Evidence-Based Reviews

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Treatment nonadherence among patients with chronic illness is high, and bipolar disorder (BD) is no exception. Approximately 21% to 50% of patients with BD do not adhere to their recommended treatment regimen,¹ which adds to the burden of illness and worsens prognosis.

Although treatment nonadherence is a concern with any psychiatric disorder, we focus on BD because of the high prevalence of the disorder, the lifelong nature of the illness, and its resulting disability. BD is challenging to treat even with motivated patients, and psychiatrists cannot count on individuals to follow their prescribed regimen just because they were told to do so. Choosing the best treatment for each patient is complicated, and as physicians, we need to learn how to connect with our patients, increase our insight into their concerns, and work collaboratively to find a treatment they can follow.

This article describes methods of assessing adherence, factors that affect adherence, and pharmacologic and psychosocial interventions to enhance adherence and improve outcomes.

What is adherence?

As the doctor-patient relationship and medical treatment evolved to become more patient-centered, so have the terms used to describe individuals’ treatment-related behavior. Compliance, a physician-centered term that mandates following instructions to achieve treatment goals, evolved to adherence, the extent to which a person fulfills their part of an agreed-upon treatment plan, followed by concordance, which describes a decision-making alliance between patient and provider that strongly considers patients’ input.

Adherence is considered adequate when it occurs at the minimum level necessary for the patient to respond to treatment and avoid relapse.² Research on adherence in BD can be difficult to interpret because results may be influenced by:

• selection bias (patients who are adherent and insightful are more likely to consent to research)
• complications caused by polypharmacy and comorbidity
• investigators’ ability to choose the proper measure to delineate medication adherence attitudes and behaviors
• patients’ compliance with the adherence-enhancing interventions.²

Assessment methods. Several tools can be used to measure adherence to mental illness treatment. Attitudinal scales capture a person’s subjective feelings (such as being on a medication, insight, perceived strength of the therapeutic alliance, and level of stigma faced) and can reflect attitude change that may result from adherence-enhancing interventions. Adherence behavior scales may be convenient to administer in the office but tend to overestimate patients’ adherence (Table 1).^3-7

Pill counts are inexpensive but patients can manipulate unused medication. Prescription refill counts are easy to obtain but do not confirm that the patient took the medication. Electronic medication monitors capture the time of specific doses and can calculate the adherence rate, but they are expensive and do not ensure that the medication was ingested. Measuring the drug in urine or blood is an objective measure of adherence and can serve as clinical guide to pharmacotherapy, but offers limited correlation with the amount of medication taken and is expensive. A combination of measures to estimate adherence may be best.²

Table 1

Tools for measuring adherence to medications

BD adherence studies

Treatment adherence in BD is challenged by the chronic remission-relapse pattern of the disorder. Manic episodes carry the highest risk of nonadherence.² Scott and Pope⁸ evaluated self-reported adherence to mood stabilizers (lithium, carbamazepine, or valproate) among 98 patients with major depressive disorder and 78 with BD. They found that 32% of patients were partially adherent (defined as having missed >30% of doses in the past month) and >60% of these patients had sub-therapeutic plasma levels of mood stabilizers.

In a study of 106 BD outpatients treated with lithium who completed scales regarding their attitudes toward and knowledge of lithium and the Medication Adherence Rating Scale (MARS), 86% of patients had a therapeutic serum lithium level (.6 to 1.2 mEq/L), and knowledge of lithium was correlated with adherence.⁹ Jónsdóttir et al¹⁰ looked at medication adherence among 280 patients with schizophrenia and BD by comparing patient self-reports to provider reports and measuring serum drug concentrations; adherence was defined as having a serum concentration within the reference level for the specific medication. BD patients had an adherence rate of 66%, and self-reported adherence as measured by MARS and provider reports correlated with serum concentrations.

In a study of 71 adolescents with BD followed for 1 year after their first hospitalization for a manic or mixed episode, DelBello et al¹¹ defined nonadherence as taking medication <25% of the time and partial adherence as taking medication 25% to 75% of the time. They found that 42% of patients were partially adherent and 23% were nonadherent.

Strakowski¹² followed 46 adults from Taiwan and 96 from the United States for 1 year after their first manic or mixed episode and found that 79% of the Taiwanese patients and 50% of U.S. patients were adherent. Using the medication possession ratio (MPR)—which is calculated based the number of days between expected and actual prescription refills—to determine adherence, Sajatovic¹³ found that 54% of 44,637 veterans being treated for BD with lithium or anticonvulsants were fully adherent (MPR >.80), 25% were partially adherent (MPR >.50 to .80), and 21% were nonadherent (MPR ≤.50). In a survey of 131 randomly selected psychiatrists and 429 of their adult BD patients, Baldessarini¹⁴ found that 34% of patients reported missing ≥1 medication dose in past 10 days, but psychiatrists recognized only 18% of patients as nonadherent.

What affects adherence?

Although all BD patients share the same diagnosis, the factors that ultimately result in their medication adherence are as variable as the individuals themselves. Patients’ age, sex, culture, symptom severity, worldview, socioeconomic status, opinion of mental illness, and self-image influence their individual decisions on adhering to a prescribed medication regimen.^1,15

Perception of medication efficacy. Not surprisingly, if a medication does not seem to decrease debilitating symptoms, a patient is unlikely to continue taking it. Patients with BD feel more affected by depressive symptoms than by manic symptoms, and have indicated that they are more likely to adhere to and view as successful treatments that reduce depressive symptoms.^16,17

Tolerability. In an Internet-based survey, 469 patients with BD indicated that medication-related weight gain and cognitive impairment were the most important factors that affected adherence.¹⁶ Individuals’ concerns about possible side effects may contribute more to nonadherence than actually experiencing side effects.¹⁷ Concerns about long-term metabolic side effects from atypical antipsychotics also may limit adherence.¹⁷

Neurocognitive impairment. Whether caused by BD, aging, or a combination of these factors, deficits in memory, attention, and executive functioning can lead to unintentional nonadherence. In a study that assessed medication management ability among middle-aged and older adults, patients with BD were found to make 2.8 times more errors than healthy controls.¹⁸

Therapeutic alliance and psychoeducation. Patients’ expectations for pharmacotherapy vary from specific symptom relief to hopes for a complete cure, and their fears may be influenced by media and advertisements.¹⁷ Nonetheless a positive therapeutic alliance with the treating provider improves illness outcomes.¹⁹

A clinician’s ability to help patients build insight is invaluable for their current and future treatment. In a survey of 435 veterans with BD, nonadherence was greater among patients with limited insight about the role of medication in their illness.²⁰ A study of 65 BD patients that evaluated insight into medication adherence at initial interview and 1 year later found that difficulty with adherence at the initial interview predicted future nonadherence and was correlated with lack of insight.²¹ Rosa et al⁹ found that BD patients in denial of their illness and those who had little psychoeducation were more frequently nonadherent with lithium treatment.

Other factors that may contribute to medication nonadherence in BD patients include comorbid substance abuse or personality disorders, both of which are associated with more frequent relapse.¹⁵ Marriage has a beneficial affect on adherence.¹⁵ A good support system may contribute to treatment adherence; in a study of 107 children and adolescents with BD, nonadherent patients were more likely to experience family dysfunction and have a parental history of psychiatric hospitalization.²²

Adherence and BD course

Treatment adherence decreases the suicide rate among BD patients. Angst et al²³ evaluated the rate of suicide among 406 patients with BD and unipolar depression who were followed for 40 years. They found that 11% committed suicide; untreated patients had significantly higher standardized mortality rates than of those who were treated with lithium, antipsychotics, or antidepressants. Other studies confirm this finding.¹⁵

Repeated relapse may predict poorer cognitive performance. Lopez-Jaramillo et al²⁴ showed that patients with BD who had more manic episodes performed poorer on cognitive tests assessing attention, memory, and executive functioning compared with patients with less episodes and with normal subjects.

Medication adherence in BD is a priority because of potential neurodegeneration in BD and the neuroprotective effects of mood stabilizers and some atypical antipsychotics (Box).

Box

Increasing adherence

Pharmacologic strategies. Adherence in BD often is difficult when patients require a complex medication regimen to control their illness. Patients and clinicians may prefer to use once-daily dosing drug formulations, which can provide consistent serum levels and fewer adverse effects. Divalproex extended-release (ER) allows once-daily dosing and improved tolerability by reducing fluctuations in valproic acid serum concentrations compared with the delayed-release formulation. In a retrospective chart review,²⁵ most patients (62%) who switched to divalproex ER from divalproex delayed-release preferred the ER formulation; 52% showed clinical improvement, 81% did not experience side effects, and 8% demonstrated higher adherence after switching.²⁵ Similarly, an extended-release formulation of carbamazepine is approved for treating acute mania.

Many atypical antipsychotics are FDA-approved for acute mania, acute bipolar depression, and/or maintenance (Table 2). Long-acting injectable formulations (LAIs) may be used as maintenance treatment if nonadherence is an issue. LAI risperidone, which is FDA-approved for maintenance treatment of bipolar I disorder (BDI), was found to be safe and effective in stable BD patients who were switched from an oral antipsychotic.²⁶ Asenapine is provided in a rapidly absorbed, sublingual form and is FDA-approved for treating acute mania or mixed episodes associated with BDI.²⁷ Overall, however, only slightly more than one-half of BD patients are adherent to atypical antipsychotics.¹⁵

Although antidepressant use in BD is controversial, Sajatovic¹⁷ found 44% of depressed BDI patients were treated with antidepressants. Novel extended-release antidepressant formulations—including controlled-release fluvoxamine, paroxetine, extended-release bupropion and venlafaxine, once-weekly fluoxetine, rapidly dissolving mirtazapine, and transdermal selegiline—can optimize drug delivery, minimize side effects, and delay onset of action.¹

Psychosocial strategies used in BD include psychoeducation, cognitive-behavioral therapy (CBT), family-focused interventions, and interpersonal and social rhythm therapy (IPSRT) (Table 3).^28-30 Psychoeducation alone or combined with other interventions can decrease the risk of relapse and hospitalization and improve adherence.²⁸ In a 2-year study of 50 euthymic BD patients treated with lithium who participated in a brief hospital-based psychoeducation program, Even et al³¹ found patients’ knowledge about lithium but not their attitudes changed significantly after the program. The changes persisted 2 years after the intervention, with a trend toward a decreased hospitalization rate.

Miklowitz³² reported on 293 BD patients randomized to receive collaborative care (3 psychoeducational sessions delivered over 6 weeks) or 1 of 3 types of intensive psychotherapy: CBT, IPSRT, or family-focused therapy. Attrition was similar for both groups. Compared with those receiving collaborative care, significantly more patients receiving intensive psychotherapy recovered after 1 year, and did so in shorter time.

In a 3-year, multi-site Veterans Administration (VA) study, 306 BD patients received psychoeducation and support from nurse care coordinators who were responsible for access, continuity of care, and information flow to psychiatrists or usual care according to VA guidelines.³³ Compared with the usual care group, patients who received psychoeducation and support from nurse care coordinators had shorter duration of manic episodes and improved function and quality of life. A meta-analysis³⁰ of 12 randomized controlled trials of CBT in BD showed a medium effect size of CBT on adherence at 6 months post-treatment.

Table 2

FDA-approved medications for adult bipolar disorder

Table 3

Psychosocial interventions for bipolar disorder

Related Resource

• Deegan PE. The importance of personal medicine: a qualitative study of resilience in people with psychiatric disabilities. Scand J Public Health Suppl. 2005;66:29-35.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Bupropion • Wellbutrin
• Carbamazepine • Carbatrol, Tegretol
• Carbamazepine extended- release • Equetro
• Clozapine • Clozaril
• Divalproex • Depakote, Depakote ER
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Olanzapine/fluoxetine • Symbyax
• Paroxetine • Paxil
• Quetiapine • Seroquel, Seroquel XR
• Risperidone • Risperdal
• Risperidone long-acting injectable • Risperdal Consta
• Selegiline • Eldepryl, Emsam
• Valproate • Depacon
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

Dr. Foster receives research/grant support from the American Psychiatric Foundation, the National Institute of Mental Health, and Sunovion Pharmaceuticals.

Dr. Sheehan and Ms. Johns 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

Treatment nonadherence among patients with chronic illness is high, and bipolar disorder (BD) is no exception. Approximately 21% to 50% of patients with BD do not adhere to their recommended treatment regimen,¹ which adds to the burden of illness and worsens prognosis.

Although treatment nonadherence is a concern with any psychiatric disorder, we focus on BD because of the high prevalence of the disorder, the lifelong nature of the illness, and its resulting disability. BD is challenging to treat even with motivated patients, and psychiatrists cannot count on individuals to follow their prescribed regimen just because they were told to do so. Choosing the best treatment for each patient is complicated, and as physicians, we need to learn how to connect with our patients, increase our insight into their concerns, and work collaboratively to find a treatment they can follow.

This article describes methods of assessing adherence, factors that affect adherence, and pharmacologic and psychosocial interventions to enhance adherence and improve outcomes.

What is adherence?

As the doctor-patient relationship and medical treatment evolved to become more patient-centered, so have the terms used to describe individuals’ treatment-related behavior. Compliance, a physician-centered term that mandates following instructions to achieve treatment goals, evolved to adherence, the extent to which a person fulfills their part of an agreed-upon treatment plan, followed by concordance, which describes a decision-making alliance between patient and provider that strongly considers patients’ input.

Adherence is considered adequate when it occurs at the minimum level necessary for the patient to respond to treatment and avoid relapse.² Research on adherence in BD can be difficult to interpret because results may be influenced by:

• selection bias (patients who are adherent and insightful are more likely to consent to research)
• complications caused by polypharmacy and comorbidity
• investigators’ ability to choose the proper measure to delineate medication adherence attitudes and behaviors
• patients’ compliance with the adherence-enhancing interventions.²

Assessment methods. Several tools can be used to measure adherence to mental illness treatment. Attitudinal scales capture a person’s subjective feelings (such as being on a medication, insight, perceived strength of the therapeutic alliance, and level of stigma faced) and can reflect attitude change that may result from adherence-enhancing interventions. Adherence behavior scales may be convenient to administer in the office but tend to overestimate patients’ adherence (Table 1).^3-7

Pill counts are inexpensive but patients can manipulate unused medication. Prescription refill counts are easy to obtain but do not confirm that the patient took the medication. Electronic medication monitors capture the time of specific doses and can calculate the adherence rate, but they are expensive and do not ensure that the medication was ingested. Measuring the drug in urine or blood is an objective measure of adherence and can serve as clinical guide to pharmacotherapy, but offers limited correlation with the amount of medication taken and is expensive. A combination of measures to estimate adherence may be best.²

Table 1

Tools for measuring adherence to medications

BD adherence studies

Treatment adherence in BD is challenged by the chronic remission-relapse pattern of the disorder. Manic episodes carry the highest risk of nonadherence.² Scott and Pope⁸ evaluated self-reported adherence to mood stabilizers (lithium, carbamazepine, or valproate) among 98 patients with major depressive disorder and 78 with BD. They found that 32% of patients were partially adherent (defined as having missed >30% of doses in the past month) and >60% of these patients had sub-therapeutic plasma levels of mood stabilizers.

In a study of 106 BD outpatients treated with lithium who completed scales regarding their attitudes toward and knowledge of lithium and the Medication Adherence Rating Scale (MARS), 86% of patients had a therapeutic serum lithium level (.6 to 1.2 mEq/L), and knowledge of lithium was correlated with adherence.⁹ Jónsdóttir et al¹⁰ looked at medication adherence among 280 patients with schizophrenia and BD by comparing patient self-reports to provider reports and measuring serum drug concentrations; adherence was defined as having a serum concentration within the reference level for the specific medication. BD patients had an adherence rate of 66%, and self-reported adherence as measured by MARS and provider reports correlated with serum concentrations.

In a study of 71 adolescents with BD followed for 1 year after their first hospitalization for a manic or mixed episode, DelBello et al¹¹ defined nonadherence as taking medication <25% of the time and partial adherence as taking medication 25% to 75% of the time. They found that 42% of patients were partially adherent and 23% were nonadherent.

Strakowski¹² followed 46 adults from Taiwan and 96 from the United States for 1 year after their first manic or mixed episode and found that 79% of the Taiwanese patients and 50% of U.S. patients were adherent. Using the medication possession ratio (MPR)—which is calculated based the number of days between expected and actual prescription refills—to determine adherence, Sajatovic¹³ found that 54% of 44,637 veterans being treated for BD with lithium or anticonvulsants were fully adherent (MPR >.80), 25% were partially adherent (MPR >.50 to .80), and 21% were nonadherent (MPR ≤.50). In a survey of 131 randomly selected psychiatrists and 429 of their adult BD patients, Baldessarini¹⁴ found that 34% of patients reported missing ≥1 medication dose in past 10 days, but psychiatrists recognized only 18% of patients as nonadherent.

What affects adherence?

Although all BD patients share the same diagnosis, the factors that ultimately result in their medication adherence are as variable as the individuals themselves. Patients’ age, sex, culture, symptom severity, worldview, socioeconomic status, opinion of mental illness, and self-image influence their individual decisions on adhering to a prescribed medication regimen.^1,15

Perception of medication efficacy. Not surprisingly, if a medication does not seem to decrease debilitating symptoms, a patient is unlikely to continue taking it. Patients with BD feel more affected by depressive symptoms than by manic symptoms, and have indicated that they are more likely to adhere to and view as successful treatments that reduce depressive symptoms.^16,17

Tolerability. In an Internet-based survey, 469 patients with BD indicated that medication-related weight gain and cognitive impairment were the most important factors that affected adherence.¹⁶ Individuals’ concerns about possible side effects may contribute more to nonadherence than actually experiencing side effects.¹⁷ Concerns about long-term metabolic side effects from atypical antipsychotics also may limit adherence.¹⁷

Neurocognitive impairment. Whether caused by BD, aging, or a combination of these factors, deficits in memory, attention, and executive functioning can lead to unintentional nonadherence. In a study that assessed medication management ability among middle-aged and older adults, patients with BD were found to make 2.8 times more errors than healthy controls.¹⁸

Therapeutic alliance and psychoeducation. Patients’ expectations for pharmacotherapy vary from specific symptom relief to hopes for a complete cure, and their fears may be influenced by media and advertisements.¹⁷ Nonetheless a positive therapeutic alliance with the treating provider improves illness outcomes.¹⁹

A clinician’s ability to help patients build insight is invaluable for their current and future treatment. In a survey of 435 veterans with BD, nonadherence was greater among patients with limited insight about the role of medication in their illness.²⁰ A study of 65 BD patients that evaluated insight into medication adherence at initial interview and 1 year later found that difficulty with adherence at the initial interview predicted future nonadherence and was correlated with lack of insight.²¹ Rosa et al⁹ found that BD patients in denial of their illness and those who had little psychoeducation were more frequently nonadherent with lithium treatment.

Other factors that may contribute to medication nonadherence in BD patients include comorbid substance abuse or personality disorders, both of which are associated with more frequent relapse.¹⁵ Marriage has a beneficial affect on adherence.¹⁵ A good support system may contribute to treatment adherence; in a study of 107 children and adolescents with BD, nonadherent patients were more likely to experience family dysfunction and have a parental history of psychiatric hospitalization.²²

Adherence and BD course

Treatment adherence decreases the suicide rate among BD patients. Angst et al²³ evaluated the rate of suicide among 406 patients with BD and unipolar depression who were followed for 40 years. They found that 11% committed suicide; untreated patients had significantly higher standardized mortality rates than of those who were treated with lithium, antipsychotics, or antidepressants. Other studies confirm this finding.¹⁵

Repeated relapse may predict poorer cognitive performance. Lopez-Jaramillo et al²⁴ showed that patients with BD who had more manic episodes performed poorer on cognitive tests assessing attention, memory, and executive functioning compared with patients with less episodes and with normal subjects.

Medication adherence in BD is a priority because of potential neurodegeneration in BD and the neuroprotective effects of mood stabilizers and some atypical antipsychotics (Box).

Box

Increasing adherence

Pharmacologic strategies. Adherence in BD often is difficult when patients require a complex medication regimen to control their illness. Patients and clinicians may prefer to use once-daily dosing drug formulations, which can provide consistent serum levels and fewer adverse effects. Divalproex extended-release (ER) allows once-daily dosing and improved tolerability by reducing fluctuations in valproic acid serum concentrations compared with the delayed-release formulation. In a retrospective chart review,²⁵ most patients (62%) who switched to divalproex ER from divalproex delayed-release preferred the ER formulation; 52% showed clinical improvement, 81% did not experience side effects, and 8% demonstrated higher adherence after switching.²⁵ Similarly, an extended-release formulation of carbamazepine is approved for treating acute mania.

Many atypical antipsychotics are FDA-approved for acute mania, acute bipolar depression, and/or maintenance (Table 2). Long-acting injectable formulations (LAIs) may be used as maintenance treatment if nonadherence is an issue. LAI risperidone, which is FDA-approved for maintenance treatment of bipolar I disorder (BDI), was found to be safe and effective in stable BD patients who were switched from an oral antipsychotic.²⁶ Asenapine is provided in a rapidly absorbed, sublingual form and is FDA-approved for treating acute mania or mixed episodes associated with BDI.²⁷ Overall, however, only slightly more than one-half of BD patients are adherent to atypical antipsychotics.¹⁵

Although antidepressant use in BD is controversial, Sajatovic¹⁷ found 44% of depressed BDI patients were treated with antidepressants. Novel extended-release antidepressant formulations—including controlled-release fluvoxamine, paroxetine, extended-release bupropion and venlafaxine, once-weekly fluoxetine, rapidly dissolving mirtazapine, and transdermal selegiline—can optimize drug delivery, minimize side effects, and delay onset of action.¹

Psychosocial strategies used in BD include psychoeducation, cognitive-behavioral therapy (CBT), family-focused interventions, and interpersonal and social rhythm therapy (IPSRT) (Table 3).^28-30 Psychoeducation alone or combined with other interventions can decrease the risk of relapse and hospitalization and improve adherence.²⁸ In a 2-year study of 50 euthymic BD patients treated with lithium who participated in a brief hospital-based psychoeducation program, Even et al³¹ found patients’ knowledge about lithium but not their attitudes changed significantly after the program. The changes persisted 2 years after the intervention, with a trend toward a decreased hospitalization rate.

Miklowitz³² reported on 293 BD patients randomized to receive collaborative care (3 psychoeducational sessions delivered over 6 weeks) or 1 of 3 types of intensive psychotherapy: CBT, IPSRT, or family-focused therapy. Attrition was similar for both groups. Compared with those receiving collaborative care, significantly more patients receiving intensive psychotherapy recovered after 1 year, and did so in shorter time.

In a 3-year, multi-site Veterans Administration (VA) study, 306 BD patients received psychoeducation and support from nurse care coordinators who were responsible for access, continuity of care, and information flow to psychiatrists or usual care according to VA guidelines.³³ Compared with the usual care group, patients who received psychoeducation and support from nurse care coordinators had shorter duration of manic episodes and improved function and quality of life. A meta-analysis³⁰ of 12 randomized controlled trials of CBT in BD showed a medium effect size of CBT on adherence at 6 months post-treatment.

Table 2

FDA-approved medications for adult bipolar disorder

Table 3

Psychosocial interventions for bipolar disorder

Related Resource

• Deegan PE. The importance of personal medicine: a qualitative study of resilience in people with psychiatric disabilities. Scand J Public Health Suppl. 2005;66:29-35.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Bupropion • Wellbutrin
• Carbamazepine • Carbatrol, Tegretol
• Carbamazepine extended- release • Equetro
• Clozapine • Clozaril
• Divalproex • Depakote, Depakote ER
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Olanzapine/fluoxetine • Symbyax
• Paroxetine • Paxil
• Quetiapine • Seroquel, Seroquel XR
• Risperidone • Risperdal
• Risperidone long-acting injectable • Risperdal Consta
• Selegiline • Eldepryl, Emsam
• Valproate • Depacon
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

Dr. Foster receives research/grant support from the American Psychiatric Foundation, the National Institute of Mental Health, and Sunovion Pharmaceuticals.

Dr. Sheehan and Ms. Johns 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

Treatment nonadherence among patients with chronic illness is high, and bipolar disorder (BD) is no exception. Approximately 21% to 50% of patients with BD do not adhere to their recommended treatment regimen,¹ which adds to the burden of illness and worsens prognosis.

Although treatment nonadherence is a concern with any psychiatric disorder, we focus on BD because of the high prevalence of the disorder, the lifelong nature of the illness, and its resulting disability. BD is challenging to treat even with motivated patients, and psychiatrists cannot count on individuals to follow their prescribed regimen just because they were told to do so. Choosing the best treatment for each patient is complicated, and as physicians, we need to learn how to connect with our patients, increase our insight into their concerns, and work collaboratively to find a treatment they can follow.

This article describes methods of assessing adherence, factors that affect adherence, and pharmacologic and psychosocial interventions to enhance adherence and improve outcomes.

What is adherence?

As the doctor-patient relationship and medical treatment evolved to become more patient-centered, so have the terms used to describe individuals’ treatment-related behavior. Compliance, a physician-centered term that mandates following instructions to achieve treatment goals, evolved to adherence, the extent to which a person fulfills their part of an agreed-upon treatment plan, followed by concordance, which describes a decision-making alliance between patient and provider that strongly considers patients’ input.

Adherence is considered adequate when it occurs at the minimum level necessary for the patient to respond to treatment and avoid relapse.² Research on adherence in BD can be difficult to interpret because results may be influenced by:

• selection bias (patients who are adherent and insightful are more likely to consent to research)
• complications caused by polypharmacy and comorbidity
• investigators’ ability to choose the proper measure to delineate medication adherence attitudes and behaviors
• patients’ compliance with the adherence-enhancing interventions.²

Assessment methods. Several tools can be used to measure adherence to mental illness treatment. Attitudinal scales capture a person’s subjective feelings (such as being on a medication, insight, perceived strength of the therapeutic alliance, and level of stigma faced) and can reflect attitude change that may result from adherence-enhancing interventions. Adherence behavior scales may be convenient to administer in the office but tend to overestimate patients’ adherence (Table 1).^3-7

Pill counts are inexpensive but patients can manipulate unused medication. Prescription refill counts are easy to obtain but do not confirm that the patient took the medication. Electronic medication monitors capture the time of specific doses and can calculate the adherence rate, but they are expensive and do not ensure that the medication was ingested. Measuring the drug in urine or blood is an objective measure of adherence and can serve as clinical guide to pharmacotherapy, but offers limited correlation with the amount of medication taken and is expensive. A combination of measures to estimate adherence may be best.²

Table 1

Tools for measuring adherence to medications

BD adherence studies

Treatment adherence in BD is challenged by the chronic remission-relapse pattern of the disorder. Manic episodes carry the highest risk of nonadherence.² Scott and Pope⁸ evaluated self-reported adherence to mood stabilizers (lithium, carbamazepine, or valproate) among 98 patients with major depressive disorder and 78 with BD. They found that 32% of patients were partially adherent (defined as having missed >30% of doses in the past month) and >60% of these patients had sub-therapeutic plasma levels of mood stabilizers.

In a study of 106 BD outpatients treated with lithium who completed scales regarding their attitudes toward and knowledge of lithium and the Medication Adherence Rating Scale (MARS), 86% of patients had a therapeutic serum lithium level (.6 to 1.2 mEq/L), and knowledge of lithium was correlated with adherence.⁹ Jónsdóttir et al¹⁰ looked at medication adherence among 280 patients with schizophrenia and BD by comparing patient self-reports to provider reports and measuring serum drug concentrations; adherence was defined as having a serum concentration within the reference level for the specific medication. BD patients had an adherence rate of 66%, and self-reported adherence as measured by MARS and provider reports correlated with serum concentrations.

In a study of 71 adolescents with BD followed for 1 year after their first hospitalization for a manic or mixed episode, DelBello et al¹¹ defined nonadherence as taking medication <25% of the time and partial adherence as taking medication 25% to 75% of the time. They found that 42% of patients were partially adherent and 23% were nonadherent.

Strakowski¹² followed 46 adults from Taiwan and 96 from the United States for 1 year after their first manic or mixed episode and found that 79% of the Taiwanese patients and 50% of U.S. patients were adherent. Using the medication possession ratio (MPR)—which is calculated based the number of days between expected and actual prescription refills—to determine adherence, Sajatovic¹³ found that 54% of 44,637 veterans being treated for BD with lithium or anticonvulsants were fully adherent (MPR >.80), 25% were partially adherent (MPR >.50 to .80), and 21% were nonadherent (MPR ≤.50). In a survey of 131 randomly selected psychiatrists and 429 of their adult BD patients, Baldessarini¹⁴ found that 34% of patients reported missing ≥1 medication dose in past 10 days, but psychiatrists recognized only 18% of patients as nonadherent.

What affects adherence?

Although all BD patients share the same diagnosis, the factors that ultimately result in their medication adherence are as variable as the individuals themselves. Patients’ age, sex, culture, symptom severity, worldview, socioeconomic status, opinion of mental illness, and self-image influence their individual decisions on adhering to a prescribed medication regimen.^1,15

Perception of medication efficacy. Not surprisingly, if a medication does not seem to decrease debilitating symptoms, a patient is unlikely to continue taking it. Patients with BD feel more affected by depressive symptoms than by manic symptoms, and have indicated that they are more likely to adhere to and view as successful treatments that reduce depressive symptoms.^16,17

Tolerability. In an Internet-based survey, 469 patients with BD indicated that medication-related weight gain and cognitive impairment were the most important factors that affected adherence.¹⁶ Individuals’ concerns about possible side effects may contribute more to nonadherence than actually experiencing side effects.¹⁷ Concerns about long-term metabolic side effects from atypical antipsychotics also may limit adherence.¹⁷

Neurocognitive impairment. Whether caused by BD, aging, or a combination of these factors, deficits in memory, attention, and executive functioning can lead to unintentional nonadherence. In a study that assessed medication management ability among middle-aged and older adults, patients with BD were found to make 2.8 times more errors than healthy controls.¹⁸

Therapeutic alliance and psychoeducation. Patients’ expectations for pharmacotherapy vary from specific symptom relief to hopes for a complete cure, and their fears may be influenced by media and advertisements.¹⁷ Nonetheless a positive therapeutic alliance with the treating provider improves illness outcomes.¹⁹

A clinician’s ability to help patients build insight is invaluable for their current and future treatment. In a survey of 435 veterans with BD, nonadherence was greater among patients with limited insight about the role of medication in their illness.²⁰ A study of 65 BD patients that evaluated insight into medication adherence at initial interview and 1 year later found that difficulty with adherence at the initial interview predicted future nonadherence and was correlated with lack of insight.²¹ Rosa et al⁹ found that BD patients in denial of their illness and those who had little psychoeducation were more frequently nonadherent with lithium treatment.

Other factors that may contribute to medication nonadherence in BD patients include comorbid substance abuse or personality disorders, both of which are associated with more frequent relapse.¹⁵ Marriage has a beneficial affect on adherence.¹⁵ A good support system may contribute to treatment adherence; in a study of 107 children and adolescents with BD, nonadherent patients were more likely to experience family dysfunction and have a parental history of psychiatric hospitalization.²²

Adherence and BD course

Treatment adherence decreases the suicide rate among BD patients. Angst et al²³ evaluated the rate of suicide among 406 patients with BD and unipolar depression who were followed for 40 years. They found that 11% committed suicide; untreated patients had significantly higher standardized mortality rates than of those who were treated with lithium, antipsychotics, or antidepressants. Other studies confirm this finding.¹⁵

Repeated relapse may predict poorer cognitive performance. Lopez-Jaramillo et al²⁴ showed that patients with BD who had more manic episodes performed poorer on cognitive tests assessing attention, memory, and executive functioning compared with patients with less episodes and with normal subjects.

Medication adherence in BD is a priority because of potential neurodegeneration in BD and the neuroprotective effects of mood stabilizers and some atypical antipsychotics (Box).

Box

Increasing adherence

Pharmacologic strategies. Adherence in BD often is difficult when patients require a complex medication regimen to control their illness. Patients and clinicians may prefer to use once-daily dosing drug formulations, which can provide consistent serum levels and fewer adverse effects. Divalproex extended-release (ER) allows once-daily dosing and improved tolerability by reducing fluctuations in valproic acid serum concentrations compared with the delayed-release formulation. In a retrospective chart review,²⁵ most patients (62%) who switched to divalproex ER from divalproex delayed-release preferred the ER formulation; 52% showed clinical improvement, 81% did not experience side effects, and 8% demonstrated higher adherence after switching.²⁵ Similarly, an extended-release formulation of carbamazepine is approved for treating acute mania.

Many atypical antipsychotics are FDA-approved for acute mania, acute bipolar depression, and/or maintenance (Table 2). Long-acting injectable formulations (LAIs) may be used as maintenance treatment if nonadherence is an issue. LAI risperidone, which is FDA-approved for maintenance treatment of bipolar I disorder (BDI), was found to be safe and effective in stable BD patients who were switched from an oral antipsychotic.²⁶ Asenapine is provided in a rapidly absorbed, sublingual form and is FDA-approved for treating acute mania or mixed episodes associated with BDI.²⁷ Overall, however, only slightly more than one-half of BD patients are adherent to atypical antipsychotics.¹⁵

Although antidepressant use in BD is controversial, Sajatovic¹⁷ found 44% of depressed BDI patients were treated with antidepressants. Novel extended-release antidepressant formulations—including controlled-release fluvoxamine, paroxetine, extended-release bupropion and venlafaxine, once-weekly fluoxetine, rapidly dissolving mirtazapine, and transdermal selegiline—can optimize drug delivery, minimize side effects, and delay onset of action.¹

Psychosocial strategies used in BD include psychoeducation, cognitive-behavioral therapy (CBT), family-focused interventions, and interpersonal and social rhythm therapy (IPSRT) (Table 3).^28-30 Psychoeducation alone or combined with other interventions can decrease the risk of relapse and hospitalization and improve adherence.²⁸ In a 2-year study of 50 euthymic BD patients treated with lithium who participated in a brief hospital-based psychoeducation program, Even et al³¹ found patients’ knowledge about lithium but not their attitudes changed significantly after the program. The changes persisted 2 years after the intervention, with a trend toward a decreased hospitalization rate.

Miklowitz³² reported on 293 BD patients randomized to receive collaborative care (3 psychoeducational sessions delivered over 6 weeks) or 1 of 3 types of intensive psychotherapy: CBT, IPSRT, or family-focused therapy. Attrition was similar for both groups. Compared with those receiving collaborative care, significantly more patients receiving intensive psychotherapy recovered after 1 year, and did so in shorter time.

In a 3-year, multi-site Veterans Administration (VA) study, 306 BD patients received psychoeducation and support from nurse care coordinators who were responsible for access, continuity of care, and information flow to psychiatrists or usual care according to VA guidelines.³³ Compared with the usual care group, patients who received psychoeducation and support from nurse care coordinators had shorter duration of manic episodes and improved function and quality of life. A meta-analysis³⁰ of 12 randomized controlled trials of CBT in BD showed a medium effect size of CBT on adherence at 6 months post-treatment.

Table 2

FDA-approved medications for adult bipolar disorder

Table 3

Psychosocial interventions for bipolar disorder

Related Resource

• Deegan PE. The importance of personal medicine: a qualitative study of resilience in people with psychiatric disabilities. Scand J Public Health Suppl. 2005;66:29-35.

Drug Brand Names

• Aripiprazole • Abilify
• Asenapine • Saphris
• Bupropion • Wellbutrin
• Carbamazepine • Carbatrol, Tegretol
• Carbamazepine extended- release • Equetro
• Clozapine • Clozaril
• Divalproex • Depakote, Depakote ER
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Olanzapine/fluoxetine • Symbyax
• Paroxetine • Paxil
• Quetiapine • Seroquel, Seroquel XR
• Risperidone • Risperdal
• Risperidone long-acting injectable • Risperdal Consta
• Selegiline • Eldepryl, Emsam
• Valproate • Depacon
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosures

Dr. Foster receives research/grant support from the American Psychiatric Foundation, the National Institute of Mental Health, and Sunovion Pharmaceuticals.

Dr. Sheehan and Ms. Johns report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Medication errors due to system-, provider-, or patient-related factors contribute significantly to increased costs, adverse drug events (ADEs), and morbidity and mortality.¹ One study found >60% of ADEs that led to hospitalization could have been prevented by strategies such as adequate monitoring or appropriate prescribing.² Psychiatrists have an opportunity to reduce rates of ADEs; however, the possibility of disease symptoms overlapping with these adverse events is 1 of many obstacles prescribing clinicians face.¹ Prescribers also must contend with adverse effects of polypharmacy, which are common among psychiatric patients. Patient-related factors of concern include:

• seeing multiple prescribers
• medication nonadherence
• failure to communicate use of herbal or over-the-counter products
• lack of insight
• comorbid medical and psychiatric diagnoses, such as dementia.¹

This article highlights potential ADEs and major medication safety concerns that may contribute to morbidity and mortality among patients taking psychotropics. Although many factors are beyond the prescribing clinician’s control—such as medication dispensing and administration errors—psychiatrists can substantially reduce ADEs. We will cover potential adverse events associated with key medications or medication classes, drug interactions with potentially devastating consequences, and strategies to minimize risks of ADEs, including enhanced awareness and monitoring (Table 1).

Table 1

How to avoid ADEs with psychotropics

Prescription drug overdose

Each year, unintentional drug overdoses account for >20,000 deaths in the United States.³ Prescription medications, particularly opioid analgesics, have contributed to the doubling of overdose mortality rates in recent years. A recent study reported that nearly 50% of unintentional drug overdose deaths were associated with psychotropics and one-third of these deaths were associated with benzodiazepines, many of which were not prescribed to the individual.⁴

The risk of mortality from intentional drug overdose also must be assessed. Tricyclic antidepressants (TCAs) are a particularly lethal class of medications in suicide attempts and may result in arrhythmias, coma, seizures, respiratory failure, and death.⁵ Venlafaxine and mirtazapine are associated with greater risk of death and toxicity in overdose, respectively, than selective serotonin reuptake inhibitors (SSRIs).⁶ Lithium toxicity in overdose may lead to bradycardia, seizure, coma, hyperventilation, serotonin syndrome, respiratory failure, or death.⁵ The risk of death with lithium or benzodiazepine monotherapy is low when these agents are taken as prescribed. However, prescribers must exercise caution when these agents are used in combination. Interactions involving drugs with a narrow therapeutic index—such as lithium and TCAs—are more likely to be clinically significant because small increases in drug concentration can lead to serious adverse effects or death. See Related Resources for a review article on appropriate use and monitoring of lithium.

Drug-drug interactions

Many Americans take multiple prescription and nonprescription drugs, and psychiatric patients are more likely than other individuals to have more complex medication regimens.⁷ This can result in polypharmacy and drug-drug interactions (DDIs), which can lead to undesired medication effects and serious, potentially fatal ADEs.

Pharmacokinetic interactions typically affect drug concentrations and occur when 1 drug interferes with the absorption, distribution, metabolism, or excretion of another drug. Many common pharmacokinetic interactions involve the liver cytochrome P450 (CYP) system, which is responsible for metabolizing many medications.⁸ DDIs can occur when CYP enzymes are modified by inhibitors or inducers, which can decrease or increase drug clearance, respectively. Table 2 ^5,7,9 provides examples of common CYP450 substrates, inhibitors, and inducers. Polymorphisms in the pharmacogenetics of CYP450 also can affect overall drug clearance and the impact of DDIs.⁸

Pharmacodynamic interactions are caused by additive or competing effects of multiple drugs. The most serious of these involve medications that increase a patient’s risk of serotonin syndrome or neuroleptic malignant syndrome (NMS); both are medical emergencies that require immediate hospitalization.

Although any medication with serotonergic activity can induce serotonin syndrome, combinations of serotonergic drugs in particular are associated with increased risk.¹⁰ Serotonin syndrome is characterized by hyperthermia, altered muscle tone, altered mental status, and autonomic instability; rhabdomyolysis and disseminated intravascular coagulation are potential lethal complications.¹⁰ A high index of suspicion can help clinicians rapidly detect serotonin syndrome, discontinue offending agents, and initiate supportive treatments.

NMS is a life-threatening complication of antipsychotics characterized by fever, delirium, muscle rigidity, autonomic instability, and abnormal laboratory findings that include elevated white blood count and increased creatinine kinase from muscle injury. In early stages, NMS may be mistaken for extrapyramidal symptoms. Although NMS can occur with any antipsychotic as monotherapy, additive antidopaminergic effects increase the risk. Patients with a compromised CNS as a result of mental retardation, traumatic brain injury, or metabolic abnormalities also are at increased risk of developing NMS.¹¹

Other pharmacodynamic interactions involve medications that may have additive effects on prolonging QTc intervals. For example, TCAs are pro-arrhythmic and have quinidine-like effects, which can cause cardiac conduction abnormalities and prolonged PR and QTc intervals.¹² Employ routine ECG monitoring when prescribing multiple medications known to cause QTc prolongation, such as TCAs (Table 3).^13,14 The Arizona Center for Education and Research on Therapeutics (www.azcert.org) provides a searchable list of QT-prolonging drugs (see Related Resources).

Medications also can interact with food, disease states, and herbal supplements. Alcohol interacts with many CNS-active medications, including many psychotropics. Patients taking benzodiazepines may experience oversedation and respiratory depression from alcohol’s additive sedating effects.⁵ Advise patients to limit their alcohol intake while taking CNS-depressing psychotropics such as benzodiazepines, antipsychotics, and some antidepressants. Monoamine oxidase inhibitors (MAOIs) and tyramine-containing food—such as cheese, beer, preserved meat, and soy sauce—can lead to a dangerous hypertensive crisis that requires immediate medical intervention to prevent life-threatening complications.⁵ Hypertensive crisis may be more significant in patients who have pre-existing hypertension. Finally, herbal supplements also can interact with medications. Patients who take St. John’s wort for depressive symptoms might not realize that it can reduce the efficacy of other drugs or increase their risk of serotonin syndrome.⁹

Table 2

Cytochrome P450 substrates, inhibitors, and inducers

Table 3

Psychotropics associated with QT prolongation

Black-box warnings

“Black-box” warnings issued by the FDA are included in the package insert to highlight a medication’s risks of dangerous and potentially lethal adverse effects. Table 4 highlights current black-box warnings for various psychotropics.^5,14-16

Antidepressants and suicide. All medications with antidepressant indications carry a black-box warning for risk of suicidal ideation and behavior in children, adolescents, and young adults during the early months of medication therapy. This includes not only SSRIs and serotonin-norepinephrine reuptake inhibitors, but also anticonvulsants and atypical antipsychotics indicated for treating mood disorders. Monitor young patients carefully and advise family members to alert clinicians of any signs of suicidality or unusual behavior.

Lamotrigine and aseptic meningitis. Aseptic meningitis—inflammation of the meninges that is not caused by bacteria—is a rare but serious adverse effect of lamotrigine. Symptoms include headache, fever, stiff neck, nausea and vomiting, delirium, rash, and sensitivity to light.⁵ Forty cases of aseptic meningitis in children and adults were reported over 15 years, representing <.01% of all lamotrigine prescriptions.⁵ Most of these patients required hospitalization, but symptoms resolved after lamotrigine was discontinued. Prompt identification and management of aseptic meningitis are necessary to prevent permanent brain damage and death. Other complications of aseptic meningitis include long-term neurologic sequelae such as cognitive impairment, seizure disorders, and behavioral disturbances.

Table 4

Which psychotropics carry ‘black-box’ warnings?

Other complications

Hematologic effects. All classes of psychotropics carry a risk (1 to 2 cases per year per 100,00 patients) of serious hematologic complications, including neutropenia, agranulocytosis, eosinophilia, thrombocytopenia, purpura, and anemia.¹⁷ Agranulocytosis has been associated most commonly with clozapine, carbamazepine, and typical antipsychotics.¹⁷ SSRIs, which are widely prescribed, are associated with increased risk of bruising and bleeding. Patients with bleeding or platelet disorders are at an increased risk for these complications.¹⁷

Seizures. Several classes of psychotropics are associated with an increased risk of seizures. Among antipsychotics, clozapine and chlorpromazine are the most seizurogenic.¹⁸ Among antidepressants, bupropion and clomipramine are most likely to lower seizure thresholds.¹⁸ Psychotropics’ seizure-inducing effects are dose-related. Vulnerability to seizures while taking psychotropics is related to having a history of epilepsy or brain injury.¹⁸ Seizures also can occur when benzodiazepines or anticonvulsants are withdrawn too quickly.

Heat stroke. Although a rare occurrence, psychotropics with anticholinergic side effects can contribute to heat stroke. Older patients are particularly vulnerable to the risk of body temperature dysregulation.¹⁹

Ketoacidosis and hyperosmolar coma. Medication-related deaths have occurred as a result of ketoacidosis and hyperosmolar coma associated with atypical antipsychotics. These hyperglycemia-related fatalities are most likely with clozapine and olanzapine.²⁰

Hip fractures and falls. Geriatric patients are vulnerable to falls and resultant hip fractures related to use of TCAs, SSRIs, benzodiazepines, and antipsychotics. This is not a trivial matter; hip fractures increase the mortality rate by 12% to 20% in the year after the injury.²¹ The risk of falls is related to sedation, orthostatic hypotension, arrhythmias, and confusion associated with psychotropics.^21,22

Akathisia and suicide. Unrecognized or undertreated akathisia is most commonly associated with antipsychotics, but also can occur with SSRIs. Although akathisia is commonly thought of as a motor syndrome of restlessness, patients may find the less-recognized psychic symptoms of increased inner turmoil and hallucinations just as distressing. This complex of symptoms is associated with an increased risk of suicide.²³ If discontinuing the offending agent is not feasible, akathisia can be treated with beta blockers, benzodiazepines, or anticholinergics.²⁴

Hepatotoxicity. Hepatotoxicity from psychotropics occurs in only a small percentage of patients, and can range from transient elevations in liver enzymes to fulminant liver failure. Adverse hepatic effects may be a manifestation of a hypersensitivity reaction accompanied by rash and eosinophilia.²⁵ MAOIs and TCAs can cause cholestatic liver injury, whereas nefazodone has been associated with fulminant liver failure. Other psychotropics—including SSRIs, antipsychotics, benzodiazepines, and older antiepileptics—can cause negative hepatic effects but rarely are associated with acute liver failure.^25,26 Although few medications can cause complete liver failure on their own, hepatotoxicity from medications may precipitate severe, potentially fatal outcomes in patients with underlying liver diseases such as hepatitis and cirrhosis. Additive hepatotoxicity from multiple medications also can be problematic. Although psychotropic-induced hepatotoxicity is rare, assess psychotropic doses in patients with liver dysfunction, because drug clearance may be altered, which increases the risk for other serious adverse events.²⁵

Suicide assessment is key

Ongoing monitoring for current or developing suicidal ideation is an important strategy to prevent medication-related mortality in patients vulnerable to self-harm. Initial assessments and follow-up appointments should include a detailed inquiry about suicidal ideations, plans, and behaviors. Patients taking medications that carry black-box warnings for suicide risk should be seen frequently during the first few months of treatment. Patients receiving medications that are lethal in overdose (eg, lithium and TCAs) should be carefully screened for suicide risk. Prescribe medications in limited quantities or arrange for a family member to monitor the patient if necessary. Patients with a history of suicide attempts and current suicide plans may require close observation and initiating medications while hospitalized.

Other prevention strategies

Prescribing psychotropics in a manner that promotes mental well being while minimizing negative outcomes can be challenging. By developing a personal formulary of drugs commonly encountered and prescribed in their practice, psychiatrists can increase their awareness of serious safety concerns, potential DDIs, and appropriate use based on available literature.^7,27

Medication histories and drug reconciliation—comparing a patient’s medication orders to all of the medications the patient has been taking—can help clinicians avoid making inappropriate dose adjustments, duplicating therapy, or prescribing medications patients previously have failed or did not tolerate. Establishing a collaborative practice environment with physicians, pharmacists, nurses, and social workers can minimize medication errors and risk of adverse outcomes by increasing communication regarding the patient’s treatment.⁷

Computerized drug databases and other electronic resources and consultation with pharmacists can help prescribers identify, avoid, and manage clinically significant DDIs.²⁷ Medications could interact with other drugs as long as their effects persist in the body, which could be days to months after the drug is discontinued. Future research may lead to tools to identify patient pharmacogenetic profiles.

Recognizing psychotropic DDIs and adverse effects remains a challenge because of the complexity of the affected organ, the brain. Clinicians should be vigilant to changes in a patient’s presentation because they may be a manifestation of a medication side effect.⁷ Appropriate therapeutic drug monitoring should occur on a routine, scheduled basis. Closer monitoring may be necessary with dose changes, potential DDIs, signs and symptoms of toxicity/efficacy failure, and renal or hepatic function changes.

Lastly, patients’ education and involvement in their health care may increase their awareness, responsibility, and medication adherence. For challenging patients, family involvement and “eyes on” medication administration can increase adherence and prevent psychotropic misuse.

Related Resources

• Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval and/or induce Torsades de Pointes ventricular arrhythmia. www.azcert.org/medical-pros/drug-lists/drug-lists.cfm.
• Cates ME, Sims PJ. Therapeutic drug management of lithium. Am J Pharm Educ. 2005;69(5):88.
• Wren P, Frizzell LA, Keltner NL, et al. Three potentially fatal adverse effects of psychotropic medications. Perspect Psychiatr Care. 2003;39(2):75-81.
• Bishop JR, Bishop DL. How to prevent serotonin syndrome from drug-drug interactions. Current Psychiatry. 2011;10(3):81-83.

Drug Brand Names

• Amantadine • Symmetrel
• Amiodarone • Cordarone, Pacerone
• Amitriptyline • Elavil
• Amphetamine/dextroamphetamine • Adderall, others
• Aprepitant • Emend
• Aripiprazole • Abilify
• Asenapine • Saphris
• Atomoxetine • Strattera
• Bupropion • Wellbutrin, Zyban
• Carbamazepine • Tegretol, others
• Chloral hydrate • Somnote
• Chlorpromazine • Thorazine
• Cimetidine • Tagamet
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Desvenlafaxine • Pristiq
• Diltiazem • Cardia, others
• Diphenhydramine • Benadryl, others
• Doxepin • Sinequan, Silenor
• Duloxetine • Cymbalta
• Erythromycin • Ery-Tab, others
• Fluconazole • Diflucan
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Galantamine • Razadyne
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Imatinib • Gleevec
• Imipramine • Tofranil
• Isoniazid • Nydrazid, others
• Ketoconazole • Nizoral, others
• Lamotrigine • Lamictal
• Lithium • Eskalith, others
• Methadone • Dolophine, Methadose
• Methylphenidate/ dexmethylphenidate • Ritalin, others
• Mirtazapine • Remeron
• Nafcillin • Nafcil, others
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Oxcarbazepine • Trileptal
• Paliperidone • Invega
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Phenobarbital • Luminal, others
• Phenytoin • Dilantin
• Protriptyline • Vivactil
• Quetiapine • Seroquel
• Rifampin • Rifadin, others
• Risperidone • Risperdal
• Ritonavir • Norvir
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Trimethoprim/Sulfamethoxazole • Bactrim, Septra
• Trimipramine • Surmontil
• Valproic acid • Depakote, others
• Venlafaxine • Effexor
• Verapamil • Calan, others
• Ziprasidone • Geodon

Disclosure

Drs. Yu and Bostwick report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Casher is a speaker for AstraZeneca, Pfizer Inc, and Sunovion Pharmaceuticals.

Medication errors due to system-, provider-, or patient-related factors contribute significantly to increased costs, adverse drug events (ADEs), and morbidity and mortality.¹ One study found >60% of ADEs that led to hospitalization could have been prevented by strategies such as adequate monitoring or appropriate prescribing.² Psychiatrists have an opportunity to reduce rates of ADEs; however, the possibility of disease symptoms overlapping with these adverse events is 1 of many obstacles prescribing clinicians face.¹ Prescribers also must contend with adverse effects of polypharmacy, which are common among psychiatric patients. Patient-related factors of concern include:

• seeing multiple prescribers
• medication nonadherence
• failure to communicate use of herbal or over-the-counter products
• lack of insight
• comorbid medical and psychiatric diagnoses, such as dementia.¹

This article highlights potential ADEs and major medication safety concerns that may contribute to morbidity and mortality among patients taking psychotropics. Although many factors are beyond the prescribing clinician’s control—such as medication dispensing and administration errors—psychiatrists can substantially reduce ADEs. We will cover potential adverse events associated with key medications or medication classes, drug interactions with potentially devastating consequences, and strategies to minimize risks of ADEs, including enhanced awareness and monitoring (Table 1).

Table 1

How to avoid ADEs with psychotropics

Prescription drug overdose

Each year, unintentional drug overdoses account for >20,000 deaths in the United States.³ Prescription medications, particularly opioid analgesics, have contributed to the doubling of overdose mortality rates in recent years. A recent study reported that nearly 50% of unintentional drug overdose deaths were associated with psychotropics and one-third of these deaths were associated with benzodiazepines, many of which were not prescribed to the individual.⁴

The risk of mortality from intentional drug overdose also must be assessed. Tricyclic antidepressants (TCAs) are a particularly lethal class of medications in suicide attempts and may result in arrhythmias, coma, seizures, respiratory failure, and death.⁵ Venlafaxine and mirtazapine are associated with greater risk of death and toxicity in overdose, respectively, than selective serotonin reuptake inhibitors (SSRIs).⁶ Lithium toxicity in overdose may lead to bradycardia, seizure, coma, hyperventilation, serotonin syndrome, respiratory failure, or death.⁵ The risk of death with lithium or benzodiazepine monotherapy is low when these agents are taken as prescribed. However, prescribers must exercise caution when these agents are used in combination. Interactions involving drugs with a narrow therapeutic index—such as lithium and TCAs—are more likely to be clinically significant because small increases in drug concentration can lead to serious adverse effects or death. See Related Resources for a review article on appropriate use and monitoring of lithium.

Drug-drug interactions

Many Americans take multiple prescription and nonprescription drugs, and psychiatric patients are more likely than other individuals to have more complex medication regimens.⁷ This can result in polypharmacy and drug-drug interactions (DDIs), which can lead to undesired medication effects and serious, potentially fatal ADEs.

Pharmacokinetic interactions typically affect drug concentrations and occur when 1 drug interferes with the absorption, distribution, metabolism, or excretion of another drug. Many common pharmacokinetic interactions involve the liver cytochrome P450 (CYP) system, which is responsible for metabolizing many medications.⁸ DDIs can occur when CYP enzymes are modified by inhibitors or inducers, which can decrease or increase drug clearance, respectively. Table 2 ^5,7,9 provides examples of common CYP450 substrates, inhibitors, and inducers. Polymorphisms in the pharmacogenetics of CYP450 also can affect overall drug clearance and the impact of DDIs.⁸

Pharmacodynamic interactions are caused by additive or competing effects of multiple drugs. The most serious of these involve medications that increase a patient’s risk of serotonin syndrome or neuroleptic malignant syndrome (NMS); both are medical emergencies that require immediate hospitalization.

Although any medication with serotonergic activity can induce serotonin syndrome, combinations of serotonergic drugs in particular are associated with increased risk.¹⁰ Serotonin syndrome is characterized by hyperthermia, altered muscle tone, altered mental status, and autonomic instability; rhabdomyolysis and disseminated intravascular coagulation are potential lethal complications.¹⁰ A high index of suspicion can help clinicians rapidly detect serotonin syndrome, discontinue offending agents, and initiate supportive treatments.

NMS is a life-threatening complication of antipsychotics characterized by fever, delirium, muscle rigidity, autonomic instability, and abnormal laboratory findings that include elevated white blood count and increased creatinine kinase from muscle injury. In early stages, NMS may be mistaken for extrapyramidal symptoms. Although NMS can occur with any antipsychotic as monotherapy, additive antidopaminergic effects increase the risk. Patients with a compromised CNS as a result of mental retardation, traumatic brain injury, or metabolic abnormalities also are at increased risk of developing NMS.¹¹

Other pharmacodynamic interactions involve medications that may have additive effects on prolonging QTc intervals. For example, TCAs are pro-arrhythmic and have quinidine-like effects, which can cause cardiac conduction abnormalities and prolonged PR and QTc intervals.¹² Employ routine ECG monitoring when prescribing multiple medications known to cause QTc prolongation, such as TCAs (Table 3).^13,14 The Arizona Center for Education and Research on Therapeutics (www.azcert.org) provides a searchable list of QT-prolonging drugs (see Related Resources).

Medications also can interact with food, disease states, and herbal supplements. Alcohol interacts with many CNS-active medications, including many psychotropics. Patients taking benzodiazepines may experience oversedation and respiratory depression from alcohol’s additive sedating effects.⁵ Advise patients to limit their alcohol intake while taking CNS-depressing psychotropics such as benzodiazepines, antipsychotics, and some antidepressants. Monoamine oxidase inhibitors (MAOIs) and tyramine-containing food—such as cheese, beer, preserved meat, and soy sauce—can lead to a dangerous hypertensive crisis that requires immediate medical intervention to prevent life-threatening complications.⁵ Hypertensive crisis may be more significant in patients who have pre-existing hypertension. Finally, herbal supplements also can interact with medications. Patients who take St. John’s wort for depressive symptoms might not realize that it can reduce the efficacy of other drugs or increase their risk of serotonin syndrome.⁹

Table 2

Cytochrome P450 substrates, inhibitors, and inducers

Table 3

Psychotropics associated with QT prolongation

Black-box warnings

“Black-box” warnings issued by the FDA are included in the package insert to highlight a medication’s risks of dangerous and potentially lethal adverse effects. Table 4 highlights current black-box warnings for various psychotropics.^5,14-16

Antidepressants and suicide. All medications with antidepressant indications carry a black-box warning for risk of suicidal ideation and behavior in children, adolescents, and young adults during the early months of medication therapy. This includes not only SSRIs and serotonin-norepinephrine reuptake inhibitors, but also anticonvulsants and atypical antipsychotics indicated for treating mood disorders. Monitor young patients carefully and advise family members to alert clinicians of any signs of suicidality or unusual behavior.

Lamotrigine and aseptic meningitis. Aseptic meningitis—inflammation of the meninges that is not caused by bacteria—is a rare but serious adverse effect of lamotrigine. Symptoms include headache, fever, stiff neck, nausea and vomiting, delirium, rash, and sensitivity to light.⁵ Forty cases of aseptic meningitis in children and adults were reported over 15 years, representing <.01% of all lamotrigine prescriptions.⁵ Most of these patients required hospitalization, but symptoms resolved after lamotrigine was discontinued. Prompt identification and management of aseptic meningitis are necessary to prevent permanent brain damage and death. Other complications of aseptic meningitis include long-term neurologic sequelae such as cognitive impairment, seizure disorders, and behavioral disturbances.

Table 4

Which psychotropics carry ‘black-box’ warnings?

Other complications

Hematologic effects. All classes of psychotropics carry a risk (1 to 2 cases per year per 100,00 patients) of serious hematologic complications, including neutropenia, agranulocytosis, eosinophilia, thrombocytopenia, purpura, and anemia.¹⁷ Agranulocytosis has been associated most commonly with clozapine, carbamazepine, and typical antipsychotics.¹⁷ SSRIs, which are widely prescribed, are associated with increased risk of bruising and bleeding. Patients with bleeding or platelet disorders are at an increased risk for these complications.¹⁷

Seizures. Several classes of psychotropics are associated with an increased risk of seizures. Among antipsychotics, clozapine and chlorpromazine are the most seizurogenic.¹⁸ Among antidepressants, bupropion and clomipramine are most likely to lower seizure thresholds.¹⁸ Psychotropics’ seizure-inducing effects are dose-related. Vulnerability to seizures while taking psychotropics is related to having a history of epilepsy or brain injury.¹⁸ Seizures also can occur when benzodiazepines or anticonvulsants are withdrawn too quickly.

Heat stroke. Although a rare occurrence, psychotropics with anticholinergic side effects can contribute to heat stroke. Older patients are particularly vulnerable to the risk of body temperature dysregulation.¹⁹

Ketoacidosis and hyperosmolar coma. Medication-related deaths have occurred as a result of ketoacidosis and hyperosmolar coma associated with atypical antipsychotics. These hyperglycemia-related fatalities are most likely with clozapine and olanzapine.²⁰

Hip fractures and falls. Geriatric patients are vulnerable to falls and resultant hip fractures related to use of TCAs, SSRIs, benzodiazepines, and antipsychotics. This is not a trivial matter; hip fractures increase the mortality rate by 12% to 20% in the year after the injury.²¹ The risk of falls is related to sedation, orthostatic hypotension, arrhythmias, and confusion associated with psychotropics.^21,22

Akathisia and suicide. Unrecognized or undertreated akathisia is most commonly associated with antipsychotics, but also can occur with SSRIs. Although akathisia is commonly thought of as a motor syndrome of restlessness, patients may find the less-recognized psychic symptoms of increased inner turmoil and hallucinations just as distressing. This complex of symptoms is associated with an increased risk of suicide.²³ If discontinuing the offending agent is not feasible, akathisia can be treated with beta blockers, benzodiazepines, or anticholinergics.²⁴

Hepatotoxicity. Hepatotoxicity from psychotropics occurs in only a small percentage of patients, and can range from transient elevations in liver enzymes to fulminant liver failure. Adverse hepatic effects may be a manifestation of a hypersensitivity reaction accompanied by rash and eosinophilia.²⁵ MAOIs and TCAs can cause cholestatic liver injury, whereas nefazodone has been associated with fulminant liver failure. Other psychotropics—including SSRIs, antipsychotics, benzodiazepines, and older antiepileptics—can cause negative hepatic effects but rarely are associated with acute liver failure.^25,26 Although few medications can cause complete liver failure on their own, hepatotoxicity from medications may precipitate severe, potentially fatal outcomes in patients with underlying liver diseases such as hepatitis and cirrhosis. Additive hepatotoxicity from multiple medications also can be problematic. Although psychotropic-induced hepatotoxicity is rare, assess psychotropic doses in patients with liver dysfunction, because drug clearance may be altered, which increases the risk for other serious adverse events.²⁵

Suicide assessment is key

Ongoing monitoring for current or developing suicidal ideation is an important strategy to prevent medication-related mortality in patients vulnerable to self-harm. Initial assessments and follow-up appointments should include a detailed inquiry about suicidal ideations, plans, and behaviors. Patients taking medications that carry black-box warnings for suicide risk should be seen frequently during the first few months of treatment. Patients receiving medications that are lethal in overdose (eg, lithium and TCAs) should be carefully screened for suicide risk. Prescribe medications in limited quantities or arrange for a family member to monitor the patient if necessary. Patients with a history of suicide attempts and current suicide plans may require close observation and initiating medications while hospitalized.

Other prevention strategies

Prescribing psychotropics in a manner that promotes mental well being while minimizing negative outcomes can be challenging. By developing a personal formulary of drugs commonly encountered and prescribed in their practice, psychiatrists can increase their awareness of serious safety concerns, potential DDIs, and appropriate use based on available literature.^7,27

Medication histories and drug reconciliation—comparing a patient’s medication orders to all of the medications the patient has been taking—can help clinicians avoid making inappropriate dose adjustments, duplicating therapy, or prescribing medications patients previously have failed or did not tolerate. Establishing a collaborative practice environment with physicians, pharmacists, nurses, and social workers can minimize medication errors and risk of adverse outcomes by increasing communication regarding the patient’s treatment.⁷

Computerized drug databases and other electronic resources and consultation with pharmacists can help prescribers identify, avoid, and manage clinically significant DDIs.²⁷ Medications could interact with other drugs as long as their effects persist in the body, which could be days to months after the drug is discontinued. Future research may lead to tools to identify patient pharmacogenetic profiles.

Recognizing psychotropic DDIs and adverse effects remains a challenge because of the complexity of the affected organ, the brain. Clinicians should be vigilant to changes in a patient’s presentation because they may be a manifestation of a medication side effect.⁷ Appropriate therapeutic drug monitoring should occur on a routine, scheduled basis. Closer monitoring may be necessary with dose changes, potential DDIs, signs and symptoms of toxicity/efficacy failure, and renal or hepatic function changes.

Lastly, patients’ education and involvement in their health care may increase their awareness, responsibility, and medication adherence. For challenging patients, family involvement and “eyes on” medication administration can increase adherence and prevent psychotropic misuse.

Related Resources

• Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval and/or induce Torsades de Pointes ventricular arrhythmia. www.azcert.org/medical-pros/drug-lists/drug-lists.cfm.
• Cates ME, Sims PJ. Therapeutic drug management of lithium. Am J Pharm Educ. 2005;69(5):88.
• Wren P, Frizzell LA, Keltner NL, et al. Three potentially fatal adverse effects of psychotropic medications. Perspect Psychiatr Care. 2003;39(2):75-81.
• Bishop JR, Bishop DL. How to prevent serotonin syndrome from drug-drug interactions. Current Psychiatry. 2011;10(3):81-83.

Drug Brand Names

• Amantadine • Symmetrel
• Amiodarone • Cordarone, Pacerone
• Amitriptyline • Elavil
• Amphetamine/dextroamphetamine • Adderall, others
• Aprepitant • Emend
• Aripiprazole • Abilify
• Asenapine • Saphris
• Atomoxetine • Strattera
• Bupropion • Wellbutrin, Zyban
• Carbamazepine • Tegretol, others
• Chloral hydrate • Somnote
• Chlorpromazine • Thorazine
• Cimetidine • Tagamet
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Desvenlafaxine • Pristiq
• Diltiazem • Cardia, others
• Diphenhydramine • Benadryl, others
• Doxepin • Sinequan, Silenor
• Duloxetine • Cymbalta
• Erythromycin • Ery-Tab, others
• Fluconazole • Diflucan
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Galantamine • Razadyne
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Imatinib • Gleevec
• Imipramine • Tofranil
• Isoniazid • Nydrazid, others
• Ketoconazole • Nizoral, others
• Lamotrigine • Lamictal
• Lithium • Eskalith, others
• Methadone • Dolophine, Methadose
• Methylphenidate/ dexmethylphenidate • Ritalin, others
• Mirtazapine • Remeron
• Nafcillin • Nafcil, others
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Oxcarbazepine • Trileptal
• Paliperidone • Invega
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Phenobarbital • Luminal, others
• Phenytoin • Dilantin
• Protriptyline • Vivactil
• Quetiapine • Seroquel
• Rifampin • Rifadin, others
• Risperidone • Risperdal
• Ritonavir • Norvir
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Trimethoprim/Sulfamethoxazole • Bactrim, Septra
• Trimipramine • Surmontil
• Valproic acid • Depakote, others
• Venlafaxine • Effexor
• Verapamil • Calan, others
• Ziprasidone • Geodon

Disclosure

Drs. Yu and Bostwick report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Casher is a speaker for AstraZeneca, Pfizer Inc, and Sunovion Pharmaceuticals.

Medication errors due to system-, provider-, or patient-related factors contribute significantly to increased costs, adverse drug events (ADEs), and morbidity and mortality.¹ One study found >60% of ADEs that led to hospitalization could have been prevented by strategies such as adequate monitoring or appropriate prescribing.² Psychiatrists have an opportunity to reduce rates of ADEs; however, the possibility of disease symptoms overlapping with these adverse events is 1 of many obstacles prescribing clinicians face.¹ Prescribers also must contend with adverse effects of polypharmacy, which are common among psychiatric patients. Patient-related factors of concern include:

• seeing multiple prescribers
• medication nonadherence
• failure to communicate use of herbal or over-the-counter products
• lack of insight
• comorbid medical and psychiatric diagnoses, such as dementia.¹

This article highlights potential ADEs and major medication safety concerns that may contribute to morbidity and mortality among patients taking psychotropics. Although many factors are beyond the prescribing clinician’s control—such as medication dispensing and administration errors—psychiatrists can substantially reduce ADEs. We will cover potential adverse events associated with key medications or medication classes, drug interactions with potentially devastating consequences, and strategies to minimize risks of ADEs, including enhanced awareness and monitoring (Table 1).

Table 1

How to avoid ADEs with psychotropics

Prescription drug overdose

Each year, unintentional drug overdoses account for >20,000 deaths in the United States.³ Prescription medications, particularly opioid analgesics, have contributed to the doubling of overdose mortality rates in recent years. A recent study reported that nearly 50% of unintentional drug overdose deaths were associated with psychotropics and one-third of these deaths were associated with benzodiazepines, many of which were not prescribed to the individual.⁴

The risk of mortality from intentional drug overdose also must be assessed. Tricyclic antidepressants (TCAs) are a particularly lethal class of medications in suicide attempts and may result in arrhythmias, coma, seizures, respiratory failure, and death.⁵ Venlafaxine and mirtazapine are associated with greater risk of death and toxicity in overdose, respectively, than selective serotonin reuptake inhibitors (SSRIs).⁶ Lithium toxicity in overdose may lead to bradycardia, seizure, coma, hyperventilation, serotonin syndrome, respiratory failure, or death.⁵ The risk of death with lithium or benzodiazepine monotherapy is low when these agents are taken as prescribed. However, prescribers must exercise caution when these agents are used in combination. Interactions involving drugs with a narrow therapeutic index—such as lithium and TCAs—are more likely to be clinically significant because small increases in drug concentration can lead to serious adverse effects or death. See Related Resources for a review article on appropriate use and monitoring of lithium.

Drug-drug interactions

Many Americans take multiple prescription and nonprescription drugs, and psychiatric patients are more likely than other individuals to have more complex medication regimens.⁷ This can result in polypharmacy and drug-drug interactions (DDIs), which can lead to undesired medication effects and serious, potentially fatal ADEs.

Pharmacokinetic interactions typically affect drug concentrations and occur when 1 drug interferes with the absorption, distribution, metabolism, or excretion of another drug. Many common pharmacokinetic interactions involve the liver cytochrome P450 (CYP) system, which is responsible for metabolizing many medications.⁸ DDIs can occur when CYP enzymes are modified by inhibitors or inducers, which can decrease or increase drug clearance, respectively. Table 2 ^5,7,9 provides examples of common CYP450 substrates, inhibitors, and inducers. Polymorphisms in the pharmacogenetics of CYP450 also can affect overall drug clearance and the impact of DDIs.⁸

Pharmacodynamic interactions are caused by additive or competing effects of multiple drugs. The most serious of these involve medications that increase a patient’s risk of serotonin syndrome or neuroleptic malignant syndrome (NMS); both are medical emergencies that require immediate hospitalization.

Although any medication with serotonergic activity can induce serotonin syndrome, combinations of serotonergic drugs in particular are associated with increased risk.¹⁰ Serotonin syndrome is characterized by hyperthermia, altered muscle tone, altered mental status, and autonomic instability; rhabdomyolysis and disseminated intravascular coagulation are potential lethal complications.¹⁰ A high index of suspicion can help clinicians rapidly detect serotonin syndrome, discontinue offending agents, and initiate supportive treatments.

NMS is a life-threatening complication of antipsychotics characterized by fever, delirium, muscle rigidity, autonomic instability, and abnormal laboratory findings that include elevated white blood count and increased creatinine kinase from muscle injury. In early stages, NMS may be mistaken for extrapyramidal symptoms. Although NMS can occur with any antipsychotic as monotherapy, additive antidopaminergic effects increase the risk. Patients with a compromised CNS as a result of mental retardation, traumatic brain injury, or metabolic abnormalities also are at increased risk of developing NMS.¹¹

Other pharmacodynamic interactions involve medications that may have additive effects on prolonging QTc intervals. For example, TCAs are pro-arrhythmic and have quinidine-like effects, which can cause cardiac conduction abnormalities and prolonged PR and QTc intervals.¹² Employ routine ECG monitoring when prescribing multiple medications known to cause QTc prolongation, such as TCAs (Table 3).^13,14 The Arizona Center for Education and Research on Therapeutics (www.azcert.org) provides a searchable list of QT-prolonging drugs (see Related Resources).

Medications also can interact with food, disease states, and herbal supplements. Alcohol interacts with many CNS-active medications, including many psychotropics. Patients taking benzodiazepines may experience oversedation and respiratory depression from alcohol’s additive sedating effects.⁵ Advise patients to limit their alcohol intake while taking CNS-depressing psychotropics such as benzodiazepines, antipsychotics, and some antidepressants. Monoamine oxidase inhibitors (MAOIs) and tyramine-containing food—such as cheese, beer, preserved meat, and soy sauce—can lead to a dangerous hypertensive crisis that requires immediate medical intervention to prevent life-threatening complications.⁵ Hypertensive crisis may be more significant in patients who have pre-existing hypertension. Finally, herbal supplements also can interact with medications. Patients who take St. John’s wort for depressive symptoms might not realize that it can reduce the efficacy of other drugs or increase their risk of serotonin syndrome.⁹

Table 2

Cytochrome P450 substrates, inhibitors, and inducers

Table 3

Psychotropics associated with QT prolongation

Black-box warnings

“Black-box” warnings issued by the FDA are included in the package insert to highlight a medication’s risks of dangerous and potentially lethal adverse effects. Table 4 highlights current black-box warnings for various psychotropics.^5,14-16

Antidepressants and suicide. All medications with antidepressant indications carry a black-box warning for risk of suicidal ideation and behavior in children, adolescents, and young adults during the early months of medication therapy. This includes not only SSRIs and serotonin-norepinephrine reuptake inhibitors, but also anticonvulsants and atypical antipsychotics indicated for treating mood disorders. Monitor young patients carefully and advise family members to alert clinicians of any signs of suicidality or unusual behavior.

Lamotrigine and aseptic meningitis. Aseptic meningitis—inflammation of the meninges that is not caused by bacteria—is a rare but serious adverse effect of lamotrigine. Symptoms include headache, fever, stiff neck, nausea and vomiting, delirium, rash, and sensitivity to light.⁵ Forty cases of aseptic meningitis in children and adults were reported over 15 years, representing <.01% of all lamotrigine prescriptions.⁵ Most of these patients required hospitalization, but symptoms resolved after lamotrigine was discontinued. Prompt identification and management of aseptic meningitis are necessary to prevent permanent brain damage and death. Other complications of aseptic meningitis include long-term neurologic sequelae such as cognitive impairment, seizure disorders, and behavioral disturbances.

Table 4

Which psychotropics carry ‘black-box’ warnings?

Other complications

Hematologic effects. All classes of psychotropics carry a risk (1 to 2 cases per year per 100,00 patients) of serious hematologic complications, including neutropenia, agranulocytosis, eosinophilia, thrombocytopenia, purpura, and anemia.¹⁷ Agranulocytosis has been associated most commonly with clozapine, carbamazepine, and typical antipsychotics.¹⁷ SSRIs, which are widely prescribed, are associated with increased risk of bruising and bleeding. Patients with bleeding or platelet disorders are at an increased risk for these complications.¹⁷

Seizures. Several classes of psychotropics are associated with an increased risk of seizures. Among antipsychotics, clozapine and chlorpromazine are the most seizurogenic.¹⁸ Among antidepressants, bupropion and clomipramine are most likely to lower seizure thresholds.¹⁸ Psychotropics’ seizure-inducing effects are dose-related. Vulnerability to seizures while taking psychotropics is related to having a history of epilepsy or brain injury.¹⁸ Seizures also can occur when benzodiazepines or anticonvulsants are withdrawn too quickly.

Heat stroke. Although a rare occurrence, psychotropics with anticholinergic side effects can contribute to heat stroke. Older patients are particularly vulnerable to the risk of body temperature dysregulation.¹⁹

Ketoacidosis and hyperosmolar coma. Medication-related deaths have occurred as a result of ketoacidosis and hyperosmolar coma associated with atypical antipsychotics. These hyperglycemia-related fatalities are most likely with clozapine and olanzapine.²⁰

Hip fractures and falls. Geriatric patients are vulnerable to falls and resultant hip fractures related to use of TCAs, SSRIs, benzodiazepines, and antipsychotics. This is not a trivial matter; hip fractures increase the mortality rate by 12% to 20% in the year after the injury.²¹ The risk of falls is related to sedation, orthostatic hypotension, arrhythmias, and confusion associated with psychotropics.^21,22

Akathisia and suicide. Unrecognized or undertreated akathisia is most commonly associated with antipsychotics, but also can occur with SSRIs. Although akathisia is commonly thought of as a motor syndrome of restlessness, patients may find the less-recognized psychic symptoms of increased inner turmoil and hallucinations just as distressing. This complex of symptoms is associated with an increased risk of suicide.²³ If discontinuing the offending agent is not feasible, akathisia can be treated with beta blockers, benzodiazepines, or anticholinergics.²⁴

Hepatotoxicity. Hepatotoxicity from psychotropics occurs in only a small percentage of patients, and can range from transient elevations in liver enzymes to fulminant liver failure. Adverse hepatic effects may be a manifestation of a hypersensitivity reaction accompanied by rash and eosinophilia.²⁵ MAOIs and TCAs can cause cholestatic liver injury, whereas nefazodone has been associated with fulminant liver failure. Other psychotropics—including SSRIs, antipsychotics, benzodiazepines, and older antiepileptics—can cause negative hepatic effects but rarely are associated with acute liver failure.^25,26 Although few medications can cause complete liver failure on their own, hepatotoxicity from medications may precipitate severe, potentially fatal outcomes in patients with underlying liver diseases such as hepatitis and cirrhosis. Additive hepatotoxicity from multiple medications also can be problematic. Although psychotropic-induced hepatotoxicity is rare, assess psychotropic doses in patients with liver dysfunction, because drug clearance may be altered, which increases the risk for other serious adverse events.²⁵

Suicide assessment is key

Ongoing monitoring for current or developing suicidal ideation is an important strategy to prevent medication-related mortality in patients vulnerable to self-harm. Initial assessments and follow-up appointments should include a detailed inquiry about suicidal ideations, plans, and behaviors. Patients taking medications that carry black-box warnings for suicide risk should be seen frequently during the first few months of treatment. Patients receiving medications that are lethal in overdose (eg, lithium and TCAs) should be carefully screened for suicide risk. Prescribe medications in limited quantities or arrange for a family member to monitor the patient if necessary. Patients with a history of suicide attempts and current suicide plans may require close observation and initiating medications while hospitalized.

Other prevention strategies

Prescribing psychotropics in a manner that promotes mental well being while minimizing negative outcomes can be challenging. By developing a personal formulary of drugs commonly encountered and prescribed in their practice, psychiatrists can increase their awareness of serious safety concerns, potential DDIs, and appropriate use based on available literature.^7,27

Medication histories and drug reconciliation—comparing a patient’s medication orders to all of the medications the patient has been taking—can help clinicians avoid making inappropriate dose adjustments, duplicating therapy, or prescribing medications patients previously have failed or did not tolerate. Establishing a collaborative practice environment with physicians, pharmacists, nurses, and social workers can minimize medication errors and risk of adverse outcomes by increasing communication regarding the patient’s treatment.⁷

Computerized drug databases and other electronic resources and consultation with pharmacists can help prescribers identify, avoid, and manage clinically significant DDIs.²⁷ Medications could interact with other drugs as long as their effects persist in the body, which could be days to months after the drug is discontinued. Future research may lead to tools to identify patient pharmacogenetic profiles.

Recognizing psychotropic DDIs and adverse effects remains a challenge because of the complexity of the affected organ, the brain. Clinicians should be vigilant to changes in a patient’s presentation because they may be a manifestation of a medication side effect.⁷ Appropriate therapeutic drug monitoring should occur on a routine, scheduled basis. Closer monitoring may be necessary with dose changes, potential DDIs, signs and symptoms of toxicity/efficacy failure, and renal or hepatic function changes.

Lastly, patients’ education and involvement in their health care may increase their awareness, responsibility, and medication adherence. For challenging patients, family involvement and “eyes on” medication administration can increase adherence and prevent psychotropic misuse.

Related Resources

• Arizona Center for Education and Research on Therapeutics. Drugs that prolong the QT interval and/or induce Torsades de Pointes ventricular arrhythmia. www.azcert.org/medical-pros/drug-lists/drug-lists.cfm.
• Cates ME, Sims PJ. Therapeutic drug management of lithium. Am J Pharm Educ. 2005;69(5):88.
• Wren P, Frizzell LA, Keltner NL, et al. Three potentially fatal adverse effects of psychotropic medications. Perspect Psychiatr Care. 2003;39(2):75-81.
• Bishop JR, Bishop DL. How to prevent serotonin syndrome from drug-drug interactions. Current Psychiatry. 2011;10(3):81-83.

Drug Brand Names

• Amantadine • Symmetrel
• Amiodarone • Cordarone, Pacerone
• Amitriptyline • Elavil
• Amphetamine/dextroamphetamine • Adderall, others
• Aprepitant • Emend
• Aripiprazole • Abilify
• Asenapine • Saphris
• Atomoxetine • Strattera
• Bupropion • Wellbutrin, Zyban
• Carbamazepine • Tegretol, others
• Chloral hydrate • Somnote
• Chlorpromazine • Thorazine
• Cimetidine • Tagamet
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clozapine • Clozaril
• Desipramine • Norpramin
• Desvenlafaxine • Pristiq
• Diltiazem • Cardia, others
• Diphenhydramine • Benadryl, others
• Doxepin • Sinequan, Silenor
• Duloxetine • Cymbalta
• Erythromycin • Ery-Tab, others
• Fluconazole • Diflucan
• Fluoxetine • Prozac
• Fluphenazine • Prolixin
• Galantamine • Razadyne
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Imatinib • Gleevec
• Imipramine • Tofranil
• Isoniazid • Nydrazid, others
• Ketoconazole • Nizoral, others
• Lamotrigine • Lamictal
• Lithium • Eskalith, others
• Methadone • Dolophine, Methadose
• Methylphenidate/ dexmethylphenidate • Ritalin, others
• Mirtazapine • Remeron
• Nafcillin • Nafcil, others
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Omeprazole • Prilosec
• Oxcarbazepine • Trileptal
• Paliperidone • Invega
• Paroxetine • Paxil
• Perphenazine • Trilafon
• Phenobarbital • Luminal, others
• Phenytoin • Dilantin
• Protriptyline • Vivactil
• Quetiapine • Seroquel
• Rifampin • Rifadin, others
• Risperidone • Risperdal
• Ritonavir • Norvir
• Sertraline • Zoloft
• Thioridazine • Mellaril
• Trazodone • Desyrel, Oleptro
• Trifluoperazine • Stelazine
• Trimethoprim/Sulfamethoxazole • Bactrim, Septra
• Trimipramine • Surmontil
• Valproic acid • Depakote, others
• Venlafaxine • Effexor
• Verapamil • Calan, others
• Ziprasidone • Geodon

Disclosure

Drs. Yu and Bostwick report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Casher is a speaker for AstraZeneca, Pfizer Inc, and Sunovion Pharmaceuticals.

Discuss this article at www.facebook.com/CurrentPsychiatry

Most clinical trials of major depressive disorder (MDD) have focused on diagnosis and treatment of adults, but many younger and older patients also suffer from this condition. The prevalence of MDD is estimated to be 2% in children and 6% in adolescents.¹ Up to 25% of adults age >60 experience MDD, dysthymic disorder, or “minor” depression.²

Although diagnosis and treatment of depression is similar regardless of a patient’s age, younger and older patients may not exhibit typical depressive symptoms (Table 1).^1,2 For example, older adults may be more likely to report a lack of emotions than depressed mood. Vigilance for these types of distinct clinical manifestations can improve early recognition and treatment. In addition, evidence suggests there are differences in MDD treatment for younger and older patients.

This article reviews common challenges in recognizing and treating MDD in children, adolescents, and older adults.

Table 1

Major depressive disorder: Age-related differences

Varying clinical features

Children/adolescents. The clinical presentation of MDD in children and adolescents is similar to that of adults. Children usually display anxiety, irritability, temper tantrums, and somatic complaints before verbally expressing depressive feelings. Psychotic depression in children manifests more often as auditory hallucinations than delusions.¹

Younger vs middle-age adults. Researchers who evaluated baseline clinical and sociodemographic information of 1,498 patients enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study found that the presentation of depressive symptoms in young adult patients (age 18 to 35) differed from those of middle-age (age 36 to 50) patients.³ Younger patients were more likely to be irritable, complain of weight gain and hypersomnia, and have a negative view of life and the future. They also were more likely to report previous suicide attempts and endorse symptoms consistent with generalized anxiety disorder, social phobia, panic disorder, and drug abuse. Middle-age patients had more depressive episodes, deceased libido, and middle insomnia, and more frequently reported gastrointestinal symptoms such as diarrhea or constipation.³

Older adults. In our experience, typical MDD mood symptoms often are absent in older patients. Frequently, we see somatic complaints, motor restlessness, or psychomotor retardation; these symptoms may be attributable to a concurrent medical illness. This in turn may worsen the physical illness, leading to social isolation and considerable medical morbidity.⁴

Pain plays an important role in depression, particularly in older adults. Chronic pain affects up to 65% of older adults who live in the community and up to 80% of those who are institutionalized.⁵ The most common causes of pain in these patients are osteoarthritis, osteoporosis, fibromyalgia, degenerative disk disease, lumbar spinal stenosis, and scoliosis. In addition, neuropathic pain, such as post-herpetic neuralgia and peripheral neuropathy, and injuries resulting from falls often cause long-lasting pain.⁶

The presence of pain tends to negatively affect recognizing and treating depression. Regardless of their age, when a patient presents with pain or depression, investigate and consider treating both conditions.⁷

Memory decline is likely to be depressed older adults’ chief complaint, and when objectively tested these patients often show cognitive impairment.⁸ Whether depressive symptoms in this age group are a reaction to early cognitive deficits or are an early symptom of neurodegeneration remains controversial.⁹ Some case-control studies have found a link between a history of depression and Alzheimer’s disease (AD).^10,11 In general, older patients whose first episode of depression occurs in late life have a higher relative risk of developing some form of dementia; research suggests that 50% of late-life MDD patients will develop dementia within 5 years.¹²

Researchers have considered the possibility that mild cognitive impairment (MCI) and dementia are a continuum of depression. In 1 study, 29 patients with MCI and 31 with MCI and MDD were assessed annually for an average of 4.3 years.¹³ Thirty-six patients with MCI (60%) progressed to AD. Presence of depression at the time of MCI diagnosis did not predict conversion to AD but persistence of depression for 2 to 3 years and the presence of melancholic features were associated with higher risk for AD.

Alexopoulos et al¹⁴ proposed the “vascular hypothesis theory” that cerebrovascular disease can predispose patients, particularly older adults, to depressive symptoms (Table 2).¹⁴ Whether vascular depression is a subtype of MDD remains controversial.

Table 2

Features of vascular depression

Course and prognosis

MDD has been characterized as a self-limited disease, with an average duration of 6 to 9 months. However, newer prospective studies suggest that a substantial number of patients recover more slowly or do not ever fully recover.¹⁵ Several factors, such as genetic/biologic vulnerability and psychosocial factors, influence the courses, prognosis, and risk of relapse/recurrence of MDD in all age groups.

Children and adolescents. The typical duration of a major depressive episode for clinically referred children and adolescents is 8 to 13 months.^1,16 Approximately 90% of these patients’ major depressive episodes remit by 2 years, but up to 10% persist.^1,16 Within 5 years of MDD onset, up to 70% of children and adolescents will experience a recurrence,¹⁷ a rate comparable to adults.

Anxiety disorders, panic disorders, phobias, substance abuse, conduct and oppositional disorders, and attention-deficit/hyperactivity disorder occur 2 to 6 times more frequently in children and adolescents with MDD.^18,19 Children with MDD who have significant psychiatric and psychosocial comorbidity experience poorer outcomes.¹⁸

Older adults. Despite optimal treatment conditions, ≥50% of older patients fail to respond adequately to first-line antidepressant pharmacotherapy.²⁰ Treatment-resistant MDD in older patients increases:

• nonadherence to treatment for comorbid medical disorders
• disability and cognitive impairment
• burden on caregivers
• risk for early mortality, including suicide.²⁰

Differences in treatment

Although MDD often is recurrent, episodic, and in some patients chronic, in general earlier treatment and quicker response lead to better outcomes. A large, naturalistic German study of 795 inpatients with major depression found that early improvement (20% reduction in Hamilton Depression Rating Scale-21 score within the first 2 weeks) with antidepressant therapy may predict later response and remission.²¹

Regardless of a patient’s age, MDD treatment should begin with education. All patients should be involved in their treatment. Encourage patients to become familiar with their triggers and stressors, improve their coping skills, and adopt a healthy lifestyle, which includes a nutritious diet, frequent exercise, and adequate sleep. As maintenance treatment we recommend that patients participate in frequent socialization and activities (Table 3). Refer patients to self-help books, online help guides, and handouts from sources such as National Institute of Mental Health.^22,23 Encourage patients to have patience and perseverance, and guide them through each step of recovery.

In addition to lifestyle modification, other treatment options for depression include pharmacotherapy, interpersonal psychotherapy, cognitive-behavioral therapy (CBT), and electroconvulsive therapy (ECT). All these modalities are effective for acute and maintenance treatment and should be considered when determining the best approach for each patient.

The effectiveness of antidepressants in general is comparable among and within classes.² Base your initial selection on the patient’s previous response to antidepressants and the medication’s side effects profile and cost.

The benefits of exercise for all patients cannot be underestimated.²⁴ Prescribe 20 to 30 minutes of daily exercise as part of recommended lifestyle changes. Writing “daily exercise” on a prescription pad can effectively remind patients that exercise needs to be taken as seriously as medication compliance.

Children and adolescents. For mild depression, supportive therapy seems to be as effective as CBT and medications.²⁵ A randomized controlled trial of 439 depressed adolescents found that CBT plus fluoxetine conferred quicker benefit, but in the long run may not be any more efficacious than pharmacotherapy alone.²⁵ Researchers also found that CBT plus fluoxetine was no more effective than pharmacotherapy alone for adolescents with moderate to severe depression.²⁵

Older adults. Compared with younger patients, geriatric patients typically require lower antidepressant dosages to achieve a specific blood level, but the blood levels at which antidepressants are most effective appear to be similar.² Older patients also may be more likely to relapse and less likely to achieve full response to antidepressants than younger patients.² In older adults, amitriptyline, imipramine, and doxepin are not preferred because these agents may cause orthostatic hypotension and urinary retention.² A depressed older adult who experiences weight loss might benefit from an antidepressant that improves appetite, such as mirtazapine.²⁶ Some research suggests that maintenance antidepressant therapy in older patients experiencing a first-time episode of MDD should continue for up to 2 years.²⁷

A meta-analysis of 12 studies of CBT in depressed adults age ≥60 with chronic pain found that CBT was effective at improving self-reported pain but had no significant effect on depressive symptoms, physical function, or medication use.⁶ ECT often is prescribed for depressed older adults because its safety and efficacy for these patients has been well documented.²⁸ Other neuromodulation therapies include vagus nerve, repetitive transcranial magnetic stimulation, and deep brain stimulation, but none of these treatments have been extensively evaluated in older patients.

Table 3

Avoiding reoccurrence of depression—a ‘prescription’ for patients

Related Resource

• American Psychiatric Association. Treatment of patients with major depressive disorder. 3rd ed. www.psychiatryonline.com/pracGuide/pracGuideChapToc_7.aspx.

Drug Brand Names

• Amitriptyline • Elavil
• Doxepin • Aponal, Silenor
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Mirtazapine • Remeron

Disclosure

The authors 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

Most clinical trials of major depressive disorder (MDD) have focused on diagnosis and treatment of adults, but many younger and older patients also suffer from this condition. The prevalence of MDD is estimated to be 2% in children and 6% in adolescents.¹ Up to 25% of adults age >60 experience MDD, dysthymic disorder, or “minor” depression.²

Although diagnosis and treatment of depression is similar regardless of a patient’s age, younger and older patients may not exhibit typical depressive symptoms (Table 1).^1,2 For example, older adults may be more likely to report a lack of emotions than depressed mood. Vigilance for these types of distinct clinical manifestations can improve early recognition and treatment. In addition, evidence suggests there are differences in MDD treatment for younger and older patients.

This article reviews common challenges in recognizing and treating MDD in children, adolescents, and older adults.

Table 1

Major depressive disorder: Age-related differences

Varying clinical features

Children/adolescents. The clinical presentation of MDD in children and adolescents is similar to that of adults. Children usually display anxiety, irritability, temper tantrums, and somatic complaints before verbally expressing depressive feelings. Psychotic depression in children manifests more often as auditory hallucinations than delusions.¹

Younger vs middle-age adults. Researchers who evaluated baseline clinical and sociodemographic information of 1,498 patients enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study found that the presentation of depressive symptoms in young adult patients (age 18 to 35) differed from those of middle-age (age 36 to 50) patients.³ Younger patients were more likely to be irritable, complain of weight gain and hypersomnia, and have a negative view of life and the future. They also were more likely to report previous suicide attempts and endorse symptoms consistent with generalized anxiety disorder, social phobia, panic disorder, and drug abuse. Middle-age patients had more depressive episodes, deceased libido, and middle insomnia, and more frequently reported gastrointestinal symptoms such as diarrhea or constipation.³

Older adults. In our experience, typical MDD mood symptoms often are absent in older patients. Frequently, we see somatic complaints, motor restlessness, or psychomotor retardation; these symptoms may be attributable to a concurrent medical illness. This in turn may worsen the physical illness, leading to social isolation and considerable medical morbidity.⁴

Pain plays an important role in depression, particularly in older adults. Chronic pain affects up to 65% of older adults who live in the community and up to 80% of those who are institutionalized.⁵ The most common causes of pain in these patients are osteoarthritis, osteoporosis, fibromyalgia, degenerative disk disease, lumbar spinal stenosis, and scoliosis. In addition, neuropathic pain, such as post-herpetic neuralgia and peripheral neuropathy, and injuries resulting from falls often cause long-lasting pain.⁶

The presence of pain tends to negatively affect recognizing and treating depression. Regardless of their age, when a patient presents with pain or depression, investigate and consider treating both conditions.⁷

Memory decline is likely to be depressed older adults’ chief complaint, and when objectively tested these patients often show cognitive impairment.⁸ Whether depressive symptoms in this age group are a reaction to early cognitive deficits or are an early symptom of neurodegeneration remains controversial.⁹ Some case-control studies have found a link between a history of depression and Alzheimer’s disease (AD).^10,11 In general, older patients whose first episode of depression occurs in late life have a higher relative risk of developing some form of dementia; research suggests that 50% of late-life MDD patients will develop dementia within 5 years.¹²

Researchers have considered the possibility that mild cognitive impairment (MCI) and dementia are a continuum of depression. In 1 study, 29 patients with MCI and 31 with MCI and MDD were assessed annually for an average of 4.3 years.¹³ Thirty-six patients with MCI (60%) progressed to AD. Presence of depression at the time of MCI diagnosis did not predict conversion to AD but persistence of depression for 2 to 3 years and the presence of melancholic features were associated with higher risk for AD.

Alexopoulos et al¹⁴ proposed the “vascular hypothesis theory” that cerebrovascular disease can predispose patients, particularly older adults, to depressive symptoms (Table 2).¹⁴ Whether vascular depression is a subtype of MDD remains controversial.

Table 2

Features of vascular depression

Course and prognosis

MDD has been characterized as a self-limited disease, with an average duration of 6 to 9 months. However, newer prospective studies suggest that a substantial number of patients recover more slowly or do not ever fully recover.¹⁵ Several factors, such as genetic/biologic vulnerability and psychosocial factors, influence the courses, prognosis, and risk of relapse/recurrence of MDD in all age groups.

Children and adolescents. The typical duration of a major depressive episode for clinically referred children and adolescents is 8 to 13 months.^1,16 Approximately 90% of these patients’ major depressive episodes remit by 2 years, but up to 10% persist.^1,16 Within 5 years of MDD onset, up to 70% of children and adolescents will experience a recurrence,¹⁷ a rate comparable to adults.

Anxiety disorders, panic disorders, phobias, substance abuse, conduct and oppositional disorders, and attention-deficit/hyperactivity disorder occur 2 to 6 times more frequently in children and adolescents with MDD.^18,19 Children with MDD who have significant psychiatric and psychosocial comorbidity experience poorer outcomes.¹⁸

Older adults. Despite optimal treatment conditions, ≥50% of older patients fail to respond adequately to first-line antidepressant pharmacotherapy.²⁰ Treatment-resistant MDD in older patients increases:

• nonadherence to treatment for comorbid medical disorders
• disability and cognitive impairment
• burden on caregivers
• risk for early mortality, including suicide.²⁰

Differences in treatment

Although MDD often is recurrent, episodic, and in some patients chronic, in general earlier treatment and quicker response lead to better outcomes. A large, naturalistic German study of 795 inpatients with major depression found that early improvement (20% reduction in Hamilton Depression Rating Scale-21 score within the first 2 weeks) with antidepressant therapy may predict later response and remission.²¹

Regardless of a patient’s age, MDD treatment should begin with education. All patients should be involved in their treatment. Encourage patients to become familiar with their triggers and stressors, improve their coping skills, and adopt a healthy lifestyle, which includes a nutritious diet, frequent exercise, and adequate sleep. As maintenance treatment we recommend that patients participate in frequent socialization and activities (Table 3). Refer patients to self-help books, online help guides, and handouts from sources such as National Institute of Mental Health.^22,23 Encourage patients to have patience and perseverance, and guide them through each step of recovery.

In addition to lifestyle modification, other treatment options for depression include pharmacotherapy, interpersonal psychotherapy, cognitive-behavioral therapy (CBT), and electroconvulsive therapy (ECT). All these modalities are effective for acute and maintenance treatment and should be considered when determining the best approach for each patient.

The effectiveness of antidepressants in general is comparable among and within classes.² Base your initial selection on the patient’s previous response to antidepressants and the medication’s side effects profile and cost.

The benefits of exercise for all patients cannot be underestimated.²⁴ Prescribe 20 to 30 minutes of daily exercise as part of recommended lifestyle changes. Writing “daily exercise” on a prescription pad can effectively remind patients that exercise needs to be taken as seriously as medication compliance.

Children and adolescents. For mild depression, supportive therapy seems to be as effective as CBT and medications.²⁵ A randomized controlled trial of 439 depressed adolescents found that CBT plus fluoxetine conferred quicker benefit, but in the long run may not be any more efficacious than pharmacotherapy alone.²⁵ Researchers also found that CBT plus fluoxetine was no more effective than pharmacotherapy alone for adolescents with moderate to severe depression.²⁵

Older adults. Compared with younger patients, geriatric patients typically require lower antidepressant dosages to achieve a specific blood level, but the blood levels at which antidepressants are most effective appear to be similar.² Older patients also may be more likely to relapse and less likely to achieve full response to antidepressants than younger patients.² In older adults, amitriptyline, imipramine, and doxepin are not preferred because these agents may cause orthostatic hypotension and urinary retention.² A depressed older adult who experiences weight loss might benefit from an antidepressant that improves appetite, such as mirtazapine.²⁶ Some research suggests that maintenance antidepressant therapy in older patients experiencing a first-time episode of MDD should continue for up to 2 years.²⁷

A meta-analysis of 12 studies of CBT in depressed adults age ≥60 with chronic pain found that CBT was effective at improving self-reported pain but had no significant effect on depressive symptoms, physical function, or medication use.⁶ ECT often is prescribed for depressed older adults because its safety and efficacy for these patients has been well documented.²⁸ Other neuromodulation therapies include vagus nerve, repetitive transcranial magnetic stimulation, and deep brain stimulation, but none of these treatments have been extensively evaluated in older patients.

Table 3

Avoiding reoccurrence of depression—a ‘prescription’ for patients

Related Resource

• American Psychiatric Association. Treatment of patients with major depressive disorder. 3rd ed. www.psychiatryonline.com/pracGuide/pracGuideChapToc_7.aspx.

Drug Brand Names

• Amitriptyline • Elavil
• Doxepin • Aponal, Silenor
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Mirtazapine • Remeron

Disclosure

The authors 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

Most clinical trials of major depressive disorder (MDD) have focused on diagnosis and treatment of adults, but many younger and older patients also suffer from this condition. The prevalence of MDD is estimated to be 2% in children and 6% in adolescents.¹ Up to 25% of adults age >60 experience MDD, dysthymic disorder, or “minor” depression.²

Although diagnosis and treatment of depression is similar regardless of a patient’s age, younger and older patients may not exhibit typical depressive symptoms (Table 1).^1,2 For example, older adults may be more likely to report a lack of emotions than depressed mood. Vigilance for these types of distinct clinical manifestations can improve early recognition and treatment. In addition, evidence suggests there are differences in MDD treatment for younger and older patients.

This article reviews common challenges in recognizing and treating MDD in children, adolescents, and older adults.

Table 1

Major depressive disorder: Age-related differences

Varying clinical features

Children/adolescents. The clinical presentation of MDD in children and adolescents is similar to that of adults. Children usually display anxiety, irritability, temper tantrums, and somatic complaints before verbally expressing depressive feelings. Psychotic depression in children manifests more often as auditory hallucinations than delusions.¹

Younger vs middle-age adults. Researchers who evaluated baseline clinical and sociodemographic information of 1,498 patients enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study found that the presentation of depressive symptoms in young adult patients (age 18 to 35) differed from those of middle-age (age 36 to 50) patients.³ Younger patients were more likely to be irritable, complain of weight gain and hypersomnia, and have a negative view of life and the future. They also were more likely to report previous suicide attempts and endorse symptoms consistent with generalized anxiety disorder, social phobia, panic disorder, and drug abuse. Middle-age patients had more depressive episodes, deceased libido, and middle insomnia, and more frequently reported gastrointestinal symptoms such as diarrhea or constipation.³

Older adults. In our experience, typical MDD mood symptoms often are absent in older patients. Frequently, we see somatic complaints, motor restlessness, or psychomotor retardation; these symptoms may be attributable to a concurrent medical illness. This in turn may worsen the physical illness, leading to social isolation and considerable medical morbidity.⁴

Pain plays an important role in depression, particularly in older adults. Chronic pain affects up to 65% of older adults who live in the community and up to 80% of those who are institutionalized.⁵ The most common causes of pain in these patients are osteoarthritis, osteoporosis, fibromyalgia, degenerative disk disease, lumbar spinal stenosis, and scoliosis. In addition, neuropathic pain, such as post-herpetic neuralgia and peripheral neuropathy, and injuries resulting from falls often cause long-lasting pain.⁶

The presence of pain tends to negatively affect recognizing and treating depression. Regardless of their age, when a patient presents with pain or depression, investigate and consider treating both conditions.⁷

Memory decline is likely to be depressed older adults’ chief complaint, and when objectively tested these patients often show cognitive impairment.⁸ Whether depressive symptoms in this age group are a reaction to early cognitive deficits or are an early symptom of neurodegeneration remains controversial.⁹ Some case-control studies have found a link between a history of depression and Alzheimer’s disease (AD).^10,11 In general, older patients whose first episode of depression occurs in late life have a higher relative risk of developing some form of dementia; research suggests that 50% of late-life MDD patients will develop dementia within 5 years.¹²

Researchers have considered the possibility that mild cognitive impairment (MCI) and dementia are a continuum of depression. In 1 study, 29 patients with MCI and 31 with MCI and MDD were assessed annually for an average of 4.3 years.¹³ Thirty-six patients with MCI (60%) progressed to AD. Presence of depression at the time of MCI diagnosis did not predict conversion to AD but persistence of depression for 2 to 3 years and the presence of melancholic features were associated with higher risk for AD.

Alexopoulos et al¹⁴ proposed the “vascular hypothesis theory” that cerebrovascular disease can predispose patients, particularly older adults, to depressive symptoms (Table 2).¹⁴ Whether vascular depression is a subtype of MDD remains controversial.

Table 2

Features of vascular depression

Course and prognosis

MDD has been characterized as a self-limited disease, with an average duration of 6 to 9 months. However, newer prospective studies suggest that a substantial number of patients recover more slowly or do not ever fully recover.¹⁵ Several factors, such as genetic/biologic vulnerability and psychosocial factors, influence the courses, prognosis, and risk of relapse/recurrence of MDD in all age groups.

Children and adolescents. The typical duration of a major depressive episode for clinically referred children and adolescents is 8 to 13 months.^1,16 Approximately 90% of these patients’ major depressive episodes remit by 2 years, but up to 10% persist.^1,16 Within 5 years of MDD onset, up to 70% of children and adolescents will experience a recurrence,¹⁷ a rate comparable to adults.

Anxiety disorders, panic disorders, phobias, substance abuse, conduct and oppositional disorders, and attention-deficit/hyperactivity disorder occur 2 to 6 times more frequently in children and adolescents with MDD.^18,19 Children with MDD who have significant psychiatric and psychosocial comorbidity experience poorer outcomes.¹⁸

Older adults. Despite optimal treatment conditions, ≥50% of older patients fail to respond adequately to first-line antidepressant pharmacotherapy.²⁰ Treatment-resistant MDD in older patients increases:

• nonadherence to treatment for comorbid medical disorders
• disability and cognitive impairment
• burden on caregivers
• risk for early mortality, including suicide.²⁰

Differences in treatment

Although MDD often is recurrent, episodic, and in some patients chronic, in general earlier treatment and quicker response lead to better outcomes. A large, naturalistic German study of 795 inpatients with major depression found that early improvement (20% reduction in Hamilton Depression Rating Scale-21 score within the first 2 weeks) with antidepressant therapy may predict later response and remission.²¹

Regardless of a patient’s age, MDD treatment should begin with education. All patients should be involved in their treatment. Encourage patients to become familiar with their triggers and stressors, improve their coping skills, and adopt a healthy lifestyle, which includes a nutritious diet, frequent exercise, and adequate sleep. As maintenance treatment we recommend that patients participate in frequent socialization and activities (Table 3). Refer patients to self-help books, online help guides, and handouts from sources such as National Institute of Mental Health.^22,23 Encourage patients to have patience and perseverance, and guide them through each step of recovery.

In addition to lifestyle modification, other treatment options for depression include pharmacotherapy, interpersonal psychotherapy, cognitive-behavioral therapy (CBT), and electroconvulsive therapy (ECT). All these modalities are effective for acute and maintenance treatment and should be considered when determining the best approach for each patient.

The effectiveness of antidepressants in general is comparable among and within classes.² Base your initial selection on the patient’s previous response to antidepressants and the medication’s side effects profile and cost.

The benefits of exercise for all patients cannot be underestimated.²⁴ Prescribe 20 to 30 minutes of daily exercise as part of recommended lifestyle changes. Writing “daily exercise” on a prescription pad can effectively remind patients that exercise needs to be taken as seriously as medication compliance.

Children and adolescents. For mild depression, supportive therapy seems to be as effective as CBT and medications.²⁵ A randomized controlled trial of 439 depressed adolescents found that CBT plus fluoxetine conferred quicker benefit, but in the long run may not be any more efficacious than pharmacotherapy alone.²⁵ Researchers also found that CBT plus fluoxetine was no more effective than pharmacotherapy alone for adolescents with moderate to severe depression.²⁵

Older adults. Compared with younger patients, geriatric patients typically require lower antidepressant dosages to achieve a specific blood level, but the blood levels at which antidepressants are most effective appear to be similar.² Older patients also may be more likely to relapse and less likely to achieve full response to antidepressants than younger patients.² In older adults, amitriptyline, imipramine, and doxepin are not preferred because these agents may cause orthostatic hypotension and urinary retention.² A depressed older adult who experiences weight loss might benefit from an antidepressant that improves appetite, such as mirtazapine.²⁶ Some research suggests that maintenance antidepressant therapy in older patients experiencing a first-time episode of MDD should continue for up to 2 years.²⁷

A meta-analysis of 12 studies of CBT in depressed adults age ≥60 with chronic pain found that CBT was effective at improving self-reported pain but had no significant effect on depressive symptoms, physical function, or medication use.⁶ ECT often is prescribed for depressed older adults because its safety and efficacy for these patients has been well documented.²⁸ Other neuromodulation therapies include vagus nerve, repetitive transcranial magnetic stimulation, and deep brain stimulation, but none of these treatments have been extensively evaluated in older patients.

Table 3

Avoiding reoccurrence of depression—a ‘prescription’ for patients

Related Resource

• American Psychiatric Association. Treatment of patients with major depressive disorder. 3rd ed. www.psychiatryonline.com/pracGuide/pracGuideChapToc_7.aspx.

Drug Brand Names

• Amitriptyline • Elavil
• Doxepin • Aponal, Silenor
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Mirtazapine • Remeron

Disclosure

The authors 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

Patients with treatment-resistant schizophrenia can be broadly defined to include any persons with residual symptoms that cause distress or impairment despite several treatment attempts. Unfortunately, this definition may include most of our patients with schizophrenia.

Clinical trial data on treatment-resistant schizophrenia can be contradictory, leaving “N of 1” empirical treatment trials for individual patients as the current state of the art. This article presents data from clinical trials for pharmacologic and nonpharmacologic options and offers recommendations to try to help our treatment-resistant patients.

Defining treatment resistance

Research reports regarding treatment-resistant or treatment-refractory schizophrenia have relied on operational criteria such as that found in the pivotal study for clozapine¹:

• at least 3 periods of treatment in the preceding 5 years with neuroleptic agents from at least 2 different chemical classes at dosages equivalent to ≥1000 mg/d of chlorpromazine for 6 weeks, each without significant symptomatic relief, and
• no period of good functioning within the preceding 5 years.¹ In that study, patients also underwent a prospective treatment trial with what we now know are high doses of haloperidol (up to 60 mg/d or higher) and benztropine mesylate (6 mg/d) for a period of 6 weeks to confirm lack of drug responsiveness. Other studies have more relaxed criteria, such as:
• persistent positive symptoms—hallucinations, delusions, or marked thought disorder—after at least 6 contiguous weeks of past or present treatment, with ≥1 typical antipsychotics at doses of ≥600 mg/d in chlorpromazine equivalents
• a poor level of functioning over the past 2 years, as defined by the lack of competitive employment or enrollment in an academic or vocational program and not having age-expected interpersonal relations with someone outside the biologic family with whom ongoing regular contacts were maintained.²

In this study, no prospective period of treatment to confirm lack of drug responsiveness was required.

The most clinically relevant definition of treatment resistance depends on the patient’s individual circumstances. For some patients, targeting positive symptoms is a high priority; for others it may be negative and cognitive symptoms; for others, it may be excitement. Moreover, families may complain of symptoms or behavior that are of little or no concern to your patient.

Although we desire treatment response and remission for our patients, definitions for remission and functional recovery are in flux. Proposed criteria define symptomatic remission as 6-month maintenance of simultaneous ratings of mild or less on delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms.^3,4 Emsley et al⁴ note that reported remission rates vary widely across studies (17% to 88%) and that patients in remission do better than their non-remitted counterparts in several other outcome domains. Also, patients move in and out of remission over time. Predictors of remission include:

• early treatment response
• baseline symptom severity
• subjective well-being.⁴

Recovery is a more complex construct than remission and includes social outcomes. Although recovery lacks a standard definition, it is the implied goal of treatment. Anything short of recovery can be viewed as inadequate. If we set the bar at this height, many or most of the patients we treat for schizophrenia could be considered treatment-resistant.

Confounding factors

Before concluding that a patient is treatment-resistant, address medication adherence and possible substance use. Partial or nonadherence with antipsychotic treatment is common—approximately one-half of patients are nonadherent⁵—and associated with relapse and re-hospitalization.⁶ In addition, an estimated one-half of all individuals with schizophrenia also use substances.⁷

Be aware of the optimal dose for any particular antipsychotic and factors that can interfere with achieving adequate plasma levels. This means acknowledging that dosing ranges established during registration studies may not reflect the needs of day-to-day clinical practice.⁸ Pharmacokinetic interactions with other medications, such as carbamazepine or rifampin, can induce liver enzymes and result in subtherapeutic antipsychotic levels. Cigarette smoking also may have this effect. Lowered clozapine or olanzapine plasma levels have been observed in patients who resume smoking after being discharged from a non-smoking inpatient environment. Some antipsychotics, such as ziprasidone and lurasidone, must be taken with food in order to have sufficient bioavailability.⁹

What does a patient want?

Patients with schizophrenia often have limited insight into their psychotic symptoms.¹⁰ Savvy clinicians will attempt to leverage a patient’s insight into ancillary symptoms—such as impaired sleep, anxiety, and dysphoria—to encourage a therapeutic alliance and therefore adherence. If patients feel their concerns are not addressed, they may consider treatment inadequate even though the intensity of their hallucinations and delusions may have decreased.

Which antipsychotic is best?

Meta-analyses of randomized controlled trials (RCTs) of antipsychotic treatment for schizophrenia found that, although individual response will vary, clozapine generally has better efficacy that other antipsychotics.^11-13 Olanzapine, risperidone, and amisulpride (which is not available in the United States) appear to be more efficacious than first-generation antipsychotics. Other second-generation antipsychotics do not consistently show greater efficacy than first-generation antipsychotics, although their tolerability profiles vary greatly.^11-13

Antipsychotic monotherapy. More than 25 RCTs have focused on antipsychotic monotherapy for treatment-resistant patients; for a bibliography of these studies, click here. For the most part, clozapine has consistently demonstrated superiority over comparators. Because not all patients with schizophrenia can tolerate clozapine or are willing to have their blood monitored as required, other second-generation antipsychotics have been suggested as possible substitutes. Olanzapine has established superior efficacy to first-generation antipsychotics^11-13 and perhaps comparable efficacy to clozapine in some studies.^2,14-17 Risperidone appeared to be comparable to clozapine in some studies,^18,19 whereas clozapine’s superiority was evident in others.^14,20,21 Although an RCT found comparable efficacy for ziprasidone vs clozapine,²² patients enrolled in this study may not have been treatment-resistant regarding efficacy but instead could not tolerate prior treatments. Enrolling patients on the basis of poor efficacy and/or poor tolerability to their prior antipsychotic regimen also has complicated the interpretation of studies comparing olanzapine with clozapine¹⁶ and risperidone with clozapine.¹⁸

Antipsychotic combinations. Combinations of antipsychotics are used commonly when treating chronic schizophrenia.²³ Of the approximately 20 RCTs of antipsychotic combination therapy, most tested clozapine combined with other second-generation antipsychotics, such as risperidone. For a bibliography of these studies, click here. Only 5 studies support a combination approach (Table 1).

Table 1

Antipsychotic combinations: Few studies support efficacy

What about augmentation?

Adjunctive non-antipsychotics also are commonly used when treating patients with chronic schizophrenia. For example, lithium and anticonvulsants are used in approximately one-half of all inpatients with schizophrenia in facilities operated by the State of New York Office of Mental Health.^24,25 The evidence base for these agents as adjuncts to antipsychotics generally is weak.²⁶ Specifically, early reports of benefit with adjunctive lithium have been negated by later studies. Similarly, large trials of adjunctive valproate and lamotrigine have failed to replicate early and promising efficacy signals from smaller trials, although the larger studies did not specifically target treatment-resistant schizophrenia.

Among mood stabilizers, lamotrigine may be the most promising for treatment-resistant schizophrenia. In a meta-analysis of clinical trials examining schizophrenia patients receiving clozapine (N=161) who were randomized to receive adjunctive lamotrigine or adjunctive placebo, lamotrigine was superior to placebo in total score for psychosis symptoms and scores for positive and negative symptoms.²⁷

More than 125 published RCTs have studied a wide variety of adjunctive agents other than lithium or anticonvulsants for treating persistent schizophrenia symptoms (Table 2).

Only some of the approximately 40 RCTs regarding adjunctive antidepressants in patients with chronic schizophrenia focused on patients with ongoing depressive symptoms. For a bibliography of these studies, click here. In a meta-analysis measuring improvement of negative symptoms from 23 trials (N=819),²⁸ the effect size was moderate in favor of antidepressants. Subgroup analysis revealed significant responses for fluoxetine, trazodone, and ritanserin.

More than 50 RCTs have focused on augmenting medications for cognitive dysfunction in chronic schizophrenia. Unfortunately, agents used to treat Alzheimer’s disease have shown disappointing results when tested in patients with schizophrenia, as have agents prescribed for attention-deficit/hyperactivity disorder (methylphenidate, guanfacine, atomoxetine) or agents used to promote alertness (modafinil and armodafinil).

Medications that act on glutamate receptors may offer another potential solution, although not in combination with clozapine.²⁹

Other agents that require further study where ≥2 positive studies have been reported (with ≤2 negative studies) include celecoxib, neurosteroids and hormones, purinergic agents, serotonin 5-HT1A receptor agonists, and serotonin 5-HT3 receptor antagonists.

Table 2

Agents studied as adjuncts to antipsychotics

Therapeutic neuromodulation

More than 10 RCTs of repetitive transcranial magnetic stimulation (rTMS) in patients with refractory symptoms of schizophrenia have been published; the results were mixed. For a bibliography of these studies, click here. In a meta-analysis of 9 trials (n=213),³⁰ prefrontal rTMS for treating negative symptoms demonstrated a small-to-medium effect size. In another meta-analysis³¹ of all prospective studies of rTMS for negative symptoms and for auditory hallucinations and overall positive symptoms in refractory schizophrenia, the effect sizes showed moderate effects.

Fewer controlled trials are available for electroconvulsive therapy,^32,33 but its use with clozapine appears encouraging.³⁴

Psychological and behavioral intervention. Cognitive-behavioral therapy, although labor-intensive, can be helpful even in patients considered treatment-resistant (Table 3). These interventions generally are provided together with pharmacotherapy.

Complementary and alternative therapies. Patients and their families may ask about complementary and alternative therapies, particularly when conventional approaches have not been successful. A meta-analysis of 6 studies (n=828)³⁵ that reviewed adjunctive use of ginkgo in patients with chronic schizophrenia found statistically significant moderate improvement in total and negative symptoms. Negative reports also are available, including a 5-month study of adjunctive megavitamins that did not demonstrate any benefits.³⁶ In a review of 13 RCTs of acupuncture for schizophrenia, Lee et al found the overall methodological quality was too low to draw firm conclusions.³⁷

Table 3

Cognitive-behavioral therapy for schizophrenia

Clinical recommendations

Before declaring a patient with schizophrenia as treatment-resistant, ensure that an adequate trial of medication did take place. This includes consideration of adequate dosing and pharmacokinetic issues. Awareness of potential substance use and/or partial adherence or nonadherence also is critical because these factors can impact treatment response.

When prescribing for a treatment-resistant schizophrenia patient, identify specific target symptoms to better inform medication selection—especially for symptoms that the patient feels are important. For example, consider an antidepressant for patients who have negative or depressive symptoms. Also take into account other patient-centered concerns, such as tolerability issues that may have interfered with adherence and response in the past.

Clozapine remains the medication of choice for treatment-resistant schizophrenia. Despite dozens of RCTs of potential adjunctive agents for treatment-resistant schizophrenia, no single approach has consistently shown efficacy in reducing symptoms, improving cognition, or increasing a patient’s level of function. Individual response can vary, and our search for the “outlier” who does respond to an adjunctive agent can explain our use of these strategies in clinical practice.

Related Resources

• Cochrane Database of Systematic Reviews. www.cochrane.org/reviews. This database contains reviews of additional therapeutic options for patients with treatment-resistant schizophrenia. As of February 23, 2011, 157 reviews were available.
• Citrome L. Treatment-refractory schizophrenia: What it is and what’s been done about it. Neuropsychiatry. 2011. Epub ahead of print.
• Citrome L. Clozapine for schizophrenia. Life-threatening or life-saving treatment? Current Psychiatry. 2009;8(12):56-63.

Drug Brand Names

• Aripiprazole • Abilify
• Armodafinil • Nuvigil
• Atomoxetine • Strattera
• Benztropine mesylate • Cogentin
• Carbamazepine • Tegretol
• Celecoxib • Celebrex
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Guanfacine • Tenex
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid, others
• Lurasidone • Latuda
• Methylphenidate • Ritalin, Methylin, others
• Modafinil • Provigil
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Rifampin • Rifadin
• Risperidone • Risperdal
• Trazodone • Desyrel, Oleptro
• Valproate (Divalproex) • Depakote, Depakote ER
• Ziprasidone • Geodon

Disclosure

No writing assistance or external financial support was used for this article. Dr. Citrome is a consultant for, has received honoraria from, or has conducted clinical research supported by Abbott Laboratories, AstraZeneca Pharmaceuticals, Avanir Pharmaceuticals, Azur Pharma Inc., Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Merck, Novartis, Pfizer Inc., Sunovion, Valeant Pharmaceuticals, and Vanda Pharmaceuticals.

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients with treatment-resistant schizophrenia can be broadly defined to include any persons with residual symptoms that cause distress or impairment despite several treatment attempts. Unfortunately, this definition may include most of our patients with schizophrenia.

Clinical trial data on treatment-resistant schizophrenia can be contradictory, leaving “N of 1” empirical treatment trials for individual patients as the current state of the art. This article presents data from clinical trials for pharmacologic and nonpharmacologic options and offers recommendations to try to help our treatment-resistant patients.

Defining treatment resistance

Research reports regarding treatment-resistant or treatment-refractory schizophrenia have relied on operational criteria such as that found in the pivotal study for clozapine¹:

• at least 3 periods of treatment in the preceding 5 years with neuroleptic agents from at least 2 different chemical classes at dosages equivalent to ≥1000 mg/d of chlorpromazine for 6 weeks, each without significant symptomatic relief, and
• no period of good functioning within the preceding 5 years.¹ In that study, patients also underwent a prospective treatment trial with what we now know are high doses of haloperidol (up to 60 mg/d or higher) and benztropine mesylate (6 mg/d) for a period of 6 weeks to confirm lack of drug responsiveness. Other studies have more relaxed criteria, such as:
• persistent positive symptoms—hallucinations, delusions, or marked thought disorder—after at least 6 contiguous weeks of past or present treatment, with ≥1 typical antipsychotics at doses of ≥600 mg/d in chlorpromazine equivalents
• a poor level of functioning over the past 2 years, as defined by the lack of competitive employment or enrollment in an academic or vocational program and not having age-expected interpersonal relations with someone outside the biologic family with whom ongoing regular contacts were maintained.²

In this study, no prospective period of treatment to confirm lack of drug responsiveness was required.

The most clinically relevant definition of treatment resistance depends on the patient’s individual circumstances. For some patients, targeting positive symptoms is a high priority; for others it may be negative and cognitive symptoms; for others, it may be excitement. Moreover, families may complain of symptoms or behavior that are of little or no concern to your patient.

Although we desire treatment response and remission for our patients, definitions for remission and functional recovery are in flux. Proposed criteria define symptomatic remission as 6-month maintenance of simultaneous ratings of mild or less on delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms.^3,4 Emsley et al⁴ note that reported remission rates vary widely across studies (17% to 88%) and that patients in remission do better than their non-remitted counterparts in several other outcome domains. Also, patients move in and out of remission over time. Predictors of remission include:

• early treatment response
• baseline symptom severity
• subjective well-being.⁴

Recovery is a more complex construct than remission and includes social outcomes. Although recovery lacks a standard definition, it is the implied goal of treatment. Anything short of recovery can be viewed as inadequate. If we set the bar at this height, many or most of the patients we treat for schizophrenia could be considered treatment-resistant.

Confounding factors

Before concluding that a patient is treatment-resistant, address medication adherence and possible substance use. Partial or nonadherence with antipsychotic treatment is common—approximately one-half of patients are nonadherent⁵—and associated with relapse and re-hospitalization.⁶ In addition, an estimated one-half of all individuals with schizophrenia also use substances.⁷

Be aware of the optimal dose for any particular antipsychotic and factors that can interfere with achieving adequate plasma levels. This means acknowledging that dosing ranges established during registration studies may not reflect the needs of day-to-day clinical practice.⁸ Pharmacokinetic interactions with other medications, such as carbamazepine or rifampin, can induce liver enzymes and result in subtherapeutic antipsychotic levels. Cigarette smoking also may have this effect. Lowered clozapine or olanzapine plasma levels have been observed in patients who resume smoking after being discharged from a non-smoking inpatient environment. Some antipsychotics, such as ziprasidone and lurasidone, must be taken with food in order to have sufficient bioavailability.⁹

What does a patient want?

Patients with schizophrenia often have limited insight into their psychotic symptoms.¹⁰ Savvy clinicians will attempt to leverage a patient’s insight into ancillary symptoms—such as impaired sleep, anxiety, and dysphoria—to encourage a therapeutic alliance and therefore adherence. If patients feel their concerns are not addressed, they may consider treatment inadequate even though the intensity of their hallucinations and delusions may have decreased.

Which antipsychotic is best?

Meta-analyses of randomized controlled trials (RCTs) of antipsychotic treatment for schizophrenia found that, although individual response will vary, clozapine generally has better efficacy that other antipsychotics.^11-13 Olanzapine, risperidone, and amisulpride (which is not available in the United States) appear to be more efficacious than first-generation antipsychotics. Other second-generation antipsychotics do not consistently show greater efficacy than first-generation antipsychotics, although their tolerability profiles vary greatly.^11-13

Antipsychotic monotherapy. More than 25 RCTs have focused on antipsychotic monotherapy for treatment-resistant patients; for a bibliography of these studies, click here. For the most part, clozapine has consistently demonstrated superiority over comparators. Because not all patients with schizophrenia can tolerate clozapine or are willing to have their blood monitored as required, other second-generation antipsychotics have been suggested as possible substitutes. Olanzapine has established superior efficacy to first-generation antipsychotics^11-13 and perhaps comparable efficacy to clozapine in some studies.^2,14-17 Risperidone appeared to be comparable to clozapine in some studies,^18,19 whereas clozapine’s superiority was evident in others.^14,20,21 Although an RCT found comparable efficacy for ziprasidone vs clozapine,²² patients enrolled in this study may not have been treatment-resistant regarding efficacy but instead could not tolerate prior treatments. Enrolling patients on the basis of poor efficacy and/or poor tolerability to their prior antipsychotic regimen also has complicated the interpretation of studies comparing olanzapine with clozapine¹⁶ and risperidone with clozapine.¹⁸

Antipsychotic combinations. Combinations of antipsychotics are used commonly when treating chronic schizophrenia.²³ Of the approximately 20 RCTs of antipsychotic combination therapy, most tested clozapine combined with other second-generation antipsychotics, such as risperidone. For a bibliography of these studies, click here. Only 5 studies support a combination approach (Table 1).

Table 1

Antipsychotic combinations: Few studies support efficacy

What about augmentation?

Adjunctive non-antipsychotics also are commonly used when treating patients with chronic schizophrenia. For example, lithium and anticonvulsants are used in approximately one-half of all inpatients with schizophrenia in facilities operated by the State of New York Office of Mental Health.^24,25 The evidence base for these agents as adjuncts to antipsychotics generally is weak.²⁶ Specifically, early reports of benefit with adjunctive lithium have been negated by later studies. Similarly, large trials of adjunctive valproate and lamotrigine have failed to replicate early and promising efficacy signals from smaller trials, although the larger studies did not specifically target treatment-resistant schizophrenia.

Among mood stabilizers, lamotrigine may be the most promising for treatment-resistant schizophrenia. In a meta-analysis of clinical trials examining schizophrenia patients receiving clozapine (N=161) who were randomized to receive adjunctive lamotrigine or adjunctive placebo, lamotrigine was superior to placebo in total score for psychosis symptoms and scores for positive and negative symptoms.²⁷

More than 125 published RCTs have studied a wide variety of adjunctive agents other than lithium or anticonvulsants for treating persistent schizophrenia symptoms (Table 2).

Only some of the approximately 40 RCTs regarding adjunctive antidepressants in patients with chronic schizophrenia focused on patients with ongoing depressive symptoms. For a bibliography of these studies, click here. In a meta-analysis measuring improvement of negative symptoms from 23 trials (N=819),²⁸ the effect size was moderate in favor of antidepressants. Subgroup analysis revealed significant responses for fluoxetine, trazodone, and ritanserin.

More than 50 RCTs have focused on augmenting medications for cognitive dysfunction in chronic schizophrenia. Unfortunately, agents used to treat Alzheimer’s disease have shown disappointing results when tested in patients with schizophrenia, as have agents prescribed for attention-deficit/hyperactivity disorder (methylphenidate, guanfacine, atomoxetine) or agents used to promote alertness (modafinil and armodafinil).

Medications that act on glutamate receptors may offer another potential solution, although not in combination with clozapine.²⁹

Other agents that require further study where ≥2 positive studies have been reported (with ≤2 negative studies) include celecoxib, neurosteroids and hormones, purinergic agents, serotonin 5-HT1A receptor agonists, and serotonin 5-HT3 receptor antagonists.

Table 2

Agents studied as adjuncts to antipsychotics

Therapeutic neuromodulation

More than 10 RCTs of repetitive transcranial magnetic stimulation (rTMS) in patients with refractory symptoms of schizophrenia have been published; the results were mixed. For a bibliography of these studies, click here. In a meta-analysis of 9 trials (n=213),³⁰ prefrontal rTMS for treating negative symptoms demonstrated a small-to-medium effect size. In another meta-analysis³¹ of all prospective studies of rTMS for negative symptoms and for auditory hallucinations and overall positive symptoms in refractory schizophrenia, the effect sizes showed moderate effects.

Fewer controlled trials are available for electroconvulsive therapy,^32,33 but its use with clozapine appears encouraging.³⁴

Psychological and behavioral intervention. Cognitive-behavioral therapy, although labor-intensive, can be helpful even in patients considered treatment-resistant (Table 3). These interventions generally are provided together with pharmacotherapy.

Complementary and alternative therapies. Patients and their families may ask about complementary and alternative therapies, particularly when conventional approaches have not been successful. A meta-analysis of 6 studies (n=828)³⁵ that reviewed adjunctive use of ginkgo in patients with chronic schizophrenia found statistically significant moderate improvement in total and negative symptoms. Negative reports also are available, including a 5-month study of adjunctive megavitamins that did not demonstrate any benefits.³⁶ In a review of 13 RCTs of acupuncture for schizophrenia, Lee et al found the overall methodological quality was too low to draw firm conclusions.³⁷

Table 3

Cognitive-behavioral therapy for schizophrenia

Clinical recommendations

Before declaring a patient with schizophrenia as treatment-resistant, ensure that an adequate trial of medication did take place. This includes consideration of adequate dosing and pharmacokinetic issues. Awareness of potential substance use and/or partial adherence or nonadherence also is critical because these factors can impact treatment response.

When prescribing for a treatment-resistant schizophrenia patient, identify specific target symptoms to better inform medication selection—especially for symptoms that the patient feels are important. For example, consider an antidepressant for patients who have negative or depressive symptoms. Also take into account other patient-centered concerns, such as tolerability issues that may have interfered with adherence and response in the past.

Clozapine remains the medication of choice for treatment-resistant schizophrenia. Despite dozens of RCTs of potential adjunctive agents for treatment-resistant schizophrenia, no single approach has consistently shown efficacy in reducing symptoms, improving cognition, or increasing a patient’s level of function. Individual response can vary, and our search for the “outlier” who does respond to an adjunctive agent can explain our use of these strategies in clinical practice.

Related Resources

• Cochrane Database of Systematic Reviews. www.cochrane.org/reviews. This database contains reviews of additional therapeutic options for patients with treatment-resistant schizophrenia. As of February 23, 2011, 157 reviews were available.
• Citrome L. Treatment-refractory schizophrenia: What it is and what’s been done about it. Neuropsychiatry. 2011. Epub ahead of print.
• Citrome L. Clozapine for schizophrenia. Life-threatening or life-saving treatment? Current Psychiatry. 2009;8(12):56-63.

Drug Brand Names

• Aripiprazole • Abilify
• Armodafinil • Nuvigil
• Atomoxetine • Strattera
• Benztropine mesylate • Cogentin
• Carbamazepine • Tegretol
• Celecoxib • Celebrex
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Guanfacine • Tenex
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid, others
• Lurasidone • Latuda
• Methylphenidate • Ritalin, Methylin, others
• Modafinil • Provigil
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Rifampin • Rifadin
• Risperidone • Risperdal
• Trazodone • Desyrel, Oleptro
• Valproate (Divalproex) • Depakote, Depakote ER
• Ziprasidone • Geodon

Disclosure

No writing assistance or external financial support was used for this article. Dr. Citrome is a consultant for, has received honoraria from, or has conducted clinical research supported by Abbott Laboratories, AstraZeneca Pharmaceuticals, Avanir Pharmaceuticals, Azur Pharma Inc., Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Merck, Novartis, Pfizer Inc., Sunovion, Valeant Pharmaceuticals, and Vanda Pharmaceuticals.

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Patients with treatment-resistant schizophrenia can be broadly defined to include any persons with residual symptoms that cause distress or impairment despite several treatment attempts. Unfortunately, this definition may include most of our patients with schizophrenia.

Clinical trial data on treatment-resistant schizophrenia can be contradictory, leaving “N of 1” empirical treatment trials for individual patients as the current state of the art. This article presents data from clinical trials for pharmacologic and nonpharmacologic options and offers recommendations to try to help our treatment-resistant patients.

Defining treatment resistance

Research reports regarding treatment-resistant or treatment-refractory schizophrenia have relied on operational criteria such as that found in the pivotal study for clozapine¹:

• at least 3 periods of treatment in the preceding 5 years with neuroleptic agents from at least 2 different chemical classes at dosages equivalent to ≥1000 mg/d of chlorpromazine for 6 weeks, each without significant symptomatic relief, and
• no period of good functioning within the preceding 5 years.¹ In that study, patients also underwent a prospective treatment trial with what we now know are high doses of haloperidol (up to 60 mg/d or higher) and benztropine mesylate (6 mg/d) for a period of 6 weeks to confirm lack of drug responsiveness. Other studies have more relaxed criteria, such as:
• persistent positive symptoms—hallucinations, delusions, or marked thought disorder—after at least 6 contiguous weeks of past or present treatment, with ≥1 typical antipsychotics at doses of ≥600 mg/d in chlorpromazine equivalents
• a poor level of functioning over the past 2 years, as defined by the lack of competitive employment or enrollment in an academic or vocational program and not having age-expected interpersonal relations with someone outside the biologic family with whom ongoing regular contacts were maintained.²

In this study, no prospective period of treatment to confirm lack of drug responsiveness was required.

The most clinically relevant definition of treatment resistance depends on the patient’s individual circumstances. For some patients, targeting positive symptoms is a high priority; for others it may be negative and cognitive symptoms; for others, it may be excitement. Moreover, families may complain of symptoms or behavior that are of little or no concern to your patient.

Although we desire treatment response and remission for our patients, definitions for remission and functional recovery are in flux. Proposed criteria define symptomatic remission as 6-month maintenance of simultaneous ratings of mild or less on delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, and negative symptoms.^3,4 Emsley et al⁴ note that reported remission rates vary widely across studies (17% to 88%) and that patients in remission do better than their non-remitted counterparts in several other outcome domains. Also, patients move in and out of remission over time. Predictors of remission include:

• early treatment response
• baseline symptom severity
• subjective well-being.⁴

Recovery is a more complex construct than remission and includes social outcomes. Although recovery lacks a standard definition, it is the implied goal of treatment. Anything short of recovery can be viewed as inadequate. If we set the bar at this height, many or most of the patients we treat for schizophrenia could be considered treatment-resistant.

Confounding factors

Before concluding that a patient is treatment-resistant, address medication adherence and possible substance use. Partial or nonadherence with antipsychotic treatment is common—approximately one-half of patients are nonadherent⁵—and associated with relapse and re-hospitalization.⁶ In addition, an estimated one-half of all individuals with schizophrenia also use substances.⁷

Be aware of the optimal dose for any particular antipsychotic and factors that can interfere with achieving adequate plasma levels. This means acknowledging that dosing ranges established during registration studies may not reflect the needs of day-to-day clinical practice.⁸ Pharmacokinetic interactions with other medications, such as carbamazepine or rifampin, can induce liver enzymes and result in subtherapeutic antipsychotic levels. Cigarette smoking also may have this effect. Lowered clozapine or olanzapine plasma levels have been observed in patients who resume smoking after being discharged from a non-smoking inpatient environment. Some antipsychotics, such as ziprasidone and lurasidone, must be taken with food in order to have sufficient bioavailability.⁹

What does a patient want?

Patients with schizophrenia often have limited insight into their psychotic symptoms.¹⁰ Savvy clinicians will attempt to leverage a patient’s insight into ancillary symptoms—such as impaired sleep, anxiety, and dysphoria—to encourage a therapeutic alliance and therefore adherence. If patients feel their concerns are not addressed, they may consider treatment inadequate even though the intensity of their hallucinations and delusions may have decreased.

Which antipsychotic is best?

Meta-analyses of randomized controlled trials (RCTs) of antipsychotic treatment for schizophrenia found that, although individual response will vary, clozapine generally has better efficacy that other antipsychotics.^11-13 Olanzapine, risperidone, and amisulpride (which is not available in the United States) appear to be more efficacious than first-generation antipsychotics. Other second-generation antipsychotics do not consistently show greater efficacy than first-generation antipsychotics, although their tolerability profiles vary greatly.^11-13

Antipsychotic monotherapy. More than 25 RCTs have focused on antipsychotic monotherapy for treatment-resistant patients; for a bibliography of these studies, click here. For the most part, clozapine has consistently demonstrated superiority over comparators. Because not all patients with schizophrenia can tolerate clozapine or are willing to have their blood monitored as required, other second-generation antipsychotics have been suggested as possible substitutes. Olanzapine has established superior efficacy to first-generation antipsychotics^11-13 and perhaps comparable efficacy to clozapine in some studies.^2,14-17 Risperidone appeared to be comparable to clozapine in some studies,^18,19 whereas clozapine’s superiority was evident in others.^14,20,21 Although an RCT found comparable efficacy for ziprasidone vs clozapine,²² patients enrolled in this study may not have been treatment-resistant regarding efficacy but instead could not tolerate prior treatments. Enrolling patients on the basis of poor efficacy and/or poor tolerability to their prior antipsychotic regimen also has complicated the interpretation of studies comparing olanzapine with clozapine¹⁶ and risperidone with clozapine.¹⁸

Antipsychotic combinations. Combinations of antipsychotics are used commonly when treating chronic schizophrenia.²³ Of the approximately 20 RCTs of antipsychotic combination therapy, most tested clozapine combined with other second-generation antipsychotics, such as risperidone. For a bibliography of these studies, click here. Only 5 studies support a combination approach (Table 1).

Table 1

Antipsychotic combinations: Few studies support efficacy

What about augmentation?

Adjunctive non-antipsychotics also are commonly used when treating patients with chronic schizophrenia. For example, lithium and anticonvulsants are used in approximately one-half of all inpatients with schizophrenia in facilities operated by the State of New York Office of Mental Health.^24,25 The evidence base for these agents as adjuncts to antipsychotics generally is weak.²⁶ Specifically, early reports of benefit with adjunctive lithium have been negated by later studies. Similarly, large trials of adjunctive valproate and lamotrigine have failed to replicate early and promising efficacy signals from smaller trials, although the larger studies did not specifically target treatment-resistant schizophrenia.

Among mood stabilizers, lamotrigine may be the most promising for treatment-resistant schizophrenia. In a meta-analysis of clinical trials examining schizophrenia patients receiving clozapine (N=161) who were randomized to receive adjunctive lamotrigine or adjunctive placebo, lamotrigine was superior to placebo in total score for psychosis symptoms and scores for positive and negative symptoms.²⁷

More than 125 published RCTs have studied a wide variety of adjunctive agents other than lithium or anticonvulsants for treating persistent schizophrenia symptoms (Table 2).

Only some of the approximately 40 RCTs regarding adjunctive antidepressants in patients with chronic schizophrenia focused on patients with ongoing depressive symptoms. For a bibliography of these studies, click here. In a meta-analysis measuring improvement of negative symptoms from 23 trials (N=819),²⁸ the effect size was moderate in favor of antidepressants. Subgroup analysis revealed significant responses for fluoxetine, trazodone, and ritanserin.

More than 50 RCTs have focused on augmenting medications for cognitive dysfunction in chronic schizophrenia. Unfortunately, agents used to treat Alzheimer’s disease have shown disappointing results when tested in patients with schizophrenia, as have agents prescribed for attention-deficit/hyperactivity disorder (methylphenidate, guanfacine, atomoxetine) or agents used to promote alertness (modafinil and armodafinil).

Medications that act on glutamate receptors may offer another potential solution, although not in combination with clozapine.²⁹

Other agents that require further study where ≥2 positive studies have been reported (with ≤2 negative studies) include celecoxib, neurosteroids and hormones, purinergic agents, serotonin 5-HT1A receptor agonists, and serotonin 5-HT3 receptor antagonists.

Table 2

Agents studied as adjuncts to antipsychotics

Therapeutic neuromodulation

More than 10 RCTs of repetitive transcranial magnetic stimulation (rTMS) in patients with refractory symptoms of schizophrenia have been published; the results were mixed. For a bibliography of these studies, click here. In a meta-analysis of 9 trials (n=213),³⁰ prefrontal rTMS for treating negative symptoms demonstrated a small-to-medium effect size. In another meta-analysis³¹ of all prospective studies of rTMS for negative symptoms and for auditory hallucinations and overall positive symptoms in refractory schizophrenia, the effect sizes showed moderate effects.

Fewer controlled trials are available for electroconvulsive therapy,^32,33 but its use with clozapine appears encouraging.³⁴

Psychological and behavioral intervention. Cognitive-behavioral therapy, although labor-intensive, can be helpful even in patients considered treatment-resistant (Table 3). These interventions generally are provided together with pharmacotherapy.

Complementary and alternative therapies. Patients and their families may ask about complementary and alternative therapies, particularly when conventional approaches have not been successful. A meta-analysis of 6 studies (n=828)³⁵ that reviewed adjunctive use of ginkgo in patients with chronic schizophrenia found statistically significant moderate improvement in total and negative symptoms. Negative reports also are available, including a 5-month study of adjunctive megavitamins that did not demonstrate any benefits.³⁶ In a review of 13 RCTs of acupuncture for schizophrenia, Lee et al found the overall methodological quality was too low to draw firm conclusions.³⁷

Table 3

Cognitive-behavioral therapy for schizophrenia

Clinical recommendations

Before declaring a patient with schizophrenia as treatment-resistant, ensure that an adequate trial of medication did take place. This includes consideration of adequate dosing and pharmacokinetic issues. Awareness of potential substance use and/or partial adherence or nonadherence also is critical because these factors can impact treatment response.

When prescribing for a treatment-resistant schizophrenia patient, identify specific target symptoms to better inform medication selection—especially for symptoms that the patient feels are important. For example, consider an antidepressant for patients who have negative or depressive symptoms. Also take into account other patient-centered concerns, such as tolerability issues that may have interfered with adherence and response in the past.

Clozapine remains the medication of choice for treatment-resistant schizophrenia. Despite dozens of RCTs of potential adjunctive agents for treatment-resistant schizophrenia, no single approach has consistently shown efficacy in reducing symptoms, improving cognition, or increasing a patient’s level of function. Individual response can vary, and our search for the “outlier” who does respond to an adjunctive agent can explain our use of these strategies in clinical practice.

Related Resources

• Cochrane Database of Systematic Reviews. www.cochrane.org/reviews. This database contains reviews of additional therapeutic options for patients with treatment-resistant schizophrenia. As of February 23, 2011, 157 reviews were available.
• Citrome L. Treatment-refractory schizophrenia: What it is and what’s been done about it. Neuropsychiatry. 2011. Epub ahead of print.
• Citrome L. Clozapine for schizophrenia. Life-threatening or life-saving treatment? Current Psychiatry. 2009;8(12):56-63.

Drug Brand Names

• Aripiprazole • Abilify
• Armodafinil • Nuvigil
• Atomoxetine • Strattera
• Benztropine mesylate • Cogentin
• Carbamazepine • Tegretol
• Celecoxib • Celebrex
• Chlorpromazine • Thorazine
• Clozapine • Clozaril
• Fluoxetine • Prozac
• Guanfacine • Tenex
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Lithium • Eskalith, Lithobid, others
• Lurasidone • Latuda
• Methylphenidate • Ritalin, Methylin, others
• Modafinil • Provigil
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Rifampin • Rifadin
• Risperidone • Risperdal
• Trazodone • Desyrel, Oleptro
• Valproate (Divalproex) • Depakote, Depakote ER
• Ziprasidone • Geodon

Disclosure

No writing assistance or external financial support was used for this article. Dr. Citrome is a consultant for, has received honoraria from, or has conducted clinical research supported by Abbott Laboratories, AstraZeneca Pharmaceuticals, Avanir Pharmaceuticals, Azur Pharma Inc., Barr Laboratories, Bristol-Myers Squibb, Eli Lilly and Company, Forest Research Institute, GlaxoSmithKline, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Merck, Novartis, Pfizer Inc., Sunovion, Valeant Pharmaceuticals, and Vanda Pharmaceuticals.

Discuss this article at www.facebook.com/CurrentPsychiatry

Patients who present with impairment in academic, cognitive, social, and vocational functioning might be struggling with an unrecognized learning disorder. Ten percent of the US population has some form of learning disability, and up to 40% of those with learning disorders may meet diagnostic criteria for a psychiatric disorder.^1,2 Some learning disorders affect a person’s ability to read, write, or do math, whereas less-recognized nonverbal learning disorder (NLD) impacts the social and emotional functioning of children, adolescents, and adults. Common features of NLD include:

• deficits in nonlinguistic information processing
• speech prosody deficits
• difficulty reading facial expressions
• associated impairment in interpersonal functioning.

The severity of these deficits varies among individuals with NLD. Patients may experience chronic low self-esteem, anxiety, and mood symptoms because of their limited ability to express their feelings within an appropriate social context. NLD may be first misdiagnosed as attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), or Asperger’s disorder.

In this article we review the underlying neurophysiology of NLD and present a clinical approach to these patients, including the differential diagnosis and factors that will allow clinicians to distinguish NLD from psychiatric conditions with symptomatic and syndromic overlap. We also describe treatment for patients with NLD.

The learning process

Learning is a cognitive process of acquiring and processing information and experiences from the environment that allows us to acquire knowledge, skills, and social abilities. When we learn how to relate to others, we undergo neurophysiologic changes that subsequently influence behavior and the way we understand our environment. Deficits in learning processes or the ability to acquire relational skills result in impaired affect regulation in regard to others and may lead to low self-esteem, depression, anxiety, interpersonal conflict, and anger toward others. Learning influences a person’s ability to navigate social relationships and perform academically and occupationally.

The impact of learning deficits may be magnified in adulthood after an individual has suffered years of in-securities and poor self-esteem. Adults with learning disabilities often seek psychiatric treatment as a result of their disappointment about difficulties in relationships and work. NLD may coexist with or mimic other neuropsychiatric disorders. For example, problematic behavior within a family or at the workplace is a common reason for referral to a psychiatrist. These behaviors may be influenced by a patient’s NLD symptoms, which can complicate diagnosis and treatment.

Persons with NLD are at increased risk for depression because of failures in coping, loss of self-esteem, internalized psychopathology, and other social and emotional strains. In addition, individuals with NLD may experience multiple psychosocial impairments, including difficulty maintaining employment, achieving goals, and maintaining relationships.³

A variable presentation

NLD has been associated with right hemispheric dysfunction.³ For a description of the neurophysiology of NLD, see this article at CurrentPsychiatry.com. In childhood, NLD may present as deficits in:

• processing nonlinguistic information
• expressing or comprehending nonverbal components of language such as pitch, volume, or rate of speech (aprosodia)
• reading facial expressions
• social or emotional functioning, such as difficulty understanding social situations, violations of personal space, or difficulty learning from past emotional experiences.⁴

The extent of these deficits varies among patients. As children, patients with NLD often show strengths in rote verbal memory, spoken language mechanics or form, and word reading. These children may be hyperverbal and use language at a level higher than expected for their age group, which may mask some learning difficulties and delay diagnosis.

Throughout life, NLD manifests as difficulty interacting with peers. Children with NLD may have difficulty playing with others and making friends and as result may feel socially isolated. Without the critical skills of social reciprocity or understanding social context, NLD patients often have many superficial friendships but lack deep relationships.^4,5

Patients with NLD may rely on their verbal skills for relating socially and relieving anxiety and tend to withdraw from social situations as they become aware of their deficits.

NLD can be characterized on the basis of primary, secondary, and tertiary deficits. Primary deficits in tactile and visual perception and complex psychomotor skills lead to secondary deficits in attention and exploratory behavior, which lead to tertiary deficits in memory and executive function.⁶

Given NLD’s variable presentation, clinicians must remain vigilant to this possible diagnosis in patients with a history of multiple pharmacotherapy or psychotherapy failures for axis I disorders. Using clues from symptoms described in Table 1⁷ may provide information necessary to refer for formal psychoeducational testing to diagnose NLD. Early diagnosis can help target NLD symptoms and tailor treatment of comorbid psychopathology.⁷ NLD is a chronic disability and—similar to other learning disabilities—early, targeted interventions initiated by parents, teachers, and clinicians can improve outcomes.

Neuropsychological/psychoeducational testing. Traditionally, clinicians suspected NLD if a patient had a ≥10 point difference between performance intelligence quotient (IQ) and verbal IQ on the Wechsler Intelligence Scale for Children (WISC-III).⁸ However, the most recent version—the WISC-IV⁹—incorporates changes based on new neurologic models of cognitive functioning, and performance IQ and verbal IQ are no longer calculated. Thus, interpreting this split in IQ type with regard to NLD is no longer straightforward. IQ tests, such as the Woodcock-Johnson¹⁰ battery, which assesses visual-spatial thinking and fluid reasoning, may be particularly important in characterizing NLD deficits—especially when used in conjunction with other neuropsychological batteries, which may directly assess discrete abilities related to visual and spatial processing.

A thorough social and educational history, IQ testing, neuropsychological batteries, and a psychoeducational assessment can help determine the extent of cognitive deficits that may require accommodations at school or work and characterize the complex interplay of specific deficits and functioning.

Table 1

Clinical manifestation of nonverbal learning disorder

Differential diagnosis

ADHD. Patients diagnosed with ADHD or NLD may have a history of attention difficulties and hyperactivity. These clinical similarities may include restlessness, distractibility, impulsivity, and poor attention (Table 2).^11,12 In adults, these features may attenuate and patients with NLD or ADHD could appear normoactive. Individuals with NLD demonstrate withdrawal, anxiety, and continued social skills deficits,¹³ whereas adult ADHD patients show persistent attention difficulties. Although both groups may have difficulty maintaining steady employment, NLD patients’ employment failures often are caused by cognitive and social difficulties as opposed to problems with attention.

The psychopathology of these 2 conditions differs in that ADHD is characterized primarily by prefrontal dysfunction.¹⁴ However, in a small study of children with NLD (N=20), all participants also met diagnostic criteria for ADHD; therefore, the true epidemiologic comorbidity is unknown.¹⁵

BD. Because patients with NLD may experience affective symptoms similar to those with BD, it is critical to clarify the temporal course of mood symptoms and understand the complex relationships between symptoms and external events (Table 2).^11,12 In BD, mood symptoms are cyclical, punctuated by discrete periods of euthymia. In NLD affective symptoms are clearly linked to learning difficulties and impaired information processing. Research shows cognitive deficits in individuals with BD often persist during euthymic periods.¹⁶ Literature suggests that cognitive deficits in adult BD commonly involve verbal memory, executive function, and attention, whereas patients with NLD often have strong verbal memory.^17,18

Individuals with BD may understand the intentions of others and—especially in periods of hypomania or mania—will engage others. In contrast, persons with NLD struggle to attract and engage friends, may be irritable when they misunderstand social cues, may be bullied or taken advantage of by others, and may struggle to communicate this problem to clinicians. NLD patients’ sense of frustration typically does not vary; a continuous depressed or anxious mood may improve briefly when they feel accepted in their environment. This pattern can be discerned from BD by strictly applying DSM-IV-TR criteria for variability in mood states.¹⁹ BD treatment may be complicated in patients with comorbid NLD. These patients may underreport adverse effects of medications, including metabolic effects and cognitive dulling, which results in a complicated and frustrating clinical course.²⁰

Asperger’s disorder. Patients with NLD—a neuropsychological disorder—may present with social interaction difficulties that seem similar to those of Asperger’s disorder—a behavioral disorder. Overlapping behaviors, similar cognitive processes, and coexisting conditions may challenge even experienced clinicians (Table 3).^21-23 However, impairments are more severe in Asperger’s disorder and will present as early as age 4. Patients with Asperger’s disorder show difficulty communicating characterized by unusual interactions, such as pedantic or 1-sided discussions of topics that are unusual for the patient’s age group and inattentiveness to social cues. By contrast, communication difficulties in children with NLD are not apparent until after they start school.

Both Asperger’s disorder and NLD patients will show noticeable variations in thought process that often are apparent in conversations. Individuals with Asperger’s disorder may have some concrete thinking, although they often express idiosyncratic thinking, whereas individuals with NLD often show concrete logic. An individual with NLD may be easily overwhelmed by peer group social interactions but remains emotionally aware of his or her shortcomings and may be able to handle 1-on-1 interactions. Individuals with Asperger’s disorder will demonstrate restrictive interests or repetitive behaviors, a characteristic typically not seen in individuals with NLD. Patients with Asperger’s disorder may have specific skills, such as expertise with directions and spatial reasoning, whereas individuals with NLD may get lost even when traveling to familiar places or may have difficulty relating directions. Both groups likely will have good reading skills but patients with NLD will have trouble comprehending and integrating the material, evident by difficulty with multiple choice questions or “story problems.” Individuals with either disorder may develop frustration and anger with their challenges.

In adults, many of these subtle differences in language and thought process may be masked by years of difficult and frustrating communication, making definitive diagnosis challenging. Semistructured interviews, such as the Autism Diagnostic Observation Schedule²⁴ or the Gilliam Asperger’s Disorder Scale,²⁵ may help in differentiating Asperger’s disorder from NLD. However, these 2 disorders may be comorbid, thus complicating the diagnostic process.²¹

Table 2

Differences among NLD, ADHD, and bipolar disorder

Table 3

Differences between NLD and Asperger’s disorder

Treatment implications

The day-to-day care of patients with NLD and a comorbid psychiatric disorder may include systems-level interventions, supportive psychotherapy, and psychopharmacologic treatments that are informed by the comorbid condition (Table 4).^7,26 Open, honest dialogue about strengths and challenges for individuals with NLD will help reframe expectations and frustrations. Early recognition of NLD may, in some cases, prevent internalized psychopathology and loss of self-esteem.^27,28

Children and adolescents with NLD require early intervention to help them function socially and academically. Involving family and school personnel is important to develop accommodations to improve functioning. Comprehension problems associated with NLD often become more noticeable as the student moves into upper elementary grades, where abstract thinking and the ability to manage novelty (eg, unfamiliar content or situations) are required. Many students with NLD can manage rote memorization and concrete facts, but have trouble with inference, integration, and reasoning. Academically appropriate classroom placement, limited writing, and use of voice recognition software may aid success. Parents can help by teaching and modeling social skills such as appropriate expression of emotions, which can be facilitated by watching movies or attending group activities together.

Adults. Patients with NLD may be late for appointments and often forget what is discussed. They may be at increased risk for noncompliance with pharmacotherapy for comorbid disorders and may require written instructions, frequent reminders, and reviews of treatment plan. In addition, interactions with clinicians may seem shallow and unsatisfying, despite the clinician’s best efforts to empathize. The pattern of feeling misunderstood likely exists in the patient’s other relationships, including significant others and employers. Although no systemic evaluations exist, mindfulness-based therapies might help alleviate this deficit.^29,30

Treatment plans may involve family-focused modalities where NLD patients learn to rely on family members to interpret others’ motives and intentions.³¹ Education of the patient and family and friends should emphasize the need for consistent daily schedules and frequent verbal feedback, such as taking turns in conversations. Academic accommodations in college are crucial for success. Education experts have advocated for increased use of technology for students with NLD, including voice recognition software, laptop computers, and audio recordings of class notes.³²

Table 4

Treating patients with NLD

Related Resources

• Rourke BP. Syndrome of nonverbal learning disabilities: Neurodevelopmental manifestations. New York, NY: Guilford Press; 1995.
• NLD Line. www.nldline.com.
• NLD on the Web. www.nldontheweb.org.
• Massachusetts General Hospital school psychiatry program and Mood and Anxiety Disorders Institute resource center. www2.massgeneral.org/schoolpsychiatry.

Disclosures

Drs. Delgado and Wassenaar report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Strawn has received research support from the American Academy of Child and Adolescent Psychiatry and Eli Lilly and Company.

Acknowledgements

The authors acknowledge Drs. Michele Berg and Carleen Franz for their careful review of this manuscript and for their critiques, which have greatly improved this contribution.

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Patients who present with impairment in academic, cognitive, social, and vocational functioning might be struggling with an unrecognized learning disorder. Ten percent of the US population has some form of learning disability, and up to 40% of those with learning disorders may meet diagnostic criteria for a psychiatric disorder.^1,2 Some learning disorders affect a person’s ability to read, write, or do math, whereas less-recognized nonverbal learning disorder (NLD) impacts the social and emotional functioning of children, adolescents, and adults. Common features of NLD include:

• deficits in nonlinguistic information processing
• speech prosody deficits
• difficulty reading facial expressions
• associated impairment in interpersonal functioning.

The severity of these deficits varies among individuals with NLD. Patients may experience chronic low self-esteem, anxiety, and mood symptoms because of their limited ability to express their feelings within an appropriate social context. NLD may be first misdiagnosed as attention-deficit/hyperactivity disorder (ADHD), bipolar disorder (BD), or Asperger’s disorder.

In this article we review the underlying neurophysiology of NLD and present a clinical approach to these patients, including the differential diagnosis and factors that will allow clinicians to distinguish NLD from psychiatric conditions with symptomatic and syndromic overlap. We also describe treatment for patients with NLD.

The learning process

Learning is a cognitive process of acquiring and processing information and experiences from the environment that allows us to acquire knowledge, skills, and social abilities. When we learn how to relate to others, we undergo neurophysiologic changes that subsequently influence behavior and the way we understand our environment. Deficits in learning processes or the ability to acquire relational skills result in impaired affect regulation in regard to others and may lead to low self-esteem, depression, anxiety, interpersonal conflict, and anger toward others. Learning influences a person’s ability to navigate social relationships and perform academically and occupationally.

The impact of learning deficits may be magnified in adulthood after an individual has suffered years of in-securities and poor self-esteem. Adults with learning disabilities often seek psychiatric treatment as a result of their disappointment about difficulties in relationships and work. NLD may coexist with or mimic other neuropsychiatric disorders. For example, problematic behavior within a family or at the workplace is a common reason for referral to a psychiatrist. These behaviors may be influenced by a patient’s NLD symptoms, which can complicate diagnosis and treatment.

Persons with NLD are at increased risk for depression because of failures in coping, loss of self-esteem, internalized psychopathology, and other social and emotional strains. In addition, individuals with NLD may experience multiple psychosocial impairments, including difficulty maintaining employment, achieving goals, and maintaining relationships.³

A variable presentation

NLD has been associated with right hemispheric dysfunction.³ For a description of the neurophysiology of NLD, see this article at CurrentPsychiatry.com. In childhood, NLD may present as deficits in:

• processing nonlinguistic information
• expressing or comprehending nonverbal components of language such as pitch, volume, or rate of speech (aprosodia)
• reading facial expressions
• social or emotional functioning, such as difficulty understanding social situations, violations of personal space, or difficulty learning from past emotional experiences.⁴

The extent of these deficits varies among patients. As children, patients with NLD often show strengths in rote verbal memory, spoken language mechanics or form, and word reading. These children may be hyperverbal and use language at a level higher than expected for their age group, which may mask some learning difficulties and delay diagnosis.

Throughout life, NLD manifests as difficulty interacting with peers. Children with NLD may have difficulty playing with others and making friends and as result may feel socially isolated. Without the critical skills of social reciprocity or understanding social context, NLD patients often have many superficial friendships but lack deep relationships.^4,5

Patients with NLD may rely on their verbal skills for relating socially and relieving anxiety and tend to withdraw from social situations as they become aware of their deficits.

NLD can be characterized on the basis of primary, secondary, and tertiary deficits. Primary deficits in tactile and visual perception and complex psychomotor skills lead to secondary deficits in attention and exploratory behavior, which lead to tertiary deficits in memory and executive function.⁶

Given NLD’s variable presentation, clinicians must remain vigilant to this possible diagnosis in patients with a history of multiple pharmacotherapy or psychotherapy failures for axis I disorders. Using clues from symptoms described in Table 1⁷ may provide information necessary to refer for formal psychoeducational testing to diagnose NLD. Early diagnosis can help target NLD symptoms and tailor treatment of comorbid psychopathology.⁷ NLD is a chronic disability and—similar to other learning disabilities—early, targeted interventions initiated by parents, teachers, and clinicians can improve outcomes.

Neuropsychological/psychoeducational testing. Traditionally, clinicians suspected NLD if a patient had a ≥10 point difference between performance intelligence quotient (IQ) and verbal IQ on the Wechsler Intelligence Scale for Children (WISC-III).⁸ However, the most recent version—the WISC-IV⁹—incorporates changes based on new neurologic models of cognitive functioning, and performance IQ and verbal IQ are no longer calculated. Thus, interpreting this split in IQ type with regard to NLD is no longer straightforward. IQ tests, such as the Woodcock-Johnson¹⁰ battery, which assesses visual-spatial thinking and fluid reasoning, may be particularly important in characterizing NLD deficits—especially when used in conjunction with other neuropsychological batteries, which may directly assess discrete abilities related to visual and spatial processing.

A thorough social and educational history, IQ testing, neuropsychological batteries, and a psychoeducational assessment can help determine the extent of cognitive deficits that may require accommodations at school or work and characterize the complex interplay of specific deficits and functioning.

Table 1

Clinical manifestation of nonverbal learning disorder

Differential diagnosis

ADHD. Patients diagnosed with ADHD or NLD may have a history of attention difficulties and hyperactivity. These clinical similarities may include restlessness, distractibility, impulsivity, and poor attention (Table 2).^11,12 In adults, these features may attenuate and patients with NLD or ADHD could appear normoactive. Individuals with NLD demonstrate withdrawal, anxiety, and continued social skills deficits,¹³ whereas adult ADHD patients show persistent attention difficulties. Although both groups may have difficulty maintaining steady employment, NLD patients’ employment failures often are caused by cognitive and social difficulties as opposed to problems with attention.

The psychopathology of these 2 conditions differs in that ADHD is characterized primarily by prefrontal dysfunction.¹⁴ However, in a small study of children with NLD (N=20), all participants also met diagnostic criteria for ADHD; therefore, the true epidemiologic comorbidity is unknown.¹⁵

BD. Because patients with NLD may experience affective symptoms similar to those with BD, it is critical to clarify the temporal course of mood symptoms and understand the complex relationships between symptoms and external events (Table 2).^11,12 In BD, mood symptoms are cyclical, punctuated by discrete periods of euthymia. In NLD affective symptoms are clearly linked to learning difficulties and impaired information processing. Research shows cognitive deficits in individuals with BD often persist during euthymic periods.¹⁶ Literature suggests that cognitive deficits in adult BD commonly involve verbal memory, executive function, and attention, whereas patients with NLD often have strong verbal memory.^17,18

Individuals with BD may understand the intentions of others and—especially in periods of hypomania or mania—will engage others. In contrast, persons with NLD struggle to attract and engage friends, may be irritable when they misunderstand social cues, may be bullied or taken advantage of by others, and may struggle to communicate this problem to clinicians. NLD patients’ sense of frustration typically does not vary; a continuous depressed or anxious mood may improve briefly when they feel accepted in their environment. This pattern can be discerned from BD by strictly applying DSM-IV-TR criteria for variability in mood states.¹⁹ BD treatment may be complicated in patients with comorbid NLD. These patients may underreport adverse effects of medications, including metabolic effects and cognitive dulling, which results in a complicated and frustrating clinical course.²⁰

Asperger’s disorder. Patients with NLD—a neuropsychological disorder—may present with social interaction difficulties that seem similar to those of Asperger’s disorder—a behavioral disorder. Overlapping behaviors, similar cognitive processes, and coexisting conditions may challenge even experienced clinicians (Table 3).^21-23 However, impairments are more severe in Asperger’s disorder and will present as early as age 4. Patients with Asperger’s disorder show difficulty communicating characterized by unusual interactions, such as pedantic or 1-sided discussions of topics that are unusual for the patient’s age group and inattentiveness to social cues. By contrast, communication difficulties in children with NLD are not apparent until after they start school.

Both Asperger’s disorder and NLD patients will show noticeable variations in thought process that often are apparent in conversations. Individuals with Asperger’s disorder may have some concrete thinking, although they often express idiosyncratic thinking, whereas individuals with NLD often show concrete logic. An individual with NLD may be easily overwhelmed by peer group social interactions but remains emotionally aware of his or her shortcomings and may be able to handle 1-on-1 interactions. Individuals with Asperger’s disorder will demonstrate restrictive interests or repetitive behaviors, a characteristic typically not seen in individuals with NLD. Patients with Asperger’s disorder may have specific skills, such as expertise with directions and spatial reasoning, whereas individuals with NLD may get lost even when traveling to familiar places or may have difficulty relating directions. Both groups likely will have good reading skills but patients with NLD will have trouble comprehending and integrating the material, evident by difficulty with multiple choice questions or “story problems.” Individuals with either disorder may develop frustration and anger with their challenges.

In adults, many of these subtle differences in language and thought process may be masked by years of difficult and frustrating communication, making definitive diagnosis challenging. Semistructured interviews, such as the Autism Diagnostic Observation Schedule²⁴ or the Gilliam Asperger’s Disorder Scale,²⁵ may help in differentiating Asperger’s disorder from NLD. However, these 2 disorders may be comorbid, thus complicating the diagnostic process.²¹

Table 2

Differences among NLD, ADHD, and bipolar disorder

Table 3

Differences between NLD and Asperger’s disorder

Treatment implications

The day-to-day care of patients with NLD and a comorbid psychiatric disorder may include systems-level interventions, supportive psychotherapy, and psychopharmacologic treatments that are informed by the comorbid condition (Table 4).^7,26 Open, honest dialogue about strengths and challenges for individuals with NLD will help reframe expectations and frustrations. Early recognition of NLD may, in some cases, prevent internalized psychopathology and loss of self-esteem.^27,28

Children and adolescents with NLD require early intervention to help them function socially and academically. Involving family and school personnel is important to develop accommodations to improve functioning. Comprehension problems associated with NLD often become more noticeable as the student moves into upper elementary grades, where abstract thinking and the ability to manage novelty (eg, unfamiliar content or situations) are required. Many students with NLD can manage rote memorization and concrete facts, but have trouble with inference, integration, and reasoning. Academically appropriate classroom placement, limited writing, and use of voice recognition software may aid success. Parents can help by teaching and modeling social skills such as appropriate expression of emotions, which can be facilitated by watching movies or attending group activities together.

Adults. Patients with NLD may be late for appointments and often forget what is discussed. They may be at increased risk for noncompliance with pharmacotherapy for comorbid disorders and may require written instructions, frequent reminders, and reviews of treatment plan. In addition, interactions with clinicians may seem shallow and unsatisfying, despite the clinician’s best efforts to empathize. The pattern of feeling misunderstood likely exists in the patient’s other relationships, including significant others and employers. Although no systemic evaluations exist, mindfulness-based therapies might help alleviate this deficit.^29,30

Treatment plans may involve family-focused modalities where NLD patients learn to rely on family members to interpret others’ motives and intentions.³¹ Education of the patient and family and friends should emphasize the need for consistent daily schedules and frequent verbal feedback, such as taking turns in conversations. Academic accommodations in college are crucial for success. Education experts have advocated for increased use of technology for students with NLD, including voice recognition software, laptop computers, and audio recordings of class notes.³²

Table 4

Treating patients with NLD

Related Resources

• Rourke BP. Syndrome of nonverbal learning disabilities: Neurodevelopmental manifestations. New York, NY: Guilford Press; 1995.
• NLD Line. www.nldline.com.
• NLD on the Web. www.nldontheweb.org.
• Massachusetts General Hospital school psychiatry program and Mood and Anxiety Disorders Institute resource center. www2.massgeneral.org/schoolpsychiatry.

Disclosures

Drs. Delgado and Wassenaar report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Strawn has received research support from the American Academy of Child and Adolescent Psychiatry and Eli Lilly and Company.

Acknowledgements

The authors acknowledge Drs. Michele Berg and Carleen Franz for their careful review of this manuscript and for their critiques, which have greatly improved this contribution.