Evidence-Based Reviews

Abruptly stopping common psychotropics—particularly antidepressants, benzodiazepines, or atypical antipsychotics—can trigger a discontinuation syndrome, with:

• rebound or relapse of original symptoms
• uncomfortable new physical and psychological symptoms
• physiologic withdrawal at times.

To increase health professionals’ awareness of the risk of these adverse effects,¹ this article describes discontinuation syndromes associated with various psychotropics and offers strategies to anticipate, recognize, and manage them.

Antidepressant Discontinuation Syndromes

Discontinuation syndromes can occur with tricyclic and tetracyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and other newer antidepressants. Symptoms usually start within a few days of stopping a drug—or less commonly, reducing its dosage—and are usually mild and self-limited. Serious outcomes have been reported.

Distinguishing antidepressant discontinuation symptoms from depression recurrence is important. Discontinuation symptoms emerge within 1 to 3 days, whereas depressive symptoms usually occur 2 to 3 weeks after an antidepressant is stopped. Discontinuation reactions remit within a few days, especially if the antidepressant is re-instituted.

TCAs block serotonin and norepinephrine reuptake, increasing the availability of these biogenic amines at receptor sites in the brain and other tissues. Abrupt discontinuation can cause physical symptoms—such as lethargy, headache, and tremor—and psychological symptoms including irritability, anxiety, agitation, and low mood (Table 1).²

Long-term use of TCAs with potent anticholinergic properties leads to upregulation of postsynaptic muscarinic receptors, creating a “supersensitive” state. Abrupt discontinuation can cause cholinergic rebound, with symptoms emerging as soon as 12 hours—but typically 24 to 48 hours—after the last dose.

Table 1

Discontinuation symptoms seen with TCAs

Physical symptoms	Lethargy, headache, tremor, sweating, anorexia, insomnia, nausea, vomiting, diarrhea, akathisia (rare), parkinsonism (rare)
Psychological symptoms	Irritability, anxiety/agitation, low mood, excessive dreaming, nightmares, paradoxical activation resulting in manic/hypomanic symptoms (rare)
TCA: Tricyclic antidepressants
Source: Reference 2

MAOIs such as phenelzine and tranylcypromine inhibit the enzyme monoamine oxidase, which is responsible for monoamine degradation and increases synaptic monoamine concentrations. Discontinuation syndromes may include acute confusional states, paranoid delusions, hallucinations, or worsening of depressive symptoms.³ These problems rarely occur in clinical practice, however, because MAOIs’ serious side effects discourage doctors from prescribing them.

SSRIs and other agents. SSRIs block synaptic reuptake of serotonin. Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine inhibit both serotonin and norepinephrine reuptake. Mirtazapine—an alpha2-adrenergic and heteroreceptor antagonist—increases serotonin and norepinephrine at the synapse. Bupropion increases dopamine and norepinephrine turnover in the CNS and also blocks serotonin.

Up to 30% of patients who stop taking SSRIs develop discontinuation symptoms.⁴ Six symptom clusters—disequilibrium, sensory symptoms, general somatic symptoms, sleep disturbance, GI symptoms, and affective symptoms—characterize the SSRI discontinuation syndrome (Table 2).⁵ The four most common symptoms—in decreasing order of frequency—are dizziness, nausea, lethargy, and headache.⁶ Ataxia, sensory abnormalities, and possibly aggressive and impulsive behavior differentiate this discontinuation syndrome from that of the TCAs.

Table 2

Discontinuation symptoms seen with SSRIs

Type	Symptoms
Disequilibrium	Lightheadedness/dizziness, vertigo, ataxia
Sensory symptoms	Paraesthesia, numbness, electric shock-like sensations
General somatic symptoms	Lethargy, headache, tremor, sweating, anorexia
Sleep disturbance	Insomnia, nightmares, excessive dreaming
GI symptoms	Nausea, vomiting, diarrhea
Affective symptoms	Irritability, anxiety/agitation, low mood
SSRIs: Selective serotonin reuptake inhibitors
Source: Reference 5

Risk factors. Risk factors for SSRI discontinuation syndrome have been identified (Table 3).⁷ Symptoms usually begin 1 to 3 days after an SSRI is abruptly stopped and are usually mild. However, some patients report falls, inability to work, and difficulty walking and driving. Untreated symptoms are short-lived and remit within 1 to 2 weeks. They also remit if the original antidepressant is reintroduced or a pharmacologically similar agent is substituted.

Discontinuation syndrome risk among SSRIs is highest for paroxetine, intermediate for sertraline and fluvoxamine, and lowest for fluoxetine.⁴ Citalopram may cause a mild and transient discontinuation syndrome.⁸ Citalopram’s long elimination half-life (30 to 35 hours) and fewer and much less-potent active metabolites⁹ may explain its relatively low risk of discontinuation symptoms.

Discontinuation reactions have been reported to occur 100 times more frequently with paroxetine than with fluoxetine.¹⁰ Fluoxetine’s lower rate could be explained by its 2- to 3-day half-life, compared with half-lives of 33 hours or less for paroxetine, sertraline, citalopram, and fluvoxamine. A longer half-life might protect against a discontinuation syndrome.

Among other newer antidepressants:

• venlafaxine’s discontinuation syndrome is similar to the SSRI syndrome¹¹
• no discontinuation symptoms have been reported with mirtazapine, bupropion, or duloxetine.

Table 3

SSRI discontinuation syndrome: The patient at risk…

Is taking an SSRI with a relatively short half-life
Has received antidepressant treatment > 4 weeks
Has history of treatment-emergent anxiety, discontinuation symptoms, nonadherence
SSRI: Selective serotonin reuptake inhibitor
Source: Reference 7

Causes. Theories to explain SSRI discontinuation syndrome include cholinergic rebound,¹² as described with TCAs, or a decrease in available synaptic serotonin coinciding with down-regulated serotonin receptors.¹³ Paroxetine’s pharmacologic properties—cholinergic effects, short halflife, and high potency of serotonin reuptake blockade—may explain its relatively high frequency of discontinuation symptoms.

 

Atypical Antipsychotic Discontinuation Syndromes

Except for aripiprazole—which is a partial dopamine receptor agonist—most atypical antipsychotics are serotonin-dopamine antagonists. Discontinuation syndrome occurs most commonly with clozapine.

Clozapine. Abruptly stopping clozapine can exacerbate psychosis or cause delirium, agitation, confusion, and diaphoresis. Less-common symptoms may include extrapyramidal effects, nausea, diarrhea, headache, or restlessness.¹⁴ Clozapine is a weak dopamine D2 antagonist and a potent antagonist at the serotonin 5HT2, alpha adrenergic, histaminergic, and anticholinergic receptors. Thus, rebound from cholinergic, serotonin, dopamine and/or adrenergic receptor supersensitivity is thought to cause its discontinuation syndrome.¹⁵

Other atypicals. Case reports describe tics and withdrawal-emergent dyskinesia with risperidone¹⁶ and supersensitivity psychosis and a cholinergic/serotonergic syndrome with olanzapine.^17,18 Anecdotal reports suggest that abruptly discontinuing quetiapine can cause nausea, emesis, lightheadedness, diaphoresis, orthostasis, tachycardia, and nervousness.^19,20 Although discontinuation syndromes have not been reported with ziprasidone or aripiprazole, tapering any atypical antipsychotic during discontinuation is prudent.

Benzodiazepine Discontinuation Syndromes

Benzodiazepines modulate the neurotransmitter activity of gamma-aminobutyric acid (GABA). They differ in their pharmacokinetic properties and have varying half-lives:

• chlordiazepoxide and diazepam have long half-lives (48 hours)
• clonazepam has an intermediate half-life (10 to 24 hours)
• alprazolam, lorazepam, and oxazepam have short half-lives (10 hours).

Abruptly discontinuing benzodiazepines can cause relapse or rebound of pretreatment symptoms. Rebound—with symptoms exceeding pretreatment levels—sometimes occurs after 4 weeks of therapy. The syndrome may last 1 to 3 weeks and is more common with agents having relatively short half-lives.²¹

Withdrawal. During benzodiazepine withdrawal, new symptoms emerge and pre-existing symptoms worsen. An autonomic component differentiates withdrawal from relapse or rebound. Prominent symptoms include excess sensitivity to light and sound, insomnia, tachycardia, mild systolic hypertension, anxiety, nausea, irritability, tremors, sweating, and abdominal distress. Less-common but serious symptoms include confusion, paranoid delusions, hallucinations, and seizures.²²

Withdrawal symptoms are more likely to occur after 6 months of benzodiazepine therapy, when physical dependence also can develop. More-severe benzodiazepine discontinuation syndrome is associated with higher dosages, longer duration of therapy, shorter half-lives, and rapid tapers. Patient factors associated with withdrawal symptoms include:

• personality traits such as dependency and neuroticism
• high pretreatment anxious and depressive symptoms
• history of substance abuse or dependence.²³

Preventing discontinuation syndromes

Antidepressants. For TCAs, no discontinuation protocols exist, although some experts suggest tapering regimens over 4 weeks to 3 months. For MAOIs, reducing dosages 10% per week has been suggested.²⁴ The SSRI taper rate depends on the drug’s pharmacologic profile, how long the patient has been taking the SSRI, and the dosage.²⁵

With paroxetine, for example, a gradual reduction of 10 mg/d per week is recommended, based on clinical trial experience. When you reach 20 mg/d, continue this dosage for 1 week before stopping treatment. If reducing a dosage or discontinuing paroxetine causes intolerable symptoms, consider resuming the previously prescribed dosage and then taper more gradually.²⁶

Also gradually taper other SSRIs with short half-lives. Suggested taper regimens for sertraline and fluvoxamine call for weekly reductions of 50 mg/d until you reach 25 to 50 mg. It is not unusual for this final dosage to be lower than the starting dosage.²⁵ Substituting fluoxetine—with its longer half-life—for other SSRIs at the end of treatment has been suggested to suppress withdrawal symptoms,²⁷ although the safety and efficacy of this approach is unknown.⁵ With venlafaxine, taper over a minimum of 2 to 4 weeks.²⁸

Antipsychotics. To prevent psychotic relapse when discontinuing clozapine, some experts advocate starting a new antipsychotic in a therapeutic dosage before stopping clozapine. When highdose clozapine must be withdrawn immediately, hospitalize the patient and consider using cholinergics to prevent cholinergic rebound.¹⁵

Data on managing discontinuation syndromes associated with risperidone, olanzapine, or quetiapine are limited. In some cases, reinstituting the original drug, gradually tapering the antipsychotic,^18,19 or using prochlorperazine²⁰ have been useful.

Benzodiazepines. Taper oral benzodiazepines if a patient has taken them >4 to 6 weeks. Also taper IV midazolam used >7 days to sedate a critically ill patient. For the elderly, an 8- to 10-week taper may be required to discontinue benzodiazepines used >3 months for insomnia.

The American Psychiatric Association practice guideline for patients with panic disorder²⁹ recommends tapering benzodiazepines across 2 to 4 months, reducing dosages not more than 10% weekly. Another option is to reduce the daily dosage by 25% per week, but close monitoring and flexibility are required during this taper.

Outcomes when tapering benzodiazepines, according to Rickels et al,²³ depend less on pharmacologic adjuvant treatment than on benzodiazepine dosage before the taper, initial psychopathology severity, and patient personality traits (such as passivity/dependency). Before tapering, those authors recommend that you:

• establish a stable patient-physician relationship
• aggressively treat clinically significant anxiety and depression symptoms with medication or other means while the patient continues the established benzodiazepine dosage.

 

When the taper is nearly complete, maintain the reduced benzodiazepine dosage several months before the final taper.²³ Carbamazepine, imipramine, valproate, or trazodone may help alleviate benzodiazepine discontinuation symptoms in select patients.²¹

When discontinuation occurs

Medical comorbidity. Common medical conditions, including pregnancy or acute surgical procedures, may necessitate abrupt psychotropic discontinuation (Table 4).

Because up to 30% of medical patients have a psychiatric disorder,³⁰ primary care physicians often start psychotropics to manage anxiety and depressive symptoms and may seek psychiatric advice when switching or stopping medications. Moreover, 10% to 15% of hospitalized medically ill patients require dosage reduction or discontinuation of psychotropics that are contributing to the clinical presentation.³¹

Table 4

Common conditions requiring abrupt psychotropic discontinuation

Preoperative management of elective/emergency surgery Delirium Unknown medication history Acute pancreatitis Emergent abdominal surgery Acute intoxication Pregnancy and breast feeding

Switching. When switching psychotropics, effects from the first psychotropic may appear to be adverse effects of the new psychotropic. Thus, unrecognized discontinuation syndromes may lead to unnecessary treatment changes.

In our experience, a general rule is to cross-taper and decrease the psychotropic being discontinued by 10% every 1 to 2 weeks. Prescribe adequate dosages of the new psychotropic, closely monitor vital signs, and watch for emerging discontinuation symptoms.

Pregnancy. For women who become pregnant while taking psychotropics, consider the patient’s psychiatric stability, week of pregnancy, psychotropic agent, and treatment preferences when adjusting the treatment plan. In one study of 34 women who stopped psychotropics abruptly for fear of harming the fetus:

• 26 (70%) reported physical and psychological adverse effects
• 11 (30%) reported suicidal ideation, and 4 were hospitalized.³²

Patient education. In the study described above, some of the pregnant women’s physicians were unaware of the risks associated with abrupt psychotropic discontinuation and others were aware but failed to inform their patients.³² Thus, patient and family/caregiver education is important. When stopping psychotropics, discuss their risks/benefits, address unrealistic expectations, and individualize therapy by tapering and providing adequate dosing. Watch for suicidality; a weekly telephone call might be useful.

Related resource

• Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman’s the pharmacological basis of therapeutics (10th ed). New York: McGraw-Hill, 2001.

Drug Brand Names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Carbamazepine • Equetro, Tegretol
• Chlordiazepoxide • Librium
• Citalopram • Celexa
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Diazepam • Valium
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Imipramine • Tofranil
• Lorazepam • Ativan
• Mirtazapine • Remeron
• Oxazepam • Serax
• Paroxetine • Paxil
• Phenelzine • Nardil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Tranylcypromine • Parnate
• Trazodone • Desyrel
• Sertraline • Zoloft
• Valproate • Depakene
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

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

Abruptly stopping common psychotropics—particularly antidepressants, benzodiazepines, or atypical antipsychotics—can trigger a discontinuation syndrome, with:

• rebound or relapse of original symptoms
• uncomfortable new physical and psychological symptoms
• physiologic withdrawal at times.

To increase health professionals’ awareness of the risk of these adverse effects,¹ this article describes discontinuation syndromes associated with various psychotropics and offers strategies to anticipate, recognize, and manage them.

Antidepressant Discontinuation Syndromes

Discontinuation syndromes can occur with tricyclic and tetracyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and other newer antidepressants. Symptoms usually start within a few days of stopping a drug—or less commonly, reducing its dosage—and are usually mild and self-limited. Serious outcomes have been reported.

Distinguishing antidepressant discontinuation symptoms from depression recurrence is important. Discontinuation symptoms emerge within 1 to 3 days, whereas depressive symptoms usually occur 2 to 3 weeks after an antidepressant is stopped. Discontinuation reactions remit within a few days, especially if the antidepressant is re-instituted.

TCAs block serotonin and norepinephrine reuptake, increasing the availability of these biogenic amines at receptor sites in the brain and other tissues. Abrupt discontinuation can cause physical symptoms—such as lethargy, headache, and tremor—and psychological symptoms including irritability, anxiety, agitation, and low mood (Table 1).²

Long-term use of TCAs with potent anticholinergic properties leads to upregulation of postsynaptic muscarinic receptors, creating a “supersensitive” state. Abrupt discontinuation can cause cholinergic rebound, with symptoms emerging as soon as 12 hours—but typically 24 to 48 hours—after the last dose.

Table 1

Discontinuation symptoms seen with TCAs

Physical symptoms	Lethargy, headache, tremor, sweating, anorexia, insomnia, nausea, vomiting, diarrhea, akathisia (rare), parkinsonism (rare)
Psychological symptoms	Irritability, anxiety/agitation, low mood, excessive dreaming, nightmares, paradoxical activation resulting in manic/hypomanic symptoms (rare)
TCA: Tricyclic antidepressants
Source: Reference 2

MAOIs such as phenelzine and tranylcypromine inhibit the enzyme monoamine oxidase, which is responsible for monoamine degradation and increases synaptic monoamine concentrations. Discontinuation syndromes may include acute confusional states, paranoid delusions, hallucinations, or worsening of depressive symptoms.³ These problems rarely occur in clinical practice, however, because MAOIs’ serious side effects discourage doctors from prescribing them.

SSRIs and other agents. SSRIs block synaptic reuptake of serotonin. Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine inhibit both serotonin and norepinephrine reuptake. Mirtazapine—an alpha2-adrenergic and heteroreceptor antagonist—increases serotonin and norepinephrine at the synapse. Bupropion increases dopamine and norepinephrine turnover in the CNS and also blocks serotonin.

Up to 30% of patients who stop taking SSRIs develop discontinuation symptoms.⁴ Six symptom clusters—disequilibrium, sensory symptoms, general somatic symptoms, sleep disturbance, GI symptoms, and affective symptoms—characterize the SSRI discontinuation syndrome (Table 2).⁵ The four most common symptoms—in decreasing order of frequency—are dizziness, nausea, lethargy, and headache.⁶ Ataxia, sensory abnormalities, and possibly aggressive and impulsive behavior differentiate this discontinuation syndrome from that of the TCAs.

Table 2

Discontinuation symptoms seen with SSRIs

Type	Symptoms
Disequilibrium	Lightheadedness/dizziness, vertigo, ataxia
Sensory symptoms	Paraesthesia, numbness, electric shock-like sensations
General somatic symptoms	Lethargy, headache, tremor, sweating, anorexia
Sleep disturbance	Insomnia, nightmares, excessive dreaming
GI symptoms	Nausea, vomiting, diarrhea
Affective symptoms	Irritability, anxiety/agitation, low mood
SSRIs: Selective serotonin reuptake inhibitors
Source: Reference 5

Risk factors. Risk factors for SSRI discontinuation syndrome have been identified (Table 3).⁷ Symptoms usually begin 1 to 3 days after an SSRI is abruptly stopped and are usually mild. However, some patients report falls, inability to work, and difficulty walking and driving. Untreated symptoms are short-lived and remit within 1 to 2 weeks. They also remit if the original antidepressant is reintroduced or a pharmacologically similar agent is substituted.

Discontinuation syndrome risk among SSRIs is highest for paroxetine, intermediate for sertraline and fluvoxamine, and lowest for fluoxetine.⁴ Citalopram may cause a mild and transient discontinuation syndrome.⁸ Citalopram’s long elimination half-life (30 to 35 hours) and fewer and much less-potent active metabolites⁹ may explain its relatively low risk of discontinuation symptoms.

Discontinuation reactions have been reported to occur 100 times more frequently with paroxetine than with fluoxetine.¹⁰ Fluoxetine’s lower rate could be explained by its 2- to 3-day half-life, compared with half-lives of 33 hours or less for paroxetine, sertraline, citalopram, and fluvoxamine. A longer half-life might protect against a discontinuation syndrome.

Among other newer antidepressants:

• venlafaxine’s discontinuation syndrome is similar to the SSRI syndrome¹¹
• no discontinuation symptoms have been reported with mirtazapine, bupropion, or duloxetine.

Table 3

SSRI discontinuation syndrome: The patient at risk…

Is taking an SSRI with a relatively short half-life
Has received antidepressant treatment > 4 weeks
Has history of treatment-emergent anxiety, discontinuation symptoms, nonadherence
SSRI: Selective serotonin reuptake inhibitor
Source: Reference 7

Causes. Theories to explain SSRI discontinuation syndrome include cholinergic rebound,¹² as described with TCAs, or a decrease in available synaptic serotonin coinciding with down-regulated serotonin receptors.¹³ Paroxetine’s pharmacologic properties—cholinergic effects, short halflife, and high potency of serotonin reuptake blockade—may explain its relatively high frequency of discontinuation symptoms.

 

Atypical Antipsychotic Discontinuation Syndromes

Except for aripiprazole—which is a partial dopamine receptor agonist—most atypical antipsychotics are serotonin-dopamine antagonists. Discontinuation syndrome occurs most commonly with clozapine.

Clozapine. Abruptly stopping clozapine can exacerbate psychosis or cause delirium, agitation, confusion, and diaphoresis. Less-common symptoms may include extrapyramidal effects, nausea, diarrhea, headache, or restlessness.¹⁴ Clozapine is a weak dopamine D2 antagonist and a potent antagonist at the serotonin 5HT2, alpha adrenergic, histaminergic, and anticholinergic receptors. Thus, rebound from cholinergic, serotonin, dopamine and/or adrenergic receptor supersensitivity is thought to cause its discontinuation syndrome.¹⁵

Other atypicals. Case reports describe tics and withdrawal-emergent dyskinesia with risperidone¹⁶ and supersensitivity psychosis and a cholinergic/serotonergic syndrome with olanzapine.^17,18 Anecdotal reports suggest that abruptly discontinuing quetiapine can cause nausea, emesis, lightheadedness, diaphoresis, orthostasis, tachycardia, and nervousness.^19,20 Although discontinuation syndromes have not been reported with ziprasidone or aripiprazole, tapering any atypical antipsychotic during discontinuation is prudent.

Benzodiazepine Discontinuation Syndromes

Benzodiazepines modulate the neurotransmitter activity of gamma-aminobutyric acid (GABA). They differ in their pharmacokinetic properties and have varying half-lives:

• chlordiazepoxide and diazepam have long half-lives (48 hours)
• clonazepam has an intermediate half-life (10 to 24 hours)
• alprazolam, lorazepam, and oxazepam have short half-lives (10 hours).

Abruptly discontinuing benzodiazepines can cause relapse or rebound of pretreatment symptoms. Rebound—with symptoms exceeding pretreatment levels—sometimes occurs after 4 weeks of therapy. The syndrome may last 1 to 3 weeks and is more common with agents having relatively short half-lives.²¹

Withdrawal. During benzodiazepine withdrawal, new symptoms emerge and pre-existing symptoms worsen. An autonomic component differentiates withdrawal from relapse or rebound. Prominent symptoms include excess sensitivity to light and sound, insomnia, tachycardia, mild systolic hypertension, anxiety, nausea, irritability, tremors, sweating, and abdominal distress. Less-common but serious symptoms include confusion, paranoid delusions, hallucinations, and seizures.²²

Withdrawal symptoms are more likely to occur after 6 months of benzodiazepine therapy, when physical dependence also can develop. More-severe benzodiazepine discontinuation syndrome is associated with higher dosages, longer duration of therapy, shorter half-lives, and rapid tapers. Patient factors associated with withdrawal symptoms include:

• personality traits such as dependency and neuroticism
• high pretreatment anxious and depressive symptoms
• history of substance abuse or dependence.²³

Preventing discontinuation syndromes

Antidepressants. For TCAs, no discontinuation protocols exist, although some experts suggest tapering regimens over 4 weeks to 3 months. For MAOIs, reducing dosages 10% per week has been suggested.²⁴ The SSRI taper rate depends on the drug’s pharmacologic profile, how long the patient has been taking the SSRI, and the dosage.²⁵

With paroxetine, for example, a gradual reduction of 10 mg/d per week is recommended, based on clinical trial experience. When you reach 20 mg/d, continue this dosage for 1 week before stopping treatment. If reducing a dosage or discontinuing paroxetine causes intolerable symptoms, consider resuming the previously prescribed dosage and then taper more gradually.²⁶

Also gradually taper other SSRIs with short half-lives. Suggested taper regimens for sertraline and fluvoxamine call for weekly reductions of 50 mg/d until you reach 25 to 50 mg. It is not unusual for this final dosage to be lower than the starting dosage.²⁵ Substituting fluoxetine—with its longer half-life—for other SSRIs at the end of treatment has been suggested to suppress withdrawal symptoms,²⁷ although the safety and efficacy of this approach is unknown.⁵ With venlafaxine, taper over a minimum of 2 to 4 weeks.²⁸

Antipsychotics. To prevent psychotic relapse when discontinuing clozapine, some experts advocate starting a new antipsychotic in a therapeutic dosage before stopping clozapine. When highdose clozapine must be withdrawn immediately, hospitalize the patient and consider using cholinergics to prevent cholinergic rebound.¹⁵

Data on managing discontinuation syndromes associated with risperidone, olanzapine, or quetiapine are limited. In some cases, reinstituting the original drug, gradually tapering the antipsychotic,^18,19 or using prochlorperazine²⁰ have been useful.

Benzodiazepines. Taper oral benzodiazepines if a patient has taken them >4 to 6 weeks. Also taper IV midazolam used >7 days to sedate a critically ill patient. For the elderly, an 8- to 10-week taper may be required to discontinue benzodiazepines used >3 months for insomnia.

The American Psychiatric Association practice guideline for patients with panic disorder²⁹ recommends tapering benzodiazepines across 2 to 4 months, reducing dosages not more than 10% weekly. Another option is to reduce the daily dosage by 25% per week, but close monitoring and flexibility are required during this taper.

Outcomes when tapering benzodiazepines, according to Rickels et al,²³ depend less on pharmacologic adjuvant treatment than on benzodiazepine dosage before the taper, initial psychopathology severity, and patient personality traits (such as passivity/dependency). Before tapering, those authors recommend that you:

• establish a stable patient-physician relationship
• aggressively treat clinically significant anxiety and depression symptoms with medication or other means while the patient continues the established benzodiazepine dosage.

 

When the taper is nearly complete, maintain the reduced benzodiazepine dosage several months before the final taper.²³ Carbamazepine, imipramine, valproate, or trazodone may help alleviate benzodiazepine discontinuation symptoms in select patients.²¹

When discontinuation occurs

Medical comorbidity. Common medical conditions, including pregnancy or acute surgical procedures, may necessitate abrupt psychotropic discontinuation (Table 4).

Because up to 30% of medical patients have a psychiatric disorder,³⁰ primary care physicians often start psychotropics to manage anxiety and depressive symptoms and may seek psychiatric advice when switching or stopping medications. Moreover, 10% to 15% of hospitalized medically ill patients require dosage reduction or discontinuation of psychotropics that are contributing to the clinical presentation.³¹

Table 4

Common conditions requiring abrupt psychotropic discontinuation

Preoperative management of elective/emergency surgery Delirium Unknown medication history Acute pancreatitis Emergent abdominal surgery Acute intoxication Pregnancy and breast feeding

Switching. When switching psychotropics, effects from the first psychotropic may appear to be adverse effects of the new psychotropic. Thus, unrecognized discontinuation syndromes may lead to unnecessary treatment changes.

In our experience, a general rule is to cross-taper and decrease the psychotropic being discontinued by 10% every 1 to 2 weeks. Prescribe adequate dosages of the new psychotropic, closely monitor vital signs, and watch for emerging discontinuation symptoms.

Pregnancy. For women who become pregnant while taking psychotropics, consider the patient’s psychiatric stability, week of pregnancy, psychotropic agent, and treatment preferences when adjusting the treatment plan. In one study of 34 women who stopped psychotropics abruptly for fear of harming the fetus:

• 26 (70%) reported physical and psychological adverse effects
• 11 (30%) reported suicidal ideation, and 4 were hospitalized.³²

Patient education. In the study described above, some of the pregnant women’s physicians were unaware of the risks associated with abrupt psychotropic discontinuation and others were aware but failed to inform their patients.³² Thus, patient and family/caregiver education is important. When stopping psychotropics, discuss their risks/benefits, address unrealistic expectations, and individualize therapy by tapering and providing adequate dosing. Watch for suicidality; a weekly telephone call might be useful.

Related resource

• Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman’s the pharmacological basis of therapeutics (10th ed). New York: McGraw-Hill, 2001.

Drug Brand Names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Carbamazepine • Equetro, Tegretol
• Chlordiazepoxide • Librium
• Citalopram • Celexa
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Diazepam • Valium
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Imipramine • Tofranil
• Lorazepam • Ativan
• Mirtazapine • Remeron
• Oxazepam • Serax
• Paroxetine • Paxil
• Phenelzine • Nardil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Tranylcypromine • Parnate
• Trazodone • Desyrel
• Sertraline • Zoloft
• Valproate • Depakene
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

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

Abruptly stopping common psychotropics—particularly antidepressants, benzodiazepines, or atypical antipsychotics—can trigger a discontinuation syndrome, with:

• rebound or relapse of original symptoms
• uncomfortable new physical and psychological symptoms
• physiologic withdrawal at times.

To increase health professionals’ awareness of the risk of these adverse effects,¹ this article describes discontinuation syndromes associated with various psychotropics and offers strategies to anticipate, recognize, and manage them.

Antidepressant Discontinuation Syndromes

Discontinuation syndromes can occur with tricyclic and tetracyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), and other newer antidepressants. Symptoms usually start within a few days of stopping a drug—or less commonly, reducing its dosage—and are usually mild and self-limited. Serious outcomes have been reported.

Distinguishing antidepressant discontinuation symptoms from depression recurrence is important. Discontinuation symptoms emerge within 1 to 3 days, whereas depressive symptoms usually occur 2 to 3 weeks after an antidepressant is stopped. Discontinuation reactions remit within a few days, especially if the antidepressant is re-instituted.

TCAs block serotonin and norepinephrine reuptake, increasing the availability of these biogenic amines at receptor sites in the brain and other tissues. Abrupt discontinuation can cause physical symptoms—such as lethargy, headache, and tremor—and psychological symptoms including irritability, anxiety, agitation, and low mood (Table 1).²

Long-term use of TCAs with potent anticholinergic properties leads to upregulation of postsynaptic muscarinic receptors, creating a “supersensitive” state. Abrupt discontinuation can cause cholinergic rebound, with symptoms emerging as soon as 12 hours—but typically 24 to 48 hours—after the last dose.

Table 1

Discontinuation symptoms seen with TCAs

Physical symptoms	Lethargy, headache, tremor, sweating, anorexia, insomnia, nausea, vomiting, diarrhea, akathisia (rare), parkinsonism (rare)
Psychological symptoms	Irritability, anxiety/agitation, low mood, excessive dreaming, nightmares, paradoxical activation resulting in manic/hypomanic symptoms (rare)
TCA: Tricyclic antidepressants
Source: Reference 2

MAOIs such as phenelzine and tranylcypromine inhibit the enzyme monoamine oxidase, which is responsible for monoamine degradation and increases synaptic monoamine concentrations. Discontinuation syndromes may include acute confusional states, paranoid delusions, hallucinations, or worsening of depressive symptoms.³ These problems rarely occur in clinical practice, however, because MAOIs’ serious side effects discourage doctors from prescribing them.

SSRIs and other agents. SSRIs block synaptic reuptake of serotonin. Serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine and duloxetine inhibit both serotonin and norepinephrine reuptake. Mirtazapine—an alpha2-adrenergic and heteroreceptor antagonist—increases serotonin and norepinephrine at the synapse. Bupropion increases dopamine and norepinephrine turnover in the CNS and also blocks serotonin.

Up to 30% of patients who stop taking SSRIs develop discontinuation symptoms.⁴ Six symptom clusters—disequilibrium, sensory symptoms, general somatic symptoms, sleep disturbance, GI symptoms, and affective symptoms—characterize the SSRI discontinuation syndrome (Table 2).⁵ The four most common symptoms—in decreasing order of frequency—are dizziness, nausea, lethargy, and headache.⁶ Ataxia, sensory abnormalities, and possibly aggressive and impulsive behavior differentiate this discontinuation syndrome from that of the TCAs.

Table 2

Discontinuation symptoms seen with SSRIs

Type	Symptoms
Disequilibrium	Lightheadedness/dizziness, vertigo, ataxia
Sensory symptoms	Paraesthesia, numbness, electric shock-like sensations
General somatic symptoms	Lethargy, headache, tremor, sweating, anorexia
Sleep disturbance	Insomnia, nightmares, excessive dreaming
GI symptoms	Nausea, vomiting, diarrhea
Affective symptoms	Irritability, anxiety/agitation, low mood
SSRIs: Selective serotonin reuptake inhibitors
Source: Reference 5

Risk factors. Risk factors for SSRI discontinuation syndrome have been identified (Table 3).⁷ Symptoms usually begin 1 to 3 days after an SSRI is abruptly stopped and are usually mild. However, some patients report falls, inability to work, and difficulty walking and driving. Untreated symptoms are short-lived and remit within 1 to 2 weeks. They also remit if the original antidepressant is reintroduced or a pharmacologically similar agent is substituted.

Discontinuation syndrome risk among SSRIs is highest for paroxetine, intermediate for sertraline and fluvoxamine, and lowest for fluoxetine.⁴ Citalopram may cause a mild and transient discontinuation syndrome.⁸ Citalopram’s long elimination half-life (30 to 35 hours) and fewer and much less-potent active metabolites⁹ may explain its relatively low risk of discontinuation symptoms.

Discontinuation reactions have been reported to occur 100 times more frequently with paroxetine than with fluoxetine.¹⁰ Fluoxetine’s lower rate could be explained by its 2- to 3-day half-life, compared with half-lives of 33 hours or less for paroxetine, sertraline, citalopram, and fluvoxamine. A longer half-life might protect against a discontinuation syndrome.

Among other newer antidepressants:

• venlafaxine’s discontinuation syndrome is similar to the SSRI syndrome¹¹
• no discontinuation symptoms have been reported with mirtazapine, bupropion, or duloxetine.

Table 3

SSRI discontinuation syndrome: The patient at risk…

Is taking an SSRI with a relatively short half-life
Has received antidepressant treatment > 4 weeks
Has history of treatment-emergent anxiety, discontinuation symptoms, nonadherence
SSRI: Selective serotonin reuptake inhibitor
Source: Reference 7

Causes. Theories to explain SSRI discontinuation syndrome include cholinergic rebound,¹² as described with TCAs, or a decrease in available synaptic serotonin coinciding with down-regulated serotonin receptors.¹³ Paroxetine’s pharmacologic properties—cholinergic effects, short halflife, and high potency of serotonin reuptake blockade—may explain its relatively high frequency of discontinuation symptoms.

 

Atypical Antipsychotic Discontinuation Syndromes

Except for aripiprazole—which is a partial dopamine receptor agonist—most atypical antipsychotics are serotonin-dopamine antagonists. Discontinuation syndrome occurs most commonly with clozapine.

Clozapine. Abruptly stopping clozapine can exacerbate psychosis or cause delirium, agitation, confusion, and diaphoresis. Less-common symptoms may include extrapyramidal effects, nausea, diarrhea, headache, or restlessness.¹⁴ Clozapine is a weak dopamine D2 antagonist and a potent antagonist at the serotonin 5HT2, alpha adrenergic, histaminergic, and anticholinergic receptors. Thus, rebound from cholinergic, serotonin, dopamine and/or adrenergic receptor supersensitivity is thought to cause its discontinuation syndrome.¹⁵

Other atypicals. Case reports describe tics and withdrawal-emergent dyskinesia with risperidone¹⁶ and supersensitivity psychosis and a cholinergic/serotonergic syndrome with olanzapine.^17,18 Anecdotal reports suggest that abruptly discontinuing quetiapine can cause nausea, emesis, lightheadedness, diaphoresis, orthostasis, tachycardia, and nervousness.^19,20 Although discontinuation syndromes have not been reported with ziprasidone or aripiprazole, tapering any atypical antipsychotic during discontinuation is prudent.

Benzodiazepine Discontinuation Syndromes

Benzodiazepines modulate the neurotransmitter activity of gamma-aminobutyric acid (GABA). They differ in their pharmacokinetic properties and have varying half-lives:

• chlordiazepoxide and diazepam have long half-lives (48 hours)
• clonazepam has an intermediate half-life (10 to 24 hours)
• alprazolam, lorazepam, and oxazepam have short half-lives (10 hours).

Abruptly discontinuing benzodiazepines can cause relapse or rebound of pretreatment symptoms. Rebound—with symptoms exceeding pretreatment levels—sometimes occurs after 4 weeks of therapy. The syndrome may last 1 to 3 weeks and is more common with agents having relatively short half-lives.²¹

Withdrawal. During benzodiazepine withdrawal, new symptoms emerge and pre-existing symptoms worsen. An autonomic component differentiates withdrawal from relapse or rebound. Prominent symptoms include excess sensitivity to light and sound, insomnia, tachycardia, mild systolic hypertension, anxiety, nausea, irritability, tremors, sweating, and abdominal distress. Less-common but serious symptoms include confusion, paranoid delusions, hallucinations, and seizures.²²

Withdrawal symptoms are more likely to occur after 6 months of benzodiazepine therapy, when physical dependence also can develop. More-severe benzodiazepine discontinuation syndrome is associated with higher dosages, longer duration of therapy, shorter half-lives, and rapid tapers. Patient factors associated with withdrawal symptoms include:

• personality traits such as dependency and neuroticism
• high pretreatment anxious and depressive symptoms
• history of substance abuse or dependence.²³

Preventing discontinuation syndromes

Antidepressants. For TCAs, no discontinuation protocols exist, although some experts suggest tapering regimens over 4 weeks to 3 months. For MAOIs, reducing dosages 10% per week has been suggested.²⁴ The SSRI taper rate depends on the drug’s pharmacologic profile, how long the patient has been taking the SSRI, and the dosage.²⁵

With paroxetine, for example, a gradual reduction of 10 mg/d per week is recommended, based on clinical trial experience. When you reach 20 mg/d, continue this dosage for 1 week before stopping treatment. If reducing a dosage or discontinuing paroxetine causes intolerable symptoms, consider resuming the previously prescribed dosage and then taper more gradually.²⁶

Also gradually taper other SSRIs with short half-lives. Suggested taper regimens for sertraline and fluvoxamine call for weekly reductions of 50 mg/d until you reach 25 to 50 mg. It is not unusual for this final dosage to be lower than the starting dosage.²⁵ Substituting fluoxetine—with its longer half-life—for other SSRIs at the end of treatment has been suggested to suppress withdrawal symptoms,²⁷ although the safety and efficacy of this approach is unknown.⁵ With venlafaxine, taper over a minimum of 2 to 4 weeks.²⁸

Antipsychotics. To prevent psychotic relapse when discontinuing clozapine, some experts advocate starting a new antipsychotic in a therapeutic dosage before stopping clozapine. When highdose clozapine must be withdrawn immediately, hospitalize the patient and consider using cholinergics to prevent cholinergic rebound.¹⁵

Data on managing discontinuation syndromes associated with risperidone, olanzapine, or quetiapine are limited. In some cases, reinstituting the original drug, gradually tapering the antipsychotic,^18,19 or using prochlorperazine²⁰ have been useful.

Benzodiazepines. Taper oral benzodiazepines if a patient has taken them >4 to 6 weeks. Also taper IV midazolam used >7 days to sedate a critically ill patient. For the elderly, an 8- to 10-week taper may be required to discontinue benzodiazepines used >3 months for insomnia.

The American Psychiatric Association practice guideline for patients with panic disorder²⁹ recommends tapering benzodiazepines across 2 to 4 months, reducing dosages not more than 10% weekly. Another option is to reduce the daily dosage by 25% per week, but close monitoring and flexibility are required during this taper.

Outcomes when tapering benzodiazepines, according to Rickels et al,²³ depend less on pharmacologic adjuvant treatment than on benzodiazepine dosage before the taper, initial psychopathology severity, and patient personality traits (such as passivity/dependency). Before tapering, those authors recommend that you:

• establish a stable patient-physician relationship
• aggressively treat clinically significant anxiety and depression symptoms with medication or other means while the patient continues the established benzodiazepine dosage.

 

When the taper is nearly complete, maintain the reduced benzodiazepine dosage several months before the final taper.²³ Carbamazepine, imipramine, valproate, or trazodone may help alleviate benzodiazepine discontinuation symptoms in select patients.²¹

When discontinuation occurs

Medical comorbidity. Common medical conditions, including pregnancy or acute surgical procedures, may necessitate abrupt psychotropic discontinuation (Table 4).

Because up to 30% of medical patients have a psychiatric disorder,³⁰ primary care physicians often start psychotropics to manage anxiety and depressive symptoms and may seek psychiatric advice when switching or stopping medications. Moreover, 10% to 15% of hospitalized medically ill patients require dosage reduction or discontinuation of psychotropics that are contributing to the clinical presentation.³¹

Table 4

Common conditions requiring abrupt psychotropic discontinuation

Preoperative management of elective/emergency surgery Delirium Unknown medication history Acute pancreatitis Emergent abdominal surgery Acute intoxication Pregnancy and breast feeding

Switching. When switching psychotropics, effects from the first psychotropic may appear to be adverse effects of the new psychotropic. Thus, unrecognized discontinuation syndromes may lead to unnecessary treatment changes.

In our experience, a general rule is to cross-taper and decrease the psychotropic being discontinued by 10% every 1 to 2 weeks. Prescribe adequate dosages of the new psychotropic, closely monitor vital signs, and watch for emerging discontinuation symptoms.

Pregnancy. For women who become pregnant while taking psychotropics, consider the patient’s psychiatric stability, week of pregnancy, psychotropic agent, and treatment preferences when adjusting the treatment plan. In one study of 34 women who stopped psychotropics abruptly for fear of harming the fetus:

• 26 (70%) reported physical and psychological adverse effects
• 11 (30%) reported suicidal ideation, and 4 were hospitalized.³²

Patient education. In the study described above, some of the pregnant women’s physicians were unaware of the risks associated with abrupt psychotropic discontinuation and others were aware but failed to inform their patients.³² Thus, patient and family/caregiver education is important. When stopping psychotropics, discuss their risks/benefits, address unrealistic expectations, and individualize therapy by tapering and providing adequate dosing. Watch for suicidality; a weekly telephone call might be useful.

Related resource

• Hardman JG, Limbird LE, Gilman AG. Goodman & Gilman’s the pharmacological basis of therapeutics (10th ed). New York: McGraw-Hill, 2001.

Drug Brand Names

• Alprazolam • Xanax
• Aripiprazole • Abilify
• Bupropion • Wellbutrin
• Carbamazepine • Equetro, Tegretol
• Chlordiazepoxide • Librium
• Citalopram • Celexa
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Diazepam • Valium
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Imipramine • Tofranil
• Lorazepam • Ativan
• Mirtazapine • Remeron
• Oxazepam • Serax
• Paroxetine • Paxil
• Phenelzine • Nardil
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Tranylcypromine • Parnate
• Trazodone • Desyrel
• Sertraline • Zoloft
• Valproate • Depakene
• Venlafaxine • Effexor
• Ziprasidone • Geodon

Disclosure

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

Remission is considered the standard of treatment for major depression,^1-4 but many patients fall short of this goal:

• 25% to 50% of those who respond to treatment have residual symptoms⁵
• 60% to 70% respond to treatment, but only 20% to 40% achieve remission.⁶

We offer practical, evidence-based suggestions and resources to help you take more of your patients beyond response to remission and then to recovery (Table 1).^7,8

Table 1

Outcomes in depression: Defining the 4 ‘R’s

Outcome	Definition	Comment
Response	Clinically significant reduction of symptoms	50% reduction in symptoms on psychometric scales may leave severely depressed patients with disabling symptoms
Remission	Depression resolves completely or nearly completely, with return to baseline function	Score of ≤7 on the HRSD used in many studies; ACNP Task Force defines remission by 9 core depression symptoms in DSM-IV-TR
Recovery	Remission lasts for extended time; signifies end of a major depressive episode	ACNP Task Force defines recovery as 4 months of remission
Relapse	Return to full symptoms during remission but before recovery; signifies re-emergence of current depressive episode	Residual symptoms during response or remission greatly increase chances of relapse
HRSD: Hamilton Rating Scale for Depression
ACNP: American College of Neuropsychopharmacology
DSM-IV-TR: Diagnostic and statistical manual of mental disorders, 4th ed., text rev.
Source: References 7, 8

Case report: missing the target

Ms. M, age 32, develops depressive symptoms after taking on several new projects in her work as an accountant. At first she notices difficulty falling asleep at night and that she seems tired all day. Typically efficient and neat, she finds herself absently staring at her computer screen while a messy pile of unfinished paperwork accumulates on her desk.

She begins chastising herself for falling behind, yet she feels she will never catch up. When she unexpectedly bursts out sobbing in a board meeting, she knows she needs help.

Ms. M reports that she has been taking fluoxetine, 20 mg/d, for 4 weeks as her primary care physician prescribed, with no improvement. She has no history of depression or other psychiatric illness, is taking no other medication, and has no medical illnesses. Her brother has a history of bipolar disorder.

Initial diagnostic workup includes laboratory tests such as thyroid stimulating hormone, vitamin B₁₂, and folate. All values are within normal limits. Her Hamilton Rating Scale for Depression (HRSD) score is 17, indicating moderate depression.

The psychiatrist increases fluoxetine to 40 mg/d, and after about 3 weeks Ms. M starts feeling better. Her hopelessness lifts, she is more engaged, and her sleep improves, yet she continues to feel sluggish and dazed. Her financial reports contain uncharacteristic errors, and her pace is noticeably slow. Twice her supervisor approaches her about substandard work, then a week later warns that she will lose her job unless she improves.

Barriers to remission. Patient, provider, and health care system barriers prevent patients with major depression from achieving remission (Table 2).³ Patients may feel better with antidepressant therapy but do not recognize and report residual depressive symptoms, such as Ms. M’s fatigue and substandard job performance.

Clinicians also play a role in depression undertreatment. For example, in a study of 239 patients with ≥ 5 depression symptoms,⁹ 28% did not receive treatment consistent with depression management guidelines.

Fava et al¹⁰ suggested the following reasons for depression undertreatment: “… clinicians have partial therapeutic targets, neglect residual symptoms, and equate therapeutic response with full remission.” Others have found that physicians may underdose medications or fail to plan treatment in clear phases.¹¹

Table 2

Barriers to remission during depression treatment

Who and what	Behavior and system problems
Patients	Nonadherence to treatment, underreporting of symptoms, satisfaction with suboptimal outcomes, failure to recognize depressive symptoms, underestimating depression severity, limited access to care, reluctance to see a mental health specialist
Providers	Medication under-dosing, inadequate treatment duration, inaccurate diagnosis, failure to recognize residual symptoms, limited training in interpersonal skills, inadequate time to evaluate and treat depression, failure to consider psychotherapeutic approaches
Health care systems	Limited therapeutic choices, limited number of mental health care visits, restricted access to providers
Source: Reference 3

Relapse risk

Increased risk of relapse is perhaps the greatest cost of undertreated major depression. Patients with residual subsyndromal depressive symptoms relapse five times faster than patients in full remission.¹²

Residual symptoms may be a more powerful relapse predictor than number of past depressive episodes:¹³

• Chronic mood symptoms for ≥ 2 years double the relapse risk.¹⁴
• 50% to 80% of patients in partial remission relapse.¹⁵

In a study of patients in recovery from a major depressive episode, 76% (13 of 17) with residual symptoms relapsed within 15 months, compared with 25% (10 of 40) who completely recovered.¹⁶

Illness course. After a first major depressive episode, 26 patients with residual subsyndromal symptoms showed a more-severe, chronic illness compared with 70 asymptomatic patients:

 

• those with residual symptoms had more depression recurrences, with faster relapse and shorter intervals when they felt well
• subsequent depressive episodes occurred >3 times sooner
• well intervals between depressive episodes were 7 times shorter.¹⁷

The authors noted that “patients recovering from major depressive episodes with residual subsyndromal depression experience very rapid episode relapse and have strikingly more chronic future courses of illness that are characterized by early and more frequent episode relapses and recurrences.”¹⁸ Each major depression recurrence increases the risk of a successive episode.^13,19,20

Treatment resistance. Over time, incomplete remission may contribute to treatment resistance,²¹ although this theory remains untested.

Social health costs

Residual depressive symptoms and impaired psychosocial, interpersonal, and occupational functioning are strongly correlated. In a study of patients who recovered from a major depressive episode, those with residual symptoms scored significantly worse on markers of social performance, relationships, and occupational functioning.⁶

Psychosocial costs. Compared with the general population, persons with subsyndromal depression have poorer health status and job functioning (as did Ms. M), and greater familial discord, financial strain, irritability, restricted activity, and number of days in bed.²² In 635 patients with chronic depression treated for 12 weeks with imipramine or sertraline:

• nonresponders scored lowest in psychosocial functioning
• responders scored in a mid-range
• remitters scored highest—as well or nearly as well as healthy controls did.²³

Occupational costs. Depression leads to workplace absenteeism—twice the rate of nondepressed workers—and less effectiveness. Depressed persons are seven times more likely to be unemployed, employed part-time, or in jobs below their education levels, compared with community samples.²⁴

Medical costs of depressed persons average twice those of the nondepressed,²⁵ and depressed persons use three times as many health care services.²⁶ Depression may increase the risk of:

• cardiac morbidity and mortality
• poor glycemic control in diabetic patients
• HIV progression
• cerebrovascular events
• and overall mortality.

Depression is associated with worse outcomes after myocardial infarction and among nursing home patients, stroke patients, and those with cancer or HIV infection.²¹

How to improve remission rates

To improve remission rates, we recommend that you follow a rational treatment progression and observe established guidelines, as described in the follow-up report on Ms. M:

Case continued: Part way there. Back at the psychiatrist’s office for 30-day medication monitoring, Ms. M reports that increasing her antidepressant has worked—no more crying in meetings or feeling down on herself. She even sleeps better. Her HRSD score is now 10, indicating improvement, though with some residual symptoms.

When the psychiatrist asks about her job performance, Ms. M is surprised to learn that her fatigue and disorganized thoughts might be lingering features of depression. She said she thought she just wasn’t trying hard enough.

Following practice guidelines,²⁷ the psychiatrist increases fluoxetine to 60 mg/d. This higher dosage remains less than the maximum recommended 80 mg/d, and Ms. M has shown partial improvement with fluoxetine.

Patients being treated for depression need adequate follow-up to ensure they are improving. As with Ms. M, encourage patients to describe residual symptoms and functional domains that remain suboptimal. Educate them about the importance of taking antidepressants as prescribed ( Box). If poor response continues, address possible nonadherence.

Use objective assessments. Global, haphazard, or subjective assessments of patient progress can miss important ongoing depressive symptoms. We recommend using patient- or clinician-rated symptom scales to rapidly identify and monitor residual symptoms ( Table 3).

You may wish to design your own questionnaires to elicit easily missed data or symptoms particular to a certain treatment—such as common side effects of the medication a patient is taking. Nurses or other providers in a busy practice can help assess patients between or before doctor visits.

Keep in mind that the common practice of defining treatment response as a 50% reduction in HRSD scores^7,8 leaves many patients with residual depressive symptoms. For example, an HRSD score reduction from 32 to 16 would signify treatment response, but this patient would remain quite depressed.

Box

Table 3

Useful scales to identify and monitor depressive symptoms

Scale	Administration	Features
Hamilton Rating Scale for Depression (21- or 17-item HRSD versions)	15 to 20 minutes, clinician-rated	Focuses on somatic symptoms, excellent reliability, often used to evaluate response to medications
Beck Depression Inventory (BDI versions I or II)	5 to 10 minutes, self-administered	Focuses on behavioral and cognitive elements (somatic symptoms added to BDI-II), good for measuring depression severity, not for depression screening
Zung Self-Rating Depression Scale	5 to 10 minutes, self-administered	Good for screening, not studied as extensively as Hamilton and Beck scales
Montgomery-Asberg Depression Rating Scale	5 to 10 minutes, clinician-rated	10 items, often used in research

 

A Stepwise approach

An expert panel recommends a stepwise approach for patients who respond inadequately to initial antidepressant therapy (Algorithm).²⁷

Re-evaluate the diagnosis. Patients with bipolar disorder or comorbid medical or psychiatric disorders may need medications other than antidepressants. Address concomitant substance abuse, which may interfere with depression treatment. Also exclude or appropriately treat depressive symptoms associated with general medical conditions, such as hypothyroidism.

Optimize dosages. Consider increasing medication dosages as needed until limited by side effects or the drug’s safety profile. Before exceeding an FDA-recommended dosage (Table 4), obtain the patient’s informed consent and document this discussion in the chart.

Consider augmenting or switching. For patients who continue to show partial response, consider combining the initial medication with another antidepressant or augment with another agent, such as lithium, stimulants, thyroid hormone, or even atypical antipsychotics. For patients with no response to optimal dosages of the initial medication after 3 to 4 weeks, try switching to another antidepressant—not necessarily in a different class. One switch within the same class is reasonable.

Some authors emphasize the choice of antidepressant in attaining remission. Although no antidepressant is clearly more efficacious than another, those with fewer side effects (such as selective serotonin reuptake inhibitors vs. tricyclics) may improve adherence.

Numerous trials have shown higher remission rates with serotonin/norepinephrine reuptake inhibitors such as venlafaxine or duloxetine than with other antidepressants.^28-30 This evidence is not universally accepted, however.³¹ Depressive illness probably has a heterogeneous biology, and with greater understanding we may eventually tailor treatment to individual patients’ needs.

Consider psychotherapy or ECT. Patients who do not achieve remission with medication may be candidates for combined treatment with psychotherapy or electroconvulsive therapy (ECT). Life issues—such as family or work stressors—may need to be addressed along with depressive symptoms.

Algorithm A stepwise approach to remission when antidepressant therapy falls short

Table 4

Using common antidepressants for adults with major depression

	FDA-approved maximum dosage*
Antidepressant mg/d	mg/d	(mg/kg/d)	Common side effects at maximum dosage*
SSRIs
Citalopram	80	(1.0)	Nausea, dry mouth, somnolence
Escitalopram	20		Nausea, delayed ejaculation, insomnia
Fluoxetine	80	(1.33)	Nausea, headache, insomnia
Paroxetine	50	(0.83)	Nausea, somnolence, headache
Sertraline	200	(3.33)	Nausea, headache, insomnia
SNRIs
Duloxetine	120		Nausea, dry mouth, fatigue
Venlafaxine	375	(6.25)	Nausea, somnolence, dry mouth
Tricyclics
Amitriptyline	300	(5.0)	Drowsiness, dry mouth, dizziness
Desipramine	300	(5.0)	Same as above
Imipramine	300		Same as above
Nortriptyline	200	(1.67)	Same as above
Others
Bupropion	450	(7.5)	Insomnia, dry mouth, headache
Mirtazapine	45	(0.75)	Somnolence, dry mouth, increased appetite
SSRIs: selective serotonin reuptake inhibitors
SNRIs: serotonin-norepinephrine reuptake inhibitors
* Informed consent discussion and documentation is recommended for dosages that exceed FDA-approved maximums.
Sources: Food and Drug Administration, and Kaplan HI, Sadock B. Kaplan & Sadock’s synopsis of psychiatry (9th ed). Philadelphia: Lippincott Williams & Wilkins, 2002.

Case: monitoring after remission

Ms. M feels back to normal 2 weeks after starting fluoxetine at 60 mg/d. She experienced some transient nausea and headache at this dosage but did not stop the medication because her psychiatrist had told her these side effects might occur.

Ms. M also agrees to short-term psychotherapy to address self-esteem issues that may have contributed to her depressive episode. She soon files the mountain of papers on her desk and corrects erroneous financial statements she has made. Her supervisor is relieved—and so is she.

The psychiatrist schedules monthly medication monitoring and plans to gradually reduce the fluoxetine dosage if depressive symptoms remain in remission for 6 months. Because Ms. M had no past depressive episodes, the medication trial may not need to be extended past 6 months.

Related resources

• McManamy J. McMan’s Depression and Bipolar Web. Treating to remission. http://www.mcmanweb.com/article-181.htm.
• American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (2nd ed.). http://www.psych.org/psych_pract/treatg/pg/Depression2e.book.cfm.
• Stahl S. Essential psychopharmacology: Neuroscientific basis and practical applications (2nd ed.). Cambridge, UK: Cambridge University Presss, 2004, chapters 5-7.

Drug brand names

• Amitriptyline • Elavil, Endep
• Bupropion • Wellbutrin
• Citalopram • Celexa
• Desipramine • Norpramin
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Mirtazapine • Remeron
• Nortriptyline • Pamelor
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosures

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

Dr. Gelenberg receives research grants from Pfizer Inc. and Novartis Pharmaceuticals Corp. He is a consultant or a speaker for Eli Lilly and Co., Pfizer Inc., Bristol-Myers Squibb Co., AstraZeneca Pharmaceuticals, Wyeth, GlaxoSmithKline, and Cyberonics.

Remission is considered the standard of treatment for major depression,^1-4 but many patients fall short of this goal:

• 25% to 50% of those who respond to treatment have residual symptoms⁵
• 60% to 70% respond to treatment, but only 20% to 40% achieve remission.⁶

We offer practical, evidence-based suggestions and resources to help you take more of your patients beyond response to remission and then to recovery (Table 1).^7,8

Table 1

Outcomes in depression: Defining the 4 ‘R’s

Outcome	Definition	Comment
Response	Clinically significant reduction of symptoms	50% reduction in symptoms on psychometric scales may leave severely depressed patients with disabling symptoms
Remission	Depression resolves completely or nearly completely, with return to baseline function	Score of ≤7 on the HRSD used in many studies; ACNP Task Force defines remission by 9 core depression symptoms in DSM-IV-TR
Recovery	Remission lasts for extended time; signifies end of a major depressive episode	ACNP Task Force defines recovery as 4 months of remission
Relapse	Return to full symptoms during remission but before recovery; signifies re-emergence of current depressive episode	Residual symptoms during response or remission greatly increase chances of relapse
HRSD: Hamilton Rating Scale for Depression
ACNP: American College of Neuropsychopharmacology
DSM-IV-TR: Diagnostic and statistical manual of mental disorders, 4th ed., text rev.
Source: References 7, 8

Case report: missing the target

Ms. M, age 32, develops depressive symptoms after taking on several new projects in her work as an accountant. At first she notices difficulty falling asleep at night and that she seems tired all day. Typically efficient and neat, she finds herself absently staring at her computer screen while a messy pile of unfinished paperwork accumulates on her desk.

She begins chastising herself for falling behind, yet she feels she will never catch up. When she unexpectedly bursts out sobbing in a board meeting, she knows she needs help.

Ms. M reports that she has been taking fluoxetine, 20 mg/d, for 4 weeks as her primary care physician prescribed, with no improvement. She has no history of depression or other psychiatric illness, is taking no other medication, and has no medical illnesses. Her brother has a history of bipolar disorder.

Initial diagnostic workup includes laboratory tests such as thyroid stimulating hormone, vitamin B₁₂, and folate. All values are within normal limits. Her Hamilton Rating Scale for Depression (HRSD) score is 17, indicating moderate depression.

The psychiatrist increases fluoxetine to 40 mg/d, and after about 3 weeks Ms. M starts feeling better. Her hopelessness lifts, she is more engaged, and her sleep improves, yet she continues to feel sluggish and dazed. Her financial reports contain uncharacteristic errors, and her pace is noticeably slow. Twice her supervisor approaches her about substandard work, then a week later warns that she will lose her job unless she improves.

Barriers to remission. Patient, provider, and health care system barriers prevent patients with major depression from achieving remission (Table 2).³ Patients may feel better with antidepressant therapy but do not recognize and report residual depressive symptoms, such as Ms. M’s fatigue and substandard job performance.

Clinicians also play a role in depression undertreatment. For example, in a study of 239 patients with ≥ 5 depression symptoms,⁹ 28% did not receive treatment consistent with depression management guidelines.

Fava et al¹⁰ suggested the following reasons for depression undertreatment: “… clinicians have partial therapeutic targets, neglect residual symptoms, and equate therapeutic response with full remission.” Others have found that physicians may underdose medications or fail to plan treatment in clear phases.¹¹

Table 2

Barriers to remission during depression treatment

Who and what	Behavior and system problems
Patients	Nonadherence to treatment, underreporting of symptoms, satisfaction with suboptimal outcomes, failure to recognize depressive symptoms, underestimating depression severity, limited access to care, reluctance to see a mental health specialist
Providers	Medication under-dosing, inadequate treatment duration, inaccurate diagnosis, failure to recognize residual symptoms, limited training in interpersonal skills, inadequate time to evaluate and treat depression, failure to consider psychotherapeutic approaches
Health care systems	Limited therapeutic choices, limited number of mental health care visits, restricted access to providers
Source: Reference 3

Relapse risk

Increased risk of relapse is perhaps the greatest cost of undertreated major depression. Patients with residual subsyndromal depressive symptoms relapse five times faster than patients in full remission.¹²

Residual symptoms may be a more powerful relapse predictor than number of past depressive episodes:¹³

• Chronic mood symptoms for ≥ 2 years double the relapse risk.¹⁴
• 50% to 80% of patients in partial remission relapse.¹⁵

In a study of patients in recovery from a major depressive episode, 76% (13 of 17) with residual symptoms relapsed within 15 months, compared with 25% (10 of 40) who completely recovered.¹⁶

Illness course. After a first major depressive episode, 26 patients with residual subsyndromal symptoms showed a more-severe, chronic illness compared with 70 asymptomatic patients:

 

• those with residual symptoms had more depression recurrences, with faster relapse and shorter intervals when they felt well
• subsequent depressive episodes occurred >3 times sooner
• well intervals between depressive episodes were 7 times shorter.¹⁷

The authors noted that “patients recovering from major depressive episodes with residual subsyndromal depression experience very rapid episode relapse and have strikingly more chronic future courses of illness that are characterized by early and more frequent episode relapses and recurrences.”¹⁸ Each major depression recurrence increases the risk of a successive episode.^13,19,20

Treatment resistance. Over time, incomplete remission may contribute to treatment resistance,²¹ although this theory remains untested.

Social health costs

Residual depressive symptoms and impaired psychosocial, interpersonal, and occupational functioning are strongly correlated. In a study of patients who recovered from a major depressive episode, those with residual symptoms scored significantly worse on markers of social performance, relationships, and occupational functioning.⁶

Psychosocial costs. Compared with the general population, persons with subsyndromal depression have poorer health status and job functioning (as did Ms. M), and greater familial discord, financial strain, irritability, restricted activity, and number of days in bed.²² In 635 patients with chronic depression treated for 12 weeks with imipramine or sertraline:

• nonresponders scored lowest in psychosocial functioning
• responders scored in a mid-range
• remitters scored highest—as well or nearly as well as healthy controls did.²³

Occupational costs. Depression leads to workplace absenteeism—twice the rate of nondepressed workers—and less effectiveness. Depressed persons are seven times more likely to be unemployed, employed part-time, or in jobs below their education levels, compared with community samples.²⁴

Medical costs of depressed persons average twice those of the nondepressed,²⁵ and depressed persons use three times as many health care services.²⁶ Depression may increase the risk of:

• cardiac morbidity and mortality
• poor glycemic control in diabetic patients
• HIV progression
• cerebrovascular events
• and overall mortality.

Depression is associated with worse outcomes after myocardial infarction and among nursing home patients, stroke patients, and those with cancer or HIV infection.²¹

How to improve remission rates

To improve remission rates, we recommend that you follow a rational treatment progression and observe established guidelines, as described in the follow-up report on Ms. M:

Case continued: Part way there. Back at the psychiatrist’s office for 30-day medication monitoring, Ms. M reports that increasing her antidepressant has worked—no more crying in meetings or feeling down on herself. She even sleeps better. Her HRSD score is now 10, indicating improvement, though with some residual symptoms.

When the psychiatrist asks about her job performance, Ms. M is surprised to learn that her fatigue and disorganized thoughts might be lingering features of depression. She said she thought she just wasn’t trying hard enough.

Following practice guidelines,²⁷ the psychiatrist increases fluoxetine to 60 mg/d. This higher dosage remains less than the maximum recommended 80 mg/d, and Ms. M has shown partial improvement with fluoxetine.

Patients being treated for depression need adequate follow-up to ensure they are improving. As with Ms. M, encourage patients to describe residual symptoms and functional domains that remain suboptimal. Educate them about the importance of taking antidepressants as prescribed ( Box). If poor response continues, address possible nonadherence.

Use objective assessments. Global, haphazard, or subjective assessments of patient progress can miss important ongoing depressive symptoms. We recommend using patient- or clinician-rated symptom scales to rapidly identify and monitor residual symptoms ( Table 3).

You may wish to design your own questionnaires to elicit easily missed data or symptoms particular to a certain treatment—such as common side effects of the medication a patient is taking. Nurses or other providers in a busy practice can help assess patients between or before doctor visits.

Keep in mind that the common practice of defining treatment response as a 50% reduction in HRSD scores^7,8 leaves many patients with residual depressive symptoms. For example, an HRSD score reduction from 32 to 16 would signify treatment response, but this patient would remain quite depressed.

Box

Table 3

Useful scales to identify and monitor depressive symptoms

Scale	Administration	Features
Hamilton Rating Scale for Depression (21- or 17-item HRSD versions)	15 to 20 minutes, clinician-rated	Focuses on somatic symptoms, excellent reliability, often used to evaluate response to medications
Beck Depression Inventory (BDI versions I or II)	5 to 10 minutes, self-administered	Focuses on behavioral and cognitive elements (somatic symptoms added to BDI-II), good for measuring depression severity, not for depression screening
Zung Self-Rating Depression Scale	5 to 10 minutes, self-administered	Good for screening, not studied as extensively as Hamilton and Beck scales
Montgomery-Asberg Depression Rating Scale	5 to 10 minutes, clinician-rated	10 items, often used in research

 

A Stepwise approach

An expert panel recommends a stepwise approach for patients who respond inadequately to initial antidepressant therapy (Algorithm).²⁷

Re-evaluate the diagnosis. Patients with bipolar disorder or comorbid medical or psychiatric disorders may need medications other than antidepressants. Address concomitant substance abuse, which may interfere with depression treatment. Also exclude or appropriately treat depressive symptoms associated with general medical conditions, such as hypothyroidism.

Optimize dosages. Consider increasing medication dosages as needed until limited by side effects or the drug’s safety profile. Before exceeding an FDA-recommended dosage (Table 4), obtain the patient’s informed consent and document this discussion in the chart.

Consider augmenting or switching. For patients who continue to show partial response, consider combining the initial medication with another antidepressant or augment with another agent, such as lithium, stimulants, thyroid hormone, or even atypical antipsychotics. For patients with no response to optimal dosages of the initial medication after 3 to 4 weeks, try switching to another antidepressant—not necessarily in a different class. One switch within the same class is reasonable.

Some authors emphasize the choice of antidepressant in attaining remission. Although no antidepressant is clearly more efficacious than another, those with fewer side effects (such as selective serotonin reuptake inhibitors vs. tricyclics) may improve adherence.

Numerous trials have shown higher remission rates with serotonin/norepinephrine reuptake inhibitors such as venlafaxine or duloxetine than with other antidepressants.^28-30 This evidence is not universally accepted, however.³¹ Depressive illness probably has a heterogeneous biology, and with greater understanding we may eventually tailor treatment to individual patients’ needs.

Consider psychotherapy or ECT. Patients who do not achieve remission with medication may be candidates for combined treatment with psychotherapy or electroconvulsive therapy (ECT). Life issues—such as family or work stressors—may need to be addressed along with depressive symptoms.

Algorithm A stepwise approach to remission when antidepressant therapy falls short

Table 4

Using common antidepressants for adults with major depression

	FDA-approved maximum dosage*
Antidepressant mg/d	mg/d	(mg/kg/d)	Common side effects at maximum dosage*
SSRIs
Citalopram	80	(1.0)	Nausea, dry mouth, somnolence
Escitalopram	20		Nausea, delayed ejaculation, insomnia
Fluoxetine	80	(1.33)	Nausea, headache, insomnia
Paroxetine	50	(0.83)	Nausea, somnolence, headache
Sertraline	200	(3.33)	Nausea, headache, insomnia
SNRIs
Duloxetine	120		Nausea, dry mouth, fatigue
Venlafaxine	375	(6.25)	Nausea, somnolence, dry mouth
Tricyclics
Amitriptyline	300	(5.0)	Drowsiness, dry mouth, dizziness
Desipramine	300	(5.0)	Same as above
Imipramine	300		Same as above
Nortriptyline	200	(1.67)	Same as above
Others
Bupropion	450	(7.5)	Insomnia, dry mouth, headache
Mirtazapine	45	(0.75)	Somnolence, dry mouth, increased appetite
SSRIs: selective serotonin reuptake inhibitors
SNRIs: serotonin-norepinephrine reuptake inhibitors
* Informed consent discussion and documentation is recommended for dosages that exceed FDA-approved maximums.
Sources: Food and Drug Administration, and Kaplan HI, Sadock B. Kaplan & Sadock’s synopsis of psychiatry (9th ed). Philadelphia: Lippincott Williams & Wilkins, 2002.

Case: monitoring after remission

Ms. M feels back to normal 2 weeks after starting fluoxetine at 60 mg/d. She experienced some transient nausea and headache at this dosage but did not stop the medication because her psychiatrist had told her these side effects might occur.

Ms. M also agrees to short-term psychotherapy to address self-esteem issues that may have contributed to her depressive episode. She soon files the mountain of papers on her desk and corrects erroneous financial statements she has made. Her supervisor is relieved—and so is she.

The psychiatrist schedules monthly medication monitoring and plans to gradually reduce the fluoxetine dosage if depressive symptoms remain in remission for 6 months. Because Ms. M had no past depressive episodes, the medication trial may not need to be extended past 6 months.

Related resources

• McManamy J. McMan’s Depression and Bipolar Web. Treating to remission. http://www.mcmanweb.com/article-181.htm.
• American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (2nd ed.). http://www.psych.org/psych_pract/treatg/pg/Depression2e.book.cfm.
• Stahl S. Essential psychopharmacology: Neuroscientific basis and practical applications (2nd ed.). Cambridge, UK: Cambridge University Presss, 2004, chapters 5-7.

Drug brand names

• Amitriptyline • Elavil, Endep
• Bupropion • Wellbutrin
• Citalopram • Celexa
• Desipramine • Norpramin
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Mirtazapine • Remeron
• Nortriptyline • Pamelor
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosures

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

Dr. Gelenberg receives research grants from Pfizer Inc. and Novartis Pharmaceuticals Corp. He is a consultant or a speaker for Eli Lilly and Co., Pfizer Inc., Bristol-Myers Squibb Co., AstraZeneca Pharmaceuticals, Wyeth, GlaxoSmithKline, and Cyberonics.

Remission is considered the standard of treatment for major depression,^1-4 but many patients fall short of this goal:

• 25% to 50% of those who respond to treatment have residual symptoms⁵
• 60% to 70% respond to treatment, but only 20% to 40% achieve remission.⁶

We offer practical, evidence-based suggestions and resources to help you take more of your patients beyond response to remission and then to recovery (Table 1).^7,8

Table 1

Outcomes in depression: Defining the 4 ‘R’s

Outcome	Definition	Comment
Response	Clinically significant reduction of symptoms	50% reduction in symptoms on psychometric scales may leave severely depressed patients with disabling symptoms
Remission	Depression resolves completely or nearly completely, with return to baseline function	Score of ≤7 on the HRSD used in many studies; ACNP Task Force defines remission by 9 core depression symptoms in DSM-IV-TR
Recovery	Remission lasts for extended time; signifies end of a major depressive episode	ACNP Task Force defines recovery as 4 months of remission
Relapse	Return to full symptoms during remission but before recovery; signifies re-emergence of current depressive episode	Residual symptoms during response or remission greatly increase chances of relapse
HRSD: Hamilton Rating Scale for Depression
ACNP: American College of Neuropsychopharmacology
DSM-IV-TR: Diagnostic and statistical manual of mental disorders, 4th ed., text rev.
Source: References 7, 8

Case report: missing the target

Ms. M, age 32, develops depressive symptoms after taking on several new projects in her work as an accountant. At first she notices difficulty falling asleep at night and that she seems tired all day. Typically efficient and neat, she finds herself absently staring at her computer screen while a messy pile of unfinished paperwork accumulates on her desk.

She begins chastising herself for falling behind, yet she feels she will never catch up. When she unexpectedly bursts out sobbing in a board meeting, she knows she needs help.

Ms. M reports that she has been taking fluoxetine, 20 mg/d, for 4 weeks as her primary care physician prescribed, with no improvement. She has no history of depression or other psychiatric illness, is taking no other medication, and has no medical illnesses. Her brother has a history of bipolar disorder.

Initial diagnostic workup includes laboratory tests such as thyroid stimulating hormone, vitamin B₁₂, and folate. All values are within normal limits. Her Hamilton Rating Scale for Depression (HRSD) score is 17, indicating moderate depression.

The psychiatrist increases fluoxetine to 40 mg/d, and after about 3 weeks Ms. M starts feeling better. Her hopelessness lifts, she is more engaged, and her sleep improves, yet she continues to feel sluggish and dazed. Her financial reports contain uncharacteristic errors, and her pace is noticeably slow. Twice her supervisor approaches her about substandard work, then a week later warns that she will lose her job unless she improves.

Barriers to remission. Patient, provider, and health care system barriers prevent patients with major depression from achieving remission (Table 2).³ Patients may feel better with antidepressant therapy but do not recognize and report residual depressive symptoms, such as Ms. M’s fatigue and substandard job performance.

Clinicians also play a role in depression undertreatment. For example, in a study of 239 patients with ≥ 5 depression symptoms,⁹ 28% did not receive treatment consistent with depression management guidelines.

Fava et al¹⁰ suggested the following reasons for depression undertreatment: “… clinicians have partial therapeutic targets, neglect residual symptoms, and equate therapeutic response with full remission.” Others have found that physicians may underdose medications or fail to plan treatment in clear phases.¹¹

Table 2

Barriers to remission during depression treatment

Who and what	Behavior and system problems
Patients	Nonadherence to treatment, underreporting of symptoms, satisfaction with suboptimal outcomes, failure to recognize depressive symptoms, underestimating depression severity, limited access to care, reluctance to see a mental health specialist
Providers	Medication under-dosing, inadequate treatment duration, inaccurate diagnosis, failure to recognize residual symptoms, limited training in interpersonal skills, inadequate time to evaluate and treat depression, failure to consider psychotherapeutic approaches
Health care systems	Limited therapeutic choices, limited number of mental health care visits, restricted access to providers
Source: Reference 3

Relapse risk

Increased risk of relapse is perhaps the greatest cost of undertreated major depression. Patients with residual subsyndromal depressive symptoms relapse five times faster than patients in full remission.¹²

Residual symptoms may be a more powerful relapse predictor than number of past depressive episodes:¹³

• Chronic mood symptoms for ≥ 2 years double the relapse risk.¹⁴
• 50% to 80% of patients in partial remission relapse.¹⁵

In a study of patients in recovery from a major depressive episode, 76% (13 of 17) with residual symptoms relapsed within 15 months, compared with 25% (10 of 40) who completely recovered.¹⁶

Illness course. After a first major depressive episode, 26 patients with residual subsyndromal symptoms showed a more-severe, chronic illness compared with 70 asymptomatic patients:

 

• those with residual symptoms had more depression recurrences, with faster relapse and shorter intervals when they felt well
• subsequent depressive episodes occurred >3 times sooner
• well intervals between depressive episodes were 7 times shorter.¹⁷

The authors noted that “patients recovering from major depressive episodes with residual subsyndromal depression experience very rapid episode relapse and have strikingly more chronic future courses of illness that are characterized by early and more frequent episode relapses and recurrences.”¹⁸ Each major depression recurrence increases the risk of a successive episode.^13,19,20

Treatment resistance. Over time, incomplete remission may contribute to treatment resistance,²¹ although this theory remains untested.

Social health costs

Residual depressive symptoms and impaired psychosocial, interpersonal, and occupational functioning are strongly correlated. In a study of patients who recovered from a major depressive episode, those with residual symptoms scored significantly worse on markers of social performance, relationships, and occupational functioning.⁶

Psychosocial costs. Compared with the general population, persons with subsyndromal depression have poorer health status and job functioning (as did Ms. M), and greater familial discord, financial strain, irritability, restricted activity, and number of days in bed.²² In 635 patients with chronic depression treated for 12 weeks with imipramine or sertraline:

• nonresponders scored lowest in psychosocial functioning
• responders scored in a mid-range
• remitters scored highest—as well or nearly as well as healthy controls did.²³

Occupational costs. Depression leads to workplace absenteeism—twice the rate of nondepressed workers—and less effectiveness. Depressed persons are seven times more likely to be unemployed, employed part-time, or in jobs below their education levels, compared with community samples.²⁴

Medical costs of depressed persons average twice those of the nondepressed,²⁵ and depressed persons use three times as many health care services.²⁶ Depression may increase the risk of:

• cardiac morbidity and mortality
• poor glycemic control in diabetic patients
• HIV progression
• cerebrovascular events
• and overall mortality.

Depression is associated with worse outcomes after myocardial infarction and among nursing home patients, stroke patients, and those with cancer or HIV infection.²¹

How to improve remission rates

To improve remission rates, we recommend that you follow a rational treatment progression and observe established guidelines, as described in the follow-up report on Ms. M:

Case continued: Part way there. Back at the psychiatrist’s office for 30-day medication monitoring, Ms. M reports that increasing her antidepressant has worked—no more crying in meetings or feeling down on herself. She even sleeps better. Her HRSD score is now 10, indicating improvement, though with some residual symptoms.

When the psychiatrist asks about her job performance, Ms. M is surprised to learn that her fatigue and disorganized thoughts might be lingering features of depression. She said she thought she just wasn’t trying hard enough.

Following practice guidelines,²⁷ the psychiatrist increases fluoxetine to 60 mg/d. This higher dosage remains less than the maximum recommended 80 mg/d, and Ms. M has shown partial improvement with fluoxetine.

Patients being treated for depression need adequate follow-up to ensure they are improving. As with Ms. M, encourage patients to describe residual symptoms and functional domains that remain suboptimal. Educate them about the importance of taking antidepressants as prescribed ( Box). If poor response continues, address possible nonadherence.

Use objective assessments. Global, haphazard, or subjective assessments of patient progress can miss important ongoing depressive symptoms. We recommend using patient- or clinician-rated symptom scales to rapidly identify and monitor residual symptoms ( Table 3).

You may wish to design your own questionnaires to elicit easily missed data or symptoms particular to a certain treatment—such as common side effects of the medication a patient is taking. Nurses or other providers in a busy practice can help assess patients between or before doctor visits.

Keep in mind that the common practice of defining treatment response as a 50% reduction in HRSD scores^7,8 leaves many patients with residual depressive symptoms. For example, an HRSD score reduction from 32 to 16 would signify treatment response, but this patient would remain quite depressed.

Box

Table 3

Useful scales to identify and monitor depressive symptoms

Scale	Administration	Features
Hamilton Rating Scale for Depression (21- or 17-item HRSD versions)	15 to 20 minutes, clinician-rated	Focuses on somatic symptoms, excellent reliability, often used to evaluate response to medications
Beck Depression Inventory (BDI versions I or II)	5 to 10 minutes, self-administered	Focuses on behavioral and cognitive elements (somatic symptoms added to BDI-II), good for measuring depression severity, not for depression screening
Zung Self-Rating Depression Scale	5 to 10 minutes, self-administered	Good for screening, not studied as extensively as Hamilton and Beck scales
Montgomery-Asberg Depression Rating Scale	5 to 10 minutes, clinician-rated	10 items, often used in research

 

A Stepwise approach

An expert panel recommends a stepwise approach for patients who respond inadequately to initial antidepressant therapy (Algorithm).²⁷

Re-evaluate the diagnosis. Patients with bipolar disorder or comorbid medical or psychiatric disorders may need medications other than antidepressants. Address concomitant substance abuse, which may interfere with depression treatment. Also exclude or appropriately treat depressive symptoms associated with general medical conditions, such as hypothyroidism.

Optimize dosages. Consider increasing medication dosages as needed until limited by side effects or the drug’s safety profile. Before exceeding an FDA-recommended dosage (Table 4), obtain the patient’s informed consent and document this discussion in the chart.

Consider augmenting or switching. For patients who continue to show partial response, consider combining the initial medication with another antidepressant or augment with another agent, such as lithium, stimulants, thyroid hormone, or even atypical antipsychotics. For patients with no response to optimal dosages of the initial medication after 3 to 4 weeks, try switching to another antidepressant—not necessarily in a different class. One switch within the same class is reasonable.

Some authors emphasize the choice of antidepressant in attaining remission. Although no antidepressant is clearly more efficacious than another, those with fewer side effects (such as selective serotonin reuptake inhibitors vs. tricyclics) may improve adherence.

Numerous trials have shown higher remission rates with serotonin/norepinephrine reuptake inhibitors such as venlafaxine or duloxetine than with other antidepressants.^28-30 This evidence is not universally accepted, however.³¹ Depressive illness probably has a heterogeneous biology, and with greater understanding we may eventually tailor treatment to individual patients’ needs.

Consider psychotherapy or ECT. Patients who do not achieve remission with medication may be candidates for combined treatment with psychotherapy or electroconvulsive therapy (ECT). Life issues—such as family or work stressors—may need to be addressed along with depressive symptoms.

Algorithm A stepwise approach to remission when antidepressant therapy falls short

Table 4

Using common antidepressants for adults with major depression

	FDA-approved maximum dosage*
Antidepressant mg/d	mg/d	(mg/kg/d)	Common side effects at maximum dosage*
SSRIs
Citalopram	80	(1.0)	Nausea, dry mouth, somnolence
Escitalopram	20		Nausea, delayed ejaculation, insomnia
Fluoxetine	80	(1.33)	Nausea, headache, insomnia
Paroxetine	50	(0.83)	Nausea, somnolence, headache
Sertraline	200	(3.33)	Nausea, headache, insomnia
SNRIs
Duloxetine	120		Nausea, dry mouth, fatigue
Venlafaxine	375	(6.25)	Nausea, somnolence, dry mouth
Tricyclics
Amitriptyline	300	(5.0)	Drowsiness, dry mouth, dizziness
Desipramine	300	(5.0)	Same as above
Imipramine	300		Same as above
Nortriptyline	200	(1.67)	Same as above
Others
Bupropion	450	(7.5)	Insomnia, dry mouth, headache
Mirtazapine	45	(0.75)	Somnolence, dry mouth, increased appetite
SSRIs: selective serotonin reuptake inhibitors
SNRIs: serotonin-norepinephrine reuptake inhibitors
* Informed consent discussion and documentation is recommended for dosages that exceed FDA-approved maximums.
Sources: Food and Drug Administration, and Kaplan HI, Sadock B. Kaplan & Sadock’s synopsis of psychiatry (9th ed). Philadelphia: Lippincott Williams & Wilkins, 2002.

Case: monitoring after remission

Ms. M feels back to normal 2 weeks after starting fluoxetine at 60 mg/d. She experienced some transient nausea and headache at this dosage but did not stop the medication because her psychiatrist had told her these side effects might occur.

Ms. M also agrees to short-term psychotherapy to address self-esteem issues that may have contributed to her depressive episode. She soon files the mountain of papers on her desk and corrects erroneous financial statements she has made. Her supervisor is relieved—and so is she.

The psychiatrist schedules monthly medication monitoring and plans to gradually reduce the fluoxetine dosage if depressive symptoms remain in remission for 6 months. Because Ms. M had no past depressive episodes, the medication trial may not need to be extended past 6 months.

Related resources

• McManamy J. McMan’s Depression and Bipolar Web. Treating to remission. http://www.mcmanweb.com/article-181.htm.
• American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (2nd ed.). http://www.psych.org/psych_pract/treatg/pg/Depression2e.book.cfm.
• Stahl S. Essential psychopharmacology: Neuroscientific basis and practical applications (2nd ed.). Cambridge, UK: Cambridge University Presss, 2004, chapters 5-7.

Drug brand names

• Amitriptyline • Elavil, Endep
• Bupropion • Wellbutrin
• Citalopram • Celexa
• Desipramine • Norpramin
• Duloxetine • Cymbalta
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Imipramine • Tofranil
• Mirtazapine • Remeron
• Nortriptyline • Pamelor
• Paroxetine • Paxil
• Sertraline • Zoloft
• Venlafaxine • Effexor

Disclosures

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

Dr. Gelenberg receives research grants from Pfizer Inc. and Novartis Pharmaceuticals Corp. He is a consultant or a speaker for Eli Lilly and Co., Pfizer Inc., Bristol-Myers Squibb Co., AstraZeneca Pharmaceuticals, Wyeth, GlaxoSmithKline, and Cyberonics.

Therapists once believed trauma survivors required years of treatment, yet we now know that relatively brief cognitive-behavioral interventions can yield long-term gains in psychosocial and psychological function.¹ Many psychiatric patients meet diagnostic criteria for posttraumatic stress disorder (PTSD), including:

• 33% of women experiencing sexual assault²
  
• 30% of male war veterans³
  
• 30% of the 5 million U.S. children exposed to trauma each year⁴(Box).⁵
  

We offer recommendations on how to prepare traumatized adults and children for cognitive-behavioral therapy (CBT) and discuss four tested models—prolonged exposure (PE), cognitive processing therapy (CPT), eye movement desensitization and reprocessing (EMDR), and stress inoculation training (SIT)—that psychiatrists may find effective when treating PTSD.

Box

Preparing trauma patients for CBT

Before starting CBT, evaluate patients thoroughly to determine if they meet DSM-IV-TR full or subthreshold criteria (

Not all patients are ready to confront their traumas when they arrive for psychiatric evaluation. For example:

• For a domestic violence victim, the therapist’s priority is to help begin safety planning and to address trauma after the patient is out of danger.
  
• Patients with poor coping skills and little social support often find it difficult to begin trauma treatment. For them, focus on building skills to offset the distress that accompanies trauma therapy.
  
• Patients with PTSD and substance abuse may benefit more from CBT if the therapist first addresses the substance dependence.
  

Seeking Safety⁶ is a recent cognitive therapy designed to treat PTSD and substance dependence concurrently. Initial applications appear promising, but its efficacy with various trauma groups needs further evaluation.

CBT core concepts

CBT therapists typically help patients identify and evaluate disruptive cognitions, which helps them challenge and modify emotions, thoughts, and behaviors related to traumatic experience(s). Other CBT components include:

• educating patients about PTSD
  
• exposing them to the traumatic material
  
• challenging and modifying their disruptive thoughts.
  

Some CBT outcome studies⁷ suggest that linking exposure with direct cognitive challenging may not be necessary. Patients who are exposed to the traumatic experience through mental imagery but are not challenged on their cognitive distortions still report more-adaptive thought patterns after treatment.

International Society for Traumatic Stress Studies (ISTSS) practice guidelines for PTSD⁸ include assessment and treatment suggestions (see Related resources). Whatever the model, CBT appears help patients manage their distress, not only during treatment but up to 5 years after completing therapy.⁹

Which CBT? Comparison studies have shown all four CBT interventions to be effective in treating PTSD, although initial trend data suggest that patients with:

• fear-based PTSD may do better with PE or EMDR
  
• PTSD-related guilt, anger, or other cognitive distortions may benefit more from CPT.
  

Because CPT’s written worksheets could be difficult for illiterate patients, an exposure-based treatment may work better in those cases. SIT can reduce some PTSD symptoms but has not performed as well as other therapies in comparison studies. It is most useful to help patients build coping skills before starting other treatments.

If you refer a patient, make sure the therapist is trained in CBT interventions and in working with trauma patients. To be effective, the therapist must be skilled in handling trauma processing work, suicidal thoughts/intent, and comorbid personality disorders.

Prolonged exposure

PE (Table 1) is typically conducted in 9 to 12 sessions lasting 90 minutes each and has been used to treat PTSD after sexual assault, combat, sexual abuse, and natural disasters. Although frequently offered in individual sessions, group PE has also been found to be effective.¹⁰

After educating the patient about PTSD and the treatment rationale, the therapist repeatedly asks the patient to describe the traumatic event as if it were occurring. During 45 to 60 minutes of this exposure, the therapist frequently asks the patient to rate his or her distress. This identifies “hot spots” in the account that need to be repeated. The therapist does not necessarily challenge distorted cognitions about the event (such as “I am to blame for the rape” or “No one can be trusted”).

 

Researchers hypothesize that exposing a PTSD patient to traumatic memories engages his or her brain’s pathologic “fear network,” which triggers an excessive fear response to non-threatening stimuli. Continued exposure allows the patient to habituate to this network, with subsequent extinction of fear and anxiety reactions. Foa et al¹¹ found that mentally re-experiencing a traumatic event helps patients organize memory cues about it, which encourages cognitive restructuring of the trauma.

PE has been shown to enhance the trauma survivor’s self-control and personal competence and to decrease generalization of fear to non-assault stimuli.¹² For example, many combat veterans report fear of situations—such as going to the beach or into the woods—that bring back memories of traumatic events. Their fears may keep them from enjoying a walk in the park or family vacations.

Through in vivo exposure, these patients can face associations between environmental cues and their trauma. As they learn to modify the fears associated with these cues, their personal and social functioning improves.

PE can be successful for those who complete therapy, but it has a relatively high drop-out rate, reported as 8%¹³ to 41%.¹⁴ The pain of continually reliving a traumatic event probably causes many patients to quit. To reduce drop-out rates, many therapists combine PE with cognitive restructuring or other techniques that help build patients’ coping skills.

Table 1

Using prolonged exposure therapy to treat PTSD, session by session

Session	Content
1	Education
	Treatment rationale
	Review of PTSD symptom response
	Introduce breathing retraining
2	Review handout, ‘Common reactions to trauma’
	Introduce Subjective Units of Distress
	Create fear hierarchy for in vivo exposures
3	Provide rationale for imaginal exposure
	Conduct imaginal exposure
	Assign in vivo exposure homework
4 to 8	Conduct imaginal exposure
	Discuss in vivo exposures
9 or 9 to 12	Conduct imaginal exposure
	Suggest continued in vivo exercises
	Termination
Source: Foa EB, Rothbaum BO. Treating the trauma of rape: cognitive behavioral therapy for PTSD. New York: Guilford Press, 1998.

Cognitive processing therapy

CPT (Table 2) was created as a protocol to treat PTSD and related symptoms in rape survivors.⁷ Sessions can be group, individual, or combined, depending on the needs and resources of the patients and clinic.

Originally, CPT contained 12 weekly sessions, although versions up to 17 weeks have been developed for adult survivors of child sexual abuse, domestic violence survivors, and war veterans.¹⁵ Sessions can be added or adapted to address each population’s type of traumatic experience (such as developmental impairment of sexual abuse survivors).

CPT is based on information processing theory, which suggests that as people access a traumatic memory, they experience and extinguish emotions attached to the event. Guided by the therapist, the patient identifies and challenges distortions the trauma created in three cognition domains: the self, others, and the world. Patients learn to change or replace these cognitive distortions—which therapists often call “stuck points” or “rules”—with more-adaptive, healthier beliefs.

Common byproducts of trauma are feeling out of control or hopeless. Thus, CPT focuses on personal safety, trust, power/control, esteem, and intimacy within each of the three domains. Modules on assertiveness, communication, and social support can also be added.

Although CPT is being adapted for populations other than rape survivors, comparison studies are needed to determine if it is as effective as other CBT therapies for these groups.

Table 2

Using cognitive processing therapy to treat PTSD, session by session

Session	Content
1	Education
	Review of symptoms
	Introduce ‘stuck points’/rules
	Write impact of event statement (IES)
2	Review IES
	Identify stuck points
	Introduce A-B-C sheets
3	Review A-B-C sheets
	Assign writing of traumatic account
4	Read traumatic account
	Identify stuck points
	Rewrite the account
5	Read rewritten account
	Identify stuck points
	Introduce challenging questions sheet (CQS)
	Assign writing of next-most traumatic incident and CQS
6	Review CQS
	Assign review of faulty thinking patterns (FTP)
7	Review FTP
	Assign safety module and challenging beliefs worksheets (CBW) on safety
8	Review CBWs on safety
	Assign module on trust
9	Review CBWs on trust
	Assign module on power/control
10	Review CBWs on power/control
	Assign module on esteem
11	Review CBWs on esteem
	Assign module on intimacy
	Rewrite IES
12	Review CBWs on intimacy
	Read both impact statements
	Address remaining areas of concern
	Termination
Source: Resick PA, Schnicke MK Cognitive processing therapy for rape victims: a treatment manual. Newbury Park, CA: Sage, 1993.

Eye movement desensitization and reprocessing

Like other PTSD treatments, EMDR is based on an “accelerated information-processing” model.¹⁶ Because it also incorporates dissociation and nonverbal representation of traumas (such as visual memories), EMDR is often classified as a cognitive treatment, although ISTSS practice guidelines⁸ present it as a separate category.

EMDR protocols call for the trauma patient to watch rapid, rhythmic movements of the therapist’s hand or a set of lights to distract attention from the stress he or she feels when visualizing the traumatic event. The original technique—developed by Francine Shapiro, PhD—is based on the observation that persons with PTSD often have disrupted rapid eye-movement sleep. In theory, inducing eye movements inhibits stress, allowing patients to more freely access their memory networks and process disturbances. Subsequently, Dr. Shapiro has suggested that using other auditory cues or hand taps may be as effective as eye movements.¹⁶

 

EMDR is often conducted in 12 to 15 sessions, although some studies report positive changes after 3 to 6 sessions. After obtaining a patient history, establishing rapport, and explaining the treatment, the therapist asks the patient to identify:

• visual images of the trauma
  
• his or her affective and physiologic responses to the trauma
  
• negative self-representations the trauma created
  
• positive, alternate self-representations.
  

The therapist then asks the patient to focus on an image most proximal to the trauma and associated affective and biological reactions. While the patient is thinking, the therapist introduces the distraction stimulation. After a set number of stimulations—such as 20 bilateral eye movements—the therapist asks the patient to “let go” of the memory and discusses any new reactions to the trauma. As patients become less distressed in response to the trauma, they are asked to focus increasingly on alternate positive cognitions while they imagine the trauma.

EMDR has been effective in treating male war veterans, rape victims, and other trauma groups.¹⁷ Initial dismantling studies suggest that eye movements (or other distracting cues) might not be essential for trauma reprocessing, calling into question the mechanisms thought to create change in EMDR. Studies with larger samples comparing EMDR with other CBT models are needed to assess EMDR’s efficacy for trauma survivors.¹⁷

Stress inoculation training

SIT was designed by Meichenbaum¹⁸ (Table 3) to treat anxiety and stress and was adapted for use with trauma survivors. It appears most effective in relieving fear, anxiety, and depressive symptoms associated with traumatic experiences. SIT includes education, muscle relaxation training, breathing retraining, covert modeling, role-playing, guided self-dialog, and thought stopping. Therapists often teach these skills to patients in modules that build on each other.

For example, a patient might receive relaxation training while role-playing a difficult scenario she may face in the future. This helps her learn to remain calm in anxiety-provoking situations.

Unlike PE, SIT does not directly ask patients to recount their traumatic memories, although exposure may be indirect (such as during role-playing exercises). Its purpose is to give patients new skills to manage their anxiety, which in turn decreases PTSD symptoms.

Studies suggest that PE is more effective than SIT alone or SIT/PE combined.¹³ Thus, instead of using SIT as a trauma-focused treatment, some therapists find it useful to help patients gain coping skills before beginning other trauma treatments.

Table 3

Where to learn more about cognitive therapies for PTSD

CBT model	PTSD related to…	Resources
Prolonged exposure	Combat experience, sexual assault, childhood abuse, motor vehicle accidents	Foa EB, Rothbaum BO. Treating the trauma of rape: Cognitive-behavioral therapy for PTSD. New York: Guilford Press; 1998
Cognitive processing	Sexual assault, childhood abuse, incarceration (of adolescents)	Resick P, Schnicke M. Cognitive processing therapy for rape victims: a treatment manual. Newbury Park, CA: Sage Publications; 1996
EMDR	Combat experience, sexual assault, civilian disasters (for children or adults)	Shapiro F. Eye movement desensitization and reprocessing: basic principles, protocols, and procedures (2nd ed). New York: Guilford Press; 2001
		EMDR Institute, Inc. Available at: http://www.emdr.com
Stress inoculation training	Sexual and physical assault, motor vehicle accidents	Meichenbaum D. Stress inoculation training for coping with stressors. Available at: http://www.apa.org/divisions/div12/rev_est/sit_stress.html
EMDR: Eye movement desensitization and reprocessing

Related resources

• International Society for Traumatic Stress Studies. www.istss.org.
  
• Foa EB, Keane TM, Friedman MJ. Effective treatments for PTSD. New York: Guilford Press; 2000.
  

Disclosures

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

Therapists once believed trauma survivors required years of treatment, yet we now know that relatively brief cognitive-behavioral interventions can yield long-term gains in psychosocial and psychological function.¹ Many psychiatric patients meet diagnostic criteria for posttraumatic stress disorder (PTSD), including:

• 33% of women experiencing sexual assault²
  
• 30% of male war veterans³
  
• 30% of the 5 million U.S. children exposed to trauma each year⁴(Box).⁵
  

We offer recommendations on how to prepare traumatized adults and children for cognitive-behavioral therapy (CBT) and discuss four tested models—prolonged exposure (PE), cognitive processing therapy (CPT), eye movement desensitization and reprocessing (EMDR), and stress inoculation training (SIT)—that psychiatrists may find effective when treating PTSD.

Box

Preparing trauma patients for CBT

Before starting CBT, evaluate patients thoroughly to determine if they meet DSM-IV-TR full or subthreshold criteria (

Not all patients are ready to confront their traumas when they arrive for psychiatric evaluation. For example:

• For a domestic violence victim, the therapist’s priority is to help begin safety planning and to address trauma after the patient is out of danger.
  
• Patients with poor coping skills and little social support often find it difficult to begin trauma treatment. For them, focus on building skills to offset the distress that accompanies trauma therapy.
  
• Patients with PTSD and substance abuse may benefit more from CBT if the therapist first addresses the substance dependence.
  

Seeking Safety⁶ is a recent cognitive therapy designed to treat PTSD and substance dependence concurrently. Initial applications appear promising, but its efficacy with various trauma groups needs further evaluation.

CBT core concepts

CBT therapists typically help patients identify and evaluate disruptive cognitions, which helps them challenge and modify emotions, thoughts, and behaviors related to traumatic experience(s). Other CBT components include:

• educating patients about PTSD
  
• exposing them to the traumatic material
  
• challenging and modifying their disruptive thoughts.
  

Some CBT outcome studies⁷ suggest that linking exposure with direct cognitive challenging may not be necessary. Patients who are exposed to the traumatic experience through mental imagery but are not challenged on their cognitive distortions still report more-adaptive thought patterns after treatment.

International Society for Traumatic Stress Studies (ISTSS) practice guidelines for PTSD⁸ include assessment and treatment suggestions (see Related resources). Whatever the model, CBT appears help patients manage their distress, not only during treatment but up to 5 years after completing therapy.⁹

Which CBT? Comparison studies have shown all four CBT interventions to be effective in treating PTSD, although initial trend data suggest that patients with:

• fear-based PTSD may do better with PE or EMDR
  
• PTSD-related guilt, anger, or other cognitive distortions may benefit more from CPT.
  

Because CPT’s written worksheets could be difficult for illiterate patients, an exposure-based treatment may work better in those cases. SIT can reduce some PTSD symptoms but has not performed as well as other therapies in comparison studies. It is most useful to help patients build coping skills before starting other treatments.

If you refer a patient, make sure the therapist is trained in CBT interventions and in working with trauma patients. To be effective, the therapist must be skilled in handling trauma processing work, suicidal thoughts/intent, and comorbid personality disorders.

Prolonged exposure

PE (Table 1) is typically conducted in 9 to 12 sessions lasting 90 minutes each and has been used to treat PTSD after sexual assault, combat, sexual abuse, and natural disasters. Although frequently offered in individual sessions, group PE has also been found to be effective.¹⁰

After educating the patient about PTSD and the treatment rationale, the therapist repeatedly asks the patient to describe the traumatic event as if it were occurring. During 45 to 60 minutes of this exposure, the therapist frequently asks the patient to rate his or her distress. This identifies “hot spots” in the account that need to be repeated. The therapist does not necessarily challenge distorted cognitions about the event (such as “I am to blame for the rape” or “No one can be trusted”).

 

Researchers hypothesize that exposing a PTSD patient to traumatic memories engages his or her brain’s pathologic “fear network,” which triggers an excessive fear response to non-threatening stimuli. Continued exposure allows the patient to habituate to this network, with subsequent extinction of fear and anxiety reactions. Foa et al¹¹ found that mentally re-experiencing a traumatic event helps patients organize memory cues about it, which encourages cognitive restructuring of the trauma.

PE has been shown to enhance the trauma survivor’s self-control and personal competence and to decrease generalization of fear to non-assault stimuli.¹² For example, many combat veterans report fear of situations—such as going to the beach or into the woods—that bring back memories of traumatic events. Their fears may keep them from enjoying a walk in the park or family vacations.

Through in vivo exposure, these patients can face associations between environmental cues and their trauma. As they learn to modify the fears associated with these cues, their personal and social functioning improves.

PE can be successful for those who complete therapy, but it has a relatively high drop-out rate, reported as 8%¹³ to 41%.¹⁴ The pain of continually reliving a traumatic event probably causes many patients to quit. To reduce drop-out rates, many therapists combine PE with cognitive restructuring or other techniques that help build patients’ coping skills.

Table 1

Using prolonged exposure therapy to treat PTSD, session by session

Session	Content
1	Education
	Treatment rationale
	Review of PTSD symptom response
	Introduce breathing retraining
2	Review handout, ‘Common reactions to trauma’
	Introduce Subjective Units of Distress
	Create fear hierarchy for in vivo exposures
3	Provide rationale for imaginal exposure
	Conduct imaginal exposure
	Assign in vivo exposure homework
4 to 8	Conduct imaginal exposure
	Discuss in vivo exposures
9 or 9 to 12	Conduct imaginal exposure
	Suggest continued in vivo exercises
	Termination
Source: Foa EB, Rothbaum BO. Treating the trauma of rape: cognitive behavioral therapy for PTSD. New York: Guilford Press, 1998.

Cognitive processing therapy

CPT (Table 2) was created as a protocol to treat PTSD and related symptoms in rape survivors.⁷ Sessions can be group, individual, or combined, depending on the needs and resources of the patients and clinic.

Originally, CPT contained 12 weekly sessions, although versions up to 17 weeks have been developed for adult survivors of child sexual abuse, domestic violence survivors, and war veterans.¹⁵ Sessions can be added or adapted to address each population’s type of traumatic experience (such as developmental impairment of sexual abuse survivors).

CPT is based on information processing theory, which suggests that as people access a traumatic memory, they experience and extinguish emotions attached to the event. Guided by the therapist, the patient identifies and challenges distortions the trauma created in three cognition domains: the self, others, and the world. Patients learn to change or replace these cognitive distortions—which therapists often call “stuck points” or “rules”—with more-adaptive, healthier beliefs.

Common byproducts of trauma are feeling out of control or hopeless. Thus, CPT focuses on personal safety, trust, power/control, esteem, and intimacy within each of the three domains. Modules on assertiveness, communication, and social support can also be added.

Although CPT is being adapted for populations other than rape survivors, comparison studies are needed to determine if it is as effective as other CBT therapies for these groups.

Table 2

Using cognitive processing therapy to treat PTSD, session by session

Session	Content
1	Education
	Review of symptoms
	Introduce ‘stuck points’/rules
	Write impact of event statement (IES)
2	Review IES
	Identify stuck points
	Introduce A-B-C sheets
3	Review A-B-C sheets
	Assign writing of traumatic account
4	Read traumatic account
	Identify stuck points
	Rewrite the account
5	Read rewritten account
	Identify stuck points
	Introduce challenging questions sheet (CQS)
	Assign writing of next-most traumatic incident and CQS
6	Review CQS
	Assign review of faulty thinking patterns (FTP)
7	Review FTP
	Assign safety module and challenging beliefs worksheets (CBW) on safety
8	Review CBWs on safety
	Assign module on trust
9	Review CBWs on trust
	Assign module on power/control
10	Review CBWs on power/control
	Assign module on esteem
11	Review CBWs on esteem
	Assign module on intimacy
	Rewrite IES
12	Review CBWs on intimacy
	Read both impact statements
	Address remaining areas of concern
	Termination
Source: Resick PA, Schnicke MK Cognitive processing therapy for rape victims: a treatment manual. Newbury Park, CA: Sage, 1993.

Eye movement desensitization and reprocessing

Like other PTSD treatments, EMDR is based on an “accelerated information-processing” model.¹⁶ Because it also incorporates dissociation and nonverbal representation of traumas (such as visual memories), EMDR is often classified as a cognitive treatment, although ISTSS practice guidelines⁸ present it as a separate category.

EMDR protocols call for the trauma patient to watch rapid, rhythmic movements of the therapist’s hand or a set of lights to distract attention from the stress he or she feels when visualizing the traumatic event. The original technique—developed by Francine Shapiro, PhD—is based on the observation that persons with PTSD often have disrupted rapid eye-movement sleep. In theory, inducing eye movements inhibits stress, allowing patients to more freely access their memory networks and process disturbances. Subsequently, Dr. Shapiro has suggested that using other auditory cues or hand taps may be as effective as eye movements.¹⁶

 

EMDR is often conducted in 12 to 15 sessions, although some studies report positive changes after 3 to 6 sessions. After obtaining a patient history, establishing rapport, and explaining the treatment, the therapist asks the patient to identify:

• visual images of the trauma
  
• his or her affective and physiologic responses to the trauma
  
• negative self-representations the trauma created
  
• positive, alternate self-representations.
  

The therapist then asks the patient to focus on an image most proximal to the trauma and associated affective and biological reactions. While the patient is thinking, the therapist introduces the distraction stimulation. After a set number of stimulations—such as 20 bilateral eye movements—the therapist asks the patient to “let go” of the memory and discusses any new reactions to the trauma. As patients become less distressed in response to the trauma, they are asked to focus increasingly on alternate positive cognitions while they imagine the trauma.

EMDR has been effective in treating male war veterans, rape victims, and other trauma groups.¹⁷ Initial dismantling studies suggest that eye movements (or other distracting cues) might not be essential for trauma reprocessing, calling into question the mechanisms thought to create change in EMDR. Studies with larger samples comparing EMDR with other CBT models are needed to assess EMDR’s efficacy for trauma survivors.¹⁷

Stress inoculation training

SIT was designed by Meichenbaum¹⁸ (Table 3) to treat anxiety and stress and was adapted for use with trauma survivors. It appears most effective in relieving fear, anxiety, and depressive symptoms associated with traumatic experiences. SIT includes education, muscle relaxation training, breathing retraining, covert modeling, role-playing, guided self-dialog, and thought stopping. Therapists often teach these skills to patients in modules that build on each other.

For example, a patient might receive relaxation training while role-playing a difficult scenario she may face in the future. This helps her learn to remain calm in anxiety-provoking situations.

Unlike PE, SIT does not directly ask patients to recount their traumatic memories, although exposure may be indirect (such as during role-playing exercises). Its purpose is to give patients new skills to manage their anxiety, which in turn decreases PTSD symptoms.

Studies suggest that PE is more effective than SIT alone or SIT/PE combined.¹³ Thus, instead of using SIT as a trauma-focused treatment, some therapists find it useful to help patients gain coping skills before beginning other trauma treatments.

Table 3

Where to learn more about cognitive therapies for PTSD

CBT model	PTSD related to…	Resources
Prolonged exposure	Combat experience, sexual assault, childhood abuse, motor vehicle accidents	Foa EB, Rothbaum BO. Treating the trauma of rape: Cognitive-behavioral therapy for PTSD. New York: Guilford Press; 1998
Cognitive processing	Sexual assault, childhood abuse, incarceration (of adolescents)	Resick P, Schnicke M. Cognitive processing therapy for rape victims: a treatment manual. Newbury Park, CA: Sage Publications; 1996
EMDR	Combat experience, sexual assault, civilian disasters (for children or adults)	Shapiro F. Eye movement desensitization and reprocessing: basic principles, protocols, and procedures (2nd ed). New York: Guilford Press; 2001
		EMDR Institute, Inc. Available at: http://www.emdr.com
Stress inoculation training	Sexual and physical assault, motor vehicle accidents	Meichenbaum D. Stress inoculation training for coping with stressors. Available at: http://www.apa.org/divisions/div12/rev_est/sit_stress.html
EMDR: Eye movement desensitization and reprocessing

Related resources

• International Society for Traumatic Stress Studies. www.istss.org.
  
• Foa EB, Keane TM, Friedman MJ. Effective treatments for PTSD. New York: Guilford Press; 2000.
  

Disclosures

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

Therapists once believed trauma survivors required years of treatment, yet we now know that relatively brief cognitive-behavioral interventions can yield long-term gains in psychosocial and psychological function.¹ Many psychiatric patients meet diagnostic criteria for posttraumatic stress disorder (PTSD), including:

• 33% of women experiencing sexual assault²
  
• 30% of male war veterans³
  
• 30% of the 5 million U.S. children exposed to trauma each year⁴(Box).⁵
  

We offer recommendations on how to prepare traumatized adults and children for cognitive-behavioral therapy (CBT) and discuss four tested models—prolonged exposure (PE), cognitive processing therapy (CPT), eye movement desensitization and reprocessing (EMDR), and stress inoculation training (SIT)—that psychiatrists may find effective when treating PTSD.

Box

Preparing trauma patients for CBT

Before starting CBT, evaluate patients thoroughly to determine if they meet DSM-IV-TR full or subthreshold criteria (

Not all patients are ready to confront their traumas when they arrive for psychiatric evaluation. For example:

• For a domestic violence victim, the therapist’s priority is to help begin safety planning and to address trauma after the patient is out of danger.
  
• Patients with poor coping skills and little social support often find it difficult to begin trauma treatment. For them, focus on building skills to offset the distress that accompanies trauma therapy.
  
• Patients with PTSD and substance abuse may benefit more from CBT if the therapist first addresses the substance dependence.
  

Seeking Safety⁶ is a recent cognitive therapy designed to treat PTSD and substance dependence concurrently. Initial applications appear promising, but its efficacy with various trauma groups needs further evaluation.

CBT core concepts

CBT therapists typically help patients identify and evaluate disruptive cognitions, which helps them challenge and modify emotions, thoughts, and behaviors related to traumatic experience(s). Other CBT components include:

• educating patients about PTSD
  
• exposing them to the traumatic material
  
• challenging and modifying their disruptive thoughts.
  

Some CBT outcome studies⁷ suggest that linking exposure with direct cognitive challenging may not be necessary. Patients who are exposed to the traumatic experience through mental imagery but are not challenged on their cognitive distortions still report more-adaptive thought patterns after treatment.

International Society for Traumatic Stress Studies (ISTSS) practice guidelines for PTSD⁸ include assessment and treatment suggestions (see Related resources). Whatever the model, CBT appears help patients manage their distress, not only during treatment but up to 5 years after completing therapy.⁹

Which CBT? Comparison studies have shown all four CBT interventions to be effective in treating PTSD, although initial trend data suggest that patients with:

• fear-based PTSD may do better with PE or EMDR
  
• PTSD-related guilt, anger, or other cognitive distortions may benefit more from CPT.
  

Because CPT’s written worksheets could be difficult for illiterate patients, an exposure-based treatment may work better in those cases. SIT can reduce some PTSD symptoms but has not performed as well as other therapies in comparison studies. It is most useful to help patients build coping skills before starting other treatments.

If you refer a patient, make sure the therapist is trained in CBT interventions and in working with trauma patients. To be effective, the therapist must be skilled in handling trauma processing work, suicidal thoughts/intent, and comorbid personality disorders.

Prolonged exposure

PE (Table 1) is typically conducted in 9 to 12 sessions lasting 90 minutes each and has been used to treat PTSD after sexual assault, combat, sexual abuse, and natural disasters. Although frequently offered in individual sessions, group PE has also been found to be effective.¹⁰

After educating the patient about PTSD and the treatment rationale, the therapist repeatedly asks the patient to describe the traumatic event as if it were occurring. During 45 to 60 minutes of this exposure, the therapist frequently asks the patient to rate his or her distress. This identifies “hot spots” in the account that need to be repeated. The therapist does not necessarily challenge distorted cognitions about the event (such as “I am to blame for the rape” or “No one can be trusted”).

 

Researchers hypothesize that exposing a PTSD patient to traumatic memories engages his or her brain’s pathologic “fear network,” which triggers an excessive fear response to non-threatening stimuli. Continued exposure allows the patient to habituate to this network, with subsequent extinction of fear and anxiety reactions. Foa et al¹¹ found that mentally re-experiencing a traumatic event helps patients organize memory cues about it, which encourages cognitive restructuring of the trauma.

PE has been shown to enhance the trauma survivor’s self-control and personal competence and to decrease generalization of fear to non-assault stimuli.¹² For example, many combat veterans report fear of situations—such as going to the beach or into the woods—that bring back memories of traumatic events. Their fears may keep them from enjoying a walk in the park or family vacations.

Through in vivo exposure, these patients can face associations between environmental cues and their trauma. As they learn to modify the fears associated with these cues, their personal and social functioning improves.

PE can be successful for those who complete therapy, but it has a relatively high drop-out rate, reported as 8%¹³ to 41%.¹⁴ The pain of continually reliving a traumatic event probably causes many patients to quit. To reduce drop-out rates, many therapists combine PE with cognitive restructuring or other techniques that help build patients’ coping skills.

Table 1

Using prolonged exposure therapy to treat PTSD, session by session

Session	Content
1	Education
	Treatment rationale
	Review of PTSD symptom response
	Introduce breathing retraining
2	Review handout, ‘Common reactions to trauma’
	Introduce Subjective Units of Distress
	Create fear hierarchy for in vivo exposures
3	Provide rationale for imaginal exposure
	Conduct imaginal exposure
	Assign in vivo exposure homework
4 to 8	Conduct imaginal exposure
	Discuss in vivo exposures
9 or 9 to 12	Conduct imaginal exposure
	Suggest continued in vivo exercises
	Termination
Source: Foa EB, Rothbaum BO. Treating the trauma of rape: cognitive behavioral therapy for PTSD. New York: Guilford Press, 1998.

Cognitive processing therapy

CPT (Table 2) was created as a protocol to treat PTSD and related symptoms in rape survivors.⁷ Sessions can be group, individual, or combined, depending on the needs and resources of the patients and clinic.

Originally, CPT contained 12 weekly sessions, although versions up to 17 weeks have been developed for adult survivors of child sexual abuse, domestic violence survivors, and war veterans.¹⁵ Sessions can be added or adapted to address each population’s type of traumatic experience (such as developmental impairment of sexual abuse survivors).

CPT is based on information processing theory, which suggests that as people access a traumatic memory, they experience and extinguish emotions attached to the event. Guided by the therapist, the patient identifies and challenges distortions the trauma created in three cognition domains: the self, others, and the world. Patients learn to change or replace these cognitive distortions—which therapists often call “stuck points” or “rules”—with more-adaptive, healthier beliefs.

Common byproducts of trauma are feeling out of control or hopeless. Thus, CPT focuses on personal safety, trust, power/control, esteem, and intimacy within each of the three domains. Modules on assertiveness, communication, and social support can also be added.

Although CPT is being adapted for populations other than rape survivors, comparison studies are needed to determine if it is as effective as other CBT therapies for these groups.

Table 2

Using cognitive processing therapy to treat PTSD, session by session

Session	Content
1	Education
	Review of symptoms
	Introduce ‘stuck points’/rules
	Write impact of event statement (IES)
2	Review IES
	Identify stuck points
	Introduce A-B-C sheets
3	Review A-B-C sheets
	Assign writing of traumatic account
4	Read traumatic account
	Identify stuck points
	Rewrite the account
5	Read rewritten account
	Identify stuck points
	Introduce challenging questions sheet (CQS)
	Assign writing of next-most traumatic incident and CQS
6	Review CQS
	Assign review of faulty thinking patterns (FTP)
7	Review FTP
	Assign safety module and challenging beliefs worksheets (CBW) on safety
8	Review CBWs on safety
	Assign module on trust
9	Review CBWs on trust
	Assign module on power/control
10	Review CBWs on power/control
	Assign module on esteem
11	Review CBWs on esteem
	Assign module on intimacy
	Rewrite IES
12	Review CBWs on intimacy
	Read both impact statements
	Address remaining areas of concern
	Termination
Source: Resick PA, Schnicke MK Cognitive processing therapy for rape victims: a treatment manual. Newbury Park, CA: Sage, 1993.

Eye movement desensitization and reprocessing

Like other PTSD treatments, EMDR is based on an “accelerated information-processing” model.¹⁶ Because it also incorporates dissociation and nonverbal representation of traumas (such as visual memories), EMDR is often classified as a cognitive treatment, although ISTSS practice guidelines⁸ present it as a separate category.

EMDR protocols call for the trauma patient to watch rapid, rhythmic movements of the therapist’s hand or a set of lights to distract attention from the stress he or she feels when visualizing the traumatic event. The original technique—developed by Francine Shapiro, PhD—is based on the observation that persons with PTSD often have disrupted rapid eye-movement sleep. In theory, inducing eye movements inhibits stress, allowing patients to more freely access their memory networks and process disturbances. Subsequently, Dr. Shapiro has suggested that using other auditory cues or hand taps may be as effective as eye movements.¹⁶

 

EMDR is often conducted in 12 to 15 sessions, although some studies report positive changes after 3 to 6 sessions. After obtaining a patient history, establishing rapport, and explaining the treatment, the therapist asks the patient to identify:

• visual images of the trauma
  
• his or her affective and physiologic responses to the trauma
  
• negative self-representations the trauma created
  
• positive, alternate self-representations.
  

The therapist then asks the patient to focus on an image most proximal to the trauma and associated affective and biological reactions. While the patient is thinking, the therapist introduces the distraction stimulation. After a set number of stimulations—such as 20 bilateral eye movements—the therapist asks the patient to “let go” of the memory and discusses any new reactions to the trauma. As patients become less distressed in response to the trauma, they are asked to focus increasingly on alternate positive cognitions while they imagine the trauma.

EMDR has been effective in treating male war veterans, rape victims, and other trauma groups.¹⁷ Initial dismantling studies suggest that eye movements (or other distracting cues) might not be essential for trauma reprocessing, calling into question the mechanisms thought to create change in EMDR. Studies with larger samples comparing EMDR with other CBT models are needed to assess EMDR’s efficacy for trauma survivors.¹⁷

Stress inoculation training

SIT was designed by Meichenbaum¹⁸ (Table 3) to treat anxiety and stress and was adapted for use with trauma survivors. It appears most effective in relieving fear, anxiety, and depressive symptoms associated with traumatic experiences. SIT includes education, muscle relaxation training, breathing retraining, covert modeling, role-playing, guided self-dialog, and thought stopping. Therapists often teach these skills to patients in modules that build on each other.

For example, a patient might receive relaxation training while role-playing a difficult scenario she may face in the future. This helps her learn to remain calm in anxiety-provoking situations.

Unlike PE, SIT does not directly ask patients to recount their traumatic memories, although exposure may be indirect (such as during role-playing exercises). Its purpose is to give patients new skills to manage their anxiety, which in turn decreases PTSD symptoms.

Studies suggest that PE is more effective than SIT alone or SIT/PE combined.¹³ Thus, instead of using SIT as a trauma-focused treatment, some therapists find it useful to help patients gain coping skills before beginning other trauma treatments.

Table 3

Where to learn more about cognitive therapies for PTSD

CBT model	PTSD related to…	Resources
Prolonged exposure	Combat experience, sexual assault, childhood abuse, motor vehicle accidents	Foa EB, Rothbaum BO. Treating the trauma of rape: Cognitive-behavioral therapy for PTSD. New York: Guilford Press; 1998
Cognitive processing	Sexual assault, childhood abuse, incarceration (of adolescents)	Resick P, Schnicke M. Cognitive processing therapy for rape victims: a treatment manual. Newbury Park, CA: Sage Publications; 1996
EMDR	Combat experience, sexual assault, civilian disasters (for children or adults)	Shapiro F. Eye movement desensitization and reprocessing: basic principles, protocols, and procedures (2nd ed). New York: Guilford Press; 2001
		EMDR Institute, Inc. Available at: http://www.emdr.com
Stress inoculation training	Sexual and physical assault, motor vehicle accidents	Meichenbaum D. Stress inoculation training for coping with stressors. Available at: http://www.apa.org/divisions/div12/rev_est/sit_stress.html
EMDR: Eye movement desensitization and reprocessing

Related resources

• International Society for Traumatic Stress Studies. www.istss.org.
  
• Foa EB, Keane TM, Friedman MJ. Effective treatments for PTSD. New York: Guilford Press; 2000.
  

Disclosures

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

Are anticonvulsants safe and effective mood stabilizers for children and adolescents with bipolar disorder? The answer is unclear because most bipolar disorder treatment trials have included adults only, and clinicians are desperate for data.¹

To help you care for young patients, we report what is known about the potential benefits and risks of using mood stabilizers and anticonvulsants in bipolar youth. We base our dosing, target serum level, and monitoring recommendations on clinical experience and the limited published evidence.

AGENTS OF CHOICE?

Bipolar disorder’s “atypical” presentation in children—often more irritability and explosiveness than euphoria—can complicate diagnosis. Bipolar children and adolescents often have comorbid attention-deficit/hyperactivity disorder (ADHD), other disruptive behavior disorders, or anxiety disorders. Thus, comorbidities and presenting symptoms often dictate medication choice.

An expert consensus guideline acknowledges that more evidence on pediatric bipolar disorder is needed. In the meantime, the guideline suggests trying valproate or lithium first to treat nonpsychotic mania in pediatric bipolar patients.¹ It also recommends three atypical antipsychotics— olanzapine, quetiapine, and risperidone—as potential first-line treatments. Valproate and lithium may be preferred because of atypicals’ risk of weight gain and metabolic syndrome.

Trying other anticonvulsants may be justified for bipolar youths who are not functioning well with first-line agents. Lamotrigine, for example, has antidepressant and antimanic effects.² When you try anticonvulsants that lack double-blind, placebo-controlled trials, we recommend that you:

• obtain consent from the parents and child
  
• monitor carefully for side effects.
  

LITHIUM: STRONGEST EVIDENCE

Lithium is one of the most well-studied medications for pediatric bipolar disorder and the only mood stabilizer FDA-approved for children and adolescents (Table 1).³ Although approved for ages 12 and older, lithium has been used in younger children in practice and in clinical trials.

Table 1

FDA-approval status of medications used to treat bipolar disorder

Medication	Indications for adults	Indications for children
Carbamazepine	Acute manic episode and acute mixed episode	Not approved
Lamotrigine	Maintenance therapy	Not approved
Lithium	Acute manic episode and maintenance therapy	Age ≥ 12 years
Oxcarbazepine	Not approved	Not approved
Topiramate	Not approved	Not approved
Valproate	Acute manic episode	Not approved
Source: Reference 3

Efficacy. In an open-label study of 100 adolescents with type I bipolar disorder,⁴ 63% met response criteria after 4 weeks of lithium and 26% showed manic symptom remission. Symptoms worsened in both groups, however, when 40 responders were randomly assigned to continue or discontinue lithium for 2 weeks.⁵ The authors speculated that these conflicting results might indicate that mood stabilization requires longer treatment. Contrary to earlier reports,⁶ manic adolescents with comorbid ADHD did not show poor response to lithium.

In the only double-blind, placebo-controlled trial of lithium in adolescents with bipolar disorder, some subjects had secondary substance dependency disorders.⁷ For 6 weeks, 25 outpatient adolescents received lithium (13 patients) or placebo (12 patients). Lithium was effective in treating bipolar and substance dependency symptoms, with significantly improved clinical global assessment scores and decreased positive urine assays for drugs. Little difference was seen in mood item scores on the Schedule for Affective Disorders and Schizophrenia, child version (KSADS-1986), whether patients were taking lithium or placebo.

Pediatric dosing. For bipolar patients ages 6 to 12, use the child’s weight to determine lithium dosage (Table 2).⁸ Maintain serum levels between 0.8 and 1.2 mEq/L,⁹ and check them frequently when starting therapy.¹⁰ After mood stabilization, check levels every 1 to 3 months or when you suspect noncompliance. Obtain renal and thyroid function values at baseline and every 4 to 6 months.

Table 2

Guide to dosing lithium for prepubertal school-aged children*

	Doses (mg)
Child’s weight (kg)	8 AM	12 PM	6 PM	Total daily
	150	150	300	600
25 to 40	300	300	300	900
40 to 50	300	300	600	1,200
50 to 60	600	300	600	1,500
* Maintain specified dose at least 5 days, drawing serum levels 12 hrs after the last lithium dose until two consecutive levels appear in the therapeutic range (0.6 to 1.2 mEq/L). Dose may then be adjusted based on serum level, side effects, or clinical response. Do not exceed 1.4 mEq/L.
Source: Reference 8

Safety. Common side effects reported in adolescents include weight gain (55%), polydipsia (33%), polyuria (25%), headache (23%), tremor (20%), and GI complaints (up to 18%).⁴ Neurologic side effects are associated with higher serum lithium levels (0.91 to 1.36 mEq/L)¹⁰ and occur more often in younger than in older children.¹¹ The cardiac defect Ebstein’s anomaly occurs in approximately 0.05 to 0.1% of children exposed to lithium in utero (Box).^12-16

Box

 

VALPROATE: OPEN-LABEL TRIALS ONLY

Efficacy. No double-blind, placebo-controlled study has shown valproate to be effective in treating bipolar disorder in children and adolescents. When used as monotherapy in open-label studies, valproate has produced response rates of:

• 53% in a 6-week, randomized, open-label trial in which 42 outpatients (mean age 11.4 years) with bipolar disorder type I or II received lithium, divalproex sodium, or carbamazepine⁹
  
• 61% in an open-label study of 40 patients ages 7 to 19 with a manic, hypomanic, or mixed episode who received divalproex for 2 to 8 weeks¹⁷
  
• 80% in an 8-week open-label trial of 40 patients ages 6 to 17 with bipolar disorder type I (77.5%) or type II (22.5%) and a Young Mania Rating Scale (YMRS)score ≥ 14.¹⁸
  

In a prospective trial, 90 patients ages 5 to 17 with bipolar disorder type I or II were treated with lithium plus divalproex sodium. After up to 20 weeks, 47% met criteria for depressive and manic symptom remission.¹⁹ A chart review has showed valproate’s efficacy in treating aggression and irritability in adolescent mania.²⁰

Safety: Black-box warnings. Valproate therapy carries risks of hepatic failure, pancreatitis, and birth defects. Monitor blood counts and hepatic enzymes throughout therapy (Table 3).³ Rare yet potentially fatal hepatic toxicity appears to occur most often in children age 21 Other studies suggest:

• an association with congenital malformations, including spina bifida and pulmonary atresia, in children exposed to valproate in utero⁶
  
• a link between valproate and hyperammonemic encephalopathy, especially in patients with urea cycle disorders²²
  
• potential for benign thrombocytopenia²³
  
• increased incidence of polycystic ovary syndrome—ovarian cysts, hyperandrogenism, chronic anovulation—in peripubertal mentally retarded women treated with valproate for seizure disorders.²⁴
  

Because of these risks, use caution when prescribing valproate to bipolar adolescent girls. Monitor menstrual cycle regularity, and collaborate with a gynecologist to watch for potentially dangerous effects.

Table 3

Mood stabilizers’ side effects and recommended monitoring

Medication	Major side effects	Monitoring
Carbamazepine	Allergic skin rash, drowsiness, blood dyscrasias, diplopia	CBC with reticulocytes, iron, LFTs, urinalysis, BUN, TFTs, sodium, serum carbamazepine levels
Lamotrigine	Stevens-Johnson syndrome, headache, dizziness, ataxia, somnolence, nausea, diplopia, blurred vision, rhinitis	No serum monitoring recommended
Lithium	Polyuria, polydipsia, nausea, diarrhea, tininecleatremor, enuresis, fatigue, ataxia, leukocytosis, malaise, cardiac arrhythmias, weight gain	BUN/creatinine, crearance, TFTs, calcium/phosphorus, ECG, serum lithium levels every 1 to 3 months once stabilized
Oxcarbazepine	Dizziness, somnolence/fatigue, ataxia/gait disturbance, vertigo, headache, tremor, rash, hyponatremia, hypersensitivity reaction, GI symptoms, diplopia	Sodium levels (particularly ifirst 3 months)
Topiramate	Hyperchloremic metabolic acidosis, oligohydrosis and hyperthermia, acute myopia, somnolence/fatigue, nausea, anorexia/weight loss, paresthesia, tremor, difficulty concentrating	BUN/creatinine, sodium bicarbonate
Valproate	Irritability/restlessness, ataxia, headache, weight gain, hyperammonemic encephalopathy, alopecia, GI upset, pancreatitis,sedation, thrombocytopenia, liver failure, polycystic ovaries/hyperandrogenism, teratogenic effects,rash	Ammonia, LFTs, bilirubin, CBC with platelets, serum valproate levels
BUN: blood urea nitrogen; CBC: complete blood count; ECG: electrocardiography; LFT: liver function tests; TFTs: thyroid function tests
Note: Bolded items included in black-box warnings
Source: Reference 3

Body weight. Valproate has been associated with weight gain. In a study of 372 bipolar adults, 21% reported a 5% weight-gain during 52 weeks of maintenance therapy, compared with 13% of patients on lithium and 7% on placebo.²⁵ Shortterm studies of adjunctive valproate in pediatric bipolar patients raise similar concerns.²⁶ Thus, monitor for weight gain and serum lipid changes in youths starting valproate therapy.

CARBAMAZEPINE: DRUG INTERACTION RISK

Carbamazepine is used less often than lithium or divalproex for bipolar disorder. It tends to be used adjunctively when lithium alone is ineffective.

Efficacy. In an open-label study,⁹ 42 patients ages 8 to 18 with bipolar disorder type I or II were randomly assigned to lithium, divalproex sodium, or carbamazepine monotherapy for 6 weeks. Response rates—measured as a ≥ 50% change from baseline in YMRS scores—were 53% with divalproex, 38% with lithium, and 38% with carbamazepine.

A retrospective review of 44 hospitalized bipolar patients ages 5 to 12 treated for at least 7 days with lithium, valproate, or carbamazepine reported higher (ie, worse) Clinical Global Impression of Improvement scores with carbamazepine.²⁷ Small sample sizes, particularly in the carbamazepine group, limited this naturalistic study.

Safety: Black-box warnings. Carbamazepine’s hematologic “black box” warns of increased risk of aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Risks associated with carbamazepine have been estimated at:

• aplastic anemia: 5.1/million patient years
  
• agranulocytosis: 1.4/million patient years.²⁸
  

Leukopenia is relatively more common and occurs in approximately 20% of children receiving carbamazepine.²⁹ Consider stopping carbamazepine when the white cell count falls below 3,000/mm³ (or the neutrophil count drops to 3).²⁹ Advise children and parents to watch for leukopenia’s signs and symptoms, including fever, infections, sore throat, and mouth ulcers.³

Body weight. Carbamazepine is not associated with significant weight gain, which could be clinically important for some patients.

 

Drug interactions. Carbamazepine activates the cytochrome P-450 liver enzyme system, increasing the metabolism of many medications and decreasing their blood levels. Consider monitoring serum levels when using carbamazepine with valproate, imipramine, corticosteroids, warfarin, oral contraceptives, and some antibiotics. Because carbamazepine induces its own metabolism, you might need to increase its dosage if its effects appear to be waning.³

Carbamazepine and tricyclic antidepressants may show cross-sensitivity because of structural similarity. Do not use monoamine oxidase inhibitors with carbamazepine; discontinue them at least 14 days before starting carbamazepine.³

OXCARBAZEPINE: FEWER INTERACTIONS

Oxcarbazepine has similar efficacy to carbamazepine but less side effect risk and does not require plasma level monitoring. A weaker inducer of CYP-450, it causes fewer clinically important drug-drug interactions and may be useful for patients who respond to carbamazepine but cannot tolerate its side effects.³⁰

Efficacy. Case studies^31,32 have been encouraging, but no published, double-blind, placebo-controlled studies support using oxcarbazepine in bipolar children and adolescents.

Safety. Oxcarbazepine appears to be generally well-tolerated but can cause potentially serious reactions—including hyponatremia.³³ Somnolence, emesis, and ataxia are the most common side effects in pediatric patients.³

Hyponatremia —plasma sodium 125 mEq/L—occurs in 2.5% of adults taking oxcarbazepine³ and has been reported in a similar percentage of children.³⁴ This potentially severe reaction—characterized by nausea, lethargy, malaise, headache, confusion, decreased seizure threshold, or simply decreased serum sodium³⁵—is usually noted within the first 12 weeks of therapy. The risk increases with concomitant use of other sodium-altering drugs, such as antidepressants or antipsychotics.³⁶

Evaluate serum sodium when starting oxcarbazepine, periodically in the first 3 months, and if symptoms occur.^34,36 For sodium levels of 125 to 130 mEq/L, obtain repeat measurements to confirm that hyponatremia is not worsening. Intervention is often required when levels fall below 125 mEq/L.³⁶

Other serious adverse reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions; 25% to 30% of patients with hypersensitivity to carbamazepine also will react to oxcarbazepine.³³

Contraceptive concerns. Oxcarbazepine may reduce contraceptive efficacy by altering estrogen and progesterone plasma concentrations.³⁷ Consider other birth control methods for sexuallyactive bipolar adolescent girls.

LAMOTRIGINE

Neurologists often use lamotrigine for children with atypical seizure disorders, but no controlled data exist on the drug’s efficacy and safety in youths with bipolar disorder.

Efficacy. In a prospective, open-label study,³⁸ 13 adolescents with type I bipolar disorder received lamotrigine, 200 to 400 mg/d. After 12 weeks (mean dosage 241 mg/d), their symptoms had improved as shown by these mean scores:

• Montgomery-Asberg Depression Rating Scale: from 21 at baseline to 4 at endpoint
  
• Clinical Global Impressions–Severity of Illness scale: from 4 to 1
  
• Children’s Depression Rating Scale (CDRS-R): from 74 to 40
  
• YMRS: from 20 to 6.
  

In another open-label study,³⁹ 16 of 18 youths (88%) with bipolar depression or mixed mania improved with lamotrigine alone or as adjunctive therapy, as shown by Clinical Global Impression of Change scores. CDRS-R scores also decreased by ≥50% in 11 of 17 who finished the study.

Safety: Severe rash. An age-related association with Stevens-Johnson syndrome may limit pediatric use of lamotrigine. Severe and potentially life-threatening rashes have been reported in 0.8% of children treated with lamotrigine.⁴⁰ Discontinue lamotrigine if a rash develops, unless it clearly is not drug-related. Three factors that increase rash risk include:

• co-administering lamotrigine with valproate
  
• higher-than-recommended initial dosages
  
• rapid dose titration.⁴¹
  

Most rashes appear in the first 8 weeks,⁴¹ though cases can occur after prolonged treatment.

Pediatric dosing. We find no published studies of efficacious dosages and plasma levels of lamotrigine in pediatric bipolar disorder (Table 4).^3,9,17 Based on our clinical experience, we recommend starting lamotrigine at 1 to 5 mg/kg/day (1 to 3 mg/kg/day if given with valproate) divided into two daily doses. Watch for rash or skin disorders. Do not exceed the recommended daily dosage by 200 mg in children age

Table 4

Using anticonvulsants in pediatric bipolar disorder patients

Drug	Recommended dosage	Target serum level
Carbamazepine	Age 6 to 12: 20 to 30 mg/kg/d	≥ 7.0 μg/L
	Age >12: 400 to 1,200 mg/d
Lamotrigine*	Unknown	Unknown
Oxcarbazepine	11 to 16 mg/kg/d (as adjunct)	Unknown
Topiramate*	Unknown	Unknown
Valproate	15 to 20 mg/kg/d	45 to 125 μg/mL (trough)
		85 to 110 μg/mL (target)
* No published studies found for efficacious dosage and plasma levels in pediatric bipolar disorder.
Dosage supported by case reports only; no studies found examining efficacious plasma levels.
Source: References 3,9, and 17.

TOPIRAMATE: LIMITED INFORMATION

Efficacy. Little is known about using topiramate in children and adolescents. A retrospective chart review⁴² of 26 patients with bipolar disorder type I (n=23) or II (n=3) showed adjunctive topiramate to be effective, with response rates of 73% for mania and 62% overall. Topiramate was well tolerated, and no serious events were reported.

 

A randomized, controlled trial of topiramate for acute mania in youths with type I bipolar disorder⁴³ was recently halted because of lack of efficacy in adul trials. Preliminary data from 56 of the pediatric patients—analyzed before the study was halted—showed improved YMRS scores. Although results were not statistically significant, the authors suggest topiramate might be effective in treating children and adolescents with bipolar disorder.

Safety: FDA warning. Decreased sodium bicarbonate leading to hyperchloremic metabolic acidosis has been reported in youths treated with topiramate for seizure disorder,⁴⁴ leading to an FDA warning to prescribers.³ Although no monitoring guidelines exist, we recommend baseline and periodic serum bicarbonate measurements and acidbase evaluations during topiramate treatment, especially when adding other antiepileptics.⁴⁴

Other rare but serious reactions include:

• impaired sweat production and resultant hyperthermia⁴⁵
  
• ophthalmologic symptoms characterized by secondary acute angle closure glaucoma and acute myacute myopia (usually within 1 month of starting treatment)⁴⁶
  
• sedation and cognitive difficulties.⁴⁷
  

Body weight. Body weight declined an average 5.8 kg across 8 weeks among 36 bipolar adults using topiramate (mean 176 mg/d).⁴⁷ We find that bipolar teens like topiramate because of weight loss, compared with weight gain with divalproex or lithium, but any pediatric weight loss requires monitoring.

Cognitive effects? Reports of “word finding difficulties” with topiramate⁴⁷ may suggest cognitive effects. Thus, be very cautious about using this medication in children and adolescents.

Related resources

• Kowatch R, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005;44(3):213-35.
  
• Yonkers K, Wisner K, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry 2004;161(4):608-20.
  
• American Academy of Child and Adolescent Psychiatry. Treatment guidelines for childhood psychiatric disorders. www.aacap.org
  

Disclosures

Dr. Kloos, Dr. Hitchcock, and Dr. Ronald Weller report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Elizabeth Weller has been a consultant to or received research grants from GlaxoSmithKline, Johnson & Johnson, Novartis Pharmaceuticals Corp., Abbott Laboratories, and Shire Pharmaceuticals.

Drug brand names

• Carbamazepine • Tegretol
  
• Divalproex • Depakote
  
• Lamotrigine • Lamictal
  
• Lithium • Eskalith, Lithobid, others
  
• Oxcarbazepine • Trileptal
  
• Topiramate • Topamax
  

Are anticonvulsants safe and effective mood stabilizers for children and adolescents with bipolar disorder? The answer is unclear because most bipolar disorder treatment trials have included adults only, and clinicians are desperate for data.¹

To help you care for young patients, we report what is known about the potential benefits and risks of using mood stabilizers and anticonvulsants in bipolar youth. We base our dosing, target serum level, and monitoring recommendations on clinical experience and the limited published evidence.

AGENTS OF CHOICE?

Bipolar disorder’s “atypical” presentation in children—often more irritability and explosiveness than euphoria—can complicate diagnosis. Bipolar children and adolescents often have comorbid attention-deficit/hyperactivity disorder (ADHD), other disruptive behavior disorders, or anxiety disorders. Thus, comorbidities and presenting symptoms often dictate medication choice.

An expert consensus guideline acknowledges that more evidence on pediatric bipolar disorder is needed. In the meantime, the guideline suggests trying valproate or lithium first to treat nonpsychotic mania in pediatric bipolar patients.¹ It also recommends three atypical antipsychotics— olanzapine, quetiapine, and risperidone—as potential first-line treatments. Valproate and lithium may be preferred because of atypicals’ risk of weight gain and metabolic syndrome.

Trying other anticonvulsants may be justified for bipolar youths who are not functioning well with first-line agents. Lamotrigine, for example, has antidepressant and antimanic effects.² When you try anticonvulsants that lack double-blind, placebo-controlled trials, we recommend that you:

• obtain consent from the parents and child
  
• monitor carefully for side effects.
  

LITHIUM: STRONGEST EVIDENCE

Lithium is one of the most well-studied medications for pediatric bipolar disorder and the only mood stabilizer FDA-approved for children and adolescents (Table 1).³ Although approved for ages 12 and older, lithium has been used in younger children in practice and in clinical trials.

Table 1

FDA-approval status of medications used to treat bipolar disorder

Medication	Indications for adults	Indications for children
Carbamazepine	Acute manic episode and acute mixed episode	Not approved
Lamotrigine	Maintenance therapy	Not approved
Lithium	Acute manic episode and maintenance therapy	Age ≥ 12 years
Oxcarbazepine	Not approved	Not approved
Topiramate	Not approved	Not approved
Valproate	Acute manic episode	Not approved
Source: Reference 3

Efficacy. In an open-label study of 100 adolescents with type I bipolar disorder,⁴ 63% met response criteria after 4 weeks of lithium and 26% showed manic symptom remission. Symptoms worsened in both groups, however, when 40 responders were randomly assigned to continue or discontinue lithium for 2 weeks.⁵ The authors speculated that these conflicting results might indicate that mood stabilization requires longer treatment. Contrary to earlier reports,⁶ manic adolescents with comorbid ADHD did not show poor response to lithium.

In the only double-blind, placebo-controlled trial of lithium in adolescents with bipolar disorder, some subjects had secondary substance dependency disorders.⁷ For 6 weeks, 25 outpatient adolescents received lithium (13 patients) or placebo (12 patients). Lithium was effective in treating bipolar and substance dependency symptoms, with significantly improved clinical global assessment scores and decreased positive urine assays for drugs. Little difference was seen in mood item scores on the Schedule for Affective Disorders and Schizophrenia, child version (KSADS-1986), whether patients were taking lithium or placebo.

Pediatric dosing. For bipolar patients ages 6 to 12, use the child’s weight to determine lithium dosage (Table 2).⁸ Maintain serum levels between 0.8 and 1.2 mEq/L,⁹ and check them frequently when starting therapy.¹⁰ After mood stabilization, check levels every 1 to 3 months or when you suspect noncompliance. Obtain renal and thyroid function values at baseline and every 4 to 6 months.

Table 2

Guide to dosing lithium for prepubertal school-aged children*

	Doses (mg)
Child’s weight (kg)	8 AM	12 PM	6 PM	Total daily
	150	150	300	600
25 to 40	300	300	300	900
40 to 50	300	300	600	1,200
50 to 60	600	300	600	1,500
* Maintain specified dose at least 5 days, drawing serum levels 12 hrs after the last lithium dose until two consecutive levels appear in the therapeutic range (0.6 to 1.2 mEq/L). Dose may then be adjusted based on serum level, side effects, or clinical response. Do not exceed 1.4 mEq/L.
Source: Reference 8

Safety. Common side effects reported in adolescents include weight gain (55%), polydipsia (33%), polyuria (25%), headache (23%), tremor (20%), and GI complaints (up to 18%).⁴ Neurologic side effects are associated with higher serum lithium levels (0.91 to 1.36 mEq/L)¹⁰ and occur more often in younger than in older children.¹¹ The cardiac defect Ebstein’s anomaly occurs in approximately 0.05 to 0.1% of children exposed to lithium in utero (Box).^12-16

Box

 

VALPROATE: OPEN-LABEL TRIALS ONLY

Efficacy. No double-blind, placebo-controlled study has shown valproate to be effective in treating bipolar disorder in children and adolescents. When used as monotherapy in open-label studies, valproate has produced response rates of:

• 53% in a 6-week, randomized, open-label trial in which 42 outpatients (mean age 11.4 years) with bipolar disorder type I or II received lithium, divalproex sodium, or carbamazepine⁹
  
• 61% in an open-label study of 40 patients ages 7 to 19 with a manic, hypomanic, or mixed episode who received divalproex for 2 to 8 weeks¹⁷
  
• 80% in an 8-week open-label trial of 40 patients ages 6 to 17 with bipolar disorder type I (77.5%) or type II (22.5%) and a Young Mania Rating Scale (YMRS)score ≥ 14.¹⁸
  

In a prospective trial, 90 patients ages 5 to 17 with bipolar disorder type I or II were treated with lithium plus divalproex sodium. After up to 20 weeks, 47% met criteria for depressive and manic symptom remission.¹⁹ A chart review has showed valproate’s efficacy in treating aggression and irritability in adolescent mania.²⁰

Safety: Black-box warnings. Valproate therapy carries risks of hepatic failure, pancreatitis, and birth defects. Monitor blood counts and hepatic enzymes throughout therapy (Table 3).³ Rare yet potentially fatal hepatic toxicity appears to occur most often in children age 21 Other studies suggest:

• an association with congenital malformations, including spina bifida and pulmonary atresia, in children exposed to valproate in utero⁶
  
• a link between valproate and hyperammonemic encephalopathy, especially in patients with urea cycle disorders²²
  
• potential for benign thrombocytopenia²³
  
• increased incidence of polycystic ovary syndrome—ovarian cysts, hyperandrogenism, chronic anovulation—in peripubertal mentally retarded women treated with valproate for seizure disorders.²⁴
  

Because of these risks, use caution when prescribing valproate to bipolar adolescent girls. Monitor menstrual cycle regularity, and collaborate with a gynecologist to watch for potentially dangerous effects.

Table 3

Mood stabilizers’ side effects and recommended monitoring

Medication	Major side effects	Monitoring
Carbamazepine	Allergic skin rash, drowsiness, blood dyscrasias, diplopia	CBC with reticulocytes, iron, LFTs, urinalysis, BUN, TFTs, sodium, serum carbamazepine levels
Lamotrigine	Stevens-Johnson syndrome, headache, dizziness, ataxia, somnolence, nausea, diplopia, blurred vision, rhinitis	No serum monitoring recommended
Lithium	Polyuria, polydipsia, nausea, diarrhea, tininecleatremor, enuresis, fatigue, ataxia, leukocytosis, malaise, cardiac arrhythmias, weight gain	BUN/creatinine, crearance, TFTs, calcium/phosphorus, ECG, serum lithium levels every 1 to 3 months once stabilized
Oxcarbazepine	Dizziness, somnolence/fatigue, ataxia/gait disturbance, vertigo, headache, tremor, rash, hyponatremia, hypersensitivity reaction, GI symptoms, diplopia	Sodium levels (particularly ifirst 3 months)
Topiramate	Hyperchloremic metabolic acidosis, oligohydrosis and hyperthermia, acute myopia, somnolence/fatigue, nausea, anorexia/weight loss, paresthesia, tremor, difficulty concentrating	BUN/creatinine, sodium bicarbonate
Valproate	Irritability/restlessness, ataxia, headache, weight gain, hyperammonemic encephalopathy, alopecia, GI upset, pancreatitis,sedation, thrombocytopenia, liver failure, polycystic ovaries/hyperandrogenism, teratogenic effects,rash	Ammonia, LFTs, bilirubin, CBC with platelets, serum valproate levels
BUN: blood urea nitrogen; CBC: complete blood count; ECG: electrocardiography; LFT: liver function tests; TFTs: thyroid function tests
Note: Bolded items included in black-box warnings
Source: Reference 3

Body weight. Valproate has been associated with weight gain. In a study of 372 bipolar adults, 21% reported a 5% weight-gain during 52 weeks of maintenance therapy, compared with 13% of patients on lithium and 7% on placebo.²⁵ Shortterm studies of adjunctive valproate in pediatric bipolar patients raise similar concerns.²⁶ Thus, monitor for weight gain and serum lipid changes in youths starting valproate therapy.

CARBAMAZEPINE: DRUG INTERACTION RISK

Carbamazepine is used less often than lithium or divalproex for bipolar disorder. It tends to be used adjunctively when lithium alone is ineffective.

Efficacy. In an open-label study,⁹ 42 patients ages 8 to 18 with bipolar disorder type I or II were randomly assigned to lithium, divalproex sodium, or carbamazepine monotherapy for 6 weeks. Response rates—measured as a ≥ 50% change from baseline in YMRS scores—were 53% with divalproex, 38% with lithium, and 38% with carbamazepine.

A retrospective review of 44 hospitalized bipolar patients ages 5 to 12 treated for at least 7 days with lithium, valproate, or carbamazepine reported higher (ie, worse) Clinical Global Impression of Improvement scores with carbamazepine.²⁷ Small sample sizes, particularly in the carbamazepine group, limited this naturalistic study.

Safety: Black-box warnings. Carbamazepine’s hematologic “black box” warns of increased risk of aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Risks associated with carbamazepine have been estimated at:

• aplastic anemia: 5.1/million patient years
  
• agranulocytosis: 1.4/million patient years.²⁸
  

Leukopenia is relatively more common and occurs in approximately 20% of children receiving carbamazepine.²⁹ Consider stopping carbamazepine when the white cell count falls below 3,000/mm³ (or the neutrophil count drops to 3).²⁹ Advise children and parents to watch for leukopenia’s signs and symptoms, including fever, infections, sore throat, and mouth ulcers.³

Body weight. Carbamazepine is not associated with significant weight gain, which could be clinically important for some patients.

 

Drug interactions. Carbamazepine activates the cytochrome P-450 liver enzyme system, increasing the metabolism of many medications and decreasing their blood levels. Consider monitoring serum levels when using carbamazepine with valproate, imipramine, corticosteroids, warfarin, oral contraceptives, and some antibiotics. Because carbamazepine induces its own metabolism, you might need to increase its dosage if its effects appear to be waning.³

Carbamazepine and tricyclic antidepressants may show cross-sensitivity because of structural similarity. Do not use monoamine oxidase inhibitors with carbamazepine; discontinue them at least 14 days before starting carbamazepine.³

OXCARBAZEPINE: FEWER INTERACTIONS

Oxcarbazepine has similar efficacy to carbamazepine but less side effect risk and does not require plasma level monitoring. A weaker inducer of CYP-450, it causes fewer clinically important drug-drug interactions and may be useful for patients who respond to carbamazepine but cannot tolerate its side effects.³⁰

Efficacy. Case studies^31,32 have been encouraging, but no published, double-blind, placebo-controlled studies support using oxcarbazepine in bipolar children and adolescents.

Safety. Oxcarbazepine appears to be generally well-tolerated but can cause potentially serious reactions—including hyponatremia.³³ Somnolence, emesis, and ataxia are the most common side effects in pediatric patients.³

Hyponatremia —plasma sodium 125 mEq/L—occurs in 2.5% of adults taking oxcarbazepine³ and has been reported in a similar percentage of children.³⁴ This potentially severe reaction—characterized by nausea, lethargy, malaise, headache, confusion, decreased seizure threshold, or simply decreased serum sodium³⁵—is usually noted within the first 12 weeks of therapy. The risk increases with concomitant use of other sodium-altering drugs, such as antidepressants or antipsychotics.³⁶

Evaluate serum sodium when starting oxcarbazepine, periodically in the first 3 months, and if symptoms occur.^34,36 For sodium levels of 125 to 130 mEq/L, obtain repeat measurements to confirm that hyponatremia is not worsening. Intervention is often required when levels fall below 125 mEq/L.³⁶

Other serious adverse reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions; 25% to 30% of patients with hypersensitivity to carbamazepine also will react to oxcarbazepine.³³

Contraceptive concerns. Oxcarbazepine may reduce contraceptive efficacy by altering estrogen and progesterone plasma concentrations.³⁷ Consider other birth control methods for sexuallyactive bipolar adolescent girls.

LAMOTRIGINE

Neurologists often use lamotrigine for children with atypical seizure disorders, but no controlled data exist on the drug’s efficacy and safety in youths with bipolar disorder.

Efficacy. In a prospective, open-label study,³⁸ 13 adolescents with type I bipolar disorder received lamotrigine, 200 to 400 mg/d. After 12 weeks (mean dosage 241 mg/d), their symptoms had improved as shown by these mean scores:

• Montgomery-Asberg Depression Rating Scale: from 21 at baseline to 4 at endpoint
  
• Clinical Global Impressions–Severity of Illness scale: from 4 to 1
  
• Children’s Depression Rating Scale (CDRS-R): from 74 to 40
  
• YMRS: from 20 to 6.
  

In another open-label study,³⁹ 16 of 18 youths (88%) with bipolar depression or mixed mania improved with lamotrigine alone or as adjunctive therapy, as shown by Clinical Global Impression of Change scores. CDRS-R scores also decreased by ≥50% in 11 of 17 who finished the study.

Safety: Severe rash. An age-related association with Stevens-Johnson syndrome may limit pediatric use of lamotrigine. Severe and potentially life-threatening rashes have been reported in 0.8% of children treated with lamotrigine.⁴⁰ Discontinue lamotrigine if a rash develops, unless it clearly is not drug-related. Three factors that increase rash risk include:

• co-administering lamotrigine with valproate
  
• higher-than-recommended initial dosages
  
• rapid dose titration.⁴¹
  

Most rashes appear in the first 8 weeks,⁴¹ though cases can occur after prolonged treatment.

Pediatric dosing. We find no published studies of efficacious dosages and plasma levels of lamotrigine in pediatric bipolar disorder (Table 4).^3,9,17 Based on our clinical experience, we recommend starting lamotrigine at 1 to 5 mg/kg/day (1 to 3 mg/kg/day if given with valproate) divided into two daily doses. Watch for rash or skin disorders. Do not exceed the recommended daily dosage by 200 mg in children age

Table 4

Using anticonvulsants in pediatric bipolar disorder patients

Drug	Recommended dosage	Target serum level
Carbamazepine	Age 6 to 12: 20 to 30 mg/kg/d	≥ 7.0 μg/L
	Age >12: 400 to 1,200 mg/d
Lamotrigine*	Unknown	Unknown
Oxcarbazepine	11 to 16 mg/kg/d (as adjunct)	Unknown
Topiramate*	Unknown	Unknown
Valproate	15 to 20 mg/kg/d	45 to 125 μg/mL (trough)
		85 to 110 μg/mL (target)
* No published studies found for efficacious dosage and plasma levels in pediatric bipolar disorder.
Dosage supported by case reports only; no studies found examining efficacious plasma levels.
Source: References 3,9, and 17.

TOPIRAMATE: LIMITED INFORMATION

Efficacy. Little is known about using topiramate in children and adolescents. A retrospective chart review⁴² of 26 patients with bipolar disorder type I (n=23) or II (n=3) showed adjunctive topiramate to be effective, with response rates of 73% for mania and 62% overall. Topiramate was well tolerated, and no serious events were reported.

 

A randomized, controlled trial of topiramate for acute mania in youths with type I bipolar disorder⁴³ was recently halted because of lack of efficacy in adul trials. Preliminary data from 56 of the pediatric patients—analyzed before the study was halted—showed improved YMRS scores. Although results were not statistically significant, the authors suggest topiramate might be effective in treating children and adolescents with bipolar disorder.

Safety: FDA warning. Decreased sodium bicarbonate leading to hyperchloremic metabolic acidosis has been reported in youths treated with topiramate for seizure disorder,⁴⁴ leading to an FDA warning to prescribers.³ Although no monitoring guidelines exist, we recommend baseline and periodic serum bicarbonate measurements and acidbase evaluations during topiramate treatment, especially when adding other antiepileptics.⁴⁴

Other rare but serious reactions include:

• impaired sweat production and resultant hyperthermia⁴⁵
  
• ophthalmologic symptoms characterized by secondary acute angle closure glaucoma and acute myacute myopia (usually within 1 month of starting treatment)⁴⁶
  
• sedation and cognitive difficulties.⁴⁷
  

Body weight. Body weight declined an average 5.8 kg across 8 weeks among 36 bipolar adults using topiramate (mean 176 mg/d).⁴⁷ We find that bipolar teens like topiramate because of weight loss, compared with weight gain with divalproex or lithium, but any pediatric weight loss requires monitoring.

Cognitive effects? Reports of “word finding difficulties” with topiramate⁴⁷ may suggest cognitive effects. Thus, be very cautious about using this medication in children and adolescents.

Related resources

• Kowatch R, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005;44(3):213-35.
  
• Yonkers K, Wisner K, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry 2004;161(4):608-20.
  
• American Academy of Child and Adolescent Psychiatry. Treatment guidelines for childhood psychiatric disorders. www.aacap.org
  

Disclosures

Dr. Kloos, Dr. Hitchcock, and Dr. Ronald Weller report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Elizabeth Weller has been a consultant to or received research grants from GlaxoSmithKline, Johnson & Johnson, Novartis Pharmaceuticals Corp., Abbott Laboratories, and Shire Pharmaceuticals.

Drug brand names

• Carbamazepine • Tegretol
  
• Divalproex • Depakote
  
• Lamotrigine • Lamictal
  
• Lithium • Eskalith, Lithobid, others
  
• Oxcarbazepine • Trileptal
  
• Topiramate • Topamax
  

Are anticonvulsants safe and effective mood stabilizers for children and adolescents with bipolar disorder? The answer is unclear because most bipolar disorder treatment trials have included adults only, and clinicians are desperate for data.¹

To help you care for young patients, we report what is known about the potential benefits and risks of using mood stabilizers and anticonvulsants in bipolar youth. We base our dosing, target serum level, and monitoring recommendations on clinical experience and the limited published evidence.

AGENTS OF CHOICE?

Bipolar disorder’s “atypical” presentation in children—often more irritability and explosiveness than euphoria—can complicate diagnosis. Bipolar children and adolescents often have comorbid attention-deficit/hyperactivity disorder (ADHD), other disruptive behavior disorders, or anxiety disorders. Thus, comorbidities and presenting symptoms often dictate medication choice.

An expert consensus guideline acknowledges that more evidence on pediatric bipolar disorder is needed. In the meantime, the guideline suggests trying valproate or lithium first to treat nonpsychotic mania in pediatric bipolar patients.¹ It also recommends three atypical antipsychotics— olanzapine, quetiapine, and risperidone—as potential first-line treatments. Valproate and lithium may be preferred because of atypicals’ risk of weight gain and metabolic syndrome.

Trying other anticonvulsants may be justified for bipolar youths who are not functioning well with first-line agents. Lamotrigine, for example, has antidepressant and antimanic effects.² When you try anticonvulsants that lack double-blind, placebo-controlled trials, we recommend that you:

• obtain consent from the parents and child
  
• monitor carefully for side effects.
  

LITHIUM: STRONGEST EVIDENCE

Lithium is one of the most well-studied medications for pediatric bipolar disorder and the only mood stabilizer FDA-approved for children and adolescents (Table 1).³ Although approved for ages 12 and older, lithium has been used in younger children in practice and in clinical trials.

Table 1

FDA-approval status of medications used to treat bipolar disorder

Medication	Indications for adults	Indications for children
Carbamazepine	Acute manic episode and acute mixed episode	Not approved
Lamotrigine	Maintenance therapy	Not approved
Lithium	Acute manic episode and maintenance therapy	Age ≥ 12 years
Oxcarbazepine	Not approved	Not approved
Topiramate	Not approved	Not approved
Valproate	Acute manic episode	Not approved
Source: Reference 3

Efficacy. In an open-label study of 100 adolescents with type I bipolar disorder,⁴ 63% met response criteria after 4 weeks of lithium and 26% showed manic symptom remission. Symptoms worsened in both groups, however, when 40 responders were randomly assigned to continue or discontinue lithium for 2 weeks.⁵ The authors speculated that these conflicting results might indicate that mood stabilization requires longer treatment. Contrary to earlier reports,⁶ manic adolescents with comorbid ADHD did not show poor response to lithium.

In the only double-blind, placebo-controlled trial of lithium in adolescents with bipolar disorder, some subjects had secondary substance dependency disorders.⁷ For 6 weeks, 25 outpatient adolescents received lithium (13 patients) or placebo (12 patients). Lithium was effective in treating bipolar and substance dependency symptoms, with significantly improved clinical global assessment scores and decreased positive urine assays for drugs. Little difference was seen in mood item scores on the Schedule for Affective Disorders and Schizophrenia, child version (KSADS-1986), whether patients were taking lithium or placebo.

Pediatric dosing. For bipolar patients ages 6 to 12, use the child’s weight to determine lithium dosage (Table 2).⁸ Maintain serum levels between 0.8 and 1.2 mEq/L,⁹ and check them frequently when starting therapy.¹⁰ After mood stabilization, check levels every 1 to 3 months or when you suspect noncompliance. Obtain renal and thyroid function values at baseline and every 4 to 6 months.

Table 2

Guide to dosing lithium for prepubertal school-aged children*

	Doses (mg)
Child’s weight (kg)	8 AM	12 PM	6 PM	Total daily
	150	150	300	600
25 to 40	300	300	300	900
40 to 50	300	300	600	1,200
50 to 60	600	300	600	1,500
* Maintain specified dose at least 5 days, drawing serum levels 12 hrs after the last lithium dose until two consecutive levels appear in the therapeutic range (0.6 to 1.2 mEq/L). Dose may then be adjusted based on serum level, side effects, or clinical response. Do not exceed 1.4 mEq/L.
Source: Reference 8

Safety. Common side effects reported in adolescents include weight gain (55%), polydipsia (33%), polyuria (25%), headache (23%), tremor (20%), and GI complaints (up to 18%).⁴ Neurologic side effects are associated with higher serum lithium levels (0.91 to 1.36 mEq/L)¹⁰ and occur more often in younger than in older children.¹¹ The cardiac defect Ebstein’s anomaly occurs in approximately 0.05 to 0.1% of children exposed to lithium in utero (Box).^12-16

Box

 

VALPROATE: OPEN-LABEL TRIALS ONLY

Efficacy. No double-blind, placebo-controlled study has shown valproate to be effective in treating bipolar disorder in children and adolescents. When used as monotherapy in open-label studies, valproate has produced response rates of:

• 53% in a 6-week, randomized, open-label trial in which 42 outpatients (mean age 11.4 years) with bipolar disorder type I or II received lithium, divalproex sodium, or carbamazepine⁹
  
• 61% in an open-label study of 40 patients ages 7 to 19 with a manic, hypomanic, or mixed episode who received divalproex for 2 to 8 weeks¹⁷
  
• 80% in an 8-week open-label trial of 40 patients ages 6 to 17 with bipolar disorder type I (77.5%) or type II (22.5%) and a Young Mania Rating Scale (YMRS)score ≥ 14.¹⁸
  

In a prospective trial, 90 patients ages 5 to 17 with bipolar disorder type I or II were treated with lithium plus divalproex sodium. After up to 20 weeks, 47% met criteria for depressive and manic symptom remission.¹⁹ A chart review has showed valproate’s efficacy in treating aggression and irritability in adolescent mania.²⁰

Safety: Black-box warnings. Valproate therapy carries risks of hepatic failure, pancreatitis, and birth defects. Monitor blood counts and hepatic enzymes throughout therapy (Table 3).³ Rare yet potentially fatal hepatic toxicity appears to occur most often in children age 21 Other studies suggest:

• an association with congenital malformations, including spina bifida and pulmonary atresia, in children exposed to valproate in utero⁶
  
• a link between valproate and hyperammonemic encephalopathy, especially in patients with urea cycle disorders²²
  
• potential for benign thrombocytopenia²³
  
• increased incidence of polycystic ovary syndrome—ovarian cysts, hyperandrogenism, chronic anovulation—in peripubertal mentally retarded women treated with valproate for seizure disorders.²⁴
  

Because of these risks, use caution when prescribing valproate to bipolar adolescent girls. Monitor menstrual cycle regularity, and collaborate with a gynecologist to watch for potentially dangerous effects.

Table 3

Mood stabilizers’ side effects and recommended monitoring

Medication	Major side effects	Monitoring
Carbamazepine	Allergic skin rash, drowsiness, blood dyscrasias, diplopia	CBC with reticulocytes, iron, LFTs, urinalysis, BUN, TFTs, sodium, serum carbamazepine levels
Lamotrigine	Stevens-Johnson syndrome, headache, dizziness, ataxia, somnolence, nausea, diplopia, blurred vision, rhinitis	No serum monitoring recommended
Lithium	Polyuria, polydipsia, nausea, diarrhea, tininecleatremor, enuresis, fatigue, ataxia, leukocytosis, malaise, cardiac arrhythmias, weight gain	BUN/creatinine, crearance, TFTs, calcium/phosphorus, ECG, serum lithium levels every 1 to 3 months once stabilized
Oxcarbazepine	Dizziness, somnolence/fatigue, ataxia/gait disturbance, vertigo, headache, tremor, rash, hyponatremia, hypersensitivity reaction, GI symptoms, diplopia	Sodium levels (particularly ifirst 3 months)
Topiramate	Hyperchloremic metabolic acidosis, oligohydrosis and hyperthermia, acute myopia, somnolence/fatigue, nausea, anorexia/weight loss, paresthesia, tremor, difficulty concentrating	BUN/creatinine, sodium bicarbonate
Valproate	Irritability/restlessness, ataxia, headache, weight gain, hyperammonemic encephalopathy, alopecia, GI upset, pancreatitis,sedation, thrombocytopenia, liver failure, polycystic ovaries/hyperandrogenism, teratogenic effects,rash	Ammonia, LFTs, bilirubin, CBC with platelets, serum valproate levels
BUN: blood urea nitrogen; CBC: complete blood count; ECG: electrocardiography; LFT: liver function tests; TFTs: thyroid function tests
Note: Bolded items included in black-box warnings
Source: Reference 3

Body weight. Valproate has been associated with weight gain. In a study of 372 bipolar adults, 21% reported a 5% weight-gain during 52 weeks of maintenance therapy, compared with 13% of patients on lithium and 7% on placebo.²⁵ Shortterm studies of adjunctive valproate in pediatric bipolar patients raise similar concerns.²⁶ Thus, monitor for weight gain and serum lipid changes in youths starting valproate therapy.

CARBAMAZEPINE: DRUG INTERACTION RISK

Carbamazepine is used less often than lithium or divalproex for bipolar disorder. It tends to be used adjunctively when lithium alone is ineffective.

Efficacy. In an open-label study,⁹ 42 patients ages 8 to 18 with bipolar disorder type I or II were randomly assigned to lithium, divalproex sodium, or carbamazepine monotherapy for 6 weeks. Response rates—measured as a ≥ 50% change from baseline in YMRS scores—were 53% with divalproex, 38% with lithium, and 38% with carbamazepine.

A retrospective review of 44 hospitalized bipolar patients ages 5 to 12 treated for at least 7 days with lithium, valproate, or carbamazepine reported higher (ie, worse) Clinical Global Impression of Improvement scores with carbamazepine.²⁷ Small sample sizes, particularly in the carbamazepine group, limited this naturalistic study.

Safety: Black-box warnings. Carbamazepine’s hematologic “black box” warns of increased risk of aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia. Risks associated with carbamazepine have been estimated at:

• aplastic anemia: 5.1/million patient years
  
• agranulocytosis: 1.4/million patient years.²⁸
  

Leukopenia is relatively more common and occurs in approximately 20% of children receiving carbamazepine.²⁹ Consider stopping carbamazepine when the white cell count falls below 3,000/mm³ (or the neutrophil count drops to 3).²⁹ Advise children and parents to watch for leukopenia’s signs and symptoms, including fever, infections, sore throat, and mouth ulcers.³

Body weight. Carbamazepine is not associated with significant weight gain, which could be clinically important for some patients.

 

Drug interactions. Carbamazepine activates the cytochrome P-450 liver enzyme system, increasing the metabolism of many medications and decreasing their blood levels. Consider monitoring serum levels when using carbamazepine with valproate, imipramine, corticosteroids, warfarin, oral contraceptives, and some antibiotics. Because carbamazepine induces its own metabolism, you might need to increase its dosage if its effects appear to be waning.³

Carbamazepine and tricyclic antidepressants may show cross-sensitivity because of structural similarity. Do not use monoamine oxidase inhibitors with carbamazepine; discontinue them at least 14 days before starting carbamazepine.³

OXCARBAZEPINE: FEWER INTERACTIONS

Oxcarbazepine has similar efficacy to carbamazepine but less side effect risk and does not require plasma level monitoring. A weaker inducer of CYP-450, it causes fewer clinically important drug-drug interactions and may be useful for patients who respond to carbamazepine but cannot tolerate its side effects.³⁰

Efficacy. Case studies^31,32 have been encouraging, but no published, double-blind, placebo-controlled studies support using oxcarbazepine in bipolar children and adolescents.

Safety. Oxcarbazepine appears to be generally well-tolerated but can cause potentially serious reactions—including hyponatremia.³³ Somnolence, emesis, and ataxia are the most common side effects in pediatric patients.³

Hyponatremia —plasma sodium 125 mEq/L—occurs in 2.5% of adults taking oxcarbazepine³ and has been reported in a similar percentage of children.³⁴ This potentially severe reaction—characterized by nausea, lethargy, malaise, headache, confusion, decreased seizure threshold, or simply decreased serum sodium³⁵—is usually noted within the first 12 weeks of therapy. The risk increases with concomitant use of other sodium-altering drugs, such as antidepressants or antipsychotics.³⁶

Evaluate serum sodium when starting oxcarbazepine, periodically in the first 3 months, and if symptoms occur.^34,36 For sodium levels of 125 to 130 mEq/L, obtain repeat measurements to confirm that hyponatremia is not worsening. Intervention is often required when levels fall below 125 mEq/L.³⁶

Other serious adverse reactions include Stevens-Johnson syndrome, toxic epidermal necrolysis, and hypersensitivity reactions; 25% to 30% of patients with hypersensitivity to carbamazepine also will react to oxcarbazepine.³³

Contraceptive concerns. Oxcarbazepine may reduce contraceptive efficacy by altering estrogen and progesterone plasma concentrations.³⁷ Consider other birth control methods for sexuallyactive bipolar adolescent girls.

LAMOTRIGINE

Neurologists often use lamotrigine for children with atypical seizure disorders, but no controlled data exist on the drug’s efficacy and safety in youths with bipolar disorder.

Efficacy. In a prospective, open-label study,³⁸ 13 adolescents with type I bipolar disorder received lamotrigine, 200 to 400 mg/d. After 12 weeks (mean dosage 241 mg/d), their symptoms had improved as shown by these mean scores:

• Montgomery-Asberg Depression Rating Scale: from 21 at baseline to 4 at endpoint
  
• Clinical Global Impressions–Severity of Illness scale: from 4 to 1
  
• Children’s Depression Rating Scale (CDRS-R): from 74 to 40
  
• YMRS: from 20 to 6.
  

In another open-label study,³⁹ 16 of 18 youths (88%) with bipolar depression or mixed mania improved with lamotrigine alone or as adjunctive therapy, as shown by Clinical Global Impression of Change scores. CDRS-R scores also decreased by ≥50% in 11 of 17 who finished the study.

Safety: Severe rash. An age-related association with Stevens-Johnson syndrome may limit pediatric use of lamotrigine. Severe and potentially life-threatening rashes have been reported in 0.8% of children treated with lamotrigine.⁴⁰ Discontinue lamotrigine if a rash develops, unless it clearly is not drug-related. Three factors that increase rash risk include:

• co-administering lamotrigine with valproate
  
• higher-than-recommended initial dosages
  
• rapid dose titration.⁴¹
  

Most rashes appear in the first 8 weeks,⁴¹ though cases can occur after prolonged treatment.

Pediatric dosing. We find no published studies of efficacious dosages and plasma levels of lamotrigine in pediatric bipolar disorder (Table 4).^3,9,17 Based on our clinical experience, we recommend starting lamotrigine at 1 to 5 mg/kg/day (1 to 3 mg/kg/day if given with valproate) divided into two daily doses. Watch for rash or skin disorders. Do not exceed the recommended daily dosage by 200 mg in children age

Table 4

Using anticonvulsants in pediatric bipolar disorder patients

Drug	Recommended dosage	Target serum level
Carbamazepine	Age 6 to 12: 20 to 30 mg/kg/d	≥ 7.0 μg/L
	Age >12: 400 to 1,200 mg/d
Lamotrigine*	Unknown	Unknown
Oxcarbazepine	11 to 16 mg/kg/d (as adjunct)	Unknown
Topiramate*	Unknown	Unknown
Valproate	15 to 20 mg/kg/d	45 to 125 μg/mL (trough)
		85 to 110 μg/mL (target)
* No published studies found for efficacious dosage and plasma levels in pediatric bipolar disorder.
Dosage supported by case reports only; no studies found examining efficacious plasma levels.
Source: References 3,9, and 17.

TOPIRAMATE: LIMITED INFORMATION

Efficacy. Little is known about using topiramate in children and adolescents. A retrospective chart review⁴² of 26 patients with bipolar disorder type I (n=23) or II (n=3) showed adjunctive topiramate to be effective, with response rates of 73% for mania and 62% overall. Topiramate was well tolerated, and no serious events were reported.

 

A randomized, controlled trial of topiramate for acute mania in youths with type I bipolar disorder⁴³ was recently halted because of lack of efficacy in adul trials. Preliminary data from 56 of the pediatric patients—analyzed before the study was halted—showed improved YMRS scores. Although results were not statistically significant, the authors suggest topiramate might be effective in treating children and adolescents with bipolar disorder.

Safety: FDA warning. Decreased sodium bicarbonate leading to hyperchloremic metabolic acidosis has been reported in youths treated with topiramate for seizure disorder,⁴⁴ leading to an FDA warning to prescribers.³ Although no monitoring guidelines exist, we recommend baseline and periodic serum bicarbonate measurements and acidbase evaluations during topiramate treatment, especially when adding other antiepileptics.⁴⁴

Other rare but serious reactions include:

• impaired sweat production and resultant hyperthermia⁴⁵
  
• ophthalmologic symptoms characterized by secondary acute angle closure glaucoma and acute myacute myopia (usually within 1 month of starting treatment)⁴⁶
  
• sedation and cognitive difficulties.⁴⁷
  

Body weight. Body weight declined an average 5.8 kg across 8 weeks among 36 bipolar adults using topiramate (mean 176 mg/d).⁴⁷ We find that bipolar teens like topiramate because of weight loss, compared with weight gain with divalproex or lithium, but any pediatric weight loss requires monitoring.

Cognitive effects? Reports of “word finding difficulties” with topiramate⁴⁷ may suggest cognitive effects. Thus, be very cautious about using this medication in children and adolescents.

Related resources

• Kowatch R, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005;44(3):213-35.
  
• Yonkers K, Wisner K, Stowe Z, et al. Management of bipolar disorder during pregnancy and the postpartum period. Am J Psychiatry 2004;161(4):608-20.
  
• American Academy of Child and Adolescent Psychiatry. Treatment guidelines for childhood psychiatric disorders. www.aacap.org
  

Disclosures

Dr. Kloos, Dr. Hitchcock, and Dr. Ronald Weller report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Elizabeth Weller has been a consultant to or received research grants from GlaxoSmithKline, Johnson & Johnson, Novartis Pharmaceuticals Corp., Abbott Laboratories, and Shire Pharmaceuticals.

Drug brand names

• Carbamazepine • Tegretol
  
• Divalproex • Depakote
  
• Lamotrigine • Lamictal
  
• Lithium • Eskalith, Lithobid, others
  
• Oxcarbazepine • Trileptal
  
• Topiramate • Topamax
  

In clinical practice, 50% to 80% of bipolar patients receive long-term antidepressants,¹ although potential benefits probably outweigh risks in 20% to 40%. This gap suggests that psychiatrists could do more to stay out of trouble when prescribing antidepressants for patients with bipolar depression.

Antidepressants have not shown efficacy in long-term treatment, and evidence of their effectiveness in acute bipolar depression is limited. They appear to pose greater risk of switching and mood destabilization for some patients and certain types of bipolar illness, and some antidepressant classes are more worrisome than others.

Because carefully analyzing risks and benefits is essential when considering antidepressants for a patient with bipolar illness, this article clarifies that delicate balance and offers evidence-based recommendations for using antidepressants in bipolar depression.

ACUTE THERAPY

Clinical trials support antidepressants as the treatment of choice for unipolar depression, but less evidence supports efficacy and safety in acute bipolar depression. Depressive episodes predominate in bipolar disorder, with chronic subsyndromal symptoms being most characteristic.^2,3 Compared with mania or hypomania, depressive episodes:

• last longer and are more frequent
• contribute to greater morbidity and mortality
• pose a greater treatment challenge.

Antidepressants have shown benefit in multiple double-blind, bipolar depression trials and were as effective as mood stabilizers in one small study.⁴ Even so, no trials have found them more effective than mood stabilizers in acute bipolar depression.

Controlled trials. Two randomized, double-blind, placebo-controlled trials have examined antidepressant use in bipolar depression.^5,6 The larger and better designed—a prospective 10-week study by Nemeroff et al⁶—examined 117 outpatients with type I bipolar disorder.

Subjects who had been taking lithium (serum levels 0.5 to 1.2 mEq/L) for ≥6 weeks and were experiencing moderate breakthrough depression then received paroxetine (mean dosage 32.6 mg/d), imipramine (mean dosage 166.7 mg/d), or placebo. Therapeutic response was defined as ≤7 on the Hamilton Rating Scale for Depression (HRSD) or ≤2 on the Clinical Global Impression (CGI) scale—normally considered criteria for depressive remission.

The authors hoped to show a statistically significant medication-placebo difference, but the antidepressants’ effects were similar to those of placebo. Thus, adding antidepressants to lithium conferred no added benefit, though the small sample size may have created a false negative.

Interestingly, a post-hoc analysis found different treatment outcomes when patients were separated into two groups by lithium serum levels:

• low therapeutic (≤0.8 mEq/L)
• high therapeutic (>0.8 mEq/L).

Adding antidepressants significantly reduced HRSD scores compared with placebo in the low lithium group but not in the high lithium group. Thus, therapeutic lithium levels may have moderate antidepressant effects, and adding antidepressants may help patients who cannot tolerate therapeutic lithium levels.

MAINTENANCE THERAPY

Antidepressants may have modest efficacy in acute bipolar depression, but they have not shown benefit—with or without mood stabilizers—in 7 studies of bipolar depression maintenance therapy. Most were double-blind, long-term trials comparing tricyclic antidepressants (TCAs) with lithium or adding TCAs to lithium; 3 were placebo-controlled.⁷ Antidepressants were not more effective than mood stabilizers such as lithium or lamotrigine in preventing bipolar depression.

Type II patients. For depression in type II bipolar disorder, the only data on using antidepressants as acute or maintenance therapy come from post-hoc analyses of unipolar depression trials and retrospective assessments of “manic switches.” No specific mania rating scales have been used.^8,9

Long-term antidepressants. Two naturalistic studies by Altshuler et al^10,11 explored continuing antidepressants as bipolar depression maintenance treatment. The larger trial¹¹ included 84 patients (most with type I bipolar disorder) who experienced breakthrough depression while taking a mood stabilizer. This subset (15%) of the Stanley Foundation Bipolar Network had tolerated antidepressants at least 2 months without switching into hypomania/mania and remained in remission at least 6 weeks. None were rapid cyclers.

With counseling from clinicians, patients chose to continue or discontinue taking antidepressants. Relapse rates after 1 year were 70% in patients who stopped antidepressants after <6 months, compared with 24% in those who continued taking them for 1 year. The authors concluded that bipolar patients may benefit from staying on antidepressants at least 6 months and perhaps 12 or more months after depressive remission.

Keep in mind, however, that these findings may not apply to all bipolar patients. This study pertains to a minority of robust responders—none of whom were rapid cyclers—who tolerated the medication well and were not randomly assigned to continue or discontinue antidepressants. Other evidence suggests that depressed bipolar patients are three times more likely than unipolar patients (54% vs 16%) to develop tolerance to antidepressants.¹²

ANTIDEPRESSANT RISKS

Risks of using antidepressants in bipolar patients include acute switches into hypo/mania, usually within 8 weeks of starting an antidepressant, and new-onset mood destabilization—with cycle acceleration or rapid cycling—or worsening of pre-existing rapid cycling (Table 1).¹

 

Table 1

Switches vs destabilization: Defining antidepressant risks

Risk	Definition
Acute switches to hypomania/mania	≤8 weeks by convention, unless dosage is increased
Mood destabilization
Cycle acceleration	Increase of ≥2 mood episodes while taking antidepressants, compared with a similar exposure time before treatment
Rapid cycling	≥4mood episodes in previous 12 months (new-onset or exacerbation of baseline pattern), according to DSM-IV-TR
Source: Reference 1

Switching risk. Some researchers have reported antidepressant-induced switches to be milder and more brief than spontaneous hypo/manias,¹³ whereas others have observed more-severe mixed¹⁴ and even psychotic episodes. Risk factors that may predispose patients to switching include:

• personal or family history of switches or mood destabilization
• family history of bipolar disorder
• exposure to multiple antidepressant trials
• history of substance abuse or dependence
• early onset (age <25) and/or treatment of mood symptoms.^15,16

True switch rates are difficult to estimate because clinical trials have used different switching definitions, durations, antidepressants (with or without mood stabilizers, and with different mood stabilizers), and cohorts (often excluding rapid cyclers). Except for the Nemeroff et al study,⁶ no prospective, double-blind, placebo-controlled studies have examined switch rates, and even this study was not large enough to detect statistically significant differences.

Thus we must rely on naturalistic evidence that is less rigorous but more applicable to clinical practice. This literature reveals switch rates of:

• 30% to 60% with TCAs and monoamine oxidase inhibitors (MAOIs)
• 15% to 27% with selective serotonin reuptake inhibitors (SSRIs), bupropion, and venlafaxine.

Average switch rates are thought to be approximately 40% with TCAs/MAOIs and 20% with the newer antidepressants.¹ Preliminary data associate venlafaxine with higher switch rates than SSRIs or bupropion, so perhaps antidepressants with some noradrenergic effects (including TCAs) facilitate the switching phenomenon.¹⁷

Mood destabilization. Three randomized, controlled trials suggest that antidepressants—especially TCAs—increase the risk of cycle acceleration or rapid cycling in bipolar patients. The best designed study—sponsored by the National Institute of Mental Health—was a 10-year, prospective, double-blind trial of 51 rapid-cycling patients. The trial’s on-off-on design showed that 20% of these patients developed rapid cycling as a direct result of taking TCAs.¹⁸

Unfortunately, most randomized, controlled trials are not designed to show a relationship between antidepressants and mood destabilization. Observational literature is mixed but suggests that antidepressant use is associated with rapid cycling. Most evidence supports a relationship between antidepressants and long-term mood destabilization—especially cycle acceleration, which is believed to occur in approximately 20% of patients using TCAs or SSRIs.¹

Are mood stabilizers protective? Some studies suggest that mood stabilizers may help protect against switches. Most of the evidence—using lithium and TCAs—suggests a 50% drop in switch rates when patients receive mood stabilizers with antidepressants. In one study, lithium was more protective than anticonvulsants for SSRI-induced mania, but the difference was not statistically significant.¹⁹

Because study data variability, we don’t know if some mood stabilizers are more effective than others in preventing antidepressant-related switching. This variability is likely caused by:

• medication-specific factors (such as higher switch rates with TCAs and possibly dual-reuptake inhibitors than with SSRIs)
• illness-specific factors (such as rapid cycling and cycle pattern)
• patient-specific factors, already described. Mood stabilizers appear to be more protective against switching than against mood destabilization, in which their effects are less clear (Table 2).¹⁵

Table 2

Frequency of switching or mood destabilization with antidepressants

Bipolar risk	Causative agents	Frequency	Mood stabilizer effect
Acute switch	TCAs, MAOIs	~ 40%	Variably protective; apparent partial risk reduction ~ 50%
	SSRIs, bupropion, venlafaxine	~ 20%
Mood destabilization	TCAs, SSRIs	~ 20%	Not as clearly protective against mood destabilization as against acute switching
TCAs: tricyclic antidepressants; MAOIs: monoamine oxidase inhibitors; SSRIs: selective serotonin reuptake inhibitors
Source: References 1, 15

TREATMENT RECOMMENDATIONS

How does a clinician decide which bipolar depressed patients should receive antidepressants?

The first step in treating bipolar depression (Algorithm) is to provide optimal dosages of the patient’s mood stabilizers. Consensus guidelines²⁰ suggest lithium or lamotrigine as first-line treatments for bipolar depression. Evidence also shows efficacy for atypical antipsychotics, including the olanzapine/fluoxetine combination (OFC)—FDA-approved for acute bipolar depression²¹—and quetiapine monotherapy.²² Dosages vary, but suggested ranges include:

• lithium: 0.6 to 1.2 mEq/L; aim for approximately 0.8 mEq/L, but some data suggest 0.6 to 0.7 mEq/L may be sufficient
• lamotrigine: 50 to 250 mg/d (the higher dosage is based on maintenance studies)
• OFC: 6 to 12 mg olanzapine/25 to 50 mg fluoxetine
• quetiapine: 300 to 600 mg/d.

The next step is an antidepressant risk/benefit analysis, weighing the considerable risks of switching/mood destabilization with the patient’s depressive illness severity, type of bipolar disorder (such as rapid cycling), and cycle pattern.

Algorithm Recommended treatment of bipolar depression

Cycle patterns. In a naturalistic study, Macqueen et al²³ used life chart data for 42 bipolar patients to assess how the mood state preceding a prospectively observed depressive episode affected treatment response:

 

• A euthymic mood state in the previous 2 months represented a uniphasic pattern and an isolated depressive episode.
• A preceding hypomanic/manic mood state indicated a biphasic pattern.

Approximately 60% of bipolar patients show a biphasic pattern, although the episode sequence is usually depression-hypomania/mania rather than hypomania/mania-depression. These authors included patients whose breakthrough depressive episodes were treated with an antidepressant or a putative mood stabilizer but not an atypical antipsychotic.

In patients treated with an antidepressant, the response-to-switch ratio was 10:1 for those previously euthymic, compared with a less beneficial 0.75:1 in previously hypomanic/manic patients. This small study suggests that a patient’s cycle pattern may help you decide whether to use an antidepressant for bipolar depression.

How to use antidepressants. As described, some depressed bipolar patients are better candidates for antidepressant therapy than others (Table 3).

Table 3

Antidepressants for bipolar depression? Consider ‘ideal patient’ traits

Severe depression refractory to optimal doses of ≥1 mood stabilizers
Uniphasic cycle pattern
Not rapid cycling
No history of switching or mood destabilization
No comorbid substance abuse

Use antidepressants cautiously and conservatively in a minority of bipolar patients (approximately 20% to 40%) and usually for short periods (discussed below). SSRIs or bupropion are first-line agents because:

• they appear to be relatively less likely to cause switching than other antidepressant classes
• controlled trials have examined these antidepressants in bipolar depression.

Depressed patients with very mild, nonrapid-cycling, bipolar II disorder and no more than three previous hypomanic episodes might be candidates for antidepressant monotherapy. In other bipolar patients, always use at least one mood stabilizer if you decide to use an antidepressant.

TREATMENT DURATION

No randomized, controlled trial has examined what duration of antidepressant treatment may be optimum for bipolar depression, but consensus guidelines recommend:

• approximately 3 to 7 months, depending on depression severity
• approximately one-half that duration (2 to 4 months) for rapid-cycling bipolar disorder.²⁰

Because of the switching risk, one could also argue for a shorter treatment duration in patients with a biphasic cycle pattern—especially with an episode sequence of depression to hypomania/mania to euthymia.

Ideally, patients would stay on antidepressants no longer than the natural course of their depression (usually 2 to 6 months in bipolar depression), although it could be shorter in rapid cyclers. Approximately 15% to 20% of patients may have a robust initial response to antidepressants and need to be maintained on these medications, especially after several tapers and relapses have failed.

Related resources

• Bipolar Clinic and Research Program. Massachusetts General Hospital. Includes tools for clinicians and the clinical site for the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). www.manicdepressive.org.
• Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press, 1990.

Drug brand names

• Bupropion • Wellbutrin
• Imipramine • Tofranil
• Lamotrigine • Lamictal
• Lithium • Lithobid, others
• Olanzapine/fluoxetine • Symbyax
• Paroxetine • Paxil
• Quetiapine • Seroquel
• Venlafaxine • Effexor

Disclosures

Dr. Altman is a speaker for Forest Pharmaceuticals, Janssen Pharmaceutica, AstraZeneca Pharmaceuticals, and Abbott Laboratories.