P. Brittany Vickery, PharmD, BCPS, BCPP

Ms. L, age 53, presents to an inpatient psychiatric unit with depression, difficulty concentrating, fatigue, cognitive blunting, loss of appetite, increased alcohol intake, and recent suicidal ideation. Her symptoms began 3 months ago and gradually worsened. Her medical and psychiatric history is significant for hypertension, fibromyalgia, and chronic pain (back and neck), major depressive disorder (MDD; recurrent, severe), and generalized anxiety disorder (GAD). Ms. L’s current medication regimen includes lisinopril, 40 mg daily; fluoxetine, 60 mg daily; mirtazapine, 30 mg at bedtime; gabapentin, 300 mg twice daily; alprazolam, 0.5 mg twice daily as needed for anxiety; and oral docusate, 100 mg twice daily as needed. Her blood pressure is 124/85 mm Hg, heart rate is 66 beats per minute, and an electrocardiogram is normal. Laboratory workup reveals a potassium level of 4.4 mEq/L, blood urea nitrogen level of 20 mg/dL, serum creatinine level of 0.8 mg/dL, estimated creatinine clearance of 89.6 mL/min, free triiodothyronine (T3) levels of 2.7 pg/mL, thyroid-stimulating hormone (TSH) level of 7.68 mIU/L, free thyroxine (T4) level of 1.3 ng/dL, and blood ethanol level <10 mg/dL. In addition to the symptoms Ms. L initially described, a review of systems reveals word-finding difficulty, cold intolerance, constipation, hair loss, brittle nails, and dry skin.

To target Ms. L’s MDD, GAD, fibromyalgia, and chronic pain, fluoxetine, 60 mg daily is cross titrated beginning on Day 1 to duloxetine, 60 mg twice daily, over 4 days. Mirtazapine is decreased on Day 3 to 7.5 mg at bedtime to target Ms. L’s sleep and appetite. Due to the presence of several symptoms associated with hypothyroidism and a slightly elevated TSH level, on Day 6 we initiate adjunctive levothyroxine, 50 mcg daily each morning to target symptomatic subclinical hypothyroidism, and to potentially augment the other medications prescribed to address Ms. L’s MDD.

Thyroid hormone function is a complex physiological process controlled through the hypothalamic-pituitary-thyroid (HPT) axis. Psychotropic medications can impact thyroid hormone function and contribute to aberrations in thyroid physiology.¹ Because patients with mental illness may require multiple psychotropic medications, it is imperative to understand the potential effects of these agents.

Antidepressants can induce hypothyroidism along multiple points of hormonal synthesis and iodine utilization. Tricyclic antidepressants have been implicated in the development of drug-iodide complexes, thus reducing biologically active iodine.² Tricyclic antidepressants also can bind thyroid peroxidase, an enzyme necessary in the production of T4 and T3, altering hormonal production, resulting in a hypothyroid state.¹ Non-tricyclic antidepressants (ie, selective serotonin reuptake inhibitors [SSRIs] and non-SSRIs [including serotonin-norepinephrine reuptake inhibitors and mirtazapine]) have also been implicated in thyroid dysfunction. Selective serotonin reuptake inhibitors have the propensity to induce hypothyroidism through inhibition of thyroid hormones T4 and T3.^1,3 This inhibition is not always seen with concurrent reductions in TSH levels. Conversely, non-SSRIs can influence thyroid hormone levels with great variation, leading to thyroid hormone levels that are increased, decreased, or unchanged.¹ Patients with a history of thyroid dysfunction should receive close thyroid function monitoring, especially while taking antidepressants.

Antipsychotics have a proclivity to induce hypothyroidism by means similar to antidepressants via hormonal manipulation and immunogenicity. Phenothiazines impact thyroid function through hormonal activation and degradation, and induction of autoimmunity.¹ Autoimmunity may develop by means of antibody production or antigen immunization through the major histocompatibility complex.² Other first-generation antipsychotics (FGAs) (eg, haloperidol and loxapine) are known to antagonize dopamine receptors in the tuberoinfundibular pathway, resulting in increased prolactin levels. Hyperprolactinemia may result in increased TSH levels through HPT axis activation.¹ Additionally, FGAs can induce an immunogenic effect through production of antithyroid antibodies.¹ Similar to FGAs, second-generation antipsychotics (SGAs) can increase TSH levels through hyper­prolactinemia. Further research focused on SGAs is needed to determine how profound this effect may be.

The Table¹ outlines considerations for modifying psychotropic therapy based on the presence of concurrent thyroid dysfunction. Thyroid function should be routinely assessed in patients treated with antipsychotics.

Mood stabilizers are capable of altering thyroid function and inducing a hypothyroid state. Lithium has been implicated in both hypothyroidism and hyperthyroidism due to its inhibition of hormonal secretion, and toxicity to thyroid cells with chronic use, respectively.^1,4 Hypothyroidism can develop shortly after initiating lithium; women tend to have a greater predilection for thyroid dysfunction than men.¹ Carbamazepine (CBZ) can reduce thyroid hormone levels without having a direct effect on TSH or thyroid dysfunction.¹ As with lithium, women tend to be more susceptible to this effect. Valproic acid (VPA) has been shown to either increase, decrease, or have no impact on thyroid hormone levels, with little effect on TSH.¹ When VPA is given in combination with CBZ, significant reductions in thyroid levels with a concurrent increase in TSH can occur.¹ In patients with preexisting thyroid dysfunction, the combination of VPA and CBZ should be used with caution.

Continue to: CASE

 

 

CASE CONTINUED

By Day 8, Ms. L reports less fatigue, clearer thinking, improved concentration, and less pain. She also no longer reports suicidal ideation, and demonstrates improved appetite and mood. She is discharged on Day 9 of her hospitalization.

The treatment team refers Ms. L for outpatient follow-up in 4 weeks, with a goal TSH level <3.0. Unfortunately, the effects of levothyroxine on Ms. L’s TSH level could not be determined during her hospital stay, and she has not returned to the facility since the initial presentation.

Thyroid function and mood

Ms. L’s case illustrates how thyroid function, pain, cognition, and mood may be interconnected. It is important to address all potential underlying comorbidities and establish appropriate outpatient care and follow-up so that patients may experience a more robust recovery. Further, this case highlights the importance of ruling out other potential medical causes of MDD during the initial diagnosis, and during times of recurrence or relapse, especially when a recent stressor, medication changes, or medication nonadherence cannot be identified as potential contributors.

Related Resources

• Cojić M, Cvejanov-Kezunović L. Subclinical hypothyroidism – whether and when to start treatment? Open Access Maced J Med Sci. 2017;5(7):1042-1046.
• Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012;22(12):1200-1235.
• Iosifescu DV. ‘Supercharge’ antidepressants by adding thyroid hormones. Current Psychiatry. 2006;5(7):15-20,25.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Bupropion • Wellbutrin
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Clozapine • Clozaril
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Gabapentin • Neurontin
Haloperidol • Haldol
Levothyroxine • Synthroid
Lisinopril • Prinivil, Zestril
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Mirtazapine • Remeron
Quetiapine • Seroquel
Risperidone • Risperdal
Thioridazine • Mellaril
Valproic acid • Depakote

Ms. L, age 53, presents to an inpatient psychiatric unit with depression, difficulty concentrating, fatigue, cognitive blunting, loss of appetite, increased alcohol intake, and recent suicidal ideation. Her symptoms began 3 months ago and gradually worsened. Her medical and psychiatric history is significant for hypertension, fibromyalgia, and chronic pain (back and neck), major depressive disorder (MDD; recurrent, severe), and generalized anxiety disorder (GAD). Ms. L’s current medication regimen includes lisinopril, 40 mg daily; fluoxetine, 60 mg daily; mirtazapine, 30 mg at bedtime; gabapentin, 300 mg twice daily; alprazolam, 0.5 mg twice daily as needed for anxiety; and oral docusate, 100 mg twice daily as needed. Her blood pressure is 124/85 mm Hg, heart rate is 66 beats per minute, and an electrocardiogram is normal. Laboratory workup reveals a potassium level of 4.4 mEq/L, blood urea nitrogen level of 20 mg/dL, serum creatinine level of 0.8 mg/dL, estimated creatinine clearance of 89.6 mL/min, free triiodothyronine (T3) levels of 2.7 pg/mL, thyroid-stimulating hormone (TSH) level of 7.68 mIU/L, free thyroxine (T4) level of 1.3 ng/dL, and blood ethanol level <10 mg/dL. In addition to the symptoms Ms. L initially described, a review of systems reveals word-finding difficulty, cold intolerance, constipation, hair loss, brittle nails, and dry skin.

To target Ms. L’s MDD, GAD, fibromyalgia, and chronic pain, fluoxetine, 60 mg daily is cross titrated beginning on Day 1 to duloxetine, 60 mg twice daily, over 4 days. Mirtazapine is decreased on Day 3 to 7.5 mg at bedtime to target Ms. L’s sleep and appetite. Due to the presence of several symptoms associated with hypothyroidism and a slightly elevated TSH level, on Day 6 we initiate adjunctive levothyroxine, 50 mcg daily each morning to target symptomatic subclinical hypothyroidism, and to potentially augment the other medications prescribed to address Ms. L’s MDD.

Thyroid hormone function is a complex physiological process controlled through the hypothalamic-pituitary-thyroid (HPT) axis. Psychotropic medications can impact thyroid hormone function and contribute to aberrations in thyroid physiology.¹ Because patients with mental illness may require multiple psychotropic medications, it is imperative to understand the potential effects of these agents.

Antidepressants can induce hypothyroidism along multiple points of hormonal synthesis and iodine utilization. Tricyclic antidepressants have been implicated in the development of drug-iodide complexes, thus reducing biologically active iodine.² Tricyclic antidepressants also can bind thyroid peroxidase, an enzyme necessary in the production of T4 and T3, altering hormonal production, resulting in a hypothyroid state.¹ Non-tricyclic antidepressants (ie, selective serotonin reuptake inhibitors [SSRIs] and non-SSRIs [including serotonin-norepinephrine reuptake inhibitors and mirtazapine]) have also been implicated in thyroid dysfunction. Selective serotonin reuptake inhibitors have the propensity to induce hypothyroidism through inhibition of thyroid hormones T4 and T3.^1,3 This inhibition is not always seen with concurrent reductions in TSH levels. Conversely, non-SSRIs can influence thyroid hormone levels with great variation, leading to thyroid hormone levels that are increased, decreased, or unchanged.¹ Patients with a history of thyroid dysfunction should receive close thyroid function monitoring, especially while taking antidepressants.

Antipsychotics have a proclivity to induce hypothyroidism by means similar to antidepressants via hormonal manipulation and immunogenicity. Phenothiazines impact thyroid function through hormonal activation and degradation, and induction of autoimmunity.¹ Autoimmunity may develop by means of antibody production or antigen immunization through the major histocompatibility complex.² Other first-generation antipsychotics (FGAs) (eg, haloperidol and loxapine) are known to antagonize dopamine receptors in the tuberoinfundibular pathway, resulting in increased prolactin levels. Hyperprolactinemia may result in increased TSH levels through HPT axis activation.¹ Additionally, FGAs can induce an immunogenic effect through production of antithyroid antibodies.¹ Similar to FGAs, second-generation antipsychotics (SGAs) can increase TSH levels through hyper­prolactinemia. Further research focused on SGAs is needed to determine how profound this effect may be.

The Table¹ outlines considerations for modifying psychotropic therapy based on the presence of concurrent thyroid dysfunction. Thyroid function should be routinely assessed in patients treated with antipsychotics.

Mood stabilizers are capable of altering thyroid function and inducing a hypothyroid state. Lithium has been implicated in both hypothyroidism and hyperthyroidism due to its inhibition of hormonal secretion, and toxicity to thyroid cells with chronic use, respectively.^1,4 Hypothyroidism can develop shortly after initiating lithium; women tend to have a greater predilection for thyroid dysfunction than men.¹ Carbamazepine (CBZ) can reduce thyroid hormone levels without having a direct effect on TSH or thyroid dysfunction.¹ As with lithium, women tend to be more susceptible to this effect. Valproic acid (VPA) has been shown to either increase, decrease, or have no impact on thyroid hormone levels, with little effect on TSH.¹ When VPA is given in combination with CBZ, significant reductions in thyroid levels with a concurrent increase in TSH can occur.¹ In patients with preexisting thyroid dysfunction, the combination of VPA and CBZ should be used with caution.

Continue to: CASE

 

 

CASE CONTINUED

By Day 8, Ms. L reports less fatigue, clearer thinking, improved concentration, and less pain. She also no longer reports suicidal ideation, and demonstrates improved appetite and mood. She is discharged on Day 9 of her hospitalization.

The treatment team refers Ms. L for outpatient follow-up in 4 weeks, with a goal TSH level <3.0. Unfortunately, the effects of levothyroxine on Ms. L’s TSH level could not be determined during her hospital stay, and she has not returned to the facility since the initial presentation.

Thyroid function and mood

Ms. L’s case illustrates how thyroid function, pain, cognition, and mood may be interconnected. It is important to address all potential underlying comorbidities and establish appropriate outpatient care and follow-up so that patients may experience a more robust recovery. Further, this case highlights the importance of ruling out other potential medical causes of MDD during the initial diagnosis, and during times of recurrence or relapse, especially when a recent stressor, medication changes, or medication nonadherence cannot be identified as potential contributors.

Related Resources

• Cojić M, Cvejanov-Kezunović L. Subclinical hypothyroidism – whether and when to start treatment? Open Access Maced J Med Sci. 2017;5(7):1042-1046.
• Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012;22(12):1200-1235.
• Iosifescu DV. ‘Supercharge’ antidepressants by adding thyroid hormones. Current Psychiatry. 2006;5(7):15-20,25.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Bupropion • Wellbutrin
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Clozapine • Clozaril
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Gabapentin • Neurontin
Haloperidol • Haldol
Levothyroxine • Synthroid
Lisinopril • Prinivil, Zestril
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Mirtazapine • Remeron
Quetiapine • Seroquel
Risperidone • Risperdal
Thioridazine • Mellaril
Valproic acid • Depakote

Ms. L, age 53, presents to an inpatient psychiatric unit with depression, difficulty concentrating, fatigue, cognitive blunting, loss of appetite, increased alcohol intake, and recent suicidal ideation. Her symptoms began 3 months ago and gradually worsened. Her medical and psychiatric history is significant for hypertension, fibromyalgia, and chronic pain (back and neck), major depressive disorder (MDD; recurrent, severe), and generalized anxiety disorder (GAD). Ms. L’s current medication regimen includes lisinopril, 40 mg daily; fluoxetine, 60 mg daily; mirtazapine, 30 mg at bedtime; gabapentin, 300 mg twice daily; alprazolam, 0.5 mg twice daily as needed for anxiety; and oral docusate, 100 mg twice daily as needed. Her blood pressure is 124/85 mm Hg, heart rate is 66 beats per minute, and an electrocardiogram is normal. Laboratory workup reveals a potassium level of 4.4 mEq/L, blood urea nitrogen level of 20 mg/dL, serum creatinine level of 0.8 mg/dL, estimated creatinine clearance of 89.6 mL/min, free triiodothyronine (T3) levels of 2.7 pg/mL, thyroid-stimulating hormone (TSH) level of 7.68 mIU/L, free thyroxine (T4) level of 1.3 ng/dL, and blood ethanol level <10 mg/dL. In addition to the symptoms Ms. L initially described, a review of systems reveals word-finding difficulty, cold intolerance, constipation, hair loss, brittle nails, and dry skin.

To target Ms. L’s MDD, GAD, fibromyalgia, and chronic pain, fluoxetine, 60 mg daily is cross titrated beginning on Day 1 to duloxetine, 60 mg twice daily, over 4 days. Mirtazapine is decreased on Day 3 to 7.5 mg at bedtime to target Ms. L’s sleep and appetite. Due to the presence of several symptoms associated with hypothyroidism and a slightly elevated TSH level, on Day 6 we initiate adjunctive levothyroxine, 50 mcg daily each morning to target symptomatic subclinical hypothyroidism, and to potentially augment the other medications prescribed to address Ms. L’s MDD.

Thyroid hormone function is a complex physiological process controlled through the hypothalamic-pituitary-thyroid (HPT) axis. Psychotropic medications can impact thyroid hormone function and contribute to aberrations in thyroid physiology.¹ Because patients with mental illness may require multiple psychotropic medications, it is imperative to understand the potential effects of these agents.

Antidepressants can induce hypothyroidism along multiple points of hormonal synthesis and iodine utilization. Tricyclic antidepressants have been implicated in the development of drug-iodide complexes, thus reducing biologically active iodine.² Tricyclic antidepressants also can bind thyroid peroxidase, an enzyme necessary in the production of T4 and T3, altering hormonal production, resulting in a hypothyroid state.¹ Non-tricyclic antidepressants (ie, selective serotonin reuptake inhibitors [SSRIs] and non-SSRIs [including serotonin-norepinephrine reuptake inhibitors and mirtazapine]) have also been implicated in thyroid dysfunction. Selective serotonin reuptake inhibitors have the propensity to induce hypothyroidism through inhibition of thyroid hormones T4 and T3.^1,3 This inhibition is not always seen with concurrent reductions in TSH levels. Conversely, non-SSRIs can influence thyroid hormone levels with great variation, leading to thyroid hormone levels that are increased, decreased, or unchanged.¹ Patients with a history of thyroid dysfunction should receive close thyroid function monitoring, especially while taking antidepressants.

Antipsychotics have a proclivity to induce hypothyroidism by means similar to antidepressants via hormonal manipulation and immunogenicity. Phenothiazines impact thyroid function through hormonal activation and degradation, and induction of autoimmunity.¹ Autoimmunity may develop by means of antibody production or antigen immunization through the major histocompatibility complex.² Other first-generation antipsychotics (FGAs) (eg, haloperidol and loxapine) are known to antagonize dopamine receptors in the tuberoinfundibular pathway, resulting in increased prolactin levels. Hyperprolactinemia may result in increased TSH levels through HPT axis activation.¹ Additionally, FGAs can induce an immunogenic effect through production of antithyroid antibodies.¹ Similar to FGAs, second-generation antipsychotics (SGAs) can increase TSH levels through hyper­prolactinemia. Further research focused on SGAs is needed to determine how profound this effect may be.

The Table¹ outlines considerations for modifying psychotropic therapy based on the presence of concurrent thyroid dysfunction. Thyroid function should be routinely assessed in patients treated with antipsychotics.

Mood stabilizers are capable of altering thyroid function and inducing a hypothyroid state. Lithium has been implicated in both hypothyroidism and hyperthyroidism due to its inhibition of hormonal secretion, and toxicity to thyroid cells with chronic use, respectively.^1,4 Hypothyroidism can develop shortly after initiating lithium; women tend to have a greater predilection for thyroid dysfunction than men.¹ Carbamazepine (CBZ) can reduce thyroid hormone levels without having a direct effect on TSH or thyroid dysfunction.¹ As with lithium, women tend to be more susceptible to this effect. Valproic acid (VPA) has been shown to either increase, decrease, or have no impact on thyroid hormone levels, with little effect on TSH.¹ When VPA is given in combination with CBZ, significant reductions in thyroid levels with a concurrent increase in TSH can occur.¹ In patients with preexisting thyroid dysfunction, the combination of VPA and CBZ should be used with caution.

Continue to: CASE

 

 

CASE CONTINUED

By Day 8, Ms. L reports less fatigue, clearer thinking, improved concentration, and less pain. She also no longer reports suicidal ideation, and demonstrates improved appetite and mood. She is discharged on Day 9 of her hospitalization.

The treatment team refers Ms. L for outpatient follow-up in 4 weeks, with a goal TSH level <3.0. Unfortunately, the effects of levothyroxine on Ms. L’s TSH level could not be determined during her hospital stay, and she has not returned to the facility since the initial presentation.

Thyroid function and mood

Ms. L’s case illustrates how thyroid function, pain, cognition, and mood may be interconnected. It is important to address all potential underlying comorbidities and establish appropriate outpatient care and follow-up so that patients may experience a more robust recovery. Further, this case highlights the importance of ruling out other potential medical causes of MDD during the initial diagnosis, and during times of recurrence or relapse, especially when a recent stressor, medication changes, or medication nonadherence cannot be identified as potential contributors.

Related Resources

• Cojić M, Cvejanov-Kezunović L. Subclinical hypothyroidism – whether and when to start treatment? Open Access Maced J Med Sci. 2017;5(7):1042-1046.
• Garber JR, Cobin RH, Gharib H, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012;22(12):1200-1235.
• Iosifescu DV. ‘Supercharge’ antidepressants by adding thyroid hormones. Current Psychiatry. 2006;5(7):15-20,25.

Drug Brand Names

Alprazolam • Xanax
Aripiprazole • Abilify
Bupropion • Wellbutrin
Carbamazepine • Carbatrol, Tegretol
Chlorpromazine • Thorazine
Clozapine • Clozaril
Duloxetine • Cymbalta
Fluoxetine • Prozac
Fluphenazine • Prolixin
Gabapentin • Neurontin
Haloperidol • Haldol
Levothyroxine • Synthroid
Lisinopril • Prinivil, Zestril
Lithium • Eskalith, Lithobid
Loxapine • Loxitane
Mirtazapine • Remeron
Quetiapine • Seroquel
Risperidone • Risperdal
Thioridazine • Mellaril
Valproic acid • Depakote

CASE Combative and agitated

Ms. P, age 87, presents to the emergency department (ED) with her caregiver, who says Ms. P has new-onset altered mental status, agitation, and combativeness.

Ms. P resides at a long-term care (LTC) facility, where according to the nurses she normally is pleasant, well-oriented, and cooperative. Ms. P’s medical history includes major depressive disorder, generalized anxiety disorder, hypertension, chronic kidney disease (CKD) stage III, peptic ulcer disease, gastroesophageal reflux disease, coronary artery disease with 2 past myocardial infarctions requiring stents, chronic obstructive pulmonary disease, hyperlipidemia, bradycardia requiring a pacemaker, paroxysmal atrial fibrillation, asthma, aortic stenosis, peripheral vascular disease, esophageal stricture requiring dilation, deep vein thrombosis, and migraines.

Mr. P’s medication list includes acetaminophen, 650 mg every 6 hours; ipratropium/albuterol nebulized solution, 3 mL 4 times a day; aspirin, 81 mg/d; atorvastatin, 40 mg/d; calcitonin, 1 spray nasally at bedtime; clopidogrel, 75 mg/d; ezetimibe, 10 mg/d; fluoxetine, 20 mg/d; furosemide, 20 mg/d; isosorbide dinitrate, 120 mg/d; lisinopril, 15 mg/d; risperidone, 0.5 mg/d; magnesium oxide, 800 mg/d; pantoprazole, 40 mg/d; polyethylene glycol, 17 g/d; sotalol, 160 mg/d; olanzapine, 5 mg IM every 6 hours as needed for agitation; and tramadol, 50 mg every 8 hours as needed for headache.

Seven days before coming to the ED, Ms. P was started on ceftriaxone, 1 g/d, for suspected community-acquired pneumonia. At that time, the nursing staff noticed behavioral changes. Soon after, Ms. P began refusing all her medications. Two days before presenting to the ED, Ms. P was started on nitrofurantoin, 200 mg/d, for a suspected urinary tract infection, but it was discontinued because of an allergy.

Her caregiver reports that while at the LTC facility, Ms. P’s behavioral changes worsened. Ms. P claimed to be Jesus Christ and said she was talking to the devil; she chased other residents around the facility and slapped medications away from the nursing staff. According to caregivers, this behavior was out of character.

Shortly after arriving in the ED, Ms. P is admitted to the psychiatric unit.

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The authors’ observations

Delirium is a complex, acute alteration in a patient’s mental status compared with his/her baseline functioning¹ (Table 1²). The onset of delirium is quick, happening within hours to days, with fluctuations in mental function. Patients might present with hyperactive, hypoactive, or mixed delirium.³ Patients with hyperactive delirium often have delusions and hallucinations; these patients might be agitated and could become violent with family and caregivers.³ Patients with hypoactive delirium are less likely to experience hallucinations and more likely to show symptoms of sedation.³ Patients with hypoactive delirium can be difficult to diagnose because it is challenging to interview them and understand what might be the cause of their sedated state. Patients also can exhibit a mixed delirium in which they fluctuate between periods of hyperactivity and hypoactivity.³

Continue to: Suspected delirium...

 

Suspected delirium should be considered a medical emergency because the outcome could be fatal.¹ It is important to uncover and treat the underlying cause(s) of delirium rather than solely administering antipsychotics, which might mask the presenting symptoms. In an older study, Francis and Kapoor⁴ reported that 56% of geriatric patients with delirium had a single definite or probable etiology, while the other 44% had about 2.8 etiologies per patient on average. Delirium risk factors, causes, and factors to consider during patient evaluation are listed in Table 2^1,3,5-7 and Table 3.^1,3,5-7

A synergistic relationship between comorbidities, environment, and medications can induce delirium.⁵ Identifying irreversible and reversible causes is the key to treating delirium. After the cause has been identified, it can be addressed and the patient could return to his/her previous level of functioning. If the delirium is the result of multiple irreversible causes, it could become chronic.

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EVALUATION Cardiac dysfunction

Ms. P undergoes laboratory testing. The results include: white blood cell count, 5.9/µL; hemoglobin, 13.6 g/dL; hematocrit, 42.6%; platelets, 304 × 103/µL; sodium,143 mEq/L; potassium, 3.2 mEq/L; chloride, 96 mEq/L; carbon dioxide, 23 mEq/L; blood glucose, 87 mg/dL; creatinine, 1.2 mg/dL; estimated creatinine clearance (eCrCl) level of 33 mL/min/1.73 m²; calcium, 9.5 mg/dL; albumin, 3.6 g/dL; liver enzymes within normal limits; thyroid-stimulating hormone, 0.78 mIU/L; vitamin B₁₂, 995 pg/mL; folic acid, 16.6 ng/mL; vitamin D, 31 pg/mL; and rapid plasma reagin: nonreactive. Urinalysis is unremarkable, and no culture is performed. Urine drug screening/toxicology is positive for the benzodiazepines that she received in the ED (oral alprazolam 0.25 mg given once and oral lorazepam 0.5 mg given once).

Electrocardiogram (ECG) shows atrial flutter/tachycardia with rapid ventricular response, marked left axis deviation, nonspecific ST- and T-wave abnormality, QT/QTC of 301/387 ms, and ventricular rate 151 beats per minute. A CT scan of the head and brain without contrast shows mild atrophy and chronic white matter changes and no acute intracranial abnormality. A two-view chest radiography shows no acute cardiopulmonary findings. Her temperature is 98.4°F; heart rate is 122 beats per minute; respiratory rate is 20 breaths per minute; blood pressure is 161/98 mm Hg; and oxygen saturation is 86% on room air.

Based on this data, Ms. P’s cardiac condition seems to be worsening, which is thought to be caused by her refusal of furosemide, lisinopril, isosorbide, sotalol, clopidogrel, and aspirin. The treatment team plans to work on compliance to resolve these cardiac issues and places Ms. P on 1:1 observation with a sitter and music in attempt to calm her.

Continue to: The authors' observations

 

 

The authors’ observations

Many factors can contribute to behavioral or cognitive changes in geriatric patients. Often, a major change noted in an older patient can be attributed to new-onset dementia, dementia with behavioral disturbances, delirium, depression, or acute psychosis. These potential causes should be considered and ruled out in a step-by-step progression. Because patients are unreliable historians during acute distress, a complete history from family or caregivers and exhaustive workup is paramount.

TREATMENT Medication adjustments

In an attempt to resolve Ms. P’s disruptive behaviors, her risperidone dosage is changed to 0.5 mg twice daily. Ms. P is encouraged to use the provided oxygen to raise her saturation level.

On hospital Day 3, a loose stool prompts a Clostridium difficile test as a possible source of delirium; however, the results are negative.

On hospital Day 4, Ms. P is confused and irritable overnight, yelling profanities at staff, refusing care, inappropriately disrobing, and having difficulty falling asleep and staying asleep. Risperidone is discontinued because it appears to have had little or no effect on Ms. P’s disruptive behaviors. Olanzapine, 10 mg/d, is initiated with mirtazapine, 7.5 mg/d, to help with mood, appetite, and sleep. Fluoxetine is also discontinued because of a possible interaction with clopidogrel.

On hospital Days 6 to 8, Ms. P remains upset and unable to follow instructions. Melatonin is initiated to improve her sleep cycle. On Day 9, she continues to decline and is cursing at hospital staff; haloperidol is initiated at 5 mg every morning, 10 mg at bedtime, and 5 mg IM as needed for agitation. Her sleep improves with melatonin and mirtazapine. IV hydration also is initiated. Ms. P has a slight improvement in medication compliance. On Day 11, haloperidol is increased to 5 mg in the morning, 5 mg in the afternoon, and 10 mg at bedtime. On Day 12, haloperidol is changed to 7.5 mg twice daily; a slight improvement in Ms. P’s behavior is noted.

Continue to: On hospital Day 13...

 

On hospital Day 13, Ms. P’s behavior declines again. She screams profanities at staff and does not recognize the clinicians who have been providing care to her. The physician initiates valproic acid, 125 mg, 3 times a day, to target Ms. P’s behavioral disturbances. A pharmacist notes that the patient’s sotalol could be contributing to Ms. P’s psychiatric presentation, and that based on her eCrCl level of 33 mL/min/1.73 m², a dosage adjustment or medication change might be warranted.

On Day 14, Ms. P displays erratic behavior and intermittent tachycardia. A cardiac consultation is ordered. A repeat ECG reveals atrial fibrillation with rapid rate and a QT/QTc of 409/432 ms. Ms. P is transferred to the telemetry unit, where the cardiologist discontinues sotalol because the dosage is not properly renally adjusted. Sotalol hydrochloride has been associated with life-threatening ventricular tachycardia.⁸ Diltiazem, 30 mg every 6 hours is initiated to replace sotalol.

By Day 16, the treatment team notes improved cognition and behavior. On Day 17, the cardiologist reports that Ms. P’s atrial fibrillation is controlled. An ECG reveals mild left ventricular hypertrophy, an ejection fraction of 50% to 55%, no stenosis in the mitral or tricuspid valves, no valvular pulmonic stenosis, and moderate aortic sclerosis. Cardiac markers also are evaluated (creatinine phosphokinase: 105 U/L; creatinine kinase–MB fraction: 2.6 ng/mL; troponin: 0.01 ng/mL; pro-B-type natriuretic peptide: 2,073 pg/mL); and myocardial infarction is ruled out.

On Day 19, Ms. P’s diltiazem is consolidated to a controlled-delivery formulation, 180 mg/d, along with the addition of metoprolol, 12.5 mg twice daily. Ms. P is transferred back to the psychiatric unit.

OUTCOME Gradual improvement

On Days 20 to 23, Ms. P shows remarkable progress, and her mental status, cognition, and behavior slowly return to baseline. Haloperidol and valproic acid are tapered and discontinued. Ms. P is observed to be healthy and oriented to person, place, and time.

Continue to: On Day 25...

 

On Day 25, she is discharged from the hospital, and returns to the LTC facility.

The authors’ observations

Ms. P’s delirium was a combination of her older age, non-renally adjusted sotalol, and CKD. At admission, the hospital treatment team first thought that pneumonia or antibiotic use could have caused delirium. However, Ms. P’s condition did not improve after antibiotics were stopped. In addition, several chest radiographs found no evidence of pneumonia. It is important to check for any source of infection because infection is a common source of delirium in older patients.¹ Urine samples revealed no pathogens, a C. difficile test was negative, and the patient’s white blood cell counts remained within normal limits. Physicians began looking elsewhere for potential causes of Ms. P’s delirium.

Ms. P’s vital signs ruled out a temperature irregularity or hypertension as the cause of her delirium. She has a slightly low oxygen saturation when she first presented, but this quickly returned to normal with administration of oxygen, which ruled out hypoxemia. Laboratory results concluded that Ms. P’s glucose levels were within a normal range and she had no electrolyte imbalances. A head CT scan showed slight atrophy of white matter that is consistent with Ms. P’s age. The head CT scan also showed that Ms. P had no acute condition or head trauma.

In terms of organ function, Ms. P was in relatively healthy condition other than paroxysmal atrial fibrillation and CKD. Chronic kidney disease can interrupt the normal pharmacokinetics of medications. Reviewing Ms. P’s medication list, several agents could have induced delirium, including antidepressants, antipsychotics, cardiovascular medications (beta blocker/antiarrhythmic [sotalol]), and opioid analgesics such as tramadol.⁵ Ms. P’s condition did not improve after discontinuing fluoxetine, risperidone, or olanzapine, although haloperidol was started in their place. Ms. P scored an 8 on the Naranjo Adverse Drug Reaction Probability Scale, indicating this event was a probable adverse drug reaction.⁹

Identifying a cause

This was a unique case where sotalol was identified as the culprit for inducing Ms. P’s delirium, because her age and CKD are irreversible. It is important to note that antiarrhythmics can induce arrhythmias when present in high concentrations or administered without appropriate renal dose adjustments. Although Ms. P’s serum levels of sotalol were not evaluated, because of her renal impairment, it is possible that toxic levels of sotalol accumulated and lead to arrhythmias and delirium. Of note, a cardiologist was consulted to safely change Ms. P to a calcium channel blocker so she could undergo cardiac monitoring. With the addition of diltiazem and metoprolol, the patient’s delirium subsided and her arrhythmia was controlled. Once the source of Ms. P’s delirium had been identified, antipsy­chotics were no longer needed.

Continue to: Bottom Line

 

 

Bottom Line

Delirium is a complex disorder that often has multiple causes, both reversible and irreversible. A “process of elimination” approach should be used to accurately identify and manage delirium. If a patient with delirium has little to no response to antipsychotic medications, the underlying cause or causes likely has not yet been addressed, and the evaluation should continue.

Related Resources

• Marcantonio ER. Delirium in hospitalized older adults. N Engl J Med. 2017;377:1456-1466.
• Inouye SK, Westendorp RGJ, Saczynski JS. Delirium in elderly people. Lancet. 2014;383(9920):911-922.

Drug Brand Names

Acyclovir • Zovirax
Alprazolam • Niravam, Xanax
Amantadine • Symmetrel
Amphotericin B • Abelcet
Atorvastatin • Lipitor
Atropine • Atropen
Baclofen • EnovaRX-Baclofen
Benztropine • Cogentin
Bromocriptine • Cycloset
Calcitonin • Miacalcin
Carbamazepine • Tegretol
Carbidopa-levodopa • Duopa
Ceftriaxone • Rocephin
Chlorpromazine • Thorazine
Clonidine • Catapres
Clopidogrel • Plavix
Cyclobenzaprine • Amrix
Digoxin • Lanoxin
Diltiazem • Cardizem
Disulfiram • Antabuse
Ezetimibe • Zetia
Fluoxetine • Prozac
Fluphenazine • Prolixin
Furosemide • Lasix
Haloperidol • Haldol
Ipratropium/albuterol nebulized solution • Combivent Respimat
Isoniazid • Isotamine
Isosorbide nitrate • Dilatrate
Levetiracetam • Keppra
Levodopa • Stalevo
Linezolid • Zyvox
Lisinopril • Zestril
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Magnesium Oxide • Mag-200
Meperidine • Demerol
Methyldopa • Aldomet
Metoprolol • Lopressor
Metronidazole • Flagyl
Mirtazapine • Remeron
Nitrofurantoin • Macrobid
Olanzapine • Zyprexa
Pantoprazole • Protonix
Phenytoin • Dilantin
Pramipexole • Mirapex
Rifampin • Rifadin
Risperidone • Risperdal
Ropinirole • Requip
Sotalol hydrochloride • Betapace AF
Tramadol • Ultram
Trihexyphenidyl • Trihexane
Valproic acid • Depakote

CASE Combative and agitated

Ms. P, age 87, presents to the emergency department (ED) with her caregiver, who says Ms. P has new-onset altered mental status, agitation, and combativeness.

Ms. P resides at a long-term care (LTC) facility, where according to the nurses she normally is pleasant, well-oriented, and cooperative. Ms. P’s medical history includes major depressive disorder, generalized anxiety disorder, hypertension, chronic kidney disease (CKD) stage III, peptic ulcer disease, gastroesophageal reflux disease, coronary artery disease with 2 past myocardial infarctions requiring stents, chronic obstructive pulmonary disease, hyperlipidemia, bradycardia requiring a pacemaker, paroxysmal atrial fibrillation, asthma, aortic stenosis, peripheral vascular disease, esophageal stricture requiring dilation, deep vein thrombosis, and migraines.

Mr. P’s medication list includes acetaminophen, 650 mg every 6 hours; ipratropium/albuterol nebulized solution, 3 mL 4 times a day; aspirin, 81 mg/d; atorvastatin, 40 mg/d; calcitonin, 1 spray nasally at bedtime; clopidogrel, 75 mg/d; ezetimibe, 10 mg/d; fluoxetine, 20 mg/d; furosemide, 20 mg/d; isosorbide dinitrate, 120 mg/d; lisinopril, 15 mg/d; risperidone, 0.5 mg/d; magnesium oxide, 800 mg/d; pantoprazole, 40 mg/d; polyethylene glycol, 17 g/d; sotalol, 160 mg/d; olanzapine, 5 mg IM every 6 hours as needed for agitation; and tramadol, 50 mg every 8 hours as needed for headache.

Seven days before coming to the ED, Ms. P was started on ceftriaxone, 1 g/d, for suspected community-acquired pneumonia. At that time, the nursing staff noticed behavioral changes. Soon after, Ms. P began refusing all her medications. Two days before presenting to the ED, Ms. P was started on nitrofurantoin, 200 mg/d, for a suspected urinary tract infection, but it was discontinued because of an allergy.

Her caregiver reports that while at the LTC facility, Ms. P’s behavioral changes worsened. Ms. P claimed to be Jesus Christ and said she was talking to the devil; she chased other residents around the facility and slapped medications away from the nursing staff. According to caregivers, this behavior was out of character.

Shortly after arriving in the ED, Ms. P is admitted to the psychiatric unit.

[polldaddy:10332748]

The authors’ observations

Delirium is a complex, acute alteration in a patient’s mental status compared with his/her baseline functioning¹ (Table 1²). The onset of delirium is quick, happening within hours to days, with fluctuations in mental function. Patients might present with hyperactive, hypoactive, or mixed delirium.³ Patients with hyperactive delirium often have delusions and hallucinations; these patients might be agitated and could become violent with family and caregivers.³ Patients with hypoactive delirium are less likely to experience hallucinations and more likely to show symptoms of sedation.³ Patients with hypoactive delirium can be difficult to diagnose because it is challenging to interview them and understand what might be the cause of their sedated state. Patients also can exhibit a mixed delirium in which they fluctuate between periods of hyperactivity and hypoactivity.³

Continue to: Suspected delirium...

 

Suspected delirium should be considered a medical emergency because the outcome could be fatal.¹ It is important to uncover and treat the underlying cause(s) of delirium rather than solely administering antipsychotics, which might mask the presenting symptoms. In an older study, Francis and Kapoor⁴ reported that 56% of geriatric patients with delirium had a single definite or probable etiology, while the other 44% had about 2.8 etiologies per patient on average. Delirium risk factors, causes, and factors to consider during patient evaluation are listed in Table 2^1,3,5-7 and Table 3.^1,3,5-7

A synergistic relationship between comorbidities, environment, and medications can induce delirium.⁵ Identifying irreversible and reversible causes is the key to treating delirium. After the cause has been identified, it can be addressed and the patient could return to his/her previous level of functioning. If the delirium is the result of multiple irreversible causes, it could become chronic.

[polldaddy:10332749]

EVALUATION Cardiac dysfunction

Ms. P undergoes laboratory testing. The results include: white blood cell count, 5.9/µL; hemoglobin, 13.6 g/dL; hematocrit, 42.6%; platelets, 304 × 103/µL; sodium,143 mEq/L; potassium, 3.2 mEq/L; chloride, 96 mEq/L; carbon dioxide, 23 mEq/L; blood glucose, 87 mg/dL; creatinine, 1.2 mg/dL; estimated creatinine clearance (eCrCl) level of 33 mL/min/1.73 m²; calcium, 9.5 mg/dL; albumin, 3.6 g/dL; liver enzymes within normal limits; thyroid-stimulating hormone, 0.78 mIU/L; vitamin B₁₂, 995 pg/mL; folic acid, 16.6 ng/mL; vitamin D, 31 pg/mL; and rapid plasma reagin: nonreactive. Urinalysis is unremarkable, and no culture is performed. Urine drug screening/toxicology is positive for the benzodiazepines that she received in the ED (oral alprazolam 0.25 mg given once and oral lorazepam 0.5 mg given once).

Electrocardiogram (ECG) shows atrial flutter/tachycardia with rapid ventricular response, marked left axis deviation, nonspecific ST- and T-wave abnormality, QT/QTC of 301/387 ms, and ventricular rate 151 beats per minute. A CT scan of the head and brain without contrast shows mild atrophy and chronic white matter changes and no acute intracranial abnormality. A two-view chest radiography shows no acute cardiopulmonary findings. Her temperature is 98.4°F; heart rate is 122 beats per minute; respiratory rate is 20 breaths per minute; blood pressure is 161/98 mm Hg; and oxygen saturation is 86% on room air.

Based on this data, Ms. P’s cardiac condition seems to be worsening, which is thought to be caused by her refusal of furosemide, lisinopril, isosorbide, sotalol, clopidogrel, and aspirin. The treatment team plans to work on compliance to resolve these cardiac issues and places Ms. P on 1:1 observation with a sitter and music in attempt to calm her.

Continue to: The authors' observations

 

 

The authors’ observations

Many factors can contribute to behavioral or cognitive changes in geriatric patients. Often, a major change noted in an older patient can be attributed to new-onset dementia, dementia with behavioral disturbances, delirium, depression, or acute psychosis. These potential causes should be considered and ruled out in a step-by-step progression. Because patients are unreliable historians during acute distress, a complete history from family or caregivers and exhaustive workup is paramount.

TREATMENT Medication adjustments

In an attempt to resolve Ms. P’s disruptive behaviors, her risperidone dosage is changed to 0.5 mg twice daily. Ms. P is encouraged to use the provided oxygen to raise her saturation level.

On hospital Day 3, a loose stool prompts a Clostridium difficile test as a possible source of delirium; however, the results are negative.

On hospital Day 4, Ms. P is confused and irritable overnight, yelling profanities at staff, refusing care, inappropriately disrobing, and having difficulty falling asleep and staying asleep. Risperidone is discontinued because it appears to have had little or no effect on Ms. P’s disruptive behaviors. Olanzapine, 10 mg/d, is initiated with mirtazapine, 7.5 mg/d, to help with mood, appetite, and sleep. Fluoxetine is also discontinued because of a possible interaction with clopidogrel.

On hospital Days 6 to 8, Ms. P remains upset and unable to follow instructions. Melatonin is initiated to improve her sleep cycle. On Day 9, she continues to decline and is cursing at hospital staff; haloperidol is initiated at 5 mg every morning, 10 mg at bedtime, and 5 mg IM as needed for agitation. Her sleep improves with melatonin and mirtazapine. IV hydration also is initiated. Ms. P has a slight improvement in medication compliance. On Day 11, haloperidol is increased to 5 mg in the morning, 5 mg in the afternoon, and 10 mg at bedtime. On Day 12, haloperidol is changed to 7.5 mg twice daily; a slight improvement in Ms. P’s behavior is noted.

Continue to: On hospital Day 13...

 

On hospital Day 13, Ms. P’s behavior declines again. She screams profanities at staff and does not recognize the clinicians who have been providing care to her. The physician initiates valproic acid, 125 mg, 3 times a day, to target Ms. P’s behavioral disturbances. A pharmacist notes that the patient’s sotalol could be contributing to Ms. P’s psychiatric presentation, and that based on her eCrCl level of 33 mL/min/1.73 m², a dosage adjustment or medication change might be warranted.

On Day 14, Ms. P displays erratic behavior and intermittent tachycardia. A cardiac consultation is ordered. A repeat ECG reveals atrial fibrillation with rapid rate and a QT/QTc of 409/432 ms. Ms. P is transferred to the telemetry unit, where the cardiologist discontinues sotalol because the dosage is not properly renally adjusted. Sotalol hydrochloride has been associated with life-threatening ventricular tachycardia.⁸ Diltiazem, 30 mg every 6 hours is initiated to replace sotalol.

By Day 16, the treatment team notes improved cognition and behavior. On Day 17, the cardiologist reports that Ms. P’s atrial fibrillation is controlled. An ECG reveals mild left ventricular hypertrophy, an ejection fraction of 50% to 55%, no stenosis in the mitral or tricuspid valves, no valvular pulmonic stenosis, and moderate aortic sclerosis. Cardiac markers also are evaluated (creatinine phosphokinase: 105 U/L; creatinine kinase–MB fraction: 2.6 ng/mL; troponin: 0.01 ng/mL; pro-B-type natriuretic peptide: 2,073 pg/mL); and myocardial infarction is ruled out.

On Day 19, Ms. P’s diltiazem is consolidated to a controlled-delivery formulation, 180 mg/d, along with the addition of metoprolol, 12.5 mg twice daily. Ms. P is transferred back to the psychiatric unit.

OUTCOME Gradual improvement

On Days 20 to 23, Ms. P shows remarkable progress, and her mental status, cognition, and behavior slowly return to baseline. Haloperidol and valproic acid are tapered and discontinued. Ms. P is observed to be healthy and oriented to person, place, and time.

Continue to: On Day 25...

 

On Day 25, she is discharged from the hospital, and returns to the LTC facility.

The authors’ observations

Ms. P’s delirium was a combination of her older age, non-renally adjusted sotalol, and CKD. At admission, the hospital treatment team first thought that pneumonia or antibiotic use could have caused delirium. However, Ms. P’s condition did not improve after antibiotics were stopped. In addition, several chest radiographs found no evidence of pneumonia. It is important to check for any source of infection because infection is a common source of delirium in older patients.¹ Urine samples revealed no pathogens, a C. difficile test was negative, and the patient’s white blood cell counts remained within normal limits. Physicians began looking elsewhere for potential causes of Ms. P’s delirium.

Ms. P’s vital signs ruled out a temperature irregularity or hypertension as the cause of her delirium. She has a slightly low oxygen saturation when she first presented, but this quickly returned to normal with administration of oxygen, which ruled out hypoxemia. Laboratory results concluded that Ms. P’s glucose levels were within a normal range and she had no electrolyte imbalances. A head CT scan showed slight atrophy of white matter that is consistent with Ms. P’s age. The head CT scan also showed that Ms. P had no acute condition or head trauma.

In terms of organ function, Ms. P was in relatively healthy condition other than paroxysmal atrial fibrillation and CKD. Chronic kidney disease can interrupt the normal pharmacokinetics of medications. Reviewing Ms. P’s medication list, several agents could have induced delirium, including antidepressants, antipsychotics, cardiovascular medications (beta blocker/antiarrhythmic [sotalol]), and opioid analgesics such as tramadol.⁵ Ms. P’s condition did not improve after discontinuing fluoxetine, risperidone, or olanzapine, although haloperidol was started in their place. Ms. P scored an 8 on the Naranjo Adverse Drug Reaction Probability Scale, indicating this event was a probable adverse drug reaction.⁹

Identifying a cause

This was a unique case where sotalol was identified as the culprit for inducing Ms. P’s delirium, because her age and CKD are irreversible. It is important to note that antiarrhythmics can induce arrhythmias when present in high concentrations or administered without appropriate renal dose adjustments. Although Ms. P’s serum levels of sotalol were not evaluated, because of her renal impairment, it is possible that toxic levels of sotalol accumulated and lead to arrhythmias and delirium. Of note, a cardiologist was consulted to safely change Ms. P to a calcium channel blocker so she could undergo cardiac monitoring. With the addition of diltiazem and metoprolol, the patient’s delirium subsided and her arrhythmia was controlled. Once the source of Ms. P’s delirium had been identified, antipsy­chotics were no longer needed.

Continue to: Bottom Line

 

 

Bottom Line

Delirium is a complex disorder that often has multiple causes, both reversible and irreversible. A “process of elimination” approach should be used to accurately identify and manage delirium. If a patient with delirium has little to no response to antipsychotic medications, the underlying cause or causes likely has not yet been addressed, and the evaluation should continue.

Related Resources

• Marcantonio ER. Delirium in hospitalized older adults. N Engl J Med. 2017;377:1456-1466.
• Inouye SK, Westendorp RGJ, Saczynski JS. Delirium in elderly people. Lancet. 2014;383(9920):911-922.

Drug Brand Names

Acyclovir • Zovirax
Alprazolam • Niravam, Xanax
Amantadine • Symmetrel
Amphotericin B • Abelcet
Atorvastatin • Lipitor
Atropine • Atropen
Baclofen • EnovaRX-Baclofen
Benztropine • Cogentin
Bromocriptine • Cycloset
Calcitonin • Miacalcin
Carbamazepine • Tegretol
Carbidopa-levodopa • Duopa
Ceftriaxone • Rocephin
Chlorpromazine • Thorazine
Clonidine • Catapres
Clopidogrel • Plavix
Cyclobenzaprine • Amrix
Digoxin • Lanoxin
Diltiazem • Cardizem
Disulfiram • Antabuse
Ezetimibe • Zetia
Fluoxetine • Prozac
Fluphenazine • Prolixin
Furosemide • Lasix
Haloperidol • Haldol
Ipratropium/albuterol nebulized solution • Combivent Respimat
Isoniazid • Isotamine
Isosorbide nitrate • Dilatrate
Levetiracetam • Keppra
Levodopa • Stalevo
Linezolid • Zyvox
Lisinopril • Zestril
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Magnesium Oxide • Mag-200
Meperidine • Demerol
Methyldopa • Aldomet
Metoprolol • Lopressor
Metronidazole • Flagyl
Mirtazapine • Remeron
Nitrofurantoin • Macrobid
Olanzapine • Zyprexa
Pantoprazole • Protonix
Phenytoin • Dilantin
Pramipexole • Mirapex
Rifampin • Rifadin
Risperidone • Risperdal
Ropinirole • Requip
Sotalol hydrochloride • Betapace AF
Tramadol • Ultram
Trihexyphenidyl • Trihexane
Valproic acid • Depakote

CASE Combative and agitated

Ms. P, age 87, presents to the emergency department (ED) with her caregiver, who says Ms. P has new-onset altered mental status, agitation, and combativeness.

Ms. P resides at a long-term care (LTC) facility, where according to the nurses she normally is pleasant, well-oriented, and cooperative. Ms. P’s medical history includes major depressive disorder, generalized anxiety disorder, hypertension, chronic kidney disease (CKD) stage III, peptic ulcer disease, gastroesophageal reflux disease, coronary artery disease with 2 past myocardial infarctions requiring stents, chronic obstructive pulmonary disease, hyperlipidemia, bradycardia requiring a pacemaker, paroxysmal atrial fibrillation, asthma, aortic stenosis, peripheral vascular disease, esophageal stricture requiring dilation, deep vein thrombosis, and migraines.

Mr. P’s medication list includes acetaminophen, 650 mg every 6 hours; ipratropium/albuterol nebulized solution, 3 mL 4 times a day; aspirin, 81 mg/d; atorvastatin, 40 mg/d; calcitonin, 1 spray nasally at bedtime; clopidogrel, 75 mg/d; ezetimibe, 10 mg/d; fluoxetine, 20 mg/d; furosemide, 20 mg/d; isosorbide dinitrate, 120 mg/d; lisinopril, 15 mg/d; risperidone, 0.5 mg/d; magnesium oxide, 800 mg/d; pantoprazole, 40 mg/d; polyethylene glycol, 17 g/d; sotalol, 160 mg/d; olanzapine, 5 mg IM every 6 hours as needed for agitation; and tramadol, 50 mg every 8 hours as needed for headache.

Seven days before coming to the ED, Ms. P was started on ceftriaxone, 1 g/d, for suspected community-acquired pneumonia. At that time, the nursing staff noticed behavioral changes. Soon after, Ms. P began refusing all her medications. Two days before presenting to the ED, Ms. P was started on nitrofurantoin, 200 mg/d, for a suspected urinary tract infection, but it was discontinued because of an allergy.

Her caregiver reports that while at the LTC facility, Ms. P’s behavioral changes worsened. Ms. P claimed to be Jesus Christ and said she was talking to the devil; she chased other residents around the facility and slapped medications away from the nursing staff. According to caregivers, this behavior was out of character.

Shortly after arriving in the ED, Ms. P is admitted to the psychiatric unit.

[polldaddy:10332748]

The authors’ observations

Delirium is a complex, acute alteration in a patient’s mental status compared with his/her baseline functioning¹ (Table 1²). The onset of delirium is quick, happening within hours to days, with fluctuations in mental function. Patients might present with hyperactive, hypoactive, or mixed delirium.³ Patients with hyperactive delirium often have delusions and hallucinations; these patients might be agitated and could become violent with family and caregivers.³ Patients with hypoactive delirium are less likely to experience hallucinations and more likely to show symptoms of sedation.³ Patients with hypoactive delirium can be difficult to diagnose because it is challenging to interview them and understand what might be the cause of their sedated state. Patients also can exhibit a mixed delirium in which they fluctuate between periods of hyperactivity and hypoactivity.³

Continue to: Suspected delirium...

 

Suspected delirium should be considered a medical emergency because the outcome could be fatal.¹ It is important to uncover and treat the underlying cause(s) of delirium rather than solely administering antipsychotics, which might mask the presenting symptoms. In an older study, Francis and Kapoor⁴ reported that 56% of geriatric patients with delirium had a single definite or probable etiology, while the other 44% had about 2.8 etiologies per patient on average. Delirium risk factors, causes, and factors to consider during patient evaluation are listed in Table 2^1,3,5-7 and Table 3.^1,3,5-7

A synergistic relationship between comorbidities, environment, and medications can induce delirium.⁵ Identifying irreversible and reversible causes is the key to treating delirium. After the cause has been identified, it can be addressed and the patient could return to his/her previous level of functioning. If the delirium is the result of multiple irreversible causes, it could become chronic.

[polldaddy:10332749]

EVALUATION Cardiac dysfunction

Ms. P undergoes laboratory testing. The results include: white blood cell count, 5.9/µL; hemoglobin, 13.6 g/dL; hematocrit, 42.6%; platelets, 304 × 103/µL; sodium,143 mEq/L; potassium, 3.2 mEq/L; chloride, 96 mEq/L; carbon dioxide, 23 mEq/L; blood glucose, 87 mg/dL; creatinine, 1.2 mg/dL; estimated creatinine clearance (eCrCl) level of 33 mL/min/1.73 m²; calcium, 9.5 mg/dL; albumin, 3.6 g/dL; liver enzymes within normal limits; thyroid-stimulating hormone, 0.78 mIU/L; vitamin B₁₂, 995 pg/mL; folic acid, 16.6 ng/mL; vitamin D, 31 pg/mL; and rapid plasma reagin: nonreactive. Urinalysis is unremarkable, and no culture is performed. Urine drug screening/toxicology is positive for the benzodiazepines that she received in the ED (oral alprazolam 0.25 mg given once and oral lorazepam 0.5 mg given once).

Electrocardiogram (ECG) shows atrial flutter/tachycardia with rapid ventricular response, marked left axis deviation, nonspecific ST- and T-wave abnormality, QT/QTC of 301/387 ms, and ventricular rate 151 beats per minute. A CT scan of the head and brain without contrast shows mild atrophy and chronic white matter changes and no acute intracranial abnormality. A two-view chest radiography shows no acute cardiopulmonary findings. Her temperature is 98.4°F; heart rate is 122 beats per minute; respiratory rate is 20 breaths per minute; blood pressure is 161/98 mm Hg; and oxygen saturation is 86% on room air.

Based on this data, Ms. P’s cardiac condition seems to be worsening, which is thought to be caused by her refusal of furosemide, lisinopril, isosorbide, sotalol, clopidogrel, and aspirin. The treatment team plans to work on compliance to resolve these cardiac issues and places Ms. P on 1:1 observation with a sitter and music in attempt to calm her.

Continue to: The authors' observations

 

 

The authors’ observations

Many factors can contribute to behavioral or cognitive changes in geriatric patients. Often, a major change noted in an older patient can be attributed to new-onset dementia, dementia with behavioral disturbances, delirium, depression, or acute psychosis. These potential causes should be considered and ruled out in a step-by-step progression. Because patients are unreliable historians during acute distress, a complete history from family or caregivers and exhaustive workup is paramount.

TREATMENT Medication adjustments

In an attempt to resolve Ms. P’s disruptive behaviors, her risperidone dosage is changed to 0.5 mg twice daily. Ms. P is encouraged to use the provided oxygen to raise her saturation level.

On hospital Day 3, a loose stool prompts a Clostridium difficile test as a possible source of delirium; however, the results are negative.

On hospital Day 4, Ms. P is confused and irritable overnight, yelling profanities at staff, refusing care, inappropriately disrobing, and having difficulty falling asleep and staying asleep. Risperidone is discontinued because it appears to have had little or no effect on Ms. P’s disruptive behaviors. Olanzapine, 10 mg/d, is initiated with mirtazapine, 7.5 mg/d, to help with mood, appetite, and sleep. Fluoxetine is also discontinued because of a possible interaction with clopidogrel.

On hospital Days 6 to 8, Ms. P remains upset and unable to follow instructions. Melatonin is initiated to improve her sleep cycle. On Day 9, she continues to decline and is cursing at hospital staff; haloperidol is initiated at 5 mg every morning, 10 mg at bedtime, and 5 mg IM as needed for agitation. Her sleep improves with melatonin and mirtazapine. IV hydration also is initiated. Ms. P has a slight improvement in medication compliance. On Day 11, haloperidol is increased to 5 mg in the morning, 5 mg in the afternoon, and 10 mg at bedtime. On Day 12, haloperidol is changed to 7.5 mg twice daily; a slight improvement in Ms. P’s behavior is noted.

Continue to: On hospital Day 13...

 

On hospital Day 13, Ms. P’s behavior declines again. She screams profanities at staff and does not recognize the clinicians who have been providing care to her. The physician initiates valproic acid, 125 mg, 3 times a day, to target Ms. P’s behavioral disturbances. A pharmacist notes that the patient’s sotalol could be contributing to Ms. P’s psychiatric presentation, and that based on her eCrCl level of 33 mL/min/1.73 m², a dosage adjustment or medication change might be warranted.

On Day 14, Ms. P displays erratic behavior and intermittent tachycardia. A cardiac consultation is ordered. A repeat ECG reveals atrial fibrillation with rapid rate and a QT/QTc of 409/432 ms. Ms. P is transferred to the telemetry unit, where the cardiologist discontinues sotalol because the dosage is not properly renally adjusted. Sotalol hydrochloride has been associated with life-threatening ventricular tachycardia.⁸ Diltiazem, 30 mg every 6 hours is initiated to replace sotalol.

By Day 16, the treatment team notes improved cognition and behavior. On Day 17, the cardiologist reports that Ms. P’s atrial fibrillation is controlled. An ECG reveals mild left ventricular hypertrophy, an ejection fraction of 50% to 55%, no stenosis in the mitral or tricuspid valves, no valvular pulmonic stenosis, and moderate aortic sclerosis. Cardiac markers also are evaluated (creatinine phosphokinase: 105 U/L; creatinine kinase–MB fraction: 2.6 ng/mL; troponin: 0.01 ng/mL; pro-B-type natriuretic peptide: 2,073 pg/mL); and myocardial infarction is ruled out.

On Day 19, Ms. P’s diltiazem is consolidated to a controlled-delivery formulation, 180 mg/d, along with the addition of metoprolol, 12.5 mg twice daily. Ms. P is transferred back to the psychiatric unit.

OUTCOME Gradual improvement

On Days 20 to 23, Ms. P shows remarkable progress, and her mental status, cognition, and behavior slowly return to baseline. Haloperidol and valproic acid are tapered and discontinued. Ms. P is observed to be healthy and oriented to person, place, and time.

Continue to: On Day 25...

 

On Day 25, she is discharged from the hospital, and returns to the LTC facility.

The authors’ observations

Ms. P’s delirium was a combination of her older age, non-renally adjusted sotalol, and CKD. At admission, the hospital treatment team first thought that pneumonia or antibiotic use could have caused delirium. However, Ms. P’s condition did not improve after antibiotics were stopped. In addition, several chest radiographs found no evidence of pneumonia. It is important to check for any source of infection because infection is a common source of delirium in older patients.¹ Urine samples revealed no pathogens, a C. difficile test was negative, and the patient’s white blood cell counts remained within normal limits. Physicians began looking elsewhere for potential causes of Ms. P’s delirium.

Ms. P’s vital signs ruled out a temperature irregularity or hypertension as the cause of her delirium. She has a slightly low oxygen saturation when she first presented, but this quickly returned to normal with administration of oxygen, which ruled out hypoxemia. Laboratory results concluded that Ms. P’s glucose levels were within a normal range and she had no electrolyte imbalances. A head CT scan showed slight atrophy of white matter that is consistent with Ms. P’s age. The head CT scan also showed that Ms. P had no acute condition or head trauma.

In terms of organ function, Ms. P was in relatively healthy condition other than paroxysmal atrial fibrillation and CKD. Chronic kidney disease can interrupt the normal pharmacokinetics of medications. Reviewing Ms. P’s medication list, several agents could have induced delirium, including antidepressants, antipsychotics, cardiovascular medications (beta blocker/antiarrhythmic [sotalol]), and opioid analgesics such as tramadol.⁵ Ms. P’s condition did not improve after discontinuing fluoxetine, risperidone, or olanzapine, although haloperidol was started in their place. Ms. P scored an 8 on the Naranjo Adverse Drug Reaction Probability Scale, indicating this event was a probable adverse drug reaction.⁹

Identifying a cause

This was a unique case where sotalol was identified as the culprit for inducing Ms. P’s delirium, because her age and CKD are irreversible. It is important to note that antiarrhythmics can induce arrhythmias when present in high concentrations or administered without appropriate renal dose adjustments. Although Ms. P’s serum levels of sotalol were not evaluated, because of her renal impairment, it is possible that toxic levels of sotalol accumulated and lead to arrhythmias and delirium. Of note, a cardiologist was consulted to safely change Ms. P to a calcium channel blocker so she could undergo cardiac monitoring. With the addition of diltiazem and metoprolol, the patient’s delirium subsided and her arrhythmia was controlled. Once the source of Ms. P’s delirium had been identified, antipsy­chotics were no longer needed.

Continue to: Bottom Line

 

 

Bottom Line

Delirium is a complex disorder that often has multiple causes, both reversible and irreversible. A “process of elimination” approach should be used to accurately identify and manage delirium. If a patient with delirium has little to no response to antipsychotic medications, the underlying cause or causes likely has not yet been addressed, and the evaluation should continue.

Related Resources

• Marcantonio ER. Delirium in hospitalized older adults. N Engl J Med. 2017;377:1456-1466.
• Inouye SK, Westendorp RGJ, Saczynski JS. Delirium in elderly people. Lancet. 2014;383(9920):911-922.

Drug Brand Names

Acyclovir • Zovirax
Alprazolam • Niravam, Xanax
Amantadine • Symmetrel
Amphotericin B • Abelcet
Atorvastatin • Lipitor
Atropine • Atropen
Baclofen • EnovaRX-Baclofen
Benztropine • Cogentin
Bromocriptine • Cycloset
Calcitonin • Miacalcin
Carbamazepine • Tegretol
Carbidopa-levodopa • Duopa
Ceftriaxone • Rocephin
Chlorpromazine • Thorazine
Clonidine • Catapres
Clopidogrel • Plavix
Cyclobenzaprine • Amrix
Digoxin • Lanoxin
Diltiazem • Cardizem
Disulfiram • Antabuse
Ezetimibe • Zetia
Fluoxetine • Prozac
Fluphenazine • Prolixin
Furosemide • Lasix
Haloperidol • Haldol
Ipratropium/albuterol nebulized solution • Combivent Respimat
Isoniazid • Isotamine
Isosorbide nitrate • Dilatrate
Levetiracetam • Keppra
Levodopa • Stalevo
Linezolid • Zyvox
Lisinopril • Zestril
Lithium • Eskalith, Lithobid
Lorazepam • Ativan
Magnesium Oxide • Mag-200
Meperidine • Demerol
Methyldopa • Aldomet
Metoprolol • Lopressor
Metronidazole • Flagyl
Mirtazapine • Remeron
Nitrofurantoin • Macrobid
Olanzapine • Zyprexa
Pantoprazole • Protonix
Phenytoin • Dilantin
Pramipexole • Mirapex
Rifampin • Rifadin
Risperidone • Risperdal
Ropinirole • Requip
Sotalol hydrochloride • Betapace AF
Tramadol • Ultram
Trihexyphenidyl • Trihexane
Valproic acid • Depakote

CASE Suicidal ideation, flare-up of ulcerative colitis

Mr. J, age 56, who has a history of major depressive disorder (MDD), generalized anxiety disorder (GAD), and ulcerative colitis (UC), presents to the emergency department (ED) with suicidal ideation and a plan to overdose on his medications. He reports no current emotional or financial stressors in his personal life. Home medications documented at the time of his arrival to the ED include sertraline, 100 mg/d, bupropion, 150 mg/d, buspirone, 10 mg 3 times daily, diazepam 10 mg 3 times daily, as needed, adalimumab, 40 mg IM every 2 weeks, and diphenhydramine, 50 mg every night.

A recent flare-up of UC resulted in Mr. J being placed on a 15-week prednisone taper, beginning at 80 mg/d and decreasing by 5 mg weekly, which was completed 2 weeks before he presented to the ED. After completing the prednisone taper, Mr. J went to his primary care physician (PCP) on 3 separate occasions due to episodes of severe depression. Although the PCP prescribed multiple medications to target Mr. J’s depressive symptoms, he continued to decline.

Subsequently, Mr. J came to the ED and is admitted to the psychiatric unit for safety and stabilization. Upon admission, Mr. J becomes bedridden, and reports that his current depressive episode is the most severe that he has ever experienced in his more than 30 years of having MDD. He says that neither bupropion nor buspirone are helping with his depression, anxiety, or any related symptom.

[polldaddy:10120537]

The authors’ observations

At admission, all of Mr. J’s home medications, except sertraline and adalimumab, which had been prescribed to treat UC (Box^1,2), were discontinued. His diazepam was discontinued because the clinician felt it may have been contributing to Mr. J’s inability to walk or get out of bed. Diazepam was not tapered because it was initiated 7 days prior to admission and was thought to be exacerbating his depression and suicidal ideation. Bupropion and buspirone, which were initiated 2 weeks prior, were discontinued because Mr. J reported that neither medication was helping with his depression, anxiety, or any related symptom.

 

EVALUATION Poor appetite, anxiety, and continued suicidality

During evaluation, vital signs, laboratory findings, and diagnostic testing are found to be unremarkable. Mr. J’s presentation and complaints are entirely subjective, and include poor appetite, fatigue, difficulty sleeping, sorrow, anxiety, and continued suicidality. Mr. J reports that he feels miserable, which is reflected by his poor eye contact, soft speech, and body language.

Continued to: The authors' observations

 

 

The authors’ observations

MDD is a mood disorder characterized by depressed mood and/or loss of interest or pleasure for more than 2 weeks.³ First-line pharmacotherapy for MDD includes monotherapy with a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion.⁴ Medication selection is typically based on patient-specific factors, adverse effect profile, drug–drug interactions, and cost. Other treatments include electroconvulsive therapy (ECT) or cognitive-behavioral therapy (CBT).^4,5 Augmentation agents, such as second-generation antipsychotics, lithium, thyroid hormone supplementation, buspirone, anticonvulsants, and combinations of antidepressants, may also be considered.⁴

TREATMENT Condition worsens

On Day 2 of hospitalization, Mr. J is started on aripiprazole, 5 mg/d, clonazepam, 1 mg twice daily, and melatonin, 5 mg, each night for sleep. Aripiprazole, 5 mg/d, is initiated as an adjunct to sertraline for MDD because Mr. J reports feeling much worse and continues to report that he would “rather die than feel this way.” Mr. J begins to believe that his current state is his new baseline, and that feeling better is no longer possible.

On Day 3 of hospitalization, records are obtained from a clinician at an outside facility who previously treated Mr. J; this clinician suspected Mr. J may have bipolar disorder. On Days 3 and 5 of hospitalization, aripiprazole is titrated to 10 mg/d, and then to 20 mg/d, respectively. On Day 6, sertraline is increased to 150 mg/d because Mr. J continues to report low mood and limited sleep and is less and less interactive during interviews. He remains suicidal, and because bipolar depression is suspected (although this is not a clear diagnosis in his records), a trial of divalproex sodium, 250 mg twice daily, is initiated on Day 6.

By Day 8 of hospitalization, there is no notable change in Mr. J’s depressive symptoms. On Day 9, sertraline is increased to 200 mg/d, with little improvement from Mr. J’s perspective. The multidisciplinary team evaluates him, and when directly asked, Mr. J cites his 4 greatest complaints to be poor sleep, fatigue, no appetite, and depressed mood. Once again, he states, “I would rather be dead than go on feeling this way.”

[polldaddy:10120587]

The authors’ observations

Due to Mr. J’s severe, unrelenting depressive episode, the treatment team obtained his informed consent to undergo ECT. On Day 9, before initiating ECT, the pharmacist recommended mirtazapine, even though the patient weighed almost 89 kg (196.21 lb) and had a body mass index of 27.8 kg/m². The treatment team thought that mirtazapine augmentation could potentially help the sertraline work more quickly while targeting Mr. J’s 4 greatest complaints.

Mirtazapine is a central alpha-2 antagonist or noradrenergic and specific serotonergic antidepressant (NaSSA) that works through antagonism of the presynaptic alpha-2 adrenergic receptors to indirectly regulate release of monoamines and increase the release of serotonin and norepinephrine.⁶ Additionally, mirtazapine has antagonist actions at 5HT2A, 5HT2C, 5HT3, and histamine-1 receptors.⁶ Potential adverse effects include drowsiness and increased appetite leading to weight gain.⁷ Mirtazapine’s therapeutic efficacy is similar to SSRIs for treating depression.⁴ Mirtazapine in combination with an SNRI has been referred to as “California rocket fuel” due to the theoretical pharmacologic synergy and resulting strong antidepressant action.⁶ It was hypothesized that similar effects could be seen by augmenting the SSRI sertraline with mirtazapine.

Continued to: The time to efficacy with mirtazapine...

 

The time to efficacy with mirtazapine is approximately 2 to 4 weeks, but anxiety symptoms and poor sleep or insomnia may improve in the first week.⁸ Studies have suggested the possibility of a more rapid onset of efficacy with mirtazapine than with SSRIs, as well as potential response acceleration in MDD and other psychiatric illnesses such as anxiety disorders or obsessive-compulsive disorder (OCD).^9,10 A review that included several double-blind studies and compared mirtazapine with SSRIs found the amount of responders with persistent improvement with onset in Week 1 was more pronounced with mirtazapine.⁹

Augmenting an SSRI with mirtazapine is a potential therapeutic option because it can help boost the efficacy of the prescribed SSRI while enhancing appetite and blunting the activating or anxiety-like effects of some SSRIs, which may help with relaxation and sleep.⁴ The combination of an SSRI plus mirtazapine has been studied in patients with MDD, posttraumatic stress disorder, and OCD; it was found to improve symptoms of those conditions due to the medications’ complementary mechanisms of action.^4,11-13 Also, mirtazapine has been shown to decrease the rates of relapse after an acute phase of depression.^4,14

OUTCOME Rapid improvement


On Day 9, Mr. J receives the first dose of mirtazapine, 7.5 mg at bedtime. On Day 10, when Mr. J wakes, his mood is notably improved. He is more interactive (sitting up in bed reading and making eye contact with the staff during an interview), and he reports improved sleep and eats most of his breakfast.

After receiving 3 doses of mirtazapine, Mr. J reports that he feels back to his normal self; he is interactive, alert, and eating well. Due to the rapid improvement in mood, ECT is discontinued, and he does not receive any ECT treatment during the remainder of his hospitalization.

On Day 11, divalproex is discontinued. Because Mr. J receives only 5 days of therapy with this agent, his divalproex level is not checked. At this point, the treatment team feels confident in ruling out bipolar disorder.

On Day 15, Mr. J is discharged with sertraline, 200 mg/d, mirtazapine, 7.5 mg/d at 7 pm, aripiprazole, 20 mg/d, clonazepam, 1 mg twice daily as needed for anxiety, melatonin 5 mg/d, and adalimumab, 40 mg IM every 2 weeks. Discharge instructions include a follow-up in 2 weeks to evaluate continuation strategies for the discharge medications.

Ten months after his depressive episode, Mr. J has had no further admissions at the hospital where he received the treatment described here.

 

Bottom Line

Evidence for the treatment of major depressive disorder induced by corticosteroid withdrawal is limited. Despite trials of agents from multiple medication classes, the depressive episode may not improve. Adding mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor may prove successful.

Related Resources

• Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528.
• Kenna HA, Poon AW, de los Angeles CP, et al. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65(6):549-560.

Drug Brand Names
Adalimumab • Humira
Aripiprazole • Abilify
Bupropion • Wellbutrin, Zyban
Buspirone • Buspar
Clonazepam • Klonopin
Diazepam • Valium
Diphenhydramine • Benadryl
Divalproex • Depakote, Depakote ER
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Prednisone • Deltasone
Sertraline • Zoloft

CASE Suicidal ideation, flare-up of ulcerative colitis

Mr. J, age 56, who has a history of major depressive disorder (MDD), generalized anxiety disorder (GAD), and ulcerative colitis (UC), presents to the emergency department (ED) with suicidal ideation and a plan to overdose on his medications. He reports no current emotional or financial stressors in his personal life. Home medications documented at the time of his arrival to the ED include sertraline, 100 mg/d, bupropion, 150 mg/d, buspirone, 10 mg 3 times daily, diazepam 10 mg 3 times daily, as needed, adalimumab, 40 mg IM every 2 weeks, and diphenhydramine, 50 mg every night.

A recent flare-up of UC resulted in Mr. J being placed on a 15-week prednisone taper, beginning at 80 mg/d and decreasing by 5 mg weekly, which was completed 2 weeks before he presented to the ED. After completing the prednisone taper, Mr. J went to his primary care physician (PCP) on 3 separate occasions due to episodes of severe depression. Although the PCP prescribed multiple medications to target Mr. J’s depressive symptoms, he continued to decline.

Subsequently, Mr. J came to the ED and is admitted to the psychiatric unit for safety and stabilization. Upon admission, Mr. J becomes bedridden, and reports that his current depressive episode is the most severe that he has ever experienced in his more than 30 years of having MDD. He says that neither bupropion nor buspirone are helping with his depression, anxiety, or any related symptom.

[polldaddy:10120537]

The authors’ observations

At admission, all of Mr. J’s home medications, except sertraline and adalimumab, which had been prescribed to treat UC (Box^1,2), were discontinued. His diazepam was discontinued because the clinician felt it may have been contributing to Mr. J’s inability to walk or get out of bed. Diazepam was not tapered because it was initiated 7 days prior to admission and was thought to be exacerbating his depression and suicidal ideation. Bupropion and buspirone, which were initiated 2 weeks prior, were discontinued because Mr. J reported that neither medication was helping with his depression, anxiety, or any related symptom.

 

EVALUATION Poor appetite, anxiety, and continued suicidality

During evaluation, vital signs, laboratory findings, and diagnostic testing are found to be unremarkable. Mr. J’s presentation and complaints are entirely subjective, and include poor appetite, fatigue, difficulty sleeping, sorrow, anxiety, and continued suicidality. Mr. J reports that he feels miserable, which is reflected by his poor eye contact, soft speech, and body language.

Continued to: The authors' observations

 

 

The authors’ observations

MDD is a mood disorder characterized by depressed mood and/or loss of interest or pleasure for more than 2 weeks.³ First-line pharmacotherapy for MDD includes monotherapy with a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion.⁴ Medication selection is typically based on patient-specific factors, adverse effect profile, drug–drug interactions, and cost. Other treatments include electroconvulsive therapy (ECT) or cognitive-behavioral therapy (CBT).^4,5 Augmentation agents, such as second-generation antipsychotics, lithium, thyroid hormone supplementation, buspirone, anticonvulsants, and combinations of antidepressants, may also be considered.⁴

TREATMENT Condition worsens

On Day 2 of hospitalization, Mr. J is started on aripiprazole, 5 mg/d, clonazepam, 1 mg twice daily, and melatonin, 5 mg, each night for sleep. Aripiprazole, 5 mg/d, is initiated as an adjunct to sertraline for MDD because Mr. J reports feeling much worse and continues to report that he would “rather die than feel this way.” Mr. J begins to believe that his current state is his new baseline, and that feeling better is no longer possible.

On Day 3 of hospitalization, records are obtained from a clinician at an outside facility who previously treated Mr. J; this clinician suspected Mr. J may have bipolar disorder. On Days 3 and 5 of hospitalization, aripiprazole is titrated to 10 mg/d, and then to 20 mg/d, respectively. On Day 6, sertraline is increased to 150 mg/d because Mr. J continues to report low mood and limited sleep and is less and less interactive during interviews. He remains suicidal, and because bipolar depression is suspected (although this is not a clear diagnosis in his records), a trial of divalproex sodium, 250 mg twice daily, is initiated on Day 6.

By Day 8 of hospitalization, there is no notable change in Mr. J’s depressive symptoms. On Day 9, sertraline is increased to 200 mg/d, with little improvement from Mr. J’s perspective. The multidisciplinary team evaluates him, and when directly asked, Mr. J cites his 4 greatest complaints to be poor sleep, fatigue, no appetite, and depressed mood. Once again, he states, “I would rather be dead than go on feeling this way.”

[polldaddy:10120587]

The authors’ observations

Due to Mr. J’s severe, unrelenting depressive episode, the treatment team obtained his informed consent to undergo ECT. On Day 9, before initiating ECT, the pharmacist recommended mirtazapine, even though the patient weighed almost 89 kg (196.21 lb) and had a body mass index of 27.8 kg/m². The treatment team thought that mirtazapine augmentation could potentially help the sertraline work more quickly while targeting Mr. J’s 4 greatest complaints.

Mirtazapine is a central alpha-2 antagonist or noradrenergic and specific serotonergic antidepressant (NaSSA) that works through antagonism of the presynaptic alpha-2 adrenergic receptors to indirectly regulate release of monoamines and increase the release of serotonin and norepinephrine.⁶ Additionally, mirtazapine has antagonist actions at 5HT2A, 5HT2C, 5HT3, and histamine-1 receptors.⁶ Potential adverse effects include drowsiness and increased appetite leading to weight gain.⁷ Mirtazapine’s therapeutic efficacy is similar to SSRIs for treating depression.⁴ Mirtazapine in combination with an SNRI has been referred to as “California rocket fuel” due to the theoretical pharmacologic synergy and resulting strong antidepressant action.⁶ It was hypothesized that similar effects could be seen by augmenting the SSRI sertraline with mirtazapine.

Continued to: The time to efficacy with mirtazapine...

 

The time to efficacy with mirtazapine is approximately 2 to 4 weeks, but anxiety symptoms and poor sleep or insomnia may improve in the first week.⁸ Studies have suggested the possibility of a more rapid onset of efficacy with mirtazapine than with SSRIs, as well as potential response acceleration in MDD and other psychiatric illnesses such as anxiety disorders or obsessive-compulsive disorder (OCD).^9,10 A review that included several double-blind studies and compared mirtazapine with SSRIs found the amount of responders with persistent improvement with onset in Week 1 was more pronounced with mirtazapine.⁹

Augmenting an SSRI with mirtazapine is a potential therapeutic option because it can help boost the efficacy of the prescribed SSRI while enhancing appetite and blunting the activating or anxiety-like effects of some SSRIs, which may help with relaxation and sleep.⁴ The combination of an SSRI plus mirtazapine has been studied in patients with MDD, posttraumatic stress disorder, and OCD; it was found to improve symptoms of those conditions due to the medications’ complementary mechanisms of action.^4,11-13 Also, mirtazapine has been shown to decrease the rates of relapse after an acute phase of depression.^4,14

OUTCOME Rapid improvement


On Day 9, Mr. J receives the first dose of mirtazapine, 7.5 mg at bedtime. On Day 10, when Mr. J wakes, his mood is notably improved. He is more interactive (sitting up in bed reading and making eye contact with the staff during an interview), and he reports improved sleep and eats most of his breakfast.

After receiving 3 doses of mirtazapine, Mr. J reports that he feels back to his normal self; he is interactive, alert, and eating well. Due to the rapid improvement in mood, ECT is discontinued, and he does not receive any ECT treatment during the remainder of his hospitalization.

On Day 11, divalproex is discontinued. Because Mr. J receives only 5 days of therapy with this agent, his divalproex level is not checked. At this point, the treatment team feels confident in ruling out bipolar disorder.

On Day 15, Mr. J is discharged with sertraline, 200 mg/d, mirtazapine, 7.5 mg/d at 7 pm, aripiprazole, 20 mg/d, clonazepam, 1 mg twice daily as needed for anxiety, melatonin 5 mg/d, and adalimumab, 40 mg IM every 2 weeks. Discharge instructions include a follow-up in 2 weeks to evaluate continuation strategies for the discharge medications.

Ten months after his depressive episode, Mr. J has had no further admissions at the hospital where he received the treatment described here.

 

Bottom Line

Evidence for the treatment of major depressive disorder induced by corticosteroid withdrawal is limited. Despite trials of agents from multiple medication classes, the depressive episode may not improve. Adding mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor may prove successful.

Related Resources

• Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528.
• Kenna HA, Poon AW, de los Angeles CP, et al. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65(6):549-560.

Drug Brand Names
Adalimumab • Humira
Aripiprazole • Abilify
Bupropion • Wellbutrin, Zyban
Buspirone • Buspar
Clonazepam • Klonopin
Diazepam • Valium
Diphenhydramine • Benadryl
Divalproex • Depakote, Depakote ER
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Prednisone • Deltasone
Sertraline • Zoloft

CASE Suicidal ideation, flare-up of ulcerative colitis

Mr. J, age 56, who has a history of major depressive disorder (MDD), generalized anxiety disorder (GAD), and ulcerative colitis (UC), presents to the emergency department (ED) with suicidal ideation and a plan to overdose on his medications. He reports no current emotional or financial stressors in his personal life. Home medications documented at the time of his arrival to the ED include sertraline, 100 mg/d, bupropion, 150 mg/d, buspirone, 10 mg 3 times daily, diazepam 10 mg 3 times daily, as needed, adalimumab, 40 mg IM every 2 weeks, and diphenhydramine, 50 mg every night.

A recent flare-up of UC resulted in Mr. J being placed on a 15-week prednisone taper, beginning at 80 mg/d and decreasing by 5 mg weekly, which was completed 2 weeks before he presented to the ED. After completing the prednisone taper, Mr. J went to his primary care physician (PCP) on 3 separate occasions due to episodes of severe depression. Although the PCP prescribed multiple medications to target Mr. J’s depressive symptoms, he continued to decline.

Subsequently, Mr. J came to the ED and is admitted to the psychiatric unit for safety and stabilization. Upon admission, Mr. J becomes bedridden, and reports that his current depressive episode is the most severe that he has ever experienced in his more than 30 years of having MDD. He says that neither bupropion nor buspirone are helping with his depression, anxiety, or any related symptom.

[polldaddy:10120537]

The authors’ observations

At admission, all of Mr. J’s home medications, except sertraline and adalimumab, which had been prescribed to treat UC (Box^1,2), were discontinued. His diazepam was discontinued because the clinician felt it may have been contributing to Mr. J’s inability to walk or get out of bed. Diazepam was not tapered because it was initiated 7 days prior to admission and was thought to be exacerbating his depression and suicidal ideation. Bupropion and buspirone, which were initiated 2 weeks prior, were discontinued because Mr. J reported that neither medication was helping with his depression, anxiety, or any related symptom.

 

EVALUATION Poor appetite, anxiety, and continued suicidality

During evaluation, vital signs, laboratory findings, and diagnostic testing are found to be unremarkable. Mr. J’s presentation and complaints are entirely subjective, and include poor appetite, fatigue, difficulty sleeping, sorrow, anxiety, and continued suicidality. Mr. J reports that he feels miserable, which is reflected by his poor eye contact, soft speech, and body language.

Continued to: The authors' observations

 

 

The authors’ observations

MDD is a mood disorder characterized by depressed mood and/or loss of interest or pleasure for more than 2 weeks.³ First-line pharmacotherapy for MDD includes monotherapy with a selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), mirtazapine, or bupropion.⁴ Medication selection is typically based on patient-specific factors, adverse effect profile, drug–drug interactions, and cost. Other treatments include electroconvulsive therapy (ECT) or cognitive-behavioral therapy (CBT).^4,5 Augmentation agents, such as second-generation antipsychotics, lithium, thyroid hormone supplementation, buspirone, anticonvulsants, and combinations of antidepressants, may also be considered.⁴

TREATMENT Condition worsens

On Day 2 of hospitalization, Mr. J is started on aripiprazole, 5 mg/d, clonazepam, 1 mg twice daily, and melatonin, 5 mg, each night for sleep. Aripiprazole, 5 mg/d, is initiated as an adjunct to sertraline for MDD because Mr. J reports feeling much worse and continues to report that he would “rather die than feel this way.” Mr. J begins to believe that his current state is his new baseline, and that feeling better is no longer possible.

On Day 3 of hospitalization, records are obtained from a clinician at an outside facility who previously treated Mr. J; this clinician suspected Mr. J may have bipolar disorder. On Days 3 and 5 of hospitalization, aripiprazole is titrated to 10 mg/d, and then to 20 mg/d, respectively. On Day 6, sertraline is increased to 150 mg/d because Mr. J continues to report low mood and limited sleep and is less and less interactive during interviews. He remains suicidal, and because bipolar depression is suspected (although this is not a clear diagnosis in his records), a trial of divalproex sodium, 250 mg twice daily, is initiated on Day 6.

By Day 8 of hospitalization, there is no notable change in Mr. J’s depressive symptoms. On Day 9, sertraline is increased to 200 mg/d, with little improvement from Mr. J’s perspective. The multidisciplinary team evaluates him, and when directly asked, Mr. J cites his 4 greatest complaints to be poor sleep, fatigue, no appetite, and depressed mood. Once again, he states, “I would rather be dead than go on feeling this way.”

[polldaddy:10120587]

The authors’ observations

Due to Mr. J’s severe, unrelenting depressive episode, the treatment team obtained his informed consent to undergo ECT. On Day 9, before initiating ECT, the pharmacist recommended mirtazapine, even though the patient weighed almost 89 kg (196.21 lb) and had a body mass index of 27.8 kg/m². The treatment team thought that mirtazapine augmentation could potentially help the sertraline work more quickly while targeting Mr. J’s 4 greatest complaints.

Mirtazapine is a central alpha-2 antagonist or noradrenergic and specific serotonergic antidepressant (NaSSA) that works through antagonism of the presynaptic alpha-2 adrenergic receptors to indirectly regulate release of monoamines and increase the release of serotonin and norepinephrine.⁶ Additionally, mirtazapine has antagonist actions at 5HT2A, 5HT2C, 5HT3, and histamine-1 receptors.⁶ Potential adverse effects include drowsiness and increased appetite leading to weight gain.⁷ Mirtazapine’s therapeutic efficacy is similar to SSRIs for treating depression.⁴ Mirtazapine in combination with an SNRI has been referred to as “California rocket fuel” due to the theoretical pharmacologic synergy and resulting strong antidepressant action.⁶ It was hypothesized that similar effects could be seen by augmenting the SSRI sertraline with mirtazapine.

Continued to: The time to efficacy with mirtazapine...

 

The time to efficacy with mirtazapine is approximately 2 to 4 weeks, but anxiety symptoms and poor sleep or insomnia may improve in the first week.⁸ Studies have suggested the possibility of a more rapid onset of efficacy with mirtazapine than with SSRIs, as well as potential response acceleration in MDD and other psychiatric illnesses such as anxiety disorders or obsessive-compulsive disorder (OCD).^9,10 A review that included several double-blind studies and compared mirtazapine with SSRIs found the amount of responders with persistent improvement with onset in Week 1 was more pronounced with mirtazapine.⁹

Augmenting an SSRI with mirtazapine is a potential therapeutic option because it can help boost the efficacy of the prescribed SSRI while enhancing appetite and blunting the activating or anxiety-like effects of some SSRIs, which may help with relaxation and sleep.⁴ The combination of an SSRI plus mirtazapine has been studied in patients with MDD, posttraumatic stress disorder, and OCD; it was found to improve symptoms of those conditions due to the medications’ complementary mechanisms of action.^4,11-13 Also, mirtazapine has been shown to decrease the rates of relapse after an acute phase of depression.^4,14

OUTCOME Rapid improvement


On Day 9, Mr. J receives the first dose of mirtazapine, 7.5 mg at bedtime. On Day 10, when Mr. J wakes, his mood is notably improved. He is more interactive (sitting up in bed reading and making eye contact with the staff during an interview), and he reports improved sleep and eats most of his breakfast.

After receiving 3 doses of mirtazapine, Mr. J reports that he feels back to his normal self; he is interactive, alert, and eating well. Due to the rapid improvement in mood, ECT is discontinued, and he does not receive any ECT treatment during the remainder of his hospitalization.

On Day 11, divalproex is discontinued. Because Mr. J receives only 5 days of therapy with this agent, his divalproex level is not checked. At this point, the treatment team feels confident in ruling out bipolar disorder.

On Day 15, Mr. J is discharged with sertraline, 200 mg/d, mirtazapine, 7.5 mg/d at 7 pm, aripiprazole, 20 mg/d, clonazepam, 1 mg twice daily as needed for anxiety, melatonin 5 mg/d, and adalimumab, 40 mg IM every 2 weeks. Discharge instructions include a follow-up in 2 weeks to evaluate continuation strategies for the discharge medications.

Ten months after his depressive episode, Mr. J has had no further admissions at the hospital where he received the treatment described here.

 

Bottom Line

Evidence for the treatment of major depressive disorder induced by corticosteroid withdrawal is limited. Despite trials of agents from multiple medication classes, the depressive episode may not improve. Adding mirtazapine to a selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor may prove successful.

Related Resources

• Watanabe N, Omori IM, Nakagawa A, et al. Mirtazapine versus other antidepressive agents for depression. Cochrane Database Syst Rev. 2011;(12):CD006528.
• Kenna HA, Poon AW, de los Angeles CP, et al. Psychiatric complications of treatment with corticosteroids: review with case report. Psychiatry Clin Neurosci. 2011;65(6):549-560.

Drug Brand Names
Adalimumab • Humira
Aripiprazole • Abilify
Bupropion • Wellbutrin, Zyban
Buspirone • Buspar
Clonazepam • Klonopin
Diazepam • Valium
Diphenhydramine • Benadryl
Divalproex • Depakote, Depakote ER
Lithium • Eskalith, Lithobid
Mirtazapine • Remeron
Prednisone • Deltasone
Sertraline • Zoloft

Valproic acid (VPA) often is used to treat mania in bipolar disorder, and it has a therapeutic range of 50 to 125 µg/mL of total serum concentration.¹ VPA binds highly to albumin, resulting in free drug concentrations (5 to 15 mg/L) that are responsible for its therapeutic effect.² Monitoring total VPA levels in patients with hypoalbuminemia could reveal seemingly subtherapeutic VPA levels, which could lead to unnecessary dosage adjustments or drug toxicity. Hermida et al³ devised a correction equation to normalize total VPA serum concentrations <75 µg/mL in patients with hypoalbuminemia (Table 1, Box).

We present a case employing this equation in a patient

with reported results and validation.

Case

Ms. T, age 75, is admitted to the hospital with delusional, paranoid, assaultive, and combative behavior. By applying Ms. T’s baseline lab findings (Table 2) to the equation, a normalized total VPA level and estimated free VPA level of 70 µg/mL and 7 µg/mL, respectively, can be approximated. These estimates fall within the therapeutic range and are validated by the measured free VPA level of 9 µg/mL.

Her VPA dosage is increased from 250 mg, 3 times a day, to 375 mg, twice a day, with an additional mid-day dose of 250 mg. Ms. T’s behavioral symptoms improved 3 days following the increase to her VPA dosage, although she continued to show some confusion.
 

VPA serum levels should be assessed 2 to 4 days after initiation or dosage adjustments.¹ Also, consider patient-specific goals and intended clinical effect when adjusting VPA dosage. In practice settings, where free VPA levels are not routinely monitored or are cost prohibitive, this equation can guide clinical decision-making.³

Valproic acid (VPA) often is used to treat mania in bipolar disorder, and it has a therapeutic range of 50 to 125 µg/mL of total serum concentration.¹ VPA binds highly to albumin, resulting in free drug concentrations (5 to 15 mg/L) that are responsible for its therapeutic effect.² Monitoring total VPA levels in patients with hypoalbuminemia could reveal seemingly subtherapeutic VPA levels, which could lead to unnecessary dosage adjustments or drug toxicity. Hermida et al³ devised a correction equation to normalize total VPA serum concentrations <75 µg/mL in patients with hypoalbuminemia (Table 1, Box).

We present a case employing this equation in a patient

with reported results and validation.

Case

Ms. T, age 75, is admitted to the hospital with delusional, paranoid, assaultive, and combative behavior. By applying Ms. T’s baseline lab findings (Table 2) to the equation, a normalized total VPA level and estimated free VPA level of 70 µg/mL and 7 µg/mL, respectively, can be approximated. These estimates fall within the therapeutic range and are validated by the measured free VPA level of 9 µg/mL.

Her VPA dosage is increased from 250 mg, 3 times a day, to 375 mg, twice a day, with an additional mid-day dose of 250 mg. Ms. T’s behavioral symptoms improved 3 days following the increase to her VPA dosage, although she continued to show some confusion.
 

VPA serum levels should be assessed 2 to 4 days after initiation or dosage adjustments.¹ Also, consider patient-specific goals and intended clinical effect when adjusting VPA dosage. In practice settings, where free VPA levels are not routinely monitored or are cost prohibitive, this equation can guide clinical decision-making.³

Valproic acid (VPA) often is used to treat mania in bipolar disorder, and it has a therapeutic range of 50 to 125 µg/mL of total serum concentration.¹ VPA binds highly to albumin, resulting in free drug concentrations (5 to 15 mg/L) that are responsible for its therapeutic effect.² Monitoring total VPA levels in patients with hypoalbuminemia could reveal seemingly subtherapeutic VPA levels, which could lead to unnecessary dosage adjustments or drug toxicity. Hermida et al³ devised a correction equation to normalize total VPA serum concentrations <75 µg/mL in patients with hypoalbuminemia (Table 1, Box).

We present a case employing this equation in a patient

with reported results and validation.

Case

Ms. T, age 75, is admitted to the hospital with delusional, paranoid, assaultive, and combative behavior. By applying Ms. T’s baseline lab findings (Table 2) to the equation, a normalized total VPA level and estimated free VPA level of 70 µg/mL and 7 µg/mL, respectively, can be approximated. These estimates fall within the therapeutic range and are validated by the measured free VPA level of 9 µg/mL.

Her VPA dosage is increased from 250 mg, 3 times a day, to 375 mg, twice a day, with an additional mid-day dose of 250 mg. Ms. T’s behavioral symptoms improved 3 days following the increase to her VPA dosage, although she continued to show some confusion.
 

VPA serum levels should be assessed 2 to 4 days after initiation or dosage adjustments.¹ Also, consider patient-specific goals and intended clinical effect when adjusting VPA dosage. In practice settings, where free VPA levels are not routinely monitored or are cost prohibitive, this equation can guide clinical decision-making.³