Current Psychiatry

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Combination therapies for major depressive disorder (MDD) may enhance antidepressant efficacy and long-term results by working synergistically to regulate monoamines availability. Low levels of serum and red blood cell folate are linked to severe symptoms of depression and some patients are less likely to respond to antidepressants.¹ Even in patients with normal serum or red blood cell folate levels, CNS folate levels may be suboptimal.¹

L-methylfolate is the centrally active derivative of folate that regulates synthesis of trimonoamines serotonin, dopamine, and norepinephrine and is a key regulator of the cofactor tetrahydrobiopterin (BH4). BH4 is required by tryptophan hydroxylase for serotonin synthesis and by tyrosine hydroxylase for dopamine and norepinephrine synthesis.²

Evidence suggests adding L-methylfolate to selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs) when starting pharmacotherapy leads to greater reduction of depressive symptoms in a shorter time compared with SSRI or SNRI monotherapy.¹ In a study of patients with MDD who partially responded or did not respond to SSRIs, adjunctive L-methylfolate, 15 mg/d, produced greater response rates compared with SSRIs plus placebo.³ L-methylfolate also was well tolerated in combination with SSRI or SNRI therapy. The rates of adverse effects were not significantly different in patients taking L-methylfolate plus an SSRI or SNRI compared with those taking SSRI or SNRI monotherapy.¹

MDD patients who may benefit from L-methylfolate include those with low levels of folate and its active metabolites—such as L-methylfolate—and inadequate response to antidepressants. Patients who have an alcohol use disorder, eating disorders, genetic C677-T polymorphism (present in half of the general population), or gastrointestinal disorders are at risk for low folate levels, as well as those who are pregnant.²

Folic acid needs to be converted to L-methylfolate to cross the blood-brain barrier, whereas L-methylfolate can be used directly by the brain.² Therefore, patients who take medications that can interfere with the conversion of folate to L-methylfolate might benefit from adjunctive L-methylfolate. These medications include lamotrigine, valproate, oral contraceptives, metformin, warfarin, fenofibrates, and certain retinoids.¹ Patients with C677-T polymorphism and patients from Hispanic or Mediterranean populations have shown impaired ability to convert folic acid to L-methylfolate.²

Disclosure

Dr. Fluitt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Combination therapies for major depressive disorder (MDD) may enhance antidepressant efficacy and long-term results by working synergistically to regulate monoamines availability. Low levels of serum and red blood cell folate are linked to severe symptoms of depression and some patients are less likely to respond to antidepressants.¹ Even in patients with normal serum or red blood cell folate levels, CNS folate levels may be suboptimal.¹

L-methylfolate is the centrally active derivative of folate that regulates synthesis of trimonoamines serotonin, dopamine, and norepinephrine and is a key regulator of the cofactor tetrahydrobiopterin (BH4). BH4 is required by tryptophan hydroxylase for serotonin synthesis and by tyrosine hydroxylase for dopamine and norepinephrine synthesis.²

Evidence suggests adding L-methylfolate to selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs) when starting pharmacotherapy leads to greater reduction of depressive symptoms in a shorter time compared with SSRI or SNRI monotherapy.¹ In a study of patients with MDD who partially responded or did not respond to SSRIs, adjunctive L-methylfolate, 15 mg/d, produced greater response rates compared with SSRIs plus placebo.³ L-methylfolate also was well tolerated in combination with SSRI or SNRI therapy. The rates of adverse effects were not significantly different in patients taking L-methylfolate plus an SSRI or SNRI compared with those taking SSRI or SNRI monotherapy.¹

MDD patients who may benefit from L-methylfolate include those with low levels of folate and its active metabolites—such as L-methylfolate—and inadequate response to antidepressants. Patients who have an alcohol use disorder, eating disorders, genetic C677-T polymorphism (present in half of the general population), or gastrointestinal disorders are at risk for low folate levels, as well as those who are pregnant.²

Folic acid needs to be converted to L-methylfolate to cross the blood-brain barrier, whereas L-methylfolate can be used directly by the brain.² Therefore, patients who take medications that can interfere with the conversion of folate to L-methylfolate might benefit from adjunctive L-methylfolate. These medications include lamotrigine, valproate, oral contraceptives, metformin, warfarin, fenofibrates, and certain retinoids.¹ Patients with C677-T polymorphism and patients from Hispanic or Mediterranean populations have shown impaired ability to convert folic acid to L-methylfolate.²

Disclosure

Dr. Fluitt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Combination therapies for major depressive disorder (MDD) may enhance antidepressant efficacy and long-term results by working synergistically to regulate monoamines availability. Low levels of serum and red blood cell folate are linked to severe symptoms of depression and some patients are less likely to respond to antidepressants.¹ Even in patients with normal serum or red blood cell folate levels, CNS folate levels may be suboptimal.¹

L-methylfolate is the centrally active derivative of folate that regulates synthesis of trimonoamines serotonin, dopamine, and norepinephrine and is a key regulator of the cofactor tetrahydrobiopterin (BH4). BH4 is required by tryptophan hydroxylase for serotonin synthesis and by tyrosine hydroxylase for dopamine and norepinephrine synthesis.²

Evidence suggests adding L-methylfolate to selective serotonin reuptake inhibitors (SSRIs) or serotonin–norepinephrine reuptake inhibitors (SNRIs) when starting pharmacotherapy leads to greater reduction of depressive symptoms in a shorter time compared with SSRI or SNRI monotherapy.¹ In a study of patients with MDD who partially responded or did not respond to SSRIs, adjunctive L-methylfolate, 15 mg/d, produced greater response rates compared with SSRIs plus placebo.³ L-methylfolate also was well tolerated in combination with SSRI or SNRI therapy. The rates of adverse effects were not significantly different in patients taking L-methylfolate plus an SSRI or SNRI compared with those taking SSRI or SNRI monotherapy.¹

MDD patients who may benefit from L-methylfolate include those with low levels of folate and its active metabolites—such as L-methylfolate—and inadequate response to antidepressants. Patients who have an alcohol use disorder, eating disorders, genetic C677-T polymorphism (present in half of the general population), or gastrointestinal disorders are at risk for low folate levels, as well as those who are pregnant.²

Folic acid needs to be converted to L-methylfolate to cross the blood-brain barrier, whereas L-methylfolate can be used directly by the brain.² Therefore, patients who take medications that can interfere with the conversion of folate to L-methylfolate might benefit from adjunctive L-methylfolate. These medications include lamotrigine, valproate, oral contraceptives, metformin, warfarin, fenofibrates, and certain retinoids.¹ Patients with C677-T polymorphism and patients from Hispanic or Mediterranean populations have shown impaired ability to convert folic acid to L-methylfolate.²

Disclosure

Dr. Fluitt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Psychostimulants are recognized for their role in managing attention-deficit/hyperactivity disorder (ADHD), but also have found a treatment niche in conditions such as apathy, fatigue, and depression.¹ Psychostimulants—methylphenidate, amphetamines, and their respective isomers—are known to promote wakefulness, increase energy, and help improve attention. Although these medications can provide much-needed relief to many older patients, clinicians need to be mindful of possible side effects and safety concerns when prescribing psychostimulants for geriatric patients.

Most psychostimulant research has evaluated children and younger adults; however, geriatric patients (age >65) deserve special consideration. Although these patients’ changing physiology often presents treatment challenges and may predispose individuals to adverse events, emerging evidence suggests that psychostimulants are valuable in treating motivational and attentional symptoms that do not respond to other treatments. Older adults’ diminished treatment response to antidepressants, fatigue, and comorbid medical illness make stimulants an attractive treatment option. However, there is a paucity of research addressing psychostimulant use in geriatric patients. Moreover, psychostimulants should be used in older patients only after carefully considering potential side effects and general medical safety.

This article will focus on clinical scenarios in late life—such as apathy, ADHD, and depression in medically ill patients—when treatment with psychostimulants may be useful. Psychostimulants are FDA-approved primarily for use in ADHD and other uses are considered off-label. We will highlight research in this population and use case vignettes as examples to present a sensible approach to treating geriatric patients with psychostimulants (Table).

Table

Using psychostimulants in older adults

Stimulants and apathy

Apathy is a loss of motivation, interest, or initiative that is not attributable to cognitive impairment, diminished consciousness, or emotional suffering.² Considered a distinct entity from depression, apathy is common late in life, particularly in persons with dementia of the Alzheimer’s type (DAT); 70% to 90% of patients may experience apathy at some stage of dementia.³ Apathy is linked to impairment in activities of daily living and needing more assistance from caregivers, which increases caregiver burden. Treating apathetic symptoms may improve quality of life for the patient and caregivers. For a case study of an older patient with apathy treated with a psychostimulant, see Box 1.

Apathy has been treated successfully with a variety of stimulant medications. In an open-label study, patients with DAT who received methylphenidate, 10 to 20 mg/d, showed significant improvement in Apathy Evaluation Scale (AES) scores.⁴ Similarly, Herrmann et al⁵ also demonstrated improvements in AES scores in DAT patients taking methylphenidate, 20 mg/d, compared with placebo. Although methylphenidate appears to have the strongest evidence for treating apathy, dextroamphetamine also has been shown to produce modest improvements in apathy scale measures.⁶ A double-blind, placebo-controlled crossover study showed that dextroamphetamine, 20 mg/d, significantly improved scores on neuropsychiatric inventory scales that were driven by apathy subscales.⁶ However, this trial was small (N = 8).

Preliminary evidence indicates that psychostimulants may improve apathetic symptoms in patients with dementia. In Mr. A’s case (Box 1), he experienced apathy symptoms that affected his quality of life and that of those around him. He showed a clear lack of interest and motivation and indifference. This scenario is common among geriatric patients and may be misinterpreted as depression. Although the overlap may be considerable, screening for apathy may help determine a treatment course with psychostimulants instead of antidepressants, thus avoiding unnecessary medication trials.

Box 1

Stimulants for ADHD

ADHD is a neurobehavioral disorder that is identified in approximately 8% of children and persists in 4% of adults.⁷ ADHD is characterized by impulsivity, motor restlessness, and inattention; the latter feature generally is more prominent with advancing age.⁸ If left untreated, ADHD has societal burdens, such as educational and occupational impairments.⁹ There is little data on ADHD in older adults and no placebo-controlled trials. For a case study of an older patient with ADHD treated with stimulants, see Box 2.¹⁰

Psychostimulants are considered the mainstay of ADHD treatment. First-line treatments include methylphenidate and amphetamines. A meta-analysis found a significant improvement in ADHD symptoms in adult patients taking psychostimulants compared with placebo, with no difference between immediate-release and long-acting formulations.¹¹ Although these findings were reported in younger adults, they may be relevant for older persons as well. Wetzel and Burke¹² described how ADHD presents in older adults and argued that the benefits of treating ADHD in this age group often outweigh the risks associated with psychostimulants, which can be diminished through careful screening.

Individuals who present with ADHD symptoms in late life often appear to be high functioning. Some may describe achieving academic and professional success, but may report chronic problems associated with inefficient learning and distraction compared with their peers because of untreated inattention symptoms. Faraone et al¹³ argue that similar to other illnesses, ADHD is represented by a spectrum of disease, which may be diagnosed in late life or as subthreshold ADHD. Individuals who did not meet diagnostic criteria in childhood or were not evaluated or treated may experience unremitting symptoms that contribute to functional impairment, persistent discouragement, and distress. Frustrations with distractibility, disorganization, and incompletion of tasks may have a psychological impact reflected by low self-esteem and irritability, and be a chronic source of occupational and relationship dysfunction. Diagnosing and treating ADHD in late life can improve longstanding functional impairments and overall quality of life.

Box 2

Other uses

Depression. Although not a first-line treatment, psychostimulants have shown benefit for treating depressive disorders, particularly when patients require immediate improvement. These scenarios are common among medically ill patients, such as those with cancer, stroke, or human immunodeficiency virus (HIV), when it is urgent for patients to participate in their treatment plan. A double-blind, placebo-controlled, randomized study that looked at older depressed patients with medical comorbidities found that methylphenidate was well tolerated, worked quickly, and effectively treated depression.¹⁴ However, these results must be interpreted cautiously because the entire study was conducted in 8 days, which included a crossover design that administered methylphenidate 10 mg/d and 20 mg/d for 2 days each. A review of stimulant effectiveness in patients whose depression was associated with HIV, stroke, or cancer and in medically ill patients argued that although benefits have been reported, they must be interpreted tentatively because of a lack of randomized trials.¹⁵ However, limited evidence supports an effect of stimulants in treating fatigue, anorexia, pain, and sedation in these populations.¹⁵

Stimulants’ immediate onset of action may be particularly useful in terminally ill patients who suffer from fatigue or depression. A double-blind, placebo-controlled, randomized study demonstrated that augmenting citalopram, 20 to 40 mg/d, with methylphenidate, mean dose 15 mg/d, for 3 weeks in older depressed patients significantly improved treatment response and accelerated time to remission compared with citalopram and placebo.¹⁶ However, a recent Cochrane review did not show clear efficacy for psychostimulants to treat depression.¹⁷

Fatigue. Along with depression, fatigue frequently is seen in older patients with medical illnesses. Mood disorders, medical comorbidities, and sleep disturbances are linked to fatigue. Underlying medical causes such as hypothyroidism, anemia, and electrolyte imbalances should be ruled out before starting a psychostimulant. A review by Minton et al¹⁸ that looked at cancer-related fatigue suggested that methylphenidate can be beneficial, although the evidence is mixed.

Interferon-alpha treatment for hepatitis C can cause depression and fatigue, and psychostimulants may help treat fatigue-related side effects.¹⁹ Fatigue may present as an isolated symptom in interferon-alpha treatment and psychostimulant use may prevent patients from taking an additional medication, therefore decreasing the risk of further side effects.

Fall risk. Some evidence supports using psychostimulants to lower the risk of falling and hypoactive delirium. A recent review by Elie et al²⁰ concluded that stimulants could improve cognitive function in end-of-life hypoactive delirium. Additionally, a randomized, placebo-controlled, double-blind study that evaluated fall risk concluded that methylphenidate, 20 mg/d, might improve some aspects of executive function and gait stability in older adults.²¹ The authors hypothesized that improved cognition associated with psychostimulant use may play a role in improving fall risk.

Safety concerns

Clinicians should be aware of safety considerations and possible side effects when prescribing psychostimulants. Psychostimulants are controlled substances and are subject to restrictions (Box 3).²² In 2007, the FDA issued warnings regarding an association between psychostimulant use and sudden death, myocardial infarction, and stroke in patients with preexisting cardiac abnormalities or heart problems.²³ Also, some evidence indicates that psychostimulants can increase heart rate and systolic blood pressure. These parameters should be monitored during treatment. Reducing or stopping psychostimulants generally reverses cardiovascular effects. Although the evidence to support these events appears sparse, perform a thorough history before beginning a stimulant and make appropriate referrals as indicated. In November 2011, the FDA reported that psychostimulant use in children and young adults is not associated with adverse cardiovascular events, including stroke, heart attack, and sudden cardiac death.²⁴

Less common side effects reported with psychostimulants include anxiety, insomnia, hallucinations, anorexia, delirium, palpitations, and headache. A meta-analysis of studies of adults with ADHD found that adverse events related to psychostimulants were relatively rare; the most common side effects were diminished appetite and difficulty sleeping.²⁵ Sleep-related side effects can be avoided by dosing these medications earlier in the day, typically before 5 pm. Herrmann et al⁵ reported 2 cases of apparent delirium and 1 with irregular heartbeat in patients with DAT taking methylphenidate vs placebo. However, most patients in this study experienced mild or no adverse events.

Other safety concerns involve using methylphenidate in patients with glaucoma. In theory, stimulants could exacerbate an acute attack of glaucoma in patients with narrow-angle glaucoma. Patients at risk should be referred to an ophthalmologist for an assessment.

Review other medications the patient is taking and assess for possible drug-drug interactions. Combining monoamine oxidase inhibitors (MAOIs) and methylphenidate warrants caution because of the risk of serotonin syndrome and hypertensive crisis. However, there are case reports of successful MAOI/methylphenidate therapy.²⁶ Additionally, methylphenidate increases levels of warfarin and tricyclic antidepressants when taken with these agents.²⁷ Psychostimulants generally are well tolerated by most individuals and taking a careful history may help prevent adverse events.

Box 3

Related Resources

• Kessler RC, Adler L, Ames M, et al. The World Health Organization Adult ADHD Self-Report Scale (ASRS): a short screening scale for use in the general population. Psychol Med. 2005;35(2):245-256.
• Alexopoulos GS, Salzman C. Treatment of depression with heterocyclic antidepressants, monoamine oxidase inhibitors, and psychomotor stimulants. In: Salzman C, ed. Clinical geriatric psychopharmacology. Baltimore, MD: Williams and Wilkins; 1998:184-244.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Dexmethylphenidate • Focalin
• Dextroamphetamine • Dexedrine
• Donepezil • Aricept
• Lisdexamfetamine • Vyvanse
• Methamphetamine • Desoxyn
• Methylphenidate • Ritalin, Concerta
• Mixed amphetamine salts • Adderall
• Warfarin • Coumadin

Disclosures

Dr. Padala receives research funding from the Department of Veterans Health Administration and the Alzheimer’s Association.

Drs. Franzen, Wetzel, and Burke report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Psychostimulants are recognized for their role in managing attention-deficit/hyperactivity disorder (ADHD), but also have found a treatment niche in conditions such as apathy, fatigue, and depression.¹ Psychostimulants—methylphenidate, amphetamines, and their respective isomers—are known to promote wakefulness, increase energy, and help improve attention. Although these medications can provide much-needed relief to many older patients, clinicians need to be mindful of possible side effects and safety concerns when prescribing psychostimulants for geriatric patients.

Most psychostimulant research has evaluated children and younger adults; however, geriatric patients (age >65) deserve special consideration. Although these patients’ changing physiology often presents treatment challenges and may predispose individuals to adverse events, emerging evidence suggests that psychostimulants are valuable in treating motivational and attentional symptoms that do not respond to other treatments. Older adults’ diminished treatment response to antidepressants, fatigue, and comorbid medical illness make stimulants an attractive treatment option. However, there is a paucity of research addressing psychostimulant use in geriatric patients. Moreover, psychostimulants should be used in older patients only after carefully considering potential side effects and general medical safety.

This article will focus on clinical scenarios in late life—such as apathy, ADHD, and depression in medically ill patients—when treatment with psychostimulants may be useful. Psychostimulants are FDA-approved primarily for use in ADHD and other uses are considered off-label. We will highlight research in this population and use case vignettes as examples to present a sensible approach to treating geriatric patients with psychostimulants (Table).

Table

Using psychostimulants in older adults

Stimulants and apathy

Apathy is a loss of motivation, interest, or initiative that is not attributable to cognitive impairment, diminished consciousness, or emotional suffering.² Considered a distinct entity from depression, apathy is common late in life, particularly in persons with dementia of the Alzheimer’s type (DAT); 70% to 90% of patients may experience apathy at some stage of dementia.³ Apathy is linked to impairment in activities of daily living and needing more assistance from caregivers, which increases caregiver burden. Treating apathetic symptoms may improve quality of life for the patient and caregivers. For a case study of an older patient with apathy treated with a psychostimulant, see Box 1.

Apathy has been treated successfully with a variety of stimulant medications. In an open-label study, patients with DAT who received methylphenidate, 10 to 20 mg/d, showed significant improvement in Apathy Evaluation Scale (AES) scores.⁴ Similarly, Herrmann et al⁵ also demonstrated improvements in AES scores in DAT patients taking methylphenidate, 20 mg/d, compared with placebo. Although methylphenidate appears to have the strongest evidence for treating apathy, dextroamphetamine also has been shown to produce modest improvements in apathy scale measures.⁶ A double-blind, placebo-controlled crossover study showed that dextroamphetamine, 20 mg/d, significantly improved scores on neuropsychiatric inventory scales that were driven by apathy subscales.⁶ However, this trial was small (N = 8).

Preliminary evidence indicates that psychostimulants may improve apathetic symptoms in patients with dementia. In Mr. A’s case (Box 1), he experienced apathy symptoms that affected his quality of life and that of those around him. He showed a clear lack of interest and motivation and indifference. This scenario is common among geriatric patients and may be misinterpreted as depression. Although the overlap may be considerable, screening for apathy may help determine a treatment course with psychostimulants instead of antidepressants, thus avoiding unnecessary medication trials.

Box 1

Stimulants for ADHD

ADHD is a neurobehavioral disorder that is identified in approximately 8% of children and persists in 4% of adults.⁷ ADHD is characterized by impulsivity, motor restlessness, and inattention; the latter feature generally is more prominent with advancing age.⁸ If left untreated, ADHD has societal burdens, such as educational and occupational impairments.⁹ There is little data on ADHD in older adults and no placebo-controlled trials. For a case study of an older patient with ADHD treated with stimulants, see Box 2.¹⁰

Psychostimulants are considered the mainstay of ADHD treatment. First-line treatments include methylphenidate and amphetamines. A meta-analysis found a significant improvement in ADHD symptoms in adult patients taking psychostimulants compared with placebo, with no difference between immediate-release and long-acting formulations.¹¹ Although these findings were reported in younger adults, they may be relevant for older persons as well. Wetzel and Burke¹² described how ADHD presents in older adults and argued that the benefits of treating ADHD in this age group often outweigh the risks associated with psychostimulants, which can be diminished through careful screening.

Individuals who present with ADHD symptoms in late life often appear to be high functioning. Some may describe achieving academic and professional success, but may report chronic problems associated with inefficient learning and distraction compared with their peers because of untreated inattention symptoms. Faraone et al¹³ argue that similar to other illnesses, ADHD is represented by a spectrum of disease, which may be diagnosed in late life or as subthreshold ADHD. Individuals who did not meet diagnostic criteria in childhood or were not evaluated or treated may experience unremitting symptoms that contribute to functional impairment, persistent discouragement, and distress. Frustrations with distractibility, disorganization, and incompletion of tasks may have a psychological impact reflected by low self-esteem and irritability, and be a chronic source of occupational and relationship dysfunction. Diagnosing and treating ADHD in late life can improve longstanding functional impairments and overall quality of life.

Box 2

Other uses

Depression. Although not a first-line treatment, psychostimulants have shown benefit for treating depressive disorders, particularly when patients require immediate improvement. These scenarios are common among medically ill patients, such as those with cancer, stroke, or human immunodeficiency virus (HIV), when it is urgent for patients to participate in their treatment plan. A double-blind, placebo-controlled, randomized study that looked at older depressed patients with medical comorbidities found that methylphenidate was well tolerated, worked quickly, and effectively treated depression.¹⁴ However, these results must be interpreted cautiously because the entire study was conducted in 8 days, which included a crossover design that administered methylphenidate 10 mg/d and 20 mg/d for 2 days each. A review of stimulant effectiveness in patients whose depression was associated with HIV, stroke, or cancer and in medically ill patients argued that although benefits have been reported, they must be interpreted tentatively because of a lack of randomized trials.¹⁵ However, limited evidence supports an effect of stimulants in treating fatigue, anorexia, pain, and sedation in these populations.¹⁵

Stimulants’ immediate onset of action may be particularly useful in terminally ill patients who suffer from fatigue or depression. A double-blind, placebo-controlled, randomized study demonstrated that augmenting citalopram, 20 to 40 mg/d, with methylphenidate, mean dose 15 mg/d, for 3 weeks in older depressed patients significantly improved treatment response and accelerated time to remission compared with citalopram and placebo.¹⁶ However, a recent Cochrane review did not show clear efficacy for psychostimulants to treat depression.¹⁷

Fatigue. Along with depression, fatigue frequently is seen in older patients with medical illnesses. Mood disorders, medical comorbidities, and sleep disturbances are linked to fatigue. Underlying medical causes such as hypothyroidism, anemia, and electrolyte imbalances should be ruled out before starting a psychostimulant. A review by Minton et al¹⁸ that looked at cancer-related fatigue suggested that methylphenidate can be beneficial, although the evidence is mixed.

Interferon-alpha treatment for hepatitis C can cause depression and fatigue, and psychostimulants may help treat fatigue-related side effects.¹⁹ Fatigue may present as an isolated symptom in interferon-alpha treatment and psychostimulant use may prevent patients from taking an additional medication, therefore decreasing the risk of further side effects.

Fall risk. Some evidence supports using psychostimulants to lower the risk of falling and hypoactive delirium. A recent review by Elie et al²⁰ concluded that stimulants could improve cognitive function in end-of-life hypoactive delirium. Additionally, a randomized, placebo-controlled, double-blind study that evaluated fall risk concluded that methylphenidate, 20 mg/d, might improve some aspects of executive function and gait stability in older adults.²¹ The authors hypothesized that improved cognition associated with psychostimulant use may play a role in improving fall risk.

Safety concerns

Clinicians should be aware of safety considerations and possible side effects when prescribing psychostimulants. Psychostimulants are controlled substances and are subject to restrictions (Box 3).²² In 2007, the FDA issued warnings regarding an association between psychostimulant use and sudden death, myocardial infarction, and stroke in patients with preexisting cardiac abnormalities or heart problems.²³ Also, some evidence indicates that psychostimulants can increase heart rate and systolic blood pressure. These parameters should be monitored during treatment. Reducing or stopping psychostimulants generally reverses cardiovascular effects. Although the evidence to support these events appears sparse, perform a thorough history before beginning a stimulant and make appropriate referrals as indicated. In November 2011, the FDA reported that psychostimulant use in children and young adults is not associated with adverse cardiovascular events, including stroke, heart attack, and sudden cardiac death.²⁴

Less common side effects reported with psychostimulants include anxiety, insomnia, hallucinations, anorexia, delirium, palpitations, and headache. A meta-analysis of studies of adults with ADHD found that adverse events related to psychostimulants were relatively rare; the most common side effects were diminished appetite and difficulty sleeping.²⁵ Sleep-related side effects can be avoided by dosing these medications earlier in the day, typically before 5 pm. Herrmann et al⁵ reported 2 cases of apparent delirium and 1 with irregular heartbeat in patients with DAT taking methylphenidate vs placebo. However, most patients in this study experienced mild or no adverse events.

Other safety concerns involve using methylphenidate in patients with glaucoma. In theory, stimulants could exacerbate an acute attack of glaucoma in patients with narrow-angle glaucoma. Patients at risk should be referred to an ophthalmologist for an assessment.

Review other medications the patient is taking and assess for possible drug-drug interactions. Combining monoamine oxidase inhibitors (MAOIs) and methylphenidate warrants caution because of the risk of serotonin syndrome and hypertensive crisis. However, there are case reports of successful MAOI/methylphenidate therapy.²⁶ Additionally, methylphenidate increases levels of warfarin and tricyclic antidepressants when taken with these agents.²⁷ Psychostimulants generally are well tolerated by most individuals and taking a careful history may help prevent adverse events.

Box 3

Related Resources

• Kessler RC, Adler L, Ames M, et al. The World Health Organization Adult ADHD Self-Report Scale (ASRS): a short screening scale for use in the general population. Psychol Med. 2005;35(2):245-256.
• Alexopoulos GS, Salzman C. Treatment of depression with heterocyclic antidepressants, monoamine oxidase inhibitors, and psychomotor stimulants. In: Salzman C, ed. Clinical geriatric psychopharmacology. Baltimore, MD: Williams and Wilkins; 1998:184-244.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Dexmethylphenidate • Focalin
• Dextroamphetamine • Dexedrine
• Donepezil • Aricept
• Lisdexamfetamine • Vyvanse
• Methamphetamine • Desoxyn
• Methylphenidate • Ritalin, Concerta
• Mixed amphetamine salts • Adderall
• Warfarin • Coumadin

Disclosures

Dr. Padala receives research funding from the Department of Veterans Health Administration and the Alzheimer’s Association.

Drs. Franzen, Wetzel, and Burke report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Psychostimulants are recognized for their role in managing attention-deficit/hyperactivity disorder (ADHD), but also have found a treatment niche in conditions such as apathy, fatigue, and depression.¹ Psychostimulants—methylphenidate, amphetamines, and their respective isomers—are known to promote wakefulness, increase energy, and help improve attention. Although these medications can provide much-needed relief to many older patients, clinicians need to be mindful of possible side effects and safety concerns when prescribing psychostimulants for geriatric patients.

Most psychostimulant research has evaluated children and younger adults; however, geriatric patients (age >65) deserve special consideration. Although these patients’ changing physiology often presents treatment challenges and may predispose individuals to adverse events, emerging evidence suggests that psychostimulants are valuable in treating motivational and attentional symptoms that do not respond to other treatments. Older adults’ diminished treatment response to antidepressants, fatigue, and comorbid medical illness make stimulants an attractive treatment option. However, there is a paucity of research addressing psychostimulant use in geriatric patients. Moreover, psychostimulants should be used in older patients only after carefully considering potential side effects and general medical safety.

This article will focus on clinical scenarios in late life—such as apathy, ADHD, and depression in medically ill patients—when treatment with psychostimulants may be useful. Psychostimulants are FDA-approved primarily for use in ADHD and other uses are considered off-label. We will highlight research in this population and use case vignettes as examples to present a sensible approach to treating geriatric patients with psychostimulants (Table).

Table

Using psychostimulants in older adults

Stimulants and apathy

Apathy is a loss of motivation, interest, or initiative that is not attributable to cognitive impairment, diminished consciousness, or emotional suffering.² Considered a distinct entity from depression, apathy is common late in life, particularly in persons with dementia of the Alzheimer’s type (DAT); 70% to 90% of patients may experience apathy at some stage of dementia.³ Apathy is linked to impairment in activities of daily living and needing more assistance from caregivers, which increases caregiver burden. Treating apathetic symptoms may improve quality of life for the patient and caregivers. For a case study of an older patient with apathy treated with a psychostimulant, see Box 1.

Apathy has been treated successfully with a variety of stimulant medications. In an open-label study, patients with DAT who received methylphenidate, 10 to 20 mg/d, showed significant improvement in Apathy Evaluation Scale (AES) scores.⁴ Similarly, Herrmann et al⁵ also demonstrated improvements in AES scores in DAT patients taking methylphenidate, 20 mg/d, compared with placebo. Although methylphenidate appears to have the strongest evidence for treating apathy, dextroamphetamine also has been shown to produce modest improvements in apathy scale measures.⁶ A double-blind, placebo-controlled crossover study showed that dextroamphetamine, 20 mg/d, significantly improved scores on neuropsychiatric inventory scales that were driven by apathy subscales.⁶ However, this trial was small (N = 8).

Preliminary evidence indicates that psychostimulants may improve apathetic symptoms in patients with dementia. In Mr. A’s case (Box 1), he experienced apathy symptoms that affected his quality of life and that of those around him. He showed a clear lack of interest and motivation and indifference. This scenario is common among geriatric patients and may be misinterpreted as depression. Although the overlap may be considerable, screening for apathy may help determine a treatment course with psychostimulants instead of antidepressants, thus avoiding unnecessary medication trials.

Box 1

Stimulants for ADHD

ADHD is a neurobehavioral disorder that is identified in approximately 8% of children and persists in 4% of adults.⁷ ADHD is characterized by impulsivity, motor restlessness, and inattention; the latter feature generally is more prominent with advancing age.⁸ If left untreated, ADHD has societal burdens, such as educational and occupational impairments.⁹ There is little data on ADHD in older adults and no placebo-controlled trials. For a case study of an older patient with ADHD treated with stimulants, see Box 2.¹⁰

Psychostimulants are considered the mainstay of ADHD treatment. First-line treatments include methylphenidate and amphetamines. A meta-analysis found a significant improvement in ADHD symptoms in adult patients taking psychostimulants compared with placebo, with no difference between immediate-release and long-acting formulations.¹¹ Although these findings were reported in younger adults, they may be relevant for older persons as well. Wetzel and Burke¹² described how ADHD presents in older adults and argued that the benefits of treating ADHD in this age group often outweigh the risks associated with psychostimulants, which can be diminished through careful screening.

Individuals who present with ADHD symptoms in late life often appear to be high functioning. Some may describe achieving academic and professional success, but may report chronic problems associated with inefficient learning and distraction compared with their peers because of untreated inattention symptoms. Faraone et al¹³ argue that similar to other illnesses, ADHD is represented by a spectrum of disease, which may be diagnosed in late life or as subthreshold ADHD. Individuals who did not meet diagnostic criteria in childhood or were not evaluated or treated may experience unremitting symptoms that contribute to functional impairment, persistent discouragement, and distress. Frustrations with distractibility, disorganization, and incompletion of tasks may have a psychological impact reflected by low self-esteem and irritability, and be a chronic source of occupational and relationship dysfunction. Diagnosing and treating ADHD in late life can improve longstanding functional impairments and overall quality of life.

Box 2

Other uses

Depression. Although not a first-line treatment, psychostimulants have shown benefit for treating depressive disorders, particularly when patients require immediate improvement. These scenarios are common among medically ill patients, such as those with cancer, stroke, or human immunodeficiency virus (HIV), when it is urgent for patients to participate in their treatment plan. A double-blind, placebo-controlled, randomized study that looked at older depressed patients with medical comorbidities found that methylphenidate was well tolerated, worked quickly, and effectively treated depression.¹⁴ However, these results must be interpreted cautiously because the entire study was conducted in 8 days, which included a crossover design that administered methylphenidate 10 mg/d and 20 mg/d for 2 days each. A review of stimulant effectiveness in patients whose depression was associated with HIV, stroke, or cancer and in medically ill patients argued that although benefits have been reported, they must be interpreted tentatively because of a lack of randomized trials.¹⁵ However, limited evidence supports an effect of stimulants in treating fatigue, anorexia, pain, and sedation in these populations.¹⁵

Stimulants’ immediate onset of action may be particularly useful in terminally ill patients who suffer from fatigue or depression. A double-blind, placebo-controlled, randomized study demonstrated that augmenting citalopram, 20 to 40 mg/d, with methylphenidate, mean dose 15 mg/d, for 3 weeks in older depressed patients significantly improved treatment response and accelerated time to remission compared with citalopram and placebo.¹⁶ However, a recent Cochrane review did not show clear efficacy for psychostimulants to treat depression.¹⁷

Fatigue. Along with depression, fatigue frequently is seen in older patients with medical illnesses. Mood disorders, medical comorbidities, and sleep disturbances are linked to fatigue. Underlying medical causes such as hypothyroidism, anemia, and electrolyte imbalances should be ruled out before starting a psychostimulant. A review by Minton et al¹⁸ that looked at cancer-related fatigue suggested that methylphenidate can be beneficial, although the evidence is mixed.

Interferon-alpha treatment for hepatitis C can cause depression and fatigue, and psychostimulants may help treat fatigue-related side effects.¹⁹ Fatigue may present as an isolated symptom in interferon-alpha treatment and psychostimulant use may prevent patients from taking an additional medication, therefore decreasing the risk of further side effects.

Fall risk. Some evidence supports using psychostimulants to lower the risk of falling and hypoactive delirium. A recent review by Elie et al²⁰ concluded that stimulants could improve cognitive function in end-of-life hypoactive delirium. Additionally, a randomized, placebo-controlled, double-blind study that evaluated fall risk concluded that methylphenidate, 20 mg/d, might improve some aspects of executive function and gait stability in older adults.²¹ The authors hypothesized that improved cognition associated with psychostimulant use may play a role in improving fall risk.

Safety concerns

Clinicians should be aware of safety considerations and possible side effects when prescribing psychostimulants. Psychostimulants are controlled substances and are subject to restrictions (Box 3).²² In 2007, the FDA issued warnings regarding an association between psychostimulant use and sudden death, myocardial infarction, and stroke in patients with preexisting cardiac abnormalities or heart problems.²³ Also, some evidence indicates that psychostimulants can increase heart rate and systolic blood pressure. These parameters should be monitored during treatment. Reducing or stopping psychostimulants generally reverses cardiovascular effects. Although the evidence to support these events appears sparse, perform a thorough history before beginning a stimulant and make appropriate referrals as indicated. In November 2011, the FDA reported that psychostimulant use in children and young adults is not associated with adverse cardiovascular events, including stroke, heart attack, and sudden cardiac death.²⁴

Less common side effects reported with psychostimulants include anxiety, insomnia, hallucinations, anorexia, delirium, palpitations, and headache. A meta-analysis of studies of adults with ADHD found that adverse events related to psychostimulants were relatively rare; the most common side effects were diminished appetite and difficulty sleeping.²⁵ Sleep-related side effects can be avoided by dosing these medications earlier in the day, typically before 5 pm. Herrmann et al⁵ reported 2 cases of apparent delirium and 1 with irregular heartbeat in patients with DAT taking methylphenidate vs placebo. However, most patients in this study experienced mild or no adverse events.

Other safety concerns involve using methylphenidate in patients with glaucoma. In theory, stimulants could exacerbate an acute attack of glaucoma in patients with narrow-angle glaucoma. Patients at risk should be referred to an ophthalmologist for an assessment.

Review other medications the patient is taking and assess for possible drug-drug interactions. Combining monoamine oxidase inhibitors (MAOIs) and methylphenidate warrants caution because of the risk of serotonin syndrome and hypertensive crisis. However, there are case reports of successful MAOI/methylphenidate therapy.²⁶ Additionally, methylphenidate increases levels of warfarin and tricyclic antidepressants when taken with these agents.²⁷ Psychostimulants generally are well tolerated by most individuals and taking a careful history may help prevent adverse events.

Box 3

Related Resources

• Kessler RC, Adler L, Ames M, et al. The World Health Organization Adult ADHD Self-Report Scale (ASRS): a short screening scale for use in the general population. Psychol Med. 2005;35(2):245-256.
• Alexopoulos GS, Salzman C. Treatment of depression with heterocyclic antidepressants, monoamine oxidase inhibitors, and psychomotor stimulants. In: Salzman C, ed. Clinical geriatric psychopharmacology. Baltimore, MD: Williams and Wilkins; 1998:184-244.

Drug Brand Names

• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Dexmethylphenidate • Focalin
• Dextroamphetamine • Dexedrine
• Donepezil • Aricept
• Lisdexamfetamine • Vyvanse
• Methamphetamine • Desoxyn
• Methylphenidate • Ritalin, Concerta
• Mixed amphetamine salts • Adderall
• Warfarin • Coumadin

Disclosures

Dr. Padala receives research funding from the Department of Veterans Health Administration and the Alzheimer’s Association.

Drs. Franzen, Wetzel, and Burke report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. D, a 72-year-old Christian with a long history of schizophrenia, presents to the emergency room with concerns about evil spirits in his home who have poisoned him. He has called for police assistance on numerous occasions and has tried to kill the evil spirits with his rifle, but states “they are bulletproof.” He is unable to sleep and is “fearful for my life every night because that is when the demons come out.” Mr. D also believes that God is “more powerful than the evil spirits.” Two elders at his church have prayed with him and encouraged him to go to the hospital.

Delusions with religious content (DRC) are associated with poorer clinical outcomes and dangerousness.^1-6 Most mental health professionals will encounter patients with DRC because this type of delusion is relatively common in patients with symptoms of mania or psychosis. For example, in a study of 193 inpatients with schizophrenia, 24% had religious delusions.¹ The prevalence of DRC varies considerably among populations and can be influenced by the local religion and culture.^7-9 This article reviews clinical challenges and assessment and management strategies for patients with DRC.

A challenging course

In a UK study of 193 inpatients with schizophrenia, compared with patients with other types of delusions, those with DRC:

• had higher Positive and Negative Syndrome Scale scores and lower Global Assessment of Functioning scores
• waited longer before reengaging in treatment
• were prescribed more medications.¹

In addition, compared with patients with other types of delusions, patients with DRC often hold these delusions with greater conviction,^1,2 making them more challenging to treat.

Dangerousness in patients with DRC can manifest as self-harm or harm to others. Extreme examples include self-inflicted enucleation of the eye and autocastration. In a review of 9 cases of severe ocular self-injury, 4 patients had DRC.³ Genital self-mutilation associated with DRC is rare, but several cases of psychotic men who performed autocastration based on a literal, erroneous interpretation of a passage in the Bible (Matthew 19:12) have been reported.^4,5 Patients with DRC have committed rape and murder because they believed they were the antichrist.⁶

In this article we use the phrase “delusions with religious content” instead of “religious delusions” because this distinction highlights that many subtypes of delusions can have a religious theme. Categories of delusions with religious themes include:

• persecutory (often involving Satan)
• grandiose (messianic delusions)
• guilt delusions.

Categorizing DRC is important because some are associated with more distress or dangerousness than others. For example, case studies of self-inflicted eye injuries found that most patients had guilt delusions with religious themes that referenced punishing transgressions, controlling unacceptable sexual impulses, and attaining prescience by destroying vision.^3,10 In our example, Mr. D is experiencing a persecutory DRC. Also, using the label “religious delusion” can inadvertently pathologize religious experiences.

Tips for effective evaluation

DSM-IV-TR offers no specific guidelines for assessing DRC vs nondelusional religious beliefs.¹¹ There is risk of pathologizing religious beliefs when listening to content alone.^11-15 Instead, focus on the conviction, pervasiveness,² uniqueness or bizarreness, and associated emotional distress of the delusion to the patient (Table 1).^2,12,16-18

In the context of the patient’s spiritual history, deviations from conventional religious beliefs and practices are important factors in determining whether a religious belief is authentic or delusional. Involving family members and/or spiritual care professionals (eg, chaplains and clergy) can be especially helpful when making this differentiation.^16,17 In the hospital, chaplains often are familiar with a variety of faith traditions and may provide important insight into the patient’s beliefs. In the community, clergy members from the patient’s faith also may provide valuable perspective.

Similar to how having a basic familiarity with a patient’s culture can improve care, a better understanding of a patient’s spiritual or religious beliefs and practices can build rapport and the therapeutic alliance.^16,17 This is particularly important with patients with DRC because these individuals often have a poor therapeutic alliance and engagement with providers.¹⁹ Because many psychiatrists have limited time and may not be familiar with every patient’s spiritual or religious background, consultation with spiritual care professionals may be helpful.

Assess whether your patient has reservations about psychiatric treatment. Some may believe that seeking care from a doctor is evidence of weak faith, whereas others may feel that psychiatric treatment is forbidden or incompatible with their religious beliefs.^19-22 Mental health clinicians need to consider their own religious biases that may cause them to minimize or pathologize a patient’s religiosity.^20,23 Working collaboratively with spiritual care professionals may help reduce clinician biases or assumptions.²⁴

Table 1

Assessing patients with DRC

Evaluating safety

When constructing a differential diagnosis and evaluating patients for safety, remember that DRC are a feature of many psychiatric disorders (eg, persecutory DRC in schizophrenia, grandiose DRC in mania). Consider the course and severity of the patient’s illness, and determine if he or she has a history or evidence of self-injury or substance abuse. Be cognizant of the categories of delusions in the context of the diagnosis. For example, grandiose delusions that involve the antichrist can be associated with harm toward others.⁶ Patients who express extreme feelings of guilt or shame (as seen in psychotic depression) and the need to be physically punished may be at risk for self-harm. Finally, patients seeking evidence to support misguided and dangerous beliefs—for example, obsessing over a religious text regarding self-injury while in a delusional state—may be at high risk for self-harm.¹⁸

Researchers have suggested clinicians question patients to determine if they trust their delusions.²⁵ Patients who trust their delusions may appear calm if they already have decided to act on their thoughts.²⁵ Preventive measures for patients at risk of self-harm include close observation, hospitalization, and pharmacotherapy.

Pharmacotherapy for DRC

There are no clear recommendations on specific psychotropics or dosages for treating patients with DRC. When a patient with DRC is at high risk of self-harm or harming others, using antipsychotics, anxiolytics, hypnotics, or a combination of these agents sometimes is needed to quell agitation, along with close observation and restraints when necessary (Table 2).^5,18,25,26 Mr. D benefited from risperidone, 3 mg at bedtime, and zolpidem, 10 mg as needed for insomnia.

Table 2

Treating patients with DRC

Using spirituality to cope

Many persistently mentally ill patients identify themselves as religious and use religious activities or beliefs to cope with their illness.^27,28 In a study of 1,824 seriously mentally ill patients, self-reports of religiousness were positively associated with psychological well-being and diminished psychiatric symptoms.²⁹ Longitudinal research has shown that some aspects of spirituality and religion are associated with positive mental and physical health effects, whereas other aspects can worsen symptoms.³⁰ Specifically, positive religious coping such as benevolent religious reappraisals (eg, “Jesus is my shield and savior”), collaborative religious coping, and spiritual support are associated with positive mental health.³¹ However, negative religious coping, such as punishing God reappraisals and reappraisals of God’s power (eg, “my illness is punishment for my sins”), are associated with distress and personal loss.³²

For patients with psychotic disorders—and with schizophrenia in particular—religious beliefs can be a source of meaning, hope, strength, and recovery. In a study of 115 outpatients with psychosis, 71% used positive religious coping, compared with 14% who used negative religious coping.³³ Among 38 patients with DRC, 45% used spirituality and religion to help cope with their illness, even though they received less support from religious communities than patients with other types of delusions.¹⁹ In this study, the authors suggest that positive religious coping among patients with DRC may alleviate delusion severity by decreasing levels of conviction and fear and preventing maladjusted behaviors.¹⁹ Religious beliefs and activities are associated with fewer hospitalizations among patients with persistent mental illness²⁸ and are a significant protective factor against suicide in patients with psychotic disorders.^34,35 However, some studies have found that intense, obsessive participation in spiritual activities can worsen psychiatric symptoms and undermine recovery.^1,36,37

Addressing religion in treatment.

Although many studies have emphasized the importance of religion to patients with psychosis, evidence-based guidelines on how best to address religion/spirituality in the clinical setting in patients with psychosis have yet to be established. In a 2011 study, a spiritual assessment was well tolerated by 40 patients with psychotic disorders and improved patients’ appointment attendance compared with a control group who received traditional care only.²⁶

Many mental health providers feel ill-equipped or are uncomfortable exploring spiritual or religious issues with patients. Enlisting the help of spiritual care professionals when assessing patients with DRC may improve evaluation and care (Table 3). Spiritual care professionals typically are experienced in exploring subjects associated with DRC, such as guilt, morality, conscience, repentance, and confession.²⁴ Spiritual care professionals also may be able to assist patients with religious coping and provide comfort and support.

Finally, spiritual care professionals can help patients connect or reconnect to a spiritual or religious community. In Mr. D’s case, the hospital chaplain deterred him from focusing on the reason the evil spirits were trying to punish him and guided him toward positive religious coping. Mr. D felt we were listening to him on a deeper level and understanding his spiritual struggles. The chaplain’s involvement also enhanced Mr. D’s relationship with the psychiatrist.

Table 3

When to elicit help from spiritual care professionals

Related Resources

• Mohr S, Borras L, Betrisey C, et al. Delusions with religious content in patients with psychosis: how they interact with spiritual coping. Psychiatry. 2010;73(2):158-172.
• Huguelet P, Mohr S, Betrisey C, et al. A randomized trial of spiritual assessment of outpatients with schizophrenia: patients’ and clinicians’ experience. Psychiatr Serv. 2011;62(1):79-86.

Drug Brand Names

• Risperidone • Risperdal
• Zolpidem • Ambien

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgements

The authors acknowledge the support and guidance of Rev. Sean Doll O’Mahoney, Rev. Julie Hanada, Rev. Stephen King, PhD, Rev. George Fitchett, PhD, Patricia Murphy, PhD, LCPC, and Kevin Flannelly, PhD.

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. D, a 72-year-old Christian with a long history of schizophrenia, presents to the emergency room with concerns about evil spirits in his home who have poisoned him. He has called for police assistance on numerous occasions and has tried to kill the evil spirits with his rifle, but states “they are bulletproof.” He is unable to sleep and is “fearful for my life every night because that is when the demons come out.” Mr. D also believes that God is “more powerful than the evil spirits.” Two elders at his church have prayed with him and encouraged him to go to the hospital.

Delusions with religious content (DRC) are associated with poorer clinical outcomes and dangerousness.^1-6 Most mental health professionals will encounter patients with DRC because this type of delusion is relatively common in patients with symptoms of mania or psychosis. For example, in a study of 193 inpatients with schizophrenia, 24% had religious delusions.¹ The prevalence of DRC varies considerably among populations and can be influenced by the local religion and culture.^7-9 This article reviews clinical challenges and assessment and management strategies for patients with DRC.

A challenging course

In a UK study of 193 inpatients with schizophrenia, compared with patients with other types of delusions, those with DRC:

• had higher Positive and Negative Syndrome Scale scores and lower Global Assessment of Functioning scores
• waited longer before reengaging in treatment
• were prescribed more medications.¹

In addition, compared with patients with other types of delusions, patients with DRC often hold these delusions with greater conviction,^1,2 making them more challenging to treat.

Dangerousness in patients with DRC can manifest as self-harm or harm to others. Extreme examples include self-inflicted enucleation of the eye and autocastration. In a review of 9 cases of severe ocular self-injury, 4 patients had DRC.³ Genital self-mutilation associated with DRC is rare, but several cases of psychotic men who performed autocastration based on a literal, erroneous interpretation of a passage in the Bible (Matthew 19:12) have been reported.^4,5 Patients with DRC have committed rape and murder because they believed they were the antichrist.⁶

In this article we use the phrase “delusions with religious content” instead of “religious delusions” because this distinction highlights that many subtypes of delusions can have a religious theme. Categories of delusions with religious themes include:

• persecutory (often involving Satan)
• grandiose (messianic delusions)
• guilt delusions.

Categorizing DRC is important because some are associated with more distress or dangerousness than others. For example, case studies of self-inflicted eye injuries found that most patients had guilt delusions with religious themes that referenced punishing transgressions, controlling unacceptable sexual impulses, and attaining prescience by destroying vision.^3,10 In our example, Mr. D is experiencing a persecutory DRC. Also, using the label “religious delusion” can inadvertently pathologize religious experiences.

Tips for effective evaluation

DSM-IV-TR offers no specific guidelines for assessing DRC vs nondelusional religious beliefs.¹¹ There is risk of pathologizing religious beliefs when listening to content alone.^11-15 Instead, focus on the conviction, pervasiveness,² uniqueness or bizarreness, and associated emotional distress of the delusion to the patient (Table 1).^2,12,16-18

In the context of the patient’s spiritual history, deviations from conventional religious beliefs and practices are important factors in determining whether a religious belief is authentic or delusional. Involving family members and/or spiritual care professionals (eg, chaplains and clergy) can be especially helpful when making this differentiation.^16,17 In the hospital, chaplains often are familiar with a variety of faith traditions and may provide important insight into the patient’s beliefs. In the community, clergy members from the patient’s faith also may provide valuable perspective.

Similar to how having a basic familiarity with a patient’s culture can improve care, a better understanding of a patient’s spiritual or religious beliefs and practices can build rapport and the therapeutic alliance.^16,17 This is particularly important with patients with DRC because these individuals often have a poor therapeutic alliance and engagement with providers.¹⁹ Because many psychiatrists have limited time and may not be familiar with every patient’s spiritual or religious background, consultation with spiritual care professionals may be helpful.

Assess whether your patient has reservations about psychiatric treatment. Some may believe that seeking care from a doctor is evidence of weak faith, whereas others may feel that psychiatric treatment is forbidden or incompatible with their religious beliefs.^19-22 Mental health clinicians need to consider their own religious biases that may cause them to minimize or pathologize a patient’s religiosity.^20,23 Working collaboratively with spiritual care professionals may help reduce clinician biases or assumptions.²⁴

Table 1

Assessing patients with DRC

Evaluating safety

When constructing a differential diagnosis and evaluating patients for safety, remember that DRC are a feature of many psychiatric disorders (eg, persecutory DRC in schizophrenia, grandiose DRC in mania). Consider the course and severity of the patient’s illness, and determine if he or she has a history or evidence of self-injury or substance abuse. Be cognizant of the categories of delusions in the context of the diagnosis. For example, grandiose delusions that involve the antichrist can be associated with harm toward others.⁶ Patients who express extreme feelings of guilt or shame (as seen in psychotic depression) and the need to be physically punished may be at risk for self-harm. Finally, patients seeking evidence to support misguided and dangerous beliefs—for example, obsessing over a religious text regarding self-injury while in a delusional state—may be at high risk for self-harm.¹⁸

Researchers have suggested clinicians question patients to determine if they trust their delusions.²⁵ Patients who trust their delusions may appear calm if they already have decided to act on their thoughts.²⁵ Preventive measures for patients at risk of self-harm include close observation, hospitalization, and pharmacotherapy.

Pharmacotherapy for DRC

There are no clear recommendations on specific psychotropics or dosages for treating patients with DRC. When a patient with DRC is at high risk of self-harm or harming others, using antipsychotics, anxiolytics, hypnotics, or a combination of these agents sometimes is needed to quell agitation, along with close observation and restraints when necessary (Table 2).^5,18,25,26 Mr. D benefited from risperidone, 3 mg at bedtime, and zolpidem, 10 mg as needed for insomnia.

Table 2

Treating patients with DRC

Using spirituality to cope

Many persistently mentally ill patients identify themselves as religious and use religious activities or beliefs to cope with their illness.^27,28 In a study of 1,824 seriously mentally ill patients, self-reports of religiousness were positively associated with psychological well-being and diminished psychiatric symptoms.²⁹ Longitudinal research has shown that some aspects of spirituality and religion are associated with positive mental and physical health effects, whereas other aspects can worsen symptoms.³⁰ Specifically, positive religious coping such as benevolent religious reappraisals (eg, “Jesus is my shield and savior”), collaborative religious coping, and spiritual support are associated with positive mental health.³¹ However, negative religious coping, such as punishing God reappraisals and reappraisals of God’s power (eg, “my illness is punishment for my sins”), are associated with distress and personal loss.³²

For patients with psychotic disorders—and with schizophrenia in particular—religious beliefs can be a source of meaning, hope, strength, and recovery. In a study of 115 outpatients with psychosis, 71% used positive religious coping, compared with 14% who used negative religious coping.³³ Among 38 patients with DRC, 45% used spirituality and religion to help cope with their illness, even though they received less support from religious communities than patients with other types of delusions.¹⁹ In this study, the authors suggest that positive religious coping among patients with DRC may alleviate delusion severity by decreasing levels of conviction and fear and preventing maladjusted behaviors.¹⁹ Religious beliefs and activities are associated with fewer hospitalizations among patients with persistent mental illness²⁸ and are a significant protective factor against suicide in patients with psychotic disorders.^34,35 However, some studies have found that intense, obsessive participation in spiritual activities can worsen psychiatric symptoms and undermine recovery.^1,36,37

Addressing religion in treatment.

Although many studies have emphasized the importance of religion to patients with psychosis, evidence-based guidelines on how best to address religion/spirituality in the clinical setting in patients with psychosis have yet to be established. In a 2011 study, a spiritual assessment was well tolerated by 40 patients with psychotic disorders and improved patients’ appointment attendance compared with a control group who received traditional care only.²⁶

Many mental health providers feel ill-equipped or are uncomfortable exploring spiritual or religious issues with patients. Enlisting the help of spiritual care professionals when assessing patients with DRC may improve evaluation and care (Table 3). Spiritual care professionals typically are experienced in exploring subjects associated with DRC, such as guilt, morality, conscience, repentance, and confession.²⁴ Spiritual care professionals also may be able to assist patients with religious coping and provide comfort and support.

Finally, spiritual care professionals can help patients connect or reconnect to a spiritual or religious community. In Mr. D’s case, the hospital chaplain deterred him from focusing on the reason the evil spirits were trying to punish him and guided him toward positive religious coping. Mr. D felt we were listening to him on a deeper level and understanding his spiritual struggles. The chaplain’s involvement also enhanced Mr. D’s relationship with the psychiatrist.

Table 3

When to elicit help from spiritual care professionals

Related Resources

• Mohr S, Borras L, Betrisey C, et al. Delusions with religious content in patients with psychosis: how they interact with spiritual coping. Psychiatry. 2010;73(2):158-172.
• Huguelet P, Mohr S, Betrisey C, et al. A randomized trial of spiritual assessment of outpatients with schizophrenia: patients’ and clinicians’ experience. Psychiatr Serv. 2011;62(1):79-86.

Drug Brand Names

• Risperidone • Risperdal
• Zolpidem • Ambien

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgements

The authors acknowledge the support and guidance of Rev. Sean Doll O’Mahoney, Rev. Julie Hanada, Rev. Stephen King, PhD, Rev. George Fitchett, PhD, Patricia Murphy, PhD, LCPC, and Kevin Flannelly, PhD.

Discuss this article at www.facebook.com/CurrentPsychiatry

Mr. D, a 72-year-old Christian with a long history of schizophrenia, presents to the emergency room with concerns about evil spirits in his home who have poisoned him. He has called for police assistance on numerous occasions and has tried to kill the evil spirits with his rifle, but states “they are bulletproof.” He is unable to sleep and is “fearful for my life every night because that is when the demons come out.” Mr. D also believes that God is “more powerful than the evil spirits.” Two elders at his church have prayed with him and encouraged him to go to the hospital.

Delusions with religious content (DRC) are associated with poorer clinical outcomes and dangerousness.^1-6 Most mental health professionals will encounter patients with DRC because this type of delusion is relatively common in patients with symptoms of mania or psychosis. For example, in a study of 193 inpatients with schizophrenia, 24% had religious delusions.¹ The prevalence of DRC varies considerably among populations and can be influenced by the local religion and culture.^7-9 This article reviews clinical challenges and assessment and management strategies for patients with DRC.

A challenging course

In a UK study of 193 inpatients with schizophrenia, compared with patients with other types of delusions, those with DRC:

• had higher Positive and Negative Syndrome Scale scores and lower Global Assessment of Functioning scores
• waited longer before reengaging in treatment
• were prescribed more medications.¹

In addition, compared with patients with other types of delusions, patients with DRC often hold these delusions with greater conviction,^1,2 making them more challenging to treat.

Dangerousness in patients with DRC can manifest as self-harm or harm to others. Extreme examples include self-inflicted enucleation of the eye and autocastration. In a review of 9 cases of severe ocular self-injury, 4 patients had DRC.³ Genital self-mutilation associated with DRC is rare, but several cases of psychotic men who performed autocastration based on a literal, erroneous interpretation of a passage in the Bible (Matthew 19:12) have been reported.^4,5 Patients with DRC have committed rape and murder because they believed they were the antichrist.⁶

In this article we use the phrase “delusions with religious content” instead of “religious delusions” because this distinction highlights that many subtypes of delusions can have a religious theme. Categories of delusions with religious themes include:

• persecutory (often involving Satan)
• grandiose (messianic delusions)
• guilt delusions.

Categorizing DRC is important because some are associated with more distress or dangerousness than others. For example, case studies of self-inflicted eye injuries found that most patients had guilt delusions with religious themes that referenced punishing transgressions, controlling unacceptable sexual impulses, and attaining prescience by destroying vision.^3,10 In our example, Mr. D is experiencing a persecutory DRC. Also, using the label “religious delusion” can inadvertently pathologize religious experiences.

Tips for effective evaluation

DSM-IV-TR offers no specific guidelines for assessing DRC vs nondelusional religious beliefs.¹¹ There is risk of pathologizing religious beliefs when listening to content alone.^11-15 Instead, focus on the conviction, pervasiveness,² uniqueness or bizarreness, and associated emotional distress of the delusion to the patient (Table 1).^2,12,16-18

In the context of the patient’s spiritual history, deviations from conventional religious beliefs and practices are important factors in determining whether a religious belief is authentic or delusional. Involving family members and/or spiritual care professionals (eg, chaplains and clergy) can be especially helpful when making this differentiation.^16,17 In the hospital, chaplains often are familiar with a variety of faith traditions and may provide important insight into the patient’s beliefs. In the community, clergy members from the patient’s faith also may provide valuable perspective.

Similar to how having a basic familiarity with a patient’s culture can improve care, a better understanding of a patient’s spiritual or religious beliefs and practices can build rapport and the therapeutic alliance.^16,17 This is particularly important with patients with DRC because these individuals often have a poor therapeutic alliance and engagement with providers.¹⁹ Because many psychiatrists have limited time and may not be familiar with every patient’s spiritual or religious background, consultation with spiritual care professionals may be helpful.

Assess whether your patient has reservations about psychiatric treatment. Some may believe that seeking care from a doctor is evidence of weak faith, whereas others may feel that psychiatric treatment is forbidden or incompatible with their religious beliefs.^19-22 Mental health clinicians need to consider their own religious biases that may cause them to minimize or pathologize a patient’s religiosity.^20,23 Working collaboratively with spiritual care professionals may help reduce clinician biases or assumptions.²⁴

Table 1

Assessing patients with DRC

Evaluating safety

When constructing a differential diagnosis and evaluating patients for safety, remember that DRC are a feature of many psychiatric disorders (eg, persecutory DRC in schizophrenia, grandiose DRC in mania). Consider the course and severity of the patient’s illness, and determine if he or she has a history or evidence of self-injury or substance abuse. Be cognizant of the categories of delusions in the context of the diagnosis. For example, grandiose delusions that involve the antichrist can be associated with harm toward others.⁶ Patients who express extreme feelings of guilt or shame (as seen in psychotic depression) and the need to be physically punished may be at risk for self-harm. Finally, patients seeking evidence to support misguided and dangerous beliefs—for example, obsessing over a religious text regarding self-injury while in a delusional state—may be at high risk for self-harm.¹⁸

Researchers have suggested clinicians question patients to determine if they trust their delusions.²⁵ Patients who trust their delusions may appear calm if they already have decided to act on their thoughts.²⁵ Preventive measures for patients at risk of self-harm include close observation, hospitalization, and pharmacotherapy.

Pharmacotherapy for DRC

There are no clear recommendations on specific psychotropics or dosages for treating patients with DRC. When a patient with DRC is at high risk of self-harm or harming others, using antipsychotics, anxiolytics, hypnotics, or a combination of these agents sometimes is needed to quell agitation, along with close observation and restraints when necessary (Table 2).^5,18,25,26 Mr. D benefited from risperidone, 3 mg at bedtime, and zolpidem, 10 mg as needed for insomnia.

Table 2

Treating patients with DRC

Using spirituality to cope

Many persistently mentally ill patients identify themselves as religious and use religious activities or beliefs to cope with their illness.^27,28 In a study of 1,824 seriously mentally ill patients, self-reports of religiousness were positively associated with psychological well-being and diminished psychiatric symptoms.²⁹ Longitudinal research has shown that some aspects of spirituality and religion are associated with positive mental and physical health effects, whereas other aspects can worsen symptoms.³⁰ Specifically, positive religious coping such as benevolent religious reappraisals (eg, “Jesus is my shield and savior”), collaborative religious coping, and spiritual support are associated with positive mental health.³¹ However, negative religious coping, such as punishing God reappraisals and reappraisals of God’s power (eg, “my illness is punishment for my sins”), are associated with distress and personal loss.³²

For patients with psychotic disorders—and with schizophrenia in particular—religious beliefs can be a source of meaning, hope, strength, and recovery. In a study of 115 outpatients with psychosis, 71% used positive religious coping, compared with 14% who used negative religious coping.³³ Among 38 patients with DRC, 45% used spirituality and religion to help cope with their illness, even though they received less support from religious communities than patients with other types of delusions.¹⁹ In this study, the authors suggest that positive religious coping among patients with DRC may alleviate delusion severity by decreasing levels of conviction and fear and preventing maladjusted behaviors.¹⁹ Religious beliefs and activities are associated with fewer hospitalizations among patients with persistent mental illness²⁸ and are a significant protective factor against suicide in patients with psychotic disorders.^34,35 However, some studies have found that intense, obsessive participation in spiritual activities can worsen psychiatric symptoms and undermine recovery.^1,36,37

Addressing religion in treatment.

Although many studies have emphasized the importance of religion to patients with psychosis, evidence-based guidelines on how best to address religion/spirituality in the clinical setting in patients with psychosis have yet to be established. In a 2011 study, a spiritual assessment was well tolerated by 40 patients with psychotic disorders and improved patients’ appointment attendance compared with a control group who received traditional care only.²⁶

Many mental health providers feel ill-equipped or are uncomfortable exploring spiritual or religious issues with patients. Enlisting the help of spiritual care professionals when assessing patients with DRC may improve evaluation and care (Table 3). Spiritual care professionals typically are experienced in exploring subjects associated with DRC, such as guilt, morality, conscience, repentance, and confession.²⁴ Spiritual care professionals also may be able to assist patients with religious coping and provide comfort and support.

Finally, spiritual care professionals can help patients connect or reconnect to a spiritual or religious community. In Mr. D’s case, the hospital chaplain deterred him from focusing on the reason the evil spirits were trying to punish him and guided him toward positive religious coping. Mr. D felt we were listening to him on a deeper level and understanding his spiritual struggles. The chaplain’s involvement also enhanced Mr. D’s relationship with the psychiatrist.

Table 3

When to elicit help from spiritual care professionals

Related Resources

• Mohr S, Borras L, Betrisey C, et al. Delusions with religious content in patients with psychosis: how they interact with spiritual coping. Psychiatry. 2010;73(2):158-172.
• Huguelet P, Mohr S, Betrisey C, et al. A randomized trial of spiritual assessment of outpatients with schizophrenia: patients’ and clinicians’ experience. Psychiatr Serv. 2011;62(1):79-86.

Drug Brand Names

• Risperidone • Risperdal
• Zolpidem • Ambien

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Acknowledgements

The authors acknowledge the support and guidance of Rev. Sean Doll O’Mahoney, Rev. Julie Hanada, Rev. Stephen King, PhD, Rev. George Fitchett, PhD, Patricia Murphy, PhD, LCPC, and Kevin Flannelly, PhD.

Ultra-rapid cycling (URC) entered the psychiatric lexicon in the 1990s as a proposed descriptor for manic/hypomanic, mixed, or depressed episodes of bipolar disorder (BD) that occur every few days or weeks. DSM-IV-TR incorporates rapid cycling (RC)—but not URC—as a course specifier that occurs in 10% to 15% of patients with BD who have ≥4 distinct affective episodes per year, each fulfilling duration criteria and separated by identifiable recovery periods (unless an episode directly changes polarity). Since then, the terms RC and URC have seemingly metamorphosed into imprecise, popular colloquialisms meant to loosely describe frequent mood changes rather than distinct episodes over extended time periods, with little regard for the associated signs that define manic or hypomanic episodes.

This article examines the meaning and validity of URC in BD, its relevance and differentiation from rapid mood shifts in patients without BD, and concepts relevant to treatment extrapolated from studies of RC BD.

Imprecise nomenclature

Post et al¹ coined the terms “ultra-rapid cycling” and “ultra-ultra-rapid cycling” (also called “ultradian cycling”) to describe mood episodes that occur monthly (URC) or over the course of as little as 1 day (ultradian cycling). These constructs are controversial because they lack demonstrated content validity and discriminant validity relative to other disorders. (“Content validity” refers to whether the features thought to comprise an entity of interest accurately and meaningfully do so; “discriminant validity” tells researchers and clinicians whether the proposed description of a clinical entity uniquely differentiates it from other disorders—avoiding “false-positive” suspected cases.) Clinicians therefore must pay careful attention to non-bipolar psychiatric problems that can present with rapid mood changes but without the psychomotor and related signs that define bipolar mood episodes. In their looser, nontechnical meanings, “rapid cycling” or “ultra-rapid cycling” may be synonymous with affective lability. RC is neither a diagnosis in itself nor a criterion for diagnosing BD. Rather, it is a course specifier to describe episode frequency in patients with past unambiguous manic or hypomanic episodes.

In children and adolescents, whose presentations often are atypical and can be hard to differentiate from other forms of behavioral or temperamental dysregulation, severe non-episodic mood dysregulation without signs of mania or hypomania may indicate a phenomenon separate from BD.² Geller and colleagues³ proposed using the term “episodes” to frame the duration of a DSM-IV-defined syndrome of mania/hypomania or depression, while reserving the term “cycling” to connote patterns of mood alternation within a given episode. It is not clear whether this concept of “cycling” differs qualitatively from mood lability that arises during a mood episode in children or adults, and notably, this perspective does not account for changes in psychomotor signs in conjunction with changes in mood.

Clinicians also sometimes blur the concept of “mixed episodes” with RC or URC. DSM-IV-TR defines mixed episodes within bipolar I disorder (BD I) based on criteria for a simultaneous manic and depressive episode, rather than on frequent oscillations between affective poles. These and other differential diagnostic considerations for suspected URC are summarized in Table 1.⁴

A further concern regarding nomenclature involves the distinction between cyclicity (ie, successive episodes regardless of pole direction) and changes in polarity (ie, switches from depression to mania/hypomania or vice versa). Some mood disorder patients may have rapid oscillations from euthymia to depression while never changing polarity to mania/hypomania and may be best described as having recurrent brief depression.

Table 1

Differential diagnosis in suspected URC

Duration criteria

Clinicians and researchers have debated the minimum duration criteria for identifying manic or hypomanic episodes, and the extent to which suspected hypomanic periods of short duration constitute distinct illness phases. Although DSM-IV-TR designates 4 days as a minimum time for classifying an episode of hypomania, empirical studies suggest that mood symptoms lasting as few as 2 days may comprise a valid and reliably distinct entity relevant to RC.⁵ More limited data (mainly case observations) identify “affective oscillations” and “mood shifts” occurring faster than once per 24 hours in BD patients without comorbid personality disorders.⁶ Phenomenologic studies that have focused on 24- to 48-hour switch cycles have described new-onset URC arising spontaneously or following closed head injuries.⁷ In children and younger adolescents, reports have identified long index manic episodes (mean durations as long as 80 weeks)⁸ that involve continual (ultradian) mood cycling in as many as 80% of cases.⁹

Is URC a valid construct?

A central controversy surrounding the validity and meaningfulness of URC as a BD subtype involves its sole focus on mood variation rather than the fuller constellation of associated signs and symptoms that define episodes of mania/hypomania or depression. Abrupt, sudden, drastic, or dramatic mood shifts from one moment to the next are nowhere to be found in the DSM-IV-TR definition of BD, and the construct of mood lability or affective instability is neither a cardinal nor defining element of BD. Although individuals with BD I or bipolar II disorder (BD II) may have periods of affective lability, rapid shifts in mood are neither necessary nor sufficient for a BD diagnosis, and may indicate other types of psychopathology when affective instability occurs in the absence of a history of discernible manic or hypomanic episodes.

Studies by our group¹⁰ and others¹¹ have shown that overattention to mood variation without considering associated cognitive, speech-language, chronobiologic, and motor signs of mania/hypomania accounts for substantial overdiagnosis of BD in patients with non-specific mood disturbances, particularly in those with active substance abuse or borderline personality disorder (BPD). Whereas the construct of RC BD attempts to account for changes in energy and psychomotor function as part of recurrent syndromes of mania/hypomania, existing literature on URC does not. Assessing mood changes in <24 hours also precludes assessing associated phenomena that occur over longer periods, such as changes in the sleep-wake cycle.

A rigorous, systematic approach to differential diagnosis for patients with affective instability is essential.

Borderline personality disorder

A common diagnostic debate regarding URC involves how to differentiate it from the chronic mood instability and reactivity inherent to BPD. Although some authors have suggested that RC BD and affective instability in BPD may be the same entity,¹² others object to unifying the 2 conditions without considering their phenomenologic and other clinical differences. For example, affective instability arising from borderline character organization is thought to reflect a patient’s impaired capacity to self-regulate his or her internal state and emotional responses to interpersonal and other environmental stresses, or difficulty managing impulses. By contrast, manic or depressive phases of BD tend not to be “triggered” by interpersonal conflicts or frustrations. Furthermore, reframing intense mood reactions to the environment as bipolar variants carries several pitfalls: doing so wrongly accords patients a passive role in their reactions to life events, inaccurately reinforces a sense of victimization in response to stress, and diverts inquiry away from a patient’s active role in life decisions and circumstances that may be unsatisfying, self-defeating, or volatile.

Two key considerations may be helpful in discriminating rapid mood changes in BD vs BPD. First, some longitudinal studies indicate that RC often is a transient, rather than enduring, phenomenon in BD,¹³ in contrast to the nonvarying, trait feature of affective instability in persons with BPD. It is unknown whether URC is more enduring than transient. Notably, whereas bipolar mood episodes constitute deviations from a baseline state, affective instability in BPD is a baseline characteristic, rather than a deviation from it. Second, by definition, a BPD diagnosis hinges on additional elements unrelated to mood disturbances, such as interpersonal styles or defense mechanisms that involve splitting, projection, and projective identification, feelings of numbness, boredom, or emptiness, identity diffusion, fears of abandonment, and proclivities toward self-mutilation or other self-injurious behaviors as a means to alleviate tension and stress. These characteristics do not overlap with the core elements of BD.

Affective lability in patients with BPD entails prominent oscillations between anger and anxiety, or depression and anxiety, but not depression and elation¹⁴; by contrast, affective instability in BD has been linked with greater oscillations between euthymia and depression, and euthymia and elation, but not euthymia and anger.¹⁵ Moreover, daily mood fluctuations in patients with BD appear to occur in a relatively random fashion,¹⁶ whereas in BPD mood fluctuations are reactions that appear intimately linked to distressing interpersonal experiences.

See the table below, entitled “Rapid cycling and ultra-rapid cycling BD: A comparison,” comparing the phenomenology of RC and URC and a discussion of studies that explored genetic markers or family patterns that may be related to RC or URC.

Treatment considerations

No systematic studies exist for treating URC. Because most clinical trials of BD focus on treatment or prevention of a single episode rather than changes of mood over time, it is difficult to draw inferences about the ability of any treatment to attenuate marked, day-to-day mood variations. Some antimanic drugs, such as carbamazepine, have been suggested to offer better prophylactic efficacy compared with lithium for “non-classical” BD presentations, although the efficacy of carbamazepine has not been studied in URC.

Broadly speaking, treatment for URC, similar to RC, pragmatically involves:

• identifying and eliminating sources of mood destabilization (eg, substance abuse, erratic sleep patterns)
• treating medical comorbidities such as hypothyroidism
• optimizing treatment with mood stabilizing agents
• exercising caution when using antidepressants (see below).

Interestingly, despite frequent allusion to certain medications as “mood stabilizers,” no controlled study has examined mood instability on a day-to-day basis as a primary outcome measure in BD treatment, which limits the ability to surmise that any drug could be expected to diminish mood oscillations that occur over the course of days, or within a single day. However, a post hoc analysis by our group¹⁷ compared randomized treatment with lamotrigine or placebo over 6 months in RC BD I or BD II. Using prospective life charting, we found patients who received lamotrigine were almost twice as likely as those receiving placebo to achieve euthymia from one week to the next, which suggests the possibility that lamotrigine may offer benefit for affective instability in BD I or BD II patients, in addition to preventing discrete mood episodes.

Antidepressant controversy. Concerns that antidepressants might acutely induce mania or accelerate cycling frequency over long time periods have led to a contentious, long-standing debate within psychopharmacology. As noted in the box below, several long-term naturalistic follow-up studies have reported RC as a perceived consequence of antidepressants in most RC patients, although efforts to differentiate cycle acceleration caused by antidepressants (or other iatrogenic factors) from the natural course of illness remains exceedingly difficult without prospective randomized trials. (Antidepressants might cause more affective recurrences, but having multiple episodes may also cause more antidepressant prescriptions.) Some researchers (eg, Schneck et al¹⁸) have reported more frequent episodes among patients taking antidepressants but did not consider that patients with multiple episodes may be more likely to receive antidepressants, which fail to ameliorate acute or recurrent affective episodes. Importantly, a recent multi-site randomized trial by Ghaemi et al¹⁹ found that after a favorable acute response to antidepressants plus mood stabilizers, patients with preexisting RC who were randomized to continue antidepressants for up to 1 year had a 3-fold increased likelihood of developing a new depressive episode, which affirms suggestions that antidepressants do not help—but may exacerbate—cycling in patients with RC. No studies in BD have examined whether URC is more likely to arise as a consequence of antidepressant use.

Mood stabilizers and other biologic therapies. A small body of literature specifically addresses pharmacotherapy of URC in patients with BD (Table 2).^19-26 A limitation of most existing literature is its focus on case reports, small open trials, or anecdotal observations rather than large, randomized controlled trials using systematic outcome measures. Extrapolation from reports focusing on patients with DSM-IV-TR RC is limited because it is uncertain whether URC differs fundamentally from RC and studies of DSM-IV-TR RC typically examine acute response during an index episode or time until relapse during maintenance therapy, rather than impact on mood changes over time.

Psychotherapy. A limited database on the efficacy of adjunctive cognitive-behavioral therapy (CBT) in RC BD describes improvement in depressive symptoms over short-term follow-up.²⁷ No long-term studies of CBT or other structured psychotherapies have focused on RC or URC. Intuitively, one might expect that psychoeducation targeting sleep hygiene, substance use, stress management and coping skills, medication adherence, and prodrome recognition would be of value to patients with BD who experience frequent mood episodes, especially in those who may be unaware of or unfamiliar with basic concepts related to BD. In addition, relevant concepts from dialectical behavior therapy may be beneficial for BD patients with possible URC, such as skills to enhance emotional regulation, distress tolerance, mindfulness, and interpersonal effectiveness.

Table 2

Evidence-based treatments for ultra-rapid cycling BD

Treatment monitoring. Prospective life charting allows patients to systematically record manic/hypomanic and depressive symptoms day-to-day and week-to-week, thus creating a measure that may be particularly relevant for patients whose moods change rapidly. Simple mood charts (see Related Resources) typically take into account the severity of symptoms of either polarity with ratings of mild, moderate, or severe. Such visual records permit simple calculations over the course of a given interval (eg, week-by-week or across months) of several important parameters, including:

• number of days euthymic
• number of days with depression
• number of days with abnormal mood elevation
• number of occasions in which moods of both polarities occur on the same day.

Tracking these parameters during a treatment allows clinicians to make quantitative comparisons over time as a method of determining whether or not meaningful changes are occurring in cyclicity. See the figure below for an example of a completed mood chart and its interpretation.

Additional recommendations for assessing and managing cyclicity in BD are summarized in Table 3.

Table 3

Tips for managing suspected ultra-rapid cycling BD

Table

Rapid cycling and ultra-rapid cycling BD: A comparison

Box

Figure: Example of prospective mood charting to document changes in manic/hypomanic and depressive symptoms across time

In the above example, the prevalence and severity of mood symptoms are identified over 21 days. Note the distinctly separate phases of mood elevation followed by depression, whereas euthymia was present only 6 of 21 days (29% of the time). Symptoms of at least moderate severity were more prominently depressive (5 of 21 days, or 24% of the time) than manic/hypomanic (2 of 21 days, or approximately 10% of the time). Mood charting does not capture associate DSM-IV-TR criteria for a mood episode but instead focuses solely on longitudinal changes in mood elevation or depression

Related Resources

• American Psychiatric Association practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
• Massachusetts General Hospital Bipolar Clinic and Research Program. Sample mood chart (downloadable). www.manicdepressive.org/moodchart.html.

Drug Brand Names

• Carbamazepine • Equetro, Tegretol
• Divalproex • Depakote
• Lamotrigine • Lamictal
• Levothyroxine • Synthroid
• Lithium • Lithobid
• Nimodipine • Nimotop
• Topiramate • Topamax

Disclosures

Dr. Goldberg is on the speakers’ bureaus for AstraZeneca, Dey Pharmaceuticals, Eli Lilly and Company, Merck, and Sunovion and is a consultant for Axon Advisors, Dey Pharmaceuticals, Eli Lilly and Company, and Grünenthal Group.

Acknowledgment

The author wishes to thank David L. Dunner, MD, for his helpful comments regarding this article.

Ultra-rapid cycling (URC) entered the psychiatric lexicon in the 1990s as a proposed descriptor for manic/hypomanic, mixed, or depressed episodes of bipolar disorder (BD) that occur every few days or weeks. DSM-IV-TR incorporates rapid cycling (RC)—but not URC—as a course specifier that occurs in 10% to 15% of patients with BD who have ≥4 distinct affective episodes per year, each fulfilling duration criteria and separated by identifiable recovery periods (unless an episode directly changes polarity). Since then, the terms RC and URC have seemingly metamorphosed into imprecise, popular colloquialisms meant to loosely describe frequent mood changes rather than distinct episodes over extended time periods, with little regard for the associated signs that define manic or hypomanic episodes.

This article examines the meaning and validity of URC in BD, its relevance and differentiation from rapid mood shifts in patients without BD, and concepts relevant to treatment extrapolated from studies of RC BD.

Imprecise nomenclature

Post et al¹ coined the terms “ultra-rapid cycling” and “ultra-ultra-rapid cycling” (also called “ultradian cycling”) to describe mood episodes that occur monthly (URC) or over the course of as little as 1 day (ultradian cycling). These constructs are controversial because they lack demonstrated content validity and discriminant validity relative to other disorders. (“Content validity” refers to whether the features thought to comprise an entity of interest accurately and meaningfully do so; “discriminant validity” tells researchers and clinicians whether the proposed description of a clinical entity uniquely differentiates it from other disorders—avoiding “false-positive” suspected cases.) Clinicians therefore must pay careful attention to non-bipolar psychiatric problems that can present with rapid mood changes but without the psychomotor and related signs that define bipolar mood episodes. In their looser, nontechnical meanings, “rapid cycling” or “ultra-rapid cycling” may be synonymous with affective lability. RC is neither a diagnosis in itself nor a criterion for diagnosing BD. Rather, it is a course specifier to describe episode frequency in patients with past unambiguous manic or hypomanic episodes.

In children and adolescents, whose presentations often are atypical and can be hard to differentiate from other forms of behavioral or temperamental dysregulation, severe non-episodic mood dysregulation without signs of mania or hypomania may indicate a phenomenon separate from BD.² Geller and colleagues³ proposed using the term “episodes” to frame the duration of a DSM-IV-defined syndrome of mania/hypomania or depression, while reserving the term “cycling” to connote patterns of mood alternation within a given episode. It is not clear whether this concept of “cycling” differs qualitatively from mood lability that arises during a mood episode in children or adults, and notably, this perspective does not account for changes in psychomotor signs in conjunction with changes in mood.

Clinicians also sometimes blur the concept of “mixed episodes” with RC or URC. DSM-IV-TR defines mixed episodes within bipolar I disorder (BD I) based on criteria for a simultaneous manic and depressive episode, rather than on frequent oscillations between affective poles. These and other differential diagnostic considerations for suspected URC are summarized in Table 1.⁴

A further concern regarding nomenclature involves the distinction between cyclicity (ie, successive episodes regardless of pole direction) and changes in polarity (ie, switches from depression to mania/hypomania or vice versa). Some mood disorder patients may have rapid oscillations from euthymia to depression while never changing polarity to mania/hypomania and may be best described as having recurrent brief depression.

Table 1

Differential diagnosis in suspected URC

Duration criteria

Clinicians and researchers have debated the minimum duration criteria for identifying manic or hypomanic episodes, and the extent to which suspected hypomanic periods of short duration constitute distinct illness phases. Although DSM-IV-TR designates 4 days as a minimum time for classifying an episode of hypomania, empirical studies suggest that mood symptoms lasting as few as 2 days may comprise a valid and reliably distinct entity relevant to RC.⁵ More limited data (mainly case observations) identify “affective oscillations” and “mood shifts” occurring faster than once per 24 hours in BD patients without comorbid personality disorders.⁶ Phenomenologic studies that have focused on 24- to 48-hour switch cycles have described new-onset URC arising spontaneously or following closed head injuries.⁷ In children and younger adolescents, reports have identified long index manic episodes (mean durations as long as 80 weeks)⁸ that involve continual (ultradian) mood cycling in as many as 80% of cases.⁹

Is URC a valid construct?

A central controversy surrounding the validity and meaningfulness of URC as a BD subtype involves its sole focus on mood variation rather than the fuller constellation of associated signs and symptoms that define episodes of mania/hypomania or depression. Abrupt, sudden, drastic, or dramatic mood shifts from one moment to the next are nowhere to be found in the DSM-IV-TR definition of BD, and the construct of mood lability or affective instability is neither a cardinal nor defining element of BD. Although individuals with BD I or bipolar II disorder (BD II) may have periods of affective lability, rapid shifts in mood are neither necessary nor sufficient for a BD diagnosis, and may indicate other types of psychopathology when affective instability occurs in the absence of a history of discernible manic or hypomanic episodes.

Studies by our group¹⁰ and others¹¹ have shown that overattention to mood variation without considering associated cognitive, speech-language, chronobiologic, and motor signs of mania/hypomania accounts for substantial overdiagnosis of BD in patients with non-specific mood disturbances, particularly in those with active substance abuse or borderline personality disorder (BPD). Whereas the construct of RC BD attempts to account for changes in energy and psychomotor function as part of recurrent syndromes of mania/hypomania, existing literature on URC does not. Assessing mood changes in <24 hours also precludes assessing associated phenomena that occur over longer periods, such as changes in the sleep-wake cycle.

A rigorous, systematic approach to differential diagnosis for patients with affective instability is essential.

Borderline personality disorder

A common diagnostic debate regarding URC involves how to differentiate it from the chronic mood instability and reactivity inherent to BPD. Although some authors have suggested that RC BD and affective instability in BPD may be the same entity,¹² others object to unifying the 2 conditions without considering their phenomenologic and other clinical differences. For example, affective instability arising from borderline character organization is thought to reflect a patient’s impaired capacity to self-regulate his or her internal state and emotional responses to interpersonal and other environmental stresses, or difficulty managing impulses. By contrast, manic or depressive phases of BD tend not to be “triggered” by interpersonal conflicts or frustrations. Furthermore, reframing intense mood reactions to the environment as bipolar variants carries several pitfalls: doing so wrongly accords patients a passive role in their reactions to life events, inaccurately reinforces a sense of victimization in response to stress, and diverts inquiry away from a patient’s active role in life decisions and circumstances that may be unsatisfying, self-defeating, or volatile.

Two key considerations may be helpful in discriminating rapid mood changes in BD vs BPD. First, some longitudinal studies indicate that RC often is a transient, rather than enduring, phenomenon in BD,¹³ in contrast to the nonvarying, trait feature of affective instability in persons with BPD. It is unknown whether URC is more enduring than transient. Notably, whereas bipolar mood episodes constitute deviations from a baseline state, affective instability in BPD is a baseline characteristic, rather than a deviation from it. Second, by definition, a BPD diagnosis hinges on additional elements unrelated to mood disturbances, such as interpersonal styles or defense mechanisms that involve splitting, projection, and projective identification, feelings of numbness, boredom, or emptiness, identity diffusion, fears of abandonment, and proclivities toward self-mutilation or other self-injurious behaviors as a means to alleviate tension and stress. These characteristics do not overlap with the core elements of BD.

Affective lability in patients with BPD entails prominent oscillations between anger and anxiety, or depression and anxiety, but not depression and elation¹⁴; by contrast, affective instability in BD has been linked with greater oscillations between euthymia and depression, and euthymia and elation, but not euthymia and anger.¹⁵ Moreover, daily mood fluctuations in patients with BD appear to occur in a relatively random fashion,¹⁶ whereas in BPD mood fluctuations are reactions that appear intimately linked to distressing interpersonal experiences.

See the table below, entitled “Rapid cycling and ultra-rapid cycling BD: A comparison,” comparing the phenomenology of RC and URC and a discussion of studies that explored genetic markers or family patterns that may be related to RC or URC.

Treatment considerations

No systematic studies exist for treating URC. Because most clinical trials of BD focus on treatment or prevention of a single episode rather than changes of mood over time, it is difficult to draw inferences about the ability of any treatment to attenuate marked, day-to-day mood variations. Some antimanic drugs, such as carbamazepine, have been suggested to offer better prophylactic efficacy compared with lithium for “non-classical” BD presentations, although the efficacy of carbamazepine has not been studied in URC.

Broadly speaking, treatment for URC, similar to RC, pragmatically involves:

• identifying and eliminating sources of mood destabilization (eg, substance abuse, erratic sleep patterns)
• treating medical comorbidities such as hypothyroidism
• optimizing treatment with mood stabilizing agents
• exercising caution when using antidepressants (see below).

Interestingly, despite frequent allusion to certain medications as “mood stabilizers,” no controlled study has examined mood instability on a day-to-day basis as a primary outcome measure in BD treatment, which limits the ability to surmise that any drug could be expected to diminish mood oscillations that occur over the course of days, or within a single day. However, a post hoc analysis by our group¹⁷ compared randomized treatment with lamotrigine or placebo over 6 months in RC BD I or BD II. Using prospective life charting, we found patients who received lamotrigine were almost twice as likely as those receiving placebo to achieve euthymia from one week to the next, which suggests the possibility that lamotrigine may offer benefit for affective instability in BD I or BD II patients, in addition to preventing discrete mood episodes.

Antidepressant controversy. Concerns that antidepressants might acutely induce mania or accelerate cycling frequency over long time periods have led to a contentious, long-standing debate within psychopharmacology. As noted in the box below, several long-term naturalistic follow-up studies have reported RC as a perceived consequence of antidepressants in most RC patients, although efforts to differentiate cycle acceleration caused by antidepressants (or other iatrogenic factors) from the natural course of illness remains exceedingly difficult without prospective randomized trials. (Antidepressants might cause more affective recurrences, but having multiple episodes may also cause more antidepressant prescriptions.) Some researchers (eg, Schneck et al¹⁸) have reported more frequent episodes among patients taking antidepressants but did not consider that patients with multiple episodes may be more likely to receive antidepressants, which fail to ameliorate acute or recurrent affective episodes. Importantly, a recent multi-site randomized trial by Ghaemi et al¹⁹ found that after a favorable acute response to antidepressants plus mood stabilizers, patients with preexisting RC who were randomized to continue antidepressants for up to 1 year had a 3-fold increased likelihood of developing a new depressive episode, which affirms suggestions that antidepressants do not help—but may exacerbate—cycling in patients with RC. No studies in BD have examined whether URC is more likely to arise as a consequence of antidepressant use.

Mood stabilizers and other biologic therapies. A small body of literature specifically addresses pharmacotherapy of URC in patients with BD (Table 2).^19-26 A limitation of most existing literature is its focus on case reports, small open trials, or anecdotal observations rather than large, randomized controlled trials using systematic outcome measures. Extrapolation from reports focusing on patients with DSM-IV-TR RC is limited because it is uncertain whether URC differs fundamentally from RC and studies of DSM-IV-TR RC typically examine acute response during an index episode or time until relapse during maintenance therapy, rather than impact on mood changes over time.

Psychotherapy. A limited database on the efficacy of adjunctive cognitive-behavioral therapy (CBT) in RC BD describes improvement in depressive symptoms over short-term follow-up.²⁷ No long-term studies of CBT or other structured psychotherapies have focused on RC or URC. Intuitively, one might expect that psychoeducation targeting sleep hygiene, substance use, stress management and coping skills, medication adherence, and prodrome recognition would be of value to patients with BD who experience frequent mood episodes, especially in those who may be unaware of or unfamiliar with basic concepts related to BD. In addition, relevant concepts from dialectical behavior therapy may be beneficial for BD patients with possible URC, such as skills to enhance emotional regulation, distress tolerance, mindfulness, and interpersonal effectiveness.

Table 2

Evidence-based treatments for ultra-rapid cycling BD

Treatment monitoring. Prospective life charting allows patients to systematically record manic/hypomanic and depressive symptoms day-to-day and week-to-week, thus creating a measure that may be particularly relevant for patients whose moods change rapidly. Simple mood charts (see Related Resources) typically take into account the severity of symptoms of either polarity with ratings of mild, moderate, or severe. Such visual records permit simple calculations over the course of a given interval (eg, week-by-week or across months) of several important parameters, including:

• number of days euthymic
• number of days with depression
• number of days with abnormal mood elevation
• number of occasions in which moods of both polarities occur on the same day.

Tracking these parameters during a treatment allows clinicians to make quantitative comparisons over time as a method of determining whether or not meaningful changes are occurring in cyclicity. See the figure below for an example of a completed mood chart and its interpretation.

Additional recommendations for assessing and managing cyclicity in BD are summarized in Table 3.

Table 3

Tips for managing suspected ultra-rapid cycling BD

Table

Rapid cycling and ultra-rapid cycling BD: A comparison

Box

Figure: Example of prospective mood charting to document changes in manic/hypomanic and depressive symptoms across time

In the above example, the prevalence and severity of mood symptoms are identified over 21 days. Note the distinctly separate phases of mood elevation followed by depression, whereas euthymia was present only 6 of 21 days (29% of the time). Symptoms of at least moderate severity were more prominently depressive (5 of 21 days, or 24% of the time) than manic/hypomanic (2 of 21 days, or approximately 10% of the time). Mood charting does not capture associate DSM-IV-TR criteria for a mood episode but instead focuses solely on longitudinal changes in mood elevation or depression

Related Resources

• American Psychiatric Association practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
• Massachusetts General Hospital Bipolar Clinic and Research Program. Sample mood chart (downloadable). www.manicdepressive.org/moodchart.html.

Drug Brand Names

• Carbamazepine • Equetro, Tegretol
• Divalproex • Depakote
• Lamotrigine • Lamictal
• Levothyroxine • Synthroid
• Lithium • Lithobid
• Nimodipine • Nimotop
• Topiramate • Topamax

Disclosures

Dr. Goldberg is on the speakers’ bureaus for AstraZeneca, Dey Pharmaceuticals, Eli Lilly and Company, Merck, and Sunovion and is a consultant for Axon Advisors, Dey Pharmaceuticals, Eli Lilly and Company, and Grünenthal Group.

Acknowledgment

The author wishes to thank David L. Dunner, MD, for his helpful comments regarding this article.

Ultra-rapid cycling (URC) entered the psychiatric lexicon in the 1990s as a proposed descriptor for manic/hypomanic, mixed, or depressed episodes of bipolar disorder (BD) that occur every few days or weeks. DSM-IV-TR incorporates rapid cycling (RC)—but not URC—as a course specifier that occurs in 10% to 15% of patients with BD who have ≥4 distinct affective episodes per year, each fulfilling duration criteria and separated by identifiable recovery periods (unless an episode directly changes polarity). Since then, the terms RC and URC have seemingly metamorphosed into imprecise, popular colloquialisms meant to loosely describe frequent mood changes rather than distinct episodes over extended time periods, with little regard for the associated signs that define manic or hypomanic episodes.

This article examines the meaning and validity of URC in BD, its relevance and differentiation from rapid mood shifts in patients without BD, and concepts relevant to treatment extrapolated from studies of RC BD.

Imprecise nomenclature

Post et al¹ coined the terms “ultra-rapid cycling” and “ultra-ultra-rapid cycling” (also called “ultradian cycling”) to describe mood episodes that occur monthly (URC) or over the course of as little as 1 day (ultradian cycling). These constructs are controversial because they lack demonstrated content validity and discriminant validity relative to other disorders. (“Content validity” refers to whether the features thought to comprise an entity of interest accurately and meaningfully do so; “discriminant validity” tells researchers and clinicians whether the proposed description of a clinical entity uniquely differentiates it from other disorders—avoiding “false-positive” suspected cases.) Clinicians therefore must pay careful attention to non-bipolar psychiatric problems that can present with rapid mood changes but without the psychomotor and related signs that define bipolar mood episodes. In their looser, nontechnical meanings, “rapid cycling” or “ultra-rapid cycling” may be synonymous with affective lability. RC is neither a diagnosis in itself nor a criterion for diagnosing BD. Rather, it is a course specifier to describe episode frequency in patients with past unambiguous manic or hypomanic episodes.

In children and adolescents, whose presentations often are atypical and can be hard to differentiate from other forms of behavioral or temperamental dysregulation, severe non-episodic mood dysregulation without signs of mania or hypomania may indicate a phenomenon separate from BD.² Geller and colleagues³ proposed using the term “episodes” to frame the duration of a DSM-IV-defined syndrome of mania/hypomania or depression, while reserving the term “cycling” to connote patterns of mood alternation within a given episode. It is not clear whether this concept of “cycling” differs qualitatively from mood lability that arises during a mood episode in children or adults, and notably, this perspective does not account for changes in psychomotor signs in conjunction with changes in mood.

Clinicians also sometimes blur the concept of “mixed episodes” with RC or URC. DSM-IV-TR defines mixed episodes within bipolar I disorder (BD I) based on criteria for a simultaneous manic and depressive episode, rather than on frequent oscillations between affective poles. These and other differential diagnostic considerations for suspected URC are summarized in Table 1.⁴

A further concern regarding nomenclature involves the distinction between cyclicity (ie, successive episodes regardless of pole direction) and changes in polarity (ie, switches from depression to mania/hypomania or vice versa). Some mood disorder patients may have rapid oscillations from euthymia to depression while never changing polarity to mania/hypomania and may be best described as having recurrent brief depression.

Table 1

Differential diagnosis in suspected URC

Duration criteria

Clinicians and researchers have debated the minimum duration criteria for identifying manic or hypomanic episodes, and the extent to which suspected hypomanic periods of short duration constitute distinct illness phases. Although DSM-IV-TR designates 4 days as a minimum time for classifying an episode of hypomania, empirical studies suggest that mood symptoms lasting as few as 2 days may comprise a valid and reliably distinct entity relevant to RC.⁵ More limited data (mainly case observations) identify “affective oscillations” and “mood shifts” occurring faster than once per 24 hours in BD patients without comorbid personality disorders.⁶ Phenomenologic studies that have focused on 24- to 48-hour switch cycles have described new-onset URC arising spontaneously or following closed head injuries.⁷ In children and younger adolescents, reports have identified long index manic episodes (mean durations as long as 80 weeks)⁸ that involve continual (ultradian) mood cycling in as many as 80% of cases.⁹

Is URC a valid construct?

A central controversy surrounding the validity and meaningfulness of URC as a BD subtype involves its sole focus on mood variation rather than the fuller constellation of associated signs and symptoms that define episodes of mania/hypomania or depression. Abrupt, sudden, drastic, or dramatic mood shifts from one moment to the next are nowhere to be found in the DSM-IV-TR definition of BD, and the construct of mood lability or affective instability is neither a cardinal nor defining element of BD. Although individuals with BD I or bipolar II disorder (BD II) may have periods of affective lability, rapid shifts in mood are neither necessary nor sufficient for a BD diagnosis, and may indicate other types of psychopathology when affective instability occurs in the absence of a history of discernible manic or hypomanic episodes.

Studies by our group¹⁰ and others¹¹ have shown that overattention to mood variation without considering associated cognitive, speech-language, chronobiologic, and motor signs of mania/hypomania accounts for substantial overdiagnosis of BD in patients with non-specific mood disturbances, particularly in those with active substance abuse or borderline personality disorder (BPD). Whereas the construct of RC BD attempts to account for changes in energy and psychomotor function as part of recurrent syndromes of mania/hypomania, existing literature on URC does not. Assessing mood changes in <24 hours also precludes assessing associated phenomena that occur over longer periods, such as changes in the sleep-wake cycle.

A rigorous, systematic approach to differential diagnosis for patients with affective instability is essential.

Borderline personality disorder

A common diagnostic debate regarding URC involves how to differentiate it from the chronic mood instability and reactivity inherent to BPD. Although some authors have suggested that RC BD and affective instability in BPD may be the same entity,¹² others object to unifying the 2 conditions without considering their phenomenologic and other clinical differences. For example, affective instability arising from borderline character organization is thought to reflect a patient’s impaired capacity to self-regulate his or her internal state and emotional responses to interpersonal and other environmental stresses, or difficulty managing impulses. By contrast, manic or depressive phases of BD tend not to be “triggered” by interpersonal conflicts or frustrations. Furthermore, reframing intense mood reactions to the environment as bipolar variants carries several pitfalls: doing so wrongly accords patients a passive role in their reactions to life events, inaccurately reinforces a sense of victimization in response to stress, and diverts inquiry away from a patient’s active role in life decisions and circumstances that may be unsatisfying, self-defeating, or volatile.

Two key considerations may be helpful in discriminating rapid mood changes in BD vs BPD. First, some longitudinal studies indicate that RC often is a transient, rather than enduring, phenomenon in BD,¹³ in contrast to the nonvarying, trait feature of affective instability in persons with BPD. It is unknown whether URC is more enduring than transient. Notably, whereas bipolar mood episodes constitute deviations from a baseline state, affective instability in BPD is a baseline characteristic, rather than a deviation from it. Second, by definition, a BPD diagnosis hinges on additional elements unrelated to mood disturbances, such as interpersonal styles or defense mechanisms that involve splitting, projection, and projective identification, feelings of numbness, boredom, or emptiness, identity diffusion, fears of abandonment, and proclivities toward self-mutilation or other self-injurious behaviors as a means to alleviate tension and stress. These characteristics do not overlap with the core elements of BD.

Affective lability in patients with BPD entails prominent oscillations between anger and anxiety, or depression and anxiety, but not depression and elation¹⁴; by contrast, affective instability in BD has been linked with greater oscillations between euthymia and depression, and euthymia and elation, but not euthymia and anger.¹⁵ Moreover, daily mood fluctuations in patients with BD appear to occur in a relatively random fashion,¹⁶ whereas in BPD mood fluctuations are reactions that appear intimately linked to distressing interpersonal experiences.

See the table below, entitled “Rapid cycling and ultra-rapid cycling BD: A comparison,” comparing the phenomenology of RC and URC and a discussion of studies that explored genetic markers or family patterns that may be related to RC or URC.

Treatment considerations

No systematic studies exist for treating URC. Because most clinical trials of BD focus on treatment or prevention of a single episode rather than changes of mood over time, it is difficult to draw inferences about the ability of any treatment to attenuate marked, day-to-day mood variations. Some antimanic drugs, such as carbamazepine, have been suggested to offer better prophylactic efficacy compared with lithium for “non-classical” BD presentations, although the efficacy of carbamazepine has not been studied in URC.

Broadly speaking, treatment for URC, similar to RC, pragmatically involves:

• identifying and eliminating sources of mood destabilization (eg, substance abuse, erratic sleep patterns)
• treating medical comorbidities such as hypothyroidism
• optimizing treatment with mood stabilizing agents
• exercising caution when using antidepressants (see below).

Interestingly, despite frequent allusion to certain medications as “mood stabilizers,” no controlled study has examined mood instability on a day-to-day basis as a primary outcome measure in BD treatment, which limits the ability to surmise that any drug could be expected to diminish mood oscillations that occur over the course of days, or within a single day. However, a post hoc analysis by our group¹⁷ compared randomized treatment with lamotrigine or placebo over 6 months in RC BD I or BD II. Using prospective life charting, we found patients who received lamotrigine were almost twice as likely as those receiving placebo to achieve euthymia from one week to the next, which suggests the possibility that lamotrigine may offer benefit for affective instability in BD I or BD II patients, in addition to preventing discrete mood episodes.

Antidepressant controversy. Concerns that antidepressants might acutely induce mania or accelerate cycling frequency over long time periods have led to a contentious, long-standing debate within psychopharmacology. As noted in the box below, several long-term naturalistic follow-up studies have reported RC as a perceived consequence of antidepressants in most RC patients, although efforts to differentiate cycle acceleration caused by antidepressants (or other iatrogenic factors) from the natural course of illness remains exceedingly difficult without prospective randomized trials. (Antidepressants might cause more affective recurrences, but having multiple episodes may also cause more antidepressant prescriptions.) Some researchers (eg, Schneck et al¹⁸) have reported more frequent episodes among patients taking antidepressants but did not consider that patients with multiple episodes may be more likely to receive antidepressants, which fail to ameliorate acute or recurrent affective episodes. Importantly, a recent multi-site randomized trial by Ghaemi et al¹⁹ found that after a favorable acute response to antidepressants plus mood stabilizers, patients with preexisting RC who were randomized to continue antidepressants for up to 1 year had a 3-fold increased likelihood of developing a new depressive episode, which affirms suggestions that antidepressants do not help—but may exacerbate—cycling in patients with RC. No studies in BD have examined whether URC is more likely to arise as a consequence of antidepressant use.

Mood stabilizers and other biologic therapies. A small body of literature specifically addresses pharmacotherapy of URC in patients with BD (Table 2).^19-26 A limitation of most existing literature is its focus on case reports, small open trials, or anecdotal observations rather than large, randomized controlled trials using systematic outcome measures. Extrapolation from reports focusing on patients with DSM-IV-TR RC is limited because it is uncertain whether URC differs fundamentally from RC and studies of DSM-IV-TR RC typically examine acute response during an index episode or time until relapse during maintenance therapy, rather than impact on mood changes over time.

Psychotherapy. A limited database on the efficacy of adjunctive cognitive-behavioral therapy (CBT) in RC BD describes improvement in depressive symptoms over short-term follow-up.²⁷ No long-term studies of CBT or other structured psychotherapies have focused on RC or URC. Intuitively, one might expect that psychoeducation targeting sleep hygiene, substance use, stress management and coping skills, medication adherence, and prodrome recognition would be of value to patients with BD who experience frequent mood episodes, especially in those who may be unaware of or unfamiliar with basic concepts related to BD. In addition, relevant concepts from dialectical behavior therapy may be beneficial for BD patients with possible URC, such as skills to enhance emotional regulation, distress tolerance, mindfulness, and interpersonal effectiveness.

Table 2

Evidence-based treatments for ultra-rapid cycling BD

Treatment monitoring. Prospective life charting allows patients to systematically record manic/hypomanic and depressive symptoms day-to-day and week-to-week, thus creating a measure that may be particularly relevant for patients whose moods change rapidly. Simple mood charts (see Related Resources) typically take into account the severity of symptoms of either polarity with ratings of mild, moderate, or severe. Such visual records permit simple calculations over the course of a given interval (eg, week-by-week or across months) of several important parameters, including:

• number of days euthymic
• number of days with depression
• number of days with abnormal mood elevation
• number of occasions in which moods of both polarities occur on the same day.

Tracking these parameters during a treatment allows clinicians to make quantitative comparisons over time as a method of determining whether or not meaningful changes are occurring in cyclicity. See the figure below for an example of a completed mood chart and its interpretation.

Additional recommendations for assessing and managing cyclicity in BD are summarized in Table 3.

Table 3

Tips for managing suspected ultra-rapid cycling BD

Table

Rapid cycling and ultra-rapid cycling BD: A comparison

Box

Figure: Example of prospective mood charting to document changes in manic/hypomanic and depressive symptoms across time

In the above example, the prevalence and severity of mood symptoms are identified over 21 days. Note the distinctly separate phases of mood elevation followed by depression, whereas euthymia was present only 6 of 21 days (29% of the time). Symptoms of at least moderate severity were more prominently depressive (5 of 21 days, or 24% of the time) than manic/hypomanic (2 of 21 days, or approximately 10% of the time). Mood charting does not capture associate DSM-IV-TR criteria for a mood episode but instead focuses solely on longitudinal changes in mood elevation or depression

Related Resources

• American Psychiatric Association practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 suppl):1-50.
• Massachusetts General Hospital Bipolar Clinic and Research Program. Sample mood chart (downloadable). www.manicdepressive.org/moodchart.html.

Drug Brand Names

• Carbamazepine • Equetro, Tegretol
• Divalproex • Depakote
• Lamotrigine • Lamictal
• Levothyroxine • Synthroid
• Lithium • Lithobid
• Nimodipine • Nimotop
• Topiramate • Topamax

Disclosures

Dr. Goldberg is on the speakers’ bureaus for AstraZeneca, Dey Pharmaceuticals, Eli Lilly and Company, Merck, and Sunovion and is a consultant for Axon Advisors, Dey Pharmaceuticals, Eli Lilly and Company, and Grünenthal Group.

Acknowledgment

The author wishes to thank David L. Dunner, MD, for his helpful comments regarding this article.