Evidence-Based Reviews

Most evidence supporting antipsychotics as a treatment for migraine headaches and cluster headaches is based on small studies and chart reviews. Some research suggests antipsychotics may effectively treat nausea but side effects such as akathisia may limit their use.

Migraine headaches

Antipsychotic treatment of migraines is supported by the theory that dopaminergic hyperactivity leads to migraine headaches (Table 1). Antipsychotics have been used off-label in migraine patients who do not tolerate triptans or have status migrainosus—intense, debilitating migraine lasting >72 hours.¹ Primarily a result of D2 receptor blockade, the serotonergic effects of some second-generation antipsychotics (SGAs) may prevent migraine recurrence. The first-generation antipsychotics (FGAs) prochlorperazine, droperidol, haloperidol, and chlorpromazine have been used for migraine headaches (Table 2).^1-27

Prochlorperazine may be an effective treatment of acute headaches⁹ and refractory chronic daily headache.¹⁰ Studies show that buccal prochlorperazine is more effective than oral ergotamine tartrate¹¹ and IV prochlorperazine is more effective than IV ketorolac¹² or valproate²⁸ for treating acute headache.

Evidence suggests that chlorpromazine administered IM² or IV³ is better than placebo for managing migraine pain. In a study comparing IV chlorpromazine, lidocaine, and dihydroergotamine, patients treated with chlorpromazine showed more persistent headache relief 12 to 24 hours post-dose.⁴ In another study, IV chlorpromazine, 25 mg, was as effective as IM ketorolac, 60 mg.⁵

Droperidol has been shown to be effective for managing headache, specifically status migrainosus.⁶ Patients with “benign headache”—headache not caused by an underlying medical disorder—who received droperidol reported greater reduction in visual analog pain scores within 1 hour of dosing compared with those taking prochlorperazine.⁷ In a randomized trial comparing IM droperidol and IM meperidine, patients with an acute migraine who received droperidol had improved scores on the visual pain analog scale and required less “rescue medication” for breakthrough pain.⁸ The FDA has issued a “black-box” warning of QTc prolongation with droperidol.

In a double blind, placebo-controlled trial, IV haloperidol, 5 mg, effectively treated migraine headache in 80% of patients compared with 15% of those who received placebo. However, 16% of patients considered the side effects—mainly sedation and akathisia—intolerable and 7% had symptom relapse.¹³ In an open-label trial of 6 patients with migraine headache, all patients achieved complete or substantial headache relief 25 to 65 minutes after receiving IV haloperidol, 5 mg.¹⁴

SGAs often antagonize 5-HT1D receptors and theoretically can render triptan therapy—which stimulates pre-synaptic 5-HT1D receptors—ineffective. This has not been seen clinically and instead, dose-related, non-specific headaches are a common adverse event with SGAs.^29,30 A retrospective chart review found olanzapine provided relief for refractory headaches in patients who had failed ≥4 preventive medications. Olanzapine significantly decreased headache days, from 27.5±4.9 before treatment to 21.1±10.7 after treatment. Olanzapine also improved headache severity (measured on a 0 to 10 scale) from 8.7±1.6 before treatment to 2.2±2.1 after treatment.¹⁶ Researchers found that 2.5 or 5 mg of olanzapine relieved acute migraines for most patients, with repeat dosing as needed up to 20 mg/d. For prophylactic treatment, 5 or 10 mg of olanzapine was used. Olanzapine’s antinociceptive effect may be related to its action on α-2 adrenoreceptors and to a lesser extent on involvement of opioid and serotonergic receptors.¹⁷

In a case series, 3 migraine patients who met criteria for chronic daily headache and migraines but did not have a psychiatric disorder reported significant and sustained headache improvement when treated with risperidone.¹⁹ In a case series of 3 migraine patients with co-occurring psychiatric disorders, aripiprazole decreased migraine frequency and severity.¹⁵ Although limited data support quetiapine’s efficacy in treating acute migraines, in an open-label, pilot study, patients taking quetiapine, 25 to 75 mg/d, demonstrated a decrease in mean frequency of migraine days from 10.2 to 6.2 and decreased use of rescue medications from 2.3 to 1.2 days per week.¹⁸

Table 1

Possible rationale for antipsychotic use for headaches and nausea

Condition	Possible rationale
Migraine	Patients are hypersensitive to dopamine agonists or dopamine transporter dysfunction. Some evidence that the dopamine D2 (DRD2) gene is involved
Cluster headache	Pain alleviation possibly related to dopamine receptor antagonism
Nausea	D2 and H1 receptor blockage

Table 2

Antipsychotics for headache and nausea: Strength of the evidence

Condition	Strength of evidencea
Migraine	Intermediate: Chlorpromazine,2-5 droperidol,6-8 prochlorperazine1,10-12
	Weak: Haloperidol13,14
	Very weak: Aripiprazole,15 olanzapine,16,17 quetiapine,18 ziprasidone19
Cluster headache	Weak: Chlorpromazine20
	Very weak: Clozapine,21 olanzapine22
Nausea/vomiting	Intermediate: Droperidol,23 metoclopramide,24 prochlorperazine,25 promethazine25
	Weak: Olanzapine26,27
aStrong: Multiple, well-designed RCTs directly relevant to the recommendation, yielding consistent findings Intermediate: Some evidence from RCTs that support the recommendation, but the scientific support was not optimal Weak: Consensus recommendation in the absence of relevant randomized controlled trials and better evidence than case report or series Very weak: Case reports or case series or preliminary studies RCTs: randomized controlled trials

 

Cluster headaches

Subcutaneous sumatriptan and inhaled oxygen are first-line treatments for cluster headaches.³¹ A single, small study²⁰ reported that chlorpromazine may prevent cluster headaches, which suggests that D2 receptor blockade may treat such headaches. However, limited supporting evidence relegates its use to a second- or third-line therapy.

In an open-label study (N = 5), olanzapine provided some relief of pain associated with cluster headache within 20 minutes of administration.²² In another study, patients with schizophrenia and comorbid cluster headaches improved with olanzapine.²¹

Because evidence is limited to small prospective studies, antipsychotic treatment of cluster headache is not well established.^20-22 However, olanzapine may benefit patients with comorbid cluster headaches and schizophrenia.

Nausea

The signaling pathways that mediate emesis involve 5-HT3, D2, muscarinic, and histamine receptors.³² Before 5-HT3 antagonists were available, the FGAs metoclopramide, droperidol, prochlorperazine, and promethazine were used to manage acute emesis in emergency departments.²³ A double-blind, placebo-controlled trial found IV droperidol, 1.25 mg, was more effective than metoclopramide, 10 mg, or prochlorperazine, 10 mg, for relieving moderate to severe nausea in adult patients.²³ However, droperidol and prochlorperazine were associated with akathisia. In addition, this trial did not find a clinically significant difference between groups—including placebo—in anxiety, sedation, or need for rescue medications.²³ Use of droperidol to treat nausea decreased after the drug received a “black-box” warning for QT prolongation and torsades de pointes.

Metoclopramide is effective for treating acute migraine and associated nausea²⁴ and has been used to treat gastroparesis because of its effect on upper GI motility. Phenothiazines have been used to treat nausea and studies have shown prochlorperazine to be more effective than promethazine.²⁵ Some studies of prochlorperazine have reported a 44% incidence of akathisia, which limits the drug’s use in patients who may be sensitive to such effects.³³ Promethazine can cause sedation and risk of tissue necrosis at the injection site.³⁴

Among SGAs, olanzapine effectively prevented acute and delayed chemotherapy-induced nausea and vomiting in a proof-of-concept study of patients receiving high and moderate emetogenic therapies.^26,27 National Comprehensive Cancer Network guidelines cite olanzapine as a potential option for treating refractory and breakthrough emesis.³⁵ In a small study (N = 50), olanzapine showed comparable anti-nausea effect to aprepitant—a neurokinin 1 receptor antagonist—and effectively prevented chemotherapy-induced nausea and vomiting in highly emetogenic chemotherapy.³⁶

Related Resources

• Kelley NE, Tepper DE. Rescue therapy for acute migraine, part 2: neuroleptics, antihistamines, and others. Headache. 2012;52(2):292-306.
• Dusitanond P, Young WB. Neuroleptics and migraine. Cent Nerv Syst Agents Med Chem. 2009;9(1):63-70.

Drug Brand Names

• Aprepitant • Emend
• Aripiprazole • Abilify
• Chlorpromazine • Thorazine
• Dihydroergotamine • D.H.E 45
• Droperidol • Inapsine
• Ergotamine tartrate • Ergostat
• Haloperidol • Haldol
• Ketorolac • Toradol
• Lidocaine • Xylocaine, Lidoderm
• Meperidine • Demerol
• Metoclopramide • Reglan
• Olanzapine • Zyprexa
• Prochlorperazine • Compazine
• Promethazine • Phenergan
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sumatriptan • Imitrex
• Valproate • Depakote

Disclosures

Dr. Macaluso has received grant or research support from EnVivo Pharmaceuticals, Janssen L.P., and Pfizer, Inc.

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

Most evidence supporting antipsychotics as a treatment for migraine headaches and cluster headaches is based on small studies and chart reviews. Some research suggests antipsychotics may effectively treat nausea but side effects such as akathisia may limit their use.

Migraine headaches

Antipsychotic treatment of migraines is supported by the theory that dopaminergic hyperactivity leads to migraine headaches (Table 1). Antipsychotics have been used off-label in migraine patients who do not tolerate triptans or have status migrainosus—intense, debilitating migraine lasting >72 hours.¹ Primarily a result of D2 receptor blockade, the serotonergic effects of some second-generation antipsychotics (SGAs) may prevent migraine recurrence. The first-generation antipsychotics (FGAs) prochlorperazine, droperidol, haloperidol, and chlorpromazine have been used for migraine headaches (Table 2).^1-27

Prochlorperazine may be an effective treatment of acute headaches⁹ and refractory chronic daily headache.¹⁰ Studies show that buccal prochlorperazine is more effective than oral ergotamine tartrate¹¹ and IV prochlorperazine is more effective than IV ketorolac¹² or valproate²⁸ for treating acute headache.

Evidence suggests that chlorpromazine administered IM² or IV³ is better than placebo for managing migraine pain. In a study comparing IV chlorpromazine, lidocaine, and dihydroergotamine, patients treated with chlorpromazine showed more persistent headache relief 12 to 24 hours post-dose.⁴ In another study, IV chlorpromazine, 25 mg, was as effective as IM ketorolac, 60 mg.⁵

Droperidol has been shown to be effective for managing headache, specifically status migrainosus.⁶ Patients with “benign headache”—headache not caused by an underlying medical disorder—who received droperidol reported greater reduction in visual analog pain scores within 1 hour of dosing compared with those taking prochlorperazine.⁷ In a randomized trial comparing IM droperidol and IM meperidine, patients with an acute migraine who received droperidol had improved scores on the visual pain analog scale and required less “rescue medication” for breakthrough pain.⁸ The FDA has issued a “black-box” warning of QTc prolongation with droperidol.

In a double blind, placebo-controlled trial, IV haloperidol, 5 mg, effectively treated migraine headache in 80% of patients compared with 15% of those who received placebo. However, 16% of patients considered the side effects—mainly sedation and akathisia—intolerable and 7% had symptom relapse.¹³ In an open-label trial of 6 patients with migraine headache, all patients achieved complete or substantial headache relief 25 to 65 minutes after receiving IV haloperidol, 5 mg.¹⁴

SGAs often antagonize 5-HT1D receptors and theoretically can render triptan therapy—which stimulates pre-synaptic 5-HT1D receptors—ineffective. This has not been seen clinically and instead, dose-related, non-specific headaches are a common adverse event with SGAs.^29,30 A retrospective chart review found olanzapine provided relief for refractory headaches in patients who had failed ≥4 preventive medications. Olanzapine significantly decreased headache days, from 27.5±4.9 before treatment to 21.1±10.7 after treatment. Olanzapine also improved headache severity (measured on a 0 to 10 scale) from 8.7±1.6 before treatment to 2.2±2.1 after treatment.¹⁶ Researchers found that 2.5 or 5 mg of olanzapine relieved acute migraines for most patients, with repeat dosing as needed up to 20 mg/d. For prophylactic treatment, 5 or 10 mg of olanzapine was used. Olanzapine’s antinociceptive effect may be related to its action on α-2 adrenoreceptors and to a lesser extent on involvement of opioid and serotonergic receptors.¹⁷

In a case series, 3 migraine patients who met criteria for chronic daily headache and migraines but did not have a psychiatric disorder reported significant and sustained headache improvement when treated with risperidone.¹⁹ In a case series of 3 migraine patients with co-occurring psychiatric disorders, aripiprazole decreased migraine frequency and severity.¹⁵ Although limited data support quetiapine’s efficacy in treating acute migraines, in an open-label, pilot study, patients taking quetiapine, 25 to 75 mg/d, demonstrated a decrease in mean frequency of migraine days from 10.2 to 6.2 and decreased use of rescue medications from 2.3 to 1.2 days per week.¹⁸

Table 1

Possible rationale for antipsychotic use for headaches and nausea

Condition	Possible rationale
Migraine	Patients are hypersensitive to dopamine agonists or dopamine transporter dysfunction. Some evidence that the dopamine D2 (DRD2) gene is involved
Cluster headache	Pain alleviation possibly related to dopamine receptor antagonism
Nausea	D2 and H1 receptor blockage

Table 2

Antipsychotics for headache and nausea: Strength of the evidence

Condition	Strength of evidencea
Migraine	Intermediate: Chlorpromazine,2-5 droperidol,6-8 prochlorperazine1,10-12
	Weak: Haloperidol13,14
	Very weak: Aripiprazole,15 olanzapine,16,17 quetiapine,18 ziprasidone19
Cluster headache	Weak: Chlorpromazine20
	Very weak: Clozapine,21 olanzapine22
Nausea/vomiting	Intermediate: Droperidol,23 metoclopramide,24 prochlorperazine,25 promethazine25
	Weak: Olanzapine26,27
aStrong: Multiple, well-designed RCTs directly relevant to the recommendation, yielding consistent findings Intermediate: Some evidence from RCTs that support the recommendation, but the scientific support was not optimal Weak: Consensus recommendation in the absence of relevant randomized controlled trials and better evidence than case report or series Very weak: Case reports or case series or preliminary studies RCTs: randomized controlled trials

 

Cluster headaches

Subcutaneous sumatriptan and inhaled oxygen are first-line treatments for cluster headaches.³¹ A single, small study²⁰ reported that chlorpromazine may prevent cluster headaches, which suggests that D2 receptor blockade may treat such headaches. However, limited supporting evidence relegates its use to a second- or third-line therapy.

In an open-label study (N = 5), olanzapine provided some relief of pain associated with cluster headache within 20 minutes of administration.²² In another study, patients with schizophrenia and comorbid cluster headaches improved with olanzapine.²¹

Because evidence is limited to small prospective studies, antipsychotic treatment of cluster headache is not well established.^20-22 However, olanzapine may benefit patients with comorbid cluster headaches and schizophrenia.

Nausea

The signaling pathways that mediate emesis involve 5-HT3, D2, muscarinic, and histamine receptors.³² Before 5-HT3 antagonists were available, the FGAs metoclopramide, droperidol, prochlorperazine, and promethazine were used to manage acute emesis in emergency departments.²³ A double-blind, placebo-controlled trial found IV droperidol, 1.25 mg, was more effective than metoclopramide, 10 mg, or prochlorperazine, 10 mg, for relieving moderate to severe nausea in adult patients.²³ However, droperidol and prochlorperazine were associated with akathisia. In addition, this trial did not find a clinically significant difference between groups—including placebo—in anxiety, sedation, or need for rescue medications.²³ Use of droperidol to treat nausea decreased after the drug received a “black-box” warning for QT prolongation and torsades de pointes.

Metoclopramide is effective for treating acute migraine and associated nausea²⁴ and has been used to treat gastroparesis because of its effect on upper GI motility. Phenothiazines have been used to treat nausea and studies have shown prochlorperazine to be more effective than promethazine.²⁵ Some studies of prochlorperazine have reported a 44% incidence of akathisia, which limits the drug’s use in patients who may be sensitive to such effects.³³ Promethazine can cause sedation and risk of tissue necrosis at the injection site.³⁴

Among SGAs, olanzapine effectively prevented acute and delayed chemotherapy-induced nausea and vomiting in a proof-of-concept study of patients receiving high and moderate emetogenic therapies.^26,27 National Comprehensive Cancer Network guidelines cite olanzapine as a potential option for treating refractory and breakthrough emesis.³⁵ In a small study (N = 50), olanzapine showed comparable anti-nausea effect to aprepitant—a neurokinin 1 receptor antagonist—and effectively prevented chemotherapy-induced nausea and vomiting in highly emetogenic chemotherapy.³⁶

Related Resources

• Kelley NE, Tepper DE. Rescue therapy for acute migraine, part 2: neuroleptics, antihistamines, and others. Headache. 2012;52(2):292-306.
• Dusitanond P, Young WB. Neuroleptics and migraine. Cent Nerv Syst Agents Med Chem. 2009;9(1):63-70.

Drug Brand Names

• Aprepitant • Emend
• Aripiprazole • Abilify
• Chlorpromazine • Thorazine
• Dihydroergotamine • D.H.E 45
• Droperidol • Inapsine
• Ergotamine tartrate • Ergostat
• Haloperidol • Haldol
• Ketorolac • Toradol
• Lidocaine • Xylocaine, Lidoderm
• Meperidine • Demerol
• Metoclopramide • Reglan
• Olanzapine • Zyprexa
• Prochlorperazine • Compazine
• Promethazine • Phenergan
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sumatriptan • Imitrex
• Valproate • Depakote

Disclosures

Dr. Macaluso has received grant or research support from EnVivo Pharmaceuticals, Janssen L.P., and Pfizer, Inc.

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

Most evidence supporting antipsychotics as a treatment for migraine headaches and cluster headaches is based on small studies and chart reviews. Some research suggests antipsychotics may effectively treat nausea but side effects such as akathisia may limit their use.

Migraine headaches

Antipsychotic treatment of migraines is supported by the theory that dopaminergic hyperactivity leads to migraine headaches (Table 1). Antipsychotics have been used off-label in migraine patients who do not tolerate triptans or have status migrainosus—intense, debilitating migraine lasting >72 hours.¹ Primarily a result of D2 receptor blockade, the serotonergic effects of some second-generation antipsychotics (SGAs) may prevent migraine recurrence. The first-generation antipsychotics (FGAs) prochlorperazine, droperidol, haloperidol, and chlorpromazine have been used for migraine headaches (Table 2).^1-27

Prochlorperazine may be an effective treatment of acute headaches⁹ and refractory chronic daily headache.¹⁰ Studies show that buccal prochlorperazine is more effective than oral ergotamine tartrate¹¹ and IV prochlorperazine is more effective than IV ketorolac¹² or valproate²⁸ for treating acute headache.

Evidence suggests that chlorpromazine administered IM² or IV³ is better than placebo for managing migraine pain. In a study comparing IV chlorpromazine, lidocaine, and dihydroergotamine, patients treated with chlorpromazine showed more persistent headache relief 12 to 24 hours post-dose.⁴ In another study, IV chlorpromazine, 25 mg, was as effective as IM ketorolac, 60 mg.⁵

Droperidol has been shown to be effective for managing headache, specifically status migrainosus.⁶ Patients with “benign headache”—headache not caused by an underlying medical disorder—who received droperidol reported greater reduction in visual analog pain scores within 1 hour of dosing compared with those taking prochlorperazine.⁷ In a randomized trial comparing IM droperidol and IM meperidine, patients with an acute migraine who received droperidol had improved scores on the visual pain analog scale and required less “rescue medication” for breakthrough pain.⁸ The FDA has issued a “black-box” warning of QTc prolongation with droperidol.

In a double blind, placebo-controlled trial, IV haloperidol, 5 mg, effectively treated migraine headache in 80% of patients compared with 15% of those who received placebo. However, 16% of patients considered the side effects—mainly sedation and akathisia—intolerable and 7% had symptom relapse.¹³ In an open-label trial of 6 patients with migraine headache, all patients achieved complete or substantial headache relief 25 to 65 minutes after receiving IV haloperidol, 5 mg.¹⁴

SGAs often antagonize 5-HT1D receptors and theoretically can render triptan therapy—which stimulates pre-synaptic 5-HT1D receptors—ineffective. This has not been seen clinically and instead, dose-related, non-specific headaches are a common adverse event with SGAs.^29,30 A retrospective chart review found olanzapine provided relief for refractory headaches in patients who had failed ≥4 preventive medications. Olanzapine significantly decreased headache days, from 27.5±4.9 before treatment to 21.1±10.7 after treatment. Olanzapine also improved headache severity (measured on a 0 to 10 scale) from 8.7±1.6 before treatment to 2.2±2.1 after treatment.¹⁶ Researchers found that 2.5 or 5 mg of olanzapine relieved acute migraines for most patients, with repeat dosing as needed up to 20 mg/d. For prophylactic treatment, 5 or 10 mg of olanzapine was used. Olanzapine’s antinociceptive effect may be related to its action on α-2 adrenoreceptors and to a lesser extent on involvement of opioid and serotonergic receptors.¹⁷

In a case series, 3 migraine patients who met criteria for chronic daily headache and migraines but did not have a psychiatric disorder reported significant and sustained headache improvement when treated with risperidone.¹⁹ In a case series of 3 migraine patients with co-occurring psychiatric disorders, aripiprazole decreased migraine frequency and severity.¹⁵ Although limited data support quetiapine’s efficacy in treating acute migraines, in an open-label, pilot study, patients taking quetiapine, 25 to 75 mg/d, demonstrated a decrease in mean frequency of migraine days from 10.2 to 6.2 and decreased use of rescue medications from 2.3 to 1.2 days per week.¹⁸

Table 1

Possible rationale for antipsychotic use for headaches and nausea

Condition	Possible rationale
Migraine	Patients are hypersensitive to dopamine agonists or dopamine transporter dysfunction. Some evidence that the dopamine D2 (DRD2) gene is involved
Cluster headache	Pain alleviation possibly related to dopamine receptor antagonism
Nausea	D2 and H1 receptor blockage

Table 2

Antipsychotics for headache and nausea: Strength of the evidence

Condition	Strength of evidencea
Migraine	Intermediate: Chlorpromazine,2-5 droperidol,6-8 prochlorperazine1,10-12
	Weak: Haloperidol13,14
	Very weak: Aripiprazole,15 olanzapine,16,17 quetiapine,18 ziprasidone19
Cluster headache	Weak: Chlorpromazine20
	Very weak: Clozapine,21 olanzapine22
Nausea/vomiting	Intermediate: Droperidol,23 metoclopramide,24 prochlorperazine,25 promethazine25
	Weak: Olanzapine26,27
aStrong: Multiple, well-designed RCTs directly relevant to the recommendation, yielding consistent findings Intermediate: Some evidence from RCTs that support the recommendation, but the scientific support was not optimal Weak: Consensus recommendation in the absence of relevant randomized controlled trials and better evidence than case report or series Very weak: Case reports or case series or preliminary studies RCTs: randomized controlled trials

 

Cluster headaches

Subcutaneous sumatriptan and inhaled oxygen are first-line treatments for cluster headaches.³¹ A single, small study²⁰ reported that chlorpromazine may prevent cluster headaches, which suggests that D2 receptor blockade may treat such headaches. However, limited supporting evidence relegates its use to a second- or third-line therapy.

In an open-label study (N = 5), olanzapine provided some relief of pain associated with cluster headache within 20 minutes of administration.²² In another study, patients with schizophrenia and comorbid cluster headaches improved with olanzapine.²¹

Because evidence is limited to small prospective studies, antipsychotic treatment of cluster headache is not well established.^20-22 However, olanzapine may benefit patients with comorbid cluster headaches and schizophrenia.

Nausea

The signaling pathways that mediate emesis involve 5-HT3, D2, muscarinic, and histamine receptors.³² Before 5-HT3 antagonists were available, the FGAs metoclopramide, droperidol, prochlorperazine, and promethazine were used to manage acute emesis in emergency departments.²³ A double-blind, placebo-controlled trial found IV droperidol, 1.25 mg, was more effective than metoclopramide, 10 mg, or prochlorperazine, 10 mg, for relieving moderate to severe nausea in adult patients.²³ However, droperidol and prochlorperazine were associated with akathisia. In addition, this trial did not find a clinically significant difference between groups—including placebo—in anxiety, sedation, or need for rescue medications.²³ Use of droperidol to treat nausea decreased after the drug received a “black-box” warning for QT prolongation and torsades de pointes.

Metoclopramide is effective for treating acute migraine and associated nausea²⁴ and has been used to treat gastroparesis because of its effect on upper GI motility. Phenothiazines have been used to treat nausea and studies have shown prochlorperazine to be more effective than promethazine.²⁵ Some studies of prochlorperazine have reported a 44% incidence of akathisia, which limits the drug’s use in patients who may be sensitive to such effects.³³ Promethazine can cause sedation and risk of tissue necrosis at the injection site.³⁴

Among SGAs, olanzapine effectively prevented acute and delayed chemotherapy-induced nausea and vomiting in a proof-of-concept study of patients receiving high and moderate emetogenic therapies.^26,27 National Comprehensive Cancer Network guidelines cite olanzapine as a potential option for treating refractory and breakthrough emesis.³⁵ In a small study (N = 50), olanzapine showed comparable anti-nausea effect to aprepitant—a neurokinin 1 receptor antagonist—and effectively prevented chemotherapy-induced nausea and vomiting in highly emetogenic chemotherapy.³⁶

Related Resources

• Kelley NE, Tepper DE. Rescue therapy for acute migraine, part 2: neuroleptics, antihistamines, and others. Headache. 2012;52(2):292-306.
• Dusitanond P, Young WB. Neuroleptics and migraine. Cent Nerv Syst Agents Med Chem. 2009;9(1):63-70.

Drug Brand Names

• Aprepitant • Emend
• Aripiprazole • Abilify
• Chlorpromazine • Thorazine
• Dihydroergotamine • D.H.E 45
• Droperidol • Inapsine
• Ergotamine tartrate • Ergostat
• Haloperidol • Haldol
• Ketorolac • Toradol
• Lidocaine • Xylocaine, Lidoderm
• Meperidine • Demerol
• Metoclopramide • Reglan
• Olanzapine • Zyprexa
• Prochlorperazine • Compazine
• Promethazine • Phenergan
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sumatriptan • Imitrex
• Valproate • Depakote

Disclosures

Dr. Macaluso has received grant or research support from EnVivo Pharmaceuticals, Janssen L.P., and Pfizer, Inc.

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

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In 2000, the American Board of Medical Specialties (ABMS) made a commitment to develop a maintenance of certification (MOC) system for their 24 specialty boards. MOC aims to keep physicians up to date because medical knowledge and practice are rapidly evolving and health care systems expect greater accountability linked with performance and outcomes. Previously, board certification for most specialties was limited to a 1-time board exam; upon passing, a clinician was considered board certified for life. The American Board of Psychiatry and Neurology (ABPN) first issued time-limited certificates for board certification in 1994; 2007 was the first year of initial MOC enrollment for ABPN. Diplomates whose certificates were issued before October 1, 1994 are not required to participate in the MOC program.

The ABPN time-limited certificates are on 10-year cycles and require diplomates to fulfill 4 MOC program components: Professional Standing, Self-Assessment and Continuing Medical Education (CME), Cognitive Expertise, and Performance in Practice (PIP) (Table).¹ Requirement details are available at www.abpn.com.

The ABMS MOC initiative is closely aligned with other initiatives, such as maintenance of licensure (MOL), that will impact all physicians, including those who are not board certified and those who were certified before October 1, 1994 and therefore not required to participate in MOC. Licensure, reimbursement, and institutional credentials are developing required measures based on self-assessment and performance.

Table

Maintenance of certification: 4 components

Component	Description
Professional Standing	Diplomates must hold an active and unrestricted license to practice medicine in ≥1 state commonwealth territory or possession of the United States or province of Canada
Self-Assessment and CME	Self-assessment: Diplomates must participate in ≥2 major broad-based self-assessment activities that must cover new knowledge and/or current best practices and provide feedback to the diplomate that can be used as the basis for focused CME lifelong learning and/or career development
	CME activities: Diplomates are required to complete an average of 30 specialty or subspecialty Category 1 CME credits per year over the 10-year MOC cycle. At least an average of 8 of the CME credits per year (averaged over 2 to 5 years) should involve self-assessment
Cognitive Expertise	Diplomates must pass a cognitive examination before the expiration date of their certificates
Performance in Practice (PIP)	Diplomates will be required to complete 3 PIP units over the 10-year MOC cycle each consisting of both a clinical module (chart review) and a feedback module (patient/peer second-party external review)
CME: continuing medical education; MOC: maintenance of certification Source: Adapted from reference 1

MOC requirements

The ABMS developed its MOC program around 6 general competencies identified by the Accreditation Council for Graduate Medical Education:

• professionalism
  
• patient care and procedural skills
  
• medical knowledge
  
• practice-based learning and improvement
  
• interpersonal and communications skills
  
• systems-based practice.
  

The ABPN implemented a 10-year MOC program for diplomates certified or recertified before 2012. Requirements for recertification are phased in over a period of time, depending on the diplomate’s most recent certification year.² Diplomates certified in 2012 or later will be enrolled automatically in ABPN’s Continuous Pathway to Lifelong Learning Program, a web-based system that maintains progress records and helps direct diplomates to activities that meet the 4 MOC program components.¹ Clinicians certified before 2012 may choose to participate in the program.

Physicians with “lifetime” certificates are not required to participate in MOC; there are no consequences for physicians who are not required to participate in MOC and choose not to participate, because MOC is a voluntary system. Physicians with time-limited certificates can choose not to participate, but would forfeit their certification. Physicians with certifications in multiple specialties may consider the value of maintaining all of their certifications because it would require them to participate in multiple MOC programs.

Two of the 4 parts of MOC (Parts I and III) are extensions of existing board certification requirements. Part I stipulates a diplomate hold a valid and unrestricted license in ≥1 states or jurisdictions in the United States, its territories, or Canada. Part III (Cognitive Expertise) requires that he or she must pass a cognitive examination every 10 years. To qualify to take the cognitive exam, a diplomate must meet all current MOC requirements.

Parts II and IV integrate continuing education, self-assessment, and the ability to apply both to practice improvements. Part II requires an average of 8 CME credit hours that include a self-assessment component; this likely would eliminate most traditional CME activities. The ABPN stipulates that feedback from the self-assessment must include a comparison with peers and specific literature recommendations for each question in the self-assessment. A small but growing number of accredited CME providers have developed self-directed CME activities that meet these criteria. As of 2014, only ABPN-approved self-assessment activities can be used to meet Part II requirements.

 

Part IV, the PIP activity, has raised the most concern. The PIP component focuses on quality improvement in 2 parts: a clinical module and a feedback module. This targets active clinicians, and both modules focus on quality improvement activities. The clinical module consists of a baseline chart review by the physician MOC applicant in which results are compared with best practices or practice guidelines. The practitioner-applicant repeats a second chart review after a period of time to determine if intervening practice improvements had a positive impact.

The feedback module consists of reviews of clinical performance by patients, peers, or other second parties such as other practice staff or administrators. These are repeated after a period of time to determine whether practice improvements have been effective.

The PIP model (assessment, practice improvement, reassessment) parallels requirements for Performance Improvement CME (PICME) activities. The American Medical Association (AMA) developed PICME at approximately the same time ABMS was creating MOC. PICME is aimed at changing physician behavior within the context of their clinical practice and is divided into 3 stages:

• Stage A: learning from current practice performance assessment
  
• Stage B: learning from the application of performance improvement to patient care
  
• Stage C: learning from the evaluation of the PICME effort.
  

Clinicians can earn 5 AMA Physician’s Recognition Award (PRA) Category 1 Credits^™ by completing each of the first 2 stages, and 10 additional credits by completing Stage C.³ Many accredited CME providers have developed PICME activities that meet the MOC Part IV criteria for ABPN. A list of available activities to meet ABPN Part IV of MOC can be found on the ABPN’s website (see Related Resources). Many of these activities also meet requirements for other specialty certifications and/or provide alternative CME credit (eg, American Academy of Family Physicians [AAFP] credit).

For example, a coalition of academic, nonprofit, and business organizations—the NOW Coalition for Bipolar Disorder— developed an online quality improvement activity (see Related Resources), which the ABPN certified for assessment and PIP points. It also is certified for 20 points toward the Self-Evaluation of Practice Performance MOC requirement through the American Board of Internal Medicine’s Approved Quality Improvement Pathway, 20 AMA PRA Category 1 Credits™, and 20 Prescribed Credits by the AAFP. Many physicians hold multiple board certificates, and this kind of activity can simultaneously meet requirements for licensure and several MOC programs.

Merging requirements

Although many ABPN diplomates are not subject to the MOC process because of “grandfather” provisions, the basic components of ABMS’ MOC are being integrated into relicensure, institutional credentials, and reimbursement models. In 2004, the Federation of State Medical Boards (FSMB) began work on a plan for MOL. This was in response to concerns about the current focus on CME credit as a measure of continuous professional development while recognizing that health care has intensified its focus on patient safety, measuring patient outcomes, and system-based health care delivery.⁴ The core components of MOL include:

• reflective self-assessment
  
• assessment of knowledge and skills
  
• PIP.
  

The FSMB plan does not include a mandatory exam and does not require physicians to participate in MOC or Osteopathic Continuous Certification for DOs. However, because of the similarities between MOL and MOC, the FSMB recommends that state medical boards recognize physicians who are actively participating in an MOC program as essentially meeting the MOL requirements. The first group of state medical boards began testing MOL during summer 2012. Each state and territorial medical board will adopt its own version of MOL as it has with its current licensing requirements. Adopting MOL by all medical boards could take several years. However, there is no question that the principles behind MOC will become part of new state licensing requirements.

Effects on reimbursement

In 2012, the Centers for Medicare and Medicaid Services’ Physician Quality Reporting System MOC Program Incentive provided a 0.5% incentive payment to physicians participating in a qualified MOC program.⁵ Other insurers are examining similar reimbursement incentives tied to practice assessment and improvement. Public reporting of quality metrics also is becoming more prevalent in practice and reimbursement incentives.

Related Resources

• Pinals DA. Ready or not, here it comes: maintenance of certification. J Am Acad Psychiatry Law. 2011;39(3):294-296.
  
• American Board of Psychiatry and Neurology, Inc. www.abpn.com.
  
• Maintenance of certification. American Board of Psychiatry and Neurology, Inc. www.abpn.com/moc_products.asp.
  
• NOW coalition performance improvement (PI) CME activity. NOW Coalition for Bipolar Disorder. www.nowbipolar.org/pi-cme.php.
  

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

In 2000, the American Board of Medical Specialties (ABMS) made a commitment to develop a maintenance of certification (MOC) system for their 24 specialty boards. MOC aims to keep physicians up to date because medical knowledge and practice are rapidly evolving and health care systems expect greater accountability linked with performance and outcomes. Previously, board certification for most specialties was limited to a 1-time board exam; upon passing, a clinician was considered board certified for life. The American Board of Psychiatry and Neurology (ABPN) first issued time-limited certificates for board certification in 1994; 2007 was the first year of initial MOC enrollment for ABPN. Diplomates whose certificates were issued before October 1, 1994 are not required to participate in the MOC program.

The ABPN time-limited certificates are on 10-year cycles and require diplomates to fulfill 4 MOC program components: Professional Standing, Self-Assessment and Continuing Medical Education (CME), Cognitive Expertise, and Performance in Practice (PIP) (Table).¹ Requirement details are available at www.abpn.com.

The ABMS MOC initiative is closely aligned with other initiatives, such as maintenance of licensure (MOL), that will impact all physicians, including those who are not board certified and those who were certified before October 1, 1994 and therefore not required to participate in MOC. Licensure, reimbursement, and institutional credentials are developing required measures based on self-assessment and performance.

Table

Maintenance of certification: 4 components

Component	Description
Professional Standing	Diplomates must hold an active and unrestricted license to practice medicine in ≥1 state commonwealth territory or possession of the United States or province of Canada
Self-Assessment and CME	Self-assessment: Diplomates must participate in ≥2 major broad-based self-assessment activities that must cover new knowledge and/or current best practices and provide feedback to the diplomate that can be used as the basis for focused CME lifelong learning and/or career development
	CME activities: Diplomates are required to complete an average of 30 specialty or subspecialty Category 1 CME credits per year over the 10-year MOC cycle. At least an average of 8 of the CME credits per year (averaged over 2 to 5 years) should involve self-assessment
Cognitive Expertise	Diplomates must pass a cognitive examination before the expiration date of their certificates
Performance in Practice (PIP)	Diplomates will be required to complete 3 PIP units over the 10-year MOC cycle each consisting of both a clinical module (chart review) and a feedback module (patient/peer second-party external review)
CME: continuing medical education; MOC: maintenance of certification Source: Adapted from reference 1

MOC requirements

The ABMS developed its MOC program around 6 general competencies identified by the Accreditation Council for Graduate Medical Education:

• professionalism
  
• patient care and procedural skills
  
• medical knowledge
  
• practice-based learning and improvement
  
• interpersonal and communications skills
  
• systems-based practice.
  

The ABPN implemented a 10-year MOC program for diplomates certified or recertified before 2012. Requirements for recertification are phased in over a period of time, depending on the diplomate’s most recent certification year.² Diplomates certified in 2012 or later will be enrolled automatically in ABPN’s Continuous Pathway to Lifelong Learning Program, a web-based system that maintains progress records and helps direct diplomates to activities that meet the 4 MOC program components.¹ Clinicians certified before 2012 may choose to participate in the program.

Physicians with “lifetime” certificates are not required to participate in MOC; there are no consequences for physicians who are not required to participate in MOC and choose not to participate, because MOC is a voluntary system. Physicians with time-limited certificates can choose not to participate, but would forfeit their certification. Physicians with certifications in multiple specialties may consider the value of maintaining all of their certifications because it would require them to participate in multiple MOC programs.

Two of the 4 parts of MOC (Parts I and III) are extensions of existing board certification requirements. Part I stipulates a diplomate hold a valid and unrestricted license in ≥1 states or jurisdictions in the United States, its territories, or Canada. Part III (Cognitive Expertise) requires that he or she must pass a cognitive examination every 10 years. To qualify to take the cognitive exam, a diplomate must meet all current MOC requirements.

Parts II and IV integrate continuing education, self-assessment, and the ability to apply both to practice improvements. Part II requires an average of 8 CME credit hours that include a self-assessment component; this likely would eliminate most traditional CME activities. The ABPN stipulates that feedback from the self-assessment must include a comparison with peers and specific literature recommendations for each question in the self-assessment. A small but growing number of accredited CME providers have developed self-directed CME activities that meet these criteria. As of 2014, only ABPN-approved self-assessment activities can be used to meet Part II requirements.

 

Part IV, the PIP activity, has raised the most concern. The PIP component focuses on quality improvement in 2 parts: a clinical module and a feedback module. This targets active clinicians, and both modules focus on quality improvement activities. The clinical module consists of a baseline chart review by the physician MOC applicant in which results are compared with best practices or practice guidelines. The practitioner-applicant repeats a second chart review after a period of time to determine if intervening practice improvements had a positive impact.

The feedback module consists of reviews of clinical performance by patients, peers, or other second parties such as other practice staff or administrators. These are repeated after a period of time to determine whether practice improvements have been effective.

The PIP model (assessment, practice improvement, reassessment) parallels requirements for Performance Improvement CME (PICME) activities. The American Medical Association (AMA) developed PICME at approximately the same time ABMS was creating MOC. PICME is aimed at changing physician behavior within the context of their clinical practice and is divided into 3 stages:

• Stage A: learning from current practice performance assessment
  
• Stage B: learning from the application of performance improvement to patient care
  
• Stage C: learning from the evaluation of the PICME effort.
  

Clinicians can earn 5 AMA Physician’s Recognition Award (PRA) Category 1 Credits^™ by completing each of the first 2 stages, and 10 additional credits by completing Stage C.³ Many accredited CME providers have developed PICME activities that meet the MOC Part IV criteria for ABPN. A list of available activities to meet ABPN Part IV of MOC can be found on the ABPN’s website (see Related Resources). Many of these activities also meet requirements for other specialty certifications and/or provide alternative CME credit (eg, American Academy of Family Physicians [AAFP] credit).

For example, a coalition of academic, nonprofit, and business organizations—the NOW Coalition for Bipolar Disorder— developed an online quality improvement activity (see Related Resources), which the ABPN certified for assessment and PIP points. It also is certified for 20 points toward the Self-Evaluation of Practice Performance MOC requirement through the American Board of Internal Medicine’s Approved Quality Improvement Pathway, 20 AMA PRA Category 1 Credits™, and 20 Prescribed Credits by the AAFP. Many physicians hold multiple board certificates, and this kind of activity can simultaneously meet requirements for licensure and several MOC programs.

Merging requirements

Although many ABPN diplomates are not subject to the MOC process because of “grandfather” provisions, the basic components of ABMS’ MOC are being integrated into relicensure, institutional credentials, and reimbursement models. In 2004, the Federation of State Medical Boards (FSMB) began work on a plan for MOL. This was in response to concerns about the current focus on CME credit as a measure of continuous professional development while recognizing that health care has intensified its focus on patient safety, measuring patient outcomes, and system-based health care delivery.⁴ The core components of MOL include:

• reflective self-assessment
  
• assessment of knowledge and skills
  
• PIP.
  

The FSMB plan does not include a mandatory exam and does not require physicians to participate in MOC or Osteopathic Continuous Certification for DOs. However, because of the similarities between MOL and MOC, the FSMB recommends that state medical boards recognize physicians who are actively participating in an MOC program as essentially meeting the MOL requirements. The first group of state medical boards began testing MOL during summer 2012. Each state and territorial medical board will adopt its own version of MOL as it has with its current licensing requirements. Adopting MOL by all medical boards could take several years. However, there is no question that the principles behind MOC will become part of new state licensing requirements.

Effects on reimbursement

In 2012, the Centers for Medicare and Medicaid Services’ Physician Quality Reporting System MOC Program Incentive provided a 0.5% incentive payment to physicians participating in a qualified MOC program.⁵ Other insurers are examining similar reimbursement incentives tied to practice assessment and improvement. Public reporting of quality metrics also is becoming more prevalent in practice and reimbursement incentives.

Related Resources

• Pinals DA. Ready or not, here it comes: maintenance of certification. J Am Acad Psychiatry Law. 2011;39(3):294-296.
  
• American Board of Psychiatry and Neurology, Inc. www.abpn.com.
  
• Maintenance of certification. American Board of Psychiatry and Neurology, Inc. www.abpn.com/moc_products.asp.
  
• NOW coalition performance improvement (PI) CME activity. NOW Coalition for Bipolar Disorder. www.nowbipolar.org/pi-cme.php.
  

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

In 2000, the American Board of Medical Specialties (ABMS) made a commitment to develop a maintenance of certification (MOC) system for their 24 specialty boards. MOC aims to keep physicians up to date because medical knowledge and practice are rapidly evolving and health care systems expect greater accountability linked with performance and outcomes. Previously, board certification for most specialties was limited to a 1-time board exam; upon passing, a clinician was considered board certified for life. The American Board of Psychiatry and Neurology (ABPN) first issued time-limited certificates for board certification in 1994; 2007 was the first year of initial MOC enrollment for ABPN. Diplomates whose certificates were issued before October 1, 1994 are not required to participate in the MOC program.

The ABPN time-limited certificates are on 10-year cycles and require diplomates to fulfill 4 MOC program components: Professional Standing, Self-Assessment and Continuing Medical Education (CME), Cognitive Expertise, and Performance in Practice (PIP) (Table).¹ Requirement details are available at www.abpn.com.

The ABMS MOC initiative is closely aligned with other initiatives, such as maintenance of licensure (MOL), that will impact all physicians, including those who are not board certified and those who were certified before October 1, 1994 and therefore not required to participate in MOC. Licensure, reimbursement, and institutional credentials are developing required measures based on self-assessment and performance.

Table

Maintenance of certification: 4 components

Component	Description
Professional Standing	Diplomates must hold an active and unrestricted license to practice medicine in ≥1 state commonwealth territory or possession of the United States or province of Canada
Self-Assessment and CME	Self-assessment: Diplomates must participate in ≥2 major broad-based self-assessment activities that must cover new knowledge and/or current best practices and provide feedback to the diplomate that can be used as the basis for focused CME lifelong learning and/or career development
	CME activities: Diplomates are required to complete an average of 30 specialty or subspecialty Category 1 CME credits per year over the 10-year MOC cycle. At least an average of 8 of the CME credits per year (averaged over 2 to 5 years) should involve self-assessment
Cognitive Expertise	Diplomates must pass a cognitive examination before the expiration date of their certificates
Performance in Practice (PIP)	Diplomates will be required to complete 3 PIP units over the 10-year MOC cycle each consisting of both a clinical module (chart review) and a feedback module (patient/peer second-party external review)
CME: continuing medical education; MOC: maintenance of certification Source: Adapted from reference 1

MOC requirements

The ABMS developed its MOC program around 6 general competencies identified by the Accreditation Council for Graduate Medical Education:

• professionalism
  
• patient care and procedural skills
  
• medical knowledge
  
• practice-based learning and improvement
  
• interpersonal and communications skills
  
• systems-based practice.
  

The ABPN implemented a 10-year MOC program for diplomates certified or recertified before 2012. Requirements for recertification are phased in over a period of time, depending on the diplomate’s most recent certification year.² Diplomates certified in 2012 or later will be enrolled automatically in ABPN’s Continuous Pathway to Lifelong Learning Program, a web-based system that maintains progress records and helps direct diplomates to activities that meet the 4 MOC program components.¹ Clinicians certified before 2012 may choose to participate in the program.

Physicians with “lifetime” certificates are not required to participate in MOC; there are no consequences for physicians who are not required to participate in MOC and choose not to participate, because MOC is a voluntary system. Physicians with time-limited certificates can choose not to participate, but would forfeit their certification. Physicians with certifications in multiple specialties may consider the value of maintaining all of their certifications because it would require them to participate in multiple MOC programs.

Two of the 4 parts of MOC (Parts I and III) are extensions of existing board certification requirements. Part I stipulates a diplomate hold a valid and unrestricted license in ≥1 states or jurisdictions in the United States, its territories, or Canada. Part III (Cognitive Expertise) requires that he or she must pass a cognitive examination every 10 years. To qualify to take the cognitive exam, a diplomate must meet all current MOC requirements.

Parts II and IV integrate continuing education, self-assessment, and the ability to apply both to practice improvements. Part II requires an average of 8 CME credit hours that include a self-assessment component; this likely would eliminate most traditional CME activities. The ABPN stipulates that feedback from the self-assessment must include a comparison with peers and specific literature recommendations for each question in the self-assessment. A small but growing number of accredited CME providers have developed self-directed CME activities that meet these criteria. As of 2014, only ABPN-approved self-assessment activities can be used to meet Part II requirements.

 

Part IV, the PIP activity, has raised the most concern. The PIP component focuses on quality improvement in 2 parts: a clinical module and a feedback module. This targets active clinicians, and both modules focus on quality improvement activities. The clinical module consists of a baseline chart review by the physician MOC applicant in which results are compared with best practices or practice guidelines. The practitioner-applicant repeats a second chart review after a period of time to determine if intervening practice improvements had a positive impact.

The feedback module consists of reviews of clinical performance by patients, peers, or other second parties such as other practice staff or administrators. These are repeated after a period of time to determine whether practice improvements have been effective.

The PIP model (assessment, practice improvement, reassessment) parallels requirements for Performance Improvement CME (PICME) activities. The American Medical Association (AMA) developed PICME at approximately the same time ABMS was creating MOC. PICME is aimed at changing physician behavior within the context of their clinical practice and is divided into 3 stages:

• Stage A: learning from current practice performance assessment
  
• Stage B: learning from the application of performance improvement to patient care
  
• Stage C: learning from the evaluation of the PICME effort.
  

Clinicians can earn 5 AMA Physician’s Recognition Award (PRA) Category 1 Credits^™ by completing each of the first 2 stages, and 10 additional credits by completing Stage C.³ Many accredited CME providers have developed PICME activities that meet the MOC Part IV criteria for ABPN. A list of available activities to meet ABPN Part IV of MOC can be found on the ABPN’s website (see Related Resources). Many of these activities also meet requirements for other specialty certifications and/or provide alternative CME credit (eg, American Academy of Family Physicians [AAFP] credit).

For example, a coalition of academic, nonprofit, and business organizations—the NOW Coalition for Bipolar Disorder— developed an online quality improvement activity (see Related Resources), which the ABPN certified for assessment and PIP points. It also is certified for 20 points toward the Self-Evaluation of Practice Performance MOC requirement through the American Board of Internal Medicine’s Approved Quality Improvement Pathway, 20 AMA PRA Category 1 Credits™, and 20 Prescribed Credits by the AAFP. Many physicians hold multiple board certificates, and this kind of activity can simultaneously meet requirements for licensure and several MOC programs.

Merging requirements

Although many ABPN diplomates are not subject to the MOC process because of “grandfather” provisions, the basic components of ABMS’ MOC are being integrated into relicensure, institutional credentials, and reimbursement models. In 2004, the Federation of State Medical Boards (FSMB) began work on a plan for MOL. This was in response to concerns about the current focus on CME credit as a measure of continuous professional development while recognizing that health care has intensified its focus on patient safety, measuring patient outcomes, and system-based health care delivery.⁴ The core components of MOL include:

• reflective self-assessment
  
• assessment of knowledge and skills
  
• PIP.
  

The FSMB plan does not include a mandatory exam and does not require physicians to participate in MOC or Osteopathic Continuous Certification for DOs. However, because of the similarities between MOL and MOC, the FSMB recommends that state medical boards recognize physicians who are actively participating in an MOC program as essentially meeting the MOL requirements. The first group of state medical boards began testing MOL during summer 2012. Each state and territorial medical board will adopt its own version of MOL as it has with its current licensing requirements. Adopting MOL by all medical boards could take several years. However, there is no question that the principles behind MOC will become part of new state licensing requirements.

Effects on reimbursement

In 2012, the Centers for Medicare and Medicaid Services’ Physician Quality Reporting System MOC Program Incentive provided a 0.5% incentive payment to physicians participating in a qualified MOC program.⁵ Other insurers are examining similar reimbursement incentives tied to practice assessment and improvement. Public reporting of quality metrics also is becoming more prevalent in practice and reimbursement incentives.

Related Resources

• Pinals DA. Ready or not, here it comes: maintenance of certification. J Am Acad Psychiatry Law. 2011;39(3):294-296.
  
• American Board of Psychiatry and Neurology, Inc. www.abpn.com.
  
• Maintenance of certification. American Board of Psychiatry and Neurology, Inc. www.abpn.com/moc_products.asp.
  
• NOW coalition performance improvement (PI) CME activity. NOW Coalition for Bipolar Disorder. www.nowbipolar.org/pi-cme.php.
  

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Recently there has been an increase in advertising soliciting participants for class-action lawsuits involving birth defects and antidepressants, particularly sertraline. Many psychiatrists are unsure why these ads are running in seemingly every medium because there has been no change in the FDA pregnancy classification for most selective serotonin reuptake inhibitors (SSRIs), except for paroxetine going from a C to a D rating in 2005.¹ Some studies have found SSRIs increase the risk of adverse birth outcomes and others have not, which makes it difficult for clinicians to know what to discuss with patients regarding the risks and benefits of using antidepressants during pregnancy, as well as the risks of untreated major depressive disorder (MDD).

It can be hard to encourage some patients to take necessary medications in the best of circumstances, let alone suggest that a pregnant woman take a medication that has been labeled “dangerous.” This article seeks to alleviate physicians’ fears about being caught in a no-win situation by:

• explaining factors that may have led to this increase in class-action lawsuits
  
• clarifying the risks of using certain medications and not treating depression
  
• suggesting ways physicians can protect themselves and their patients.
  

The FDA’s position

In July 2006, the FDA issued a public health advisory regarding SSRI use during pregnancy and the possibility of persistent pulmonary hypertension (PPHN).² This warning was based on a single study that found the risk of developing PPHN (baseline rate: 1 to 2 per 1,000 births) was 6 times greater for fetuses exposed to SSRIs in late pregnancy.³ Many legal websites highlight this 2006 warning as proof of SSRIs’ danger. However, because subsequent studies have had conflicting results, the FDA’s current position is that the risks of using SSRIs during pregnancy are “unknown” (Box).^1-4

Box

Risks of depression

Although most physicians know the risks of untreated MDD, they tend to minimize or forget these risks when a woman becomes pregnant. Pregnant women with MDD face not only the expected risks of their psychiatric illness but additionally face risks of pre-eclampsia, suicide (20% of deaths in the postpartum period are due to suicide), and infanticide.^5-10 Risks to the fetus include poor prenatal care, increased risk of intrauterine exposure to drugs or alcohol, increased exposure to maternal cortisol with resulting neurodevelopmental changes, preterm delivery, low birth weight, and failure to thrive.^6-8 Later difficulties for the child of a mother with untreated depression may include poor stress adaptation, decreased cognitive performance, and behavioral difficulties because of poor mother-child bonding and other factors.⁶

See Table 1 for key statistics regarding pregnancy and depression.

Table 1

Statistics on pregnancy and depression

There are approximately 6 million pregnancies each year in the United Statesa
There are approximately 4 million live births each year in the United Statesa
Two percent to 3% of healthy pregnancies result in a birth defect or miscarriageb-d
Sixty percent to 70% of birth complications occur due to an unknown caused
Rates of depression during pregnancy are 7% to 25%b,e,f
Approximately 13% of pregnant women take an antidepressant during pregnancye
Fifteen percent of women with untreated depression in pregnancy attempt suicideb
Twenty percent of deaths in the postpartum period are due to suicidee
Women who discontinue antidepressants are 5 times more likely than women who continue medications in pregnancy to have a relapse of depressiong,h
SSRIs are the antidepressant class most frequently prescribed to pregnant womeni
Sertraline is one of the most frequently prescribed antidepressants perinatally and has low concentration in breast milk and infant serumj,k
SSRIs: selective serotonin reuptake inhibitors American Pregnancy Association. Statistics. http://www.americanpregnancy.org/main/statistics.html. Accessed December 20, 2012. Hasser C, Brizendine L, Spielvogel A. SSRI use during pregnancy. Current Psychiatry. 2006;5(4):31-40. Altshuler L, Richards M, Yonkers K. Treating bipolar disorder during pregnancy. Current Psychiatry. 2003;2(7):14-26. Cott A, Wisner K. Psychiatric disorders during pregnancy. Internat Rev Psychiatry. 2003;15(3):217-230. Meltzer-Brody S. New insights into perinatal depression: pathogenesis and treatment during pregnancy and postpartum. Dialogues Clin Neurosci. 2011;13(1):89-100. Kieler H, Artama M, Engeland A, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. BMJ. 2012;344:d8012. doi:10.1136/bmj.d801. U.S. Food and Drug Administration. Public health advisory: treatment challenges of depression in pregnancy and the possibility of persistent pulmonary hypertension in newborns. http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders /DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm124348.htm. Published July 19, 2006. Accessed December 20, 2012. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499-507. Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Gen Hosp Psychiatry. 2009;31(5):403-413. Berle JO, Spigset O. Antidepressant use during breastfeeding. Curr Womens Health Rev. 2011;7(1):28-34. Friedman SH, Nagle-Yang S, Parsons S. Maternal mental health in the neonatal intensive care unit. NeoReviews. 2011;12(2):e85-e93.

 

Limitations of research

Because of ethical difficulties in studying MDD treatment during pregnancy, most data are retrospective and prone to detection and confounding biases, such as^11-15:

• the risks associated with depression
  
• comorbid conditions such as obesity
  
• maternal age
  
• poor prenatal care
  
• how the baby was delivered (eg, Caesarean sections have higher rates of PPHN)¹³
  
• illicit substance use
  
• effects of other medications (80% of pregnant women use medications, including nonsteroidal anti-inflammatory drugs [NSAIDs], which are associated with PPHN).^11,16
  

No medication is 100% safe during pregnancy and all pregnancies have risks. In the United States, 2% to 3% of pregnancies produce infants with malformations,¹⁷ which makes it hard to determine if a defect is caused by a medication or occurred spontaneously. This is the baseline risk of all malformations; individual malformations are rare and it is difficult to conduct studies that have adequate power to demonstrate the risk for a specific malformation.

There are several potential adverse outcomes to consider when prescribing psychotropics to a pregnant woman, including miscarriage, malformation, preterm delivery, perinatal toxicity, and behavioral teratogenesis (Table 2).^6,7 SSRIs have been implicated in adverse outcomes, but there is no strong evidence that they increase the miscarriage rate, and several studies found no increase in birth defects.^6,13,18-20 Regarding teratogenesis, the FDA switched paroxetine from class C to class D because of a potential 1.5% to 2% risk of fetal cardiac malformation, compared with a 1% baseline rate in the general population.²¹ Drug toxicity or withdrawal in a neonate also is a risk; however, this condition is self-limited and managed supportively by neonatology.²² Behavioral teratogenesis—neurobehavioral problems that develop later in a child’s life—remains a hypothetical concern; research has been conflicting, and studies often used flawed methodology.

Evidence linking SSRIs to an increased risk of adverse birth outcomes often has been based on large, retrospective health system database cohort studies looking at SSRI exposure and associations with conditions such as PPHN, cardiac anomalies, attention-deficit/hyperactivity disorder, and autism.^10,23,24 However, correlation is not the same as causation. It is difficult to prove or disprove the causative factor of adverse outcomes in these studies because:

• these databases were not designed to answer these types of exposure questions (eg, limitations in data collected, such as other potential causes not recorded)
  
• they have many confounding biases (undocumented illicit substance use, possible minimization of smoking history, publication basis for positive findings, etc.)
  
• individuals who provided the data did not follow a standardized method (eg, variability among individual clinicians).
  

Many of these limitations are evident in a 2009 study by Pedersen et al,²³ who reported the prevalence of septal heart defects was 0.5% (2,315/493,113) among unexposed children and 0.9% (12/1,370) among children exposed to 1 SSRI during early pregnancy (odds ratio [OR]=1.99 [1.13 to 3.53]). Based on this study’s data, the number needed to harm—the number of patients you would need to treat to encounter 1 adverse outcome—was 246, which suggests a relatively low risk. When data for the entire study is reviewed, the ORs for either minor birth defects (control: 7,373/493,113 vs SSRI exposed: 39/1,370; OR=0.88 [0.54 to 1.41]) or major birth defects (control: 15,518/493,113 vs SSRI exposed: 55/1,370; OR 1.21 [0.91 to 1.62]) were not statistically significant (major and minor malformations were defined using European Surveillance of Congenital Anomalies coding).

Not to case aspersions on this group’s work, it should be noted that this study had limitations, including that the researchers:

• did not take into account SSRI dosage
  
• did not measure depression severity or remittance
  
• were not able to fully account for potential exposures (eg, over-the-counter NSAIDs)
  
• were unable to confirm that patients took their medications because the variable measured was prescriptions filled
  
• did not interview participants about their medication use or symptoms.
  

In addition, researchers noted that mothers who filled their antidepressant prescription at least twice also were likely to have other factors that put them at higher risk for having a child with birth defects—such as older age or smoking. The biggest problem with the study was a lack of a control group, such as depressed women who did not receive medication (eg, the risk of depression itself could explain the rise, or those with more severe depression could be prescribed antidepressants).¹⁵

In a more recent study,²⁴ 33 of 11,014 infants exposed to SSRIs after gestational week 20 developed PPHN (absolute risk: 3 per 1,000 births, compared with an incidence of 1.2 per 1,000 births in the general population), with an adjusted OR of 2.1 (95% CI 1.5 to 3.0). Although the authors warned that the results suggest a “class effect,” the rate of PPHN also was higher for mothers with a history of a psychiatric hospitalization within the last 10 years who were not taking medication (OR=1.3, 95% CI 1.0 to 1.6) and the OR for escitalopram (1.5, CI 0.2 to 10.5) was not statistically significant. This study did include a control group, but the 10-year window may have been too wide to represent a group with similar comorbid risks. Similar to the previously discussed study, mothers prescribed SSRIs were older, 1.7 times more likely to be smokers, and twice as likely to be prescribed NSAIDs. The study did not analyze the risk factors of smoking and body mass index because of an initial subset analysis (which was not reported) finding that these known risk factors for PPHN “did not confound the results.”²⁴

 

Table 2

Potential concerns when treating pregnant women with psychotropics

Miscarriage (spontaneous abortion)
Malformation (teratogenesis)
Preterm delivery
Perinatal syndrome (toxicity or withdrawal in neonate; usually self-limited and related to serotonin overstimulation or withdrawal; symptoms may include disrupted sleep irritability jitteriness or abnormal breathing)
Behavioral teratogenesis (later behavioral problems in child eg lower IQ developmental delays or autism)
Lactation compatibility or plans to bottle-feed
Source: References 6,7

The basis of class-action lawsuits

Interest in class-action lawsuits involving birth defects and antidepressants, particularly sertraline, appears to be increasing. Many websites advertising these lawsuits quote unnamed articles from reputable medical journals to support the claim that the medications are dangerous and cause a wide range of birth defects. Although some of the birth defects mentioned are specific, others (eg, “breathing problems” or “gastrointestinal side effects”) are so broad that any problem or complication could conceivably be attributed to the antidepressant. The degree of causation—if any at all—for many of these conditions has not been determined. A national advertising campaign looking for any problem may be occurring because the exact risks are “unknown.”¹

The 2009 U.S. Supreme Court ruling in Wyeth v Levine²⁵ allows individuals to sue manufacturers of branded medications in state and federal court for lack of proper labeling. However, the 2011 U.S. Supreme Court case of PLIVA, Inc. v Mensing²⁶ prohibits state lawsuits against manufacturers of generic medications over labeling because by federal (superseding) law, generic manufacturers must use the same warnings as the branded medication. This may in part explain why many medications targeted in commercials and websites for class-action lawsuits are branded products, even though generics are available.

The focus of these types of lawsuits has been on drug manufacturers, in part because of the success of past litigation. Past class- and single-action lawsuits involving birth defects against pharmaceutical companies, such as Richardson-Merrell Inc.—the manufacturer of thalidomide and Bendectin, the branded version of a combination of pyridoxine and doxylamine used to treat nausea and vomiting during pregnancy—were successful. Although limb defects with thalidomide were scientifically proven, Bendectin was never conclusively shown to cause birth defects even though it had been prescribed to 40% of pregnant women at one point. The legal theory behind the lawsuits is that the manufacturers should have done more research to determine the potential for birth defects.²⁷ In a case against SmithKline Beecham Corporation,²⁸ which makes Paxil, the branded version of the SSRI paroxetine, a jury found the manufacturer negligent for failing to warn about Paxil’s association with cardiac defects. The result was a $2.5 million jury verdict. Since that case, the manufacturer has settled >800 additional suits for >$1 billion. Because this risk of using paroxetine has been established, physicians should discuss this risk with their patients as part of an informed consent because they could be liable if they don’t.²¹ This legal concept is known as the “learned intermediary doctrine,” which states that once the risk is known, the intermediary (eg, the physician) is responsible to ensure that a product (eg, medication) is used appropriately. The 2011 FDA statement saying the risk for SSRIs during pregnancy is unknown¹ is important because it removes physicians as “learned intermediaries.”

Protect your patient and yourself

An estimated 13% of pregnant women take antidepressants; SSRIs are the most commonly used antidepressant during and after pregnancy.⁹ Although not every depressed pregnant woman requires medication, those with moderate to severe depression often do. Rational medication decisions, informed consent, and good documentation are important when treating these women. Discuss the risks of untreated illness as well as the risks of medications to ensure that the patient understands that avoiding medication does not guarantee a safe pregnancy. Suggest psychotherapy and electroconvulsive therapy as options when appropriate. When possible, include the patient’s partner and family in the discussion to help improve compliance and potentially reduce strife.²⁹ The psychiatrist or patient should discuss the medication plan with the patient’s obstetrician or family physician.

Whenever possible, consider using monotherapy, continuing a previously “successful” medication, and using the lowest effective dose.⁵ Clinicians may “underdose” medications because they believe this will lessen the risk from exposure, but this is risky because the fetus is still being exposed to the medication as well as the negative effects of undertreated MDD. If SSRIs are used throughout the pregnancy, the newborn may require additional observation to monitor for potential perinatal syndromes or PPHN.

 

^6,22

Many women become pregnant while being treated for depression. Approximately one-half of all pregnancies are unplanned, so women using antidepressants may unknowingly expose their fetus to medication.³⁰ For this reason, it is important to discuss potential pregnancy and birth control concerns with all women of childbearing age before initiating pharmacotherapy.³¹ If an unintended pregnancy occurs, tell your patient to contact you before stopping any medications. Lawsuits also can occur because of wrongful death by suicide or infanticide because of lack of treatment; risk of untreated illness should not be treated lightly.

Related Resources

• Motherisk. www.motherisk.org.
  
• Organization of Teratology Information Specialists. www.otispregnancy.org.
  
• Massachusetts General Hospital Center for Women’s Mental Health. www.womensmentalhealth.org.
  

Drug Brand Names

• Escitalopram • Lexapro
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  

Disclosure

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

Acknowledgments

The authors appreciate suggestions on prior versions of the manuscript from Miriam Rosenthal, Jaina Amin, Sarah Nagle-Yang, Sonal Moratschek, J.P. Shand, and Scott R. Miller.

Discuss this article at www.facebook.com/CurrentPsychiatry

Recently there has been an increase in advertising soliciting participants for class-action lawsuits involving birth defects and antidepressants, particularly sertraline. Many psychiatrists are unsure why these ads are running in seemingly every medium because there has been no change in the FDA pregnancy classification for most selective serotonin reuptake inhibitors (SSRIs), except for paroxetine going from a C to a D rating in 2005.¹ Some studies have found SSRIs increase the risk of adverse birth outcomes and others have not, which makes it difficult for clinicians to know what to discuss with patients regarding the risks and benefits of using antidepressants during pregnancy, as well as the risks of untreated major depressive disorder (MDD).

It can be hard to encourage some patients to take necessary medications in the best of circumstances, let alone suggest that a pregnant woman take a medication that has been labeled “dangerous.” This article seeks to alleviate physicians’ fears about being caught in a no-win situation by:

• explaining factors that may have led to this increase in class-action lawsuits
  
• clarifying the risks of using certain medications and not treating depression
  
• suggesting ways physicians can protect themselves and their patients.
  

The FDA’s position

In July 2006, the FDA issued a public health advisory regarding SSRI use during pregnancy and the possibility of persistent pulmonary hypertension (PPHN).² This warning was based on a single study that found the risk of developing PPHN (baseline rate: 1 to 2 per 1,000 births) was 6 times greater for fetuses exposed to SSRIs in late pregnancy.³ Many legal websites highlight this 2006 warning as proof of SSRIs’ danger. However, because subsequent studies have had conflicting results, the FDA’s current position is that the risks of using SSRIs during pregnancy are “unknown” (Box).^1-4

Box

Risks of depression

Although most physicians know the risks of untreated MDD, they tend to minimize or forget these risks when a woman becomes pregnant. Pregnant women with MDD face not only the expected risks of their psychiatric illness but additionally face risks of pre-eclampsia, suicide (20% of deaths in the postpartum period are due to suicide), and infanticide.^5-10 Risks to the fetus include poor prenatal care, increased risk of intrauterine exposure to drugs or alcohol, increased exposure to maternal cortisol with resulting neurodevelopmental changes, preterm delivery, low birth weight, and failure to thrive.^6-8 Later difficulties for the child of a mother with untreated depression may include poor stress adaptation, decreased cognitive performance, and behavioral difficulties because of poor mother-child bonding and other factors.⁶

See Table 1 for key statistics regarding pregnancy and depression.

Table 1

Statistics on pregnancy and depression

There are approximately 6 million pregnancies each year in the United Statesa
There are approximately 4 million live births each year in the United Statesa
Two percent to 3% of healthy pregnancies result in a birth defect or miscarriageb-d
Sixty percent to 70% of birth complications occur due to an unknown caused
Rates of depression during pregnancy are 7% to 25%b,e,f
Approximately 13% of pregnant women take an antidepressant during pregnancye
Fifteen percent of women with untreated depression in pregnancy attempt suicideb
Twenty percent of deaths in the postpartum period are due to suicidee
Women who discontinue antidepressants are 5 times more likely than women who continue medications in pregnancy to have a relapse of depressiong,h
SSRIs are the antidepressant class most frequently prescribed to pregnant womeni
Sertraline is one of the most frequently prescribed antidepressants perinatally and has low concentration in breast milk and infant serumj,k
SSRIs: selective serotonin reuptake inhibitors American Pregnancy Association. Statistics. http://www.americanpregnancy.org/main/statistics.html. Accessed December 20, 2012. Hasser C, Brizendine L, Spielvogel A. SSRI use during pregnancy. Current Psychiatry. 2006;5(4):31-40. Altshuler L, Richards M, Yonkers K. Treating bipolar disorder during pregnancy. Current Psychiatry. 2003;2(7):14-26. Cott A, Wisner K. Psychiatric disorders during pregnancy. Internat Rev Psychiatry. 2003;15(3):217-230. Meltzer-Brody S. New insights into perinatal depression: pathogenesis and treatment during pregnancy and postpartum. Dialogues Clin Neurosci. 2011;13(1):89-100. Kieler H, Artama M, Engeland A, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. BMJ. 2012;344:d8012. doi:10.1136/bmj.d801. U.S. Food and Drug Administration. Public health advisory: treatment challenges of depression in pregnancy and the possibility of persistent pulmonary hypertension in newborns. http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders /DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm124348.htm. Published July 19, 2006. Accessed December 20, 2012. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499-507. Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Gen Hosp Psychiatry. 2009;31(5):403-413. Berle JO, Spigset O. Antidepressant use during breastfeeding. Curr Womens Health Rev. 2011;7(1):28-34. Friedman SH, Nagle-Yang S, Parsons S. Maternal mental health in the neonatal intensive care unit. NeoReviews. 2011;12(2):e85-e93.

 

Limitations of research

Because of ethical difficulties in studying MDD treatment during pregnancy, most data are retrospective and prone to detection and confounding biases, such as^11-15:

• the risks associated with depression
  
• comorbid conditions such as obesity
  
• maternal age
  
• poor prenatal care
  
• how the baby was delivered (eg, Caesarean sections have higher rates of PPHN)¹³
  
• illicit substance use
  
• effects of other medications (80% of pregnant women use medications, including nonsteroidal anti-inflammatory drugs [NSAIDs], which are associated with PPHN).^11,16
  

No medication is 100% safe during pregnancy and all pregnancies have risks. In the United States, 2% to 3% of pregnancies produce infants with malformations,¹⁷ which makes it hard to determine if a defect is caused by a medication or occurred spontaneously. This is the baseline risk of all malformations; individual malformations are rare and it is difficult to conduct studies that have adequate power to demonstrate the risk for a specific malformation.

There are several potential adverse outcomes to consider when prescribing psychotropics to a pregnant woman, including miscarriage, malformation, preterm delivery, perinatal toxicity, and behavioral teratogenesis (Table 2).^6,7 SSRIs have been implicated in adverse outcomes, but there is no strong evidence that they increase the miscarriage rate, and several studies found no increase in birth defects.^6,13,18-20 Regarding teratogenesis, the FDA switched paroxetine from class C to class D because of a potential 1.5% to 2% risk of fetal cardiac malformation, compared with a 1% baseline rate in the general population.²¹ Drug toxicity or withdrawal in a neonate also is a risk; however, this condition is self-limited and managed supportively by neonatology.²² Behavioral teratogenesis—neurobehavioral problems that develop later in a child’s life—remains a hypothetical concern; research has been conflicting, and studies often used flawed methodology.

Evidence linking SSRIs to an increased risk of adverse birth outcomes often has been based on large, retrospective health system database cohort studies looking at SSRI exposure and associations with conditions such as PPHN, cardiac anomalies, attention-deficit/hyperactivity disorder, and autism.^10,23,24 However, correlation is not the same as causation. It is difficult to prove or disprove the causative factor of adverse outcomes in these studies because:

• these databases were not designed to answer these types of exposure questions (eg, limitations in data collected, such as other potential causes not recorded)
  
• they have many confounding biases (undocumented illicit substance use, possible minimization of smoking history, publication basis for positive findings, etc.)
  
• individuals who provided the data did not follow a standardized method (eg, variability among individual clinicians).
  

Many of these limitations are evident in a 2009 study by Pedersen et al,²³ who reported the prevalence of septal heart defects was 0.5% (2,315/493,113) among unexposed children and 0.9% (12/1,370) among children exposed to 1 SSRI during early pregnancy (odds ratio [OR]=1.99 [1.13 to 3.53]). Based on this study’s data, the number needed to harm—the number of patients you would need to treat to encounter 1 adverse outcome—was 246, which suggests a relatively low risk. When data for the entire study is reviewed, the ORs for either minor birth defects (control: 7,373/493,113 vs SSRI exposed: 39/1,370; OR=0.88 [0.54 to 1.41]) or major birth defects (control: 15,518/493,113 vs SSRI exposed: 55/1,370; OR 1.21 [0.91 to 1.62]) were not statistically significant (major and minor malformations were defined using European Surveillance of Congenital Anomalies coding).

Not to case aspersions on this group’s work, it should be noted that this study had limitations, including that the researchers:

• did not take into account SSRI dosage
  
• did not measure depression severity or remittance
  
• were not able to fully account for potential exposures (eg, over-the-counter NSAIDs)
  
• were unable to confirm that patients took their medications because the variable measured was prescriptions filled
  
• did not interview participants about their medication use or symptoms.
  

In addition, researchers noted that mothers who filled their antidepressant prescription at least twice also were likely to have other factors that put them at higher risk for having a child with birth defects—such as older age or smoking. The biggest problem with the study was a lack of a control group, such as depressed women who did not receive medication (eg, the risk of depression itself could explain the rise, or those with more severe depression could be prescribed antidepressants).¹⁵

In a more recent study,²⁴ 33 of 11,014 infants exposed to SSRIs after gestational week 20 developed PPHN (absolute risk: 3 per 1,000 births, compared with an incidence of 1.2 per 1,000 births in the general population), with an adjusted OR of 2.1 (95% CI 1.5 to 3.0). Although the authors warned that the results suggest a “class effect,” the rate of PPHN also was higher for mothers with a history of a psychiatric hospitalization within the last 10 years who were not taking medication (OR=1.3, 95% CI 1.0 to 1.6) and the OR for escitalopram (1.5, CI 0.2 to 10.5) was not statistically significant. This study did include a control group, but the 10-year window may have been too wide to represent a group with similar comorbid risks. Similar to the previously discussed study, mothers prescribed SSRIs were older, 1.7 times more likely to be smokers, and twice as likely to be prescribed NSAIDs. The study did not analyze the risk factors of smoking and body mass index because of an initial subset analysis (which was not reported) finding that these known risk factors for PPHN “did not confound the results.”²⁴

 

Table 2

Potential concerns when treating pregnant women with psychotropics

Miscarriage (spontaneous abortion)
Malformation (teratogenesis)
Preterm delivery
Perinatal syndrome (toxicity or withdrawal in neonate; usually self-limited and related to serotonin overstimulation or withdrawal; symptoms may include disrupted sleep irritability jitteriness or abnormal breathing)
Behavioral teratogenesis (later behavioral problems in child eg lower IQ developmental delays or autism)
Lactation compatibility or plans to bottle-feed
Source: References 6,7

The basis of class-action lawsuits

Interest in class-action lawsuits involving birth defects and antidepressants, particularly sertraline, appears to be increasing. Many websites advertising these lawsuits quote unnamed articles from reputable medical journals to support the claim that the medications are dangerous and cause a wide range of birth defects. Although some of the birth defects mentioned are specific, others (eg, “breathing problems” or “gastrointestinal side effects”) are so broad that any problem or complication could conceivably be attributed to the antidepressant. The degree of causation—if any at all—for many of these conditions has not been determined. A national advertising campaign looking for any problem may be occurring because the exact risks are “unknown.”¹

The 2009 U.S. Supreme Court ruling in Wyeth v Levine²⁵ allows individuals to sue manufacturers of branded medications in state and federal court for lack of proper labeling. However, the 2011 U.S. Supreme Court case of PLIVA, Inc. v Mensing²⁶ prohibits state lawsuits against manufacturers of generic medications over labeling because by federal (superseding) law, generic manufacturers must use the same warnings as the branded medication. This may in part explain why many medications targeted in commercials and websites for class-action lawsuits are branded products, even though generics are available.

The focus of these types of lawsuits has been on drug manufacturers, in part because of the success of past litigation. Past class- and single-action lawsuits involving birth defects against pharmaceutical companies, such as Richardson-Merrell Inc.—the manufacturer of thalidomide and Bendectin, the branded version of a combination of pyridoxine and doxylamine used to treat nausea and vomiting during pregnancy—were successful. Although limb defects with thalidomide were scientifically proven, Bendectin was never conclusively shown to cause birth defects even though it had been prescribed to 40% of pregnant women at one point. The legal theory behind the lawsuits is that the manufacturers should have done more research to determine the potential for birth defects.²⁷ In a case against SmithKline Beecham Corporation,²⁸ which makes Paxil, the branded version of the SSRI paroxetine, a jury found the manufacturer negligent for failing to warn about Paxil’s association with cardiac defects. The result was a $2.5 million jury verdict. Since that case, the manufacturer has settled >800 additional suits for >$1 billion. Because this risk of using paroxetine has been established, physicians should discuss this risk with their patients as part of an informed consent because they could be liable if they don’t.²¹ This legal concept is known as the “learned intermediary doctrine,” which states that once the risk is known, the intermediary (eg, the physician) is responsible to ensure that a product (eg, medication) is used appropriately. The 2011 FDA statement saying the risk for SSRIs during pregnancy is unknown¹ is important because it removes physicians as “learned intermediaries.”

Protect your patient and yourself

An estimated 13% of pregnant women take antidepressants; SSRIs are the most commonly used antidepressant during and after pregnancy.⁹ Although not every depressed pregnant woman requires medication, those with moderate to severe depression often do. Rational medication decisions, informed consent, and good documentation are important when treating these women. Discuss the risks of untreated illness as well as the risks of medications to ensure that the patient understands that avoiding medication does not guarantee a safe pregnancy. Suggest psychotherapy and electroconvulsive therapy as options when appropriate. When possible, include the patient’s partner and family in the discussion to help improve compliance and potentially reduce strife.²⁹ The psychiatrist or patient should discuss the medication plan with the patient’s obstetrician or family physician.

Whenever possible, consider using monotherapy, continuing a previously “successful” medication, and using the lowest effective dose.⁵ Clinicians may “underdose” medications because they believe this will lessen the risk from exposure, but this is risky because the fetus is still being exposed to the medication as well as the negative effects of undertreated MDD. If SSRIs are used throughout the pregnancy, the newborn may require additional observation to monitor for potential perinatal syndromes or PPHN.

 

^6,22

Many women become pregnant while being treated for depression. Approximately one-half of all pregnancies are unplanned, so women using antidepressants may unknowingly expose their fetus to medication.³⁰ For this reason, it is important to discuss potential pregnancy and birth control concerns with all women of childbearing age before initiating pharmacotherapy.³¹ If an unintended pregnancy occurs, tell your patient to contact you before stopping any medications. Lawsuits also can occur because of wrongful death by suicide or infanticide because of lack of treatment; risk of untreated illness should not be treated lightly.

Related Resources

• Motherisk. www.motherisk.org.
  
• Organization of Teratology Information Specialists. www.otispregnancy.org.
  
• Massachusetts General Hospital Center for Women’s Mental Health. www.womensmentalhealth.org.
  

Drug Brand Names

• Escitalopram • Lexapro
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  

Disclosure

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

Acknowledgments

The authors appreciate suggestions on prior versions of the manuscript from Miriam Rosenthal, Jaina Amin, Sarah Nagle-Yang, Sonal Moratschek, J.P. Shand, and Scott R. Miller.

Discuss this article at www.facebook.com/CurrentPsychiatry

Recently there has been an increase in advertising soliciting participants for class-action lawsuits involving birth defects and antidepressants, particularly sertraline. Many psychiatrists are unsure why these ads are running in seemingly every medium because there has been no change in the FDA pregnancy classification for most selective serotonin reuptake inhibitors (SSRIs), except for paroxetine going from a C to a D rating in 2005.¹ Some studies have found SSRIs increase the risk of adverse birth outcomes and others have not, which makes it difficult for clinicians to know what to discuss with patients regarding the risks and benefits of using antidepressants during pregnancy, as well as the risks of untreated major depressive disorder (MDD).

It can be hard to encourage some patients to take necessary medications in the best of circumstances, let alone suggest that a pregnant woman take a medication that has been labeled “dangerous.” This article seeks to alleviate physicians’ fears about being caught in a no-win situation by:

• explaining factors that may have led to this increase in class-action lawsuits
  
• clarifying the risks of using certain medications and not treating depression
  
• suggesting ways physicians can protect themselves and their patients.
  

The FDA’s position

In July 2006, the FDA issued a public health advisory regarding SSRI use during pregnancy and the possibility of persistent pulmonary hypertension (PPHN).² This warning was based on a single study that found the risk of developing PPHN (baseline rate: 1 to 2 per 1,000 births) was 6 times greater for fetuses exposed to SSRIs in late pregnancy.³ Many legal websites highlight this 2006 warning as proof of SSRIs’ danger. However, because subsequent studies have had conflicting results, the FDA’s current position is that the risks of using SSRIs during pregnancy are “unknown” (Box).^1-4

Box

Risks of depression

Although most physicians know the risks of untreated MDD, they tend to minimize or forget these risks when a woman becomes pregnant. Pregnant women with MDD face not only the expected risks of their psychiatric illness but additionally face risks of pre-eclampsia, suicide (20% of deaths in the postpartum period are due to suicide), and infanticide.^5-10 Risks to the fetus include poor prenatal care, increased risk of intrauterine exposure to drugs or alcohol, increased exposure to maternal cortisol with resulting neurodevelopmental changes, preterm delivery, low birth weight, and failure to thrive.^6-8 Later difficulties for the child of a mother with untreated depression may include poor stress adaptation, decreased cognitive performance, and behavioral difficulties because of poor mother-child bonding and other factors.⁶

See Table 1 for key statistics regarding pregnancy and depression.

Table 1

Statistics on pregnancy and depression

There are approximately 6 million pregnancies each year in the United Statesa
There are approximately 4 million live births each year in the United Statesa
Two percent to 3% of healthy pregnancies result in a birth defect or miscarriageb-d
Sixty percent to 70% of birth complications occur due to an unknown caused
Rates of depression during pregnancy are 7% to 25%b,e,f
Approximately 13% of pregnant women take an antidepressant during pregnancye
Fifteen percent of women with untreated depression in pregnancy attempt suicideb
Twenty percent of deaths in the postpartum period are due to suicidee
Women who discontinue antidepressants are 5 times more likely than women who continue medications in pregnancy to have a relapse of depressiong,h
SSRIs are the antidepressant class most frequently prescribed to pregnant womeni
Sertraline is one of the most frequently prescribed antidepressants perinatally and has low concentration in breast milk and infant serumj,k
SSRIs: selective serotonin reuptake inhibitors American Pregnancy Association. Statistics. http://www.americanpregnancy.org/main/statistics.html. Accessed December 20, 2012. Hasser C, Brizendine L, Spielvogel A. SSRI use during pregnancy. Current Psychiatry. 2006;5(4):31-40. Altshuler L, Richards M, Yonkers K. Treating bipolar disorder during pregnancy. Current Psychiatry. 2003;2(7):14-26. Cott A, Wisner K. Psychiatric disorders during pregnancy. Internat Rev Psychiatry. 2003;15(3):217-230. Meltzer-Brody S. New insights into perinatal depression: pathogenesis and treatment during pregnancy and postpartum. Dialogues Clin Neurosci. 2011;13(1):89-100. Kieler H, Artama M, Engeland A, et al. Selective serotonin reuptake inhibitors during pregnancy and risk of persistent pulmonary hypertension in the newborn: population based cohort study from the five Nordic countries. BMJ. 2012;344:d8012. doi:10.1136/bmj.d801. U.S. Food and Drug Administration. Public health advisory: treatment challenges of depression in pregnancy and the possibility of persistent pulmonary hypertension in newborns. http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders /DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm124348.htm. Published July 19, 2006. Accessed December 20, 2012. Cohen LS, Altshuler LL, Harlow BL, et al. Relapse of major depression during pregnancy in women who maintain or discontinue antidepressant treatment. JAMA. 2006;295(5):499-507. Yonkers KA, Wisner KL, Stewart DE, et al. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. Gen Hosp Psychiatry. 2009;31(5):403-413. Berle JO, Spigset O. Antidepressant use during breastfeeding. Curr Womens Health Rev. 2011;7(1):28-34. Friedman SH, Nagle-Yang S, Parsons S. Maternal mental health in the neonatal intensive care unit. NeoReviews. 2011;12(2):e85-e93.

 

Limitations of research

Because of ethical difficulties in studying MDD treatment during pregnancy, most data are retrospective and prone to detection and confounding biases, such as^11-15:

• the risks associated with depression
  
• comorbid conditions such as obesity
  
• maternal age
  
• poor prenatal care
  
• how the baby was delivered (eg, Caesarean sections have higher rates of PPHN)¹³
  
• illicit substance use
  
• effects of other medications (80% of pregnant women use medications, including nonsteroidal anti-inflammatory drugs [NSAIDs], which are associated with PPHN).^11,16
  

No medication is 100% safe during pregnancy and all pregnancies have risks. In the United States, 2% to 3% of pregnancies produce infants with malformations,¹⁷ which makes it hard to determine if a defect is caused by a medication or occurred spontaneously. This is the baseline risk of all malformations; individual malformations are rare and it is difficult to conduct studies that have adequate power to demonstrate the risk for a specific malformation.

There are several potential adverse outcomes to consider when prescribing psychotropics to a pregnant woman, including miscarriage, malformation, preterm delivery, perinatal toxicity, and behavioral teratogenesis (Table 2).^6,7 SSRIs have been implicated in adverse outcomes, but there is no strong evidence that they increase the miscarriage rate, and several studies found no increase in birth defects.^6,13,18-20 Regarding teratogenesis, the FDA switched paroxetine from class C to class D because of a potential 1.5% to 2% risk of fetal cardiac malformation, compared with a 1% baseline rate in the general population.²¹ Drug toxicity or withdrawal in a neonate also is a risk; however, this condition is self-limited and managed supportively by neonatology.²² Behavioral teratogenesis—neurobehavioral problems that develop later in a child’s life—remains a hypothetical concern; research has been conflicting, and studies often used flawed methodology.

Evidence linking SSRIs to an increased risk of adverse birth outcomes often has been based on large, retrospective health system database cohort studies looking at SSRI exposure and associations with conditions such as PPHN, cardiac anomalies, attention-deficit/hyperactivity disorder, and autism.^10,23,24 However, correlation is not the same as causation. It is difficult to prove or disprove the causative factor of adverse outcomes in these studies because:

• these databases were not designed to answer these types of exposure questions (eg, limitations in data collected, such as other potential causes not recorded)
  
• they have many confounding biases (undocumented illicit substance use, possible minimization of smoking history, publication basis for positive findings, etc.)
  
• individuals who provided the data did not follow a standardized method (eg, variability among individual clinicians).
  

Many of these limitations are evident in a 2009 study by Pedersen et al,²³ who reported the prevalence of septal heart defects was 0.5% (2,315/493,113) among unexposed children and 0.9% (12/1,370) among children exposed to 1 SSRI during early pregnancy (odds ratio [OR]=1.99 [1.13 to 3.53]). Based on this study’s data, the number needed to harm—the number of patients you would need to treat to encounter 1 adverse outcome—was 246, which suggests a relatively low risk. When data for the entire study is reviewed, the ORs for either minor birth defects (control: 7,373/493,113 vs SSRI exposed: 39/1,370; OR=0.88 [0.54 to 1.41]) or major birth defects (control: 15,518/493,113 vs SSRI exposed: 55/1,370; OR 1.21 [0.91 to 1.62]) were not statistically significant (major and minor malformations were defined using European Surveillance of Congenital Anomalies coding).

Not to case aspersions on this group’s work, it should be noted that this study had limitations, including that the researchers:

• did not take into account SSRI dosage
  
• did not measure depression severity or remittance
  
• were not able to fully account for potential exposures (eg, over-the-counter NSAIDs)
  
• were unable to confirm that patients took their medications because the variable measured was prescriptions filled
  
• did not interview participants about their medication use or symptoms.
  

In addition, researchers noted that mothers who filled their antidepressant prescription at least twice also were likely to have other factors that put them at higher risk for having a child with birth defects—such as older age or smoking. The biggest problem with the study was a lack of a control group, such as depressed women who did not receive medication (eg, the risk of depression itself could explain the rise, or those with more severe depression could be prescribed antidepressants).¹⁵

In a more recent study,²⁴ 33 of 11,014 infants exposed to SSRIs after gestational week 20 developed PPHN (absolute risk: 3 per 1,000 births, compared with an incidence of 1.2 per 1,000 births in the general population), with an adjusted OR of 2.1 (95% CI 1.5 to 3.0). Although the authors warned that the results suggest a “class effect,” the rate of PPHN also was higher for mothers with a history of a psychiatric hospitalization within the last 10 years who were not taking medication (OR=1.3, 95% CI 1.0 to 1.6) and the OR for escitalopram (1.5, CI 0.2 to 10.5) was not statistically significant. This study did include a control group, but the 10-year window may have been too wide to represent a group with similar comorbid risks. Similar to the previously discussed study, mothers prescribed SSRIs were older, 1.7 times more likely to be smokers, and twice as likely to be prescribed NSAIDs. The study did not analyze the risk factors of smoking and body mass index because of an initial subset analysis (which was not reported) finding that these known risk factors for PPHN “did not confound the results.”²⁴

 

Table 2

Potential concerns when treating pregnant women with psychotropics

Miscarriage (spontaneous abortion)
Malformation (teratogenesis)
Preterm delivery
Perinatal syndrome (toxicity or withdrawal in neonate; usually self-limited and related to serotonin overstimulation or withdrawal; symptoms may include disrupted sleep irritability jitteriness or abnormal breathing)
Behavioral teratogenesis (later behavioral problems in child eg lower IQ developmental delays or autism)
Lactation compatibility or plans to bottle-feed
Source: References 6,7

The basis of class-action lawsuits

Interest in class-action lawsuits involving birth defects and antidepressants, particularly sertraline, appears to be increasing. Many websites advertising these lawsuits quote unnamed articles from reputable medical journals to support the claim that the medications are dangerous and cause a wide range of birth defects. Although some of the birth defects mentioned are specific, others (eg, “breathing problems” or “gastrointestinal side effects”) are so broad that any problem or complication could conceivably be attributed to the antidepressant. The degree of causation—if any at all—for many of these conditions has not been determined. A national advertising campaign looking for any problem may be occurring because the exact risks are “unknown.”¹

The 2009 U.S. Supreme Court ruling in Wyeth v Levine²⁵ allows individuals to sue manufacturers of branded medications in state and federal court for lack of proper labeling. However, the 2011 U.S. Supreme Court case of PLIVA, Inc. v Mensing²⁶ prohibits state lawsuits against manufacturers of generic medications over labeling because by federal (superseding) law, generic manufacturers must use the same warnings as the branded medication. This may in part explain why many medications targeted in commercials and websites for class-action lawsuits are branded products, even though generics are available.

The focus of these types of lawsuits has been on drug manufacturers, in part because of the success of past litigation. Past class- and single-action lawsuits involving birth defects against pharmaceutical companies, such as Richardson-Merrell Inc.—the manufacturer of thalidomide and Bendectin, the branded version of a combination of pyridoxine and doxylamine used to treat nausea and vomiting during pregnancy—were successful. Although limb defects with thalidomide were scientifically proven, Bendectin was never conclusively shown to cause birth defects even though it had been prescribed to 40% of pregnant women at one point. The legal theory behind the lawsuits is that the manufacturers should have done more research to determine the potential for birth defects.²⁷ In a case against SmithKline Beecham Corporation,²⁸ which makes Paxil, the branded version of the SSRI paroxetine, a jury found the manufacturer negligent for failing to warn about Paxil’s association with cardiac defects. The result was a $2.5 million jury verdict. Since that case, the manufacturer has settled >800 additional suits for >$1 billion. Because this risk of using paroxetine has been established, physicians should discuss this risk with their patients as part of an informed consent because they could be liable if they don’t.²¹ This legal concept is known as the “learned intermediary doctrine,” which states that once the risk is known, the intermediary (eg, the physician) is responsible to ensure that a product (eg, medication) is used appropriately. The 2011 FDA statement saying the risk for SSRIs during pregnancy is unknown¹ is important because it removes physicians as “learned intermediaries.”

Protect your patient and yourself

An estimated 13% of pregnant women take antidepressants; SSRIs are the most commonly used antidepressant during and after pregnancy.⁹ Although not every depressed pregnant woman requires medication, those with moderate to severe depression often do. Rational medication decisions, informed consent, and good documentation are important when treating these women. Discuss the risks of untreated illness as well as the risks of medications to ensure that the patient understands that avoiding medication does not guarantee a safe pregnancy. Suggest psychotherapy and electroconvulsive therapy as options when appropriate. When possible, include the patient’s partner and family in the discussion to help improve compliance and potentially reduce strife.²⁹ The psychiatrist or patient should discuss the medication plan with the patient’s obstetrician or family physician.

Whenever possible, consider using monotherapy, continuing a previously “successful” medication, and using the lowest effective dose.⁵ Clinicians may “underdose” medications because they believe this will lessen the risk from exposure, but this is risky because the fetus is still being exposed to the medication as well as the negative effects of undertreated MDD. If SSRIs are used throughout the pregnancy, the newborn may require additional observation to monitor for potential perinatal syndromes or PPHN.

 

^6,22

Many women become pregnant while being treated for depression. Approximately one-half of all pregnancies are unplanned, so women using antidepressants may unknowingly expose their fetus to medication.³⁰ For this reason, it is important to discuss potential pregnancy and birth control concerns with all women of childbearing age before initiating pharmacotherapy.³¹ If an unintended pregnancy occurs, tell your patient to contact you before stopping any medications. Lawsuits also can occur because of wrongful death by suicide or infanticide because of lack of treatment; risk of untreated illness should not be treated lightly.

Related Resources

• Motherisk. www.motherisk.org.
  
• Organization of Teratology Information Specialists. www.otispregnancy.org.
  
• Massachusetts General Hospital Center for Women’s Mental Health. www.womensmentalhealth.org.
  

Drug Brand Names

• Escitalopram • Lexapro
  
• Paroxetine • Paxil
  
• Sertraline • Zoloft
  

Disclosure

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

Acknowledgments

The authors appreciate suggestions on prior versions of the manuscript from Miriam Rosenthal, Jaina Amin, Sarah Nagle-Yang, Sonal Moratschek, J.P. Shand, and Scott R. Miller.

Discuss this article at www.facebook.com/CurrentPsychiatry

With a lifetime prevalence of 30%, alcohol use disorders (AUDs)—which in DSM-IV-TR include alcohol abuse and alcohol dependence—are among the most common psychiatric disorders.¹ Depressive disorders, including major depressive disorder (MDD) and dysthymia, frequently co-occur with AUDs.^2-4 This pattern of comorbidity adversely affects the prognosis, course, and treatment of both MDD and AUDs.⁵ High severity in 1 of these disorders is associated with high severity in the other.^2,6 Alcohol dependence appears to prolong the course of depression^7,8 and increases the risk of suicidal symptoms and behaviors.^9,10 Patients with depression and AUDs are at increased risk of relapse to heavy drinking.^7,11

Whether the high comorbidity rate of depressive disorders and AUDs is a result of 1 disorder causing the other (ie, AUDs leading to depression or vice versa) or can be attributed to shared etiology is unknown. Clinicians need to consider this question when treating patients with this pattern of comorbidity because distinguishing primary depression from secondary depression influences treatment decisions.¹²

There is a great need for pharmacologic interventions that can concurrently treat both depression and AUDs. This article reviews the evidence for current treatments for dually diagnosed patients and highlights novel agents that are worthy of further study for this complex patient population.

Current treatment options

Pharmacotherapy for MDD and alcohol dependence is common when these conditions occur alone. FDA-approved medications for treating depression include monoamine oxidase inhibitors, tricyclic antidepressants (TCAs), tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors.

SSRIs are the most widely used class of antidepressants. They gained FDA approval based on studies conducted in non-comorbid patients because patients with comorbid conditions usually are excluded from research studies.¹³ Few trials have evaluated patients with depression and AUDs; TCAs and SSRIs are best studied in these patients.

Serotonergic antidepressants

SSRIs are first-line medications for MDD because of their low abuse potential, favorable side effect profile, and relative safety in overdose.

Findings regarding the efficacy of SSRIs in patients with comorbid depression and AUDs have been mixed (Table 1).^14-20 Only fluoxetine and sertraline have been evaluated in double-blind, placebo-controlled trials; 4 studies were conducted with adults and 1 with adolescents. In a 12-week trial, Cornelius et al¹⁴ found that fluoxetine reduced depressive symptoms and alcohol use in 51 patients with MDD and alcohol dependence. Others researchers have reported that the SSRIs sertraline and fluoxetine reduced depressive symptoms but had few direct effects on drinking outcomes.^15,16 A 2003 study¹⁷ compared sertraline, 200 mg/d maximum, with placebo for 12 weeks in 82 patients with MDD and alcohol dependence. Depressive symptoms and alcohol consumption decreased substantially over time for both groups. However, further analyses revealed that depression-related outcomes differed based on severity of depressive symptoms—patients with more severe depressive symptoms at baseline benefited the most from sertraline.

Table 1

Serotonergic antidepressants for patients with AUDs and depression

Study	Sample	Results
Cornelius et al, 199714	Outpatients with severe major depression and AD 1. Fluoxetine (20 to 40 mg/d; n = 25) 2. Placebo (n = 26)	Greater reductions in depressive symptoms and drinking in patients treated with fluoxetine compared with placebo
Roy, 199815	Inpatients with current major depression and AD who were abstinent for ≥2 weeks 1. Sertraline (100 mg/d; n = 18) 2. Placebo (n = 18)	Greater reductions in depressive symptoms in patients treated with sertraline compared with placebo. Drinking outcomes were not emphasized because 35 of 36 patients reported continuous abstinence throughout the trial
Kranzler et al, 199516	Outpatients with AD. Fourteen percent had current major depression. All received weekly individual or group CBT focused on relapse prevention and skills building 1. Fluoxetine (mean daily dose: 48 mg; n = 51) 2. Placebo (n = 50)	Significant decrease in alcohol consumption for both groups during the trial. No significant differences in alcohol consumption between groups. Among those with current depression, patients treated with fluoxetine experienced greater reduction in depressive symptoms vs placebo
Moak et al, 200317	Currently depressed, actively drinking, alcohol-dependent outpatients. All received individual CBT 1. Sertraline (mean daily dose: 186 mg; n = 38) 2. Placebo (n = 44)	Sertraline had an advantage over placebo in reducing depressive symptoms in women but not in men. Sertraline reduced drinks per drinking day but not other drinking-related outcomes
Cornelius et al, 200918	Adolescents (age 15 to 20) with AA or AD and MDD. All received intensive manual-based therapy (CBT for MDD and AUD, MET for AUD) almost weekly 1. Fluoxetine (20 mg/d; n = 24) 2. Placebo (n = 26)	All improved during the course of trial. No significant differences between fluoxetine and placebo groups in depression- or drinking-related outcomes
Roy-Byrne et al, 200019	Actively drinking alcohol-dependent outpatients with history of ≥1 depressive episode. All received weekly group therapy for alcoholism 1. Nefazodone (mean daily dose: 460 mg; n = 32) 2. Placebo (n = 32)	Greater reduction in depressive symptoms but not in drinking-related outcomes in patients treated with nefazodone
Hernandez-Avila et al, 200420	Outpatients with AD and current major depression. All received supportive psychotherapy for 10 weeks 1. Nefazodone (mean daily dose: 413 mg; n = 21) 2. Placebo (n = 20)	Depressive and anxiety symptoms declined significantly over time, but no statistically significant differences in depressive or anxiety symptoms between nefazodone and placebo. Patients treated with nefazodone had significantly greater reductions in heavy drinking days and in total drinks compared with placebo-treated patients
AA: alcohol abuse; AD: alcohol dependence; AUDs: alcohol use disorders; CBT: cognitive-behavioral therapy; MDD: major depressive disorder; MET: motivational enhancement therapy

 

In a study of adolescents, Cornelius et al¹⁸ failed to find any differences between fluoxetine and placebo in any depression or drinking-related outcomes. This study compared the efficacy of fluoxetine, 20 mg/d, with placebo in 50 adolescents with MDD and AUDs who also received intensive, manual-based cognitive-behavioral therapy and motivational enhancement therapy. All patients improved during the trial, but there were no significant differences between fluoxetine- and placebo-treated adolescents.

Other serotonergic medications. Two studies have evaluated nefazodone, a serotonin (5-HT2) antagonist, in dually diagnosed patients. In a 12-week trial, Roy-Byrne et al¹⁹ evaluated the efficacy of nefazodone (mean daily dose: 460 mg) vs placebo in 64 actively drinking alcohol-dependent patients who had ≥1 prior episode of depression; all participated in a weekly psychoeducation group on alcoholism. Nefazodone was associated with significantly greater reduction in depressive symptoms but no reductions in drinking compared with placebo. However, a 10-week study of nefazodone²⁰ (mean daily dose: 413 mg) vs placebo in 41 alcohol-dependent patients with current major depression found that those who received nefazodone significantly reduced heavy drinking days compared with the placebo group. There were no significant differences in depressive symptoms between groups.

Older studies of SSRIs conducted in patients with AUDs but not depression suggested that these medications may exacerbate AUDs in certain populations, specifically women and individuals with early onset AUD.^21-23 Use caution if you prescribe SSRIs to alcohol-dependent patients without comorbid depression. When prescribing SSRIs for those with comorbid AUDs, carefully monitor patients’ drinking.

Conflicting evidence on TCAs

Although several studies suggest TCAs may help reduce depressive symptoms in patients with AUDs, results on their ability to reduce drinking are conflicting (Table 2).^24-26 In 1 study, 6 months of desipramine (mean daily dose: 200 mg) reduced drinking in 28 alcohol-dependent individuals with secondary depression²⁴; in another, 12 weeks of imipramine plus weekly relapse prevention psychotherapy did not affect drinking-related outcomes in 69 actively drinking alcoholic outpatients with current depressive disorders.²⁵

Table 2

Limited evidence supports TCAs for comorbid depression and AUDs

Study	Sample	Results
Mason et al, 199624	Outpatients with AD and secondary depression. Part of larger study including non-depressed patients with AD (N = 71) 1. Desipramine (mean daily dose 200 mg; n = 15) 2. Placebo (n = 13)	Greater reduction in depressive symptoms and drinking in desipramine-treated patients compared with placebo-treated patients
McGrath et al, 199625	Outpatients with AD or AA and major depression, dysthymia, or depressive disorder NOS 1. Imipramine (mean daily dose 260 mg; n = 36) 2. Placebo (n = 33)	Greater reduction in depressive symptoms for imipramine-treated patients compared with placebo-treated patients. Drinking-related outcomes were not directly affected by medication except improvements in mood led to reduced alcohol use
Altintoprak et al, 200826	Inpatients with AD and MDD 1. Mirtazapine (30 mg/d; n = 24) 2. Amitriptyline (100 mg/d; n = 20)	Drinking-related outcomes were not emphasized because all patients were required to abstain from drinking during the study. Both treatments reduced depressive symptoms; there were no significant differences between groups
AA: alcohol abuse; AD: alcohol dependence; AUDs: alcohol use disorders; MDD: major depressive disorder; NOS: not otherwise specified; TCAs: tricyclic antidepressants

Studies of TCAs largely were abandoned when SSRIs were introduced because SSRIs have a better safety profile. However, disappointing results with SSRIs have rekindled an interest in TCAs and other types of antidepressants.

Altintoprak et al²⁶ compared the efficacy of the antidepressant mirtazapine, 30 mg/d, with the TCA amitriptyline, 100 mg/d, in 44 patients with comorbid alcohol dependence and MDD. All patients were required to abstain from drinking alcohol during the study. Both medications resulted in steady reductions in depressive symptoms and alcohol cravings; however, researchers found no significant differences between the 2 treatment groups.

Analyses of combined studies

Pettinati²⁷ conducted a qualitative review of antidepressants for patients with depression and alcohol dependence that included 8 controlled clinical trials (2 on TCAs and 6 on serotonergic medications) conducted between 1994 and 2004. In this review, both TCAs and serotonergic medications were similarly effective in reducing depressive symptoms but not consistently effective in reducing drinking.

Nunes and Levin²⁸ conducted a systematic, meta-analysis of the efficacy of antidepressants for patients with depression and alcohol and/or other substance use disorders that reviewed 8 placebo-controlled trials that included patients with depression and AUDs. Of these 8 trials, 2 used TCAs, 5 used serotonergic agents, and 1 used viloxazine, a bicyclic antidepressant morpholine derivative not available in the United States that acts as a selective norepinephrine reuptake inhibitor. Similar to Pettinati,

 

²⁷ this review suggested that antidepressants can reduce depressive symptoms but not drinking. The authors also found evidence that the more the antidepressant reduced depressive symptoms, the more it reduced alcohol use. Studies published after these reviews have not substantially altered these findings.

Alcohol abuse medications

Four medications are FDA-approved for treating alcohol dependence:

• disulfiram
  
• naltrexone (in 2 formulations: oral and long-acting injectable)
  
• acamprosate.
  

After a few smaller studies suggested that naltrexone might reduce alcohol use among dually diagnosed individuals, several larger studies were initiated (Table 3).^29-31 In a 12-week study, 254 outpatients with alcohol dependence plus an additional axis I disorder (including depression) were randomized to naltrexone, disulfiram, naltrexone plus disulfiram, or no medication.³¹ Overall, medication was more effective than no medication in consecutive abstinence, but researchers found no advantage for 1 medication over the other, and no advantage to the combination. In a secondary analysis that compared 139 patients with depression to those with other axis I diagnoses, medication offered no advantage over placebo in alcohol use outcomes.²⁹ There was a significant interaction among depression, medication group, and craving—depressed patients assigned to disulfiram reported lower cravings over time than depressed patients receiving naltrexone. In this study, most patients also received medication for their comorbid condition, but no standard medication was used.

Table 3

Can medications that target alcohol use also improve depression?

Study	Sample	Results
Petrakis et al, 200729	Outpatients with AD and an axis I disorder, including depression (secondary analysis of Petrakis et al, 200531) 1. Naltrexone (50 mg/d; n = 34) 2. Disulfiram (250 mg/d; n = 43) 3. Naltrexone + disulfiram (n = 28) 4. Placebo (n = 34)	Generally, medication was more effective than no medication. No advantage of 1 medication over the other. There was no relationship between depression diagnosis and medication condition, which suggests that for patients with depression, there was no advantage to medication
Pettinati et al, 201030	Outpatients with AD and MDD 1. Sertraline (200 mg/d; n = 40) 2. Naltrexone (100 mg/d; n = 49) 3. Sertraline + naltrexone (n = 42) 4. Placebo (n = 39)	Greater proportion of patients in combined medication group abstained from alcohol and refrained from heavy alcohol use during the trial compared with those in sertraline-only or naltrexone-only groups. No significant differences among groups on depression-related outcomes
AD: alcohol dependence; MDD: major depressive disorder

In a double-blind, placebo-controlled study that compared sertraline, naltrexone, and sertraline plus naltrexone in 170 patients with comorbid alcohol dependence and MDD, a greater proportion of patients in the combined medication group abstained from alcohol or refrained from heavy alcohol use during the 14-week trial compared with those receiving sertraline or naltrexone alone.³⁰ Patients in the combined medication group also reported a longer time before relapse to any drinking. There were no significant differences between the 3 groups on depression-related outcomes, although the combined medication group reported fewer depressive symptoms in the last 3 weeks of treatment. This study suggests that when used together, combining medications to treat the underlying psychiatric disorder with medications to treat AUDs may be more effective than either medication alone.

Nevertheless, these studies suggest that medications for treating depression or AUDs have, at best, only a modest effect in patients with both disorders.

Novel agents

Several novel medications have been evaluated as possible treatments for comorbid depression and AUDs because they target the underlying neurobiology of both disorders:

• agents that target the neurotransmitter glutamate, including the N-methyl-d-aspartate glutamate receptor antagonists memantine and ketamine
  
• dopaminergic agents such as quetiapine
  
• corticotropin-releasing factor (CRF) receptor 1 (CRF₁) antagonists.
  

Research has implicated glutamate system dysfunction in both AUDs and depression and suggested that memantine and ketamine may reduce depressive symptoms and alcohol craving. Muhonen et al³² compared memantine, 20 mg/d, to the SSRI escitalopram, 20 mg/d, in 80 outpatients with MDD and alcohol dependence. Although both medications reduced symptoms of depression and anxiety, there were no significant differences between treatments; the study did not evaluate alcohol-related outcomes.

In a case study, a 55-year-old man with treatment-resistant major depression and co-occurring alcohol and benzodiazepine dependence who received a single dose of IV ketamine, 0.5 mg/kg over 50 minutes, experienced “significant improvements” in depressive symptoms that lasted throughout the 7-day follow-up.³³ This study did not report on ketamine’s effects on his alcohol use.

 

The atypical antipsychotic quetiapine acts as a serotonin (5-HT1A and 5-HT2) and dopamine (D1 and D2) antagonist, and reports suggest it reduces alcohol craving and affective symptoms in patients with AUDs.^34,35 In a 16-week, open-label study, quetiapine decreased alcohol consumption, alcohol craving, and intensity of some psychiatric symptoms in 28 alcohol-dependent patients with bipolar disorder, schizoaffective disorder, or borderline personality disorder.³⁶

See the Box for a description of the role CRF₁ antagonists may play in treating patients with concurrent MDD and AUDs. See Table 4 for studies of memantine and quetiapine in treating depression with AUDs.

Box

Table 4

Other agents may play a role in treating depression with AUDs

Study	Sample	Results
Muhonen et al, 200832	Outpatients with MDD and AD 1. Memantine (20 mg/d; n = 40) 2. Escitalopram (20 mg/d; n = 40)	Both treatments reduced depressive and anxiety symptoms. No significant differences between groups. Study did not examine alcohol-related outcomes
Martinotti et al, 200833	Outpatients with comorbid AD and either bipolar disorder, schizoaffective disorder or borderline personality disorder. Open-label study 1. Quetiapine (300 to 800 mg/d; n = 28)	Quetiapine was associated with reduced alcohol consumption, alcohol craving, and intensity of psychiatric symptoms
AD: alcohol dependence; AUDs: alcohol use disorders; MDD: major depressive disorder

Interpreting the evidence

The co-occurrence of MDD and AUDs is a common and difficult clinical problem. Although FDA-approved medications targeting depression and AUD are effective when these conditions occur alone, their efficacy when these conditions co-occur is still under investigation. Antidepressants have modest efficacy in reducing depressive symptoms but are less effective in reducing alcohol consumption, which suggests that their action on mood has little direct impact on alcohol consumption. Evidence for the efficacy of medications to treat alcohol consumption is less robust. Results from studies of using a combination of antidepressants and medications that directly target alcohol use have been conflicting and disappointing.

These findings underscore the importance of thorough evaluations. SSRIs are a first-line treatment for depression and as such probably should be the first choice for patients with comorbid AUDs. Drinking should be monitored closely and abstinence encouraged. Using medications that target AUDs is safe and modestly effective in patients with comorbid depression. Evidence suggests that treating both disorders simultaneously is more effective than treating either alone. Medications should be prescribed as part of a comprehensive treatment plan that also includes psychotherapy.

Related Resources

• Pettinati H. Antidepressant treatment of co-occurring depression and alcohol dependence. Biol Psychiatry. 2004;56(10):785-792.
  
• Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004;291(15):1887-1896.
  

Drug Brand Names

• Acamprosate • Campral
  
• Amitriptyline • Elavil
  
• Desipramine • Norpramin
  
• Disulfiram • Antabuse
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Imipramine • Tofranil
  
• Ketamine • Ketalar
  
• Memantine • Namenda
  
• Mirtazapine • Remeron
  
• Naltrexone • Revia, Vivitrol
  
• Nefazodone • Serzone
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  

Disclosures

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

Dr. Petrakis receives research or grant support from the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, the U.S. Department of Defense, and the U.S. Department of Veterans Affairs.

 

This work has been supported by a grant from the Veterans Affairs New England Mental Illness Research, Education, and Clinical Center and by the National Institute of Mental Health (T32MH062994-07).

Acknowledgements

The authors thank Elizabeth Guidone for her helpful comments and Diana Limoncelli for her assistance in manuscript preparation.

Discuss this article at www.facebook.com/CurrentPsychiatry

With a lifetime prevalence of 30%, alcohol use disorders (AUDs)—which in DSM-IV-TR include alcohol abuse and alcohol dependence—are among the most common psychiatric disorders.¹ Depressive disorders, including major depressive disorder (MDD) and dysthymia, frequently co-occur with AUDs.^2-4 This pattern of comorbidity adversely affects the prognosis, course, and treatment of both MDD and AUDs.⁵ High severity in 1 of these disorders is associated with high severity in the other.^2,6 Alcohol dependence appears to prolong the course of depression^7,8 and increases the risk of suicidal symptoms and behaviors.^9,10 Patients with depression and AUDs are at increased risk of relapse to heavy drinking.^7,11

Whether the high comorbidity rate of depressive disorders and AUDs is a result of 1 disorder causing the other (ie, AUDs leading to depression or vice versa) or can be attributed to shared etiology is unknown. Clinicians need to consider this question when treating patients with this pattern of comorbidity because distinguishing primary depression from secondary depression influences treatment decisions.¹²

There is a great need for pharmacologic interventions that can concurrently treat both depression and AUDs. This article reviews the evidence for current treatments for dually diagnosed patients and highlights novel agents that are worthy of further study for this complex patient population.

Current treatment options

Pharmacotherapy for MDD and alcohol dependence is common when these conditions occur alone. FDA-approved medications for treating depression include monoamine oxidase inhibitors, tricyclic antidepressants (TCAs), tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors.

SSRIs are the most widely used class of antidepressants. They gained FDA approval based on studies conducted in non-comorbid patients because patients with comorbid conditions usually are excluded from research studies.¹³ Few trials have evaluated patients with depression and AUDs; TCAs and SSRIs are best studied in these patients.

Serotonergic antidepressants

SSRIs are first-line medications for MDD because of their low abuse potential, favorable side effect profile, and relative safety in overdose.

Findings regarding the efficacy of SSRIs in patients with comorbid depression and AUDs have been mixed (Table 1).^14-20 Only fluoxetine and sertraline have been evaluated in double-blind, placebo-controlled trials; 4 studies were conducted with adults and 1 with adolescents. In a 12-week trial, Cornelius et al¹⁴ found that fluoxetine reduced depressive symptoms and alcohol use in 51 patients with MDD and alcohol dependence. Others researchers have reported that the SSRIs sertraline and fluoxetine reduced depressive symptoms but had few direct effects on drinking outcomes.^15,16 A 2003 study¹⁷ compared sertraline, 200 mg/d maximum, with placebo for 12 weeks in 82 patients with MDD and alcohol dependence. Depressive symptoms and alcohol consumption decreased substantially over time for both groups. However, further analyses revealed that depression-related outcomes differed based on severity of depressive symptoms—patients with more severe depressive symptoms at baseline benefited the most from sertraline.

Table 1

Serotonergic antidepressants for patients with AUDs and depression

Study	Sample	Results
Cornelius et al, 199714	Outpatients with severe major depression and AD 1. Fluoxetine (20 to 40 mg/d; n = 25) 2. Placebo (n = 26)	Greater reductions in depressive symptoms and drinking in patients treated with fluoxetine compared with placebo
Roy, 199815	Inpatients with current major depression and AD who were abstinent for ≥2 weeks 1. Sertraline (100 mg/d; n = 18) 2. Placebo (n = 18)	Greater reductions in depressive symptoms in patients treated with sertraline compared with placebo. Drinking outcomes were not emphasized because 35 of 36 patients reported continuous abstinence throughout the trial
Kranzler et al, 199516	Outpatients with AD. Fourteen percent had current major depression. All received weekly individual or group CBT focused on relapse prevention and skills building 1. Fluoxetine (mean daily dose: 48 mg; n = 51) 2. Placebo (n = 50)	Significant decrease in alcohol consumption for both groups during the trial. No significant differences in alcohol consumption between groups. Among those with current depression, patients treated with fluoxetine experienced greater reduction in depressive symptoms vs placebo
Moak et al, 200317	Currently depressed, actively drinking, alcohol-dependent outpatients. All received individual CBT 1. Sertraline (mean daily dose: 186 mg; n = 38) 2. Placebo (n = 44)	Sertraline had an advantage over placebo in reducing depressive symptoms in women but not in men. Sertraline reduced drinks per drinking day but not other drinking-related outcomes
Cornelius et al, 200918	Adolescents (age 15 to 20) with AA or AD and MDD. All received intensive manual-based therapy (CBT for MDD and AUD, MET for AUD) almost weekly 1. Fluoxetine (20 mg/d; n = 24) 2. Placebo (n = 26)	All improved during the course of trial. No significant differences between fluoxetine and placebo groups in depression- or drinking-related outcomes
Roy-Byrne et al, 200019	Actively drinking alcohol-dependent outpatients with history of ≥1 depressive episode. All received weekly group therapy for alcoholism 1. Nefazodone (mean daily dose: 460 mg; n = 32) 2. Placebo (n = 32)	Greater reduction in depressive symptoms but not in drinking-related outcomes in patients treated with nefazodone
Hernandez-Avila et al, 200420	Outpatients with AD and current major depression. All received supportive psychotherapy for 10 weeks 1. Nefazodone (mean daily dose: 413 mg; n = 21) 2. Placebo (n = 20)	Depressive and anxiety symptoms declined significantly over time, but no statistically significant differences in depressive or anxiety symptoms between nefazodone and placebo. Patients treated with nefazodone had significantly greater reductions in heavy drinking days and in total drinks compared with placebo-treated patients
AA: alcohol abuse; AD: alcohol dependence; AUDs: alcohol use disorders; CBT: cognitive-behavioral therapy; MDD: major depressive disorder; MET: motivational enhancement therapy

 

In a study of adolescents, Cornelius et al¹⁸ failed to find any differences between fluoxetine and placebo in any depression or drinking-related outcomes. This study compared the efficacy of fluoxetine, 20 mg/d, with placebo in 50 adolescents with MDD and AUDs who also received intensive, manual-based cognitive-behavioral therapy and motivational enhancement therapy. All patients improved during the trial, but there were no significant differences between fluoxetine- and placebo-treated adolescents.

Other serotonergic medications. Two studies have evaluated nefazodone, a serotonin (5-HT2) antagonist, in dually diagnosed patients. In a 12-week trial, Roy-Byrne et al¹⁹ evaluated the efficacy of nefazodone (mean daily dose: 460 mg) vs placebo in 64 actively drinking alcohol-dependent patients who had ≥1 prior episode of depression; all participated in a weekly psychoeducation group on alcoholism. Nefazodone was associated with significantly greater reduction in depressive symptoms but no reductions in drinking compared with placebo. However, a 10-week study of nefazodone²⁰ (mean daily dose: 413 mg) vs placebo in 41 alcohol-dependent patients with current major depression found that those who received nefazodone significantly reduced heavy drinking days compared with the placebo group. There were no significant differences in depressive symptoms between groups.

Older studies of SSRIs conducted in patients with AUDs but not depression suggested that these medications may exacerbate AUDs in certain populations, specifically women and individuals with early onset AUD.^21-23 Use caution if you prescribe SSRIs to alcohol-dependent patients without comorbid depression. When prescribing SSRIs for those with comorbid AUDs, carefully monitor patients’ drinking.

Conflicting evidence on TCAs

Although several studies suggest TCAs may help reduce depressive symptoms in patients with AUDs, results on their ability to reduce drinking are conflicting (Table 2).^24-26 In 1 study, 6 months of desipramine (mean daily dose: 200 mg) reduced drinking in 28 alcohol-dependent individuals with secondary depression²⁴; in another, 12 weeks of imipramine plus weekly relapse prevention psychotherapy did not affect drinking-related outcomes in 69 actively drinking alcoholic outpatients with current depressive disorders.²⁵

Table 2

Limited evidence supports TCAs for comorbid depression and AUDs

Study	Sample	Results
Mason et al, 199624	Outpatients with AD and secondary depression. Part of larger study including non-depressed patients with AD (N = 71) 1. Desipramine (mean daily dose 200 mg; n = 15) 2. Placebo (n = 13)	Greater reduction in depressive symptoms and drinking in desipramine-treated patients compared with placebo-treated patients
McGrath et al, 199625	Outpatients with AD or AA and major depression, dysthymia, or depressive disorder NOS 1. Imipramine (mean daily dose 260 mg; n = 36) 2. Placebo (n = 33)	Greater reduction in depressive symptoms for imipramine-treated patients compared with placebo-treated patients. Drinking-related outcomes were not directly affected by medication except improvements in mood led to reduced alcohol use
Altintoprak et al, 200826	Inpatients with AD and MDD 1. Mirtazapine (30 mg/d; n = 24) 2. Amitriptyline (100 mg/d; n = 20)	Drinking-related outcomes were not emphasized because all patients were required to abstain from drinking during the study. Both treatments reduced depressive symptoms; there were no significant differences between groups
AA: alcohol abuse; AD: alcohol dependence; AUDs: alcohol use disorders; MDD: major depressive disorder; NOS: not otherwise specified; TCAs: tricyclic antidepressants

Studies of TCAs largely were abandoned when SSRIs were introduced because SSRIs have a better safety profile. However, disappointing results with SSRIs have rekindled an interest in TCAs and other types of antidepressants.

Altintoprak et al²⁶ compared the efficacy of the antidepressant mirtazapine, 30 mg/d, with the TCA amitriptyline, 100 mg/d, in 44 patients with comorbid alcohol dependence and MDD. All patients were required to abstain from drinking alcohol during the study. Both medications resulted in steady reductions in depressive symptoms and alcohol cravings; however, researchers found no significant differences between the 2 treatment groups.

Analyses of combined studies

Pettinati²⁷ conducted a qualitative review of antidepressants for patients with depression and alcohol dependence that included 8 controlled clinical trials (2 on TCAs and 6 on serotonergic medications) conducted between 1994 and 2004. In this review, both TCAs and serotonergic medications were similarly effective in reducing depressive symptoms but not consistently effective in reducing drinking.

Nunes and Levin²⁸ conducted a systematic, meta-analysis of the efficacy of antidepressants for patients with depression and alcohol and/or other substance use disorders that reviewed 8 placebo-controlled trials that included patients with depression and AUDs. Of these 8 trials, 2 used TCAs, 5 used serotonergic agents, and 1 used viloxazine, a bicyclic antidepressant morpholine derivative not available in the United States that acts as a selective norepinephrine reuptake inhibitor. Similar to Pettinati,

 

²⁷ this review suggested that antidepressants can reduce depressive symptoms but not drinking. The authors also found evidence that the more the antidepressant reduced depressive symptoms, the more it reduced alcohol use. Studies published after these reviews have not substantially altered these findings.

Alcohol abuse medications

Four medications are FDA-approved for treating alcohol dependence:

• disulfiram
  
• naltrexone (in 2 formulations: oral and long-acting injectable)
  
• acamprosate.
  

After a few smaller studies suggested that naltrexone might reduce alcohol use among dually diagnosed individuals, several larger studies were initiated (Table 3).^29-31 In a 12-week study, 254 outpatients with alcohol dependence plus an additional axis I disorder (including depression) were randomized to naltrexone, disulfiram, naltrexone plus disulfiram, or no medication.³¹ Overall, medication was more effective than no medication in consecutive abstinence, but researchers found no advantage for 1 medication over the other, and no advantage to the combination. In a secondary analysis that compared 139 patients with depression to those with other axis I diagnoses, medication offered no advantage over placebo in alcohol use outcomes.²⁹ There was a significant interaction among depression, medication group, and craving—depressed patients assigned to disulfiram reported lower cravings over time than depressed patients receiving naltrexone. In this study, most patients also received medication for their comorbid condition, but no standard medication was used.

Table 3

Can medications that target alcohol use also improve depression?

Study	Sample	Results
Petrakis et al, 200729	Outpatients with AD and an axis I disorder, including depression (secondary analysis of Petrakis et al, 200531) 1. Naltrexone (50 mg/d; n = 34) 2. Disulfiram (250 mg/d; n = 43) 3. Naltrexone + disulfiram (n = 28) 4. Placebo (n = 34)	Generally, medication was more effective than no medication. No advantage of 1 medication over the other. There was no relationship between depression diagnosis and medication condition, which suggests that for patients with depression, there was no advantage to medication
Pettinati et al, 201030	Outpatients with AD and MDD 1. Sertraline (200 mg/d; n = 40) 2. Naltrexone (100 mg/d; n = 49) 3. Sertraline + naltrexone (n = 42) 4. Placebo (n = 39)	Greater proportion of patients in combined medication group abstained from alcohol and refrained from heavy alcohol use during the trial compared with those in sertraline-only or naltrexone-only groups. No significant differences among groups on depression-related outcomes
AD: alcohol dependence; MDD: major depressive disorder

In a double-blind, placebo-controlled study that compared sertraline, naltrexone, and sertraline plus naltrexone in 170 patients with comorbid alcohol dependence and MDD, a greater proportion of patients in the combined medication group abstained from alcohol or refrained from heavy alcohol use during the 14-week trial compared with those receiving sertraline or naltrexone alone.³⁰ Patients in the combined medication group also reported a longer time before relapse to any drinking. There were no significant differences between the 3 groups on depression-related outcomes, although the combined medication group reported fewer depressive symptoms in the last 3 weeks of treatment. This study suggests that when used together, combining medications to treat the underlying psychiatric disorder with medications to treat AUDs may be more effective than either medication alone.

Nevertheless, these studies suggest that medications for treating depression or AUDs have, at best, only a modest effect in patients with both disorders.

Novel agents

Several novel medications have been evaluated as possible treatments for comorbid depression and AUDs because they target the underlying neurobiology of both disorders:

• agents that target the neurotransmitter glutamate, including the N-methyl-d-aspartate glutamate receptor antagonists memantine and ketamine
  
• dopaminergic agents such as quetiapine
  
• corticotropin-releasing factor (CRF) receptor 1 (CRF₁) antagonists.
  

Research has implicated glutamate system dysfunction in both AUDs and depression and suggested that memantine and ketamine may reduce depressive symptoms and alcohol craving. Muhonen et al³² compared memantine, 20 mg/d, to the SSRI escitalopram, 20 mg/d, in 80 outpatients with MDD and alcohol dependence. Although both medications reduced symptoms of depression and anxiety, there were no significant differences between treatments; the study did not evaluate alcohol-related outcomes.

In a case study, a 55-year-old man with treatment-resistant major depression and co-occurring alcohol and benzodiazepine dependence who received a single dose of IV ketamine, 0.5 mg/kg over 50 minutes, experienced “significant improvements” in depressive symptoms that lasted throughout the 7-day follow-up.³³ This study did not report on ketamine’s effects on his alcohol use.

 

The atypical antipsychotic quetiapine acts as a serotonin (5-HT1A and 5-HT2) and dopamine (D1 and D2) antagonist, and reports suggest it reduces alcohol craving and affective symptoms in patients with AUDs.^34,35 In a 16-week, open-label study, quetiapine decreased alcohol consumption, alcohol craving, and intensity of some psychiatric symptoms in 28 alcohol-dependent patients with bipolar disorder, schizoaffective disorder, or borderline personality disorder.³⁶

See the Box for a description of the role CRF₁ antagonists may play in treating patients with concurrent MDD and AUDs. See Table 4 for studies of memantine and quetiapine in treating depression with AUDs.

Box

Table 4

Other agents may play a role in treating depression with AUDs

Study	Sample	Results
Muhonen et al, 200832	Outpatients with MDD and AD 1. Memantine (20 mg/d; n = 40) 2. Escitalopram (20 mg/d; n = 40)	Both treatments reduced depressive and anxiety symptoms. No significant differences between groups. Study did not examine alcohol-related outcomes
Martinotti et al, 200833	Outpatients with comorbid AD and either bipolar disorder, schizoaffective disorder or borderline personality disorder. Open-label study 1. Quetiapine (300 to 800 mg/d; n = 28)	Quetiapine was associated with reduced alcohol consumption, alcohol craving, and intensity of psychiatric symptoms
AD: alcohol dependence; AUDs: alcohol use disorders; MDD: major depressive disorder

Interpreting the evidence

The co-occurrence of MDD and AUDs is a common and difficult clinical problem. Although FDA-approved medications targeting depression and AUD are effective when these conditions occur alone, their efficacy when these conditions co-occur is still under investigation. Antidepressants have modest efficacy in reducing depressive symptoms but are less effective in reducing alcohol consumption, which suggests that their action on mood has little direct impact on alcohol consumption. Evidence for the efficacy of medications to treat alcohol consumption is less robust. Results from studies of using a combination of antidepressants and medications that directly target alcohol use have been conflicting and disappointing.

These findings underscore the importance of thorough evaluations. SSRIs are a first-line treatment for depression and as such probably should be the first choice for patients with comorbid AUDs. Drinking should be monitored closely and abstinence encouraged. Using medications that target AUDs is safe and modestly effective in patients with comorbid depression. Evidence suggests that treating both disorders simultaneously is more effective than treating either alone. Medications should be prescribed as part of a comprehensive treatment plan that also includes psychotherapy.

Related Resources

• Pettinati H. Antidepressant treatment of co-occurring depression and alcohol dependence. Biol Psychiatry. 2004;56(10):785-792.
  
• Nunes EV, Levin FR. Treatment of depression in patients with alcohol or other drug dependence: a meta-analysis. JAMA. 2004;291(15):1887-1896.
  

Drug Brand Names

• Acamprosate • Campral
  
• Amitriptyline • Elavil
  
• Desipramine • Norpramin
  
• Disulfiram • Antabuse
  
• Escitalopram • Lexapro
  
• Fluoxetine • Prozac
  
• Imipramine • Tofranil
  
• Ketamine • Ketalar
  
• Memantine • Namenda
  
• Mirtazapine • Remeron
  
• Naltrexone • Revia, Vivitrol
  
• Nefazodone • Serzone
  
• Quetiapine • Seroquel
  
• Sertraline • Zoloft
  

Disclosures

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

Dr. Petrakis receives research or grant support from the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, the U.S. Department of Defense, and the U.S. Department of Veterans Affairs.

 

This work has been supported by a grant from the Veterans Affairs New England Mental Illness Research, Education, and Clinical Center and by the National Institute of Mental Health (T32MH062994-07).

Acknowledgements

The authors thank Elizabeth Guidone for her helpful comments and Diana Limoncelli for her assistance in manuscript preparation.