Mr. R, age 29, was diagnosed with schizophrenia 6 years ago. To manage his disorder, he has been receiving paliperidone palmitate long-acting injectable (LAI) 156 mg once a month for 2 years. Prior to maintenance with paliperidone palmitate, Mr. R was stabilized on oral paliperidone 9 mg/d. Though he was originally initiated on paliperidone palmitate due to nonadherence concerns, Mr. R has been adherent with each injection for 1 year.

At a recent visit, Mr. R says he wants to discontinue the injection because he is not interested in receiving an ongoing injectable medication and is not able to continue monthly clinic visits. He wants to take a daily oral antipsychotic again, despite the availability of longer-acting products.

A paucity of evidence exists regarding the discontinuation of LAI antipsychotics and the next steps that follow in treatment. There is neither a consensus nor recognized guidelines advising how and when to discontinue an LAI and restart an oral antipsychotic. A recent systematic review and meta-analysis evaluated different maintenance treatment strategies; however, switching from an LAI antipsychotic to an oral medication was not a focus.¹ In this article, we outline a possible approach to discontinuing an LAI antipsychotic and restarting an oral formulation. Before discontinuing an LAI antipsychotic, clinicians should review with the patient the risks and benefits of switching medications, including the risk of decompensation and potential adverse effects.

Switching to an oral antipsychotic

The first step in the discontinuation process is to determine whether the patient will continue the same oral medication as the LAI antipsychotic or if a different oral antipsychotic will be initiated. Next, determining when to initiate the oral medication requires several pieces of information, including the oral dose equivalent of the patient’s current LAI, the half-life of the LAI, and the release mechanism of the LAI (Table 1).^2-5 To determine the appropriate time frame for restarting oral treatment, it is also vital to know the date of the last injection.

Based on the date of the next injection, the clinician will utilize the LAI’s half-life and its release mechanism to determine the appropriate time to start a new oral antipsychotic. Research demonstrates that in patients who have achieved steady state with a first-generation antipsychotic, plasma concentrations stay relatively consistent for 6 to 7 weeks after the last injection, which suggests oral medications may not need to be initiated until that time.^6-9

For many second-generation LAI antipsychotics, oral medications may be initiated at the date of the next injection. Initiation of an oral antipsychotic may require more time between the last injection dose and the date of administration for oral medication due to the pharmacokinetic profile of risperidone microspheres. Once a patient is at steady state with risperidone microspheres, trough levels are not observed until 3 to 4 weeks after discontinuation.¹⁰

Previous pharmacokinetic model–based stimulations of active moiety plasma concentrations of risperidone microspheres demonstrate that 2 weeks after an injection of risperidone microspheres, the concentration of active moiety continued to approximate the steady-state concentration for 3 to 5 weeks.¹¹ This is likely due to the product’s delay in release being 3 weeks from the time of injection to the last release phase. Of note, there was a rapid decline in the active moiety concentration; it reached nearly 0 by Week 5.¹¹ The same pharmacokinetic model–based stimulation demonstrated a steady and slow decline of the concentration of active moiety of paliperidone palmitate after discontinuation of the LAI.¹¹

Continue to: No guidance exists for...

No guidance exists for aripiprazole LAI medications; however, based on the pharmacokinetic data, administration of oral medications should be initiated at the date of next injection. Given the long half-life of aripiprazole, a cross-titration of the LAI with oral medication is reasonable.

Monitoring drug levels

In addition to utilizing the pharmacokinetic data from LAI antipsychotics, therapeutic drug levels can be instrumental in determining the dose of oral medication to use and when to begin titration (Table 2).^12-14 Obtaining a drug level on the date of the next injection can provide the clinician with data regarding the release of the medication specific to the patient. Based on the level and the current symptomatology, the clinician could choose to start the oral medication at a lower dose and titrate back to the LAI equivalent oral dose, or initiate the oral dose at the LAI equivalent oral dose. Continued therapeutic drug levels can aid in this determination.

No guidance exists on the appropriate discontinuation of LAI antipsychotics. Utilizing a medication’s half-life and release mechanism, as well as the patient’s previous medication history, date of last injection, and therapeutic drug levels, should be considered when determining the schedule for restarting an oral antipsychotic.

CASE CONTINUED

Based on the current dosing of paliperidone palmitate of 156 mg once a month, Mr. R likely requires 9 mg/d of oral paliperidone upon discontinuation of the LAI. On the date of the next injection, the clinician could decide to initiate a lower dose of paliperidone, such as to 3 mg/d or 6 mg/d, and increase the dose as tolerated over the next 10 to 14 days as the paliperidone palmitate is further metabolized. Additionally, the clinician may consider obtaining a therapeutic drug level to determine the current paliperidone level prior to initiating the oral medication. Each treatment option offers individual risks and benefits. The decision on when and how to initiate the oral medication will be based on the individual patient’s situation and history, as well as the comfort and discretion of the clinician. The clinician should arrange appropriate monitoring for potential increased symptomatology during the transition, and adverse effects should be assessed regularly until steady state is achieved with the targeted oral dose of medication.

Related Resources

• Parmentier BL. Second-generation long-acting injectable antipsychotics: a practical guide. Current Psychiatry. 2020;19(3):24-32.
• Thippaiah SM, Fargason RE, Birur B. Switching antipsychotics: a guide to dose equivalents. Current Psychiatry. 2021;20(4):13-14. doi:10.12788/cp.0103

Drug Brand Names

Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Maintena
Haloperidol injection • Haldol decanoate
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone • Invega
Paliperidone palmitate once monthly • Invega Sustenna
Paliperidone palmitate every 3 months • Invega Trinza
Paliperidone palmitate every 6 months • Invega Hafyera
Risperidone microspheres • Risperdal Consta
Risperidone polymer • Perseris

Mr. R, age 29, was diagnosed with schizophrenia 6 years ago. To manage his disorder, he has been receiving paliperidone palmitate long-acting injectable (LAI) 156 mg once a month for 2 years. Prior to maintenance with paliperidone palmitate, Mr. R was stabilized on oral paliperidone 9 mg/d. Though he was originally initiated on paliperidone palmitate due to nonadherence concerns, Mr. R has been adherent with each injection for 1 year.

At a recent visit, Mr. R says he wants to discontinue the injection because he is not interested in receiving an ongoing injectable medication and is not able to continue monthly clinic visits. He wants to take a daily oral antipsychotic again, despite the availability of longer-acting products.

A paucity of evidence exists regarding the discontinuation of LAI antipsychotics and the next steps that follow in treatment. There is neither a consensus nor recognized guidelines advising how and when to discontinue an LAI and restart an oral antipsychotic. A recent systematic review and meta-analysis evaluated different maintenance treatment strategies; however, switching from an LAI antipsychotic to an oral medication was not a focus.¹ In this article, we outline a possible approach to discontinuing an LAI antipsychotic and restarting an oral formulation. Before discontinuing an LAI antipsychotic, clinicians should review with the patient the risks and benefits of switching medications, including the risk of decompensation and potential adverse effects.

Switching to an oral antipsychotic

The first step in the discontinuation process is to determine whether the patient will continue the same oral medication as the LAI antipsychotic or if a different oral antipsychotic will be initiated. Next, determining when to initiate the oral medication requires several pieces of information, including the oral dose equivalent of the patient’s current LAI, the half-life of the LAI, and the release mechanism of the LAI (Table 1).^2-5 To determine the appropriate time frame for restarting oral treatment, it is also vital to know the date of the last injection.

Based on the date of the next injection, the clinician will utilize the LAI’s half-life and its release mechanism to determine the appropriate time to start a new oral antipsychotic. Research demonstrates that in patients who have achieved steady state with a first-generation antipsychotic, plasma concentrations stay relatively consistent for 6 to 7 weeks after the last injection, which suggests oral medications may not need to be initiated until that time.^6-9

For many second-generation LAI antipsychotics, oral medications may be initiated at the date of the next injection. Initiation of an oral antipsychotic may require more time between the last injection dose and the date of administration for oral medication due to the pharmacokinetic profile of risperidone microspheres. Once a patient is at steady state with risperidone microspheres, trough levels are not observed until 3 to 4 weeks after discontinuation.¹⁰

Previous pharmacokinetic model–based stimulations of active moiety plasma concentrations of risperidone microspheres demonstrate that 2 weeks after an injection of risperidone microspheres, the concentration of active moiety continued to approximate the steady-state concentration for 3 to 5 weeks.¹¹ This is likely due to the product’s delay in release being 3 weeks from the time of injection to the last release phase. Of note, there was a rapid decline in the active moiety concentration; it reached nearly 0 by Week 5.¹¹ The same pharmacokinetic model–based stimulation demonstrated a steady and slow decline of the concentration of active moiety of paliperidone palmitate after discontinuation of the LAI.¹¹

Continue to: No guidance exists for...

No guidance exists for aripiprazole LAI medications; however, based on the pharmacokinetic data, administration of oral medications should be initiated at the date of next injection. Given the long half-life of aripiprazole, a cross-titration of the LAI with oral medication is reasonable.

Monitoring drug levels

In addition to utilizing the pharmacokinetic data from LAI antipsychotics, therapeutic drug levels can be instrumental in determining the dose of oral medication to use and when to begin titration (Table 2).^12-14 Obtaining a drug level on the date of the next injection can provide the clinician with data regarding the release of the medication specific to the patient. Based on the level and the current symptomatology, the clinician could choose to start the oral medication at a lower dose and titrate back to the LAI equivalent oral dose, or initiate the oral dose at the LAI equivalent oral dose. Continued therapeutic drug levels can aid in this determination.

No guidance exists on the appropriate discontinuation of LAI antipsychotics. Utilizing a medication’s half-life and release mechanism, as well as the patient’s previous medication history, date of last injection, and therapeutic drug levels, should be considered when determining the schedule for restarting an oral antipsychotic.

CASE CONTINUED

Based on the current dosing of paliperidone palmitate of 156 mg once a month, Mr. R likely requires 9 mg/d of oral paliperidone upon discontinuation of the LAI. On the date of the next injection, the clinician could decide to initiate a lower dose of paliperidone, such as to 3 mg/d or 6 mg/d, and increase the dose as tolerated over the next 10 to 14 days as the paliperidone palmitate is further metabolized. Additionally, the clinician may consider obtaining a therapeutic drug level to determine the current paliperidone level prior to initiating the oral medication. Each treatment option offers individual risks and benefits. The decision on when and how to initiate the oral medication will be based on the individual patient’s situation and history, as well as the comfort and discretion of the clinician. The clinician should arrange appropriate monitoring for potential increased symptomatology during the transition, and adverse effects should be assessed regularly until steady state is achieved with the targeted oral dose of medication.

Related Resources

• Parmentier BL. Second-generation long-acting injectable antipsychotics: a practical guide. Current Psychiatry. 2020;19(3):24-32.
• Thippaiah SM, Fargason RE, Birur B. Switching antipsychotics: a guide to dose equivalents. Current Psychiatry. 2021;20(4):13-14. doi:10.12788/cp.0103

Drug Brand Names

Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Maintena
Haloperidol injection • Haldol decanoate
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone • Invega
Paliperidone palmitate once monthly • Invega Sustenna
Paliperidone palmitate every 3 months • Invega Trinza
Paliperidone palmitate every 6 months • Invega Hafyera
Risperidone microspheres • Risperdal Consta
Risperidone polymer • Perseris

Mr. R, age 29, was diagnosed with schizophrenia 6 years ago. To manage his disorder, he has been receiving paliperidone palmitate long-acting injectable (LAI) 156 mg once a month for 2 years. Prior to maintenance with paliperidone palmitate, Mr. R was stabilized on oral paliperidone 9 mg/d. Though he was originally initiated on paliperidone palmitate due to nonadherence concerns, Mr. R has been adherent with each injection for 1 year.

At a recent visit, Mr. R says he wants to discontinue the injection because he is not interested in receiving an ongoing injectable medication and is not able to continue monthly clinic visits. He wants to take a daily oral antipsychotic again, despite the availability of longer-acting products.

A paucity of evidence exists regarding the discontinuation of LAI antipsychotics and the next steps that follow in treatment. There is neither a consensus nor recognized guidelines advising how and when to discontinue an LAI and restart an oral antipsychotic. A recent systematic review and meta-analysis evaluated different maintenance treatment strategies; however, switching from an LAI antipsychotic to an oral medication was not a focus.¹ In this article, we outline a possible approach to discontinuing an LAI antipsychotic and restarting an oral formulation. Before discontinuing an LAI antipsychotic, clinicians should review with the patient the risks and benefits of switching medications, including the risk of decompensation and potential adverse effects.

Switching to an oral antipsychotic

The first step in the discontinuation process is to determine whether the patient will continue the same oral medication as the LAI antipsychotic or if a different oral antipsychotic will be initiated. Next, determining when to initiate the oral medication requires several pieces of information, including the oral dose equivalent of the patient’s current LAI, the half-life of the LAI, and the release mechanism of the LAI (Table 1).^2-5 To determine the appropriate time frame for restarting oral treatment, it is also vital to know the date of the last injection.

Based on the date of the next injection, the clinician will utilize the LAI’s half-life and its release mechanism to determine the appropriate time to start a new oral antipsychotic. Research demonstrates that in patients who have achieved steady state with a first-generation antipsychotic, plasma concentrations stay relatively consistent for 6 to 7 weeks after the last injection, which suggests oral medications may not need to be initiated until that time.^6-9

For many second-generation LAI antipsychotics, oral medications may be initiated at the date of the next injection. Initiation of an oral antipsychotic may require more time between the last injection dose and the date of administration for oral medication due to the pharmacokinetic profile of risperidone microspheres. Once a patient is at steady state with risperidone microspheres, trough levels are not observed until 3 to 4 weeks after discontinuation.¹⁰

Previous pharmacokinetic model–based stimulations of active moiety plasma concentrations of risperidone microspheres demonstrate that 2 weeks after an injection of risperidone microspheres, the concentration of active moiety continued to approximate the steady-state concentration for 3 to 5 weeks.¹¹ This is likely due to the product’s delay in release being 3 weeks from the time of injection to the last release phase. Of note, there was a rapid decline in the active moiety concentration; it reached nearly 0 by Week 5.¹¹ The same pharmacokinetic model–based stimulation demonstrated a steady and slow decline of the concentration of active moiety of paliperidone palmitate after discontinuation of the LAI.¹¹

Continue to: No guidance exists for...

No guidance exists for aripiprazole LAI medications; however, based on the pharmacokinetic data, administration of oral medications should be initiated at the date of next injection. Given the long half-life of aripiprazole, a cross-titration of the LAI with oral medication is reasonable.

Monitoring drug levels

In addition to utilizing the pharmacokinetic data from LAI antipsychotics, therapeutic drug levels can be instrumental in determining the dose of oral medication to use and when to begin titration (Table 2).^12-14 Obtaining a drug level on the date of the next injection can provide the clinician with data regarding the release of the medication specific to the patient. Based on the level and the current symptomatology, the clinician could choose to start the oral medication at a lower dose and titrate back to the LAI equivalent oral dose, or initiate the oral dose at the LAI equivalent oral dose. Continued therapeutic drug levels can aid in this determination.

No guidance exists on the appropriate discontinuation of LAI antipsychotics. Utilizing a medication’s half-life and release mechanism, as well as the patient’s previous medication history, date of last injection, and therapeutic drug levels, should be considered when determining the schedule for restarting an oral antipsychotic.

CASE CONTINUED

Based on the current dosing of paliperidone palmitate of 156 mg once a month, Mr. R likely requires 9 mg/d of oral paliperidone upon discontinuation of the LAI. On the date of the next injection, the clinician could decide to initiate a lower dose of paliperidone, such as to 3 mg/d or 6 mg/d, and increase the dose as tolerated over the next 10 to 14 days as the paliperidone palmitate is further metabolized. Additionally, the clinician may consider obtaining a therapeutic drug level to determine the current paliperidone level prior to initiating the oral medication. Each treatment option offers individual risks and benefits. The decision on when and how to initiate the oral medication will be based on the individual patient’s situation and history, as well as the comfort and discretion of the clinician. The clinician should arrange appropriate monitoring for potential increased symptomatology during the transition, and adverse effects should be assessed regularly until steady state is achieved with the targeted oral dose of medication.

Related Resources

• Parmentier BL. Second-generation long-acting injectable antipsychotics: a practical guide. Current Psychiatry. 2020;19(3):24-32.
• Thippaiah SM, Fargason RE, Birur B. Switching antipsychotics: a guide to dose equivalents. Current Psychiatry. 2021;20(4):13-14. doi:10.12788/cp.0103

Drug Brand Names

Aripiprazole lauroxil • Aristada
Aripiprazole monohydrate • Maintena
Haloperidol injection • Haldol decanoate
Olanzapine pamoate • Zyprexa Relprevv
Paliperidone • Invega
Paliperidone palmitate once monthly • Invega Sustenna
Paliperidone palmitate every 3 months • Invega Trinza
Paliperidone palmitate every 6 months • Invega Hafyera
Risperidone microspheres • Risperdal Consta
Risperidone polymer • Perseris

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

Ms. A, age 32, has a history of anxiety, bipolar disorder, and borderline personality disorder. She is undergoing treatment with lamotrigine 200 mg/d at bedtime, aripiprazole 5 mg/d, trazodone 100 mg/d at bedtime, clonazepam 0.5 mg twice a day, and hydroxyzine 25 mg twice a day. She presents to the emergency department with myalgia, left upper and lower extremity numbness, and weakness. These symptoms started at approximately 3 am the same day. She denies fever, chills, shortness of breath, chest pain, abdominal pain, lightheadedness, or dizziness, as well as any history of similar symptoms.

Ms. A’s vital signs are hemodynamically stable, but her pulse is 113 bpm. On examination, she appears anxious and has decreased sensation in her upper and lower extremities, with 3/5 strength on the left side. Her laboratory results indicate mild leukocytosis, hyponatremia (129 mmol/L; reference range 136 to 145 mmol/L), and elevations in serum creatinine (3.7 mg/dL; reference range 0.6 to 1.2 mg/dL), aspartate aminotransferase (654 U/L; reference range 10 to 42 U/L), alanine transaminase (234 U/L; reference range 10 to 60 U/L), and troponin (2.11 ng/mL; reference range 0 to 0.04 ng/mL). A urinalysis reveals darkly colored urine with large red blood cells.

Neurology and Cardiology consultations are requested to rule out stroke and acute coronary syndromes. A computed tomography scan of the head shows no acute intracranial findings. Her creatinine kinase (CK) level is elevated (>42,670 U/L; reference range 22 to 232 U/L), which prompts a search for causes of rhabdomyolysis, a breakdown of muscle tissue that releases muscle fiber contents into the blood. Ms. A reports no history of recent trauma or strenuous exercise. Infectious, endocrine, and other workups are negative. After a consult to Psychiatry, the treating clinicians suspect that the most likely cause for rhabdomyolysis is aripiprazole.

Ms. A is treated with IV isotonic fluids. Aripiprazole is stopped and her CK levels are closely monitored. CK levels continue to trend down, and by Day 6 of hospitalization her CK level is 1,648 U/L. Her transaminase levels also improve; these elevations are considered likely secondary to rhabdomyolysis. Because there is notable improvement in CK and transaminase levels after stopping aripiprazole, Ms. A is discharged and instructed to follow up with a psychiatrist for further management.

Aripiprazole and rhabdomyolysis

According to the National Institute of Mental Health, an estimated 2.8% of the US population has bipolar disorder and 0.24% to 0.64% has schizophrenia.^1,2 Antipsychotics are often used to treat these disorders. The prevalence of antipsychotic use in the general adult population is 1.6%.³ The use of second-generation antipsychotics (SGAs) has increased over recent years with the availability of a variety of formulations, such as immediate-release injectable, long-acting injectable, and orally disintegrating tablets in addition to the customary oral tablets. SGAs can cause several adverse effects, including weight gain, hyperlipidemia, diabetes, QTc prolongation, extrapyramidal side effects, myocarditis, agranulocytosis, cataracts, and sexual adverse effects.⁴

Antipsychotic use is more commonly associated with serotonin syndrome and neuroleptic malignant syndrome than it is with rhabdomyolysis. Rhabdomyolysis as an adverse effect of antipsychotic use has not been well understood or reported. One study found the prevalence of rhabdomyolysis was approximately 10% among patients who received an antipsychotic medication.⁵ There have been 4 case reports of clozapine use, 6 of olanzapine use, and 3 of aripiprazole use associated with rhabdomyolysis.^6-8 Therefore, this would be the fourth case report to describe aripiprazole-associated rhabdomyolysis.

Aripiprazole is FDA-approved for the treatment of schizophrenia. In this case report, we found that aripiprazole could have led to rhabdomyolysis. Aripiprazole is a quinoline derivative that acts by binding to the 5-HT1A and 5-HT2A receptors.^9,10 It acts as a partial agonist at 5-HT1A receptors, an antagonist at 5-HT2A receptors, and a partial agonist and stabilizer at the D2 receptor. By binding to the dopamine receptor in its G protein–coupled state, aripiprazole blocks the receptor in the presence of excessive dopamine.^11-13 The mechanism of how aripiprazole could cause rhabdomyolysis is unclear. One proposed mechanism is that it can increase the permeability of skeletal muscle by 5-HT2A antagonism. This leads to a decrease in glucose reuptake in the cell and increases the permeability of the cell membrane, leading to elevations in CK levels.¹⁴ Another proposed mechanism is that dopamine blockade in the nigrostriatal pathway can result in muscle stiffness, rigidity, parkinsonian-like symptoms, and akathisia, which can result in elevated CK levels.¹⁵ There are only 3 other published cases of aripiprazole-induced rhabdomyolysis; we hope this case report will add value to the available literature. More evidence is needed to establish the safety profile of aripiprazole.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

Ms. A, age 32, has a history of anxiety, bipolar disorder, and borderline personality disorder. She is undergoing treatment with lamotrigine 200 mg/d at bedtime, aripiprazole 5 mg/d, trazodone 100 mg/d at bedtime, clonazepam 0.5 mg twice a day, and hydroxyzine 25 mg twice a day. She presents to the emergency department with myalgia, left upper and lower extremity numbness, and weakness. These symptoms started at approximately 3 am the same day. She denies fever, chills, shortness of breath, chest pain, abdominal pain, lightheadedness, or dizziness, as well as any history of similar symptoms.

Ms. A’s vital signs are hemodynamically stable, but her pulse is 113 bpm. On examination, she appears anxious and has decreased sensation in her upper and lower extremities, with 3/5 strength on the left side. Her laboratory results indicate mild leukocytosis, hyponatremia (129 mmol/L; reference range 136 to 145 mmol/L), and elevations in serum creatinine (3.7 mg/dL; reference range 0.6 to 1.2 mg/dL), aspartate aminotransferase (654 U/L; reference range 10 to 42 U/L), alanine transaminase (234 U/L; reference range 10 to 60 U/L), and troponin (2.11 ng/mL; reference range 0 to 0.04 ng/mL). A urinalysis reveals darkly colored urine with large red blood cells.

Neurology and Cardiology consultations are requested to rule out stroke and acute coronary syndromes. A computed tomography scan of the head shows no acute intracranial findings. Her creatinine kinase (CK) level is elevated (>42,670 U/L; reference range 22 to 232 U/L), which prompts a search for causes of rhabdomyolysis, a breakdown of muscle tissue that releases muscle fiber contents into the blood. Ms. A reports no history of recent trauma or strenuous exercise. Infectious, endocrine, and other workups are negative. After a consult to Psychiatry, the treating clinicians suspect that the most likely cause for rhabdomyolysis is aripiprazole.

Ms. A is treated with IV isotonic fluids. Aripiprazole is stopped and her CK levels are closely monitored. CK levels continue to trend down, and by Day 6 of hospitalization her CK level is 1,648 U/L. Her transaminase levels also improve; these elevations are considered likely secondary to rhabdomyolysis. Because there is notable improvement in CK and transaminase levels after stopping aripiprazole, Ms. A is discharged and instructed to follow up with a psychiatrist for further management.

Aripiprazole and rhabdomyolysis

According to the National Institute of Mental Health, an estimated 2.8% of the US population has bipolar disorder and 0.24% to 0.64% has schizophrenia.^1,2 Antipsychotics are often used to treat these disorders. The prevalence of antipsychotic use in the general adult population is 1.6%.³ The use of second-generation antipsychotics (SGAs) has increased over recent years with the availability of a variety of formulations, such as immediate-release injectable, long-acting injectable, and orally disintegrating tablets in addition to the customary oral tablets. SGAs can cause several adverse effects, including weight gain, hyperlipidemia, diabetes, QTc prolongation, extrapyramidal side effects, myocarditis, agranulocytosis, cataracts, and sexual adverse effects.⁴

Antipsychotic use is more commonly associated with serotonin syndrome and neuroleptic malignant syndrome than it is with rhabdomyolysis. Rhabdomyolysis as an adverse effect of antipsychotic use has not been well understood or reported. One study found the prevalence of rhabdomyolysis was approximately 10% among patients who received an antipsychotic medication.⁵ There have been 4 case reports of clozapine use, 6 of olanzapine use, and 3 of aripiprazole use associated with rhabdomyolysis.^6-8 Therefore, this would be the fourth case report to describe aripiprazole-associated rhabdomyolysis.

Aripiprazole is FDA-approved for the treatment of schizophrenia. In this case report, we found that aripiprazole could have led to rhabdomyolysis. Aripiprazole is a quinoline derivative that acts by binding to the 5-HT1A and 5-HT2A receptors.^9,10 It acts as a partial agonist at 5-HT1A receptors, an antagonist at 5-HT2A receptors, and a partial agonist and stabilizer at the D2 receptor. By binding to the dopamine receptor in its G protein–coupled state, aripiprazole blocks the receptor in the presence of excessive dopamine.^11-13 The mechanism of how aripiprazole could cause rhabdomyolysis is unclear. One proposed mechanism is that it can increase the permeability of skeletal muscle by 5-HT2A antagonism. This leads to a decrease in glucose reuptake in the cell and increases the permeability of the cell membrane, leading to elevations in CK levels.¹⁴ Another proposed mechanism is that dopamine blockade in the nigrostriatal pathway can result in muscle stiffness, rigidity, parkinsonian-like symptoms, and akathisia, which can result in elevated CK levels.¹⁵ There are only 3 other published cases of aripiprazole-induced rhabdomyolysis; we hope this case report will add value to the available literature. More evidence is needed to establish the safety profile of aripiprazole.

Editor’s note: Readers’ Forum is a department for correspondence from readers that is not in response to articles published in Current Psychiatry. All submissions to Readers’ Forum undergo peer review and are subject to editing for length and style. For more information, contact letters@currentpsychiatry.com.

Ms. A, age 32, has a history of anxiety, bipolar disorder, and borderline personality disorder. She is undergoing treatment with lamotrigine 200 mg/d at bedtime, aripiprazole 5 mg/d, trazodone 100 mg/d at bedtime, clonazepam 0.5 mg twice a day, and hydroxyzine 25 mg twice a day. She presents to the emergency department with myalgia, left upper and lower extremity numbness, and weakness. These symptoms started at approximately 3 am the same day. She denies fever, chills, shortness of breath, chest pain, abdominal pain, lightheadedness, or dizziness, as well as any history of similar symptoms.

Ms. A’s vital signs are hemodynamically stable, but her pulse is 113 bpm. On examination, she appears anxious and has decreased sensation in her upper and lower extremities, with 3/5 strength on the left side. Her laboratory results indicate mild leukocytosis, hyponatremia (129 mmol/L; reference range 136 to 145 mmol/L), and elevations in serum creatinine (3.7 mg/dL; reference range 0.6 to 1.2 mg/dL), aspartate aminotransferase (654 U/L; reference range 10 to 42 U/L), alanine transaminase (234 U/L; reference range 10 to 60 U/L), and troponin (2.11 ng/mL; reference range 0 to 0.04 ng/mL). A urinalysis reveals darkly colored urine with large red blood cells.

Neurology and Cardiology consultations are requested to rule out stroke and acute coronary syndromes. A computed tomography scan of the head shows no acute intracranial findings. Her creatinine kinase (CK) level is elevated (>42,670 U/L; reference range 22 to 232 U/L), which prompts a search for causes of rhabdomyolysis, a breakdown of muscle tissue that releases muscle fiber contents into the blood. Ms. A reports no history of recent trauma or strenuous exercise. Infectious, endocrine, and other workups are negative. After a consult to Psychiatry, the treating clinicians suspect that the most likely cause for rhabdomyolysis is aripiprazole.

Ms. A is treated with IV isotonic fluids. Aripiprazole is stopped and her CK levels are closely monitored. CK levels continue to trend down, and by Day 6 of hospitalization her CK level is 1,648 U/L. Her transaminase levels also improve; these elevations are considered likely secondary to rhabdomyolysis. Because there is notable improvement in CK and transaminase levels after stopping aripiprazole, Ms. A is discharged and instructed to follow up with a psychiatrist for further management.

Aripiprazole and rhabdomyolysis

According to the National Institute of Mental Health, an estimated 2.8% of the US population has bipolar disorder and 0.24% to 0.64% has schizophrenia.^1,2 Antipsychotics are often used to treat these disorders. The prevalence of antipsychotic use in the general adult population is 1.6%.³ The use of second-generation antipsychotics (SGAs) has increased over recent years with the availability of a variety of formulations, such as immediate-release injectable, long-acting injectable, and orally disintegrating tablets in addition to the customary oral tablets. SGAs can cause several adverse effects, including weight gain, hyperlipidemia, diabetes, QTc prolongation, extrapyramidal side effects, myocarditis, agranulocytosis, cataracts, and sexual adverse effects.⁴

Antipsychotic use is more commonly associated with serotonin syndrome and neuroleptic malignant syndrome than it is with rhabdomyolysis. Rhabdomyolysis as an adverse effect of antipsychotic use has not been well understood or reported. One study found the prevalence of rhabdomyolysis was approximately 10% among patients who received an antipsychotic medication.⁵ There have been 4 case reports of clozapine use, 6 of olanzapine use, and 3 of aripiprazole use associated with rhabdomyolysis.^6-8 Therefore, this would be the fourth case report to describe aripiprazole-associated rhabdomyolysis.

Aripiprazole is FDA-approved for the treatment of schizophrenia. In this case report, we found that aripiprazole could have led to rhabdomyolysis. Aripiprazole is a quinoline derivative that acts by binding to the 5-HT1A and 5-HT2A receptors.^9,10 It acts as a partial agonist at 5-HT1A receptors, an antagonist at 5-HT2A receptors, and a partial agonist and stabilizer at the D2 receptor. By binding to the dopamine receptor in its G protein–coupled state, aripiprazole blocks the receptor in the presence of excessive dopamine.^11-13 The mechanism of how aripiprazole could cause rhabdomyolysis is unclear. One proposed mechanism is that it can increase the permeability of skeletal muscle by 5-HT2A antagonism. This leads to a decrease in glucose reuptake in the cell and increases the permeability of the cell membrane, leading to elevations in CK levels.¹⁴ Another proposed mechanism is that dopamine blockade in the nigrostriatal pathway can result in muscle stiffness, rigidity, parkinsonian-like symptoms, and akathisia, which can result in elevated CK levels.¹⁵ There are only 3 other published cases of aripiprazole-induced rhabdomyolysis; we hope this case report will add value to the available literature. More evidence is needed to establish the safety profile of aripiprazole.

CASE Anxious and confused

Mr. M, age 53, a surgeon, presents to the emergency department (ED) following a panic attack and concerns from his staff that he appears confused. Specifically, staff members report that in the past 4 months, Mr. M was observed having problems completing some postoperative tasks related to chart documentation. Mr. M has a history of major depressive disorder (MDD), hypertension, hyperlipidemia, and type 2 diabetes.

HISTORY A long-standing diagnosis of depression

Mr. M reports that 30 years ago, he received care from a psychiatrist to address symptoms of MDD. He says that around the time he arrived at the ED, he had noticed subtle but gradual changes in his cognition, which led him to skip words and often struggle to find the correct words. These episodes left him confused. Mr. M started getting anxious about these cognitive issues because they disrupted his work and forced him to reduce his duties. He does not have any known family history of mental illness, is single, and lives alone.

EVALUATION After stroke is ruled out, a psychiatric workup

In the ED, a comprehensive exam rules out an acute cerebrovascular event. A neurologic evaluation notes some delay in processing information and observes Mr. M having difficulty following simple commands. Laboratory investigations, including a comprehensive metabolic panel, are unremarkable. An MRI of Mr. M’s brain, with and without contrast, notes no acute findings. He is discharged from the ED with a diagnosis of MDD.

Before he presented to the ED, Mr. M’s medication regimen included duloxetine 60 mg/d, buspirone 10 mg 3 times a day, and aripiprazole 5 mg/d for MDD and anxiety. After the ED visit, Mr. M’s physician refers him to an outpatient psychiatrist for management of worsening depression and panic attacks. During the psychiatrist’s evaluation, Mr. M reports a decreased interest in activities, decreased motivation, being easily fatigued, and having poor sleep. He denies having a depressed mood, difficulty concentrating, or having problems with his appetite. He also denies suicidal thoughts, both past and present.

Mr. M describes his mood as anxious, primarily surrounding his recent cognitive changes. He does not have a substance use disorder, psychotic illness, mania or hypomania, posttraumatic stress disorder, or obsessive-compulsive disorder. He reports adherence to his psychiatric medications. A mental status exam reveals Mr. M to be anxious. His attention is not well sustained, and he has difficulty describing details of his cognitive struggles, providing vague descriptions such as “skipping thought” and “skipping words.” Mr. M’s affect is congruent to his mood with some restriction and the psychiatrist notes that he is experiencing thought latency, poverty of content of thoughts, word-finding difficulties, and circumlocution. Mr. M denies any perceptual abnormalities, and there is no evidence of delusions.

[polldaddy:11320112]

The authors’ observations

Mr. M’s symptoms are significant for subacute cognitive decline that is subtle but gradual and can be easily missed, especially in the beginning. Though his ED evaluation—including brain imaging—ruled out acute or focal neurologic findings and his primary psychiatric presentation was anxiety, Mr. M’s medical history and mental status exam were suggestive of cognitive deficits.

Collateral information was obtained from his work colleagues, which confirmed both cognitive problems and comorbid anxiety. Additionally, given Mr. M’s high cognitive baseline as a surgeon, the new-onset cognitive changes over 4 months warranted further cognitive and neurologic evaluation. There are many causes of cognitive impairment (vascular, cancer, infection, autoimmune, medications, substances or toxins, neurodegenerative, psychiatric, vitamin deficiencies), all of which need to be considered in a patient with a nonspecific presentation such as Mr. M’s. The psychiatrist confirmed Mr. M’s current medication regimen, and discussed tapering aripiprazole while continuing duloxetine and buspirone.

Continue to: EVALUATION A closer look at cognitive deficits

 

 

EVALUATION A closer look at cognitive deficits

Mr. M scores 12/30 on the Montreal Cognitive Assessment (MoCA), indicating moderate cognitive impairment (Table 1). The psychiatrist refers Mr. M to Neurology. During his neurologic evaluation, Mr. M continues to report feeling anxious that “something is wrong” and skips his words. The neurologist confirms Mr. M’s symptoms may have started 2 to 3 months before he presented to the ED. Mr. M reports unusual eating habits, including yogurt and cookies for breakfast, Mexican food for lunch, and more cookies for dinner. He denies having a fever, gaining or losing weight, rashes, headaches, neck stiffness, tingling or weakness or stiffness of limbs, vertigo, visual changes, photo­phobia, unsteady gait, bowel or bladder incontinence, or tremors.

When the neurologist repeats the MoCA, Mr. M again scores 12. The neurologist notes that Mr. M answers questions a little slowly and pauses for thoughts when unable to find an answer. Mr. M has difficulty following some simple commands, such as “touch a finger to your nose.” Other in-office neurologic physical exams (cranial nerves, involuntary movements or tremors, sensation, muscle strength, reflexes, cerebellar signs) are unremarkable except for mildly decreased vibration sense of his toes. The neurologist concludes that Mr. M’s presentation is suggestive of subacute to chronic bradyphrenia and orders additional evaluation, including neuropsychological testing.

[polldaddy:11320114]

The authors’ observations

Physical and neurologic exams were not suggestive of any obvious causes of cognitive decline. Both the mental status exam and 2 serial MoCAs suggested deficits in executive function, language, and memory. Each of the differential diagnoses considered was ruled out with workup or exams (Table 2), which led to a most likely diagnosis of neurodegenerative disorder with PPA. Neuropsychological testing confirmed the diagnosis of nonfluent PPA.

Primary progressive aphasia

PPA is an uncommon, heterogeneous group of disorders stemming from focal degeneration of language-governing centers of the brain.^1,2 The estimated prevalence of PPA is 3 in 100,000 cases.^2,3 There are 4 major variants of PPA (Table 3⁴), and each presents with distinct language, cognitive, neuroanatomical, and neuropathological characteristics.⁴ PPA is usually diagnosed in late middle life; however, diagnosis is often delayed due to the relative obscurity of the disorder.⁴ In Mr. M’s case, it took approximately 4 months of evaluations by various specialists before a diagnosis was confirmed.

The initial phase of PPA can present as a diagnostic challenge because patients can have difficulty articulating their cognitive and language deficits. PPA can be commonly mistaken for a primary psychiatric disorder such as MDD or anxiety, which can further delay an accurate diagnosis and treatment. Special attention to the mental status exam, close observation of the patient’s language, and assessment of cognitive abilities using standardized screenings such as the MoCA or Mini-Mental State Examination can be helpful in clarifying the diagnosis. It is also important to rule out developmental problems (eg, dyslexia) and hearing difficulties, particularly in older patients.⁴

Continue to: TREATMENT Adjusting the medication regimen

 

 

TREATMENT Adjusting the medication regimen

The neurologist completes additional examinations to rule out causes of rare neurodegenerative disorders, including CSF autoimmune disorders, Creutzfeldt-Jakob disease, and Alzheimer disease (AD) (Table 4). Mr. M continues to follow up with his outpatient psychiatrist and his medication regimen is adjusted. Aripiprazole and buspirone are discontinued, and duloxetine is titrated to 60 mg twice a day. During follow-up visits, Mr. M discusses his understanding of his neurologic condition. His concerns shift to his illness and prognosis. During these visits, he continues to deny suicidality.

[polldaddy:11320115]

The authors’ observations

Mr. M’s neurodegenerative workup identified an intriguing diagnostic challenge. A repeat brain MRI (Figure) showed atrophy patterns suggestive of frontotemporal lobar degeneration (FTLD). On the other hand, his CSF ATI (A-beta 42/T-tau index, a value used to aid in the diagnosis of AD) was <1, suggesting early-onset AD.^5,6 Although significant advances have been made to distinguish AD and FTLD following an autopsy, there are still no reliable or definitive biomarkers to distinguish AD from FTLD (particularly in the early stages of FTLD). This can often leave the confirmatory diagnosis as a question.⁷

A PPA diagnosis (and other dementias) can have a significant impact on the patient and their family due to the uncertain nature of the progression of the disease and quality-of-life issues related to language and other cognitive deficits. Early identification and accurate diagnosis of PPA and its etiology (ie, AD vs FTLD) is important to avoid unnecessary exposure to medications or the use of polypharmacy to treat an inaccurate diagnosis of a primary psychiatric illness. For example, Mr. M was being treated with 3 psychiatric medications (aripiprazole, buspirone, and duloxetine) for depression and anxiety prior to the diagnosis of PPA.

Nonpharmacologic interventions can play an important role in the management of patients with PPA. These include educating the patient and their family about the diagnosis and discussions about future planning, including appropriate social support, employment, and finances.⁴ Pharmacologic interventions may be limited, as there are currently no disease-modifying treatments for PPA or FTLD. For patients with nonfluent PPA or AD, cholinesterase inhibitors such as donepezil or N-methyl-d-aspartate receptor antagonists such as memantine may be utilized, though benefits can be limited.⁴ Recent research has explored the role of transcranial magnetic stimulation and suggest short-term benefits, as have case reports of behavioral interventions targeting language.⁸

Psychiatrists should continue to treat patients with PPA for comorbid anxiety or depression, with appropriate medications and/or supportive therapy to guide the patient through the process of grief. Assessing for suicide risk is also important in patients diagnosed with dementia. A retrospective cohort study of patients age ≥60 with a diagnosis of dementia suggested that the majority of suicides occurred in those with a new dementia diagnosis.⁹ End-of-life decisions such as advanced directives should be made when the patient still has legal capacity, ideally as soon as possible after diagnosis.¹⁰

OUTCOME Remaining engaged in treatment

Mr. M continues to follow-up with the Neurology team. He has also been regularly seeing his psychiatric team for medication management and supportive therapy, and his psychiatric medications have been optimized to reduce polypharmacy. During his sessions, Mr. M discusses his grief and plans for the future. Despite his anxiety about the uncertainty of his prognosis, Mr. M continues to report that he is doing reasonably well and remains engaged in treatment.

Bottom Line

Patients with primary progressive aphasia and rare neurodegenerative disorders may present to an outpatient or emergency setting with symptoms of anxiety and confusion. They are frequently misdiagnosed with a primary psychiatric disorder due to the nature of cognitive and language deficits, particularly in the early stages of the disease. Paying close attention to language and conducting cognitive screening are critical in identifying the true cause of a patient’s symptoms.

Related Resources

• Primary progressive aphasia. National Center for Advancing Translational Sciences. Genetic and Rare Diseases Information Center. https://rarediseases.info.nih.gov/diseases/8541/primary-progressive-aphasia
• Moller MD, Parmenter BA, Lane DW. Neuropsychological testing: A useful but underutilized resource. Current Psychiatry. 2019;18(11):40-46,51.

Drug Brand Names

Aripiprazole • Abilify
Donepezil • Aricept
Duloxetine • Cymbalta
Memantine • Namenda

CASE Anxious and confused

Mr. M, age 53, a surgeon, presents to the emergency department (ED) following a panic attack and concerns from his staff that he appears confused. Specifically, staff members report that in the past 4 months, Mr. M was observed having problems completing some postoperative tasks related to chart documentation. Mr. M has a history of major depressive disorder (MDD), hypertension, hyperlipidemia, and type 2 diabetes.

HISTORY A long-standing diagnosis of depression

Mr. M reports that 30 years ago, he received care from a psychiatrist to address symptoms of MDD. He says that around the time he arrived at the ED, he had noticed subtle but gradual changes in his cognition, which led him to skip words and often struggle to find the correct words. These episodes left him confused. Mr. M started getting anxious about these cognitive issues because they disrupted his work and forced him to reduce his duties. He does not have any known family history of mental illness, is single, and lives alone.

EVALUATION After stroke is ruled out, a psychiatric workup

In the ED, a comprehensive exam rules out an acute cerebrovascular event. A neurologic evaluation notes some delay in processing information and observes Mr. M having difficulty following simple commands. Laboratory investigations, including a comprehensive metabolic panel, are unremarkable. An MRI of Mr. M’s brain, with and without contrast, notes no acute findings. He is discharged from the ED with a diagnosis of MDD.

Before he presented to the ED, Mr. M’s medication regimen included duloxetine 60 mg/d, buspirone 10 mg 3 times a day, and aripiprazole 5 mg/d for MDD and anxiety. After the ED visit, Mr. M’s physician refers him to an outpatient psychiatrist for management of worsening depression and panic attacks. During the psychiatrist’s evaluation, Mr. M reports a decreased interest in activities, decreased motivation, being easily fatigued, and having poor sleep. He denies having a depressed mood, difficulty concentrating, or having problems with his appetite. He also denies suicidal thoughts, both past and present.

Mr. M describes his mood as anxious, primarily surrounding his recent cognitive changes. He does not have a substance use disorder, psychotic illness, mania or hypomania, posttraumatic stress disorder, or obsessive-compulsive disorder. He reports adherence to his psychiatric medications. A mental status exam reveals Mr. M to be anxious. His attention is not well sustained, and he has difficulty describing details of his cognitive struggles, providing vague descriptions such as “skipping thought” and “skipping words.” Mr. M’s affect is congruent to his mood with some restriction and the psychiatrist notes that he is experiencing thought latency, poverty of content of thoughts, word-finding difficulties, and circumlocution. Mr. M denies any perceptual abnormalities, and there is no evidence of delusions.

[polldaddy:11320112]

The authors’ observations

Mr. M’s symptoms are significant for subacute cognitive decline that is subtle but gradual and can be easily missed, especially in the beginning. Though his ED evaluation—including brain imaging—ruled out acute or focal neurologic findings and his primary psychiatric presentation was anxiety, Mr. M’s medical history and mental status exam were suggestive of cognitive deficits.

Collateral information was obtained from his work colleagues, which confirmed both cognitive problems and comorbid anxiety. Additionally, given Mr. M’s high cognitive baseline as a surgeon, the new-onset cognitive changes over 4 months warranted further cognitive and neurologic evaluation. There are many causes of cognitive impairment (vascular, cancer, infection, autoimmune, medications, substances or toxins, neurodegenerative, psychiatric, vitamin deficiencies), all of which need to be considered in a patient with a nonspecific presentation such as Mr. M’s. The psychiatrist confirmed Mr. M’s current medication regimen, and discussed tapering aripiprazole while continuing duloxetine and buspirone.

Continue to: EVALUATION A closer look at cognitive deficits

 

 

EVALUATION A closer look at cognitive deficits

Mr. M scores 12/30 on the Montreal Cognitive Assessment (MoCA), indicating moderate cognitive impairment (Table 1). The psychiatrist refers Mr. M to Neurology. During his neurologic evaluation, Mr. M continues to report feeling anxious that “something is wrong” and skips his words. The neurologist confirms Mr. M’s symptoms may have started 2 to 3 months before he presented to the ED. Mr. M reports unusual eating habits, including yogurt and cookies for breakfast, Mexican food for lunch, and more cookies for dinner. He denies having a fever, gaining or losing weight, rashes, headaches, neck stiffness, tingling or weakness or stiffness of limbs, vertigo, visual changes, photo­phobia, unsteady gait, bowel or bladder incontinence, or tremors.

When the neurologist repeats the MoCA, Mr. M again scores 12. The neurologist notes that Mr. M answers questions a little slowly and pauses for thoughts when unable to find an answer. Mr. M has difficulty following some simple commands, such as “touch a finger to your nose.” Other in-office neurologic physical exams (cranial nerves, involuntary movements or tremors, sensation, muscle strength, reflexes, cerebellar signs) are unremarkable except for mildly decreased vibration sense of his toes. The neurologist concludes that Mr. M’s presentation is suggestive of subacute to chronic bradyphrenia and orders additional evaluation, including neuropsychological testing.

[polldaddy:11320114]

The authors’ observations

Physical and neurologic exams were not suggestive of any obvious causes of cognitive decline. Both the mental status exam and 2 serial MoCAs suggested deficits in executive function, language, and memory. Each of the differential diagnoses considered was ruled out with workup or exams (Table 2), which led to a most likely diagnosis of neurodegenerative disorder with PPA. Neuropsychological testing confirmed the diagnosis of nonfluent PPA.

Primary progressive aphasia

PPA is an uncommon, heterogeneous group of disorders stemming from focal degeneration of language-governing centers of the brain.^1,2 The estimated prevalence of PPA is 3 in 100,000 cases.^2,3 There are 4 major variants of PPA (Table 3⁴), and each presents with distinct language, cognitive, neuroanatomical, and neuropathological characteristics.⁴ PPA is usually diagnosed in late middle life; however, diagnosis is often delayed due to the relative obscurity of the disorder.⁴ In Mr. M’s case, it took approximately 4 months of evaluations by various specialists before a diagnosis was confirmed.

The initial phase of PPA can present as a diagnostic challenge because patients can have difficulty articulating their cognitive and language deficits. PPA can be commonly mistaken for a primary psychiatric disorder such as MDD or anxiety, which can further delay an accurate diagnosis and treatment. Special attention to the mental status exam, close observation of the patient’s language, and assessment of cognitive abilities using standardized screenings such as the MoCA or Mini-Mental State Examination can be helpful in clarifying the diagnosis. It is also important to rule out developmental problems (eg, dyslexia) and hearing difficulties, particularly in older patients.⁴

Continue to: TREATMENT Adjusting the medication regimen

 

 

TREATMENT Adjusting the medication regimen

The neurologist completes additional examinations to rule out causes of rare neurodegenerative disorders, including CSF autoimmune disorders, Creutzfeldt-Jakob disease, and Alzheimer disease (AD) (Table 4). Mr. M continues to follow up with his outpatient psychiatrist and his medication regimen is adjusted. Aripiprazole and buspirone are discontinued, and duloxetine is titrated to 60 mg twice a day. During follow-up visits, Mr. M discusses his understanding of his neurologic condition. His concerns shift to his illness and prognosis. During these visits, he continues to deny suicidality.

[polldaddy:11320115]

The authors’ observations

Mr. M’s neurodegenerative workup identified an intriguing diagnostic challenge. A repeat brain MRI (Figure) showed atrophy patterns suggestive of frontotemporal lobar degeneration (FTLD). On the other hand, his CSF ATI (A-beta 42/T-tau index, a value used to aid in the diagnosis of AD) was <1, suggesting early-onset AD.^5,6 Although significant advances have been made to distinguish AD and FTLD following an autopsy, there are still no reliable or definitive biomarkers to distinguish AD from FTLD (particularly in the early stages of FTLD). This can often leave the confirmatory diagnosis as a question.⁷

A PPA diagnosis (and other dementias) can have a significant impact on the patient and their family due to the uncertain nature of the progression of the disease and quality-of-life issues related to language and other cognitive deficits. Early identification and accurate diagnosis of PPA and its etiology (ie, AD vs FTLD) is important to avoid unnecessary exposure to medications or the use of polypharmacy to treat an inaccurate diagnosis of a primary psychiatric illness. For example, Mr. M was being treated with 3 psychiatric medications (aripiprazole, buspirone, and duloxetine) for depression and anxiety prior to the diagnosis of PPA.

Nonpharmacologic interventions can play an important role in the management of patients with PPA. These include educating the patient and their family about the diagnosis and discussions about future planning, including appropriate social support, employment, and finances.⁴ Pharmacologic interventions may be limited, as there are currently no disease-modifying treatments for PPA or FTLD. For patients with nonfluent PPA or AD, cholinesterase inhibitors such as donepezil or N-methyl-d-aspartate receptor antagonists such as memantine may be utilized, though benefits can be limited.⁴ Recent research has explored the role of transcranial magnetic stimulation and suggest short-term benefits, as have case reports of behavioral interventions targeting language.⁸

Psychiatrists should continue to treat patients with PPA for comorbid anxiety or depression, with appropriate medications and/or supportive therapy to guide the patient through the process of grief. Assessing for suicide risk is also important in patients diagnosed with dementia. A retrospective cohort study of patients age ≥60 with a diagnosis of dementia suggested that the majority of suicides occurred in those with a new dementia diagnosis.⁹ End-of-life decisions such as advanced directives should be made when the patient still has legal capacity, ideally as soon as possible after diagnosis.¹⁰

OUTCOME Remaining engaged in treatment

Mr. M continues to follow-up with the Neurology team. He has also been regularly seeing his psychiatric team for medication management and supportive therapy, and his psychiatric medications have been optimized to reduce polypharmacy. During his sessions, Mr. M discusses his grief and plans for the future. Despite his anxiety about the uncertainty of his prognosis, Mr. M continues to report that he is doing reasonably well and remains engaged in treatment.

Bottom Line

Patients with primary progressive aphasia and rare neurodegenerative disorders may present to an outpatient or emergency setting with symptoms of anxiety and confusion. They are frequently misdiagnosed with a primary psychiatric disorder due to the nature of cognitive and language deficits, particularly in the early stages of the disease. Paying close attention to language and conducting cognitive screening are critical in identifying the true cause of a patient’s symptoms.

Related Resources

• Primary progressive aphasia. National Center for Advancing Translational Sciences. Genetic and Rare Diseases Information Center. https://rarediseases.info.nih.gov/diseases/8541/primary-progressive-aphasia
• Moller MD, Parmenter BA, Lane DW. Neuropsychological testing: A useful but underutilized resource. Current Psychiatry. 2019;18(11):40-46,51.

Drug Brand Names

Aripiprazole • Abilify
Donepezil • Aricept
Duloxetine • Cymbalta
Memantine • Namenda

CASE Anxious and confused

Mr. M, age 53, a surgeon, presents to the emergency department (ED) following a panic attack and concerns from his staff that he appears confused. Specifically, staff members report that in the past 4 months, Mr. M was observed having problems completing some postoperative tasks related to chart documentation. Mr. M has a history of major depressive disorder (MDD), hypertension, hyperlipidemia, and type 2 diabetes.

HISTORY A long-standing diagnosis of depression

Mr. M reports that 30 years ago, he received care from a psychiatrist to address symptoms of MDD. He says that around the time he arrived at the ED, he had noticed subtle but gradual changes in his cognition, which led him to skip words and often struggle to find the correct words. These episodes left him confused. Mr. M started getting anxious about these cognitive issues because they disrupted his work and forced him to reduce his duties. He does not have any known family history of mental illness, is single, and lives alone.

EVALUATION After stroke is ruled out, a psychiatric workup

In the ED, a comprehensive exam rules out an acute cerebrovascular event. A neurologic evaluation notes some delay in processing information and observes Mr. M having difficulty following simple commands. Laboratory investigations, including a comprehensive metabolic panel, are unremarkable. An MRI of Mr. M’s brain, with and without contrast, notes no acute findings. He is discharged from the ED with a diagnosis of MDD.

Before he presented to the ED, Mr. M’s medication regimen included duloxetine 60 mg/d, buspirone 10 mg 3 times a day, and aripiprazole 5 mg/d for MDD and anxiety. After the ED visit, Mr. M’s physician refers him to an outpatient psychiatrist for management of worsening depression and panic attacks. During the psychiatrist’s evaluation, Mr. M reports a decreased interest in activities, decreased motivation, being easily fatigued, and having poor sleep. He denies having a depressed mood, difficulty concentrating, or having problems with his appetite. He also denies suicidal thoughts, both past and present.

Mr. M describes his mood as anxious, primarily surrounding his recent cognitive changes. He does not have a substance use disorder, psychotic illness, mania or hypomania, posttraumatic stress disorder, or obsessive-compulsive disorder. He reports adherence to his psychiatric medications. A mental status exam reveals Mr. M to be anxious. His attention is not well sustained, and he has difficulty describing details of his cognitive struggles, providing vague descriptions such as “skipping thought” and “skipping words.” Mr. M’s affect is congruent to his mood with some restriction and the psychiatrist notes that he is experiencing thought latency, poverty of content of thoughts, word-finding difficulties, and circumlocution. Mr. M denies any perceptual abnormalities, and there is no evidence of delusions.

[polldaddy:11320112]

The authors’ observations

Mr. M’s symptoms are significant for subacute cognitive decline that is subtle but gradual and can be easily missed, especially in the beginning. Though his ED evaluation—including brain imaging—ruled out acute or focal neurologic findings and his primary psychiatric presentation was anxiety, Mr. M’s medical history and mental status exam were suggestive of cognitive deficits.

Collateral information was obtained from his work colleagues, which confirmed both cognitive problems and comorbid anxiety. Additionally, given Mr. M’s high cognitive baseline as a surgeon, the new-onset cognitive changes over 4 months warranted further cognitive and neurologic evaluation. There are many causes of cognitive impairment (vascular, cancer, infection, autoimmune, medications, substances or toxins, neurodegenerative, psychiatric, vitamin deficiencies), all of which need to be considered in a patient with a nonspecific presentation such as Mr. M’s. The psychiatrist confirmed Mr. M’s current medication regimen, and discussed tapering aripiprazole while continuing duloxetine and buspirone.

Continue to: EVALUATION A closer look at cognitive deficits

 

 

EVALUATION A closer look at cognitive deficits

Mr. M scores 12/30 on the Montreal Cognitive Assessment (MoCA), indicating moderate cognitive impairment (Table 1). The psychiatrist refers Mr. M to Neurology. During his neurologic evaluation, Mr. M continues to report feeling anxious that “something is wrong” and skips his words. The neurologist confirms Mr. M’s symptoms may have started 2 to 3 months before he presented to the ED. Mr. M reports unusual eating habits, including yogurt and cookies for breakfast, Mexican food for lunch, and more cookies for dinner. He denies having a fever, gaining or losing weight, rashes, headaches, neck stiffness, tingling or weakness or stiffness of limbs, vertigo, visual changes, photo­phobia, unsteady gait, bowel or bladder incontinence, or tremors.

When the neurologist repeats the MoCA, Mr. M again scores 12. The neurologist notes that Mr. M answers questions a little slowly and pauses for thoughts when unable to find an answer. Mr. M has difficulty following some simple commands, such as “touch a finger to your nose.” Other in-office neurologic physical exams (cranial nerves, involuntary movements or tremors, sensation, muscle strength, reflexes, cerebellar signs) are unremarkable except for mildly decreased vibration sense of his toes. The neurologist concludes that Mr. M’s presentation is suggestive of subacute to chronic bradyphrenia and orders additional evaluation, including neuropsychological testing.

[polldaddy:11320114]

The authors’ observations

Physical and neurologic exams were not suggestive of any obvious causes of cognitive decline. Both the mental status exam and 2 serial MoCAs suggested deficits in executive function, language, and memory. Each of the differential diagnoses considered was ruled out with workup or exams (Table 2), which led to a most likely diagnosis of neurodegenerative disorder with PPA. Neuropsychological testing confirmed the diagnosis of nonfluent PPA.

Primary progressive aphasia

PPA is an uncommon, heterogeneous group of disorders stemming from focal degeneration of language-governing centers of the brain.^1,2 The estimated prevalence of PPA is 3 in 100,000 cases.^2,3 There are 4 major variants of PPA (Table 3⁴), and each presents with distinct language, cognitive, neuroanatomical, and neuropathological characteristics.⁴ PPA is usually diagnosed in late middle life; however, diagnosis is often delayed due to the relative obscurity of the disorder.⁴ In Mr. M’s case, it took approximately 4 months of evaluations by various specialists before a diagnosis was confirmed.

The initial phase of PPA can present as a diagnostic challenge because patients can have difficulty articulating their cognitive and language deficits. PPA can be commonly mistaken for a primary psychiatric disorder such as MDD or anxiety, which can further delay an accurate diagnosis and treatment. Special attention to the mental status exam, close observation of the patient’s language, and assessment of cognitive abilities using standardized screenings such as the MoCA or Mini-Mental State Examination can be helpful in clarifying the diagnosis. It is also important to rule out developmental problems (eg, dyslexia) and hearing difficulties, particularly in older patients.⁴

Continue to: TREATMENT Adjusting the medication regimen

 

 

TREATMENT Adjusting the medication regimen

The neurologist completes additional examinations to rule out causes of rare neurodegenerative disorders, including CSF autoimmune disorders, Creutzfeldt-Jakob disease, and Alzheimer disease (AD) (Table 4). Mr. M continues to follow up with his outpatient psychiatrist and his medication regimen is adjusted. Aripiprazole and buspirone are discontinued, and duloxetine is titrated to 60 mg twice a day. During follow-up visits, Mr. M discusses his understanding of his neurologic condition. His concerns shift to his illness and prognosis. During these visits, he continues to deny suicidality.

[polldaddy:11320115]

The authors’ observations

Mr. M’s neurodegenerative workup identified an intriguing diagnostic challenge. A repeat brain MRI (Figure) showed atrophy patterns suggestive of frontotemporal lobar degeneration (FTLD). On the other hand, his CSF ATI (A-beta 42/T-tau index, a value used to aid in the diagnosis of AD) was <1, suggesting early-onset AD.^5,6 Although significant advances have been made to distinguish AD and FTLD following an autopsy, there are still no reliable or definitive biomarkers to distinguish AD from FTLD (particularly in the early stages of FTLD). This can often leave the confirmatory diagnosis as a question.⁷

A PPA diagnosis (and other dementias) can have a significant impact on the patient and their family due to the uncertain nature of the progression of the disease and quality-of-life issues related to language and other cognitive deficits. Early identification and accurate diagnosis of PPA and its etiology (ie, AD vs FTLD) is important to avoid unnecessary exposure to medications or the use of polypharmacy to treat an inaccurate diagnosis of a primary psychiatric illness. For example, Mr. M was being treated with 3 psychiatric medications (aripiprazole, buspirone, and duloxetine) for depression and anxiety prior to the diagnosis of PPA.

Nonpharmacologic interventions can play an important role in the management of patients with PPA. These include educating the patient and their family about the diagnosis and discussions about future planning, including appropriate social support, employment, and finances.⁴ Pharmacologic interventions may be limited, as there are currently no disease-modifying treatments for PPA or FTLD. For patients with nonfluent PPA or AD, cholinesterase inhibitors such as donepezil or N-methyl-d-aspartate receptor antagonists such as memantine may be utilized, though benefits can be limited.⁴ Recent research has explored the role of transcranial magnetic stimulation and suggest short-term benefits, as have case reports of behavioral interventions targeting language.⁸

Psychiatrists should continue to treat patients with PPA for comorbid anxiety or depression, with appropriate medications and/or supportive therapy to guide the patient through the process of grief. Assessing for suicide risk is also important in patients diagnosed with dementia. A retrospective cohort study of patients age ≥60 with a diagnosis of dementia suggested that the majority of suicides occurred in those with a new dementia diagnosis.⁹ End-of-life decisions such as advanced directives should be made when the patient still has legal capacity, ideally as soon as possible after diagnosis.¹⁰

OUTCOME Remaining engaged in treatment

Mr. M continues to follow-up with the Neurology team. He has also been regularly seeing his psychiatric team for medication management and supportive therapy, and his psychiatric medications have been optimized to reduce polypharmacy. During his sessions, Mr. M discusses his grief and plans for the future. Despite his anxiety about the uncertainty of his prognosis, Mr. M continues to report that he is doing reasonably well and remains engaged in treatment.

Bottom Line

Patients with primary progressive aphasia and rare neurodegenerative disorders may present to an outpatient or emergency setting with symptoms of anxiety and confusion. They are frequently misdiagnosed with a primary psychiatric disorder due to the nature of cognitive and language deficits, particularly in the early stages of the disease. Paying close attention to language and conducting cognitive screening are critical in identifying the true cause of a patient’s symptoms.

Related Resources

• Primary progressive aphasia. National Center for Advancing Translational Sciences. Genetic and Rare Diseases Information Center. https://rarediseases.info.nih.gov/diseases/8541/primary-progressive-aphasia
• Moller MD, Parmenter BA, Lane DW. Neuropsychological testing: A useful but underutilized resource. Current Psychiatry. 2019;18(11):40-46,51.

Drug Brand Names

Aripiprazole • Abilify
Donepezil • Aricept
Duloxetine • Cymbalta
Memantine • Namenda

I would like to remark on “Psychedelics for treating psychiatric disorders: Are they safe?” (Current Psychiatry, December 2022, p. 14-22, doi:10.12788/cp.0309), specifically “psilocybin use has been decriminalized … and some states (such as Oregon) have legalized it for therapeutic use.” I wanted to briefly clarify regarding the legal status of psilocybin.

The Oregon Psilocybin Services that will begin in 2023 are not specific to therapeutic use; this is a common misconception. These are specifically referred to as “psilocybin services” in the Oregon Administrative Rules (OAR), and psilocybin facilitators are required to limit their scope such that they are not practicing psychotherapy or other interventions, even if they do have a medical or psychotherapy background. The intention of the Oregon Psilocybin Services rollout was that these services would not be of the medical model. In the spirit of this, services do not require a medical diagnosis or referral, and services are not a medical or clinical treatment (OAR 333-333-5040). Additionally, services cannot be provided in a health care facility (OAR 441). Facilitators receive robust training as defined by Oregon law, and licensed facilitators provide this information during preparation for services. When discussing this model on a large public scale, I have noticed substantial misconceptions; it is imperative that we refer to these services as they are defined so that individuals with mental health conditions who seek them are aware that such services are different from psilocybin-assisted psychotherapy. Instead, Oregon Psilocybin Services might be better categorized as supported psilocybin use.

I would like to remark on “Psychedelics for treating psychiatric disorders: Are they safe?” (Current Psychiatry, December 2022, p. 14-22, doi:10.12788/cp.0309), specifically “psilocybin use has been decriminalized … and some states (such as Oregon) have legalized it for therapeutic use.” I wanted to briefly clarify regarding the legal status of psilocybin.

The Oregon Psilocybin Services that will begin in 2023 are not specific to therapeutic use; this is a common misconception. These are specifically referred to as “psilocybin services” in the Oregon Administrative Rules (OAR), and psilocybin facilitators are required to limit their scope such that they are not practicing psychotherapy or other interventions, even if they do have a medical or psychotherapy background. The intention of the Oregon Psilocybin Services rollout was that these services would not be of the medical model. In the spirit of this, services do not require a medical diagnosis or referral, and services are not a medical or clinical treatment (OAR 333-333-5040). Additionally, services cannot be provided in a health care facility (OAR 441). Facilitators receive robust training as defined by Oregon law, and licensed facilitators provide this information during preparation for services. When discussing this model on a large public scale, I have noticed substantial misconceptions; it is imperative that we refer to these services as they are defined so that individuals with mental health conditions who seek them are aware that such services are different from psilocybin-assisted psychotherapy. Instead, Oregon Psilocybin Services might be better categorized as supported psilocybin use.

I would like to remark on “Psychedelics for treating psychiatric disorders: Are they safe?” (Current Psychiatry, December 2022, p. 14-22, doi:10.12788/cp.0309), specifically “psilocybin use has been decriminalized … and some states (such as Oregon) have legalized it for therapeutic use.” I wanted to briefly clarify regarding the legal status of psilocybin.

The Oregon Psilocybin Services that will begin in 2023 are not specific to therapeutic use; this is a common misconception. These are specifically referred to as “psilocybin services” in the Oregon Administrative Rules (OAR), and psilocybin facilitators are required to limit their scope such that they are not practicing psychotherapy or other interventions, even if they do have a medical or psychotherapy background. The intention of the Oregon Psilocybin Services rollout was that these services would not be of the medical model. In the spirit of this, services do not require a medical diagnosis or referral, and services are not a medical or clinical treatment (OAR 333-333-5040). Additionally, services cannot be provided in a health care facility (OAR 441). Facilitators receive robust training as defined by Oregon law, and licensed facilitators provide this information during preparation for services. When discussing this model on a large public scale, I have noticed substantial misconceptions; it is imperative that we refer to these services as they are defined so that individuals with mental health conditions who seek them are aware that such services are different from psilocybin-assisted psychotherapy. Instead, Oregon Psilocybin Services might be better categorized as supported psilocybin use.

From the first obscure reference until the 19th century, the maternal mortality rate from an ectopic pregnancy was nearly 100%. In the past 140 years, because of early detection and prompt surgical management, the mortality rate from an ectopic pregnancy declined from 72%-90% in 1880 to 0.48% from 2004 to 2008.¹ Given this remarkable reduction in mortality, the 20th-century approach to ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing conservative treatment with methotrexate and/or tubal surgery.

Why the reference to ectopic pregnancy? Advances in oncology have comparably affected our approach to cancer patients. The increase in survival rates following a cancer diagnosis has fostered revolutionary developments in fertility preservation to obviate the effect of gonadotoxic therapy. We have evolved from shielding and transposing ovaries to ovarian tissue cryopreservation^2,3 with rapid implementation.

One of the leaders in the field of female fertility preservation is Kutluk Oktay, MD, of Yale University, New Haven, Conn. I posed the following salient questions to him on the state of fertility preservation as well as expectations for the future.

Q1. What medication/treatment is gonadotoxic that warrants a consultation for fertility preservation?

A: While new drugs for cancer treatment continue to be approved and require testing for gonadotoxicity, evidence is clear on the damaging effects of alkylating agents such as cyclophosphamide, ifosfamide, chlorambucil, and melphalan on primordial follicle reserve.⁴ A useful tool to determine the risk of alkylating agents affecting fertility is the Cyclophosphamide Equivalent Dose (CED) Calculator. Likewise, topoisomerase inhibitors, such as doxorubicin⁴ induce ovarian reserve damage by causing double-strand DNA breaks (DSBs) in oocytes.^5-7 Contrary to common belief, chemotherapy exposure suppresses the mechanisms that can initiate follicle growth.⁶ When DSBs occur, some oocytes may be able to repair such damage, otherwise apoptosis is triggered, which results in irreversible ovarian reserve loss.⁷ Younger individuals have much higher repair capacity, the magnitude of damage can be hard to predict, and it is variable.^8,9 So, prior exposure to gonadotoxic drugs does not preclude consideration of fertility preservation.¹⁰

In addition, pelvic radiation, in a dose-dependent manner, causes severe DSBs and triggers the same cell suicide mechanisms while also potentially damaging uterine function. Additional information can be found in the American Society of Clinical Oncology Fertility Preservation Guidelines.⁴
 

Q2. What are the current options for fertility preservation in patients who will be exposed to gonadotoxic medication/treatment?

A: The current fertility preservation options for female patients faced with gonadotoxic treatments are embryo, oocyte, and ovarian tissue cryopreservation (OTC). Selection of fertility preservation is typically contingent upon the timetable of treatment. Oocyte and embryo cryopreservation have been the standard of care. Recently, OTC had its experimental designation removed by American Society for Reproductive Medicine¹¹ with the advantage of not requiring ovarian stimulation or sexual maturity; and it may to be performed while patients are receiving chemotherapy. If successful, OTC followed by orthotopic transplantation has the potential to restore natural ovarian function, thereby allowing spontaneous conception.¹⁰ Especially in young adults, ovarian reserve loss is fractional and can remain at reasonable levels after a few courses of chemotherapy. Ovarian stimulation is risky after the initiation of chemotherapy because of the severe DNA damage to oocytes of developing follicles and the associated poor response.⁷ Hence, ovarian stimulation should be initiated and completed before the initiation of chemotherapy.

Q3. How successful are the approved fertility preservation options in obtaining oocytes for future utilization by ART?

A: We have decades of experience with embryo cryopreservation and proven success rates that patients can check on the SART.org website for individual clinics. For oocyte cryopreservation, models are used to provide calculation estimates because the technique is less established.¹² Although success rates are approaching those with fresh oocytes, they are still not equal.¹³ OTC followed by orthotopic tissue transplantation has the least outcomes data (approximately 200 reported livebirths to date with a 25% live birth rate per recipient worldwide¹⁰ since the first success was reported in 2000.^2,14

With our robotic surgical approach to orthotopic and heterotopic ovarian tissue transplantation and the utility of neovascularizing agents, we have found that ovarian graft longevity is extended. Oocytes/embryos can be obtained and has resulted in one to two livebirths in all our recipients to date.¹⁰ Unfortunately, if any of the critical steps are not up to standards (freezing, thawing, or transplantation), success rates can dramatically decline. Therefore, providers and patients should seek centers with experience in all three stages of this procedure to maximize outcomes.
 

Q4. Are there concerns of increasing recurrence/mortality with fertility preservation given hormonal exposure?

A: Yes, this concern exists, at least in theory for estrogen-sensitive cancers, most commonly breast cancer. We developed ovarian stimulation protocols supplemented with anti-estrogen treatments (tamoxifen, an estrogen-receptor antagonist, and letrozole, an aromatase inhibitor) that appear equally effective and reduce estrogen exposure in any susceptible cancer.^15,16 Even in estrogen receptor–negative tumors, high estrogen exposure may activate non–estrogen receptor–dependent pathways. In addition, even those tumors that are practically deemed estrogen receptor negative may still contain a small percentage of estrogen receptors, which may become active at high estrogen levels.

Therefore, when we approach women with estrogen-sensitive cancers, e.g., breast and endometrial, we do not alter our approach based on receptor status. One exception occurs in women with BRCA mutations, especially the BRCA1, as they have 25% lower serum anti-müllerian hormone (AMH) levels,^8,17 yield fewer oocytes in response to ovarian stimulation,^18,19 and have lower fertilization rates and embryo numbers²⁰ compared with those without the mutations.
 

Q5. Are all reproductive centers capable of offering fertility preservation? If not, how does a patient find a center?

A: All IVF clinics offer embryo and, presumably, oocyte cryopreservation. Pregnancy outcomes vary based on the center’s experience. Globally, major differences exist in the availability and competency of OTC along with the subsequent transplantation approach. A limited number of centers have competency in all aspects of OTC, i.e., cryopreservation, thawing, and transplantation. In general, fertility preservation patients have a multitude of medical issues that necessitate management expertise and the bandwidth to coordinate with cancer health professionals. The reproductive centers offering fertility preservation should be prepared to respond immediately and accommodate patients about to undergo gonadotoxic treatment.
 

Q6. How should a patient be counseled before proceeding with fertility preservation?

A: The candidate should be counseled on the likelihood of damage from gonadotoxic therapy and all fertility preservation options, on the basis of the urgency of treatment and the woman’s long-term goals. For example, the desire for a large family may compel a patient to undergo multiple cycles of ovarian stimulation or a combination of oocyte/embryo cryopreservation with OTC. In patients who are undergoing embryo cryopreservation, I recommend preimplantation genetic testing for aneuploidies, although there are limitations to its application. Other novel pieces of information we are using in counseling are baseline AMH levels and BRCA mutation status for women with breast cancer. In an 8-year-long NIH-funded prospective longitudinal study we found that women with both baseline AMH < 2 ng/mL and BRCA mutations are at significantly higher risk of losing their ovarian reserve and developing amenorrhea.²¹ Because the oocytes of women with BRCA mutations are deficient in DNA repair as we have previously shown,¹⁹ they are more liable to death upon exposure to DNA-damaging cancer drugs such as cyclophosphamide and doxorubicin.²²

Q7. What is the time limit for use of cryopreserved oocytes/tissue?

A: Under optimal storage conditions, cryopreserved oocytes/tissue can be utilized indefinitely without a negative effect on pregnancy outcomes.
 

Q8. What does the future hold for fertility preservation?

A: The future holds promise for both the medical and nonmedical (planned) utility of fertility preservation. With the former, we will see that the utility of OTC and orthotopic and heterotopic tissue transplantation increase as success rates improve. Improved neovascularizing agents will make the transplants last longer and enhance pregnancy outcomes.^23,24 I see planned fertility preservation increasing, based on the experience gained from cancer patients and some preliminary experience with planned OTC, especially for healthy women who wish to consider delaying menopause.^25,26

Because of attrition from apoptosis, approximately 2,000 oocytes are wasted per ovulation. Through calculation models, we predict that if an equivalent of one-third of a woman’s ovarian cortex can be cryopreserved (which may not significantly affect the age at natural menopause) before age 40 years, transplantation at perimenopause may provide sufficient primordial follicles to delay menopause for 5 years or longer.²⁶ Because ovarian tissue can also be transplanted subcutaneously under local anesthesia, as we have shown,^27,28 repeated heterotopic transplants can be performed in an office setting at reduced cost, invasiveness, and with enhanced effectiveness. We can expect increasing reports and progress on this planned use of OTC and transplantation in the future. 
 

Dr. Oktay is professor of obstetrics & gynecology and reproductive sciences and director of the Laboratory of Molecular Reproduction and Fertility Preservation at Yale University, New Haven, Conn. Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

References

1. Lurie S. Eur J Obstet Gynecol Reprod Biol. 1992 Jan 9;43(1):1-7.

2. Oktay K and Karlikaya G. N Engl J Med. 2000 Jun 22;342(25):1919.

3. Sonmezer and Oktay K. Hum Reprod Update. 2004;10(3):251-66.

4. Oktay K et al. J Clin Oncol. 2018 Jul 1;36(19):1994-2001.

5. Goldfarb SB et al. Breast Cancer Res Treat. 2021;185:165-73.

6. Titus S et al. Sci Rep. 2021 Jan 11;11(1):407.

7. Soleimani R et al. Aging (Albany NY). 2011 Aug;3(8):782-93.

8. Titus S et al. Sci Transl Med. 2013 Feb 13;5(172):172ra21.

9. Oktay KH et al. Fertil Steril. 2022 Jan 5:S0015-0282(21)02293-7.

10. Oktay K et al. Fertil Steril. 2022;117(1):181-92.

11. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2019;112(6):1022–33.

12. Cil A et al. Fertil Steril. 2013 Aug;100(2):492-9.e3.

13. Goldman KN et al. Fertil Steril. 2013 Sep;100(3):712-7.

14. Marin L and Oktay K. Scientific history of ovarian tissue cryopreservation and transplantation. In: Oktay K (ed.), Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier;2022:1-10.

15. Oktay K et al. J Clin Oncol. 2005 Jul 1;23(19):4347-53.

16. Kim JY et al. J Clin Endocrinol Metab. 2016 Apr;101(4):1364-71.

17. Turan V et al. J Clin Oncol. 2021;39:18.

18. Oktay K et al. J Clin Oncol. 2010 Jan 10;28(2):240-4.

19. Lin W et al. J Clin Endocrinol Metab. 2017;102(10):3839-47.

20. Turan V et al. Reprod Sci. 2018;(25):26-32.

21. Oktay K et al. Presence of BRCA mutations and a pre-chemotherapy AMH level of < 2ng/mL strongly predict risk of amenorrhea in women with breast cancer P-291. Presented at the American Society for Reproductive Medicine 78th annual meeting, Anaheim, Calif. Oct. 22-26, 2022.

22. Oktay KH et al. Fertil Steril. 2020;113(6):1251‐60.e1.

23. Soleimani R et al. PLoS One. 2011 Apr 29;6(4):e19475.

24. Marin L et al. Future aspects of ovarian cryopreservation and transplantation. In: Oktay K (ed.). Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier; 2022;223-30.

25. Oktay KH et al. Trends Mol Med. 2021;27(8):753-61.

26. Oktay K and Marin L. Ovarian tissue cryopreservation for delaying childbearing and menopause. In: Oktay, K. (Ed.), Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier;2022:195-204.

27. Oktay K et al. JAMA. 2001 Sep 26;286(12):1490-3.

28. Oktay K et al. Lancet. 2004 Mar 13;363(9412):837-40.

From the first obscure reference until the 19th century, the maternal mortality rate from an ectopic pregnancy was nearly 100%. In the past 140 years, because of early detection and prompt surgical management, the mortality rate from an ectopic pregnancy declined from 72%-90% in 1880 to 0.48% from 2004 to 2008.¹ Given this remarkable reduction in mortality, the 20th-century approach to ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing conservative treatment with methotrexate and/or tubal surgery.

Why the reference to ectopic pregnancy? Advances in oncology have comparably affected our approach to cancer patients. The increase in survival rates following a cancer diagnosis has fostered revolutionary developments in fertility preservation to obviate the effect of gonadotoxic therapy. We have evolved from shielding and transposing ovaries to ovarian tissue cryopreservation^2,3 with rapid implementation.

One of the leaders in the field of female fertility preservation is Kutluk Oktay, MD, of Yale University, New Haven, Conn. I posed the following salient questions to him on the state of fertility preservation as well as expectations for the future.

Q1. What medication/treatment is gonadotoxic that warrants a consultation for fertility preservation?

A: While new drugs for cancer treatment continue to be approved and require testing for gonadotoxicity, evidence is clear on the damaging effects of alkylating agents such as cyclophosphamide, ifosfamide, chlorambucil, and melphalan on primordial follicle reserve.⁴ A useful tool to determine the risk of alkylating agents affecting fertility is the Cyclophosphamide Equivalent Dose (CED) Calculator. Likewise, topoisomerase inhibitors, such as doxorubicin⁴ induce ovarian reserve damage by causing double-strand DNA breaks (DSBs) in oocytes.^5-7 Contrary to common belief, chemotherapy exposure suppresses the mechanisms that can initiate follicle growth.⁶ When DSBs occur, some oocytes may be able to repair such damage, otherwise apoptosis is triggered, which results in irreversible ovarian reserve loss.⁷ Younger individuals have much higher repair capacity, the magnitude of damage can be hard to predict, and it is variable.^8,9 So, prior exposure to gonadotoxic drugs does not preclude consideration of fertility preservation.¹⁰

In addition, pelvic radiation, in a dose-dependent manner, causes severe DSBs and triggers the same cell suicide mechanisms while also potentially damaging uterine function. Additional information can be found in the American Society of Clinical Oncology Fertility Preservation Guidelines.⁴
 

Q2. What are the current options for fertility preservation in patients who will be exposed to gonadotoxic medication/treatment?

A: The current fertility preservation options for female patients faced with gonadotoxic treatments are embryo, oocyte, and ovarian tissue cryopreservation (OTC). Selection of fertility preservation is typically contingent upon the timetable of treatment. Oocyte and embryo cryopreservation have been the standard of care. Recently, OTC had its experimental designation removed by American Society for Reproductive Medicine¹¹ with the advantage of not requiring ovarian stimulation or sexual maturity; and it may to be performed while patients are receiving chemotherapy. If successful, OTC followed by orthotopic transplantation has the potential to restore natural ovarian function, thereby allowing spontaneous conception.¹⁰ Especially in young adults, ovarian reserve loss is fractional and can remain at reasonable levels after a few courses of chemotherapy. Ovarian stimulation is risky after the initiation of chemotherapy because of the severe DNA damage to oocytes of developing follicles and the associated poor response.⁷ Hence, ovarian stimulation should be initiated and completed before the initiation of chemotherapy.

Q3. How successful are the approved fertility preservation options in obtaining oocytes for future utilization by ART?

A: We have decades of experience with embryo cryopreservation and proven success rates that patients can check on the SART.org website for individual clinics. For oocyte cryopreservation, models are used to provide calculation estimates because the technique is less established.¹² Although success rates are approaching those with fresh oocytes, they are still not equal.¹³ OTC followed by orthotopic tissue transplantation has the least outcomes data (approximately 200 reported livebirths to date with a 25% live birth rate per recipient worldwide¹⁰ since the first success was reported in 2000.^2,14

With our robotic surgical approach to orthotopic and heterotopic ovarian tissue transplantation and the utility of neovascularizing agents, we have found that ovarian graft longevity is extended. Oocytes/embryos can be obtained and has resulted in one to two livebirths in all our recipients to date.¹⁰ Unfortunately, if any of the critical steps are not up to standards (freezing, thawing, or transplantation), success rates can dramatically decline. Therefore, providers and patients should seek centers with experience in all three stages of this procedure to maximize outcomes.
 

Q4. Are there concerns of increasing recurrence/mortality with fertility preservation given hormonal exposure?

A: Yes, this concern exists, at least in theory for estrogen-sensitive cancers, most commonly breast cancer. We developed ovarian stimulation protocols supplemented with anti-estrogen treatments (tamoxifen, an estrogen-receptor antagonist, and letrozole, an aromatase inhibitor) that appear equally effective and reduce estrogen exposure in any susceptible cancer.^15,16 Even in estrogen receptor–negative tumors, high estrogen exposure may activate non–estrogen receptor–dependent pathways. In addition, even those tumors that are practically deemed estrogen receptor negative may still contain a small percentage of estrogen receptors, which may become active at high estrogen levels.

Therefore, when we approach women with estrogen-sensitive cancers, e.g., breast and endometrial, we do not alter our approach based on receptor status. One exception occurs in women with BRCA mutations, especially the BRCA1, as they have 25% lower serum anti-müllerian hormone (AMH) levels,^8,17 yield fewer oocytes in response to ovarian stimulation,^18,19 and have lower fertilization rates and embryo numbers²⁰ compared with those without the mutations.
 

Q5. Are all reproductive centers capable of offering fertility preservation? If not, how does a patient find a center?

A: All IVF clinics offer embryo and, presumably, oocyte cryopreservation. Pregnancy outcomes vary based on the center’s experience. Globally, major differences exist in the availability and competency of OTC along with the subsequent transplantation approach. A limited number of centers have competency in all aspects of OTC, i.e., cryopreservation, thawing, and transplantation. In general, fertility preservation patients have a multitude of medical issues that necessitate management expertise and the bandwidth to coordinate with cancer health professionals. The reproductive centers offering fertility preservation should be prepared to respond immediately and accommodate patients about to undergo gonadotoxic treatment.
 

Q6. How should a patient be counseled before proceeding with fertility preservation?

A: The candidate should be counseled on the likelihood of damage from gonadotoxic therapy and all fertility preservation options, on the basis of the urgency of treatment and the woman’s long-term goals. For example, the desire for a large family may compel a patient to undergo multiple cycles of ovarian stimulation or a combination of oocyte/embryo cryopreservation with OTC. In patients who are undergoing embryo cryopreservation, I recommend preimplantation genetic testing for aneuploidies, although there are limitations to its application. Other novel pieces of information we are using in counseling are baseline AMH levels and BRCA mutation status for women with breast cancer. In an 8-year-long NIH-funded prospective longitudinal study we found that women with both baseline AMH < 2 ng/mL and BRCA mutations are at significantly higher risk of losing their ovarian reserve and developing amenorrhea.²¹ Because the oocytes of women with BRCA mutations are deficient in DNA repair as we have previously shown,¹⁹ they are more liable to death upon exposure to DNA-damaging cancer drugs such as cyclophosphamide and doxorubicin.²²

Q7. What is the time limit for use of cryopreserved oocytes/tissue?

A: Under optimal storage conditions, cryopreserved oocytes/tissue can be utilized indefinitely without a negative effect on pregnancy outcomes.
 

Q8. What does the future hold for fertility preservation?

A: The future holds promise for both the medical and nonmedical (planned) utility of fertility preservation. With the former, we will see that the utility of OTC and orthotopic and heterotopic tissue transplantation increase as success rates improve. Improved neovascularizing agents will make the transplants last longer and enhance pregnancy outcomes.^23,24 I see planned fertility preservation increasing, based on the experience gained from cancer patients and some preliminary experience with planned OTC, especially for healthy women who wish to consider delaying menopause.^25,26

Because of attrition from apoptosis, approximately 2,000 oocytes are wasted per ovulation. Through calculation models, we predict that if an equivalent of one-third of a woman’s ovarian cortex can be cryopreserved (which may not significantly affect the age at natural menopause) before age 40 years, transplantation at perimenopause may provide sufficient primordial follicles to delay menopause for 5 years or longer.²⁶ Because ovarian tissue can also be transplanted subcutaneously under local anesthesia, as we have shown,^27,28 repeated heterotopic transplants can be performed in an office setting at reduced cost, invasiveness, and with enhanced effectiveness. We can expect increasing reports and progress on this planned use of OTC and transplantation in the future. 
 

Dr. Oktay is professor of obstetrics & gynecology and reproductive sciences and director of the Laboratory of Molecular Reproduction and Fertility Preservation at Yale University, New Haven, Conn. Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

References

1. Lurie S. Eur J Obstet Gynecol Reprod Biol. 1992 Jan 9;43(1):1-7.

2. Oktay K and Karlikaya G. N Engl J Med. 2000 Jun 22;342(25):1919.

3. Sonmezer and Oktay K. Hum Reprod Update. 2004;10(3):251-66.

4. Oktay K et al. J Clin Oncol. 2018 Jul 1;36(19):1994-2001.

5. Goldfarb SB et al. Breast Cancer Res Treat. 2021;185:165-73.

6. Titus S et al. Sci Rep. 2021 Jan 11;11(1):407.

7. Soleimani R et al. Aging (Albany NY). 2011 Aug;3(8):782-93.

8. Titus S et al. Sci Transl Med. 2013 Feb 13;5(172):172ra21.

9. Oktay KH et al. Fertil Steril. 2022 Jan 5:S0015-0282(21)02293-7.

10. Oktay K et al. Fertil Steril. 2022;117(1):181-92.

11. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2019;112(6):1022–33.

12. Cil A et al. Fertil Steril. 2013 Aug;100(2):492-9.e3.

13. Goldman KN et al. Fertil Steril. 2013 Sep;100(3):712-7.

14. Marin L and Oktay K. Scientific history of ovarian tissue cryopreservation and transplantation. In: Oktay K (ed.), Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier;2022:1-10.

15. Oktay K et al. J Clin Oncol. 2005 Jul 1;23(19):4347-53.

16. Kim JY et al. J Clin Endocrinol Metab. 2016 Apr;101(4):1364-71.

17. Turan V et al. J Clin Oncol. 2021;39:18.

18. Oktay K et al. J Clin Oncol. 2010 Jan 10;28(2):240-4.

19. Lin W et al. J Clin Endocrinol Metab. 2017;102(10):3839-47.

20. Turan V et al. Reprod Sci. 2018;(25):26-32.

21. Oktay K et al. Presence of BRCA mutations and a pre-chemotherapy AMH level of < 2ng/mL strongly predict risk of amenorrhea in women with breast cancer P-291. Presented at the American Society for Reproductive Medicine 78th annual meeting, Anaheim, Calif. Oct. 22-26, 2022.

22. Oktay KH et al. Fertil Steril. 2020;113(6):1251‐60.e1.

23. Soleimani R et al. PLoS One. 2011 Apr 29;6(4):e19475.

24. Marin L et al. Future aspects of ovarian cryopreservation and transplantation. In: Oktay K (ed.). Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier; 2022;223-30.

25. Oktay KH et al. Trends Mol Med. 2021;27(8):753-61.

26. Oktay K and Marin L. Ovarian tissue cryopreservation for delaying childbearing and menopause. In: Oktay, K. (Ed.), Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier;2022:195-204.

27. Oktay K et al. JAMA. 2001 Sep 26;286(12):1490-3.

28. Oktay K et al. Lancet. 2004 Mar 13;363(9412):837-40.

From the first obscure reference until the 19th century, the maternal mortality rate from an ectopic pregnancy was nearly 100%. In the past 140 years, because of early detection and prompt surgical management, the mortality rate from an ectopic pregnancy declined from 72%-90% in 1880 to 0.48% from 2004 to 2008.¹ Given this remarkable reduction in mortality, the 20th-century approach to ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing conservative treatment with methotrexate and/or tubal surgery.

Why the reference to ectopic pregnancy? Advances in oncology have comparably affected our approach to cancer patients. The increase in survival rates following a cancer diagnosis has fostered revolutionary developments in fertility preservation to obviate the effect of gonadotoxic therapy. We have evolved from shielding and transposing ovaries to ovarian tissue cryopreservation^2,3 with rapid implementation.

One of the leaders in the field of female fertility preservation is Kutluk Oktay, MD, of Yale University, New Haven, Conn. I posed the following salient questions to him on the state of fertility preservation as well as expectations for the future.

Q1. What medication/treatment is gonadotoxic that warrants a consultation for fertility preservation?

A: While new drugs for cancer treatment continue to be approved and require testing for gonadotoxicity, evidence is clear on the damaging effects of alkylating agents such as cyclophosphamide, ifosfamide, chlorambucil, and melphalan on primordial follicle reserve.⁴ A useful tool to determine the risk of alkylating agents affecting fertility is the Cyclophosphamide Equivalent Dose (CED) Calculator. Likewise, topoisomerase inhibitors, such as doxorubicin⁴ induce ovarian reserve damage by causing double-strand DNA breaks (DSBs) in oocytes.^5-7 Contrary to common belief, chemotherapy exposure suppresses the mechanisms that can initiate follicle growth.⁶ When DSBs occur, some oocytes may be able to repair such damage, otherwise apoptosis is triggered, which results in irreversible ovarian reserve loss.⁷ Younger individuals have much higher repair capacity, the magnitude of damage can be hard to predict, and it is variable.^8,9 So, prior exposure to gonadotoxic drugs does not preclude consideration of fertility preservation.¹⁰

In addition, pelvic radiation, in a dose-dependent manner, causes severe DSBs and triggers the same cell suicide mechanisms while also potentially damaging uterine function. Additional information can be found in the American Society of Clinical Oncology Fertility Preservation Guidelines.⁴
 

Q2. What are the current options for fertility preservation in patients who will be exposed to gonadotoxic medication/treatment?

A: The current fertility preservation options for female patients faced with gonadotoxic treatments are embryo, oocyte, and ovarian tissue cryopreservation (OTC). Selection of fertility preservation is typically contingent upon the timetable of treatment. Oocyte and embryo cryopreservation have been the standard of care. Recently, OTC had its experimental designation removed by American Society for Reproductive Medicine¹¹ with the advantage of not requiring ovarian stimulation or sexual maturity; and it may to be performed while patients are receiving chemotherapy. If successful, OTC followed by orthotopic transplantation has the potential to restore natural ovarian function, thereby allowing spontaneous conception.¹⁰ Especially in young adults, ovarian reserve loss is fractional and can remain at reasonable levels after a few courses of chemotherapy. Ovarian stimulation is risky after the initiation of chemotherapy because of the severe DNA damage to oocytes of developing follicles and the associated poor response.⁷ Hence, ovarian stimulation should be initiated and completed before the initiation of chemotherapy.

Q3. How successful are the approved fertility preservation options in obtaining oocytes for future utilization by ART?

A: We have decades of experience with embryo cryopreservation and proven success rates that patients can check on the SART.org website for individual clinics. For oocyte cryopreservation, models are used to provide calculation estimates because the technique is less established.¹² Although success rates are approaching those with fresh oocytes, they are still not equal.¹³ OTC followed by orthotopic tissue transplantation has the least outcomes data (approximately 200 reported livebirths to date with a 25% live birth rate per recipient worldwide¹⁰ since the first success was reported in 2000.^2,14

With our robotic surgical approach to orthotopic and heterotopic ovarian tissue transplantation and the utility of neovascularizing agents, we have found that ovarian graft longevity is extended. Oocytes/embryos can be obtained and has resulted in one to two livebirths in all our recipients to date.¹⁰ Unfortunately, if any of the critical steps are not up to standards (freezing, thawing, or transplantation), success rates can dramatically decline. Therefore, providers and patients should seek centers with experience in all three stages of this procedure to maximize outcomes.
 

Q4. Are there concerns of increasing recurrence/mortality with fertility preservation given hormonal exposure?

A: Yes, this concern exists, at least in theory for estrogen-sensitive cancers, most commonly breast cancer. We developed ovarian stimulation protocols supplemented with anti-estrogen treatments (tamoxifen, an estrogen-receptor antagonist, and letrozole, an aromatase inhibitor) that appear equally effective and reduce estrogen exposure in any susceptible cancer.^15,16 Even in estrogen receptor–negative tumors, high estrogen exposure may activate non–estrogen receptor–dependent pathways. In addition, even those tumors that are practically deemed estrogen receptor negative may still contain a small percentage of estrogen receptors, which may become active at high estrogen levels.

Therefore, when we approach women with estrogen-sensitive cancers, e.g., breast and endometrial, we do not alter our approach based on receptor status. One exception occurs in women with BRCA mutations, especially the BRCA1, as they have 25% lower serum anti-müllerian hormone (AMH) levels,^8,17 yield fewer oocytes in response to ovarian stimulation,^18,19 and have lower fertilization rates and embryo numbers²⁰ compared with those without the mutations.
 

Q5. Are all reproductive centers capable of offering fertility preservation? If not, how does a patient find a center?

A: All IVF clinics offer embryo and, presumably, oocyte cryopreservation. Pregnancy outcomes vary based on the center’s experience. Globally, major differences exist in the availability and competency of OTC along with the subsequent transplantation approach. A limited number of centers have competency in all aspects of OTC, i.e., cryopreservation, thawing, and transplantation. In general, fertility preservation patients have a multitude of medical issues that necessitate management expertise and the bandwidth to coordinate with cancer health professionals. The reproductive centers offering fertility preservation should be prepared to respond immediately and accommodate patients about to undergo gonadotoxic treatment.
 

Q6. How should a patient be counseled before proceeding with fertility preservation?

A: The candidate should be counseled on the likelihood of damage from gonadotoxic therapy and all fertility preservation options, on the basis of the urgency of treatment and the woman’s long-term goals. For example, the desire for a large family may compel a patient to undergo multiple cycles of ovarian stimulation or a combination of oocyte/embryo cryopreservation with OTC. In patients who are undergoing embryo cryopreservation, I recommend preimplantation genetic testing for aneuploidies, although there are limitations to its application. Other novel pieces of information we are using in counseling are baseline AMH levels and BRCA mutation status for women with breast cancer. In an 8-year-long NIH-funded prospective longitudinal study we found that women with both baseline AMH < 2 ng/mL and BRCA mutations are at significantly higher risk of losing their ovarian reserve and developing amenorrhea.²¹ Because the oocytes of women with BRCA mutations are deficient in DNA repair as we have previously shown,¹⁹ they are more liable to death upon exposure to DNA-damaging cancer drugs such as cyclophosphamide and doxorubicin.²²

Q7. What is the time limit for use of cryopreserved oocytes/tissue?

A: Under optimal storage conditions, cryopreserved oocytes/tissue can be utilized indefinitely without a negative effect on pregnancy outcomes.
 

Q8. What does the future hold for fertility preservation?

A: The future holds promise for both the medical and nonmedical (planned) utility of fertility preservation. With the former, we will see that the utility of OTC and orthotopic and heterotopic tissue transplantation increase as success rates improve. Improved neovascularizing agents will make the transplants last longer and enhance pregnancy outcomes.^23,24 I see planned fertility preservation increasing, based on the experience gained from cancer patients and some preliminary experience with planned OTC, especially for healthy women who wish to consider delaying menopause.^25,26

Because of attrition from apoptosis, approximately 2,000 oocytes are wasted per ovulation. Through calculation models, we predict that if an equivalent of one-third of a woman’s ovarian cortex can be cryopreserved (which may not significantly affect the age at natural menopause) before age 40 years, transplantation at perimenopause may provide sufficient primordial follicles to delay menopause for 5 years or longer.²⁶ Because ovarian tissue can also be transplanted subcutaneously under local anesthesia, as we have shown,^27,28 repeated heterotopic transplants can be performed in an office setting at reduced cost, invasiveness, and with enhanced effectiveness. We can expect increasing reports and progress on this planned use of OTC and transplantation in the future. 
 

Dr. Oktay is professor of obstetrics & gynecology and reproductive sciences and director of the Laboratory of Molecular Reproduction and Fertility Preservation at Yale University, New Haven, Conn. Dr. Trolice is director of The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando.

References

1. Lurie S. Eur J Obstet Gynecol Reprod Biol. 1992 Jan 9;43(1):1-7.

2. Oktay K and Karlikaya G. N Engl J Med. 2000 Jun 22;342(25):1919.

3. Sonmezer and Oktay K. Hum Reprod Update. 2004;10(3):251-66.

4. Oktay K et al. J Clin Oncol. 2018 Jul 1;36(19):1994-2001.

5. Goldfarb SB et al. Breast Cancer Res Treat. 2021;185:165-73.

6. Titus S et al. Sci Rep. 2021 Jan 11;11(1):407.

7. Soleimani R et al. Aging (Albany NY). 2011 Aug;3(8):782-93.

8. Titus S et al. Sci Transl Med. 2013 Feb 13;5(172):172ra21.

9. Oktay KH et al. Fertil Steril. 2022 Jan 5:S0015-0282(21)02293-7.

10. Oktay K et al. Fertil Steril. 2022;117(1):181-92.

11. Practice Committee of the American Society for Reproductive Medicine. Fertil Steril. 2019;112(6):1022–33.

12. Cil A et al. Fertil Steril. 2013 Aug;100(2):492-9.e3.

13. Goldman KN et al. Fertil Steril. 2013 Sep;100(3):712-7.

14. Marin L and Oktay K. Scientific history of ovarian tissue cryopreservation and transplantation. In: Oktay K (ed.), Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier;2022:1-10.

15. Oktay K et al. J Clin Oncol. 2005 Jul 1;23(19):4347-53.

16. Kim JY et al. J Clin Endocrinol Metab. 2016 Apr;101(4):1364-71.

17. Turan V et al. J Clin Oncol. 2021;39:18.

18. Oktay K et al. J Clin Oncol. 2010 Jan 10;28(2):240-4.

19. Lin W et al. J Clin Endocrinol Metab. 2017;102(10):3839-47.

20. Turan V et al. Reprod Sci. 2018;(25):26-32.

21. Oktay K et al. Presence of BRCA mutations and a pre-chemotherapy AMH level of < 2ng/mL strongly predict risk of amenorrhea in women with breast cancer P-291. Presented at the American Society for Reproductive Medicine 78th annual meeting, Anaheim, Calif. Oct. 22-26, 2022.

22. Oktay KH et al. Fertil Steril. 2020;113(6):1251‐60.e1.

23. Soleimani R et al. PLoS One. 2011 Apr 29;6(4):e19475.

24. Marin L et al. Future aspects of ovarian cryopreservation and transplantation. In: Oktay K (ed.). Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier; 2022;223-30.

25. Oktay KH et al. Trends Mol Med. 2021;27(8):753-61.

26. Oktay K and Marin L. Ovarian tissue cryopreservation for delaying childbearing and menopause. In: Oktay, K. (Ed.), Principles and Practice of Ovarian Tissue Cryopreservation and Transplantation. Elsevier;2022:195-204.

27. Oktay K et al. JAMA. 2001 Sep 26;286(12):1490-3.

28. Oktay K et al. Lancet. 2004 Mar 13;363(9412):837-40.

Systemic mastocytosis is widely underdiagnosed, and many more hematologic oncologists should be looking for it. This call to action was issued late in 2022 by Stanford (Calif.) Cancer Institute’s Jason Gotlib, MD, speaking at the Lymphoma, Leukemia & Myeloma Congress in New York.

Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.

More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.

Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.

“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”

Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).

In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.

ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.

The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”

Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.

“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.

A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.

The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.

Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.

Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”

Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.

Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.

As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.

How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.

This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.

Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).

Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.

As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.

“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.

“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.

Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.

Systemic mastocytosis is widely underdiagnosed, and many more hematologic oncologists should be looking for it. This call to action was issued late in 2022 by Stanford (Calif.) Cancer Institute’s Jason Gotlib, MD, speaking at the Lymphoma, Leukemia & Myeloma Congress in New York.

Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.

More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.

Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.

“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”

Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).

In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.

ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.

The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”

Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.

“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.

A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.

The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.

Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.

Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”

Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.

Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.

As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.

How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.

This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.

Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).

Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.

As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.

“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.

“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.

Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.

Systemic mastocytosis is widely underdiagnosed, and many more hematologic oncologists should be looking for it. This call to action was issued late in 2022 by Stanford (Calif.) Cancer Institute’s Jason Gotlib, MD, speaking at the Lymphoma, Leukemia & Myeloma Congress in New York.

Nationwide, approximately 1,000 adults are diagnosed with systemic mastocytosis annually. This rare disease is a myeloid neoplasm with a highly variable phenotypic expression, in which abnormal mast cells proliferate and infiltrate organs and tissues. It swings widely from a nonadvanced form, composed of indolent or smoldering disease, to advanced disease that progresses to leukemia in 6% of cases.

More than 80% of systemic mastocytosis is driven by the KIT D816V mutation. Along with a host of other rare KIT mutations, KIT D816V activates KIT-receptor tyrosine kinase to trigger mast cell proliferation.

Dr. Gotlib could not be contacted for an interview. However, there are many good reasons to identify patients with systemic mastocytosis, according to Attilio Orazi, MD, professor and chair of the department of pathology at Texas Tech University, El Paso. The chief reason is that the patient may be in grave peril.

“The degree of heterogeneity is amazing. ... There’s very indolent [disease], which is really not a big deal. And then you have a disease in which you’re dead in 3 months,” Dr. Orazi said. “So you run the gamut between an indolent, no-problem cutaneous disease to a very nasty systemic, aggressive leukemia-like neoplasm.”

Since 2001, the diagnosis of mastocytosis has been guided by the World Health Organization Classification of Tumours, or “Blue Book.” In 2022, Dr. Orazi along with 137 other senior experts, most of whom were involved in past editions of the Blue Book, published their own version: The International Consensus Classification of Myeloid Neoplasms and Acute Leukemias (the ICC 2022).

In September 2021, this group of specialists held a virtual/in-person advisory committee meeting at the University of Chicago to create the document. One factor in their decision to go it alone, Dr. Orazi said, was that WHO decided to proceed with the fifth edition of the Blue Book using its own internal editorial group without convening an advisory committee, despite repeated requests to do so.

ICC 2022 divides advanced systemic mastocytosis into three subtypes: aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Median survival is 3.5 years for patients with ASM, 2 years for those with SM-AHN and as low as 2 months for MCL.

The second key reason to increase awareness of mastocytosis among physicians, said Dr. Orazi, is that patients falling through the net are likely to be ambulatory, and their presentation can be “a little confusing.”

Patients with indolent disease are relatively straightforward to recognize, explained Dr. Orazi. Similarly, very sick patients with SM-AHN or MCL are easily recognized by hem-oncs.

“But if you see a patient in an ambulatory setting, in your clinic or whatever, and you’re suspicious, then you need to decide [how] you’re going to investigate that patient further,” he said, Dr. Orazi noted the next step is not always obvious, especially for primary-practice or internal medicine physicians likely to be unfamiliar with such a rare disease.

A practice survey published in 2022 by other researchers backed up Dr. Orazi’s remarks. The study found that community/solo-practice physicians were less likely to have tested systemic mastocytosis patients for KIT816V mutation than academic/specialty physicians (58% vs. 80%; P = .004; n = 111). Clinicians treating these patients estimated that it took an average of 8.5 months for a “typical” patient to receive the diagnosis from the time of symptom onset.

The research was headed by Ruben Mesa, MD, director of University of Texas Health, San Antonio, and funded by Blueprint Medicines, the manufacturer of avapritinib (Ayvakit), a new drug for the disease.

Dr. Orazi urged clinicians to have a high degree of suspicion for mastocytosis in a patient who walks into the clinic with any combination of the following: urticarial-type skin manifestations, especially if persistent into adulthood; history of undue reaction to an insect sting; a big spleen in a patient with a history of cutaneous flushing or rash; chronic diarrhea, especially if a biopsy has shown “too many mast cells” in the lamina propria of the small bowel; and positivity for KIT816V mutation.

Dr. Orazi stressed that the majority of patients will have indolent disease, but for the few patients for whom immediate treatment is essential, “the distinction between indolent and aggressive [disease] is really very, very important.”

Patients with advanced systemic mastocytosis can now be effectively treated, following the arrival of midostaurin (Rydapt, Tauritmo) and avapritinib.

Midostaurin, a multikinase/KIT inhibitor, was approved by the Food and Drug Administration in 2017 for the treatment of advanced systemic mastocytosis (ASM, SM-AHN, and MCL). Avapritinib, a selective kinase inhibitor of KIT816V and platelet-derived growth factor receptor alpha as well as multiple KIT exon 11, 11/17 and 17 mutants, gained the same indication in June 2021.

As with all rare diseases, it is challenging to obtain accurate numbers on how many patients are affected by systemic mastocytosis. The first population-based study of the disorder, presented at the 2018 annual meeting of the American Society of Hematology, used the Surveillance, Epidemiology, and End Results database from 2000 to 2014 to estimate incidence at 0.046 per 10,000, which translates to 1,050 new adult cases per year. The study data have never been published in full.

How many of these cases are advanced disease? There are no U.S. data but extrapolating from a Danish registry study that found 82% of systemic mastocytosis cases to be indolent disease, the incidence of advanced systemic mastocytosis in the United States could be as low as 200 adults a year.

This information, in turn, suggests that identifying more patients with advanced disease would not only benefit those patients but would also benefit clinical trial investigators who are seeking the proverbial needle in the haystack.

Nationwide, five clinical trials are recruiting individuals with advanced systemic mastocytosis, collectively looking for 352 patients in the United States. Two of the studies focus on mast-cell activation (NCT0544944) and cutaneous mastocytoses (NCT04846348). Two trials in a range of hematological malignancies are testing bispecific antibodies flotetuzumab and MGD024 (both from Macrogenics; NCT04681105, NCT05362773).

Apex, a phase 2 study of tyrosine-kinase inhibitor bezuclastinib (a Cogent hopeful), is specifically focusing on advanced disease. Dr. Gotlib and coinvestigators are aiming for 140 participants.

As a pathologist, Dr. Orazi said he find mastocytosis fascinating because he believes he has “a truly useful role,” contrasting with some other hematological diseases in which the molecular profile rules.

“Pathology plays a major role here,” he explained, “because you have to correlate what you see at the microscope with the full clinical picture, selected laboratory tests such as CBC and serum tryptase, and molecular results. You often need integration through a pathologist to put all the pieces together.

“It’s easier to treat once you know exactly what disease you’re dealing with and whether it is an aggressive or indolent subtype,” Dr. Orazi concluded.

Dr. Orazi disclosed no conflicts of interest. Dr. Gotlib has disclosed ties with Blueprint Medicines, Deciphera, Incyte, and Kartos Therapeutics, and has led committees for Blueprint Medicine’s EXPLORER and PATHFINDER studies, Deciphera’s Study Steering Committee for ripretinib in AdvSM, and the Central Response Review Committee for the phase 2 study of bezuclastinib in AdvSM.

PCSK9 inhibitors may best be known for their powerful LDL-lowering effects but are less appreciated as anti-inflammatory agents with potential beyond cardiovascular health.

In a small pilot trial, for example, patients hospitalized with severe COVID-19 who received a single injection of PCSK9 inhibitor became less sick and more likely to survive than those given a placebo. Their 30-day risk of death or intubation fell significantly, as did their levels of the inflammatory cytokine interleukin 6 (IL-6).

Indeed, survival gains in the PCSK9-inhibitor group were greatest among patients with higher baseline concentrations of IL-6. Although the trial wasn’t powered for clinical outcomes, it suggests the drugs’ efficacy in COVID-19 tracks with intensity of inflammation, proposes a report published  in the Journal of the American College of Cardiology.

Therefore, “PCSK9 inhibition may represent a novel therapeutic pathway in addition to currently recommended therapeutic approaches for severe COVID-19,” conclude the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.
 

PCSK9 inhibitors as anti-inflammatories

Although the study was small and only hypothesis-generating, the fact that outcomes for actively treated patients were proportional to baseline IL-6 levels “strongly suggests that PCSK9 inhibition can directly modulate inflammation in COVID-19,” argues an editorial accompanying the report.

The study adds to “our clinical arsenal against COVID-19,” and likely sheds light on “mechanisms through which PCSK9 inhibition dually modulates lipoprotein metabolism and inflammation,” write Sascha N. Goonewardena, MD, University of Michigan, Ann Arbor, and Robert S. Rosenson, MD, Icahn School of Medicine at Mount Sinai, New York.

The results are consistent with prior evidence that the drugs are anti-inflammatory at least partly because of their interference with inflammatory pathways triggered by PCSK9 and mediated by IL-6, as described by Dr. Navarese and colleagues.

Indeed, they write, PCSK9 inhibitors may improve COVID outcomes mostly through mechanisms unrelated to LDL-receptor expression, “including direct inhibition of PCSK9-triggered inflammation.”

If true, the authors observe, it might explain “why the positive findings of the present study have not been consistently observed in trials involving other lipid-lowering agents, such as statins.” Those drugs are well-known to decrease levels of the inflammatory biomarker C-reactive protein.

In patients with stable coronary disease, in whom inflammation is typically tracked by measuring CRP, “the PCSK9 inhibitors have not been shown to have an anti-inflammatory effect,” Dr. Rosenson further explained.

But the current study’s patients with acute, severe COVID-19, a “profound inflammatory insult” with upregulation of IL-6, were “a good population” for evaluating the drugs’ potential anti-inflammatory effects, Dr. Rosenson said in an interview. The results “are quite enticing but require corroboration in a larger trial.”
 

A single injection

The IMPACT-SIRIO 5 trial entered 60 adults hospitalized with severe COVID-19 and elevated IL-6 at four centers in Poland. Patients with other known active infections were excluded.  

They were randomly assigned double-blind to receive a 140 mg injection of evolocumab (Repatha) or placebo. The 2 groups were similar with respect to demographics, body-mass index, time since symptom onset, and treatments for managing COVID-19 and its complications.

Rates of death or need for intubation at 30 days, the primary endpoint, were 23.3% in the PCSK9-inhibitor group and 53.3% for controls, a risk difference of 30% (95% confidence interval –53.4% to –6.6%). The median durations of oxygen therapy were significantly different at 13 days and 20 days, respectively, the report states.

Serum IL-6 levels fell further over 30 days in the PCSK9-inhibitor group (–56% vs. –21% among controls). A drop by more than 90% was seen in 60% of patients in the PCSK9-inhibitor group and in 27% of controls.

The average hospital stay was shorter for those getting the PCSK9 inhibitor, compared with placebo, 16 days versus 22 days, and their 30-day mortality was numerically lower, 16% versus 33.3%.

Patients’ baseline IL-6 levels above the median, the report states, had a lower mortality on the PCSK9 inhibitor versus placebo (risk difference –37.5%; 95% CI –68.2% to –6.70%).

A larger trial to corroborate these results would potentially enter similar patients hospitalized with COVID-19 with reproducible evidence of an ongoing cytokine storm, such as elevated levels of IL-6, who would be assigned to either a PCSK9 inhibitor or placebo, Dr. Rosenson proposed.

Although the current primary endpoint that combines mortality and intubation was “reasonable” for a small pilot trial, he said, if the researchers embark on a larger study, “they’ll want to look at those events separately.”

Dr. Navarese discloses receiving speaker and consultancy fees from Amgen, Sanofi-Regeneron, Bayer; and grants from Abbott. Disclosures for the other authors are in the report. Rosenson discloses receiving research funding to his institution from Amgen, Arrowhead, Eli Lilly, Novartis, and Regeneron; consulting fees from Amgen, Arrowhead, CRISPR Therapeutics, Eli Lilly, Lipigon, Novartis, Precision Biosciences, Regeneron, Ultragenyx, and Verve; speaking fees from Amgen, Kowa, and Regeneron; and royalties from Wolters Kluwer; and owning stock in MediMergent. Dr. Goonewardena reports no relevant financial relationships.

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

PCSK9 inhibitors may best be known for their powerful LDL-lowering effects but are less appreciated as anti-inflammatory agents with potential beyond cardiovascular health.

In a small pilot trial, for example, patients hospitalized with severe COVID-19 who received a single injection of PCSK9 inhibitor became less sick and more likely to survive than those given a placebo. Their 30-day risk of death or intubation fell significantly, as did their levels of the inflammatory cytokine interleukin 6 (IL-6).

Indeed, survival gains in the PCSK9-inhibitor group were greatest among patients with higher baseline concentrations of IL-6. Although the trial wasn’t powered for clinical outcomes, it suggests the drugs’ efficacy in COVID-19 tracks with intensity of inflammation, proposes a report published  in the Journal of the American College of Cardiology.

Therefore, “PCSK9 inhibition may represent a novel therapeutic pathway in addition to currently recommended therapeutic approaches for severe COVID-19,” conclude the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.
 

PCSK9 inhibitors as anti-inflammatories

Although the study was small and only hypothesis-generating, the fact that outcomes for actively treated patients were proportional to baseline IL-6 levels “strongly suggests that PCSK9 inhibition can directly modulate inflammation in COVID-19,” argues an editorial accompanying the report.

The study adds to “our clinical arsenal against COVID-19,” and likely sheds light on “mechanisms through which PCSK9 inhibition dually modulates lipoprotein metabolism and inflammation,” write Sascha N. Goonewardena, MD, University of Michigan, Ann Arbor, and Robert S. Rosenson, MD, Icahn School of Medicine at Mount Sinai, New York.

The results are consistent with prior evidence that the drugs are anti-inflammatory at least partly because of their interference with inflammatory pathways triggered by PCSK9 and mediated by IL-6, as described by Dr. Navarese and colleagues.

Indeed, they write, PCSK9 inhibitors may improve COVID outcomes mostly through mechanisms unrelated to LDL-receptor expression, “including direct inhibition of PCSK9-triggered inflammation.”

If true, the authors observe, it might explain “why the positive findings of the present study have not been consistently observed in trials involving other lipid-lowering agents, such as statins.” Those drugs are well-known to decrease levels of the inflammatory biomarker C-reactive protein.

In patients with stable coronary disease, in whom inflammation is typically tracked by measuring CRP, “the PCSK9 inhibitors have not been shown to have an anti-inflammatory effect,” Dr. Rosenson further explained.

But the current study’s patients with acute, severe COVID-19, a “profound inflammatory insult” with upregulation of IL-6, were “a good population” for evaluating the drugs’ potential anti-inflammatory effects, Dr. Rosenson said in an interview. The results “are quite enticing but require corroboration in a larger trial.”
 

A single injection

The IMPACT-SIRIO 5 trial entered 60 adults hospitalized with severe COVID-19 and elevated IL-6 at four centers in Poland. Patients with other known active infections were excluded.  

They were randomly assigned double-blind to receive a 140 mg injection of evolocumab (Repatha) or placebo. The 2 groups were similar with respect to demographics, body-mass index, time since symptom onset, and treatments for managing COVID-19 and its complications.

Rates of death or need for intubation at 30 days, the primary endpoint, were 23.3% in the PCSK9-inhibitor group and 53.3% for controls, a risk difference of 30% (95% confidence interval –53.4% to –6.6%). The median durations of oxygen therapy were significantly different at 13 days and 20 days, respectively, the report states.

Serum IL-6 levels fell further over 30 days in the PCSK9-inhibitor group (–56% vs. –21% among controls). A drop by more than 90% was seen in 60% of patients in the PCSK9-inhibitor group and in 27% of controls.

The average hospital stay was shorter for those getting the PCSK9 inhibitor, compared with placebo, 16 days versus 22 days, and their 30-day mortality was numerically lower, 16% versus 33.3%.

Patients’ baseline IL-6 levels above the median, the report states, had a lower mortality on the PCSK9 inhibitor versus placebo (risk difference –37.5%; 95% CI –68.2% to –6.70%).

A larger trial to corroborate these results would potentially enter similar patients hospitalized with COVID-19 with reproducible evidence of an ongoing cytokine storm, such as elevated levels of IL-6, who would be assigned to either a PCSK9 inhibitor or placebo, Dr. Rosenson proposed.

Although the current primary endpoint that combines mortality and intubation was “reasonable” for a small pilot trial, he said, if the researchers embark on a larger study, “they’ll want to look at those events separately.”

Dr. Navarese discloses receiving speaker and consultancy fees from Amgen, Sanofi-Regeneron, Bayer; and grants from Abbott. Disclosures for the other authors are in the report. Rosenson discloses receiving research funding to his institution from Amgen, Arrowhead, Eli Lilly, Novartis, and Regeneron; consulting fees from Amgen, Arrowhead, CRISPR Therapeutics, Eli Lilly, Lipigon, Novartis, Precision Biosciences, Regeneron, Ultragenyx, and Verve; speaking fees from Amgen, Kowa, and Regeneron; and royalties from Wolters Kluwer; and owning stock in MediMergent. Dr. Goonewardena reports no relevant financial relationships.

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

PCSK9 inhibitors may best be known for their powerful LDL-lowering effects but are less appreciated as anti-inflammatory agents with potential beyond cardiovascular health.

In a small pilot trial, for example, patients hospitalized with severe COVID-19 who received a single injection of PCSK9 inhibitor became less sick and more likely to survive than those given a placebo. Their 30-day risk of death or intubation fell significantly, as did their levels of the inflammatory cytokine interleukin 6 (IL-6).

Indeed, survival gains in the PCSK9-inhibitor group were greatest among patients with higher baseline concentrations of IL-6. Although the trial wasn’t powered for clinical outcomes, it suggests the drugs’ efficacy in COVID-19 tracks with intensity of inflammation, proposes a report published  in the Journal of the American College of Cardiology.

Therefore, “PCSK9 inhibition may represent a novel therapeutic pathway in addition to currently recommended therapeutic approaches for severe COVID-19,” conclude the authors, led by Eliano P. Navarese, MD, PhD, Nicolaus Copernicus University, Bydgoszcz, Poland.
 

PCSK9 inhibitors as anti-inflammatories

Although the study was small and only hypothesis-generating, the fact that outcomes for actively treated patients were proportional to baseline IL-6 levels “strongly suggests that PCSK9 inhibition can directly modulate inflammation in COVID-19,” argues an editorial accompanying the report.

The study adds to “our clinical arsenal against COVID-19,” and likely sheds light on “mechanisms through which PCSK9 inhibition dually modulates lipoprotein metabolism and inflammation,” write Sascha N. Goonewardena, MD, University of Michigan, Ann Arbor, and Robert S. Rosenson, MD, Icahn School of Medicine at Mount Sinai, New York.

The results are consistent with prior evidence that the drugs are anti-inflammatory at least partly because of their interference with inflammatory pathways triggered by PCSK9 and mediated by IL-6, as described by Dr. Navarese and colleagues.

Indeed, they write, PCSK9 inhibitors may improve COVID outcomes mostly through mechanisms unrelated to LDL-receptor expression, “including direct inhibition of PCSK9-triggered inflammation.”

If true, the authors observe, it might explain “why the positive findings of the present study have not been consistently observed in trials involving other lipid-lowering agents, such as statins.” Those drugs are well-known to decrease levels of the inflammatory biomarker C-reactive protein.

In patients with stable coronary disease, in whom inflammation is typically tracked by measuring CRP, “the PCSK9 inhibitors have not been shown to have an anti-inflammatory effect,” Dr. Rosenson further explained.

But the current study’s patients with acute, severe COVID-19, a “profound inflammatory insult” with upregulation of IL-6, were “a good population” for evaluating the drugs’ potential anti-inflammatory effects, Dr. Rosenson said in an interview. The results “are quite enticing but require corroboration in a larger trial.”
 

A single injection

The IMPACT-SIRIO 5 trial entered 60 adults hospitalized with severe COVID-19 and elevated IL-6 at four centers in Poland. Patients with other known active infections were excluded.  

They were randomly assigned double-blind to receive a 140 mg injection of evolocumab (Repatha) or placebo. The 2 groups were similar with respect to demographics, body-mass index, time since symptom onset, and treatments for managing COVID-19 and its complications.

Rates of death or need for intubation at 30 days, the primary endpoint, were 23.3% in the PCSK9-inhibitor group and 53.3% for controls, a risk difference of 30% (95% confidence interval –53.4% to –6.6%). The median durations of oxygen therapy were significantly different at 13 days and 20 days, respectively, the report states.

Serum IL-6 levels fell further over 30 days in the PCSK9-inhibitor group (–56% vs. –21% among controls). A drop by more than 90% was seen in 60% of patients in the PCSK9-inhibitor group and in 27% of controls.

The average hospital stay was shorter for those getting the PCSK9 inhibitor, compared with placebo, 16 days versus 22 days, and their 30-day mortality was numerically lower, 16% versus 33.3%.

Patients’ baseline IL-6 levels above the median, the report states, had a lower mortality on the PCSK9 inhibitor versus placebo (risk difference –37.5%; 95% CI –68.2% to –6.70%).

A larger trial to corroborate these results would potentially enter similar patients hospitalized with COVID-19 with reproducible evidence of an ongoing cytokine storm, such as elevated levels of IL-6, who would be assigned to either a PCSK9 inhibitor or placebo, Dr. Rosenson proposed.

Although the current primary endpoint that combines mortality and intubation was “reasonable” for a small pilot trial, he said, if the researchers embark on a larger study, “they’ll want to look at those events separately.”

Dr. Navarese discloses receiving speaker and consultancy fees from Amgen, Sanofi-Regeneron, Bayer; and grants from Abbott. Disclosures for the other authors are in the report. Rosenson discloses receiving research funding to his institution from Amgen, Arrowhead, Eli Lilly, Novartis, and Regeneron; consulting fees from Amgen, Arrowhead, CRISPR Therapeutics, Eli Lilly, Lipigon, Novartis, Precision Biosciences, Regeneron, Ultragenyx, and Verve; speaking fees from Amgen, Kowa, and Regeneron; and royalties from Wolters Kluwer; and owning stock in MediMergent. Dr. Goonewardena reports no relevant financial relationships.

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

To the Editor:

Microneedling is a percutaneous collagen induction therapy frequently used in cosmetic dermatology to promote skin rejuvenation and hair growth and to treat scars by taking advantage of the body’s natural wound-healing cascade.¹ The procedure works by generating thousands of microscopic wounds in the dermis with minimal damage to the epidermis, thus initiating the wound-healing cascade and subsequently promoting collagen production in a manner safe for all Fitzpatrick classification skin types.^1-3 This therapy effectively treats scars by breaking down scarred collagen and replacing it with new healthy collagen. Microneedling also has application in drug delivery by increasing the permeability of the skin; the microwounds generated can serve as a portal for drug delivery.⁴

Bimatoprost is a prostaglandin analogue typically used to treat hypotrichosis and open-angle glaucoma.^5-7 A known side effect of bimatoprost is hyperpigmentation of surrounding skin; the drug increases melanogenesis, melanocyte proliferation, and melanocyte dendricity, resulting in activation of the inflammatory response and subsequent prostaglandin release, which stimulates melanogenesis. This effect is similar to UV radiation–induced inflammation and hyperpigmentation.^6,8

Capitalizing on this effect, a novel application of bimatoprost has been proposed—treating vitiligo, in which hypopigmentation results from destruction of melanocytes in certain areas of the skin. Bimatoprost ophthalmic solution 0.3% utilized as an off-label treatment for vitiligo has been shown to notably increase melanogenesis and return pigmentation to hypopigmented areas.^8-10

A 32-year-old Black woman presented to our clinic with a 40×15-cm scar that was marked by postinflammatory hypopigmentation from a second-degree burn on the right proximal arm. The patient had been burned 5 months prior by boiling water that was spilled on the arm while cooking. She had immediately sought treatment at an emergency department and subsequently in a burn unit, where the burn was debrided twice; medication was not prescribed to continue treatment. The patient reported that the scarring and hypopigmentation had taken a psychologic toll; her hope was to have pigmentation restored to the affected area to boost her confidence.

Physical examination revealed that the burn wound had healed but visible scarring and severe hypopigmentation due to destroyed melanocytes remained (Figure 1). To inhibit inflammation and stimulate repigmentation, we prescribed the calcineurin inhibitor tacrolimus ointment 0.1% to be applied daily to the affected area. The patient returned to the clinic 1 month later. Perifollicular hyperpigmentation was noted at the site of the scar.

Monthly microneedling sessions with bimatoprost ophthalmic solution 0.3% were started. To avoid damaging any potentially remaining unhealed hypodermis and vasculature, the first microneedling session was performed with 9 needles set at minimal needle depth and frequency. The number of needles and their depth and frequency gradually were increased with each subsequent treatment. The patient continued tacrolimus ointment 0.1% throughout the course of treatment.

For each microneedling procedure, a handheld motorized microneedling device was applied to the skin at a depth of 0.25 mm, which was gradually increased until pinpoint petechiae were achieved. Bimatoprost ophthalmic solution 0.3% was then painted on the skin and allowed to absorb. Microneedling was performed again, ensuring that bimatoprost entered the skin in the area of the burn scar.

Microneedling procedures were performed monthly for 6 months, then once 3 months later, and once more 3 months later—8 treatments in total over the course of 1 year. Improvement in skin pigmentation was noted at each visit (Figure 2). Repigmentation was first noticed surrounding hair follicles; after later visits, it was observed that pigmentation began to spread from hair follicles to fill in remaining skin. The darkest areas of pigmentation were first noted around hair follicles; over time, melanocytes appeared to spontaneously regenerate and fill in surrounding areas as the scar continued to heal. The patient continued use of tacrolimus during the entire course of microneedling treatments and for the following 4 months. Sixteen months after initiation of treatment, the appearance of the skin was texturally smooth and returned to almost its original pigmentation (Figure 3).

We report a successful outcome in a patient with a hypopigmented burn scar who was treated with bimatoprost administered with traditional microneedling and alongside a tacrolimus regimen. Tacrolimus ointment inhibited the inflammatory response to allow melanocytes to heal and regenerate; bimatoprost and microneedling promoted hyperpigmentation of hair follicles in the affected area, eventually restoring pigmentation to the entire area. Our patient was extremely satisfied with the results of this combination treatment. She has reported feeling more confident going out and wearing short-sleeved clothing. Percutaneous drug delivery of bimatoprost ophthalmic solution 0.3% combined with topical tacrolimus may be an effective treatment for skin repigmentation. Further investigation of this regimen is needed to develop standardized treatment protocols.

To the Editor:

Microneedling is a percutaneous collagen induction therapy frequently used in cosmetic dermatology to promote skin rejuvenation and hair growth and to treat scars by taking advantage of the body’s natural wound-healing cascade.¹ The procedure works by generating thousands of microscopic wounds in the dermis with minimal damage to the epidermis, thus initiating the wound-healing cascade and subsequently promoting collagen production in a manner safe for all Fitzpatrick classification skin types.^1-3 This therapy effectively treats scars by breaking down scarred collagen and replacing it with new healthy collagen. Microneedling also has application in drug delivery by increasing the permeability of the skin; the microwounds generated can serve as a portal for drug delivery.⁴

Bimatoprost is a prostaglandin analogue typically used to treat hypotrichosis and open-angle glaucoma.^5-7 A known side effect of bimatoprost is hyperpigmentation of surrounding skin; the drug increases melanogenesis, melanocyte proliferation, and melanocyte dendricity, resulting in activation of the inflammatory response and subsequent prostaglandin release, which stimulates melanogenesis. This effect is similar to UV radiation–induced inflammation and hyperpigmentation.^6,8

Capitalizing on this effect, a novel application of bimatoprost has been proposed—treating vitiligo, in which hypopigmentation results from destruction of melanocytes in certain areas of the skin. Bimatoprost ophthalmic solution 0.3% utilized as an off-label treatment for vitiligo has been shown to notably increase melanogenesis and return pigmentation to hypopigmented areas.^8-10

A 32-year-old Black woman presented to our clinic with a 40×15-cm scar that was marked by postinflammatory hypopigmentation from a second-degree burn on the right proximal arm. The patient had been burned 5 months prior by boiling water that was spilled on the arm while cooking. She had immediately sought treatment at an emergency department and subsequently in a burn unit, where the burn was debrided twice; medication was not prescribed to continue treatment. The patient reported that the scarring and hypopigmentation had taken a psychologic toll; her hope was to have pigmentation restored to the affected area to boost her confidence.

Physical examination revealed that the burn wound had healed but visible scarring and severe hypopigmentation due to destroyed melanocytes remained (Figure 1). To inhibit inflammation and stimulate repigmentation, we prescribed the calcineurin inhibitor tacrolimus ointment 0.1% to be applied daily to the affected area. The patient returned to the clinic 1 month later. Perifollicular hyperpigmentation was noted at the site of the scar.

Monthly microneedling sessions with bimatoprost ophthalmic solution 0.3% were started. To avoid damaging any potentially remaining unhealed hypodermis and vasculature, the first microneedling session was performed with 9 needles set at minimal needle depth and frequency. The number of needles and their depth and frequency gradually were increased with each subsequent treatment. The patient continued tacrolimus ointment 0.1% throughout the course of treatment.

For each microneedling procedure, a handheld motorized microneedling device was applied to the skin at a depth of 0.25 mm, which was gradually increased until pinpoint petechiae were achieved. Bimatoprost ophthalmic solution 0.3% was then painted on the skin and allowed to absorb. Microneedling was performed again, ensuring that bimatoprost entered the skin in the area of the burn scar.

Microneedling procedures were performed monthly for 6 months, then once 3 months later, and once more 3 months later—8 treatments in total over the course of 1 year. Improvement in skin pigmentation was noted at each visit (Figure 2). Repigmentation was first noticed surrounding hair follicles; after later visits, it was observed that pigmentation began to spread from hair follicles to fill in remaining skin. The darkest areas of pigmentation were first noted around hair follicles; over time, melanocytes appeared to spontaneously regenerate and fill in surrounding areas as the scar continued to heal. The patient continued use of tacrolimus during the entire course of microneedling treatments and for the following 4 months. Sixteen months after initiation of treatment, the appearance of the skin was texturally smooth and returned to almost its original pigmentation (Figure 3).

We report a successful outcome in a patient with a hypopigmented burn scar who was treated with bimatoprost administered with traditional microneedling and alongside a tacrolimus regimen. Tacrolimus ointment inhibited the inflammatory response to allow melanocytes to heal and regenerate; bimatoprost and microneedling promoted hyperpigmentation of hair follicles in the affected area, eventually restoring pigmentation to the entire area. Our patient was extremely satisfied with the results of this combination treatment. She has reported feeling more confident going out and wearing short-sleeved clothing. Percutaneous drug delivery of bimatoprost ophthalmic solution 0.3% combined with topical tacrolimus may be an effective treatment for skin repigmentation. Further investigation of this regimen is needed to develop standardized treatment protocols.

To the Editor:

Microneedling is a percutaneous collagen induction therapy frequently used in cosmetic dermatology to promote skin rejuvenation and hair growth and to treat scars by taking advantage of the body’s natural wound-healing cascade.¹ The procedure works by generating thousands of microscopic wounds in the dermis with minimal damage to the epidermis, thus initiating the wound-healing cascade and subsequently promoting collagen production in a manner safe for all Fitzpatrick classification skin types.^1-3 This therapy effectively treats scars by breaking down scarred collagen and replacing it with new healthy collagen. Microneedling also has application in drug delivery by increasing the permeability of the skin; the microwounds generated can serve as a portal for drug delivery.⁴

Bimatoprost is a prostaglandin analogue typically used to treat hypotrichosis and open-angle glaucoma.^5-7 A known side effect of bimatoprost is hyperpigmentation of surrounding skin; the drug increases melanogenesis, melanocyte proliferation, and melanocyte dendricity, resulting in activation of the inflammatory response and subsequent prostaglandin release, which stimulates melanogenesis. This effect is similar to UV radiation–induced inflammation and hyperpigmentation.^6,8

Capitalizing on this effect, a novel application of bimatoprost has been proposed—treating vitiligo, in which hypopigmentation results from destruction of melanocytes in certain areas of the skin. Bimatoprost ophthalmic solution 0.3% utilized as an off-label treatment for vitiligo has been shown to notably increase melanogenesis and return pigmentation to hypopigmented areas.^8-10

A 32-year-old Black woman presented to our clinic with a 40×15-cm scar that was marked by postinflammatory hypopigmentation from a second-degree burn on the right proximal arm. The patient had been burned 5 months prior by boiling water that was spilled on the arm while cooking. She had immediately sought treatment at an emergency department and subsequently in a burn unit, where the burn was debrided twice; medication was not prescribed to continue treatment. The patient reported that the scarring and hypopigmentation had taken a psychologic toll; her hope was to have pigmentation restored to the affected area to boost her confidence.

Physical examination revealed that the burn wound had healed but visible scarring and severe hypopigmentation due to destroyed melanocytes remained (Figure 1). To inhibit inflammation and stimulate repigmentation, we prescribed the calcineurin inhibitor tacrolimus ointment 0.1% to be applied daily to the affected area. The patient returned to the clinic 1 month later. Perifollicular hyperpigmentation was noted at the site of the scar.

Monthly microneedling sessions with bimatoprost ophthalmic solution 0.3% were started. To avoid damaging any potentially remaining unhealed hypodermis and vasculature, the first microneedling session was performed with 9 needles set at minimal needle depth and frequency. The number of needles and their depth and frequency gradually were increased with each subsequent treatment. The patient continued tacrolimus ointment 0.1% throughout the course of treatment.

For each microneedling procedure, a handheld motorized microneedling device was applied to the skin at a depth of 0.25 mm, which was gradually increased until pinpoint petechiae were achieved. Bimatoprost ophthalmic solution 0.3% was then painted on the skin and allowed to absorb. Microneedling was performed again, ensuring that bimatoprost entered the skin in the area of the burn scar.

Microneedling procedures were performed monthly for 6 months, then once 3 months later, and once more 3 months later—8 treatments in total over the course of 1 year. Improvement in skin pigmentation was noted at each visit (Figure 2). Repigmentation was first noticed surrounding hair follicles; after later visits, it was observed that pigmentation began to spread from hair follicles to fill in remaining skin. The darkest areas of pigmentation were first noted around hair follicles; over time, melanocytes appeared to spontaneously regenerate and fill in surrounding areas as the scar continued to heal. The patient continued use of tacrolimus during the entire course of microneedling treatments and for the following 4 months. Sixteen months after initiation of treatment, the appearance of the skin was texturally smooth and returned to almost its original pigmentation (Figure 3).

We report a successful outcome in a patient with a hypopigmented burn scar who was treated with bimatoprost administered with traditional microneedling and alongside a tacrolimus regimen. Tacrolimus ointment inhibited the inflammatory response to allow melanocytes to heal and regenerate; bimatoprost and microneedling promoted hyperpigmentation of hair follicles in the affected area, eventually restoring pigmentation to the entire area. Our patient was extremely satisfied with the results of this combination treatment. She has reported feeling more confident going out and wearing short-sleeved clothing. Percutaneous drug delivery of bimatoprost ophthalmic solution 0.3% combined with topical tacrolimus may be an effective treatment for skin repigmentation. Further investigation of this regimen is needed to develop standardized treatment protocols.

The American College of Physicians has issued new guidelines for managing acute major depressive disorder, suggesting those with moderate to severe depression may start with cognitive-behavioral therapy (CBT) alone or a second-generation antidepressant (SGA) alone.

The guidelines also state that patients with mild depression should start with CBT alone, and if a patient with moderate to severe depression prefers, they can use a combination of both CBT and an SGA.

These nuanced recommendations contrast sharply with the 2016 ACP guidelines for depression, which lumped all stages and severity levels together, and came with just one recommendation: Clinicians should choose between CBT and an SGA.

More data have come to light over the years, requiring the present update, reported lead author Amir Qaseem, MD, PhD, vice president of Clinical Policy and the Center for Evidence Reviews at the ACP, and adjunct faculty at Thomas Jefferson University, Philadelphia, and colleagues.

In addition to the focus on acute depression, Dr. Qaseem and colleagues highlighted the new guidelines' “consideration of patient values and preferences, and costs,” as well as responses to therapy.

Recommendations were derived from a network meta-analysis that included studies evaluating nonpharmacologic and pharmacologic therapies, the authors wrote in Annals of Internal Medicine. They compared effectiveness across a range of SGAs, “including selective serotonin reuptake inhibitors; serotonin-norepinephrine reuptake inhibitors; and others such as bupropion, mirtazapine, nefazodone, trazodone, vilazodone, and vortioxetine.”

This analysis yielded three pieces of clinical advice.

First, patients in the acute phase of mild depression should receive CBT alone as their initial treatment.

Dr. Qaseem and colleagues noted that many depression studies for pharmacologic therapies excluded these patients in favor of those with moderate to severe depression, leaving an evidence gap.

“Furthermore, the Clinical Guidelines Committee had concerns about adverse effects of SGAs in these patients and suggests that the use of SGAs as initial treatment of these patients should be based on additional considerations, such as limited access to or cost of CBT, history of moderate or severe major depressive disorder, or patient preferences,” they added.

The committee’s next recommendation, based on moderate-certainty evidence, suggested that CBT alone or an SGA alone should be considered for patients in the acute phase of moderate to severe depression. This call for monotherapy is balanced by a conditional recommendation based on low-certainty evidence that the same group may benefit from initial combination therapy with both CBT and an SGA.

“The informed decision on the options of monotherapy with CBT versus SGAs, or combination therapy, should be personalized and based on discussion of potential treatment benefits, harms, adverse effect profiles, cost, feasibility, patients’ specific symptoms (such as insomnia, hypersomnia, or fluctuation in appetite), comorbidities, concomitant medication use, and patient preferences,” the guidelines state.

The third and final recommendation offers an algorithm for patients who do not respond to initial therapy with an SGA. Multiple pathways are provided: Switch to CBT or augment with CBT; or switch to a different SGA or augment with a second pharmacologic therapy, such as mirtazapine, bupropion, or buspirone.

“These second-line treatment strategies show similar efficacy when compared with each other,” the guidelines committee noted.

Again, the guidelines suggest that second-line choices should be personalized based on the various factors previously discussed.

A timely update

“The new guideline is very different from the last guideline,” said Ryan Mire, MD, president of the ACP and practicing internal medicine physician in Nashville, Tenn. in a written comment. “ACP decided to update the depression guidelines with a focus on acute depression because approximately 70% of patients with major depressive disorder do not achieve remission and remain in the acute phase after the initial pharmacologic treatment attempt. In addition, there is new evidence on second-line treatments since the 2016 ACP guideline was published.”

Neil S. Skolnik, MD, of Thomas Jefferson University, Philadelphia, agreed that the guidelines offer a necessary and fresh perspective on caring for patients with depression.

“These guidelines are a helpful update, assuring us that we are using the latest, evidence-based therapies, and [they] are written in a practical, easy-to-implement manner,” Dr. Skolnik said in a written comment.

“First, the guidelines reaffirm that CBT is an effective first-line option, with or without the concurrent use of an SGA,” Dr. Skolnik said, noting that CBT alone may reduce likelihood of recurrence, compared with an SGA alone. “Many patients do not like the idea of medication, or the potential side effects of medications, and CBT is an evidenced-based approach that can be very helpful for patients.”

Dr. Skolnik also applauded the guidelines authors for offering a clear path forward for patients who do not have full remission after treatment – a common clinical scenario.

Valuable despite the gaps

Other experts expressed mixed impressions of the update, noting both highs and lows.

“Although [this guideline] has some gaps, it is more valuable in several ways than other widely consulted practice guidelines for depression,” wrote Miriam Shuchman, MD and Elia Abi-Jaoude, MSc, MD, PhD, of the University of Toronto, in an accompanying editorial.

Specifically, they praised the publication’s focus on shared decision-making in the treatment planning process.

“This effort to respond to patient preferences is crucial and may even increase the chance that patients will improve with treatment,” they wrote.

They also applauded the ACP’s efforts to recuse any committee members who may have had conflicts of interest “that could affect their judgment about treatments for depression.”

After highlighting these attributes, Dr. Shuchman and Dr. Abi-Jaoude noted that the guidelines still contain “significant gaps.”

Foremost, they pointed out the guidelines' emphasis on CBT to the exclusion of other nonpharmacologic options.

“The guideline does patients a disservice by leaving out several nonmedication treatment options that clinicians can offer as first- or second-line therapies,” they wrote.

This oversight may increase risk that patients simply hop from one SGA to another, which is a common, and often ineffective, strategy, according to Dr. Shuchman and Dr. Abi-Jaoude.

“Patients often go from one drug to the next in the hopes of landing on one that ‘works,’ ” the editorialists wrote. “This narrow clinical approach of pursuing medication-based treatments ignores the ways difficulties in a person’s work or relationships may contribute to their struggles with depression. At a time when the COVID-19 pandemic has underscored the importance of the social context of mental health, clinicians may need to consider other forms of support and tailor prescribing to what is most relevant and accessible for a particular patient.”

Dr. Shuchman and Dr. Abi-Jaoude went on to suggest several nonpharmacologic options beyond CBT, including interpersonal therapy, psychodynamic therapy, problem solving, behavioral activation, and guided self-help.

The other key gap they pointed out relates to withdrawal.

Although the guideline does advise physicians to taper antidepressants to reduce risk of withdrawal, the editorialists suggested that this recommendation lacked sufficient emphasis, as it can be a particularly difficult period in the treatment process.

“Tapering of an antidepressant may need to be done over months or years, not weeks, and a patient may need to visit a compounding pharmacy to obtain doses of a second-generation antidepressant not marketed by drug manufacturers so that prescriptions can be tapered even more slowly,” they suggested.

Financial costs remain unclear

Beyond the above medical considerations, one other piece of the depression puzzle remains unsolved: cost.

In a simultaneously published rapid review, Andreea Dobrescu, MD, PhD, of Cochrane Austria, and colleagues evaluated the relative cost-effectiveness of first- and second-step treatment strategies.

For most comparisons, evidence was insufficient to reach a conclusion, although they suggested that CBT may be more cost effective at the 5-year mark.

“For most pharmacologic and nonpharmacologic interventions for major depressive disorder, evidence was missing or was insufficient to draw conclusions about the cost-effectiveness of first- or second-step treatments for MDD,” Dr. Dobrescu and colleagues wrote. “The strongest evidence (albeit still low certainty of evidence) was for the cost-effectiveness of CBT compared with SGA as a first-step treatment over a 5-year time horizon from the societal and health care sector perspectives. However, this evidence should also be interpreted cautiously considering it is based on a single study.”

When asked about the financial findings, Dr. Mire agreed that more data are needed, especially because CBT and SGA costs range widely. He suggested that cost, for each patient, should be considered in the personalized approach now highlighted by the new guidelines.

The guidelines and the Cochrane cost-effectiveness study were supported by the ACP. The guidelines' authors and other individuals quoted in this article reported no conflicts of interest.

The American College of Physicians has issued new guidelines for managing acute major depressive disorder, suggesting those with moderate to severe depression may start with cognitive-behavioral therapy (CBT) alone or a second-generation antidepressant (SGA) alone.

The guidelines also state that patients with mild depression should start with CBT alone, and if a patient with moderate to severe depression prefers, they can use a combination of both CBT and an SGA.

These nuanced recommendations contrast sharply with the 2016 ACP guidelines for depression, which lumped all stages and severity levels together, and came with just one recommendation: Clinicians should choose between CBT and an SGA.

More data have come to light over the years, requiring the present update, reported lead author Amir Qaseem, MD, PhD, vice president of Clinical Policy and the Center for Evidence Reviews at the ACP, and adjunct faculty at Thomas Jefferson University, Philadelphia, and colleagues.

In addition to the focus on acute depression, Dr. Qaseem and colleagues highlighted the new guidelines' “consideration of patient values and preferences, and costs,” as well as responses to therapy.

Recommendations were derived from a network meta-analysis that included studies evaluating nonpharmacologic and pharmacologic therapies, the authors wrote in Annals of Internal Medicine. They compared effectiveness across a range of SGAs, “including selective serotonin reuptake inhibitors; serotonin-norepinephrine reuptake inhibitors; and others such as bupropion, mirtazapine, nefazodone, trazodone, vilazodone, and vortioxetine.”

This analysis yielded three pieces of clinical advice.

First, patients in the acute phase of mild depression should receive CBT alone as their initial treatment.

Dr. Qaseem and colleagues noted that many depression studies for pharmacologic therapies excluded these patients in favor of those with moderate to severe depression, leaving an evidence gap.

“Furthermore, the Clinical Guidelines Committee had concerns about adverse effects of SGAs in these patients and suggests that the use of SGAs as initial treatment of these patients should be based on additional considerations, such as limited access to or cost of CBT, history of moderate or severe major depressive disorder, or patient preferences,” they added.

The committee’s next recommendation, based on moderate-certainty evidence, suggested that CBT alone or an SGA alone should be considered for patients in the acute phase of moderate to severe depression. This call for monotherapy is balanced by a conditional recommendation based on low-certainty evidence that the same group may benefit from initial combination therapy with both CBT and an SGA.

“The informed decision on the options of monotherapy with CBT versus SGAs, or combination therapy, should be personalized and based on discussion of potential treatment benefits, harms, adverse effect profiles, cost, feasibility, patients’ specific symptoms (such as insomnia, hypersomnia, or fluctuation in appetite), comorbidities, concomitant medication use, and patient preferences,” the guidelines state.

The third and final recommendation offers an algorithm for patients who do not respond to initial therapy with an SGA. Multiple pathways are provided: Switch to CBT or augment with CBT; or switch to a different SGA or augment with a second pharmacologic therapy, such as mirtazapine, bupropion, or buspirone.

“These second-line treatment strategies show similar efficacy when compared with each other,” the guidelines committee noted.

Again, the guidelines suggest that second-line choices should be personalized based on the various factors previously discussed.

A timely update

“The new guideline is very different from the last guideline,” said Ryan Mire, MD, president of the ACP and practicing internal medicine physician in Nashville, Tenn. in a written comment. “ACP decided to update the depression guidelines with a focus on acute depression because approximately 70% of patients with major depressive disorder do not achieve remission and remain in the acute phase after the initial pharmacologic treatment attempt. In addition, there is new evidence on second-line treatments since the 2016 ACP guideline was published.”

Neil S. Skolnik, MD, of Thomas Jefferson University, Philadelphia, agreed that the guidelines offer a necessary and fresh perspective on caring for patients with depression.

“These guidelines are a helpful update, assuring us that we are using the latest, evidence-based therapies, and [they] are written in a practical, easy-to-implement manner,” Dr. Skolnik said in a written comment.

“First, the guidelines reaffirm that CBT is an effective first-line option, with or without the concurrent use of an SGA,” Dr. Skolnik said, noting that CBT alone may reduce likelihood of recurrence, compared with an SGA alone. “Many patients do not like the idea of medication, or the potential side effects of medications, and CBT is an evidenced-based approach that can be very helpful for patients.”

Dr. Skolnik also applauded the guidelines authors for offering a clear path forward for patients who do not have full remission after treatment – a common clinical scenario.

Valuable despite the gaps

Other experts expressed mixed impressions of the update, noting both highs and lows.

“Although [this guideline] has some gaps, it is more valuable in several ways than other widely consulted practice guidelines for depression,” wrote Miriam Shuchman, MD and Elia Abi-Jaoude, MSc, MD, PhD, of the University of Toronto, in an accompanying editorial.

Specifically, they praised the publication’s focus on shared decision-making in the treatment planning process.

“This effort to respond to patient preferences is crucial and may even increase the chance that patients will improve with treatment,” they wrote.

They also applauded the ACP’s efforts to recuse any committee members who may have had conflicts of interest “that could affect their judgment about treatments for depression.”

After highlighting these attributes, Dr. Shuchman and Dr. Abi-Jaoude noted that the guidelines still contain “significant gaps.”

Foremost, they pointed out the guidelines' emphasis on CBT to the exclusion of other nonpharmacologic options.

“The guideline does patients a disservice by leaving out several nonmedication treatment options that clinicians can offer as first- or second-line therapies,” they wrote.

This oversight may increase risk that patients simply hop from one SGA to another, which is a common, and often ineffective, strategy, according to Dr. Shuchman and Dr. Abi-Jaoude.

“Patients often go from one drug to the next in the hopes of landing on one that ‘works,’ ” the editorialists wrote. “This narrow clinical approach of pursuing medication-based treatments ignores the ways difficulties in a person’s work or relationships may contribute to their struggles with depression. At a time when the COVID-19 pandemic has underscored the importance of the social context of mental health, clinicians may need to consider other forms of support and tailor prescribing to what is most relevant and accessible for a particular patient.”

Dr. Shuchman and Dr. Abi-Jaoude went on to suggest several nonpharmacologic options beyond CBT, including interpersonal therapy, psychodynamic therapy, problem solving, behavioral activation, and guided self-help.

The other key gap they pointed out relates to withdrawal.

Although the guideline does advise physicians to taper antidepressants to reduce risk of withdrawal, the editorialists suggested that this recommendation lacked sufficient emphasis, as it can be a particularly difficult period in the treatment process.

“Tapering of an antidepressant may need to be done over months or years, not weeks, and a patient may need to visit a compounding pharmacy to obtain doses of a second-generation antidepressant not marketed by drug manufacturers so that prescriptions can be tapered even more slowly,” they suggested.

Financial costs remain unclear

Beyond the above medical considerations, one other piece of the depression puzzle remains unsolved: cost.

In a simultaneously published rapid review, Andreea Dobrescu, MD, PhD, of Cochrane Austria, and colleagues evaluated the relative cost-effectiveness of first- and second-step treatment strategies.

For most comparisons, evidence was insufficient to reach a conclusion, although they suggested that CBT may be more cost effective at the 5-year mark.

“For most pharmacologic and nonpharmacologic interventions for major depressive disorder, evidence was missing or was insufficient to draw conclusions about the cost-effectiveness of first- or second-step treatments for MDD,” Dr. Dobrescu and colleagues wrote. “The strongest evidence (albeit still low certainty of evidence) was for the cost-effectiveness of CBT compared with SGA as a first-step treatment over a 5-year time horizon from the societal and health care sector perspectives. However, this evidence should also be interpreted cautiously considering it is based on a single study.”

When asked about the financial findings, Dr. Mire agreed that more data are needed, especially because CBT and SGA costs range widely. He suggested that cost, for each patient, should be considered in the personalized approach now highlighted by the new guidelines.

The guidelines and the Cochrane cost-effectiveness study were supported by the ACP. The guidelines' authors and other individuals quoted in this article reported no conflicts of interest.

The American College of Physicians has issued new guidelines for managing acute major depressive disorder, suggesting those with moderate to severe depression may start with cognitive-behavioral therapy (CBT) alone or a second-generation antidepressant (SGA) alone.

The guidelines also state that patients with mild depression should start with CBT alone, and if a patient with moderate to severe depression prefers, they can use a combination of both CBT and an SGA.

These nuanced recommendations contrast sharply with the 2016 ACP guidelines for depression, which lumped all stages and severity levels together, and came with just one recommendation: Clinicians should choose between CBT and an SGA.

More data have come to light over the years, requiring the present update, reported lead author Amir Qaseem, MD, PhD, vice president of Clinical Policy and the Center for Evidence Reviews at the ACP, and adjunct faculty at Thomas Jefferson University, Philadelphia, and colleagues.

In addition to the focus on acute depression, Dr. Qaseem and colleagues highlighted the new guidelines' “consideration of patient values and preferences, and costs,” as well as responses to therapy.

Recommendations were derived from a network meta-analysis that included studies evaluating nonpharmacologic and pharmacologic therapies, the authors wrote in Annals of Internal Medicine. They compared effectiveness across a range of SGAs, “including selective serotonin reuptake inhibitors; serotonin-norepinephrine reuptake inhibitors; and others such as bupropion, mirtazapine, nefazodone, trazodone, vilazodone, and vortioxetine.”

This analysis yielded three pieces of clinical advice.

First, patients in the acute phase of mild depression should receive CBT alone as their initial treatment.

Dr. Qaseem and colleagues noted that many depression studies for pharmacologic therapies excluded these patients in favor of those with moderate to severe depression, leaving an evidence gap.

“Furthermore, the Clinical Guidelines Committee had concerns about adverse effects of SGAs in these patients and suggests that the use of SGAs as initial treatment of these patients should be based on additional considerations, such as limited access to or cost of CBT, history of moderate or severe major depressive disorder, or patient preferences,” they added.

The committee’s next recommendation, based on moderate-certainty evidence, suggested that CBT alone or an SGA alone should be considered for patients in the acute phase of moderate to severe depression. This call for monotherapy is balanced by a conditional recommendation based on low-certainty evidence that the same group may benefit from initial combination therapy with both CBT and an SGA.

“The informed decision on the options of monotherapy with CBT versus SGAs, or combination therapy, should be personalized and based on discussion of potential treatment benefits, harms, adverse effect profiles, cost, feasibility, patients’ specific symptoms (such as insomnia, hypersomnia, or fluctuation in appetite), comorbidities, concomitant medication use, and patient preferences,” the guidelines state.

The third and final recommendation offers an algorithm for patients who do not respond to initial therapy with an SGA. Multiple pathways are provided: Switch to CBT or augment with CBT; or switch to a different SGA or augment with a second pharmacologic therapy, such as mirtazapine, bupropion, or buspirone.

“These second-line treatment strategies show similar efficacy when compared with each other,” the guidelines committee noted.

Again, the guidelines suggest that second-line choices should be personalized based on the various factors previously discussed.

A timely update

“The new guideline is very different from the last guideline,” said Ryan Mire, MD, president of the ACP and practicing internal medicine physician in Nashville, Tenn. in a written comment. “ACP decided to update the depression guidelines with a focus on acute depression because approximately 70% of patients with major depressive disorder do not achieve remission and remain in the acute phase after the initial pharmacologic treatment attempt. In addition, there is new evidence on second-line treatments since the 2016 ACP guideline was published.”

Neil S. Skolnik, MD, of Thomas Jefferson University, Philadelphia, agreed that the guidelines offer a necessary and fresh perspective on caring for patients with depression.

“These guidelines are a helpful update, assuring us that we are using the latest, evidence-based therapies, and [they] are written in a practical, easy-to-implement manner,” Dr. Skolnik said in a written comment.

“First, the guidelines reaffirm that CBT is an effective first-line option, with or without the concurrent use of an SGA,” Dr. Skolnik said, noting that CBT alone may reduce likelihood of recurrence, compared with an SGA alone. “Many patients do not like the idea of medication, or the potential side effects of medications, and CBT is an evidenced-based approach that can be very helpful for patients.”

Dr. Skolnik also applauded the guidelines authors for offering a clear path forward for patients who do not have full remission after treatment – a common clinical scenario.

Valuable despite the gaps

Other experts expressed mixed impressions of the update, noting both highs and lows.

“Although [this guideline] has some gaps, it is more valuable in several ways than other widely consulted practice guidelines for depression,” wrote Miriam Shuchman, MD and Elia Abi-Jaoude, MSc, MD, PhD, of the University of Toronto, in an accompanying editorial.

Specifically, they praised the publication’s focus on shared decision-making in the treatment planning process.

“This effort to respond to patient preferences is crucial and may even increase the chance that patients will improve with treatment,” they wrote.

They also applauded the ACP’s efforts to recuse any committee members who may have had conflicts of interest “that could affect their judgment about treatments for depression.”

After highlighting these attributes, Dr. Shuchman and Dr. Abi-Jaoude noted that the guidelines still contain “significant gaps.”

Foremost, they pointed out the guidelines' emphasis on CBT to the exclusion of other nonpharmacologic options.

“The guideline does patients a disservice by leaving out several nonmedication treatment options that clinicians can offer as first- or second-line therapies,” they wrote.

This oversight may increase risk that patients simply hop from one SGA to another, which is a common, and often ineffective, strategy, according to Dr. Shuchman and Dr. Abi-Jaoude.

“Patients often go from one drug to the next in the hopes of landing on one that ‘works,’ ” the editorialists wrote. “This narrow clinical approach of pursuing medication-based treatments ignores the ways difficulties in a person’s work or relationships may contribute to their struggles with depression. At a time when the COVID-19 pandemic has underscored the importance of the social context of mental health, clinicians may need to consider other forms of support and tailor prescribing to what is most relevant and accessible for a particular patient.”

Dr. Shuchman and Dr. Abi-Jaoude went on to suggest several nonpharmacologic options beyond CBT, including interpersonal therapy, psychodynamic therapy, problem solving, behavioral activation, and guided self-help.

The other key gap they pointed out relates to withdrawal.

Although the guideline does advise physicians to taper antidepressants to reduce risk of withdrawal, the editorialists suggested that this recommendation lacked sufficient emphasis, as it can be a particularly difficult period in the treatment process.

“Tapering of an antidepressant may need to be done over months or years, not weeks, and a patient may need to visit a compounding pharmacy to obtain doses of a second-generation antidepressant not marketed by drug manufacturers so that prescriptions can be tapered even more slowly,” they suggested.

Financial costs remain unclear

Beyond the above medical considerations, one other piece of the depression puzzle remains unsolved: cost.

In a simultaneously published rapid review, Andreea Dobrescu, MD, PhD, of Cochrane Austria, and colleagues evaluated the relative cost-effectiveness of first- and second-step treatment strategies.

For most comparisons, evidence was insufficient to reach a conclusion, although they suggested that CBT may be more cost effective at the 5-year mark.

“For most pharmacologic and nonpharmacologic interventions for major depressive disorder, evidence was missing or was insufficient to draw conclusions about the cost-effectiveness of first- or second-step treatments for MDD,” Dr. Dobrescu and colleagues wrote. “The strongest evidence (albeit still low certainty of evidence) was for the cost-effectiveness of CBT compared with SGA as a first-step treatment over a 5-year time horizon from the societal and health care sector perspectives. However, this evidence should also be interpreted cautiously considering it is based on a single study.”

When asked about the financial findings, Dr. Mire agreed that more data are needed, especially because CBT and SGA costs range widely. He suggested that cost, for each patient, should be considered in the personalized approach now highlighted by the new guidelines.

The guidelines and the Cochrane cost-effectiveness study were supported by the ACP. The guidelines' authors and other individuals quoted in this article reported no conflicts of interest.

The U.S. Food and Drug Administration has approved bexagliflozin (Brenzavvy, TheracosBio) for the treatment of adults with type 2 diabetes.
 

Olivier Le Moal/Getty Images

The once-daily 20-mg oral sodium-glucose cotransporter 2 (SGLT2) inhibitor is indicated as an adjunct to diet and exercise to improve glycemic control for those with type 2 diabetes, but not type 1 diabetes. It can be used in adults with an estimated glomerular filtration rate (eGFR) > 30 mL/min per 1.73 m².

Approval was based on results from 23 clinical trials with more than 5,000 participants, including more than 300 patients with stage 3 kidney disease (eGFR < 60 and > 30 mL/min per 1.73 m²).

In the phase 3 studies, bexagliflozin significantly reduced hemoglobin A1c and fasting blood glucose at 24 weeks as monotherapy or as add-on to metformin and other glucose-lowering drugs and combinations. It also produced modest reductions in body weight and systolic blood pressure.

In the phase 3 Bexagliflozin Efficacy and Safety Trial (BEST) cardiovascular outcomes trial, the drug met its efficacy and safety objectives in patients at high cardiovascular risk. Noninferiority was demonstrated for the composite outcome of cardiovascular death, myocardial infarction, stroke, or unstable angina.

“As a class of drugs, SGLT2 inhibitors have shown tremendous benefit in treating adults with type 2 diabetes,” said Mason Freeman, MD, director of the Translational Research Center at Massachusetts General Hospital, Boston, in a press release from TheracosBio.

“Being involved in all of the clinical trials for Brenzavvy, I am greatly impressed with the efficacy of the drug in reducing blood glucose levels and I believe it is an important addition to the SGLT2 inhibitor class of drugs.”

As with other SGLT2 inhibitors, adverse events seen in the trials include ketoacidosis, lower limb amputation, volume depletion, urosepsis, pyelonephritis, Fournier’s gangrene, genital mycotic infections, and hypoglycemia when used with insulin or insulin secretagogues.

Bexagliflozin joins an already crowded field of SGLT2 inhibitors, some of which have been approved for additional cardiovascular and kidney indications.

Of interest, bexagliflozin was approved by the FDA for diabetes in cats in December 2022, as the first oral new animal drug to improve glycemic control in otherwise healthy cats with diabetes not previously treated with insulin.

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

The U.S. Food and Drug Administration has approved bexagliflozin (Brenzavvy, TheracosBio) for the treatment of adults with type 2 diabetes.
 

Olivier Le Moal/Getty Images

The once-daily 20-mg oral sodium-glucose cotransporter 2 (SGLT2) inhibitor is indicated as an adjunct to diet and exercise to improve glycemic control for those with type 2 diabetes, but not type 1 diabetes. It can be used in adults with an estimated glomerular filtration rate (eGFR) > 30 mL/min per 1.73 m².

Approval was based on results from 23 clinical trials with more than 5,000 participants, including more than 300 patients with stage 3 kidney disease (eGFR < 60 and > 30 mL/min per 1.73 m²).

In the phase 3 studies, bexagliflozin significantly reduced hemoglobin A1c and fasting blood glucose at 24 weeks as monotherapy or as add-on to metformin and other glucose-lowering drugs and combinations. It also produced modest reductions in body weight and systolic blood pressure.

In the phase 3 Bexagliflozin Efficacy and Safety Trial (BEST) cardiovascular outcomes trial, the drug met its efficacy and safety objectives in patients at high cardiovascular risk. Noninferiority was demonstrated for the composite outcome of cardiovascular death, myocardial infarction, stroke, or unstable angina.

“As a class of drugs, SGLT2 inhibitors have shown tremendous benefit in treating adults with type 2 diabetes,” said Mason Freeman, MD, director of the Translational Research Center at Massachusetts General Hospital, Boston, in a press release from TheracosBio.

“Being involved in all of the clinical trials for Brenzavvy, I am greatly impressed with the efficacy of the drug in reducing blood glucose levels and I believe it is an important addition to the SGLT2 inhibitor class of drugs.”

As with other SGLT2 inhibitors, adverse events seen in the trials include ketoacidosis, lower limb amputation, volume depletion, urosepsis, pyelonephritis, Fournier’s gangrene, genital mycotic infections, and hypoglycemia when used with insulin or insulin secretagogues.

Bexagliflozin joins an already crowded field of SGLT2 inhibitors, some of which have been approved for additional cardiovascular and kidney indications.

Of interest, bexagliflozin was approved by the FDA for diabetes in cats in December 2022, as the first oral new animal drug to improve glycemic control in otherwise healthy cats with diabetes not previously treated with insulin.

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

The U.S. Food and Drug Administration has approved bexagliflozin (Brenzavvy, TheracosBio) for the treatment of adults with type 2 diabetes.
 

Olivier Le Moal/Getty Images

The once-daily 20-mg oral sodium-glucose cotransporter 2 (SGLT2) inhibitor is indicated as an adjunct to diet and exercise to improve glycemic control for those with type 2 diabetes, but not type 1 diabetes. It can be used in adults with an estimated glomerular filtration rate (eGFR) > 30 mL/min per 1.73 m².

Approval was based on results from 23 clinical trials with more than 5,000 participants, including more than 300 patients with stage 3 kidney disease (eGFR < 60 and > 30 mL/min per 1.73 m²).

In the phase 3 studies, bexagliflozin significantly reduced hemoglobin A1c and fasting blood glucose at 24 weeks as monotherapy or as add-on to metformin and other glucose-lowering drugs and combinations. It also produced modest reductions in body weight and systolic blood pressure.

In the phase 3 Bexagliflozin Efficacy and Safety Trial (BEST) cardiovascular outcomes trial, the drug met its efficacy and safety objectives in patients at high cardiovascular risk. Noninferiority was demonstrated for the composite outcome of cardiovascular death, myocardial infarction, stroke, or unstable angina.

“As a class of drugs, SGLT2 inhibitors have shown tremendous benefit in treating adults with type 2 diabetes,” said Mason Freeman, MD, director of the Translational Research Center at Massachusetts General Hospital, Boston, in a press release from TheracosBio.

“Being involved in all of the clinical trials for Brenzavvy, I am greatly impressed with the efficacy of the drug in reducing blood glucose levels and I believe it is an important addition to the SGLT2 inhibitor class of drugs.”

As with other SGLT2 inhibitors, adverse events seen in the trials include ketoacidosis, lower limb amputation, volume depletion, urosepsis, pyelonephritis, Fournier’s gangrene, genital mycotic infections, and hypoglycemia when used with insulin or insulin secretagogues.

Bexagliflozin joins an already crowded field of SGLT2 inhibitors, some of which have been approved for additional cardiovascular and kidney indications.

Of interest, bexagliflozin was approved by the FDA for diabetes in cats in December 2022, as the first oral new animal drug to improve glycemic control in otherwise healthy cats with diabetes not previously treated with insulin.

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