight a study that I believe illustrates some conclusions scholars have come to regarding police use of lethal force and subsequent mortality in African American men. A recent study by Frank Edwards, PhD, and colleagues, published in the Proceedings of the National Academy of Sciences, showed that Black men were 2.5 times more likely to be killed by police over their life course than White men.

The researchers also developed predictive models that about 1 in 1,000 Black men and boys will be killed by police over their life course, and that among all age groups Black men and boys face the highest lifetime risk. The authors concluded that “Our analysis shows that the risk of being killed by police is jointly patterned by one’s race, gender, and age. Police violence is a leading cause of death for young men, and young men of color face an exceptionally high risk of being killed by police. Inequalities in risk are pronounced throughout the life course. This study reinforces calls to treat police violence as a public health issue.”

Research such as this helps validate on a visceral level what I already was taught: “As a Black male, encounters with police can quickly become deadly, and you must remain calm, or you could die.” This thought process informed much of my thinking whenever I heard about a Black male being fatally shot by police. My first response was to ask, “Was he resisting arrest?” At this time, my naive impression was that “if you don’t resist or conflict, you’ll live.” It wasn’t until my training in psychiatry that I realized that the duty to calm, support, and most importantly, protect was the responsibility of the person who is given the trust of the public. As a psychiatrist, I am humbled by the trust the public places in physicians to restrain patients and take part in their involuntary hospitalizations. Over the years, I learned from my attending physicians, colleagues in security, social work, nursing, assertive community treatment (ACT) teams, and many other allied health professions that the responsibility to show restraint, calm, and compassion lies with those who have the power and trust of the public.

Mostly, I learned from my patients. They taught me to meet distress with compassion and humanity and not simply with force. With those lessons in mind, I now fast forward to July 17, 2014, and the death of Eric Garner. On July 17, New York Police Department officers approached Mr. Garner on the suspicion that he was selling loose cigarettes. Amid this encounter, Mr. Garner was subjected to a chokehold, and his face was pinned to the ground while he can be heard saying, “I can’t breathe.” At this time in my professional career, I had just become a dean of student affairs at the George Washington School of Medicine and Health Sciences. I can still remember the response of my minority students, and the sense of pain and anguish they felt watching the video of a chokehold being used on a man stating, “I can’t breathe.” At this point, my training would not allow me to see this as anything other than an unnecessary use of lethal force that would subsequently be ruled a homicide. I hoped that we as a nation had reached a “reckoning “ because of Mr. Garner’s death and Michael Brown Jr.’s subsequent death in Ferguson, Mo., in St. Louis County, on Aug. 9, 2014. I hoped we were ready to finally address police brutality and excessive use of force that had disproportionately affected Black men. I was utterly wrong. Black men such as Alton Sterling, Jamar Clark, and many others would die in fatal police encounters. So would Tamir Rice, who was 12 years old when he was shot and killed by a police officer.

This brings me back to the death of Mr. Floyd. As I listened to the witnesses’ testimony, it triggered an emotional response from sadness, fear, shock, but mostly anger. Some would consider it progress that the Minneapolis Police Department’s top homicide detective testified that kneeling on Mr. Floyd’s neck after he had been restrained was “unnecessary.” The officer stated, “If your knee is on someone’s neck, that could kill him.” While I acknowledge this is a form of progress, we must ultimately address the other “substantial causal factor of death” for Mr. Floyd. Namely, the systemic racism present in a criminal justice system in the form of policies and procedures that allow for continued racial disparities and inequities.

There will be coverage of the court proceedings and a detailed dissection of the legal arguments. Questions regarding Mr. Floyd’s physical health and struggle with opiate use disorder will be raised by the defense. The debate about the substantial causal factor will be played out in the court and the media. Ultimately, we, as health professionals, need to ask ourselves, “Who has the power and the duty to do no harm?”

Dr. Norris is associate dean of student affairs and administration at George Washington University, Washington. He has no disclosures.

Exhaustion, numbness, dissociation, and most notably, anger are my emotional response when viewing the video of George Floyd’s death. The homicide trial of former Minneapolis police officer Derek Chauvin activates the shared stress of those who experienced intergenerational trauma and the legacy of racism in the United States of America.

On May 25, 2020, Mr. Floyd died after Derek Chauvin used a lethal maneuver and placed his knee on Mr. Floyd’s neck for 9 minutes and 29 seconds. Mr. Floyd has died physically, but his death is replayed through high-definition social media daily, if not hourly, as I write this article and think of the generational legacy of trauma that African Americans must cope with on an everyday basis. I struggle daily to explain this legacy to my daughters, students, residents, and colleagues. I hope to share with you some of my perspectives on the current trial and give you some insight as to how my training and personal life experience have affected my views on police brutality and the use of lethal force toward African American men.

My earliest recollection of public video-recorded images of police brutality occurred when Rodney King was beaten and assaulted by the Los Angeles Police Department on March 3, 1991. At that time, I was a senior in high school, and the world was different. My clear expectation was that any attempt to resist police arrest would be met with overwhelming and potentially lethal force. This was simply a matter of my daily reality, so, while witnessing the assault of Mr. King, the 17-year-old child didn’t expect much, if any, real change to come about in regard to police brutality. At that time, my mother kept me focused on one singular goal – becoming a physician – and protected me as best she could from the effects of intergenerational trauma woven into the African American experience.

The issue of police brutality and police-involved deaths has been recognized as a significant public health concern for some time. Over the 3 decades since the assault on Mr. King, several researchers have examined these issues. A review of all the research is beyond the scope of this opinion piece. Still, I will highlight a study that I believe illustrates some conclusions scholars have come to regarding police use of lethal force and subsequent mortality in African American men. A recent study by Frank Edwards, PhD, and colleagues, published in the Proceedings of the National Academy of Sciences, showed that Black men were 2.5 times more likely to be killed by police over their life course than White men.

The researchers also developed predictive models that about 1 in 1,000 Black men and boys will be killed by police over their life course, and that among all age groups Black men and boys face the highest lifetime risk. The authors concluded that “Our analysis shows that the risk of being killed by police is jointly patterned by one’s race, gender, and age. Police violence is a leading cause of death for young men, and young men of color face an exceptionally high risk of being killed by police. Inequalities in risk are pronounced throughout the life course. This study reinforces calls to treat police violence as a public health issue.”

Research such as this helps validate on a visceral level what I already was taught: “As a Black male, encounters with police can quickly become deadly, and you must remain calm, or you could die.” This thought process informed much of my thinking whenever I heard about a Black male being fatally shot by police. My first response was to ask, “Was he resisting arrest?” At this time, my naive impression was that “if you don’t resist or conflict, you’ll live.” It wasn’t until my training in psychiatry that I realized that the duty to calm, support, and most importantly, protect was the responsibility of the person who is given the trust of the public. As a psychiatrist, I am humbled by the trust the public places in physicians to restrain patients and take part in their involuntary hospitalizations. Over the years, I learned from my attending physicians, colleagues in security, social work, nursing, assertive community treatment (ACT) teams, and many other allied health professions that the responsibility to show restraint, calm, and compassion lies with those who have the power and trust of the public.

Mostly, I learned from my patients. They taught me to meet distress with compassion and humanity and not simply with force. With those lessons in mind, I now fast forward to July 17, 2014, and the death of Eric Garner. On July 17, New York Police Department officers approached Mr. Garner on the suspicion that he was selling loose cigarettes. Amid this encounter, Mr. Garner was subjected to a chokehold, and his face was pinned to the ground while he can be heard saying, “I can’t breathe.” At this time in my professional career, I had just become a dean of student affairs at the George Washington School of Medicine and Health Sciences. I can still remember the response of my minority students, and the sense of pain and anguish they felt watching the video of a chokehold being used on a man stating, “I can’t breathe.” At this point, my training would not allow me to see this as anything other than an unnecessary use of lethal force that would subsequently be ruled a homicide. I hoped that we as a nation had reached a “reckoning “ because of Mr. Garner’s death and Michael Brown Jr.’s subsequent death in Ferguson, Mo., in St. Louis County, on Aug. 9, 2014. I hoped we were ready to finally address police brutality and excessive use of force that had disproportionately affected Black men. I was utterly wrong. Black men such as Alton Sterling, Jamar Clark, and many others would die in fatal police encounters. So would Tamir Rice, who was 12 years old when he was shot and killed by a police officer.

This brings me back to the death of Mr. Floyd. As I listened to the witnesses’ testimony, it triggered an emotional response from sadness, fear, shock, but mostly anger. Some would consider it progress that the Minneapolis Police Department’s top homicide detective testified that kneeling on Mr. Floyd’s neck after he had been restrained was “unnecessary.” The officer stated, “If your knee is on someone’s neck, that could kill him.” While I acknowledge this is a form of progress, we must ultimately address the other “substantial causal factor of death” for Mr. Floyd. Namely, the systemic racism present in a criminal justice system in the form of policies and procedures that allow for continued racial disparities and inequities.

There will be coverage of the court proceedings and a detailed dissection of the legal arguments. Questions regarding Mr. Floyd’s physical health and struggle with opiate use disorder will be raised by the defense. The debate about the substantial causal factor will be played out in the court and the media. Ultimately, we, as health professionals, need to ask ourselves, “Who has the power and the duty to do no harm?”

Dr. Norris is associate dean of student affairs and administration at George Washington University, Washington. He has no disclosures.

Exhaustion, numbness, dissociation, and most notably, anger are my emotional response when viewing the video of George Floyd’s death. The homicide trial of former Minneapolis police officer Derek Chauvin activates the shared stress of those who experienced intergenerational trauma and the legacy of racism in the United States of America.

On May 25, 2020, Mr. Floyd died after Derek Chauvin used a lethal maneuver and placed his knee on Mr. Floyd’s neck for 9 minutes and 29 seconds. Mr. Floyd has died physically, but his death is replayed through high-definition social media daily, if not hourly, as I write this article and think of the generational legacy of trauma that African Americans must cope with on an everyday basis. I struggle daily to explain this legacy to my daughters, students, residents, and colleagues. I hope to share with you some of my perspectives on the current trial and give you some insight as to how my training and personal life experience have affected my views on police brutality and the use of lethal force toward African American men.

My earliest recollection of public video-recorded images of police brutality occurred when Rodney King was beaten and assaulted by the Los Angeles Police Department on March 3, 1991. At that time, I was a senior in high school, and the world was different. My clear expectation was that any attempt to resist police arrest would be met with overwhelming and potentially lethal force. This was simply a matter of my daily reality, so, while witnessing the assault of Mr. King, the 17-year-old child didn’t expect much, if any, real change to come about in regard to police brutality. At that time, my mother kept me focused on one singular goal – becoming a physician – and protected me as best she could from the effects of intergenerational trauma woven into the African American experience.

The issue of police brutality and police-involved deaths has been recognized as a significant public health concern for some time. Over the 3 decades since the assault on Mr. King, several researchers have examined these issues. A review of all the research is beyond the scope of this opinion piece. Still, I will highlight a study that I believe illustrates some conclusions scholars have come to regarding police use of lethal force and subsequent mortality in African American men. A recent study by Frank Edwards, PhD, and colleagues, published in the Proceedings of the National Academy of Sciences, showed that Black men were 2.5 times more likely to be killed by police over their life course than White men.

The researchers also developed predictive models that about 1 in 1,000 Black men and boys will be killed by police over their life course, and that among all age groups Black men and boys face the highest lifetime risk. The authors concluded that “Our analysis shows that the risk of being killed by police is jointly patterned by one’s race, gender, and age. Police violence is a leading cause of death for young men, and young men of color face an exceptionally high risk of being killed by police. Inequalities in risk are pronounced throughout the life course. This study reinforces calls to treat police violence as a public health issue.”

Research such as this helps validate on a visceral level what I already was taught: “As a Black male, encounters with police can quickly become deadly, and you must remain calm, or you could die.” This thought process informed much of my thinking whenever I heard about a Black male being fatally shot by police. My first response was to ask, “Was he resisting arrest?” At this time, my naive impression was that “if you don’t resist or conflict, you’ll live.” It wasn’t until my training in psychiatry that I realized that the duty to calm, support, and most importantly, protect was the responsibility of the person who is given the trust of the public. As a psychiatrist, I am humbled by the trust the public places in physicians to restrain patients and take part in their involuntary hospitalizations. Over the years, I learned from my attending physicians, colleagues in security, social work, nursing, assertive community treatment (ACT) teams, and many other allied health professions that the responsibility to show restraint, calm, and compassion lies with those who have the power and trust of the public.

Mostly, I learned from my patients. They taught me to meet distress with compassion and humanity and not simply with force. With those lessons in mind, I now fast forward to July 17, 2014, and the death of Eric Garner. On July 17, New York Police Department officers approached Mr. Garner on the suspicion that he was selling loose cigarettes. Amid this encounter, Mr. Garner was subjected to a chokehold, and his face was pinned to the ground while he can be heard saying, “I can’t breathe.” At this time in my professional career, I had just become a dean of student affairs at the George Washington School of Medicine and Health Sciences. I can still remember the response of my minority students, and the sense of pain and anguish they felt watching the video of a chokehold being used on a man stating, “I can’t breathe.” At this point, my training would not allow me to see this as anything other than an unnecessary use of lethal force that would subsequently be ruled a homicide. I hoped that we as a nation had reached a “reckoning “ because of Mr. Garner’s death and Michael Brown Jr.’s subsequent death in Ferguson, Mo., in St. Louis County, on Aug. 9, 2014. I hoped we were ready to finally address police brutality and excessive use of force that had disproportionately affected Black men. I was utterly wrong. Black men such as Alton Sterling, Jamar Clark, and many others would die in fatal police encounters. So would Tamir Rice, who was 12 years old when he was shot and killed by a police officer.

This brings me back to the death of Mr. Floyd. As I listened to the witnesses’ testimony, it triggered an emotional response from sadness, fear, shock, but mostly anger. Some would consider it progress that the Minneapolis Police Department’s top homicide detective testified that kneeling on Mr. Floyd’s neck after he had been restrained was “unnecessary.” The officer stated, “If your knee is on someone’s neck, that could kill him.” While I acknowledge this is a form of progress, we must ultimately address the other “substantial causal factor of death” for Mr. Floyd. Namely, the systemic racism present in a criminal justice system in the form of policies and procedures that allow for continued racial disparities and inequities.

There will be coverage of the court proceedings and a detailed dissection of the legal arguments. Questions regarding Mr. Floyd’s physical health and struggle with opiate use disorder will be raised by the defense. The debate about the substantial causal factor will be played out in the court and the media. Ultimately, we, as health professionals, need to ask ourselves, “Who has the power and the duty to do no harm?”

Dr. Norris is associate dean of student affairs and administration at George Washington University, Washington. He has no disclosures.

Screen time may be associated with a range of psychosocial symptoms at age 5 years, according to a study of Finnish children that was published online in BMJ Open

Janette Niiranen, a researcher in the department of public health solutions at the Finnish Institute for Health and Welfare in Helsinki, and colleagues examined the frequency of electronic media use by 699 preschool children.

They analyzed longitudinal associations between media use at age 18 months and psychosocial symptoms at age 5 years. They also looked at whether media use at age 5 years was associated with the presence of psychosocial symptoms at that time.

The study relied on data collected between 2011 and 2017 as part of the Finnish CHILD-SLEEP longitudinal birth cohort study. Parents reported child media use via questionnaires at age 18 months and age 5 years. Researchers measured psychosocial symptoms at age 5 years using two parent-reported questionnaires: Five-to-Fifteen (FTF) and the Strengths and Difficulties Questionnaire (SDQ).

At age 5 years, a high amount of total screen time – at least 135 minutes per day, representing the 75th percentile of use – was associated with increased likelihood of attention and concentration difficulties, hyperactivity and impulsivity, emotional internalizing and externalizing symptoms, and conduct problems, the researchers reported. Odds ratios ranged from 1.57 to 2.18. In a model that adjusted for confounding factors, internalizing symptoms was the only symptom significantly associated with screen time (OR, 2.01).

In a longitudinal analysis, increased media use at 18 months was associated with peer problems at age 5 years (OR, 1.59).

Compared with program viewing, electronic game playing at age 5 years appeared to be associated with fewer psychosocial risks, the researchers noted. In an unadjusted model, a high amount of game playing was associated with hyperactivity, whereas program viewing was associated with a broad range of symptoms.

Use of electronic media beyond recommended amounts was common.

“The results of our study show that 95% of preschool aged children exceed the recommended daily e-media use of 1 hour,” the authors wrote.
 

No causal link

Amy Orben, DPhil, a researcher at Emmanuel College and the MRC Cognition and Brain Sciences Unit, University of Cambridge (England) highlighted limitations of the research.

The study is “purely observational” and does not “establish a causal link between time spent on electronic media and developmental outcomes in small children,” Dr. Orben said. Factors that may influence how much time a child spends on electronic media – such as whether both parents work and where a child lives – may also influence psychosocial symptoms.

“This means that an association can exist even if no causal link is present,” Dr. Orben said. Furthermore, the statistically significant associations found in the study “could well be noise,” she added.

As the study authors note, associations between screen time and children’s psychosocial well-being “may be bidirectional,” commented Karalyn Kinsella, MD, a pediatrician in private practice in Cheshire, Conn.

“There is no way to tell if the families who allow more screen time are doing that because the child already has some psychosocial issues like hyperactivity or dysregulation, and they are using media to calm them,” Dr. Kinsella said. “Or perhaps parents do not have the ability to interact as much with the child due to lack of time/work.” The lack of interaction, rather than electronic media use, may interfere with typical development.

“The end result is still pertinent, as we know children learn through play and social interaction,” Dr. Kinsella added. “I did find it interesting that electronic game playing when played with friends or family was less of a risk.”
 

Brainstorming alternatives

Libby Matile Milkovich, MD, a developmental pediatrician at Children’s Mercy Hospital, Kansas City, Mo., sees family electronic media use as an environmental factor that has significant variability for each patient.

“The need for electronic media to connect to others, to access entertainment, and to learn intensified with the pandemic,” Dr. Milkovich said. “In practice, after I identify concerning media habits, I try to help families create alternatives to their current habits as opposed to being prescriptive and saying to stop or limit media use. ... An alternative may not be limiting screen time but may be changing to more appropriate media content or sharing the media as a family activity.”

Seeing media use in the clinic can provide useful information and opportunities for discussion, Dr. Milkovich noted.

“When I see parents in the clinic room using media to calm a toddler or using their own media, these are great opportunities to open the door to brainstorming alternatives,” Dr. Milkovich said. “Commonly, family media use comes up when children have difficulty sleeping or disruptive behaviors related to media use, but I would challenge medical providers to think about problematic media use in all chief complaints where a behavioral component exists like toileting and feeding.”

The research was supported by the Academy of Finland, the Signe and Ane Gyllenberg Foundation, the Yrjö Jahnsson Foundation, the Foundation for Pediatric Research, the Finnish Cultural Foundation, and the Tampere University Hospital and Doctors’ Association in Tampere. The study authors, Dr. Milkovich, Dr. Orben, and Dr. Kinsella had no relevant financial disclosures. Dr. Kinsella serves on the Pediatric News editorial advisory board.

jremaly@mdedge.com

Screen time may be associated with a range of psychosocial symptoms at age 5 years, according to a study of Finnish children that was published online in BMJ Open

Janette Niiranen, a researcher in the department of public health solutions at the Finnish Institute for Health and Welfare in Helsinki, and colleagues examined the frequency of electronic media use by 699 preschool children.

They analyzed longitudinal associations between media use at age 18 months and psychosocial symptoms at age 5 years. They also looked at whether media use at age 5 years was associated with the presence of psychosocial symptoms at that time.

The study relied on data collected between 2011 and 2017 as part of the Finnish CHILD-SLEEP longitudinal birth cohort study. Parents reported child media use via questionnaires at age 18 months and age 5 years. Researchers measured psychosocial symptoms at age 5 years using two parent-reported questionnaires: Five-to-Fifteen (FTF) and the Strengths and Difficulties Questionnaire (SDQ).

At age 5 years, a high amount of total screen time – at least 135 minutes per day, representing the 75th percentile of use – was associated with increased likelihood of attention and concentration difficulties, hyperactivity and impulsivity, emotional internalizing and externalizing symptoms, and conduct problems, the researchers reported. Odds ratios ranged from 1.57 to 2.18. In a model that adjusted for confounding factors, internalizing symptoms was the only symptom significantly associated with screen time (OR, 2.01).

In a longitudinal analysis, increased media use at 18 months was associated with peer problems at age 5 years (OR, 1.59).

Compared with program viewing, electronic game playing at age 5 years appeared to be associated with fewer psychosocial risks, the researchers noted. In an unadjusted model, a high amount of game playing was associated with hyperactivity, whereas program viewing was associated with a broad range of symptoms.

Use of electronic media beyond recommended amounts was common.

“The results of our study show that 95% of preschool aged children exceed the recommended daily e-media use of 1 hour,” the authors wrote.
 

No causal link

Amy Orben, DPhil, a researcher at Emmanuel College and the MRC Cognition and Brain Sciences Unit, University of Cambridge (England) highlighted limitations of the research.

The study is “purely observational” and does not “establish a causal link between time spent on electronic media and developmental outcomes in small children,” Dr. Orben said. Factors that may influence how much time a child spends on electronic media – such as whether both parents work and where a child lives – may also influence psychosocial symptoms.

“This means that an association can exist even if no causal link is present,” Dr. Orben said. Furthermore, the statistically significant associations found in the study “could well be noise,” she added.

As the study authors note, associations between screen time and children’s psychosocial well-being “may be bidirectional,” commented Karalyn Kinsella, MD, a pediatrician in private practice in Cheshire, Conn.

“There is no way to tell if the families who allow more screen time are doing that because the child already has some psychosocial issues like hyperactivity or dysregulation, and they are using media to calm them,” Dr. Kinsella said. “Or perhaps parents do not have the ability to interact as much with the child due to lack of time/work.” The lack of interaction, rather than electronic media use, may interfere with typical development.

“The end result is still pertinent, as we know children learn through play and social interaction,” Dr. Kinsella added. “I did find it interesting that electronic game playing when played with friends or family was less of a risk.”
 

Brainstorming alternatives

Libby Matile Milkovich, MD, a developmental pediatrician at Children’s Mercy Hospital, Kansas City, Mo., sees family electronic media use as an environmental factor that has significant variability for each patient.

“The need for electronic media to connect to others, to access entertainment, and to learn intensified with the pandemic,” Dr. Milkovich said. “In practice, after I identify concerning media habits, I try to help families create alternatives to their current habits as opposed to being prescriptive and saying to stop or limit media use. ... An alternative may not be limiting screen time but may be changing to more appropriate media content or sharing the media as a family activity.”

Seeing media use in the clinic can provide useful information and opportunities for discussion, Dr. Milkovich noted.

“When I see parents in the clinic room using media to calm a toddler or using their own media, these are great opportunities to open the door to brainstorming alternatives,” Dr. Milkovich said. “Commonly, family media use comes up when children have difficulty sleeping or disruptive behaviors related to media use, but I would challenge medical providers to think about problematic media use in all chief complaints where a behavioral component exists like toileting and feeding.”

The research was supported by the Academy of Finland, the Signe and Ane Gyllenberg Foundation, the Yrjö Jahnsson Foundation, the Foundation for Pediatric Research, the Finnish Cultural Foundation, and the Tampere University Hospital and Doctors’ Association in Tampere. The study authors, Dr. Milkovich, Dr. Orben, and Dr. Kinsella had no relevant financial disclosures. Dr. Kinsella serves on the Pediatric News editorial advisory board.

jremaly@mdedge.com

Screen time may be associated with a range of psychosocial symptoms at age 5 years, according to a study of Finnish children that was published online in BMJ Open

Janette Niiranen, a researcher in the department of public health solutions at the Finnish Institute for Health and Welfare in Helsinki, and colleagues examined the frequency of electronic media use by 699 preschool children.

They analyzed longitudinal associations between media use at age 18 months and psychosocial symptoms at age 5 years. They also looked at whether media use at age 5 years was associated with the presence of psychosocial symptoms at that time.

The study relied on data collected between 2011 and 2017 as part of the Finnish CHILD-SLEEP longitudinal birth cohort study. Parents reported child media use via questionnaires at age 18 months and age 5 years. Researchers measured psychosocial symptoms at age 5 years using two parent-reported questionnaires: Five-to-Fifteen (FTF) and the Strengths and Difficulties Questionnaire (SDQ).

At age 5 years, a high amount of total screen time – at least 135 minutes per day, representing the 75th percentile of use – was associated with increased likelihood of attention and concentration difficulties, hyperactivity and impulsivity, emotional internalizing and externalizing symptoms, and conduct problems, the researchers reported. Odds ratios ranged from 1.57 to 2.18. In a model that adjusted for confounding factors, internalizing symptoms was the only symptom significantly associated with screen time (OR, 2.01).

In a longitudinal analysis, increased media use at 18 months was associated with peer problems at age 5 years (OR, 1.59).

Compared with program viewing, electronic game playing at age 5 years appeared to be associated with fewer psychosocial risks, the researchers noted. In an unadjusted model, a high amount of game playing was associated with hyperactivity, whereas program viewing was associated with a broad range of symptoms.

Use of electronic media beyond recommended amounts was common.

“The results of our study show that 95% of preschool aged children exceed the recommended daily e-media use of 1 hour,” the authors wrote.
 

No causal link

Amy Orben, DPhil, a researcher at Emmanuel College and the MRC Cognition and Brain Sciences Unit, University of Cambridge (England) highlighted limitations of the research.

The study is “purely observational” and does not “establish a causal link between time spent on electronic media and developmental outcomes in small children,” Dr. Orben said. Factors that may influence how much time a child spends on electronic media – such as whether both parents work and where a child lives – may also influence psychosocial symptoms.

“This means that an association can exist even if no causal link is present,” Dr. Orben said. Furthermore, the statistically significant associations found in the study “could well be noise,” she added.

As the study authors note, associations between screen time and children’s psychosocial well-being “may be bidirectional,” commented Karalyn Kinsella, MD, a pediatrician in private practice in Cheshire, Conn.

“There is no way to tell if the families who allow more screen time are doing that because the child already has some psychosocial issues like hyperactivity or dysregulation, and they are using media to calm them,” Dr. Kinsella said. “Or perhaps parents do not have the ability to interact as much with the child due to lack of time/work.” The lack of interaction, rather than electronic media use, may interfere with typical development.

“The end result is still pertinent, as we know children learn through play and social interaction,” Dr. Kinsella added. “I did find it interesting that electronic game playing when played with friends or family was less of a risk.”
 

Brainstorming alternatives

Libby Matile Milkovich, MD, a developmental pediatrician at Children’s Mercy Hospital, Kansas City, Mo., sees family electronic media use as an environmental factor that has significant variability for each patient.

“The need for electronic media to connect to others, to access entertainment, and to learn intensified with the pandemic,” Dr. Milkovich said. “In practice, after I identify concerning media habits, I try to help families create alternatives to their current habits as opposed to being prescriptive and saying to stop or limit media use. ... An alternative may not be limiting screen time but may be changing to more appropriate media content or sharing the media as a family activity.”

Seeing media use in the clinic can provide useful information and opportunities for discussion, Dr. Milkovich noted.

“When I see parents in the clinic room using media to calm a toddler or using their own media, these are great opportunities to open the door to brainstorming alternatives,” Dr. Milkovich said. “Commonly, family media use comes up when children have difficulty sleeping or disruptive behaviors related to media use, but I would challenge medical providers to think about problematic media use in all chief complaints where a behavioral component exists like toileting and feeding.”

The research was supported by the Academy of Finland, the Signe and Ane Gyllenberg Foundation, the Yrjö Jahnsson Foundation, the Foundation for Pediatric Research, the Finnish Cultural Foundation, and the Tampere University Hospital and Doctors’ Association in Tampere. The study authors, Dr. Milkovich, Dr. Orben, and Dr. Kinsella had no relevant financial disclosures. Dr. Kinsella serves on the Pediatric News editorial advisory board.

jremaly@mdedge.com

In 1967, when the United Nations Convention on Drugs classified psychedelics as schedule I substances, it effectively ended research into these agents as potential therapeutics for psychiatric disorders.

eskymaks/iStock/Getty Images

Psychedelics induce altered states of perception. They bind to the 5-hydroxytryptamine 2A (5-HT2A) receptor and include psilocybin, which is derived from “magic mushrooms”; N,N-dimethyltryptamine (DMT), a component of ayahuasca and mescaline (peyote cactus); and the synthesized compound D-lysergic acid diethylamide (LSD). Other agents, such as ketamine and 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, are sometimes considered psychedelics as well.

Before they were classified as schedule I agents, psychedelics had been shown to be particularly beneficial for patients with treatment-resistant conditions, including depression and posttraumatic stress disorder (PTSD), especially when administered in a supportive, therapeutic setting.

Now, after a hiatus of almost 50 years, there is renewed global interest in the scientific investigation of psychedelics. The attention was spurred in part by several exploratory studies of DMT in humans conducted in the 1990s by Rick Strassman, MD, and colleagues at the University of New Mexico, Albuquerque.

Around the same time, Franz X. Vollenweider, MD, and colleagues at the University of Zürich began researching psilocybin and its effects on human behavior. However, it was a 2006 study of psilocybin by a team of researchers at Johns Hopkins University, Baltimore, that is widely cited as a catalyst for the current renaissance in psychedelic research.

To provide a broad-based, international perspective on these agents, including their current legal status and indications, treatment regimens, safety, efficacy, and future considerations, this news organization interviewed nine expert researchers from around the globe.
 

Global legal status

In most, if not all, countries, it is still illegal to prescribe psychedelics in other than a research setting.

In the United States, classic psychedelics remain schedule I substances and therefore are unavailable for clinical use. They can be used in research, but only with approval from the Food and Drug Administration under licensure from the Drug Enforcement Administration.

France lists all synthetic hallucinogens and hallucinogenic mushrooms as narcotic. As a result, possession, use, transportation, and collection are subject to criminal sanctions.

In France, NMDA antagonists such as ketamine and nitrous oxide are regarded as psychedelic molecules and can be used off label for various conditions or as part of research protocols authorized by the French public health code.

Although psychedelics are illegal under Mexican law, they are commonly used in indigenous communities as part of traditional rituals.

“The line between traditional consumption and psychedelic tourism is very thin,” José J. Mendoza Velásquez, MD, professor in the department of mental health, National Autonomous University of Mexico, Mexico City, said in an interview.

Psychedelics also are illegal in the United Kingdom, although government agencies have recently allowed research groups to investigate them. Psychedelics cannot be prescribed in Germany, Spain, or Italy. However, investigators in these countries can request permission from regulatory agencies to conduct research.

Brazil allows psychedelic substances to be researched, particularly ayahuasca, which has long traditional and religious roots in the country.

However, as in other countries, none of the classic psychedelics is regulated for therapeutic use in Brazil. It is widely expected that the Brazilian government will approve MDMA sometime in 2024 for use in the treatment of PTSD.
 

Potential indications

Psychedelics are currently under investigation as potential treatments for major depression, treatment-resistant depression, PTSD, pain management, and anorexia, among other conditions.

In France, Florian Ferreri, MD, PhD, at Hospital Saint-Antoine, Paris, is researching ketamine for treatment of patients with suicidal crisis/ideation and treatment-resistant depression.

In the United Kingdom, David Nutt, FMedSci, Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, and his team have conducted studies of the use of psychedelics in conjunction with psychological support for patients with treatment-resistant depression, and they are currently exploring their use in the treatment of anorexia and various pain syndromes.

In Germany, Gerhard Gründer, MD, professor of psychiatry at the Central Institute of Mental Health, in Mannheim, noted that a study of psilocybin for treatment-resistant depression will launch sometime in 2021. In Italy, current research is focusing on MDMA and ketamine in the laboratory environment and in animal models for treating depression and drug abuse.

Researcher Helen Dolengevich-Segal, MD, a psychiatrist at Hospital Universitario del Henares, Madrid, noted that although research on esketamine for the treatment of severe depressive disorder with suicidal thoughts is underway, there is very limited published research from that country into the use of classic psychedelics for various psychiatric disorders, given their current illegal status.

Mexico’s Dr. Velásquez noted that although he is prohibited from prescribing psychedelics, he does have patients who take the drugs to augment medical treatment. For instance, he said, his patients frequently use psilocybin to help with severe depression, pain, and insomnia.
 

Environment is key

Most researchers agree that for psychedelics to be safe and effective, patient education and administration in a controlled environment by experienced clinicians are key to successful treatment.

Roland R. Griffiths, PhD, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins, said that ongoing U.S. psilocybin research – primarily in major depressive disorder and psychological distress associated with life-threatening illness, drug addiction, anorexia nervosa, obsessive-compulsive disorder, and headache – generally includes one or two treatment sessions, each of which lasts 6-8 hours.

Such sessions typically involve oral administration of a moderately high dose of a psychedelic under what he characterizes as “psychologically supported conditions.”

For Dr. Griffiths, there are serious potential risks associated with the use of psilocybin and other psychedelics outside such environments.

“When taken in uncontrolled conditions, classic psychedelics can produce confusion and disorientation resulting in behavior dangerous to the participant and others, including life-threatening risk,” he said.

Dr. Gründer agreed.

“At the moment, I cannot imagine that you would go to the pharmacy with a prescription for psilocybin and get yourself a pill and then take it in a quiet little room,” he said. Dr. Dolengevich-Segal and Dr. Velásquez echoed these sentiments, noting the optimal location for administration is one that is quiet and secure and where patients feel safe.

Luís Fernando Tófoli, MD, PhD, professor of medical psychology and psychiatry at the University of Campinas, and Eduardo Schenberg, PhD, founder and CEO of Instituto Phaneros in São Paulo, Brazil, said more research is needed to determine the optimal therapeutic environment for individual agents.

“Most studies have a low number of participants (around 20 or 30), especially in neuroimaging, with high unblinding rates,” Dr. Schenberg said. “Therefore, novel methodological approaches are also necessary, as these substances do not easily fit into the traditional pharmacology epistemic model.”
 

Risks, abuse potential

The abuse potential of psychedelics is an ongoing concern for the public, researchers, and regulators, but the consensus among nearly all of these experts is that when administered by medical professionals in controlled settings, these drugs are associated with extremely low risk.

It is recreational use that presents an abuse concern, said Dr. Ferreri, but with the low doses used in psychiatry, the risk is “very limited or even nonexistent.”

Dr. Nutt said the abuse potential of psychedelics is so low that they can be used to treat addiction.

“Functionally, psychedelics are antiaddictive,” Dr. Nutt said. “The fact is, if you take them repeatedly, you develop tolerance, and the effect disappears. You can’t overcome it. But everyone believes they’re addictive because they’re scheduled drugs.”

Dr. Velásquez is something of an outlier. He believes the abuse potential with psychedelics is poorly understood and that some patients may develop tolerance, which is a potential gateway to dependence.

“Such is the case with LSD,” he said, “where this substance also favors tolerance to other psychedelic drugs such as psilocybin.”

Dosing also seems to play a key role in mitigating potential abuse, said Luca Pani, MD, professor of pharmacology and psychiatry at the University of Modena, Italy. Dr. Pani explained that with low doses and microdoses of psychedelics, the potential for abuse is eliminated.

Dr. Nutt, Dr. Pani, and Dr. Ferreri also noted the importance of medical supervision. For instance, said Dr. Ferreri, when administering ketamine, his team closely monitors both mental and physical parameters – heart rate and blood pressure, in particular – because the drug can have hypertensive effects.

Dr. Schenberg noted that ibogaine, a naturally occurring psychedelic frequently used by traditional communities in Africa in rituals and for healing purposes, could cause potentially fatal arrhythmias, so it’s critical that the treatment is administered in a hospital setting that has a cardiac unit.

Dr. Pani said there is a need for more research, especially regarding the molecular mechanisms behind the behavioral effects of low-dose psychedelic therapy and the potential risks of multiple treatments with the drugs.

“Although extensive toxicology has been conducted on a single active dose of psilocybin, which has been proven to be safe, further research is required to understand better the possible health risks, especially in relation to cardiac and lung tissue,” he said.
 

Psychologically challenging

The experts note that given the relative lack of experience with psychedelic therapy, preparing patients for potential adverse effects is paramount. This is particularly relevant in the research setting and highlights the need for adequate patient screening and aftercare.

Dr. Gründer and Dr. Dolengevich-Segal emphasized the importance of having qualified personnel available in the event that patients experience adverse psychological events during treatment.

For Dr. Gründer, the potential for psilocybin to cause patients to lose control, experience psychotic symptoms, or become paranoid warrants considerable preparation by treating physicians.

Patients occasionally experience fear and anxiety during treatment, though it’s usually short-lived, said Dr. Griffiths. Nevertheless, these experiences may open the door to greater insight. “A number of people report that these psychologically challenging states are a valuable part of the overall experience,” he said.

The situation is similar in Spain, where Dr. Dolengevich-Segal noted that typical treatment regimens have a strong focus on the patient’s experience as a therapeutic tool. As in the United Kingdom and the United States, her team guides patients to what they call a “peak experience,” which allows them to gain a better understanding of the trauma underlying their mental health problems.

Dr. Nutt said that in the United Kingdom, they haven’t seen adverse reactions in patients receiving psychedelic therapy, although sedatives such as benzodiazepines could be used to manage them. He added that at his center, two therapists are present at every treatment session, and all personnel are “trained medics or psychologists.”
 

Patient education

Preparing and educating patients about the therapy are critical, said Dr. Gründer, especially given the intense response psychedelic treatment often invokes.

Echoing Dr. Gründer, Dr. Tófoli said explaining the nature of psychedelic treatment to potential patients helps ease anxiety.

Dr. Griffiths noted that in the United States, study participants are not only educated about the potential effects of psychedelic agents but also undergo several hours of psychological preparation in advance of their first treatment session and are provided with psychological support after treatment.

There is also a strong emphasis on patient preparation and education in the United Kingdom, where patients meet with therapists before and after treatment. During these posttreatment debriefings, clinicians use the patients’ experience with psychedelics to help them gain insight into the underlying cause of their depression.

Dr. Schenberg noted that at his institution in São Paulo, there are online courses to teach clinicians about psychedelic therapy for psychiatric disorders. Next year, he added, a new training program in MDMA-assisted psychotherapy will begin.
 

Working out treatment protocols

Treatment protocols for psychedelics vary by agent and indication from country to country. For instance, Dr. Pani noted that current psychedelic research in Italy predominantly focuses more on microdosing, which involves administering 1% of the pharmacologically active dose to a maximum of 100 mcg, in contrast to low dosing or full dosing.

Therapeutic regimens in Brazil, said Dr. Schenberg, also differ by agent but share common elements. For instance, psychedelics are always administered in a research setting, and sessions include concomitant psychotherapy.

In Germany, investigators are working to determine optimal treatment regimen for psilocybin for resistant depression in a randomized three-arm study planned for 2021.

For Mexico’s Dr. Velásquez, treatment regimens are complex and varied. Either way, he said, patients always require long-term follow-up.

With ketamine therapy, Dr. Ferreri said his team administers the drug in 45- to 60-minute intravenous infusion sessions in a hospital room without light or sound stimulation. Regardless of the drug’s immediate effect, he said, the protocol is repeated within a 6-month period.

The question of the duration of treatment effect is important. Dr. Griffiths said research suggests that the positive effects of psilocybin are long lasting and that most individuals report positive changes in mood, attitude, and behavior that endure for months or even years after the session.

“Our research has shown that the benefits of these experiences can last as long as 14 months, often longer, and that many participants characterize their psilocybin experience as among the most profound and personally meaningful experiences of their lives,” said Dr. Griffiths.

Dr. Nutt agreed, noting that a single intense “trip” can improve mood for weeks, months, or even years. Nevertheless, he said, in his experience, approximately three-quarters of patients treated with psychedelics for major depression relapse within 3-9 months.

“Most get better,” he said, “but the majority of depression comes back over a period of months.”

Given the current illegal status of the drugs, he said it’s nearly impossible to provide patients with regular, subsequent treatment with psychedelics over time.

“My suspicion is that you might well have to dose four or five times over a couple of years to get people to escape from very severe depression,” said Dr. Nutt. “The longer they’ve been depressed, the harder it is for them to make a full recovery, because it’s more entrenched in the brain.”

All experts agree that exciting times are ahead for psychedelics as therapeutics for a wide range of psychiatric disorders.

“We can look forward to continued growth and expansion of this research,” said Dr. Griffiths, “including the refinement of protocols for a variety of therapeutic indications and to the development of a variety of new classic psychedelic compounds.”

A version of this article first appeared on Medscape.com.

In 1967, when the United Nations Convention on Drugs classified psychedelics as schedule I substances, it effectively ended research into these agents as potential therapeutics for psychiatric disorders.

eskymaks/iStock/Getty Images

Psychedelics induce altered states of perception. They bind to the 5-hydroxytryptamine 2A (5-HT2A) receptor and include psilocybin, which is derived from “magic mushrooms”; N,N-dimethyltryptamine (DMT), a component of ayahuasca and mescaline (peyote cactus); and the synthesized compound D-lysergic acid diethylamide (LSD). Other agents, such as ketamine and 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, are sometimes considered psychedelics as well.

Before they were classified as schedule I agents, psychedelics had been shown to be particularly beneficial for patients with treatment-resistant conditions, including depression and posttraumatic stress disorder (PTSD), especially when administered in a supportive, therapeutic setting.

Now, after a hiatus of almost 50 years, there is renewed global interest in the scientific investigation of psychedelics. The attention was spurred in part by several exploratory studies of DMT in humans conducted in the 1990s by Rick Strassman, MD, and colleagues at the University of New Mexico, Albuquerque.

Around the same time, Franz X. Vollenweider, MD, and colleagues at the University of Zürich began researching psilocybin and its effects on human behavior. However, it was a 2006 study of psilocybin by a team of researchers at Johns Hopkins University, Baltimore, that is widely cited as a catalyst for the current renaissance in psychedelic research.

To provide a broad-based, international perspective on these agents, including their current legal status and indications, treatment regimens, safety, efficacy, and future considerations, this news organization interviewed nine expert researchers from around the globe.
 

Global legal status

In most, if not all, countries, it is still illegal to prescribe psychedelics in other than a research setting.

In the United States, classic psychedelics remain schedule I substances and therefore are unavailable for clinical use. They can be used in research, but only with approval from the Food and Drug Administration under licensure from the Drug Enforcement Administration.

France lists all synthetic hallucinogens and hallucinogenic mushrooms as narcotic. As a result, possession, use, transportation, and collection are subject to criminal sanctions.

In France, NMDA antagonists such as ketamine and nitrous oxide are regarded as psychedelic molecules and can be used off label for various conditions or as part of research protocols authorized by the French public health code.

Although psychedelics are illegal under Mexican law, they are commonly used in indigenous communities as part of traditional rituals.

“The line between traditional consumption and psychedelic tourism is very thin,” José J. Mendoza Velásquez, MD, professor in the department of mental health, National Autonomous University of Mexico, Mexico City, said in an interview.

Psychedelics also are illegal in the United Kingdom, although government agencies have recently allowed research groups to investigate them. Psychedelics cannot be prescribed in Germany, Spain, or Italy. However, investigators in these countries can request permission from regulatory agencies to conduct research.

Brazil allows psychedelic substances to be researched, particularly ayahuasca, which has long traditional and religious roots in the country.

However, as in other countries, none of the classic psychedelics is regulated for therapeutic use in Brazil. It is widely expected that the Brazilian government will approve MDMA sometime in 2024 for use in the treatment of PTSD.
 

Potential indications

Psychedelics are currently under investigation as potential treatments for major depression, treatment-resistant depression, PTSD, pain management, and anorexia, among other conditions.

In France, Florian Ferreri, MD, PhD, at Hospital Saint-Antoine, Paris, is researching ketamine for treatment of patients with suicidal crisis/ideation and treatment-resistant depression.

In the United Kingdom, David Nutt, FMedSci, Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, and his team have conducted studies of the use of psychedelics in conjunction with psychological support for patients with treatment-resistant depression, and they are currently exploring their use in the treatment of anorexia and various pain syndromes.

In Germany, Gerhard Gründer, MD, professor of psychiatry at the Central Institute of Mental Health, in Mannheim, noted that a study of psilocybin for treatment-resistant depression will launch sometime in 2021. In Italy, current research is focusing on MDMA and ketamine in the laboratory environment and in animal models for treating depression and drug abuse.

Researcher Helen Dolengevich-Segal, MD, a psychiatrist at Hospital Universitario del Henares, Madrid, noted that although research on esketamine for the treatment of severe depressive disorder with suicidal thoughts is underway, there is very limited published research from that country into the use of classic psychedelics for various psychiatric disorders, given their current illegal status.

Mexico’s Dr. Velásquez noted that although he is prohibited from prescribing psychedelics, he does have patients who take the drugs to augment medical treatment. For instance, he said, his patients frequently use psilocybin to help with severe depression, pain, and insomnia.
 

Environment is key

Most researchers agree that for psychedelics to be safe and effective, patient education and administration in a controlled environment by experienced clinicians are key to successful treatment.

Roland R. Griffiths, PhD, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins, said that ongoing U.S. psilocybin research – primarily in major depressive disorder and psychological distress associated with life-threatening illness, drug addiction, anorexia nervosa, obsessive-compulsive disorder, and headache – generally includes one or two treatment sessions, each of which lasts 6-8 hours.

Such sessions typically involve oral administration of a moderately high dose of a psychedelic under what he characterizes as “psychologically supported conditions.”

For Dr. Griffiths, there are serious potential risks associated with the use of psilocybin and other psychedelics outside such environments.

“When taken in uncontrolled conditions, classic psychedelics can produce confusion and disorientation resulting in behavior dangerous to the participant and others, including life-threatening risk,” he said.

Dr. Gründer agreed.

“At the moment, I cannot imagine that you would go to the pharmacy with a prescription for psilocybin and get yourself a pill and then take it in a quiet little room,” he said. Dr. Dolengevich-Segal and Dr. Velásquez echoed these sentiments, noting the optimal location for administration is one that is quiet and secure and where patients feel safe.

Luís Fernando Tófoli, MD, PhD, professor of medical psychology and psychiatry at the University of Campinas, and Eduardo Schenberg, PhD, founder and CEO of Instituto Phaneros in São Paulo, Brazil, said more research is needed to determine the optimal therapeutic environment for individual agents.

“Most studies have a low number of participants (around 20 or 30), especially in neuroimaging, with high unblinding rates,” Dr. Schenberg said. “Therefore, novel methodological approaches are also necessary, as these substances do not easily fit into the traditional pharmacology epistemic model.”
 

Risks, abuse potential

The abuse potential of psychedelics is an ongoing concern for the public, researchers, and regulators, but the consensus among nearly all of these experts is that when administered by medical professionals in controlled settings, these drugs are associated with extremely low risk.

It is recreational use that presents an abuse concern, said Dr. Ferreri, but with the low doses used in psychiatry, the risk is “very limited or even nonexistent.”

Dr. Nutt said the abuse potential of psychedelics is so low that they can be used to treat addiction.

“Functionally, psychedelics are antiaddictive,” Dr. Nutt said. “The fact is, if you take them repeatedly, you develop tolerance, and the effect disappears. You can’t overcome it. But everyone believes they’re addictive because they’re scheduled drugs.”

Dr. Velásquez is something of an outlier. He believes the abuse potential with psychedelics is poorly understood and that some patients may develop tolerance, which is a potential gateway to dependence.

“Such is the case with LSD,” he said, “where this substance also favors tolerance to other psychedelic drugs such as psilocybin.”

Dosing also seems to play a key role in mitigating potential abuse, said Luca Pani, MD, professor of pharmacology and psychiatry at the University of Modena, Italy. Dr. Pani explained that with low doses and microdoses of psychedelics, the potential for abuse is eliminated.

Dr. Nutt, Dr. Pani, and Dr. Ferreri also noted the importance of medical supervision. For instance, said Dr. Ferreri, when administering ketamine, his team closely monitors both mental and physical parameters – heart rate and blood pressure, in particular – because the drug can have hypertensive effects.

Dr. Schenberg noted that ibogaine, a naturally occurring psychedelic frequently used by traditional communities in Africa in rituals and for healing purposes, could cause potentially fatal arrhythmias, so it’s critical that the treatment is administered in a hospital setting that has a cardiac unit.

Dr. Pani said there is a need for more research, especially regarding the molecular mechanisms behind the behavioral effects of low-dose psychedelic therapy and the potential risks of multiple treatments with the drugs.

“Although extensive toxicology has been conducted on a single active dose of psilocybin, which has been proven to be safe, further research is required to understand better the possible health risks, especially in relation to cardiac and lung tissue,” he said.
 

Psychologically challenging

The experts note that given the relative lack of experience with psychedelic therapy, preparing patients for potential adverse effects is paramount. This is particularly relevant in the research setting and highlights the need for adequate patient screening and aftercare.

Dr. Gründer and Dr. Dolengevich-Segal emphasized the importance of having qualified personnel available in the event that patients experience adverse psychological events during treatment.

For Dr. Gründer, the potential for psilocybin to cause patients to lose control, experience psychotic symptoms, or become paranoid warrants considerable preparation by treating physicians.

Patients occasionally experience fear and anxiety during treatment, though it’s usually short-lived, said Dr. Griffiths. Nevertheless, these experiences may open the door to greater insight. “A number of people report that these psychologically challenging states are a valuable part of the overall experience,” he said.

The situation is similar in Spain, where Dr. Dolengevich-Segal noted that typical treatment regimens have a strong focus on the patient’s experience as a therapeutic tool. As in the United Kingdom and the United States, her team guides patients to what they call a “peak experience,” which allows them to gain a better understanding of the trauma underlying their mental health problems.

Dr. Nutt said that in the United Kingdom, they haven’t seen adverse reactions in patients receiving psychedelic therapy, although sedatives such as benzodiazepines could be used to manage them. He added that at his center, two therapists are present at every treatment session, and all personnel are “trained medics or psychologists.”
 

Patient education

Preparing and educating patients about the therapy are critical, said Dr. Gründer, especially given the intense response psychedelic treatment often invokes.

Echoing Dr. Gründer, Dr. Tófoli said explaining the nature of psychedelic treatment to potential patients helps ease anxiety.

Dr. Griffiths noted that in the United States, study participants are not only educated about the potential effects of psychedelic agents but also undergo several hours of psychological preparation in advance of their first treatment session and are provided with psychological support after treatment.

There is also a strong emphasis on patient preparation and education in the United Kingdom, where patients meet with therapists before and after treatment. During these posttreatment debriefings, clinicians use the patients’ experience with psychedelics to help them gain insight into the underlying cause of their depression.

Dr. Schenberg noted that at his institution in São Paulo, there are online courses to teach clinicians about psychedelic therapy for psychiatric disorders. Next year, he added, a new training program in MDMA-assisted psychotherapy will begin.
 

Working out treatment protocols

Treatment protocols for psychedelics vary by agent and indication from country to country. For instance, Dr. Pani noted that current psychedelic research in Italy predominantly focuses more on microdosing, which involves administering 1% of the pharmacologically active dose to a maximum of 100 mcg, in contrast to low dosing or full dosing.

Therapeutic regimens in Brazil, said Dr. Schenberg, also differ by agent but share common elements. For instance, psychedelics are always administered in a research setting, and sessions include concomitant psychotherapy.

In Germany, investigators are working to determine optimal treatment regimen for psilocybin for resistant depression in a randomized three-arm study planned for 2021.

For Mexico’s Dr. Velásquez, treatment regimens are complex and varied. Either way, he said, patients always require long-term follow-up.

With ketamine therapy, Dr. Ferreri said his team administers the drug in 45- to 60-minute intravenous infusion sessions in a hospital room without light or sound stimulation. Regardless of the drug’s immediate effect, he said, the protocol is repeated within a 6-month period.

The question of the duration of treatment effect is important. Dr. Griffiths said research suggests that the positive effects of psilocybin are long lasting and that most individuals report positive changes in mood, attitude, and behavior that endure for months or even years after the session.

“Our research has shown that the benefits of these experiences can last as long as 14 months, often longer, and that many participants characterize their psilocybin experience as among the most profound and personally meaningful experiences of their lives,” said Dr. Griffiths.

Dr. Nutt agreed, noting that a single intense “trip” can improve mood for weeks, months, or even years. Nevertheless, he said, in his experience, approximately three-quarters of patients treated with psychedelics for major depression relapse within 3-9 months.

“Most get better,” he said, “but the majority of depression comes back over a period of months.”

Given the current illegal status of the drugs, he said it’s nearly impossible to provide patients with regular, subsequent treatment with psychedelics over time.

“My suspicion is that you might well have to dose four or five times over a couple of years to get people to escape from very severe depression,” said Dr. Nutt. “The longer they’ve been depressed, the harder it is for them to make a full recovery, because it’s more entrenched in the brain.”

All experts agree that exciting times are ahead for psychedelics as therapeutics for a wide range of psychiatric disorders.

“We can look forward to continued growth and expansion of this research,” said Dr. Griffiths, “including the refinement of protocols for a variety of therapeutic indications and to the development of a variety of new classic psychedelic compounds.”

A version of this article first appeared on Medscape.com.

In 1967, when the United Nations Convention on Drugs classified psychedelics as schedule I substances, it effectively ended research into these agents as potential therapeutics for psychiatric disorders.

eskymaks/iStock/Getty Images

Psychedelics induce altered states of perception. They bind to the 5-hydroxytryptamine 2A (5-HT2A) receptor and include psilocybin, which is derived from “magic mushrooms”; N,N-dimethyltryptamine (DMT), a component of ayahuasca and mescaline (peyote cactus); and the synthesized compound D-lysergic acid diethylamide (LSD). Other agents, such as ketamine and 3,4-methylenedioxymethamphetamine (MDMA), also known as ecstasy, are sometimes considered psychedelics as well.

Before they were classified as schedule I agents, psychedelics had been shown to be particularly beneficial for patients with treatment-resistant conditions, including depression and posttraumatic stress disorder (PTSD), especially when administered in a supportive, therapeutic setting.

Now, after a hiatus of almost 50 years, there is renewed global interest in the scientific investigation of psychedelics. The attention was spurred in part by several exploratory studies of DMT in humans conducted in the 1990s by Rick Strassman, MD, and colleagues at the University of New Mexico, Albuquerque.

Around the same time, Franz X. Vollenweider, MD, and colleagues at the University of Zürich began researching psilocybin and its effects on human behavior. However, it was a 2006 study of psilocybin by a team of researchers at Johns Hopkins University, Baltimore, that is widely cited as a catalyst for the current renaissance in psychedelic research.

To provide a broad-based, international perspective on these agents, including their current legal status and indications, treatment regimens, safety, efficacy, and future considerations, this news organization interviewed nine expert researchers from around the globe.
 

Global legal status

In most, if not all, countries, it is still illegal to prescribe psychedelics in other than a research setting.

In the United States, classic psychedelics remain schedule I substances and therefore are unavailable for clinical use. They can be used in research, but only with approval from the Food and Drug Administration under licensure from the Drug Enforcement Administration.

France lists all synthetic hallucinogens and hallucinogenic mushrooms as narcotic. As a result, possession, use, transportation, and collection are subject to criminal sanctions.

In France, NMDA antagonists such as ketamine and nitrous oxide are regarded as psychedelic molecules and can be used off label for various conditions or as part of research protocols authorized by the French public health code.

Although psychedelics are illegal under Mexican law, they are commonly used in indigenous communities as part of traditional rituals.

“The line between traditional consumption and psychedelic tourism is very thin,” José J. Mendoza Velásquez, MD, professor in the department of mental health, National Autonomous University of Mexico, Mexico City, said in an interview.

Psychedelics also are illegal in the United Kingdom, although government agencies have recently allowed research groups to investigate them. Psychedelics cannot be prescribed in Germany, Spain, or Italy. However, investigators in these countries can request permission from regulatory agencies to conduct research.

Brazil allows psychedelic substances to be researched, particularly ayahuasca, which has long traditional and religious roots in the country.

However, as in other countries, none of the classic psychedelics is regulated for therapeutic use in Brazil. It is widely expected that the Brazilian government will approve MDMA sometime in 2024 for use in the treatment of PTSD.
 

Potential indications

Psychedelics are currently under investigation as potential treatments for major depression, treatment-resistant depression, PTSD, pain management, and anorexia, among other conditions.

In France, Florian Ferreri, MD, PhD, at Hospital Saint-Antoine, Paris, is researching ketamine for treatment of patients with suicidal crisis/ideation and treatment-resistant depression.

In the United Kingdom, David Nutt, FMedSci, Edmond J. Safra Professor of Neuropsychopharmacology at Imperial College London, and his team have conducted studies of the use of psychedelics in conjunction with psychological support for patients with treatment-resistant depression, and they are currently exploring their use in the treatment of anorexia and various pain syndromes.

In Germany, Gerhard Gründer, MD, professor of psychiatry at the Central Institute of Mental Health, in Mannheim, noted that a study of psilocybin for treatment-resistant depression will launch sometime in 2021. In Italy, current research is focusing on MDMA and ketamine in the laboratory environment and in animal models for treating depression and drug abuse.

Researcher Helen Dolengevich-Segal, MD, a psychiatrist at Hospital Universitario del Henares, Madrid, noted that although research on esketamine for the treatment of severe depressive disorder with suicidal thoughts is underway, there is very limited published research from that country into the use of classic psychedelics for various psychiatric disorders, given their current illegal status.

Mexico’s Dr. Velásquez noted that although he is prohibited from prescribing psychedelics, he does have patients who take the drugs to augment medical treatment. For instance, he said, his patients frequently use psilocybin to help with severe depression, pain, and insomnia.
 

Environment is key

Most researchers agree that for psychedelics to be safe and effective, patient education and administration in a controlled environment by experienced clinicians are key to successful treatment.

Roland R. Griffiths, PhD, director of the Center for Psychedelic and Consciousness Research at Johns Hopkins, said that ongoing U.S. psilocybin research – primarily in major depressive disorder and psychological distress associated with life-threatening illness, drug addiction, anorexia nervosa, obsessive-compulsive disorder, and headache – generally includes one or two treatment sessions, each of which lasts 6-8 hours.

Such sessions typically involve oral administration of a moderately high dose of a psychedelic under what he characterizes as “psychologically supported conditions.”

For Dr. Griffiths, there are serious potential risks associated with the use of psilocybin and other psychedelics outside such environments.

“When taken in uncontrolled conditions, classic psychedelics can produce confusion and disorientation resulting in behavior dangerous to the participant and others, including life-threatening risk,” he said.

Dr. Gründer agreed.

“At the moment, I cannot imagine that you would go to the pharmacy with a prescription for psilocybin and get yourself a pill and then take it in a quiet little room,” he said. Dr. Dolengevich-Segal and Dr. Velásquez echoed these sentiments, noting the optimal location for administration is one that is quiet and secure and where patients feel safe.

Luís Fernando Tófoli, MD, PhD, professor of medical psychology and psychiatry at the University of Campinas, and Eduardo Schenberg, PhD, founder and CEO of Instituto Phaneros in São Paulo, Brazil, said more research is needed to determine the optimal therapeutic environment for individual agents.

“Most studies have a low number of participants (around 20 or 30), especially in neuroimaging, with high unblinding rates,” Dr. Schenberg said. “Therefore, novel methodological approaches are also necessary, as these substances do not easily fit into the traditional pharmacology epistemic model.”
 

Risks, abuse potential

The abuse potential of psychedelics is an ongoing concern for the public, researchers, and regulators, but the consensus among nearly all of these experts is that when administered by medical professionals in controlled settings, these drugs are associated with extremely low risk.

It is recreational use that presents an abuse concern, said Dr. Ferreri, but with the low doses used in psychiatry, the risk is “very limited or even nonexistent.”

Dr. Nutt said the abuse potential of psychedelics is so low that they can be used to treat addiction.

“Functionally, psychedelics are antiaddictive,” Dr. Nutt said. “The fact is, if you take them repeatedly, you develop tolerance, and the effect disappears. You can’t overcome it. But everyone believes they’re addictive because they’re scheduled drugs.”

Dr. Velásquez is something of an outlier. He believes the abuse potential with psychedelics is poorly understood and that some patients may develop tolerance, which is a potential gateway to dependence.

“Such is the case with LSD,” he said, “where this substance also favors tolerance to other psychedelic drugs such as psilocybin.”

Dosing also seems to play a key role in mitigating potential abuse, said Luca Pani, MD, professor of pharmacology and psychiatry at the University of Modena, Italy. Dr. Pani explained that with low doses and microdoses of psychedelics, the potential for abuse is eliminated.

Dr. Nutt, Dr. Pani, and Dr. Ferreri also noted the importance of medical supervision. For instance, said Dr. Ferreri, when administering ketamine, his team closely monitors both mental and physical parameters – heart rate and blood pressure, in particular – because the drug can have hypertensive effects.

Dr. Schenberg noted that ibogaine, a naturally occurring psychedelic frequently used by traditional communities in Africa in rituals and for healing purposes, could cause potentially fatal arrhythmias, so it’s critical that the treatment is administered in a hospital setting that has a cardiac unit.

Dr. Pani said there is a need for more research, especially regarding the molecular mechanisms behind the behavioral effects of low-dose psychedelic therapy and the potential risks of multiple treatments with the drugs.

“Although extensive toxicology has been conducted on a single active dose of psilocybin, which has been proven to be safe, further research is required to understand better the possible health risks, especially in relation to cardiac and lung tissue,” he said.
 

Psychologically challenging

The experts note that given the relative lack of experience with psychedelic therapy, preparing patients for potential adverse effects is paramount. This is particularly relevant in the research setting and highlights the need for adequate patient screening and aftercare.

Dr. Gründer and Dr. Dolengevich-Segal emphasized the importance of having qualified personnel available in the event that patients experience adverse psychological events during treatment.

For Dr. Gründer, the potential for psilocybin to cause patients to lose control, experience psychotic symptoms, or become paranoid warrants considerable preparation by treating physicians.

Patients occasionally experience fear and anxiety during treatment, though it’s usually short-lived, said Dr. Griffiths. Nevertheless, these experiences may open the door to greater insight. “A number of people report that these psychologically challenging states are a valuable part of the overall experience,” he said.

The situation is similar in Spain, where Dr. Dolengevich-Segal noted that typical treatment regimens have a strong focus on the patient’s experience as a therapeutic tool. As in the United Kingdom and the United States, her team guides patients to what they call a “peak experience,” which allows them to gain a better understanding of the trauma underlying their mental health problems.

Dr. Nutt said that in the United Kingdom, they haven’t seen adverse reactions in patients receiving psychedelic therapy, although sedatives such as benzodiazepines could be used to manage them. He added that at his center, two therapists are present at every treatment session, and all personnel are “trained medics or psychologists.”
 

Patient education

Preparing and educating patients about the therapy are critical, said Dr. Gründer, especially given the intense response psychedelic treatment often invokes.

Echoing Dr. Gründer, Dr. Tófoli said explaining the nature of psychedelic treatment to potential patients helps ease anxiety.

Dr. Griffiths noted that in the United States, study participants are not only educated about the potential effects of psychedelic agents but also undergo several hours of psychological preparation in advance of their first treatment session and are provided with psychological support after treatment.

There is also a strong emphasis on patient preparation and education in the United Kingdom, where patients meet with therapists before and after treatment. During these posttreatment debriefings, clinicians use the patients’ experience with psychedelics to help them gain insight into the underlying cause of their depression.

Dr. Schenberg noted that at his institution in São Paulo, there are online courses to teach clinicians about psychedelic therapy for psychiatric disorders. Next year, he added, a new training program in MDMA-assisted psychotherapy will begin.
 

Working out treatment protocols

Treatment protocols for psychedelics vary by agent and indication from country to country. For instance, Dr. Pani noted that current psychedelic research in Italy predominantly focuses more on microdosing, which involves administering 1% of the pharmacologically active dose to a maximum of 100 mcg, in contrast to low dosing or full dosing.

Therapeutic regimens in Brazil, said Dr. Schenberg, also differ by agent but share common elements. For instance, psychedelics are always administered in a research setting, and sessions include concomitant psychotherapy.

In Germany, investigators are working to determine optimal treatment regimen for psilocybin for resistant depression in a randomized three-arm study planned for 2021.

For Mexico’s Dr. Velásquez, treatment regimens are complex and varied. Either way, he said, patients always require long-term follow-up.

With ketamine therapy, Dr. Ferreri said his team administers the drug in 45- to 60-minute intravenous infusion sessions in a hospital room without light or sound stimulation. Regardless of the drug’s immediate effect, he said, the protocol is repeated within a 6-month period.

The question of the duration of treatment effect is important. Dr. Griffiths said research suggests that the positive effects of psilocybin are long lasting and that most individuals report positive changes in mood, attitude, and behavior that endure for months or even years after the session.

“Our research has shown that the benefits of these experiences can last as long as 14 months, often longer, and that many participants characterize their psilocybin experience as among the most profound and personally meaningful experiences of their lives,” said Dr. Griffiths.

Dr. Nutt agreed, noting that a single intense “trip” can improve mood for weeks, months, or even years. Nevertheless, he said, in his experience, approximately three-quarters of patients treated with psychedelics for major depression relapse within 3-9 months.

“Most get better,” he said, “but the majority of depression comes back over a period of months.”

Given the current illegal status of the drugs, he said it’s nearly impossible to provide patients with regular, subsequent treatment with psychedelics over time.

“My suspicion is that you might well have to dose four or five times over a couple of years to get people to escape from very severe depression,” said Dr. Nutt. “The longer they’ve been depressed, the harder it is for them to make a full recovery, because it’s more entrenched in the brain.”

All experts agree that exciting times are ahead for psychedelics as therapeutics for a wide range of psychiatric disorders.

“We can look forward to continued growth and expansion of this research,” said Dr. Griffiths, “including the refinement of protocols for a variety of therapeutic indications and to the development of a variety of new classic psychedelic compounds.”

A version of this article first appeared on Medscape.com.

More adolescent girls than boys experienced nonfatal opioid overdose and reported baseline levels of anxiety, depression, and self-harm, according to data from a retrospective cohort study of more than 20,000 youth in the United States.

Previous studies have identified sex-based differences in opioid overdose such as a higher prevalence of co-occurring psychiatric disorders in women compared with men, wrote Sarah M. Bagley, MD, of Boston University, and colleagues. “However, few studies have examined whether such sex-based differences in opioid overdose risk extend to the population of adolescents and young adults,” they said.

In a retrospective cohort study published in JAMA Network Open, the researchers identified 20,312 commercially insured youth aged 11-24 years who experienced a nonfatal opioid overdose between Jan. 1, 2006, and Dec. 31, 2017, and reviewed data using the IBM MarketScan Commercial Database. The average age of the study population was 20 years and approximately 42% were female.

Females aged 11-16 years had a significantly higher incidence of nonfatal opioid overdose (60%) compared with males, but this trend reversed at age 17 years, after which the incidence of nonfatal opioid overdose became significantly higher in males. “Our finding that females younger than 17 years had a higher incidence of NFOD is consistent with epidemiologic data that have indicated changes in alcohol and drug prevalence among female youths,” the researchers wrote.

Overall, 57.8% of the cohort had mood and anxiety disorders, 12.8% had trauma- or stress-related disorders, and 11.7% had attention-deficit/hyperactivity disorder.

When analyzed by sex, females had a significantly higher prevalence than that of males of mood or anxiety disorders (65.5% vs. 51.9%) trauma or stress-related disorders (16.4% vs. 10.1%) and attempts at suicide or self-harm (14.6% vs. 9.9%). Males had significantly higher prevalence than that of females of opioid use disorder (44.7% vs. 29.2%), cannabis use disorder (18.3% vs. 11.3%), and alcohol use disorder (20.3% vs. 14.4%).

“Although in our study, female youths had a lower prevalence of all substance use disorders, including OUD [opioid use disorder], and a higher prevalence of mood and trauma-associated disorders, both male and female youths had a higher prevalence of psychiatric illness and substance use disorder than youths in the general population,” the researchers noted.

The study findings were limited by several factors including the inclusion only of youth with commercial insurance, with no uninsured or publicly insured youth, and only those youth who sought health care after a nonfatal opioid overdose, the researchers noted. The prevalence of substance use and mental health disorders may be over- or underdiagnosed, and race was not included as a variable because of unreliable data, they added. The database also did not allow for gender identity beyond sex as listed by the insurance carrier, they said.

However, the results indicate significant differences in the incidence of nonfatal opioid overdose and accompanying mental health and substance use disorders based on age and sex, they said.

“These differences may have important implications for developing effective interventions to prevent first-time NFOD and to engage youths in care after an NFOD,” they concluded.

The study was supported by grants to several researchers from the National Institute on Drug Abuse, National Institutes of Health, and the Charles A. King Trust. The researchers had no financial conflicts to disclose. 

More adolescent girls than boys experienced nonfatal opioid overdose and reported baseline levels of anxiety, depression, and self-harm, according to data from a retrospective cohort study of more than 20,000 youth in the United States.

Previous studies have identified sex-based differences in opioid overdose such as a higher prevalence of co-occurring psychiatric disorders in women compared with men, wrote Sarah M. Bagley, MD, of Boston University, and colleagues. “However, few studies have examined whether such sex-based differences in opioid overdose risk extend to the population of adolescents and young adults,” they said.

In a retrospective cohort study published in JAMA Network Open, the researchers identified 20,312 commercially insured youth aged 11-24 years who experienced a nonfatal opioid overdose between Jan. 1, 2006, and Dec. 31, 2017, and reviewed data using the IBM MarketScan Commercial Database. The average age of the study population was 20 years and approximately 42% were female.

Females aged 11-16 years had a significantly higher incidence of nonfatal opioid overdose (60%) compared with males, but this trend reversed at age 17 years, after which the incidence of nonfatal opioid overdose became significantly higher in males. “Our finding that females younger than 17 years had a higher incidence of NFOD is consistent with epidemiologic data that have indicated changes in alcohol and drug prevalence among female youths,” the researchers wrote.

Overall, 57.8% of the cohort had mood and anxiety disorders, 12.8% had trauma- or stress-related disorders, and 11.7% had attention-deficit/hyperactivity disorder.

When analyzed by sex, females had a significantly higher prevalence than that of males of mood or anxiety disorders (65.5% vs. 51.9%) trauma or stress-related disorders (16.4% vs. 10.1%) and attempts at suicide or self-harm (14.6% vs. 9.9%). Males had significantly higher prevalence than that of females of opioid use disorder (44.7% vs. 29.2%), cannabis use disorder (18.3% vs. 11.3%), and alcohol use disorder (20.3% vs. 14.4%).

“Although in our study, female youths had a lower prevalence of all substance use disorders, including OUD [opioid use disorder], and a higher prevalence of mood and trauma-associated disorders, both male and female youths had a higher prevalence of psychiatric illness and substance use disorder than youths in the general population,” the researchers noted.

The study findings were limited by several factors including the inclusion only of youth with commercial insurance, with no uninsured or publicly insured youth, and only those youth who sought health care after a nonfatal opioid overdose, the researchers noted. The prevalence of substance use and mental health disorders may be over- or underdiagnosed, and race was not included as a variable because of unreliable data, they added. The database also did not allow for gender identity beyond sex as listed by the insurance carrier, they said.

However, the results indicate significant differences in the incidence of nonfatal opioid overdose and accompanying mental health and substance use disorders based on age and sex, they said.

“These differences may have important implications for developing effective interventions to prevent first-time NFOD and to engage youths in care after an NFOD,” they concluded.

The study was supported by grants to several researchers from the National Institute on Drug Abuse, National Institutes of Health, and the Charles A. King Trust. The researchers had no financial conflicts to disclose. 

More adolescent girls than boys experienced nonfatal opioid overdose and reported baseline levels of anxiety, depression, and self-harm, according to data from a retrospective cohort study of more than 20,000 youth in the United States.

Previous studies have identified sex-based differences in opioid overdose such as a higher prevalence of co-occurring psychiatric disorders in women compared with men, wrote Sarah M. Bagley, MD, of Boston University, and colleagues. “However, few studies have examined whether such sex-based differences in opioid overdose risk extend to the population of adolescents and young adults,” they said.

In a retrospective cohort study published in JAMA Network Open, the researchers identified 20,312 commercially insured youth aged 11-24 years who experienced a nonfatal opioid overdose between Jan. 1, 2006, and Dec. 31, 2017, and reviewed data using the IBM MarketScan Commercial Database. The average age of the study population was 20 years and approximately 42% were female.

Females aged 11-16 years had a significantly higher incidence of nonfatal opioid overdose (60%) compared with males, but this trend reversed at age 17 years, after which the incidence of nonfatal opioid overdose became significantly higher in males. “Our finding that females younger than 17 years had a higher incidence of NFOD is consistent with epidemiologic data that have indicated changes in alcohol and drug prevalence among female youths,” the researchers wrote.

Overall, 57.8% of the cohort had mood and anxiety disorders, 12.8% had trauma- or stress-related disorders, and 11.7% had attention-deficit/hyperactivity disorder.

When analyzed by sex, females had a significantly higher prevalence than that of males of mood or anxiety disorders (65.5% vs. 51.9%) trauma or stress-related disorders (16.4% vs. 10.1%) and attempts at suicide or self-harm (14.6% vs. 9.9%). Males had significantly higher prevalence than that of females of opioid use disorder (44.7% vs. 29.2%), cannabis use disorder (18.3% vs. 11.3%), and alcohol use disorder (20.3% vs. 14.4%).

“Although in our study, female youths had a lower prevalence of all substance use disorders, including OUD [opioid use disorder], and a higher prevalence of mood and trauma-associated disorders, both male and female youths had a higher prevalence of psychiatric illness and substance use disorder than youths in the general population,” the researchers noted.

The study findings were limited by several factors including the inclusion only of youth with commercial insurance, with no uninsured or publicly insured youth, and only those youth who sought health care after a nonfatal opioid overdose, the researchers noted. The prevalence of substance use and mental health disorders may be over- or underdiagnosed, and race was not included as a variable because of unreliable data, they added. The database also did not allow for gender identity beyond sex as listed by the insurance carrier, they said.

However, the results indicate significant differences in the incidence of nonfatal opioid overdose and accompanying mental health and substance use disorders based on age and sex, they said.

“These differences may have important implications for developing effective interventions to prevent first-time NFOD and to engage youths in care after an NFOD,” they concluded.

The study was supported by grants to several researchers from the National Institute on Drug Abuse, National Institutes of Health, and the Charles A. King Trust. The researchers had no financial conflicts to disclose.