Somatic Disorders

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

Table 2

Antipsychotics for headache and nausea: Strength of the evidence

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

Table 2

Antipsychotics for headache and nausea: Strength of the evidence

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

Table 2

Antipsychotics for headache and nausea: Strength of the evidence

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.

LOS ANGELES – The use of selective serotonin reuptake inhibitors in treating combat posttraumatic stress disorder in middle-aged veterans was associated with sharply reduced cardiovascular mortality in a large observational study, according to Dr. Naser Ahmadi of the VA Greater Los Angeles Healthcare System.

Treatment with a selective serotonin reuptake inhibitor also appeared to protect against development of metabolic syndrome in this patient population, he added at the annual scientific sessions of the American Heart Association.

Dr. Ahmadi reported on 1,142 veterans with combat-induced PTSD, 433 of whom had received SSRI therapy for the disorder. Fifty-three percent of subjects met criteria for metabolic syndrome.

During a median 5 years of follow-up through the Veterans Affairs system’s electronic medical record system, the cardiovascular mortality was 21% in patients with PTSD and metabolic syndrome, compared with 14% in those without metabolic syndrome. Thus, comorbid metabolic syndrome in patients with combat PTSD was associated with a 68% increase in the risk of cardiovascular mortality.

The prevalence of metabolic syndrome was 32% among SSRI recipients, compared with 45% in those whose PTSD was not treated SSRIs. After adjusting for age, gender, and conventional cardiovascular risk factors in a multivariate analysis, the relative risk of metabolic syndrome in patients with PTSD was 71% lower with SSRI therapy than without it.

Moreover, the adjusted risk of cardiovascular mortality over the course of a median 5 years of follow-up in this hypothesis-generating observational study was 36% lower in SSRI-treated patients with PTSD and metabolic syndrome than in those not on an SSRI, and 64% lower in SSRI-treated patients with PTSD without metabolic syndrome.

This study received funding from the American Heart Association. Dr. Ahmadi reported having no financial conflicts.

[email protected]

LOS ANGELES – The use of selective serotonin reuptake inhibitors in treating combat posttraumatic stress disorder in middle-aged veterans was associated with sharply reduced cardiovascular mortality in a large observational study, according to Dr. Naser Ahmadi of the VA Greater Los Angeles Healthcare System.

Treatment with a selective serotonin reuptake inhibitor also appeared to protect against development of metabolic syndrome in this patient population, he added at the annual scientific sessions of the American Heart Association.

Dr. Ahmadi reported on 1,142 veterans with combat-induced PTSD, 433 of whom had received SSRI therapy for the disorder. Fifty-three percent of subjects met criteria for metabolic syndrome.

During a median 5 years of follow-up through the Veterans Affairs system’s electronic medical record system, the cardiovascular mortality was 21% in patients with PTSD and metabolic syndrome, compared with 14% in those without metabolic syndrome. Thus, comorbid metabolic syndrome in patients with combat PTSD was associated with a 68% increase in the risk of cardiovascular mortality.

The prevalence of metabolic syndrome was 32% among SSRI recipients, compared with 45% in those whose PTSD was not treated SSRIs. After adjusting for age, gender, and conventional cardiovascular risk factors in a multivariate analysis, the relative risk of metabolic syndrome in patients with PTSD was 71% lower with SSRI therapy than without it.

Moreover, the adjusted risk of cardiovascular mortality over the course of a median 5 years of follow-up in this hypothesis-generating observational study was 36% lower in SSRI-treated patients with PTSD and metabolic syndrome than in those not on an SSRI, and 64% lower in SSRI-treated patients with PTSD without metabolic syndrome.

This study received funding from the American Heart Association. Dr. Ahmadi reported having no financial conflicts.

[email protected]

LOS ANGELES – The use of selective serotonin reuptake inhibitors in treating combat posttraumatic stress disorder in middle-aged veterans was associated with sharply reduced cardiovascular mortality in a large observational study, according to Dr. Naser Ahmadi of the VA Greater Los Angeles Healthcare System.

Treatment with a selective serotonin reuptake inhibitor also appeared to protect against development of metabolic syndrome in this patient population, he added at the annual scientific sessions of the American Heart Association.

Dr. Ahmadi reported on 1,142 veterans with combat-induced PTSD, 433 of whom had received SSRI therapy for the disorder. Fifty-three percent of subjects met criteria for metabolic syndrome.

During a median 5 years of follow-up through the Veterans Affairs system’s electronic medical record system, the cardiovascular mortality was 21% in patients with PTSD and metabolic syndrome, compared with 14% in those without metabolic syndrome. Thus, comorbid metabolic syndrome in patients with combat PTSD was associated with a 68% increase in the risk of cardiovascular mortality.

The prevalence of metabolic syndrome was 32% among SSRI recipients, compared with 45% in those whose PTSD was not treated SSRIs. After adjusting for age, gender, and conventional cardiovascular risk factors in a multivariate analysis, the relative risk of metabolic syndrome in patients with PTSD was 71% lower with SSRI therapy than without it.

Moreover, the adjusted risk of cardiovascular mortality over the course of a median 5 years of follow-up in this hypothesis-generating observational study was 36% lower in SSRI-treated patients with PTSD and metabolic syndrome than in those not on an SSRI, and 64% lower in SSRI-treated patients with PTSD without metabolic syndrome.

This study received funding from the American Heart Association. Dr. Ahmadi reported having no financial conflicts.

[email protected]

Stiff person syndrome (SPS) is a rare autoimmune condition characterized by stiffness and rigidity in the lower limb muscles. Because SPS often is misdiagnosed as a psychiatric illness and psychiatric comorbidities are common in patients with this disorder,¹ awareness and recognition of this unique condition is essential.

An insidious presentation

Patients with SPS present with:²

• axial muscle stiffness slowly progressing to proximal muscles
• unremarkable motor, sensory, and cranial nerve examinations with normal intellectual functioning
• normal muscle strength, although electromyography shows continuous motor activity
• spasms evoked by sudden movements, jarring noise, and emotional distress
• slow and cautious gait to avoid triggering spasms and falls.

Symptoms start slowly and insidiously. Axial muscle stiffness can result in spinal deformity. Involvement is asymmetrical, with a predilection for proximal lower limb and lumbar paraspinal muscles. Affected muscles reveal tight, hard, board-like rigidity. In later stages of SPS, mild atrophy and muscle weakness are likely.

Frequent misdiagnosis

Because facial muscle spasticity is prominent, SPS patients may be misdiagnosed with Parkinson’s disease, primary lateral sclerosis, or multiple sclerosis. Spasms affecting respiratory and thoracic paraspinal muscles (status spasticus) may be misdiagnosed as an anxiety-related condition. These spasms can be life-threatening and require IV diazepam and supportive measures.

More than 60% of SPS patients have a comorbid psychiatric disorder.³ Anxiety disorders—generalized anxiety disorder, agoraphobia, and panic disorder—major depression, and alcohol abuse are the most frequent psychiatric comorbidities seen in SPS patients.³

SPS patients who panic when in public may be misdiagnosed with agoraphobia.³ Emotional stimuli may cause muscle spasms leading to falls. Treating muscle spasticity with γ-aminobutyric acid (GABA) agonists and narcotics can lead to drug abuse and dependence. Muscle spasticity can fluctuate from hour to hour, abate with sleep, and get worse with emotional distress. These findings are why approximately 70% of SPS patients are initially misdiagnosed; conversion disorder is a frequent misdiagnosis.⁴ Mood disorder in SPS patients may be resistant to antidepressants until these patients are treated with immunotherapy.⁴

Treating SPS patients

Although early intervention can reduce long-term disability, approximately 50% of SPS patients eventually have to use a wheelchair as a result of pain and immobility.⁵

Antibodies to glutamic acid decarboxylase, which is the rate-limiting enzyme for GABA synthesis, are present in 85% of SPS patients.⁵ Therefore, treatment usually includes GABA-enhancing drugs, including sedative anxiolytics (clonazepam and diazepam), antiepileptics (gabapentin, levetiracetam, tiagabine, and vigabatrin), antispasticity drugs (baclofen, dantrolene, and tizanidine), and immunotherapy (corticosteroids, IV immunoglobulins, and rituximab).⁵ Antidepressants, biofeedback, and relaxation training also can offer relief. Psychotherapy and substance dependency interventions may be needed.

To achieve optimum outcomes in SPS patients, a close collaborative relationship among all treating clinicians—including primary care physicians, neurologists, anesthesiologists, and psychiatrists—is necessary.

Disclosure

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

Stiff person syndrome (SPS) is a rare autoimmune condition characterized by stiffness and rigidity in the lower limb muscles. Because SPS often is misdiagnosed as a psychiatric illness and psychiatric comorbidities are common in patients with this disorder,¹ awareness and recognition of this unique condition is essential.

An insidious presentation

Patients with SPS present with:²

• axial muscle stiffness slowly progressing to proximal muscles
• unremarkable motor, sensory, and cranial nerve examinations with normal intellectual functioning
• normal muscle strength, although electromyography shows continuous motor activity
• spasms evoked by sudden movements, jarring noise, and emotional distress
• slow and cautious gait to avoid triggering spasms and falls.

Symptoms start slowly and insidiously. Axial muscle stiffness can result in spinal deformity. Involvement is asymmetrical, with a predilection for proximal lower limb and lumbar paraspinal muscles. Affected muscles reveal tight, hard, board-like rigidity. In later stages of SPS, mild atrophy and muscle weakness are likely.

Frequent misdiagnosis

Because facial muscle spasticity is prominent, SPS patients may be misdiagnosed with Parkinson’s disease, primary lateral sclerosis, or multiple sclerosis. Spasms affecting respiratory and thoracic paraspinal muscles (status spasticus) may be misdiagnosed as an anxiety-related condition. These spasms can be life-threatening and require IV diazepam and supportive measures.

More than 60% of SPS patients have a comorbid psychiatric disorder.³ Anxiety disorders—generalized anxiety disorder, agoraphobia, and panic disorder—major depression, and alcohol abuse are the most frequent psychiatric comorbidities seen in SPS patients.³

SPS patients who panic when in public may be misdiagnosed with agoraphobia.³ Emotional stimuli may cause muscle spasms leading to falls. Treating muscle spasticity with γ-aminobutyric acid (GABA) agonists and narcotics can lead to drug abuse and dependence. Muscle spasticity can fluctuate from hour to hour, abate with sleep, and get worse with emotional distress. These findings are why approximately 70% of SPS patients are initially misdiagnosed; conversion disorder is a frequent misdiagnosis.⁴ Mood disorder in SPS patients may be resistant to antidepressants until these patients are treated with immunotherapy.⁴

Treating SPS patients

Although early intervention can reduce long-term disability, approximately 50% of SPS patients eventually have to use a wheelchair as a result of pain and immobility.⁵

Antibodies to glutamic acid decarboxylase, which is the rate-limiting enzyme for GABA synthesis, are present in 85% of SPS patients.⁵ Therefore, treatment usually includes GABA-enhancing drugs, including sedative anxiolytics (clonazepam and diazepam), antiepileptics (gabapentin, levetiracetam, tiagabine, and vigabatrin), antispasticity drugs (baclofen, dantrolene, and tizanidine), and immunotherapy (corticosteroids, IV immunoglobulins, and rituximab).⁵ Antidepressants, biofeedback, and relaxation training also can offer relief. Psychotherapy and substance dependency interventions may be needed.

To achieve optimum outcomes in SPS patients, a close collaborative relationship among all treating clinicians—including primary care physicians, neurologists, anesthesiologists, and psychiatrists—is necessary.

Disclosure

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

Stiff person syndrome (SPS) is a rare autoimmune condition characterized by stiffness and rigidity in the lower limb muscles. Because SPS often is misdiagnosed as a psychiatric illness and psychiatric comorbidities are common in patients with this disorder,¹ awareness and recognition of this unique condition is essential.

An insidious presentation

Patients with SPS present with:²

• axial muscle stiffness slowly progressing to proximal muscles
• unremarkable motor, sensory, and cranial nerve examinations with normal intellectual functioning
• normal muscle strength, although electromyography shows continuous motor activity
• spasms evoked by sudden movements, jarring noise, and emotional distress
• slow and cautious gait to avoid triggering spasms and falls.

Symptoms start slowly and insidiously. Axial muscle stiffness can result in spinal deformity. Involvement is asymmetrical, with a predilection for proximal lower limb and lumbar paraspinal muscles. Affected muscles reveal tight, hard, board-like rigidity. In later stages of SPS, mild atrophy and muscle weakness are likely.

Frequent misdiagnosis

Because facial muscle spasticity is prominent, SPS patients may be misdiagnosed with Parkinson’s disease, primary lateral sclerosis, or multiple sclerosis. Spasms affecting respiratory and thoracic paraspinal muscles (status spasticus) may be misdiagnosed as an anxiety-related condition. These spasms can be life-threatening and require IV diazepam and supportive measures.

More than 60% of SPS patients have a comorbid psychiatric disorder.³ Anxiety disorders—generalized anxiety disorder, agoraphobia, and panic disorder—major depression, and alcohol abuse are the most frequent psychiatric comorbidities seen in SPS patients.³

SPS patients who panic when in public may be misdiagnosed with agoraphobia.³ Emotional stimuli may cause muscle spasms leading to falls. Treating muscle spasticity with γ-aminobutyric acid (GABA) agonists and narcotics can lead to drug abuse and dependence. Muscle spasticity can fluctuate from hour to hour, abate with sleep, and get worse with emotional distress. These findings are why approximately 70% of SPS patients are initially misdiagnosed; conversion disorder is a frequent misdiagnosis.⁴ Mood disorder in SPS patients may be resistant to antidepressants until these patients are treated with immunotherapy.⁴

Treating SPS patients

Although early intervention can reduce long-term disability, approximately 50% of SPS patients eventually have to use a wheelchair as a result of pain and immobility.⁵

Antibodies to glutamic acid decarboxylase, which is the rate-limiting enzyme for GABA synthesis, are present in 85% of SPS patients.⁵ Therefore, treatment usually includes GABA-enhancing drugs, including sedative anxiolytics (clonazepam and diazepam), antiepileptics (gabapentin, levetiracetam, tiagabine, and vigabatrin), antispasticity drugs (baclofen, dantrolene, and tizanidine), and immunotherapy (corticosteroids, IV immunoglobulins, and rituximab).⁵ Antidepressants, biofeedback, and relaxation training also can offer relief. Psychotherapy and substance dependency interventions may be needed.

To achieve optimum outcomes in SPS patients, a close collaborative relationship among all treating clinicians—including primary care physicians, neurologists, anesthesiologists, and psychiatrists—is necessary.

Disclosure

Dr. Jain 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

Many endocrine disorders can manifest as depression, including relatively rare disorders such as Cushing’s syndrome (hypercortisolism) or Conn’s syndrome (primary hyperaldosteronism) as well as common ones such as diabetes mellitus. Most clinicians do not routinely screen for adrenal disorders when evaluating depressed patients because the yield is low, but do screen for thyroid disease because these disorders often mimic depression. The following 3 cases from my practice illustrate some nuances of screening and treating depressed patients with suspected thyroid abnormalities.

CASE 1: Feeling ‘like an 80-year-old’

Ms. A, age 25, has a gastrointestinal stromal tumor (GIST) and states that she feels “like an 80-year-old woman.” She is sore all over with facial swelling, abdominal cramping, and fatigue. This feeling has worsened since she started chemotherapy with sunitinib for the GIST. Her Patient Health Questionnaire-9 (PHQ-9) score is 14 out of 27, indicating moderate depression. As part of a workup for her depression, what general laboratory tests would be most helpful?

Because Ms. A is of menstruating age, check hemoglobin/hematocrit levels to evaluate for anemia. Monitoring electrolytes would allow you to assess for hypernatremia/hyponatremia, hyperkalemia/hypokalemia, and impaired renal function, all of which could cause depressive symptoms. Depending on Ms. A’s habitus or risk of metabolic syndrome, a fasting blood glucose or hemoglobin A1C test to screen for diabetes mellitus might be valuable because depression may be associated with diabetes.¹ A1C is a preferred primary screening test for diabetes (≥6.5% constitutes a positive screen) based on revised clinical practice recommendations of the American Diabetes Association. A1C is available as an office-based test that requires just a drop of blood from a finger prick and does not require a fasting blood sample or a full laboratory analysis.

A popular test for a workup of depression is serum 25-hydroxyvitamin D [25(OH)D] (vitamin D), particularly for patients who live in areas with limited exposure to ultraviolet B radiation from sunlight.² In a study of older adults, vitamin D levels were 14% lower in patients with minor depression and 14% lower in patients with major depressive disorder compared with controls. This study suggests that depression severity is associated with decreased serum vitamin D levels,³ but the association between depression and vitamin D insufficiency and deficiency is unknown. Checking sex hormones also may be helpful depending on the patient’s symptoms, because testosterone deficiency in men and dehydroepiandrosterone deficiency in women can have a direct impact on a patient’s libido and overall sense of well-being. If repleted, improved levels of sex hormones can lead to a dramatic improvement in mood as well.

Because more than one-half of the estimated 27 million Americans with hyperthyroidism or hypothyroidism are undiagnosed, the American Thyroid Association recommends universal screening for thyroid dysfunction after age 35, with a recheck every 5 years.⁴ However, checking serum thyroid-stimulating hormone (TSH) levels this often may not be cost-effective. Typically, I do not follow this recommendation when assessing or treating asymptomatic individuals, but Ms. A has symptoms of hypothyroidism (Table 1) and is taking a medication—sunitinib—thought to be associated with hypothyroidism.⁵ Her serum TSH was very high (110 mIU/L; range 0.28 to 5.00) and her serum free T4 (FT4) was low (0.5 ng/dL; range 0.7 to 1.8). These values were consistent with overt hypothyroidism, defined as low FT4 and elevated TSH levels. This is in contrast to subclinical hypothyroidism (SH), which is defined as having an elevated serum TSH with normal thyroid hormone (T3 and T4) levels. SH presents in 5% of young patients (age <45) and increasingly is being diagnoses in older patients (age >55), who are most likely to suffer adverse effects in mood or cognition.⁶

Table 1

Hypothyroidism symptoms

CASE 1 CONTINUED: A classic case

Ms. A is started on a full levothyroxine replacement dose of 1.6 μg/kg/d. For hypothyroid patients who do not have cardiac symptoms, weight-based replacement is thought to be safe and more convenient than starting with a low dose and titrating up.⁷ Ms. A responds quickly. At 6-week follow-up—the recommended time interval for repeat thyroid lab testing after initiating thyroid replacement—her depressive symptoms are markedly improved and her PHQ-9 score is 6, indicating mild depression.

CASE 2: Chronic pain, low mood, and fatigue

Ms. B, age 62, has fibromyalgia and chronic back pain. She takes cyclobenzaprine, 5 mg 2 to 3 times daily, and oxycodone, 40 mg/d, and describes mild depressive symptoms when she presents for routine follow-up. Most of her complaints are related to chronic pain, but she has a history of low mood and fatigue. She says she was prescribed levothyroxine, but is unable to remember if she stopped taking it because of financial constraints or laboratory/clinical improvement. Her neurologist recently checked her serum TSH, which was elevated at 8.1 mIU/L. Is it best to restart thyroid replacement or wait 6 weeks and recheck her thyroid panel?

Mild SH typically is defined as TSH between 4.5 and 10 mIU/L. In contrast, TSH between 10 and 20 mIU/L is considered severe SH. Because Ms. B did not have prominent new symptoms, I felt it was reasonable to wait the recommended 6 weeks before rechecking her thyroid function. At follow-up, Ms. B’s TSH was 4.64 mIU/L and her FT4 was normal: 0.7 ng/dL. Thyroid replacement was not indicated because she did not have obvious symptoms and treating SH does not impact overall mood and cognition until TSH is ≥10 mIU/L.^8,9

CASE 2 CONTINUED: Prominent symptoms emerge

Ms. B returns several months later. Another clinician prescribed duloxetine, titrated from 30 mg to 60 mg, for worsening fibromyalgia. Her depressive symptoms are more prominent at this visit, and her PHQ-9 score has risen from 7 to 14, indicating moderate depression. She says previously she failed or poorly tolerated several antidepressants—fluoxetine, sertraline, and citalopram—but was hoping for a pharmacologic adjustment. Most evidence-based augmentation algorithms for treating major depression start with adding a second “traditional” antidepressant such as bupropion, then move to lithium, second-generation antipsychotics, or lamotrigine.¹⁰ But what about thyroid hormone augmentation?

Thyroid hormone often is on the lower rungs of depression treatment algorithms despite Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial data. The data suggest triiodothyronine’s (T3) lower side effect burden and ease of use may offer an advantage over lithium augmentation for depressed patients who have failed several medication trials.¹¹ Liothyronine sodium (triiodothyronine) is a relatively benign medication with potential for augmentation when started at 25 to 50 mcg/d concurrently with antidepressants such as sertraline.¹² Unfortunately, most augmentation trials with T3 have been short-term—generally 4 to 8 weeks. In my practice, T3 has limited application; I use it mainly for patients with treatment-resistant depression who have failed several other treatments.

Lithium, the comparison medication to thyroid hormone in the third augmentation arm of the STAR*D trial, requires an annual check of thyroid function (TSH testing) to properly monitor for potential lithium-related hypothyroidism or thyroiditis. Hypothyroidism, for which thyroid replacement is required, with lithium therapy is common, affecting 8% to 27% of patients.¹³ Patients who rapidly gain weight at the beginning of lithium treatment seem to have a higher risk of developing hypothyroidism.¹³ However, the risk of developing lithium-induced hypothyroidism is tied to the length of treatment; the longer a patient has been treated with lithium, the greater the risk of developing lithium-induced hypothyroidism.

CASE 3: Unable to slow down

Mr. C, age 45, has a 20-year history of major depression controlled reasonably well with paroxetine, 40 mg. He presents with escalating anxiety, depression, and irritability. His wife is concerned about his overwhelming thoughts of death, especially because Mr. C’s father committed suicide 30 years ago under similar circumstances. Mr. C has been tremulous for the past month and has not been sleeping well. He feels like he is “in constant motion” and unable to slow down. He screens in the “highly likely” range for bipolar disorder on the Bipolar Spectrum Diagnostic Scale¹⁴ and is started on divalproex ER, 500 mg/d.

His thyroid function tests returns with a suppressed TSH of 0.03 mIU/L and an elevated FT4 of 3.26 ng/dL. Divalproex is discontinued and he is started on the beta blocker atenolol, 25 mg/d, to target his anxiety, tachycardia, and akathisia. TSH receptor antibody testing was positive, which, along with an abnormal radioactive iodine uptake scan, confirmed a diagnosis of Graves’ disease. He receives methimazole, 20 mg/d, as a temporizing measure. An endocrinologist completes a radioactive iodine (I-131) ablation procedure on Mr. C, which resolves his mood and anxiety symptoms.

Although hypothyroidism commonly is associated with depressive symptoms, hyperthyroidism also may present as depression. Most cases of overt hyperthyroidism are directly referred to an endocrinologist because when treating disorders such as Graves’ disease—the most common cause of hyperthyroidism, especially among women age 20 to 40—many nuclear medicine teams require the expert guidance of an endocrinologist before considering radioiodine ablation. Hyperthyroidism often is accompanied by psychiatric and somatic symptoms of an “overactive” nature (Table 2). However, older patients (age >65) with hyperthyroidism may develop apathetic hyperthyroidism, a subset that comprises approximately 10% to 15% of all hyperthyroidism cases in older adults.¹⁵ Rather than becoming nervous, jittery, and restless, patients with apathetic hyperthyroidism are depressed, lethargic, and weak, and may develop proximal myopathy or cardiomyopathy. It is essential to differentiate apathetic hyperthyroidism from typical hyperthyroidism because accurately diagnosing and treating apathetic hyperthyroidism will improve outcomes.¹⁵

Table 2

Hyperthyroidism symptoms

Using beta blockers to treat hyperthyroidism can help control tachycardia or palpitations, tremulousness, and anxiety that often are inherent in hyperthyroidism. But can beta blockers induce depressive symptoms? A 1-year prospective Dutch study of patients who had survived a myocardial infarction did not find evidence that beta blockers induced depressive symptoms.¹⁶ However, the long-term and high-dosage effects of beta blockers still are in question.¹⁶ In Mr. C’s case, beta blockers had only positive effects on his symptoms and did not exacerbate his depressive symptoms.

Related Resources

• National Women’s Health Resource Center, Inc. Thyroid disorders. www.healthywomen.org/condition/thyroid-disorders.
• American Thyroid Association. www.thyroid.org.
• American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. www.aace.com/files/hypo-hyper.pdf.

Drug Brand Names

• Atenolol • Tenormin
• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Cyclobenzaprine • Flexeril
• Divalproex ER • Depakote ER
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Levothyroxine • Levoxyl, Synthroid
• Liothyronine sodium • Cytomel, Triostat
• Lithium • Eskalith, Lithobid
• Methimazole • Tapazole
• Oxycodone • OxyContin
• Paroxetine • Paxil
• Sertraline • Zoloft
• Sunitinib • Sutent

Disclosure

Dr. Raj is a speaker for AstraZeneca and Merck.

Discuss this article at www.facebook.com/CurrentPsychiatry

Many endocrine disorders can manifest as depression, including relatively rare disorders such as Cushing’s syndrome (hypercortisolism) or Conn’s syndrome (primary hyperaldosteronism) as well as common ones such as diabetes mellitus. Most clinicians do not routinely screen for adrenal disorders when evaluating depressed patients because the yield is low, but do screen for thyroid disease because these disorders often mimic depression. The following 3 cases from my practice illustrate some nuances of screening and treating depressed patients with suspected thyroid abnormalities.

CASE 1: Feeling ‘like an 80-year-old’

Ms. A, age 25, has a gastrointestinal stromal tumor (GIST) and states that she feels “like an 80-year-old woman.” She is sore all over with facial swelling, abdominal cramping, and fatigue. This feeling has worsened since she started chemotherapy with sunitinib for the GIST. Her Patient Health Questionnaire-9 (PHQ-9) score is 14 out of 27, indicating moderate depression. As part of a workup for her depression, what general laboratory tests would be most helpful?

Because Ms. A is of menstruating age, check hemoglobin/hematocrit levels to evaluate for anemia. Monitoring electrolytes would allow you to assess for hypernatremia/hyponatremia, hyperkalemia/hypokalemia, and impaired renal function, all of which could cause depressive symptoms. Depending on Ms. A’s habitus or risk of metabolic syndrome, a fasting blood glucose or hemoglobin A1C test to screen for diabetes mellitus might be valuable because depression may be associated with diabetes.¹ A1C is a preferred primary screening test for diabetes (≥6.5% constitutes a positive screen) based on revised clinical practice recommendations of the American Diabetes Association. A1C is available as an office-based test that requires just a drop of blood from a finger prick and does not require a fasting blood sample or a full laboratory analysis.

A popular test for a workup of depression is serum 25-hydroxyvitamin D [25(OH)D] (vitamin D), particularly for patients who live in areas with limited exposure to ultraviolet B radiation from sunlight.² In a study of older adults, vitamin D levels were 14% lower in patients with minor depression and 14% lower in patients with major depressive disorder compared with controls. This study suggests that depression severity is associated with decreased serum vitamin D levels,³ but the association between depression and vitamin D insufficiency and deficiency is unknown. Checking sex hormones also may be helpful depending on the patient’s symptoms, because testosterone deficiency in men and dehydroepiandrosterone deficiency in women can have a direct impact on a patient’s libido and overall sense of well-being. If repleted, improved levels of sex hormones can lead to a dramatic improvement in mood as well.

Because more than one-half of the estimated 27 million Americans with hyperthyroidism or hypothyroidism are undiagnosed, the American Thyroid Association recommends universal screening for thyroid dysfunction after age 35, with a recheck every 5 years.⁴ However, checking serum thyroid-stimulating hormone (TSH) levels this often may not be cost-effective. Typically, I do not follow this recommendation when assessing or treating asymptomatic individuals, but Ms. A has symptoms of hypothyroidism (Table 1) and is taking a medication—sunitinib—thought to be associated with hypothyroidism.⁵ Her serum TSH was very high (110 mIU/L; range 0.28 to 5.00) and her serum free T4 (FT4) was low (0.5 ng/dL; range 0.7 to 1.8). These values were consistent with overt hypothyroidism, defined as low FT4 and elevated TSH levels. This is in contrast to subclinical hypothyroidism (SH), which is defined as having an elevated serum TSH with normal thyroid hormone (T3 and T4) levels. SH presents in 5% of young patients (age <45) and increasingly is being diagnoses in older patients (age >55), who are most likely to suffer adverse effects in mood or cognition.⁶

Table 1

Hypothyroidism symptoms

CASE 1 CONTINUED: A classic case

Ms. A is started on a full levothyroxine replacement dose of 1.6 μg/kg/d. For hypothyroid patients who do not have cardiac symptoms, weight-based replacement is thought to be safe and more convenient than starting with a low dose and titrating up.⁷ Ms. A responds quickly. At 6-week follow-up—the recommended time interval for repeat thyroid lab testing after initiating thyroid replacement—her depressive symptoms are markedly improved and her PHQ-9 score is 6, indicating mild depression.

CASE 2: Chronic pain, low mood, and fatigue

Ms. B, age 62, has fibromyalgia and chronic back pain. She takes cyclobenzaprine, 5 mg 2 to 3 times daily, and oxycodone, 40 mg/d, and describes mild depressive symptoms when she presents for routine follow-up. Most of her complaints are related to chronic pain, but she has a history of low mood and fatigue. She says she was prescribed levothyroxine, but is unable to remember if she stopped taking it because of financial constraints or laboratory/clinical improvement. Her neurologist recently checked her serum TSH, which was elevated at 8.1 mIU/L. Is it best to restart thyroid replacement or wait 6 weeks and recheck her thyroid panel?

Mild SH typically is defined as TSH between 4.5 and 10 mIU/L. In contrast, TSH between 10 and 20 mIU/L is considered severe SH. Because Ms. B did not have prominent new symptoms, I felt it was reasonable to wait the recommended 6 weeks before rechecking her thyroid function. At follow-up, Ms. B’s TSH was 4.64 mIU/L and her FT4 was normal: 0.7 ng/dL. Thyroid replacement was not indicated because she did not have obvious symptoms and treating SH does not impact overall mood and cognition until TSH is ≥10 mIU/L.^8,9

CASE 2 CONTINUED: Prominent symptoms emerge

Ms. B returns several months later. Another clinician prescribed duloxetine, titrated from 30 mg to 60 mg, for worsening fibromyalgia. Her depressive symptoms are more prominent at this visit, and her PHQ-9 score has risen from 7 to 14, indicating moderate depression. She says previously she failed or poorly tolerated several antidepressants—fluoxetine, sertraline, and citalopram—but was hoping for a pharmacologic adjustment. Most evidence-based augmentation algorithms for treating major depression start with adding a second “traditional” antidepressant such as bupropion, then move to lithium, second-generation antipsychotics, or lamotrigine.¹⁰ But what about thyroid hormone augmentation?

Thyroid hormone often is on the lower rungs of depression treatment algorithms despite Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial data. The data suggest triiodothyronine’s (T3) lower side effect burden and ease of use may offer an advantage over lithium augmentation for depressed patients who have failed several medication trials.¹¹ Liothyronine sodium (triiodothyronine) is a relatively benign medication with potential for augmentation when started at 25 to 50 mcg/d concurrently with antidepressants such as sertraline.¹² Unfortunately, most augmentation trials with T3 have been short-term—generally 4 to 8 weeks. In my practice, T3 has limited application; I use it mainly for patients with treatment-resistant depression who have failed several other treatments.

Lithium, the comparison medication to thyroid hormone in the third augmentation arm of the STAR*D trial, requires an annual check of thyroid function (TSH testing) to properly monitor for potential lithium-related hypothyroidism or thyroiditis. Hypothyroidism, for which thyroid replacement is required, with lithium therapy is common, affecting 8% to 27% of patients.¹³ Patients who rapidly gain weight at the beginning of lithium treatment seem to have a higher risk of developing hypothyroidism.¹³ However, the risk of developing lithium-induced hypothyroidism is tied to the length of treatment; the longer a patient has been treated with lithium, the greater the risk of developing lithium-induced hypothyroidism.

CASE 3: Unable to slow down

Mr. C, age 45, has a 20-year history of major depression controlled reasonably well with paroxetine, 40 mg. He presents with escalating anxiety, depression, and irritability. His wife is concerned about his overwhelming thoughts of death, especially because Mr. C’s father committed suicide 30 years ago under similar circumstances. Mr. C has been tremulous for the past month and has not been sleeping well. He feels like he is “in constant motion” and unable to slow down. He screens in the “highly likely” range for bipolar disorder on the Bipolar Spectrum Diagnostic Scale¹⁴ and is started on divalproex ER, 500 mg/d.

His thyroid function tests returns with a suppressed TSH of 0.03 mIU/L and an elevated FT4 of 3.26 ng/dL. Divalproex is discontinued and he is started on the beta blocker atenolol, 25 mg/d, to target his anxiety, tachycardia, and akathisia. TSH receptor antibody testing was positive, which, along with an abnormal radioactive iodine uptake scan, confirmed a diagnosis of Graves’ disease. He receives methimazole, 20 mg/d, as a temporizing measure. An endocrinologist completes a radioactive iodine (I-131) ablation procedure on Mr. C, which resolves his mood and anxiety symptoms.

Although hypothyroidism commonly is associated with depressive symptoms, hyperthyroidism also may present as depression. Most cases of overt hyperthyroidism are directly referred to an endocrinologist because when treating disorders such as Graves’ disease—the most common cause of hyperthyroidism, especially among women age 20 to 40—many nuclear medicine teams require the expert guidance of an endocrinologist before considering radioiodine ablation. Hyperthyroidism often is accompanied by psychiatric and somatic symptoms of an “overactive” nature (Table 2). However, older patients (age >65) with hyperthyroidism may develop apathetic hyperthyroidism, a subset that comprises approximately 10% to 15% of all hyperthyroidism cases in older adults.¹⁵ Rather than becoming nervous, jittery, and restless, patients with apathetic hyperthyroidism are depressed, lethargic, and weak, and may develop proximal myopathy or cardiomyopathy. It is essential to differentiate apathetic hyperthyroidism from typical hyperthyroidism because accurately diagnosing and treating apathetic hyperthyroidism will improve outcomes.¹⁵

Table 2

Hyperthyroidism symptoms

Using beta blockers to treat hyperthyroidism can help control tachycardia or palpitations, tremulousness, and anxiety that often are inherent in hyperthyroidism. But can beta blockers induce depressive symptoms? A 1-year prospective Dutch study of patients who had survived a myocardial infarction did not find evidence that beta blockers induced depressive symptoms.¹⁶ However, the long-term and high-dosage effects of beta blockers still are in question.¹⁶ In Mr. C’s case, beta blockers had only positive effects on his symptoms and did not exacerbate his depressive symptoms.

Related Resources

• National Women’s Health Resource Center, Inc. Thyroid disorders. www.healthywomen.org/condition/thyroid-disorders.
• American Thyroid Association. www.thyroid.org.
• American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. www.aace.com/files/hypo-hyper.pdf.

Drug Brand Names

• Atenolol • Tenormin
• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Cyclobenzaprine • Flexeril
• Divalproex ER • Depakote ER
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Levothyroxine • Levoxyl, Synthroid
• Liothyronine sodium • Cytomel, Triostat
• Lithium • Eskalith, Lithobid
• Methimazole • Tapazole
• Oxycodone • OxyContin
• Paroxetine • Paxil
• Sertraline • Zoloft
• Sunitinib • Sutent

Disclosure

Dr. Raj is a speaker for AstraZeneca and Merck.

Discuss this article at www.facebook.com/CurrentPsychiatry

Many endocrine disorders can manifest as depression, including relatively rare disorders such as Cushing’s syndrome (hypercortisolism) or Conn’s syndrome (primary hyperaldosteronism) as well as common ones such as diabetes mellitus. Most clinicians do not routinely screen for adrenal disorders when evaluating depressed patients because the yield is low, but do screen for thyroid disease because these disorders often mimic depression. The following 3 cases from my practice illustrate some nuances of screening and treating depressed patients with suspected thyroid abnormalities.

CASE 1: Feeling ‘like an 80-year-old’

Ms. A, age 25, has a gastrointestinal stromal tumor (GIST) and states that she feels “like an 80-year-old woman.” She is sore all over with facial swelling, abdominal cramping, and fatigue. This feeling has worsened since she started chemotherapy with sunitinib for the GIST. Her Patient Health Questionnaire-9 (PHQ-9) score is 14 out of 27, indicating moderate depression. As part of a workup for her depression, what general laboratory tests would be most helpful?

Because Ms. A is of menstruating age, check hemoglobin/hematocrit levels to evaluate for anemia. Monitoring electrolytes would allow you to assess for hypernatremia/hyponatremia, hyperkalemia/hypokalemia, and impaired renal function, all of which could cause depressive symptoms. Depending on Ms. A’s habitus or risk of metabolic syndrome, a fasting blood glucose or hemoglobin A1C test to screen for diabetes mellitus might be valuable because depression may be associated with diabetes.¹ A1C is a preferred primary screening test for diabetes (≥6.5% constitutes a positive screen) based on revised clinical practice recommendations of the American Diabetes Association. A1C is available as an office-based test that requires just a drop of blood from a finger prick and does not require a fasting blood sample or a full laboratory analysis.

A popular test for a workup of depression is serum 25-hydroxyvitamin D [25(OH)D] (vitamin D), particularly for patients who live in areas with limited exposure to ultraviolet B radiation from sunlight.² In a study of older adults, vitamin D levels were 14% lower in patients with minor depression and 14% lower in patients with major depressive disorder compared with controls. This study suggests that depression severity is associated with decreased serum vitamin D levels,³ but the association between depression and vitamin D insufficiency and deficiency is unknown. Checking sex hormones also may be helpful depending on the patient’s symptoms, because testosterone deficiency in men and dehydroepiandrosterone deficiency in women can have a direct impact on a patient’s libido and overall sense of well-being. If repleted, improved levels of sex hormones can lead to a dramatic improvement in mood as well.

Because more than one-half of the estimated 27 million Americans with hyperthyroidism or hypothyroidism are undiagnosed, the American Thyroid Association recommends universal screening for thyroid dysfunction after age 35, with a recheck every 5 years.⁴ However, checking serum thyroid-stimulating hormone (TSH) levels this often may not be cost-effective. Typically, I do not follow this recommendation when assessing or treating asymptomatic individuals, but Ms. A has symptoms of hypothyroidism (Table 1) and is taking a medication—sunitinib—thought to be associated with hypothyroidism.⁵ Her serum TSH was very high (110 mIU/L; range 0.28 to 5.00) and her serum free T4 (FT4) was low (0.5 ng/dL; range 0.7 to 1.8). These values were consistent with overt hypothyroidism, defined as low FT4 and elevated TSH levels. This is in contrast to subclinical hypothyroidism (SH), which is defined as having an elevated serum TSH with normal thyroid hormone (T3 and T4) levels. SH presents in 5% of young patients (age <45) and increasingly is being diagnoses in older patients (age >55), who are most likely to suffer adverse effects in mood or cognition.⁶

Table 1

Hypothyroidism symptoms

CASE 1 CONTINUED: A classic case

Ms. A is started on a full levothyroxine replacement dose of 1.6 μg/kg/d. For hypothyroid patients who do not have cardiac symptoms, weight-based replacement is thought to be safe and more convenient than starting with a low dose and titrating up.⁷ Ms. A responds quickly. At 6-week follow-up—the recommended time interval for repeat thyroid lab testing after initiating thyroid replacement—her depressive symptoms are markedly improved and her PHQ-9 score is 6, indicating mild depression.

CASE 2: Chronic pain, low mood, and fatigue

Ms. B, age 62, has fibromyalgia and chronic back pain. She takes cyclobenzaprine, 5 mg 2 to 3 times daily, and oxycodone, 40 mg/d, and describes mild depressive symptoms when she presents for routine follow-up. Most of her complaints are related to chronic pain, but she has a history of low mood and fatigue. She says she was prescribed levothyroxine, but is unable to remember if she stopped taking it because of financial constraints or laboratory/clinical improvement. Her neurologist recently checked her serum TSH, which was elevated at 8.1 mIU/L. Is it best to restart thyroid replacement or wait 6 weeks and recheck her thyroid panel?

Mild SH typically is defined as TSH between 4.5 and 10 mIU/L. In contrast, TSH between 10 and 20 mIU/L is considered severe SH. Because Ms. B did not have prominent new symptoms, I felt it was reasonable to wait the recommended 6 weeks before rechecking her thyroid function. At follow-up, Ms. B’s TSH was 4.64 mIU/L and her FT4 was normal: 0.7 ng/dL. Thyroid replacement was not indicated because she did not have obvious symptoms and treating SH does not impact overall mood and cognition until TSH is ≥10 mIU/L.^8,9

CASE 2 CONTINUED: Prominent symptoms emerge

Ms. B returns several months later. Another clinician prescribed duloxetine, titrated from 30 mg to 60 mg, for worsening fibromyalgia. Her depressive symptoms are more prominent at this visit, and her PHQ-9 score has risen from 7 to 14, indicating moderate depression. She says previously she failed or poorly tolerated several antidepressants—fluoxetine, sertraline, and citalopram—but was hoping for a pharmacologic adjustment. Most evidence-based augmentation algorithms for treating major depression start with adding a second “traditional” antidepressant such as bupropion, then move to lithium, second-generation antipsychotics, or lamotrigine.¹⁰ But what about thyroid hormone augmentation?

Thyroid hormone often is on the lower rungs of depression treatment algorithms despite Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial data. The data suggest triiodothyronine’s (T3) lower side effect burden and ease of use may offer an advantage over lithium augmentation for depressed patients who have failed several medication trials.¹¹ Liothyronine sodium (triiodothyronine) is a relatively benign medication with potential for augmentation when started at 25 to 50 mcg/d concurrently with antidepressants such as sertraline.¹² Unfortunately, most augmentation trials with T3 have been short-term—generally 4 to 8 weeks. In my practice, T3 has limited application; I use it mainly for patients with treatment-resistant depression who have failed several other treatments.

Lithium, the comparison medication to thyroid hormone in the third augmentation arm of the STAR*D trial, requires an annual check of thyroid function (TSH testing) to properly monitor for potential lithium-related hypothyroidism or thyroiditis. Hypothyroidism, for which thyroid replacement is required, with lithium therapy is common, affecting 8% to 27% of patients.¹³ Patients who rapidly gain weight at the beginning of lithium treatment seem to have a higher risk of developing hypothyroidism.¹³ However, the risk of developing lithium-induced hypothyroidism is tied to the length of treatment; the longer a patient has been treated with lithium, the greater the risk of developing lithium-induced hypothyroidism.

CASE 3: Unable to slow down

Mr. C, age 45, has a 20-year history of major depression controlled reasonably well with paroxetine, 40 mg. He presents with escalating anxiety, depression, and irritability. His wife is concerned about his overwhelming thoughts of death, especially because Mr. C’s father committed suicide 30 years ago under similar circumstances. Mr. C has been tremulous for the past month and has not been sleeping well. He feels like he is “in constant motion” and unable to slow down. He screens in the “highly likely” range for bipolar disorder on the Bipolar Spectrum Diagnostic Scale¹⁴ and is started on divalproex ER, 500 mg/d.

His thyroid function tests returns with a suppressed TSH of 0.03 mIU/L and an elevated FT4 of 3.26 ng/dL. Divalproex is discontinued and he is started on the beta blocker atenolol, 25 mg/d, to target his anxiety, tachycardia, and akathisia. TSH receptor antibody testing was positive, which, along with an abnormal radioactive iodine uptake scan, confirmed a diagnosis of Graves’ disease. He receives methimazole, 20 mg/d, as a temporizing measure. An endocrinologist completes a radioactive iodine (I-131) ablation procedure on Mr. C, which resolves his mood and anxiety symptoms.

Although hypothyroidism commonly is associated with depressive symptoms, hyperthyroidism also may present as depression. Most cases of overt hyperthyroidism are directly referred to an endocrinologist because when treating disorders such as Graves’ disease—the most common cause of hyperthyroidism, especially among women age 20 to 40—many nuclear medicine teams require the expert guidance of an endocrinologist before considering radioiodine ablation. Hyperthyroidism often is accompanied by psychiatric and somatic symptoms of an “overactive” nature (Table 2). However, older patients (age >65) with hyperthyroidism may develop apathetic hyperthyroidism, a subset that comprises approximately 10% to 15% of all hyperthyroidism cases in older adults.¹⁵ Rather than becoming nervous, jittery, and restless, patients with apathetic hyperthyroidism are depressed, lethargic, and weak, and may develop proximal myopathy or cardiomyopathy. It is essential to differentiate apathetic hyperthyroidism from typical hyperthyroidism because accurately diagnosing and treating apathetic hyperthyroidism will improve outcomes.¹⁵

Table 2

Hyperthyroidism symptoms

Using beta blockers to treat hyperthyroidism can help control tachycardia or palpitations, tremulousness, and anxiety that often are inherent in hyperthyroidism. But can beta blockers induce depressive symptoms? A 1-year prospective Dutch study of patients who had survived a myocardial infarction did not find evidence that beta blockers induced depressive symptoms.¹⁶ However, the long-term and high-dosage effects of beta blockers still are in question.¹⁶ In Mr. C’s case, beta blockers had only positive effects on his symptoms and did not exacerbate his depressive symptoms.

Related Resources

• National Women’s Health Resource Center, Inc. Thyroid disorders. www.healthywomen.org/condition/thyroid-disorders.
• American Thyroid Association. www.thyroid.org.
• American Association of Clinical Endocrinologists. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. www.aace.com/files/hypo-hyper.pdf.

Drug Brand Names

• Atenolol • Tenormin
• Bupropion • Wellbutrin, Zyban
• Citalopram • Celexa
• Cyclobenzaprine • Flexeril
• Divalproex ER • Depakote ER
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Levothyroxine • Levoxyl, Synthroid
• Liothyronine sodium • Cytomel, Triostat
• Lithium • Eskalith, Lithobid
• Methimazole • Tapazole
• Oxycodone • OxyContin
• Paroxetine • Paxil
• Sertraline • Zoloft
• Sunitinib • Sutent

Disclosure

Dr. Raj is a speaker for AstraZeneca and Merck.

SAN DIEGO – Patients who have been newly diagnosed with psychogenic nonepileptic seizures probably benefit from counseling and group therapy sessions before being referred to psychiatrists for treatment of their underlying mental health problem.

That’s what researchers from the Baylor College of Medicine in Houston found when they compared outcomes for 16 patients immediately referred to mental health services following diagnosis – the standard practice – with 19 others who had three educational group sessions beforehand where they learned about their condition and shared coping strategies.

Following their sessions, support group patients were more likely than were control group patients to agree that "my attacks do not really bother me or affect my life that much anymore" (P less than .001) and that "I have some control over my attacks" (P = .003). Perhaps most tellingly, patients in the treatment group were significantly less likely to return to the emergency department 3 months later (7% vs. 22%, P = .018).

"Clearly what we are seeing is that these patients need significant follow-up, perhaps with a neurologist rather than simply a mental health professional. Psychiatrists don’t feel comfortable addressing this issue; having a team approach with both a neurologist and a psychiatrist probably gives the best outcomes," lead investigator Dr. Atul Maheshwari of the department of neurology at Baylor said at the annual meeting of the American Epilepsy Society.

The patients in the randomized study were adults, mostly male, and had at least one seizure per week. They were diagnosed with psychogenic nonepileptic events (PNEE) in the epilepsy monitoring unit of Houston Veterans Affairs Medical Center, where the study was conducted. Psychiatric problems included depression, posttraumatic stress disorder, and childhood abuse.

The diagnosis of PNEE is often a hard blow to patients convinced that they have epilepsy or a brain tumor and feel like doctors aren’t taking them seriously; accepting that their seizures are caused by underlying psychiatric stress is difficult, Dr. Maheshwari said.

A nurse practitioner led the group sessions with talking points and instructions from a neurologist. "The first session helped [patients] understand [that] PNEE are nonpathologic, don’t cause the brain to be fried or cause long-term brain damage, but still require treatment. They were also shown videos of what PNEE look like and what epileptic seizures look like so they could better understand what’s going on. [Ultimately,] the goal was to take away the negative associations people have with the diagnosis," Dr. Maheshwari said.

"Subsequent sessions focused on finding constructive channels for stress release, focusing on the idea that [PNEE] are manifestations of inner-stress. Patients were allowed to discuss what strategies they found helpful. Peer-to-peer acceptance and evaluation helps," Dr. Maheshwari said.

Identification of triggers, including those for PTSD, was key, Dr. Maheshwari said. "For some people, [that means] identifying the aura so they can use stress-release strategies to avoid the seizure. It’s helpful to share those things with other people who have the same symptoms so they can appreciate they are not alone."

He cautioned that research is ongoing and the trial’s results are preliminary. Also, more people in the treatment group were married. Dr. Maheshwari noted that "we didn’t help out with the frequency and intensity of events, but there were significant improvements in patients’ perceptions of the problem" and quality of life.

Dr. Maheshwari said that he had no relevant disclosures.

SAN DIEGO – Patients who have been newly diagnosed with psychogenic nonepileptic seizures probably benefit from counseling and group therapy sessions before being referred to psychiatrists for treatment of their underlying mental health problem.

That’s what researchers from the Baylor College of Medicine in Houston found when they compared outcomes for 16 patients immediately referred to mental health services following diagnosis – the standard practice – with 19 others who had three educational group sessions beforehand where they learned about their condition and shared coping strategies.

Following their sessions, support group patients were more likely than were control group patients to agree that "my attacks do not really bother me or affect my life that much anymore" (P less than .001) and that "I have some control over my attacks" (P = .003). Perhaps most tellingly, patients in the treatment group were significantly less likely to return to the emergency department 3 months later (7% vs. 22%, P = .018).

"Clearly what we are seeing is that these patients need significant follow-up, perhaps with a neurologist rather than simply a mental health professional. Psychiatrists don’t feel comfortable addressing this issue; having a team approach with both a neurologist and a psychiatrist probably gives the best outcomes," lead investigator Dr. Atul Maheshwari of the department of neurology at Baylor said at the annual meeting of the American Epilepsy Society.

The patients in the randomized study were adults, mostly male, and had at least one seizure per week. They were diagnosed with psychogenic nonepileptic events (PNEE) in the epilepsy monitoring unit of Houston Veterans Affairs Medical Center, where the study was conducted. Psychiatric problems included depression, posttraumatic stress disorder, and childhood abuse.

The diagnosis of PNEE is often a hard blow to patients convinced that they have epilepsy or a brain tumor and feel like doctors aren’t taking them seriously; accepting that their seizures are caused by underlying psychiatric stress is difficult, Dr. Maheshwari said.

A nurse practitioner led the group sessions with talking points and instructions from a neurologist. "The first session helped [patients] understand [that] PNEE are nonpathologic, don’t cause the brain to be fried or cause long-term brain damage, but still require treatment. They were also shown videos of what PNEE look like and what epileptic seizures look like so they could better understand what’s going on. [Ultimately,] the goal was to take away the negative associations people have with the diagnosis," Dr. Maheshwari said.

"Subsequent sessions focused on finding constructive channels for stress release, focusing on the idea that [PNEE] are manifestations of inner-stress. Patients were allowed to discuss what strategies they found helpful. Peer-to-peer acceptance and evaluation helps," Dr. Maheshwari said.

Identification of triggers, including those for PTSD, was key, Dr. Maheshwari said. "For some people, [that means] identifying the aura so they can use stress-release strategies to avoid the seizure. It’s helpful to share those things with other people who have the same symptoms so they can appreciate they are not alone."

He cautioned that research is ongoing and the trial’s results are preliminary. Also, more people in the treatment group were married. Dr. Maheshwari noted that "we didn’t help out with the frequency and intensity of events, but there were significant improvements in patients’ perceptions of the problem" and quality of life.

Dr. Maheshwari said that he had no relevant disclosures.

SAN DIEGO – Patients who have been newly diagnosed with psychogenic nonepileptic seizures probably benefit from counseling and group therapy sessions before being referred to psychiatrists for treatment of their underlying mental health problem.

That’s what researchers from the Baylor College of Medicine in Houston found when they compared outcomes for 16 patients immediately referred to mental health services following diagnosis – the standard practice – with 19 others who had three educational group sessions beforehand where they learned about their condition and shared coping strategies.

Following their sessions, support group patients were more likely than were control group patients to agree that "my attacks do not really bother me or affect my life that much anymore" (P less than .001) and that "I have some control over my attacks" (P = .003). Perhaps most tellingly, patients in the treatment group were significantly less likely to return to the emergency department 3 months later (7% vs. 22%, P = .018).

"Clearly what we are seeing is that these patients need significant follow-up, perhaps with a neurologist rather than simply a mental health professional. Psychiatrists don’t feel comfortable addressing this issue; having a team approach with both a neurologist and a psychiatrist probably gives the best outcomes," lead investigator Dr. Atul Maheshwari of the department of neurology at Baylor said at the annual meeting of the American Epilepsy Society.

The patients in the randomized study were adults, mostly male, and had at least one seizure per week. They were diagnosed with psychogenic nonepileptic events (PNEE) in the epilepsy monitoring unit of Houston Veterans Affairs Medical Center, where the study was conducted. Psychiatric problems included depression, posttraumatic stress disorder, and childhood abuse.

The diagnosis of PNEE is often a hard blow to patients convinced that they have epilepsy or a brain tumor and feel like doctors aren’t taking them seriously; accepting that their seizures are caused by underlying psychiatric stress is difficult, Dr. Maheshwari said.

A nurse practitioner led the group sessions with talking points and instructions from a neurologist. "The first session helped [patients] understand [that] PNEE are nonpathologic, don’t cause the brain to be fried or cause long-term brain damage, but still require treatment. They were also shown videos of what PNEE look like and what epileptic seizures look like so they could better understand what’s going on. [Ultimately,] the goal was to take away the negative associations people have with the diagnosis," Dr. Maheshwari said.

"Subsequent sessions focused on finding constructive channels for stress release, focusing on the idea that [PNEE] are manifestations of inner-stress. Patients were allowed to discuss what strategies they found helpful. Peer-to-peer acceptance and evaluation helps," Dr. Maheshwari said.

Identification of triggers, including those for PTSD, was key, Dr. Maheshwari said. "For some people, [that means] identifying the aura so they can use stress-release strategies to avoid the seizure. It’s helpful to share those things with other people who have the same symptoms so they can appreciate they are not alone."

He cautioned that research is ongoing and the trial’s results are preliminary. Also, more people in the treatment group were married. Dr. Maheshwari noted that "we didn’t help out with the frequency and intensity of events, but there were significant improvements in patients’ perceptions of the problem" and quality of life.

Dr. Maheshwari said that he had no relevant disclosures.

Since September 11, 2001, many Arab Americans have faced increased discrimination, which puts them at greater risk for depression and low self-esteem.¹ Children and adolescents in particular have been the victims of teasing and taunts. Many Muslim Arab Americans turned to their imams—a mosque’s spiritual leader—rather than a mental health clinician to help them deal with the national tragedy and the fallout that followed.²

Arab Americans may struggle to bridge their personal identity with their cultural one. Traditional Arab values stress the importance of family—both immediate and extended—loyalty to parents, religious adherence, and respect for elders and authority. Adapting those values to typical American values can cause dissonance as Arab Americans grapple to find a balance between renouncing their Arab culture in hopes of fitting in and feeling like outcasts in the country they call home.

Understanding cultural nuances

Be aware of the stigma of mental illness within Arab American communities. Unlike diabetes or heart disease, psychiatric disorders can carry a negative connotation for many Arab Americans.³ They may view mental illness as a personal shortcoming or ascribe their symptoms to supernatural spirits. The fear of being discriminated against for being culturally different and mentally ill may delay or prevent individuals from seeking care.

Understanding these dynamics, as well as Arab American culture, is the first step to evaluating these patients. Being aware of cultural nuances also is important. Patients may say they don’t smoke, but some prodding may reveal that they use a tobacco water pipe, or hookah.

Be cognizant of any preconceived notions that can seep into an assessment. It’s easy to assume that Arab American patients fall into stereotypical gender roles or are unhappy with what may be perceived as inadequate assimilation. Conversely, a patient’s appearance, devotion to cultural and religious values, and family support may lead to an assumption that the patient does not abuse substances or engage in high-risk behavior.

In addition, note that Arab Americans tend to present their mental illness as somatic complaints, which may make them more comfortable seeing a primary care physician than a psychiatrist.

Adjusting treatment

Many Arab Americans’ first choice is to seek support from family, friends, and religious leaders.⁴ A patient may need to be convinced to take psychotropics the same as they would other medications. Therefore, it may be necessary to involve family members to ensure treatment compliance. Clinicians may need to spend more time with Arab American patients, which can help the clinician grasp the complexity of their issues and allow patients to feel that they’re being cared for by a clinician who respects their cultural and religious beliefs. In conjunction, these steps will help you provide culturally sensitive care that best addresses Arab Americans’ mental health needs.

Since September 11, 2001, many Arab Americans have faced increased discrimination, which puts them at greater risk for depression and low self-esteem.¹ Children and adolescents in particular have been the victims of teasing and taunts. Many Muslim Arab Americans turned to their imams—a mosque’s spiritual leader—rather than a mental health clinician to help them deal with the national tragedy and the fallout that followed.²

Arab Americans may struggle to bridge their personal identity with their cultural one. Traditional Arab values stress the importance of family—both immediate and extended—loyalty to parents, religious adherence, and respect for elders and authority. Adapting those values to typical American values can cause dissonance as Arab Americans grapple to find a balance between renouncing their Arab culture in hopes of fitting in and feeling like outcasts in the country they call home.

Understanding cultural nuances

Be aware of the stigma of mental illness within Arab American communities. Unlike diabetes or heart disease, psychiatric disorders can carry a negative connotation for many Arab Americans.³ They may view mental illness as a personal shortcoming or ascribe their symptoms to supernatural spirits. The fear of being discriminated against for being culturally different and mentally ill may delay or prevent individuals from seeking care.

Understanding these dynamics, as well as Arab American culture, is the first step to evaluating these patients. Being aware of cultural nuances also is important. Patients may say they don’t smoke, but some prodding may reveal that they use a tobacco water pipe, or hookah.

Be cognizant of any preconceived notions that can seep into an assessment. It’s easy to assume that Arab American patients fall into stereotypical gender roles or are unhappy with what may be perceived as inadequate assimilation. Conversely, a patient’s appearance, devotion to cultural and religious values, and family support may lead to an assumption that the patient does not abuse substances or engage in high-risk behavior.

In addition, note that Arab Americans tend to present their mental illness as somatic complaints, which may make them more comfortable seeing a primary care physician than a psychiatrist.

Adjusting treatment

Many Arab Americans’ first choice is to seek support from family, friends, and religious leaders.⁴ A patient may need to be convinced to take psychotropics the same as they would other medications. Therefore, it may be necessary to involve family members to ensure treatment compliance. Clinicians may need to spend more time with Arab American patients, which can help the clinician grasp the complexity of their issues and allow patients to feel that they’re being cared for by a clinician who respects their cultural and religious beliefs. In conjunction, these steps will help you provide culturally sensitive care that best addresses Arab Americans’ mental health needs.

Since September 11, 2001, many Arab Americans have faced increased discrimination, which puts them at greater risk for depression and low self-esteem.¹ Children and adolescents in particular have been the victims of teasing and taunts. Many Muslim Arab Americans turned to their imams—a mosque’s spiritual leader—rather than a mental health clinician to help them deal with the national tragedy and the fallout that followed.²

Arab Americans may struggle to bridge their personal identity with their cultural one. Traditional Arab values stress the importance of family—both immediate and extended—loyalty to parents, religious adherence, and respect for elders and authority. Adapting those values to typical American values can cause dissonance as Arab Americans grapple to find a balance between renouncing their Arab culture in hopes of fitting in and feeling like outcasts in the country they call home.

Understanding cultural nuances

Be aware of the stigma of mental illness within Arab American communities. Unlike diabetes or heart disease, psychiatric disorders can carry a negative connotation for many Arab Americans.³ They may view mental illness as a personal shortcoming or ascribe their symptoms to supernatural spirits. The fear of being discriminated against for being culturally different and mentally ill may delay or prevent individuals from seeking care.

Understanding these dynamics, as well as Arab American culture, is the first step to evaluating these patients. Being aware of cultural nuances also is important. Patients may say they don’t smoke, but some prodding may reveal that they use a tobacco water pipe, or hookah.

Be cognizant of any preconceived notions that can seep into an assessment. It’s easy to assume that Arab American patients fall into stereotypical gender roles or are unhappy with what may be perceived as inadequate assimilation. Conversely, a patient’s appearance, devotion to cultural and religious values, and family support may lead to an assumption that the patient does not abuse substances or engage in high-risk behavior.

In addition, note that Arab Americans tend to present their mental illness as somatic complaints, which may make them more comfortable seeing a primary care physician than a psychiatrist.

Adjusting treatment

Many Arab Americans’ first choice is to seek support from family, friends, and religious leaders.⁴ A patient may need to be convinced to take psychotropics the same as they would other medications. Therefore, it may be necessary to involve family members to ensure treatment compliance. Clinicians may need to spend more time with Arab American patients, which can help the clinician grasp the complexity of their issues and allow patients to feel that they’re being cared for by a clinician who respects their cultural and religious beliefs. In conjunction, these steps will help you provide culturally sensitive care that best addresses Arab Americans’ mental health needs.

CASE: Depressed and hopeless

Ms. D, age 69, has a 20-year history of bipolar II disorder, for which she is taking citalopram, 30 mg/d. She presents to her outpatient psychotherapist with a chief complaint of depressed mood. The therapist refers her for psychiatric hospitalization and electroconvulsive therapy consultation. Upon admission, Ms. D reports that her depressed mood has worsened over the past 5 weeks after a trip to the Dominican Republic. Ms. D had a negative encounter with airport security that she attributed to her 2 artificial knees and caused her to miss her flight. She endorses poor appetite, loss of energy, anhedonia, difficulty concentrating, poor memory, and feelings of hopelessness.

Ms. D reports increasingly frequent panic attacks as well as intermittent right-sided discomfort, unusual noxious smells, and increased falls. She says the falls likely are a result of new bilateral lower extremity weakness coupled with long-standing imbalance. Ms. D says she has experienced brief occasions of foul-smelling odors while showering without evidence of an offending substance. She also reports a mild, occipitally located headache.

Four years ago, Ms. D was hospitalized for a depressive episode without psychotic features and diagnosed with generalized anxiety disorder, for which she is taking clonazepam, 1.5 mg/d. Her last hypomanic episode was several years ago, and was characterized by increased energy with decreased need for sleep, flight of ideas, increased productivity, and impulsivity. Her medical history includes non-insulin dependent diabetes mellitus, chronic low back pain, hyperlipidemia, arthritis, and gastroesophageal reflux disease; her medications include pioglitazone, 30 mg/d, oxybutynin, 15 mg/d, rosuvastatin, 20 mg/d, losartan, 50 mg/d, and omeprazole, 20 mg/d. She also had bilateral knee replacements 9 years ago and an L4-S1 spinal fusion 11 years ago. She has no history of head injuries or seizures. Ms. D’s father had major depressive disorder, her mother died of a cerebrovascular accident at an unknown age, and her brother died of a myocardial infarction at age 52.

The authors’ observations

A striking aspect of Ms. D’s presenting complaints was her intermittent experience of foul smells. Although olfactory hallucinations can occur with psychotic and affective states, they also may be harbingers of an organic etiology involving the temporal lobe.¹ Olfactory hallucinations associated with a psychiatric disorder often have an accompanying delusional belief regarding the cause of the smell.²

Olfactory hallucinations have been associated with migraines, epilepsy, and Parkinson’s disease.^1-3 Neoplasms, cerebrovascular events, or traumatic brain injuries that result in focal mesial temporal lobe lesions can present as a partial complex seizure with olfactory or gustatory hallucinations and progress to automatisms.⁴ Characteristic odors in these hallucinations are unpleasant; patients with temporal lobe epilepsy describe the smells as “bad,” “rotten,” “sickening,” and “like burning food.”² Ms. D’s report of unusual smells warranted consideration of an organic etiology for her mood change and a thorough neurologic examination.

EVALUATION: Neurologic signs

At the time of admission, Ms. D has a blood pressure of 127/68 mm Hg, heart rate of 74 beats per minute, respiratory rate of 16 breaths per minute, and temperature of 36.5°C. Neurologic examination reveals a left facial droop of unknown duration. Motor strength is weak throughout with left-sided focal weakness. Ms. D’s daughter notes that her mother’s smile appears “funny” in her admission photograph but is unsure when the asymmetry in her facial appearance began. Ms. D had been ambulatory before admission. Nursing staff observes Ms. D leans toward her left side and exhibits possible left-sided neglect during the first 12 hours of hospitalization.

When asked about her facial droop, Ms. D replies that she had not noticed any change in her appearance lately. She does not appear to be concerned about her worsening ambulation. On hospital day 2, Ms. D seems to have difficulty using utensils to eat breakfast. Ms. D is dismissive of her worsening motor function and asks to be left alone to finish her meal.

The authors’ observations

Ms. D’s focal neurologic deficits and complaint of a headache on admission were concerning because they could be caused by a cerebrovascular event or space-occupying brain lesion with potential for increased intracranial pressure. Neurologic examination with evaluation for papilledema is indicated, followed by medical transport to the closest medical center for emergent brain imaging. Neither Ms. D nor her daughter could pinpoint the onset of Ms. D’s left-sided facial droop, which precluded administering tissue plasminogen activator for a potential acute ischemic stroke.⁵

Ms. D’s case prompted us to consider what constitutes timely brain imaging in a patient who presents with psychiatric symptoms. Several neurologic conditions may present first with neurobehavioral symptoms before findings on physical exam. Two series of autopsies conducted >70 years ago at psychiatric hospitals found incidences of brain tumors of 3.45%⁶ and 13.5%.⁷ In a 5-year retrospective study, 21% of meningioma cases presented with psychiatric symptoms alone.⁸ These historical cases suggest that affective, behavioral, and psychotic symptoms may be the only clinical indicators of brain lesions that merit surgery.^9-11

Imaging and radiation exposure

With the advent of CT scans in the 1970s, psychiatrists gained a new method of investigating potential structural CNS pathology in patients presenting with psychiatric symptoms. The dramatic increase in CT scan use in recent years and resulting radiation exposure is responsible for 1.5% to 2% of all cancers in the United States.^12,13 Certainly, physicians must balance the advantage of early detection of brain lesions with cost-effectiveness and exposure to radiation.¹⁴

There is no consensus regarding use of brain imaging in a patient who presents with new-onset psychiatric symptoms. Certainly, patients with localizing neurologic deficits or symptoms of increased intracranial pressure should undergo brain imaging. As for psychiatric patients without neurologic findings, Filley and Kleinschmidt-DeMasters¹⁵ provide recommendations based on their 1995 case series, and other authors have recommended imaging for patients age ≥40¹⁶ vs ≥50^17,18 who present with atypical mental status changes.

OUTCOME: Scan, then surgery

Ms. D’s head CT reveals a large right-sided temporoparietal low-density lesion with 8-mm left lower midline shift (Figure). She undergoes a right temporal craniotomy with resection of the mass, which is confirmed by surgical pathology to be a glioblastoma multiforme World Health Organization grade 4 tumor. Postoperative MRI shows evidence of infarction in the right posterior cerebral artery distribution and residual tumor is identified on follow-up imaging. Ms. D is referred to radiation oncology, where she receives a prognostic median life expectancy of 14 months with radiation and temozolomide treatment.¹⁹

Figure: Ms. D’s MRI results
MRI with contrast shows a large right temporal heterogeneous mass consistent with glioblastoma multiforme

The authors’ observations

Glioblastoma is a rare cancer that comprises 25% of all malignant nervous system tumors.²⁰ It is associated with a poor prognosis, with a <30% relative survival rate for adults at 1 year and 3% at 5 years.²⁰ Headaches, seizures, motor weakness, and progressive neurologic deficits are common symptoms of glioblastoma at diagnosis.²⁰ Ms. D was offered the standard of care treatment for a high-grade glioma, including surgical resection followed by concomitant external-beam radiotherapy and chemotherapy.²¹

Consider structural brain lesions in patients who present with neurobehavioral symptoms, although most of these patients will be diagnosed with a primary psychiatric disorder. Ms. D had a known psychiatric disorder that predated the onset of neurologic symptoms and diagnosis of a rare brain cancer. Before she developed neurologic signs, Ms. D experienced symptoms uncharacteristic of her previous depressive episodes, including olfactory hallucinations, that provided an early indicator of a CNS lesion. Consider brain imaging in patients of any age who do not respond to medications targeting the presumed psychiatric diagnosis to ensure that insidious brain tumors are not missed (Table 1).¹⁵

Table 1

When to order neuroimaging for psychiatric patients

Compared with cerebrovascular lesions, neoplasms are more difficult to clinically correlate with their anatomic location. Neurobehavioral symptoms are more frequently associated with tumors originating in the frontal lobe or temporolimbic regions of the brain. The 3 types of frontal lobe syndromes are dorsolateral, orbitofrontal, and medial-frontal (Table 2).¹⁵ Temporolimbic tumors may present with hallucinations, mania, panic attacks, or amnesia. A meta-analysis found a statistically significant association between anorexia and hypothalamic tumors.²² Reports of neuropsychiatric symptoms that respond to pharmacologic treatment further confound the clinical picture.¹⁶

Table 2

Frontal lobe syndromes

It is uncommon for a patient with a long-standing mood disorder to develop a primary brain cancer. However, Ms. D’s case serves as an important reminder to consider medical comorbidities in our aging psychiatric population. In particular, a patient who develops unusual symptoms or does not respond to previously effective treatments should be more closely examined and the differential diagnosis broadened.

Related Resources

• MD Anderson Cancer Center. Brain tumor videos and podcasts. www.mdanderson.org/patient-and-cancer-information/cancer-information/cancer-types/brain-tumor/videos-and-podcasts/index.html.
• Braun CM, Dumont M, Duval J, et al. Brain modules of hallucination: an analysis of multiple patients with brain lesions. J Psychiatry Neurosci. 2003;28(6):432-449.

Drug Brand Names

• Citalopram • Celexa
• Clonazepam • Klonopin
• Losartan • Cozaar
• Omeprazole • Prilosec
• Oxybutynin • Ditropan
• Pioglitazone • Actos
• Rosuvastatin • Crestor
• Temozolomide • Temodar

Disclosure

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

CASE: Depressed and hopeless

Ms. D, age 69, has a 20-year history of bipolar II disorder, for which she is taking citalopram, 30 mg/d. She presents to her outpatient psychotherapist with a chief complaint of depressed mood. The therapist refers her for psychiatric hospitalization and electroconvulsive therapy consultation. Upon admission, Ms. D reports that her depressed mood has worsened over the past 5 weeks after a trip to the Dominican Republic. Ms. D had a negative encounter with airport security that she attributed to her 2 artificial knees and caused her to miss her flight. She endorses poor appetite, loss of energy, anhedonia, difficulty concentrating, poor memory, and feelings of hopelessness.

Ms. D reports increasingly frequent panic attacks as well as intermittent right-sided discomfort, unusual noxious smells, and increased falls. She says the falls likely are a result of new bilateral lower extremity weakness coupled with long-standing imbalance. Ms. D says she has experienced brief occasions of foul-smelling odors while showering without evidence of an offending substance. She also reports a mild, occipitally located headache.

Four years ago, Ms. D was hospitalized for a depressive episode without psychotic features and diagnosed with generalized anxiety disorder, for which she is taking clonazepam, 1.5 mg/d. Her last hypomanic episode was several years ago, and was characterized by increased energy with decreased need for sleep, flight of ideas, increased productivity, and impulsivity. Her medical history includes non-insulin dependent diabetes mellitus, chronic low back pain, hyperlipidemia, arthritis, and gastroesophageal reflux disease; her medications include pioglitazone, 30 mg/d, oxybutynin, 15 mg/d, rosuvastatin, 20 mg/d, losartan, 50 mg/d, and omeprazole, 20 mg/d. She also had bilateral knee replacements 9 years ago and an L4-S1 spinal fusion 11 years ago. She has no history of head injuries or seizures. Ms. D’s father had major depressive disorder, her mother died of a cerebrovascular accident at an unknown age, and her brother died of a myocardial infarction at age 52.

The authors’ observations

A striking aspect of Ms. D’s presenting complaints was her intermittent experience of foul smells. Although olfactory hallucinations can occur with psychotic and affective states, they also may be harbingers of an organic etiology involving the temporal lobe.¹ Olfactory hallucinations associated with a psychiatric disorder often have an accompanying delusional belief regarding the cause of the smell.²

Olfactory hallucinations have been associated with migraines, epilepsy, and Parkinson’s disease.^1-3 Neoplasms, cerebrovascular events, or traumatic brain injuries that result in focal mesial temporal lobe lesions can present as a partial complex seizure with olfactory or gustatory hallucinations and progress to automatisms.⁴ Characteristic odors in these hallucinations are unpleasant; patients with temporal lobe epilepsy describe the smells as “bad,” “rotten,” “sickening,” and “like burning food.”² Ms. D’s report of unusual smells warranted consideration of an organic etiology for her mood change and a thorough neurologic examination.

EVALUATION: Neurologic signs

At the time of admission, Ms. D has a blood pressure of 127/68 mm Hg, heart rate of 74 beats per minute, respiratory rate of 16 breaths per minute, and temperature of 36.5°C. Neurologic examination reveals a left facial droop of unknown duration. Motor strength is weak throughout with left-sided focal weakness. Ms. D’s daughter notes that her mother’s smile appears “funny” in her admission photograph but is unsure when the asymmetry in her facial appearance began. Ms. D had been ambulatory before admission. Nursing staff observes Ms. D leans toward her left side and exhibits possible left-sided neglect during the first 12 hours of hospitalization.

When asked about her facial droop, Ms. D replies that she had not noticed any change in her appearance lately. She does not appear to be concerned about her worsening ambulation. On hospital day 2, Ms. D seems to have difficulty using utensils to eat breakfast. Ms. D is dismissive of her worsening motor function and asks to be left alone to finish her meal.

The authors’ observations

Ms. D’s focal neurologic deficits and complaint of a headache on admission were concerning because they could be caused by a cerebrovascular event or space-occupying brain lesion with potential for increased intracranial pressure. Neurologic examination with evaluation for papilledema is indicated, followed by medical transport to the closest medical center for emergent brain imaging. Neither Ms. D nor her daughter could pinpoint the onset of Ms. D’s left-sided facial droop, which precluded administering tissue plasminogen activator for a potential acute ischemic stroke.⁵

Ms. D’s case prompted us to consider what constitutes timely brain imaging in a patient who presents with psychiatric symptoms. Several neurologic conditions may present first with neurobehavioral symptoms before findings on physical exam. Two series of autopsies conducted >70 years ago at psychiatric hospitals found incidences of brain tumors of 3.45%⁶ and 13.5%.⁷ In a 5-year retrospective study, 21% of meningioma cases presented with psychiatric symptoms alone.⁸ These historical cases suggest that affective, behavioral, and psychotic symptoms may be the only clinical indicators of brain lesions that merit surgery.^9-11

Imaging and radiation exposure

With the advent of CT scans in the 1970s, psychiatrists gained a new method of investigating potential structural CNS pathology in patients presenting with psychiatric symptoms. The dramatic increase in CT scan use in recent years and resulting radiation exposure is responsible for 1.5% to 2% of all cancers in the United States.^12,13 Certainly, physicians must balance the advantage of early detection of brain lesions with cost-effectiveness and exposure to radiation.¹⁴

There is no consensus regarding use of brain imaging in a patient who presents with new-onset psychiatric symptoms. Certainly, patients with localizing neurologic deficits or symptoms of increased intracranial pressure should undergo brain imaging. As for psychiatric patients without neurologic findings, Filley and Kleinschmidt-DeMasters¹⁵ provide recommendations based on their 1995 case series, and other authors have recommended imaging for patients age ≥40¹⁶ vs ≥50^17,18 who present with atypical mental status changes.

OUTCOME: Scan, then surgery

Ms. D’s head CT reveals a large right-sided temporoparietal low-density lesion with 8-mm left lower midline shift (Figure). She undergoes a right temporal craniotomy with resection of the mass, which is confirmed by surgical pathology to be a glioblastoma multiforme World Health Organization grade 4 tumor. Postoperative MRI shows evidence of infarction in the right posterior cerebral artery distribution and residual tumor is identified on follow-up imaging. Ms. D is referred to radiation oncology, where she receives a prognostic median life expectancy of 14 months with radiation and temozolomide treatment.¹⁹

Figure: Ms. D’s MRI results
MRI with contrast shows a large right temporal heterogeneous mass consistent with glioblastoma multiforme

The authors’ observations

Glioblastoma is a rare cancer that comprises 25% of all malignant nervous system tumors.²⁰ It is associated with a poor prognosis, with a <30% relative survival rate for adults at 1 year and 3% at 5 years.²⁰ Headaches, seizures, motor weakness, and progressive neurologic deficits are common symptoms of glioblastoma at diagnosis.²⁰ Ms. D was offered the standard of care treatment for a high-grade glioma, including surgical resection followed by concomitant external-beam radiotherapy and chemotherapy.²¹

Consider structural brain lesions in patients who present with neurobehavioral symptoms, although most of these patients will be diagnosed with a primary psychiatric disorder. Ms. D had a known psychiatric disorder that predated the onset of neurologic symptoms and diagnosis of a rare brain cancer. Before she developed neurologic signs, Ms. D experienced symptoms uncharacteristic of her previous depressive episodes, including olfactory hallucinations, that provided an early indicator of a CNS lesion. Consider brain imaging in patients of any age who do not respond to medications targeting the presumed psychiatric diagnosis to ensure that insidious brain tumors are not missed (Table 1).¹⁵

Table 1

When to order neuroimaging for psychiatric patients

Compared with cerebrovascular lesions, neoplasms are more difficult to clinically correlate with their anatomic location. Neurobehavioral symptoms are more frequently associated with tumors originating in the frontal lobe or temporolimbic regions of the brain. The 3 types of frontal lobe syndromes are dorsolateral, orbitofrontal, and medial-frontal (Table 2).¹⁵ Temporolimbic tumors may present with hallucinations, mania, panic attacks, or amnesia. A meta-analysis found a statistically significant association between anorexia and hypothalamic tumors.²² Reports of neuropsychiatric symptoms that respond to pharmacologic treatment further confound the clinical picture.¹⁶

Table 2

Frontal lobe syndromes

It is uncommon for a patient with a long-standing mood disorder to develop a primary brain cancer. However, Ms. D’s case serves as an important reminder to consider medical comorbidities in our aging psychiatric population. In particular, a patient who develops unusual symptoms or does not respond to previously effective treatments should be more closely examined and the differential diagnosis broadened.

Related Resources

• MD Anderson Cancer Center. Brain tumor videos and podcasts. www.mdanderson.org/patient-and-cancer-information/cancer-information/cancer-types/brain-tumor/videos-and-podcasts/index.html.
• Braun CM, Dumont M, Duval J, et al. Brain modules of hallucination: an analysis of multiple patients with brain lesions. J Psychiatry Neurosci. 2003;28(6):432-449.

Drug Brand Names

• Citalopram • Celexa
• Clonazepam • Klonopin
• Losartan • Cozaar
• Omeprazole • Prilosec
• Oxybutynin • Ditropan
• Pioglitazone • Actos
• Rosuvastatin • Crestor
• Temozolomide • Temodar

Disclosure

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

CASE: Depressed and hopeless

Ms. D, age 69, has a 20-year history of bipolar II disorder, for which she is taking citalopram, 30 mg/d. She presents to her outpatient psychotherapist with a chief complaint of depressed mood. The therapist refers her for psychiatric hospitalization and electroconvulsive therapy consultation. Upon admission, Ms. D reports that her depressed mood has worsened over the past 5 weeks after a trip to the Dominican Republic. Ms. D had a negative encounter with airport security that she attributed to her 2 artificial knees and caused her to miss her flight. She endorses poor appetite, loss of energy, anhedonia, difficulty concentrating, poor memory, and feelings of hopelessness.

Ms. D reports increasingly frequent panic attacks as well as intermittent right-sided discomfort, unusual noxious smells, and increased falls. She says the falls likely are a result of new bilateral lower extremity weakness coupled with long-standing imbalance. Ms. D says she has experienced brief occasions of foul-smelling odors while showering without evidence of an offending substance. She also reports a mild, occipitally located headache.

Four years ago, Ms. D was hospitalized for a depressive episode without psychotic features and diagnosed with generalized anxiety disorder, for which she is taking clonazepam, 1.5 mg/d. Her last hypomanic episode was several years ago, and was characterized by increased energy with decreased need for sleep, flight of ideas, increased productivity, and impulsivity. Her medical history includes non-insulin dependent diabetes mellitus, chronic low back pain, hyperlipidemia, arthritis, and gastroesophageal reflux disease; her medications include pioglitazone, 30 mg/d, oxybutynin, 15 mg/d, rosuvastatin, 20 mg/d, losartan, 50 mg/d, and omeprazole, 20 mg/d. She also had bilateral knee replacements 9 years ago and an L4-S1 spinal fusion 11 years ago. She has no history of head injuries or seizures. Ms. D’s father had major depressive disorder, her mother died of a cerebrovascular accident at an unknown age, and her brother died of a myocardial infarction at age 52.

The authors’ observations

A striking aspect of Ms. D’s presenting complaints was her intermittent experience of foul smells. Although olfactory hallucinations can occur with psychotic and affective states, they also may be harbingers of an organic etiology involving the temporal lobe.¹ Olfactory hallucinations associated with a psychiatric disorder often have an accompanying delusional belief regarding the cause of the smell.²

Olfactory hallucinations have been associated with migraines, epilepsy, and Parkinson’s disease.^1-3 Neoplasms, cerebrovascular events, or traumatic brain injuries that result in focal mesial temporal lobe lesions can present as a partial complex seizure with olfactory or gustatory hallucinations and progress to automatisms.⁴ Characteristic odors in these hallucinations are unpleasant; patients with temporal lobe epilepsy describe the smells as “bad,” “rotten,” “sickening,” and “like burning food.”² Ms. D’s report of unusual smells warranted consideration of an organic etiology for her mood change and a thorough neurologic examination.

EVALUATION: Neurologic signs

At the time of admission, Ms. D has a blood pressure of 127/68 mm Hg, heart rate of 74 beats per minute, respiratory rate of 16 breaths per minute, and temperature of 36.5°C. Neurologic examination reveals a left facial droop of unknown duration. Motor strength is weak throughout with left-sided focal weakness. Ms. D’s daughter notes that her mother’s smile appears “funny” in her admission photograph but is unsure when the asymmetry in her facial appearance began. Ms. D had been ambulatory before admission. Nursing staff observes Ms. D leans toward her left side and exhibits possible left-sided neglect during the first 12 hours of hospitalization.

When asked about her facial droop, Ms. D replies that she had not noticed any change in her appearance lately. She does not appear to be concerned about her worsening ambulation. On hospital day 2, Ms. D seems to have difficulty using utensils to eat breakfast. Ms. D is dismissive of her worsening motor function and asks to be left alone to finish her meal.

The authors’ observations

Ms. D’s focal neurologic deficits and complaint of a headache on admission were concerning because they could be caused by a cerebrovascular event or space-occupying brain lesion with potential for increased intracranial pressure. Neurologic examination with evaluation for papilledema is indicated, followed by medical transport to the closest medical center for emergent brain imaging. Neither Ms. D nor her daughter could pinpoint the onset of Ms. D’s left-sided facial droop, which precluded administering tissue plasminogen activator for a potential acute ischemic stroke.⁵

Ms. D’s case prompted us to consider what constitutes timely brain imaging in a patient who presents with psychiatric symptoms. Several neurologic conditions may present first with neurobehavioral symptoms before findings on physical exam. Two series of autopsies conducted >70 years ago at psychiatric hospitals found incidences of brain tumors of 3.45%⁶ and 13.5%.⁷ In a 5-year retrospective study, 21% of meningioma cases presented with psychiatric symptoms alone.⁸ These historical cases suggest that affective, behavioral, and psychotic symptoms may be the only clinical indicators of brain lesions that merit surgery.^9-11

Imaging and radiation exposure

With the advent of CT scans in the 1970s, psychiatrists gained a new method of investigating potential structural CNS pathology in patients presenting with psychiatric symptoms. The dramatic increase in CT scan use in recent years and resulting radiation exposure is responsible for 1.5% to 2% of all cancers in the United States.^12,13 Certainly, physicians must balance the advantage of early detection of brain lesions with cost-effectiveness and exposure to radiation.¹⁴

There is no consensus regarding use of brain imaging in a patient who presents with new-onset psychiatric symptoms. Certainly, patients with localizing neurologic deficits or symptoms of increased intracranial pressure should undergo brain imaging. As for psychiatric patients without neurologic findings, Filley and Kleinschmidt-DeMasters¹⁵ provide recommendations based on their 1995 case series, and other authors have recommended imaging for patients age ≥40¹⁶ vs ≥50^17,18 who present with atypical mental status changes.

OUTCOME: Scan, then surgery

Ms. D’s head CT reveals a large right-sided temporoparietal low-density lesion with 8-mm left lower midline shift (Figure). She undergoes a right temporal craniotomy with resection of the mass, which is confirmed by surgical pathology to be a glioblastoma multiforme World Health Organization grade 4 tumor. Postoperative MRI shows evidence of infarction in the right posterior cerebral artery distribution and residual tumor is identified on follow-up imaging. Ms. D is referred to radiation oncology, where she receives a prognostic median life expectancy of 14 months with radiation and temozolomide treatment.¹⁹

Figure: Ms. D’s MRI results
MRI with contrast shows a large right temporal heterogeneous mass consistent with glioblastoma multiforme

The authors’ observations

Glioblastoma is a rare cancer that comprises 25% of all malignant nervous system tumors.²⁰ It is associated with a poor prognosis, with a <30% relative survival rate for adults at 1 year and 3% at 5 years.²⁰ Headaches, seizures, motor weakness, and progressive neurologic deficits are common symptoms of glioblastoma at diagnosis.²⁰ Ms. D was offered the standard of care treatment for a high-grade glioma, including surgical resection followed by concomitant external-beam radiotherapy and chemotherapy.²¹

Consider structural brain lesions in patients who present with neurobehavioral symptoms, although most of these patients will be diagnosed with a primary psychiatric disorder. Ms. D had a known psychiatric disorder that predated the onset of neurologic symptoms and diagnosis of a rare brain cancer. Before she developed neurologic signs, Ms. D experienced symptoms uncharacteristic of her previous depressive episodes, including olfactory hallucinations, that provided an early indicator of a CNS lesion. Consider brain imaging in patients of any age who do not respond to medications targeting the presumed psychiatric diagnosis to ensure that insidious brain tumors are not missed (Table 1).¹⁵

Table 1

When to order neuroimaging for psychiatric patients

Compared with cerebrovascular lesions, neoplasms are more difficult to clinically correlate with their anatomic location. Neurobehavioral symptoms are more frequently associated with tumors originating in the frontal lobe or temporolimbic regions of the brain. The 3 types of frontal lobe syndromes are dorsolateral, orbitofrontal, and medial-frontal (Table 2).¹⁵ Temporolimbic tumors may present with hallucinations, mania, panic attacks, or amnesia. A meta-analysis found a statistically significant association between anorexia and hypothalamic tumors.²² Reports of neuropsychiatric symptoms that respond to pharmacologic treatment further confound the clinical picture.¹⁶

Table 2

Frontal lobe syndromes

It is uncommon for a patient with a long-standing mood disorder to develop a primary brain cancer. However, Ms. D’s case serves as an important reminder to consider medical comorbidities in our aging psychiatric population. In particular, a patient who develops unusual symptoms or does not respond to previously effective treatments should be more closely examined and the differential diagnosis broadened.

Related Resources

• MD Anderson Cancer Center. Brain tumor videos and podcasts. www.mdanderson.org/patient-and-cancer-information/cancer-information/cancer-types/brain-tumor/videos-and-podcasts/index.html.
• Braun CM, Dumont M, Duval J, et al. Brain modules of hallucination: an analysis of multiple patients with brain lesions. J Psychiatry Neurosci. 2003;28(6):432-449.

Drug Brand Names

• Citalopram • Celexa
• Clonazepam • Klonopin
• Losartan • Cozaar
• Omeprazole • Prilosec
• Oxybutynin • Ditropan
• Pioglitazone • Actos
• Rosuvastatin • Crestor
• Temozolomide • Temodar

Disclosure

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