Current Psychiatry

Yesterday I tried to explain electroconvulsive therapy (ECT) to my 15-year-old son. Of my three children, he comes closest to idealizing me and is most likely to consider medical school. Still, he was a tough sell. His initial reaction to ECT was “that sounds sort of primitive.”

Dr. Max Fink’s article in this issue reviews the overwhelming evidence for ECT’s efficacy in major depressive disorder and the obstacles that prevent ECT from being used as widely as research suggests it should be. Two obstacles are limited availability (few psychiatrists make it part of their practice) and social stigma. The stigma leads to low availability, which makes ECT available only as a last resort, which in turn increases the stigma.

Dr. Fink identifies a third obstacle as “academic low regard,” meaning that academic psychiatrists relegate ECT to a third- or fourth-line therapy and neglect to teach about it. ECT was introduced before psychodynamic therapies and effective medications revolutionized psychiatry. Consequently, psychiatrists trained in psychodynamics and psychopharmacology pay less attention to ECT than the data warrant.

Repetitive transcranial magnetic stimulation (rTMS)—ably reviewed in this issue by Drs. Sheila Dowd and Philip Janicak—has an advantage over ECT in being new and therefore perceived as exciting. It also is less aesthetically problematic because most people have a more positive attitude towards magnets than electric shocks.

Time will tell where rTMS might fit into our treatment algorithms for major depressive disorder. Taken together, however, ECT and rTMS illustrate how psychiatry can advance by keeping established treatments of proven efficacy while embracing new treatments.

Either because I convinced my son of the benefits of ECT—or because he wanted to avoid conflict—he eventually said, “Well, I guess you have to use whatever works, even if you don’t know exactly how it works.” So true.

Yesterday I tried to explain electroconvulsive therapy (ECT) to my 15-year-old son. Of my three children, he comes closest to idealizing me and is most likely to consider medical school. Still, he was a tough sell. His initial reaction to ECT was “that sounds sort of primitive.”

Dr. Max Fink’s article in this issue reviews the overwhelming evidence for ECT’s efficacy in major depressive disorder and the obstacles that prevent ECT from being used as widely as research suggests it should be. Two obstacles are limited availability (few psychiatrists make it part of their practice) and social stigma. The stigma leads to low availability, which makes ECT available only as a last resort, which in turn increases the stigma.

Dr. Fink identifies a third obstacle as “academic low regard,” meaning that academic psychiatrists relegate ECT to a third- or fourth-line therapy and neglect to teach about it. ECT was introduced before psychodynamic therapies and effective medications revolutionized psychiatry. Consequently, psychiatrists trained in psychodynamics and psychopharmacology pay less attention to ECT than the data warrant.

Repetitive transcranial magnetic stimulation (rTMS)—ably reviewed in this issue by Drs. Sheila Dowd and Philip Janicak—has an advantage over ECT in being new and therefore perceived as exciting. It also is less aesthetically problematic because most people have a more positive attitude towards magnets than electric shocks.

Time will tell where rTMS might fit into our treatment algorithms for major depressive disorder. Taken together, however, ECT and rTMS illustrate how psychiatry can advance by keeping established treatments of proven efficacy while embracing new treatments.

Either because I convinced my son of the benefits of ECT—or because he wanted to avoid conflict—he eventually said, “Well, I guess you have to use whatever works, even if you don’t know exactly how it works.” So true.

Yesterday I tried to explain electroconvulsive therapy (ECT) to my 15-year-old son. Of my three children, he comes closest to idealizing me and is most likely to consider medical school. Still, he was a tough sell. His initial reaction to ECT was “that sounds sort of primitive.”

Dr. Max Fink’s article in this issue reviews the overwhelming evidence for ECT’s efficacy in major depressive disorder and the obstacles that prevent ECT from being used as widely as research suggests it should be. Two obstacles are limited availability (few psychiatrists make it part of their practice) and social stigma. The stigma leads to low availability, which makes ECT available only as a last resort, which in turn increases the stigma.

Dr. Fink identifies a third obstacle as “academic low regard,” meaning that academic psychiatrists relegate ECT to a third- or fourth-line therapy and neglect to teach about it. ECT was introduced before psychodynamic therapies and effective medications revolutionized psychiatry. Consequently, psychiatrists trained in psychodynamics and psychopharmacology pay less attention to ECT than the data warrant.

Repetitive transcranial magnetic stimulation (rTMS)—ably reviewed in this issue by Drs. Sheila Dowd and Philip Janicak—has an advantage over ECT in being new and therefore perceived as exciting. It also is less aesthetically problematic because most people have a more positive attitude towards magnets than electric shocks.

Time will tell where rTMS might fit into our treatment algorithms for major depressive disorder. Taken together, however, ECT and rTMS illustrate how psychiatry can advance by keeping established treatments of proven efficacy while embracing new treatments.

Either because I convinced my son of the benefits of ECT—or because he wanted to avoid conflict—he eventually said, “Well, I guess you have to use whatever works, even if you don’t know exactly how it works.” So true.

Patients with what’s called “therapy-resistant” depression (TRD)—with subtherapeutic response to medications and psychotherapy—are often actually suffering from unrecognized, inadequately treated psychotic depression. Psychiatrists could greatly diminish the clinical challenge of TRD by recognizing psychotic depression and treating it more effectively.¹ And the most effective treatment for psychotic depression is neither antidepressants nor antipsychotic drugs but electroconvulsive therapy (ECT).

Despite ECT’s superior efficacy in TRD, however, algorithms for treating major depression relegate ECT to an option of last resort. By not considering ECT sooner, we consign many severely depressed patients to less-effective treatments and the risk of chronic illness.

Table

Diagnostic signs of psychosis in patients with major depression

It is time for a more realistic algorithm that recommends ECT earlier for major depressive episodes, with or without psychotic features. This article proposes such an algorithm and discusses the supporting evidence.

TREATING PSYCHOTIC DEPRESSION

Patients with delusions or hallucinations were classified as suffering from schizophrenia until the mid-1970s. Researchers then found that depressed patients with psychotic features responded well to ECT but poorly to adequate serum levels of imipramine.²

These observations were confirmed by a large Italian study, in which 437 depressed patients were treated with high-dose imipramine (200 to 350 mg/d). Depression remitted in 244 patients (56%). Those who remained depressed were then treated with ECT, and depression remitted in 136 of 190 (72%). Psychosis was the marker of poor response to imipramine.³ DSM-III codified these findings by separating the syndrome of “major depression with psychosis” (296.34) from “major depression without psychosis” (296.33).

As psychiatry recognized psychotic depression as a distinct form of depression, it became clear that drugs often could not adequately treat it. Less than one-third of patients with psychotic depression respond to tricyclics alone.^4-6

Response to antipsychotic monotherapy averaged 50% and increased to 75% with combined antipsychotics and antidepressants. However, high daily dosages —at least 32 mg of perphenazine and 225 mg of amitriptyline—were required for an adequate response,⁷ and side effects made sustaining such heroic dosing was difficult. The greatest improvement rates were seen with ECT.

Few other drug combinations have been reported to be effective in psychotic depression, but we lack proper studies. Schatzberg⁸ addressed the use of newer antidepressants and atypical antipsychotics without offering an algorithm based on the data. Evidence on combination therapies consists mainly of case reports, with few designed studies.

EFFICACY OF ECT

ECT is the most effective treatment for psychotic major depression—achieving remission rates >80% within 3 weeks—as demonstrated by the ongoing, four-hospital Consortium for Research in ECT (CORE), supported by the National Institute of Mental Health.

CORE researchers are studying the efficacy of bilateral ECT in treating severe unipolar depression in patients ages 18 to 85 and of continuation treatments with ECT or lithium plus nortriptyline.⁹ Under the CORE protocol, diagnoses are made by structured clinical interview using DSM-III-R criteria, and remission is defined as >60% reduction in Hamilton Rating Scale for Depression scores, with final scores 10 sustained for 1 week.

In the first 253 CORE patients treated with ECT, depression remitted in 75% and did not remit in 11%; 14% dropped out. Psychotic depression was identified in 30% (77 of 253), and the remission rate among these patients was 83%.

Among patients who completed the full ECT course (at least 12 sessions), remission rates were 96% for psychotic depression and 83% for nonpsychotic depression. The overall remission rate was 87%.

Treatments were given three times per week. Among patients who completed treatment in weeks 1 through 4, remission rates were 5%, 45%, 81%, and 100%, respectively. Psychotic depression remitted more rapidly than nonpsychotic depression.

Suicide risk. CORE findings suggest that ECT also may reduce suicide risk. In item 3 of the Hamilton Rating Scale for Depression, scores of 2 to 4 indicate preoccupation with death or suicide, or a recent suicide attempt. Nearly 60% of 404 patients (237) reported baseline scores of 2 to 4, but their scores dropped rapidly with ECT. Scores of 0 were reported in 68% after 1 week of ECT, in 87% after 2 weeks, and in 93% after 3 weeks.¹⁰

Summary. In patients with severe depressive illness, CORE’s remission rates of 95% for psychotic depression and 83% for nonpsychotic depression are remarkable. Another group is independently reporting a 92% remission rate for psychotic depression treated with ECT.¹¹

Box

ROADBLOCKS TO WIDER USE OF ECT

Many eligible patients never receive ECT, despite its track record of producing high remission rates in psychotic depression. Reasons include:

Limited access. Few psychiatrists—less than 8%—offer ECT as a treatment option, and most who do offer it practice in private hospitals.^12-14

Academic low regard. Psychiatry’s academic lecturers largely ignore ECT’s efficacy in psychotic depression and therapy-resistant depression. This low regard for ECT is codified in expert algorithms, which cite ECT as an option of last resort.

Social stigma. In a recent essay summarizing medication’s weak effect in treating psychotic depression, Schatzberg states, “While ECT is a remarkably effective treatment for psychotic depression, requirements for its use are stringent, and public perception about the overall appropriateness of shock treatment is negative.”⁸

Algorithm Treatment of major depression, with or without psychotic features

ALGORITHM FOR MAJOR DEPRESSION

Because patients with psychotic and nonpsychotic major depression clearly require different treatments, differentiating between these two types is critical. Although psychotic depression can be difficult to diagnose,^15,16 commonly recognized criteria are listed in the Table

Assessment. Assess each severely depressed patient for psychotic features, such as delusions and hallucinations. A useful assessment guide is the Brief Psychiatric Rating Scale (Box).¹⁷ Also treat those with melancholia, inanition, severe weight loss and insomnia, concentration and memory difficulty, stupor, or suicidal ideation as if they had psychotic depression. These symptoms and signs are evidence that the patient’s neuroendocrine system is disturbed, an indication of severe depression that responds poorly to antidepressant drugs alone.

Treatment. Nonpsychotic depressed patients are best offered antidepressants—tricyclics or selective serotonin reuptake inhibitors (SSRIs)—as recommended by conventional guidelines. Insufficient response to two adequate trials calls for a careful assessment for psychosis and, if found, treatment with effective drug combinations or ECT (Algorithm).¹⁸ For patients with psychotic depression—especially those who fail medication trials or whose severe symptoms would likely respond to ECT as a primary treatment—bilateral ECT is the effective standard.¹⁹

ECT is the appropriate first option for hospitalized patients with psychotic depression—especially those who are suicidal or require supplementary feeding and sedation. It may also be considered the first option in patients who have:

• attempted suicide
• lost more than 10% of body weight (approximately 15 lbs for adults) in the weeks of their illness
• or show signs of severe melancholia, such as catatonia or pseudodementia.

TREATING NONPSYCHOTIC DEPRESSION

When medications are first-line treatment for nonpsychotic depression, how long should a trial be continued before taking another tack? How many courses should you try before you declare therapy resistance and consider ECT?

Studies of clozapine provide a useful model.²⁰ Because of clozapine’s association with agranulocytosis and induced seizures, patients with schizophrenia usually do not receive this antipsychotic unless two 4- to 6-week trials of other neuroleptics have proven ineffective. Ethicists have deemed two failed medication trials to be sufficient before a more hazardous treatment is offered.

Figure Remission of major depression with ECT

• an SSRI at dosages equivalent to fluoxetine, 40 mg/d
• a tricyclic at 200 mg/d.

In depressed patients with bipolar disorder, a trial of lithium or an anticonvulsant may replace an antidepressant.

ECT is appropriate when debilitating depression persists after two adequate medication trials. Only after an adequate ECT trial has failed—and such failure is infrequent—is it reasonable to offer poorly tested augmentation and combination strategies.

What is ‘adequate’ ECT? For patients with major depression, the definition of an adequate ECT trial is complex. Although many doctors expect six ECT sessions to be sufficient, the CORE studies are finding that only 45% of patients remitted with six ECT, 81% with nine ECT, and almost all with 12 ECT sessions (Figure).⁹ These patients were treated with bitemporal electrode placement, the more effective form of ECT. When unilateral electrode placements are used, ECT courses may be inadequate, as this form requires special attention to electrical dosing.

Further, the quality of the seizure—like the dosing of medications—directly influences outcome. Seizure monitoring is essential for assessing the adequacy of each treatment and the treatment course.^21,22

Related resources

• Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus non-psychotic depressed patients: a report from CORE. J ECT 2001;17:244-53.

Drug brand names

• Amitriptyline • Elavil
• Clozapine • Clozaril
• Imipramine • Tofranil
• Nortriptyline • Pamelor
• Perphenazine • Trilafon

Disclosure

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

Acknowledgment

Preparation of this manuscript was aided by grants from the Scion Natural Science Association, Inc., St. James, NY.

Patients with what’s called “therapy-resistant” depression (TRD)—with subtherapeutic response to medications and psychotherapy—are often actually suffering from unrecognized, inadequately treated psychotic depression. Psychiatrists could greatly diminish the clinical challenge of TRD by recognizing psychotic depression and treating it more effectively.¹ And the most effective treatment for psychotic depression is neither antidepressants nor antipsychotic drugs but electroconvulsive therapy (ECT).

Despite ECT’s superior efficacy in TRD, however, algorithms for treating major depression relegate ECT to an option of last resort. By not considering ECT sooner, we consign many severely depressed patients to less-effective treatments and the risk of chronic illness.

Table

Diagnostic signs of psychosis in patients with major depression

It is time for a more realistic algorithm that recommends ECT earlier for major depressive episodes, with or without psychotic features. This article proposes such an algorithm and discusses the supporting evidence.

TREATING PSYCHOTIC DEPRESSION

Patients with delusions or hallucinations were classified as suffering from schizophrenia until the mid-1970s. Researchers then found that depressed patients with psychotic features responded well to ECT but poorly to adequate serum levels of imipramine.²

These observations were confirmed by a large Italian study, in which 437 depressed patients were treated with high-dose imipramine (200 to 350 mg/d). Depression remitted in 244 patients (56%). Those who remained depressed were then treated with ECT, and depression remitted in 136 of 190 (72%). Psychosis was the marker of poor response to imipramine.³ DSM-III codified these findings by separating the syndrome of “major depression with psychosis” (296.34) from “major depression without psychosis” (296.33).

As psychiatry recognized psychotic depression as a distinct form of depression, it became clear that drugs often could not adequately treat it. Less than one-third of patients with psychotic depression respond to tricyclics alone.^4-6

Response to antipsychotic monotherapy averaged 50% and increased to 75% with combined antipsychotics and antidepressants. However, high daily dosages —at least 32 mg of perphenazine and 225 mg of amitriptyline—were required for an adequate response,⁷ and side effects made sustaining such heroic dosing was difficult. The greatest improvement rates were seen with ECT.

Few other drug combinations have been reported to be effective in psychotic depression, but we lack proper studies. Schatzberg⁸ addressed the use of newer antidepressants and atypical antipsychotics without offering an algorithm based on the data. Evidence on combination therapies consists mainly of case reports, with few designed studies.

EFFICACY OF ECT

ECT is the most effective treatment for psychotic major depression—achieving remission rates >80% within 3 weeks—as demonstrated by the ongoing, four-hospital Consortium for Research in ECT (CORE), supported by the National Institute of Mental Health.

CORE researchers are studying the efficacy of bilateral ECT in treating severe unipolar depression in patients ages 18 to 85 and of continuation treatments with ECT or lithium plus nortriptyline.⁹ Under the CORE protocol, diagnoses are made by structured clinical interview using DSM-III-R criteria, and remission is defined as >60% reduction in Hamilton Rating Scale for Depression scores, with final scores 10 sustained for 1 week.

In the first 253 CORE patients treated with ECT, depression remitted in 75% and did not remit in 11%; 14% dropped out. Psychotic depression was identified in 30% (77 of 253), and the remission rate among these patients was 83%.

Among patients who completed the full ECT course (at least 12 sessions), remission rates were 96% for psychotic depression and 83% for nonpsychotic depression. The overall remission rate was 87%.

Treatments were given three times per week. Among patients who completed treatment in weeks 1 through 4, remission rates were 5%, 45%, 81%, and 100%, respectively. Psychotic depression remitted more rapidly than nonpsychotic depression.

Suicide risk. CORE findings suggest that ECT also may reduce suicide risk. In item 3 of the Hamilton Rating Scale for Depression, scores of 2 to 4 indicate preoccupation with death or suicide, or a recent suicide attempt. Nearly 60% of 404 patients (237) reported baseline scores of 2 to 4, but their scores dropped rapidly with ECT. Scores of 0 were reported in 68% after 1 week of ECT, in 87% after 2 weeks, and in 93% after 3 weeks.¹⁰

Summary. In patients with severe depressive illness, CORE’s remission rates of 95% for psychotic depression and 83% for nonpsychotic depression are remarkable. Another group is independently reporting a 92% remission rate for psychotic depression treated with ECT.¹¹

Box

ROADBLOCKS TO WIDER USE OF ECT

Many eligible patients never receive ECT, despite its track record of producing high remission rates in psychotic depression. Reasons include:

Limited access. Few psychiatrists—less than 8%—offer ECT as a treatment option, and most who do offer it practice in private hospitals.^12-14

Academic low regard. Psychiatry’s academic lecturers largely ignore ECT’s efficacy in psychotic depression and therapy-resistant depression. This low regard for ECT is codified in expert algorithms, which cite ECT as an option of last resort.

Social stigma. In a recent essay summarizing medication’s weak effect in treating psychotic depression, Schatzberg states, “While ECT is a remarkably effective treatment for psychotic depression, requirements for its use are stringent, and public perception about the overall appropriateness of shock treatment is negative.”⁸

Algorithm Treatment of major depression, with or without psychotic features

ALGORITHM FOR MAJOR DEPRESSION

Because patients with psychotic and nonpsychotic major depression clearly require different treatments, differentiating between these two types is critical. Although psychotic depression can be difficult to diagnose,^15,16 commonly recognized criteria are listed in the Table

Assessment. Assess each severely depressed patient for psychotic features, such as delusions and hallucinations. A useful assessment guide is the Brief Psychiatric Rating Scale (Box).¹⁷ Also treat those with melancholia, inanition, severe weight loss and insomnia, concentration and memory difficulty, stupor, or suicidal ideation as if they had psychotic depression. These symptoms and signs are evidence that the patient’s neuroendocrine system is disturbed, an indication of severe depression that responds poorly to antidepressant drugs alone.

Treatment. Nonpsychotic depressed patients are best offered antidepressants—tricyclics or selective serotonin reuptake inhibitors (SSRIs)—as recommended by conventional guidelines. Insufficient response to two adequate trials calls for a careful assessment for psychosis and, if found, treatment with effective drug combinations or ECT (Algorithm).¹⁸ For patients with psychotic depression—especially those who fail medication trials or whose severe symptoms would likely respond to ECT as a primary treatment—bilateral ECT is the effective standard.¹⁹

ECT is the appropriate first option for hospitalized patients with psychotic depression—especially those who are suicidal or require supplementary feeding and sedation. It may also be considered the first option in patients who have:

• attempted suicide
• lost more than 10% of body weight (approximately 15 lbs for adults) in the weeks of their illness
• or show signs of severe melancholia, such as catatonia or pseudodementia.

TREATING NONPSYCHOTIC DEPRESSION

When medications are first-line treatment for nonpsychotic depression, how long should a trial be continued before taking another tack? How many courses should you try before you declare therapy resistance and consider ECT?

Studies of clozapine provide a useful model.²⁰ Because of clozapine’s association with agranulocytosis and induced seizures, patients with schizophrenia usually do not receive this antipsychotic unless two 4- to 6-week trials of other neuroleptics have proven ineffective. Ethicists have deemed two failed medication trials to be sufficient before a more hazardous treatment is offered.

Figure Remission of major depression with ECT

• an SSRI at dosages equivalent to fluoxetine, 40 mg/d
• a tricyclic at 200 mg/d.

In depressed patients with bipolar disorder, a trial of lithium or an anticonvulsant may replace an antidepressant.

ECT is appropriate when debilitating depression persists after two adequate medication trials. Only after an adequate ECT trial has failed—and such failure is infrequent—is it reasonable to offer poorly tested augmentation and combination strategies.

What is ‘adequate’ ECT? For patients with major depression, the definition of an adequate ECT trial is complex. Although many doctors expect six ECT sessions to be sufficient, the CORE studies are finding that only 45% of patients remitted with six ECT, 81% with nine ECT, and almost all with 12 ECT sessions (Figure).⁹ These patients were treated with bitemporal electrode placement, the more effective form of ECT. When unilateral electrode placements are used, ECT courses may be inadequate, as this form requires special attention to electrical dosing.

Further, the quality of the seizure—like the dosing of medications—directly influences outcome. Seizure monitoring is essential for assessing the adequacy of each treatment and the treatment course.^21,22

Related resources

• Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus non-psychotic depressed patients: a report from CORE. J ECT 2001;17:244-53.

Drug brand names

• Amitriptyline • Elavil
• Clozapine • Clozaril
• Imipramine • Tofranil
• Nortriptyline • Pamelor
• Perphenazine • Trilafon

Disclosure

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

Acknowledgment

Preparation of this manuscript was aided by grants from the Scion Natural Science Association, Inc., St. James, NY.

Patients with what’s called “therapy-resistant” depression (TRD)—with subtherapeutic response to medications and psychotherapy—are often actually suffering from unrecognized, inadequately treated psychotic depression. Psychiatrists could greatly diminish the clinical challenge of TRD by recognizing psychotic depression and treating it more effectively.¹ And the most effective treatment for psychotic depression is neither antidepressants nor antipsychotic drugs but electroconvulsive therapy (ECT).

Despite ECT’s superior efficacy in TRD, however, algorithms for treating major depression relegate ECT to an option of last resort. By not considering ECT sooner, we consign many severely depressed patients to less-effective treatments and the risk of chronic illness.

Table

Diagnostic signs of psychosis in patients with major depression

It is time for a more realistic algorithm that recommends ECT earlier for major depressive episodes, with or without psychotic features. This article proposes such an algorithm and discusses the supporting evidence.

TREATING PSYCHOTIC DEPRESSION

Patients with delusions or hallucinations were classified as suffering from schizophrenia until the mid-1970s. Researchers then found that depressed patients with psychotic features responded well to ECT but poorly to adequate serum levels of imipramine.²

These observations were confirmed by a large Italian study, in which 437 depressed patients were treated with high-dose imipramine (200 to 350 mg/d). Depression remitted in 244 patients (56%). Those who remained depressed were then treated with ECT, and depression remitted in 136 of 190 (72%). Psychosis was the marker of poor response to imipramine.³ DSM-III codified these findings by separating the syndrome of “major depression with psychosis” (296.34) from “major depression without psychosis” (296.33).

As psychiatry recognized psychotic depression as a distinct form of depression, it became clear that drugs often could not adequately treat it. Less than one-third of patients with psychotic depression respond to tricyclics alone.^4-6

Response to antipsychotic monotherapy averaged 50% and increased to 75% with combined antipsychotics and antidepressants. However, high daily dosages —at least 32 mg of perphenazine and 225 mg of amitriptyline—were required for an adequate response,⁷ and side effects made sustaining such heroic dosing was difficult. The greatest improvement rates were seen with ECT.

Few other drug combinations have been reported to be effective in psychotic depression, but we lack proper studies. Schatzberg⁸ addressed the use of newer antidepressants and atypical antipsychotics without offering an algorithm based on the data. Evidence on combination therapies consists mainly of case reports, with few designed studies.

EFFICACY OF ECT

ECT is the most effective treatment for psychotic major depression—achieving remission rates >80% within 3 weeks—as demonstrated by the ongoing, four-hospital Consortium for Research in ECT (CORE), supported by the National Institute of Mental Health.

CORE researchers are studying the efficacy of bilateral ECT in treating severe unipolar depression in patients ages 18 to 85 and of continuation treatments with ECT or lithium plus nortriptyline.⁹ Under the CORE protocol, diagnoses are made by structured clinical interview using DSM-III-R criteria, and remission is defined as >60% reduction in Hamilton Rating Scale for Depression scores, with final scores 10 sustained for 1 week.

In the first 253 CORE patients treated with ECT, depression remitted in 75% and did not remit in 11%; 14% dropped out. Psychotic depression was identified in 30% (77 of 253), and the remission rate among these patients was 83%.

Among patients who completed the full ECT course (at least 12 sessions), remission rates were 96% for psychotic depression and 83% for nonpsychotic depression. The overall remission rate was 87%.

Treatments were given three times per week. Among patients who completed treatment in weeks 1 through 4, remission rates were 5%, 45%, 81%, and 100%, respectively. Psychotic depression remitted more rapidly than nonpsychotic depression.

Suicide risk. CORE findings suggest that ECT also may reduce suicide risk. In item 3 of the Hamilton Rating Scale for Depression, scores of 2 to 4 indicate preoccupation with death or suicide, or a recent suicide attempt. Nearly 60% of 404 patients (237) reported baseline scores of 2 to 4, but their scores dropped rapidly with ECT. Scores of 0 were reported in 68% after 1 week of ECT, in 87% after 2 weeks, and in 93% after 3 weeks.¹⁰

Summary. In patients with severe depressive illness, CORE’s remission rates of 95% for psychotic depression and 83% for nonpsychotic depression are remarkable. Another group is independently reporting a 92% remission rate for psychotic depression treated with ECT.¹¹

Box

ROADBLOCKS TO WIDER USE OF ECT

Many eligible patients never receive ECT, despite its track record of producing high remission rates in psychotic depression. Reasons include:

Limited access. Few psychiatrists—less than 8%—offer ECT as a treatment option, and most who do offer it practice in private hospitals.^12-14

Academic low regard. Psychiatry’s academic lecturers largely ignore ECT’s efficacy in psychotic depression and therapy-resistant depression. This low regard for ECT is codified in expert algorithms, which cite ECT as an option of last resort.

Social stigma. In a recent essay summarizing medication’s weak effect in treating psychotic depression, Schatzberg states, “While ECT is a remarkably effective treatment for psychotic depression, requirements for its use are stringent, and public perception about the overall appropriateness of shock treatment is negative.”⁸

Algorithm Treatment of major depression, with or without psychotic features

ALGORITHM FOR MAJOR DEPRESSION

Because patients with psychotic and nonpsychotic major depression clearly require different treatments, differentiating between these two types is critical. Although psychotic depression can be difficult to diagnose,^15,16 commonly recognized criteria are listed in the Table

Assessment. Assess each severely depressed patient for psychotic features, such as delusions and hallucinations. A useful assessment guide is the Brief Psychiatric Rating Scale (Box).¹⁷ Also treat those with melancholia, inanition, severe weight loss and insomnia, concentration and memory difficulty, stupor, or suicidal ideation as if they had psychotic depression. These symptoms and signs are evidence that the patient’s neuroendocrine system is disturbed, an indication of severe depression that responds poorly to antidepressant drugs alone.

Treatment. Nonpsychotic depressed patients are best offered antidepressants—tricyclics or selective serotonin reuptake inhibitors (SSRIs)—as recommended by conventional guidelines. Insufficient response to two adequate trials calls for a careful assessment for psychosis and, if found, treatment with effective drug combinations or ECT (Algorithm).¹⁸ For patients with psychotic depression—especially those who fail medication trials or whose severe symptoms would likely respond to ECT as a primary treatment—bilateral ECT is the effective standard.¹⁹

ECT is the appropriate first option for hospitalized patients with psychotic depression—especially those who are suicidal or require supplementary feeding and sedation. It may also be considered the first option in patients who have:

• attempted suicide
• lost more than 10% of body weight (approximately 15 lbs for adults) in the weeks of their illness
• or show signs of severe melancholia, such as catatonia or pseudodementia.

TREATING NONPSYCHOTIC DEPRESSION

When medications are first-line treatment for nonpsychotic depression, how long should a trial be continued before taking another tack? How many courses should you try before you declare therapy resistance and consider ECT?

Studies of clozapine provide a useful model.²⁰ Because of clozapine’s association with agranulocytosis and induced seizures, patients with schizophrenia usually do not receive this antipsychotic unless two 4- to 6-week trials of other neuroleptics have proven ineffective. Ethicists have deemed two failed medication trials to be sufficient before a more hazardous treatment is offered.

Figure Remission of major depression with ECT

• an SSRI at dosages equivalent to fluoxetine, 40 mg/d
• a tricyclic at 200 mg/d.

In depressed patients with bipolar disorder, a trial of lithium or an anticonvulsant may replace an antidepressant.

ECT is appropriate when debilitating depression persists after two adequate medication trials. Only after an adequate ECT trial has failed—and such failure is infrequent—is it reasonable to offer poorly tested augmentation and combination strategies.

What is ‘adequate’ ECT? For patients with major depression, the definition of an adequate ECT trial is complex. Although many doctors expect six ECT sessions to be sufficient, the CORE studies are finding that only 45% of patients remitted with six ECT, 81% with nine ECT, and almost all with 12 ECT sessions (Figure).⁹ These patients were treated with bitemporal electrode placement, the more effective form of ECT. When unilateral electrode placements are used, ECT courses may be inadequate, as this form requires special attention to electrical dosing.

Further, the quality of the seizure—like the dosing of medications—directly influences outcome. Seizure monitoring is essential for assessing the adequacy of each treatment and the treatment course.^21,22

Related resources

• Petrides G, Fink M, Husain MM, et al. ECT remission rates in psychotic versus non-psychotic depressed patients: a report from CORE. J ECT 2001;17:244-53.

Drug brand names

• Amitriptyline • Elavil
• Clozapine • Clozaril
• Imipramine • Tofranil
• Nortriptyline • Pamelor
• Perphenazine • Trilafon

Disclosure

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

Acknowledgment

Preparation of this manuscript was aided by grants from the Scion Natural Science Association, Inc., St. James, NY.

HISTORY: Jesus’ ‘cousin’

Mr. F, age 60, was hospitalized in May 1995 after expressing fear he would hurt—or kill—himself or someone else. He cooperated with admission procedures but refused to participate in ward activities or meetings. His hygiene was poor, he made little eye contact, and reportedly heard voices. Two days after admission, he emphatically denied suicidal or homicidal ideation and was discharged against medical advice.

Two weeks later, Mr. F was readmitted after his symptoms worsened. He said voices told him that he was a cousin to Jesus Christ and that he had telepathic abilities. He also reported visual hallucinations.

Twice divorced, Mr. F has three uncles who have been diagnosed with schizophrenia. His late father had a history of alcohol abuse, and his late mother suffered from Alzheimer’s disease.

Mr. F lived a normal life until 1975, when he began drinking heavily. Three years later, he quit his job of 11 years at the local airport. At that time, he told a psychiatrist that “people are out to get me. I feel nervous a lot.” He was diagnosed as having generalized anxiety disorder and treated with diazepam, 20 mg/d.

Four months later he complained of severe insomnia, was diagnosed with depression, and was prescribed amitriptyline, 100 mg at bedtime. He was hospitalized 1 week later after he complained of chest pain and expressed paranoid thoughts. During the 3-week hospitalization, he experienced persecutory delusions and heard voices telling him he was “damned.” He was diagnosed with paranoid schizophrenia and alcohol dependence. The amitriptyline was stopped, and Mr. F was discharged on chlorpromazine, 300 mg/d.

From 1978 to 1995, Mr. F was hospitalized 35 times, often at his family’s urging after he made threats or became violent at home. He once kicked his elderly father and another time was jailed after a domestic violence incident. Religious delusions characterized his thought content. Thought blocking, flight of ideas, and somatic and sexual delusions were also apparent.

Was Mr. F’s diagnosis accurate, or do his frequent psychotic episodes meet criteria for a type of mania?

Dr. Canive’s observations

Diagnoses of mania or mood disorder with psychotic features were not considered because Mr. F never experienced a distinct period of persistently expansive or depressed mood.

Mr. F’s initial complaints of increased anxiety and depression were considered prodromal symptoms of schizophrenia and may have reflected his inability to discuss or cope with his delusions and hallucinations during the initial evaluation. What’s more, his occupational functioning gradually deteriorated months before his initial mental health assessment.

TREATMENT: Many medications, no progress

At different times from 1978 to 1995, Mr. F had taken chlorpromazine, 100 to 300 mg/d; thioridazine, 50 to 200 mg/d; loxapine, 25 mg/d; fluphenazine, 5 to 10 mg/d; haloperidol, 2 to 4 mg/d, and fluphenazine decanoate, 3.125 to 6.25 mg biweekly, as well as concomitant anticholinergics, benzodiazepines, or other hypnotics.

A closer look at Mr. F’s chart revealed that medication noncompliance often preceded hospitalization. He was extremely prone to antipsychotic-related extrapyramidal symptoms (EPS), even at low dosages. Whenever motor symptoms surfaced, he would stop taking his antipsychotics.

Buccolingual tardive dyskinesia (TD) was first noticed in 1987. Four years later, an Abnormal Involuntary Movement Scale (AIMS) exam revealed mild TD that was managed with vitamin E, 400 IU/d.

While hospitalized, Mr. F many times received injectable antipsychotics and benzodiazepines, mostly to control violence. Depot antipsychotics also were tried in an effort to promote compliance, but recurrent alcohol abuse often triggered a relapse.

How would you confront Mr. F’s history of noncompliance? Can his delusions be controlled without prompting severe motor effects?

Dr. Canive’s observations

For Mr. F, poor tolerability, incomplete efficacy, and variable compliance have repeatedly led to symptom exacerbation and hospitalization. Low dosing because of sensitivity to EPS may partially explain his insufficient response to antipsychotics.

In 1995, after numerous unsuccessful drug treatments, we considered entering Mr. F into a phase II clinical trial of the atypical antipsychotic aripiprazole.

Now FDA-approved for treatment of schizophrenia, aripiprazole decreases dopaminergic transmission in the nigrostriatal and tuberoinfundibular pathways, thus reducing the likelihood of EPS.^1,2 Also, aripiprazole’s dopamine-serotonin stabilization effects have been reported in clinical trials to improve tolerability, compliance, and overall effectiveness in patients with schizophrenia.³

Common side effects of aripiprazole are mild nausea, insomnia, and restlessness, although data indicate that these effects have a low prevalence and disappear within 2 weeks. If insomnia and restlessness are prominent, a low-dose, short-acting benzodiazepine may be added, tapered after 1 week, and discontinued at week 2.

Table

Mr. F’s progress while taking aripiprazole, 1995-2003

What the scores mean

Clinical Global Impression-Severity of Illness (CGI-S)—Scores range from 1 to 7, with 1 meaning normal (normal, minimal, mild, moderate, moderately severe, severe, among the most extreme).

Clinical Global Impression-Global Improvement (CGI-G)—Scores range from 1 to 7, with 1 meaning very much improved (very much improved, much improved, improved, unchanged, little worse, much worse, very much worse).

Positive and Negative Syndrome Scale (PANSS) Positive—consists of 7 items (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, hostility); scores range from 7 to 49 and decrease as patients improve.

PANSS Negative—consists of 7 items (blunted affect, emotional withdrawal, poor rapport, passive pathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking); scores range from 7 to 49 and decrease as patients improve.

PANSS General—consists of 16 items (somatic concern, anxiety, guilt feelings, tension, mannerism and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, active social avoidance). Scores range from 16 to 112 and decrease as patients improve.

CONTINUED TREATMENT: A new trial

Mr. F participated in a 4-week, double-blind, placebo-controlled trial of aripiprazole, 2, 10, or 30 mg/d, versus haloperidol, 10 mg/d.

One month later, he entered a second aripiprazole trial: a 4-day, open-label study starting at 5 mg/d with titration to 20 mg/d. In the interval between the two trials, Mr. F was prescribed thiothixene, 10 mg/d, and benztropine, 2 mg at bedtime.

During the 4-day trial, he complained of insomnia and was given chloral hydrate, 500 to 1,000 mg at bedtime. He also complained of anxiety and was started on lorazepam, 2 mg bid.

After completing the open-label aripiprazole trial, Mr. F exhibited no behavioral problems and complied with ward routine. He was discharged after 17 days, at which time he denied auditory or visual hallucinations. His thinking seemed clear and his insight improved. His Global Assessment of Functioning (GAF) score at discharge was 55, suggesting moderate symptoms and difficulty in social and occupational functioning.

For the next 5 1/2 years, Mr. F was maintained on aripiprazole, 20 mg/d, as part of the same ongoing open-label trial. During that period he also took lorazepam, 1 mg bid prn; oxazepam, 15 mg bid; or clonazepam, 0.5 mg bid, for anxiety.

Mr. F. exhibited significant sustained improvement as measured with the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression scale (CGI), and GAF (Table). His TD remained mild throughout the trial, as determined through AIMS scores. He also reported no EPS, akathisia, or other adverse events.

About 18 months after starting aripiprazole, Mr. F resumed working part time. In September 2001, he stopped receiving disability benefits and started supporting himself again.

FOLLOW-UP: ‘The voices were ugly’

In December 2001, after 6 years without hospitalization, Mr. F was back in the psychiatric ward. One week before admission, he reported that he had been having panic attacks because “the voices were ugly.” He only slept 4 to 5 hours per night.

He then revealed that he had stopped taking aripiprazole for 2 weeks because he had no longer felt ill. He was still taking his lorazepam, however.

Mr. F appeared mildly anxious upon presentation and his affect was blunted. On examination, his thought processes were linear; he was once again hearing voices and experiencing delusions of telepathic control.

The patient was placed back on aripiprazole, 20 mg/d. His behavior on the ward improved dramatically, and the frequency and severity of his delusions and auditory hallucinations decreased gradually.

At discharge, Mr. F’s insight was good, his delusions had disappeared, and auditory hallucinations were rare. He was instructed to continue the aripiprazole and was prescribed clonazepam, 0.5 mg bid, for his anxiety and trazodone, 50 mg at bed-time, to help his sleep.

Since then, Mr. F has lived on his own, is working steadily, and has not required hospitalization. He stopped taking trazodone soon after discharge, but continues taking aripiprazole and clonazepam as prescribed. His hygiene is good, and he is making amends with family members. He attends church every Sunday—free of the messianic delusions that once tormented him. He also stopped abusing alcohol on his own in 1995 and has remained abstinent since.

How can we ensure that patients with schizophrenia keep taking their medications—regardless of whether symptoms are present?

Dr. Canive’s observations

Clinical trials measure a drug’s efficacy under highly controlled circumstances. In the “real world,” however, noncompliance due to intolerability can undermine a medication’s effectiveness.

Too often noncompliance—stemming from abatement of symptoms or the emergence of side effects—derails treatment of schizophrenia. Misdrahi et al found that medication noncompliance accounts for 40% of schizophrenia relapses occurring more than 1 year after patients’ first hospitalization.⁴

Given aripiprazole’s 75-hour half-life, one might not expect to see symptoms emerge so soon after discontinuation. It is possible that:

• Mr. F. abstained from aripiprazole longer than he realized—or admitted
• Unidentified stressful life events also exacerbated symptoms and precipitated hospitalization.

When Mr. F consistently followed his regimen, his positive symptoms abated and he could attempt to live a normal life.

Our patients must understand that schizophrenia is a lifelong illness and that continued adherence to medication—even when symptoms do not exist—is crucial. A strong therapeutic alliance,⁵ increased social support, adjunctive cognitive-behavioral therapy, psychosocial interventions,⁶ and medications with fewer and less-severe side effects may help patients embrace this message.

Related resources

• Tamminga CA. Partial dopamine agonists in the treatment of psychosis. J Neural Transm 2002;109:411-20.

Drug brand names

• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Diazepam • Valium
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Lorazepam • Ativan
• Loxapine • Loxitane
• Oxazepam • Serax
• Thiothixene • Navane
• Trazodone • Desyrel

Disclosure

The author receives research/grant support from and is a speaker for and consultant to Bristol-Myers Squibb Co. He also receives research/grant support from and/or is a speaker for AstraZeneca Pharmaceuticals, Janssen Pharmaceutica, and Eli Lilly and Co.

HISTORY: Jesus’ ‘cousin’

Mr. F, age 60, was hospitalized in May 1995 after expressing fear he would hurt—or kill—himself or someone else. He cooperated with admission procedures but refused to participate in ward activities or meetings. His hygiene was poor, he made little eye contact, and reportedly heard voices. Two days after admission, he emphatically denied suicidal or homicidal ideation and was discharged against medical advice.

Two weeks later, Mr. F was readmitted after his symptoms worsened. He said voices told him that he was a cousin to Jesus Christ and that he had telepathic abilities. He also reported visual hallucinations.

Twice divorced, Mr. F has three uncles who have been diagnosed with schizophrenia. His late father had a history of alcohol abuse, and his late mother suffered from Alzheimer’s disease.

Mr. F lived a normal life until 1975, when he began drinking heavily. Three years later, he quit his job of 11 years at the local airport. At that time, he told a psychiatrist that “people are out to get me. I feel nervous a lot.” He was diagnosed as having generalized anxiety disorder and treated with diazepam, 20 mg/d.

Four months later he complained of severe insomnia, was diagnosed with depression, and was prescribed amitriptyline, 100 mg at bedtime. He was hospitalized 1 week later after he complained of chest pain and expressed paranoid thoughts. During the 3-week hospitalization, he experienced persecutory delusions and heard voices telling him he was “damned.” He was diagnosed with paranoid schizophrenia and alcohol dependence. The amitriptyline was stopped, and Mr. F was discharged on chlorpromazine, 300 mg/d.

From 1978 to 1995, Mr. F was hospitalized 35 times, often at his family’s urging after he made threats or became violent at home. He once kicked his elderly father and another time was jailed after a domestic violence incident. Religious delusions characterized his thought content. Thought blocking, flight of ideas, and somatic and sexual delusions were also apparent.

Was Mr. F’s diagnosis accurate, or do his frequent psychotic episodes meet criteria for a type of mania?

Dr. Canive’s observations

Diagnoses of mania or mood disorder with psychotic features were not considered because Mr. F never experienced a distinct period of persistently expansive or depressed mood.

Mr. F’s initial complaints of increased anxiety and depression were considered prodromal symptoms of schizophrenia and may have reflected his inability to discuss or cope with his delusions and hallucinations during the initial evaluation. What’s more, his occupational functioning gradually deteriorated months before his initial mental health assessment.

TREATMENT: Many medications, no progress

At different times from 1978 to 1995, Mr. F had taken chlorpromazine, 100 to 300 mg/d; thioridazine, 50 to 200 mg/d; loxapine, 25 mg/d; fluphenazine, 5 to 10 mg/d; haloperidol, 2 to 4 mg/d, and fluphenazine decanoate, 3.125 to 6.25 mg biweekly, as well as concomitant anticholinergics, benzodiazepines, or other hypnotics.

A closer look at Mr. F’s chart revealed that medication noncompliance often preceded hospitalization. He was extremely prone to antipsychotic-related extrapyramidal symptoms (EPS), even at low dosages. Whenever motor symptoms surfaced, he would stop taking his antipsychotics.

Buccolingual tardive dyskinesia (TD) was first noticed in 1987. Four years later, an Abnormal Involuntary Movement Scale (AIMS) exam revealed mild TD that was managed with vitamin E, 400 IU/d.

While hospitalized, Mr. F many times received injectable antipsychotics and benzodiazepines, mostly to control violence. Depot antipsychotics also were tried in an effort to promote compliance, but recurrent alcohol abuse often triggered a relapse.

How would you confront Mr. F’s history of noncompliance? Can his delusions be controlled without prompting severe motor effects?

Dr. Canive’s observations

For Mr. F, poor tolerability, incomplete efficacy, and variable compliance have repeatedly led to symptom exacerbation and hospitalization. Low dosing because of sensitivity to EPS may partially explain his insufficient response to antipsychotics.

In 1995, after numerous unsuccessful drug treatments, we considered entering Mr. F into a phase II clinical trial of the atypical antipsychotic aripiprazole.

Now FDA-approved for treatment of schizophrenia, aripiprazole decreases dopaminergic transmission in the nigrostriatal and tuberoinfundibular pathways, thus reducing the likelihood of EPS.^1,2 Also, aripiprazole’s dopamine-serotonin stabilization effects have been reported in clinical trials to improve tolerability, compliance, and overall effectiveness in patients with schizophrenia.³

Common side effects of aripiprazole are mild nausea, insomnia, and restlessness, although data indicate that these effects have a low prevalence and disappear within 2 weeks. If insomnia and restlessness are prominent, a low-dose, short-acting benzodiazepine may be added, tapered after 1 week, and discontinued at week 2.

Table

Mr. F’s progress while taking aripiprazole, 1995-2003

What the scores mean

Clinical Global Impression-Severity of Illness (CGI-S)—Scores range from 1 to 7, with 1 meaning normal (normal, minimal, mild, moderate, moderately severe, severe, among the most extreme).

Clinical Global Impression-Global Improvement (CGI-G)—Scores range from 1 to 7, with 1 meaning very much improved (very much improved, much improved, improved, unchanged, little worse, much worse, very much worse).

Positive and Negative Syndrome Scale (PANSS) Positive—consists of 7 items (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, hostility); scores range from 7 to 49 and decrease as patients improve.

PANSS Negative—consists of 7 items (blunted affect, emotional withdrawal, poor rapport, passive pathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking); scores range from 7 to 49 and decrease as patients improve.

PANSS General—consists of 16 items (somatic concern, anxiety, guilt feelings, tension, mannerism and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, active social avoidance). Scores range from 16 to 112 and decrease as patients improve.

CONTINUED TREATMENT: A new trial

Mr. F participated in a 4-week, double-blind, placebo-controlled trial of aripiprazole, 2, 10, or 30 mg/d, versus haloperidol, 10 mg/d.

One month later, he entered a second aripiprazole trial: a 4-day, open-label study starting at 5 mg/d with titration to 20 mg/d. In the interval between the two trials, Mr. F was prescribed thiothixene, 10 mg/d, and benztropine, 2 mg at bedtime.

During the 4-day trial, he complained of insomnia and was given chloral hydrate, 500 to 1,000 mg at bedtime. He also complained of anxiety and was started on lorazepam, 2 mg bid.

After completing the open-label aripiprazole trial, Mr. F exhibited no behavioral problems and complied with ward routine. He was discharged after 17 days, at which time he denied auditory or visual hallucinations. His thinking seemed clear and his insight improved. His Global Assessment of Functioning (GAF) score at discharge was 55, suggesting moderate symptoms and difficulty in social and occupational functioning.

For the next 5 1/2 years, Mr. F was maintained on aripiprazole, 20 mg/d, as part of the same ongoing open-label trial. During that period he also took lorazepam, 1 mg bid prn; oxazepam, 15 mg bid; or clonazepam, 0.5 mg bid, for anxiety.

Mr. F. exhibited significant sustained improvement as measured with the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression scale (CGI), and GAF (Table). His TD remained mild throughout the trial, as determined through AIMS scores. He also reported no EPS, akathisia, or other adverse events.

About 18 months after starting aripiprazole, Mr. F resumed working part time. In September 2001, he stopped receiving disability benefits and started supporting himself again.

FOLLOW-UP: ‘The voices were ugly’

In December 2001, after 6 years without hospitalization, Mr. F was back in the psychiatric ward. One week before admission, he reported that he had been having panic attacks because “the voices were ugly.” He only slept 4 to 5 hours per night.

He then revealed that he had stopped taking aripiprazole for 2 weeks because he had no longer felt ill. He was still taking his lorazepam, however.

Mr. F appeared mildly anxious upon presentation and his affect was blunted. On examination, his thought processes were linear; he was once again hearing voices and experiencing delusions of telepathic control.

The patient was placed back on aripiprazole, 20 mg/d. His behavior on the ward improved dramatically, and the frequency and severity of his delusions and auditory hallucinations decreased gradually.

At discharge, Mr. F’s insight was good, his delusions had disappeared, and auditory hallucinations were rare. He was instructed to continue the aripiprazole and was prescribed clonazepam, 0.5 mg bid, for his anxiety and trazodone, 50 mg at bed-time, to help his sleep.

Since then, Mr. F has lived on his own, is working steadily, and has not required hospitalization. He stopped taking trazodone soon after discharge, but continues taking aripiprazole and clonazepam as prescribed. His hygiene is good, and he is making amends with family members. He attends church every Sunday—free of the messianic delusions that once tormented him. He also stopped abusing alcohol on his own in 1995 and has remained abstinent since.

How can we ensure that patients with schizophrenia keep taking their medications—regardless of whether symptoms are present?

Dr. Canive’s observations

Clinical trials measure a drug’s efficacy under highly controlled circumstances. In the “real world,” however, noncompliance due to intolerability can undermine a medication’s effectiveness.

Too often noncompliance—stemming from abatement of symptoms or the emergence of side effects—derails treatment of schizophrenia. Misdrahi et al found that medication noncompliance accounts for 40% of schizophrenia relapses occurring more than 1 year after patients’ first hospitalization.⁴

Given aripiprazole’s 75-hour half-life, one might not expect to see symptoms emerge so soon after discontinuation. It is possible that:

• Mr. F. abstained from aripiprazole longer than he realized—or admitted
• Unidentified stressful life events also exacerbated symptoms and precipitated hospitalization.

When Mr. F consistently followed his regimen, his positive symptoms abated and he could attempt to live a normal life.

Our patients must understand that schizophrenia is a lifelong illness and that continued adherence to medication—even when symptoms do not exist—is crucial. A strong therapeutic alliance,⁵ increased social support, adjunctive cognitive-behavioral therapy, psychosocial interventions,⁶ and medications with fewer and less-severe side effects may help patients embrace this message.

Related resources

• Tamminga CA. Partial dopamine agonists in the treatment of psychosis. J Neural Transm 2002;109:411-20.

Drug brand names

• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Diazepam • Valium
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Lorazepam • Ativan
• Loxapine • Loxitane
• Oxazepam • Serax
• Thiothixene • Navane
• Trazodone • Desyrel

Disclosure

The author receives research/grant support from and is a speaker for and consultant to Bristol-Myers Squibb Co. He also receives research/grant support from and/or is a speaker for AstraZeneca Pharmaceuticals, Janssen Pharmaceutica, and Eli Lilly and Co.

HISTORY: Jesus’ ‘cousin’

Mr. F, age 60, was hospitalized in May 1995 after expressing fear he would hurt—or kill—himself or someone else. He cooperated with admission procedures but refused to participate in ward activities or meetings. His hygiene was poor, he made little eye contact, and reportedly heard voices. Two days after admission, he emphatically denied suicidal or homicidal ideation and was discharged against medical advice.

Two weeks later, Mr. F was readmitted after his symptoms worsened. He said voices told him that he was a cousin to Jesus Christ and that he had telepathic abilities. He also reported visual hallucinations.

Twice divorced, Mr. F has three uncles who have been diagnosed with schizophrenia. His late father had a history of alcohol abuse, and his late mother suffered from Alzheimer’s disease.

Mr. F lived a normal life until 1975, when he began drinking heavily. Three years later, he quit his job of 11 years at the local airport. At that time, he told a psychiatrist that “people are out to get me. I feel nervous a lot.” He was diagnosed as having generalized anxiety disorder and treated with diazepam, 20 mg/d.

Four months later he complained of severe insomnia, was diagnosed with depression, and was prescribed amitriptyline, 100 mg at bedtime. He was hospitalized 1 week later after he complained of chest pain and expressed paranoid thoughts. During the 3-week hospitalization, he experienced persecutory delusions and heard voices telling him he was “damned.” He was diagnosed with paranoid schizophrenia and alcohol dependence. The amitriptyline was stopped, and Mr. F was discharged on chlorpromazine, 300 mg/d.

From 1978 to 1995, Mr. F was hospitalized 35 times, often at his family’s urging after he made threats or became violent at home. He once kicked his elderly father and another time was jailed after a domestic violence incident. Religious delusions characterized his thought content. Thought blocking, flight of ideas, and somatic and sexual delusions were also apparent.

Was Mr. F’s diagnosis accurate, or do his frequent psychotic episodes meet criteria for a type of mania?

Dr. Canive’s observations

Diagnoses of mania or mood disorder with psychotic features were not considered because Mr. F never experienced a distinct period of persistently expansive or depressed mood.

Mr. F’s initial complaints of increased anxiety and depression were considered prodromal symptoms of schizophrenia and may have reflected his inability to discuss or cope with his delusions and hallucinations during the initial evaluation. What’s more, his occupational functioning gradually deteriorated months before his initial mental health assessment.

TREATMENT: Many medications, no progress

At different times from 1978 to 1995, Mr. F had taken chlorpromazine, 100 to 300 mg/d; thioridazine, 50 to 200 mg/d; loxapine, 25 mg/d; fluphenazine, 5 to 10 mg/d; haloperidol, 2 to 4 mg/d, and fluphenazine decanoate, 3.125 to 6.25 mg biweekly, as well as concomitant anticholinergics, benzodiazepines, or other hypnotics.

A closer look at Mr. F’s chart revealed that medication noncompliance often preceded hospitalization. He was extremely prone to antipsychotic-related extrapyramidal symptoms (EPS), even at low dosages. Whenever motor symptoms surfaced, he would stop taking his antipsychotics.

Buccolingual tardive dyskinesia (TD) was first noticed in 1987. Four years later, an Abnormal Involuntary Movement Scale (AIMS) exam revealed mild TD that was managed with vitamin E, 400 IU/d.

While hospitalized, Mr. F many times received injectable antipsychotics and benzodiazepines, mostly to control violence. Depot antipsychotics also were tried in an effort to promote compliance, but recurrent alcohol abuse often triggered a relapse.

How would you confront Mr. F’s history of noncompliance? Can his delusions be controlled without prompting severe motor effects?

Dr. Canive’s observations

For Mr. F, poor tolerability, incomplete efficacy, and variable compliance have repeatedly led to symptom exacerbation and hospitalization. Low dosing because of sensitivity to EPS may partially explain his insufficient response to antipsychotics.

In 1995, after numerous unsuccessful drug treatments, we considered entering Mr. F into a phase II clinical trial of the atypical antipsychotic aripiprazole.

Now FDA-approved for treatment of schizophrenia, aripiprazole decreases dopaminergic transmission in the nigrostriatal and tuberoinfundibular pathways, thus reducing the likelihood of EPS.^1,2 Also, aripiprazole’s dopamine-serotonin stabilization effects have been reported in clinical trials to improve tolerability, compliance, and overall effectiveness in patients with schizophrenia.³

Common side effects of aripiprazole are mild nausea, insomnia, and restlessness, although data indicate that these effects have a low prevalence and disappear within 2 weeks. If insomnia and restlessness are prominent, a low-dose, short-acting benzodiazepine may be added, tapered after 1 week, and discontinued at week 2.

Table

Mr. F’s progress while taking aripiprazole, 1995-2003

What the scores mean

Clinical Global Impression-Severity of Illness (CGI-S)—Scores range from 1 to 7, with 1 meaning normal (normal, minimal, mild, moderate, moderately severe, severe, among the most extreme).

Clinical Global Impression-Global Improvement (CGI-G)—Scores range from 1 to 7, with 1 meaning very much improved (very much improved, much improved, improved, unchanged, little worse, much worse, very much worse).

Positive and Negative Syndrome Scale (PANSS) Positive—consists of 7 items (delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, hostility); scores range from 7 to 49 and decrease as patients improve.

PANSS Negative—consists of 7 items (blunted affect, emotional withdrawal, poor rapport, passive pathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking); scores range from 7 to 49 and decrease as patients improve.

PANSS General—consists of 16 items (somatic concern, anxiety, guilt feelings, tension, mannerism and posturing, depression, motor retardation, uncooperativeness, unusual thought content, disorientation, poor attention, lack of judgment and insight, disturbance of volition, poor impulse control, preoccupation, active social avoidance). Scores range from 16 to 112 and decrease as patients improve.

CONTINUED TREATMENT: A new trial

Mr. F participated in a 4-week, double-blind, placebo-controlled trial of aripiprazole, 2, 10, or 30 mg/d, versus haloperidol, 10 mg/d.

One month later, he entered a second aripiprazole trial: a 4-day, open-label study starting at 5 mg/d with titration to 20 mg/d. In the interval between the two trials, Mr. F was prescribed thiothixene, 10 mg/d, and benztropine, 2 mg at bedtime.

During the 4-day trial, he complained of insomnia and was given chloral hydrate, 500 to 1,000 mg at bedtime. He also complained of anxiety and was started on lorazepam, 2 mg bid.

After completing the open-label aripiprazole trial, Mr. F exhibited no behavioral problems and complied with ward routine. He was discharged after 17 days, at which time he denied auditory or visual hallucinations. His thinking seemed clear and his insight improved. His Global Assessment of Functioning (GAF) score at discharge was 55, suggesting moderate symptoms and difficulty in social and occupational functioning.

For the next 5 1/2 years, Mr. F was maintained on aripiprazole, 20 mg/d, as part of the same ongoing open-label trial. During that period he also took lorazepam, 1 mg bid prn; oxazepam, 15 mg bid; or clonazepam, 0.5 mg bid, for anxiety.

Mr. F. exhibited significant sustained improvement as measured with the Positive and Negative Symptom Scale (PANSS), Clinical Global Impression scale (CGI), and GAF (Table). His TD remained mild throughout the trial, as determined through AIMS scores. He also reported no EPS, akathisia, or other adverse events.

About 18 months after starting aripiprazole, Mr. F resumed working part time. In September 2001, he stopped receiving disability benefits and started supporting himself again.

FOLLOW-UP: ‘The voices were ugly’

In December 2001, after 6 years without hospitalization, Mr. F was back in the psychiatric ward. One week before admission, he reported that he had been having panic attacks because “the voices were ugly.” He only slept 4 to 5 hours per night.

He then revealed that he had stopped taking aripiprazole for 2 weeks because he had no longer felt ill. He was still taking his lorazepam, however.

Mr. F appeared mildly anxious upon presentation and his affect was blunted. On examination, his thought processes were linear; he was once again hearing voices and experiencing delusions of telepathic control.

The patient was placed back on aripiprazole, 20 mg/d. His behavior on the ward improved dramatically, and the frequency and severity of his delusions and auditory hallucinations decreased gradually.

At discharge, Mr. F’s insight was good, his delusions had disappeared, and auditory hallucinations were rare. He was instructed to continue the aripiprazole and was prescribed clonazepam, 0.5 mg bid, for his anxiety and trazodone, 50 mg at bed-time, to help his sleep.

Since then, Mr. F has lived on his own, is working steadily, and has not required hospitalization. He stopped taking trazodone soon after discharge, but continues taking aripiprazole and clonazepam as prescribed. His hygiene is good, and he is making amends with family members. He attends church every Sunday—free of the messianic delusions that once tormented him. He also stopped abusing alcohol on his own in 1995 and has remained abstinent since.

How can we ensure that patients with schizophrenia keep taking their medications—regardless of whether symptoms are present?

Dr. Canive’s observations

Clinical trials measure a drug’s efficacy under highly controlled circumstances. In the “real world,” however, noncompliance due to intolerability can undermine a medication’s effectiveness.

Too often noncompliance—stemming from abatement of symptoms or the emergence of side effects—derails treatment of schizophrenia. Misdrahi et al found that medication noncompliance accounts for 40% of schizophrenia relapses occurring more than 1 year after patients’ first hospitalization.⁴

Given aripiprazole’s 75-hour half-life, one might not expect to see symptoms emerge so soon after discontinuation. It is possible that:

• Mr. F. abstained from aripiprazole longer than he realized—or admitted
• Unidentified stressful life events also exacerbated symptoms and precipitated hospitalization.

When Mr. F consistently followed his regimen, his positive symptoms abated and he could attempt to live a normal life.

Our patients must understand that schizophrenia is a lifelong illness and that continued adherence to medication—even when symptoms do not exist—is crucial. A strong therapeutic alliance,⁵ increased social support, adjunctive cognitive-behavioral therapy, psychosocial interventions,⁶ and medications with fewer and less-severe side effects may help patients embrace this message.

Related resources

• Tamminga CA. Partial dopamine agonists in the treatment of psychosis. J Neural Transm 2002;109:411-20.

Drug brand names

• Amitriptyline • Elavil
• Aripiprazole • Abilify
• Benztropine • Cogentin
• Chlorpromazine • Thorazine
• Clonazepam • Klonopin
• Diazepam • Valium
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Lorazepam • Ativan
• Loxapine • Loxitane
• Oxazepam • Serax
• Thiothixene • Navane
• Trazodone • Desyrel

Disclosure

The author receives research/grant support from and is a speaker for and consultant to Bristol-Myers Squibb Co. He also receives research/grant support from and/or is a speaker for AstraZeneca Pharmaceuticals, Janssen Pharmaceutica, and Eli Lilly and Co.

Do you know which of your patients have alcohol problems? Though alcohol use disorders may be difficult to detect, self-report and biochemical measures followed by a thorough face-to-face assessment improve diagnostic accuracy. New tools—such as the serum carbohydrate-deficient transferrin (CDT) test—are changing how psychiatrists screen for alcohol problems, provide motivational feedback, and monitor patients for relapse.

FOUR REASONS TO SCREEN

Screening for excessive alcohol consumption is important in psychiatric practice because:

• Alcohol use disorders coexist with many psychiatric problems, most notably affective and anxiety disorders and—not surprisingly—other substance abuse disorders (Table 1).^1,2
• Patients with psychiatric comorbidity who abuse alcohol have poorer prognoses, are less adherent to treatment, and are more likely to drop out of treatment than are psychiatric patients who do not have alcohol problems.³
• Alcohol interacts with many psychotropics, and chronic heavy drinking can cause pharmacokinetic changes that affect a patient’s response to medications.
• Alcohol-dependent patients are more likely than nondrinkers to become dependent on anxiolytics and sedative-hypnotics.

Table 1

Overlap of alcohol problems with common psychiatric disorders

Because alcohol problems are common in psychiatric patients, routine screening for alcohol abuse and dependence at the onset of any treatment can be very useful. Thereafter, screening can be done periodically—perhaps annually or more often if the patient’s functioning declines.

CHOOSING A SELF-REPORT MEASURE

Many self-report alcohol screening scales are available,⁴ the most popular being the CAGE⁵ and the Michigan Alcoholism Screening Test (MAST).⁶ Though both instruments can help identify alcohol problems, each has shortcomings:

• The CAGE performs less reliably in women and adolescents than in men, and its validity depends on the patient’s sensitivity to the emotional impacts of alcohol dependence.
• The MAST is long (25 items), concentrates on late-stage alcoholism symptoms, and uses differential weighting—not validated in subsequent studies—of particular items in deriving the score.

Neither addresses drinking behavior or when symptoms occurred and thus may misclassify recovered alcoholics or former problem drinkers.

AUDIT. A more reliable choice is the Alcohol Use Disorders Identification Test (AUDIT).⁷ It was designed by the World Health Organization (WHO) to be valid across gender and culture and to identify even early stage problem drinking. The AUDIT’s 10 items deal with drinking behavior, dependence on alcohol, and adverse consequences of drinking during the past year (Box). The survey takes less than 5 minutes; can be administered orally, in writing, or online; and it retains its validity when given as part of a comprehensive health risk appraisal.⁸

The WHO offers an excellent manual detailing how to administer and interpret the AUDIT (see Related resources). A patient’s score is computed by summing the values associated with his or her responses to each item. A score of 8 or greater indicates excessive alcohol consumption, although some researchers have argued that for women a more accurate threshold might be 6 or 7 points.

Standardized for adults, the AUDIT also appears to accurately gauge drinking behavior in adolescents⁹ and in psychiatric patients, although only three studies have explored its use in the latter population.^10-12 Abbreviated AUDIT versions have been found to be psychometrically sound⁸ and may be useful in an emergency room or busy primary care clinic. In comparisons with other screening tools, the AUDIT almost always has been found to be more valid.^9,13

USING BIOCHEMICAL MEASURES

Self-report screens for alcohol problems, especially the AUDIT, are highly sensitive and specific, though their accuracy depends on the patient's memory, understanding of the questions, and candor. In chronic heavy drinkers, biochemical measures (Table 2) can augment self-reports.¹⁴

Self-report and biochemical screens have different strengths and weaknesses (Table 3). It is important to see them as complementary because each contributes to accurate screening.

CDT. Most biomarkers screen indirectly for alcohol problems by measuring damage to an end organ-typically the liver-caused by chronic excessive alcohol consumption. False positive results are common because of nonalcohol-related organ damage, medications, smoking, obesity, and other confounding factors. An exception appears to be the serum test for carbohydrate-deficient transferrin (CDT), a biomarker for heavy drinking approved in kit form 3 years ago by the Food and Drug Administration.

The value of measuring CDT levels is that few conditions other than excessive alcohol consumption elevate them. For unclear reasons,¹⁵ average daily consumption of >60 grams of alcohol (about five standard drinks) during the previous 2 weeks causes a higher percent of transferrin—a glycoenzyme that transports iron in the body—to lack its usual carbohydrate content.

Bio-Rad Laboratories (www.bio-rad.com) offers a reagent kit (%CDT Turbidimetric Immunoassay). It quantifies CDT as a percent of total serum transferrin, rather than total CDT, thus correcting for individual variations in transferrin levels. CDT values are obtained from a 100-microliter serum sample. The blood is clotted and the serum separated. The sample may be stored at 2 to 8 °C if the test is to be run within 1 week. Samples must be tested at a reference lab (Bio-Rad offers a list of labs). Results are available in a few days.

Patients who deny problem drinking may need convincing to submit to a blood draw. It may help to explain that alcohol use can exacerbate emotional problems and that the test can provide information on possible risky alcohol use.

GGT. Using a second biochemical marker may improve the sensitivity of CDT to detect heavy drinking.^16-18

The most-researched choice for a second marker is gamma glutamyltransferase (GGT). Patients are considered to have tested positive for an alcohol problem if either CDT or GGT levels are elevated. Combining these tests may be especially useful in alcohol-dependent women, in whom the reliability of CDT testing alone has been questioned.

Recommendation. Start with a self-report screening measure. If the patient scores slightly below the threshold for an alcohol problem, follow up with the more costly CDT and GGT tests.

For example, biomarkers might be useful for follow-up in men with AUDIT screening scores of 6 or 7 or women with scores of 5 to 7. Biomarkers also are recommended when you suspect an alcohol problem for another reason or question whether the patient responded accurately to the self-report measure.

Box

Table 2

Biochemical markers of heavy drinking

MONITORING PATIENTS IN TREATMENT

MET. Motivational enhancement therapy (MET) has gained popularity as a means of changing problematic drinking.¹⁹ Project MATCH—a multi-site trial on alcohol abuse treatment—studied MET and two other interventions. MET required fewer sessions but equaled the other interventions in reducing drinking days and aver-age amount of alcohol consumed.²⁰

A key component of MET—and other brief interventions—is to provide patients with empathetic, nonjudgmental feedback.^19-21 Responses to the first three AUDIT items can provide such feedback to patients with drinking problems. Amazingly, heavy drinkers and alcoholics often do not realize how much more they drink than other people. To help them develop this insight, show them their self-report responses in contrast with national normative data.

Biomarker results can be used similarly, in this case comparing the patient’s score with the test’s reference range values. Kristenson et al²² showed that giving men with elevated scores recurrent biomarker information and advice significantly reduced morbidity and mortality and improved their work performance.

Using visual aids can deepen patients’ under-standing of motivational feedback. For example, displaying sequential test results on a timeline can reinforce motivation by showing how their drinking behavior has improved with continuing treatment and sustained effort.

Table 3

Self-report and biochemical measures of drinking: Pros and cons

DETECTING RELAPSE

Although treatment for alcohol problems is often successful,²³ relapse to some level of drinking is not uncommon, especially during the first 3 or 4 months after patients complete treatment.²⁰ Recognizing relapse quickly can help you:

• decrease risk of harm from resumed alcohol use
• reduce the potential for drinking to again become habitual
• identify circumstances and cues that may have triggered the drinking episode, for use in tailoring future interventions.

In clinical practice, relapse is most often revealed via comments from the family, direct observation by the clinician, or voluntary acknowledgment by the patient. Interestingly, CDT has demonstrated a relapse “heralding effect,”²⁴ meaning that it tends to rise well before a patient will admit he or she resumed drinking.^24-26 Although other markers may also rise following relapse, their elevation tends to be delayed and less dramatic.

The sensitivity and specificity of CDT alone and with GGT in identifying relapse have been evaluated. Across male-only studies, CDT’s median sensitivity (percent of relapsed patients with elevated scores) was 0.73, with a specificity (percent of those not relapsed who had low scores) of 0.91. In the two female-only studies, median sensitivity and specificity for CDT were 0.32 and 0.86, respectively. For women, using CDT and GGT in combination substantially raised median sensitivity to 0.62, although specificity fell slightly to 0.80.²⁷

Recommendation. When using biomarkers to identify relapse, examine the temporal pattern of test results to date. Assume that an increase of 30% or more above the lowest observed lab value indicates a relapse.²⁸

Frequent testing—probably biweekly—is recommended during the first 3 or 4 months after patients complete treatment. If there is no indication of relapse, testing frequency could be tapered down.

Related resources

• AUDIT. The Alcohol Use Disorders Identification Test. Guidelines for primary care use. Available at: http://www.who.int/substance_abuse/pubs_alcohol.htm
• Allen JP, Litten RZ. Psychometric and laboratory measures to assist in the treatment of alcoholism. Clin Psychol Rev 1993;13(3):223-39.
• Salaspuro M. Carbohydrate-deficient transferrin as compared to other markers of alcoholism: a systematic review. Alcohol 1999; 19(3):261-71.

Disclosure

Dr. Allen reports that he serves as a consultant to Axis-Shield ASA and Bio-Rad Laboratories, patent holder and U.S. distributor, respectively, of the carbohydrate-deficient transferrin (%CDT) reagent kit.

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

Do you know which of your patients have alcohol problems? Though alcohol use disorders may be difficult to detect, self-report and biochemical measures followed by a thorough face-to-face assessment improve diagnostic accuracy. New tools—such as the serum carbohydrate-deficient transferrin (CDT) test—are changing how psychiatrists screen for alcohol problems, provide motivational feedback, and monitor patients for relapse.

FOUR REASONS TO SCREEN

Screening for excessive alcohol consumption is important in psychiatric practice because:

• Alcohol use disorders coexist with many psychiatric problems, most notably affective and anxiety disorders and—not surprisingly—other substance abuse disorders (Table 1).^1,2
• Patients with psychiatric comorbidity who abuse alcohol have poorer prognoses, are less adherent to treatment, and are more likely to drop out of treatment than are psychiatric patients who do not have alcohol problems.³
• Alcohol interacts with many psychotropics, and chronic heavy drinking can cause pharmacokinetic changes that affect a patient’s response to medications.
• Alcohol-dependent patients are more likely than nondrinkers to become dependent on anxiolytics and sedative-hypnotics.

Table 1

Overlap of alcohol problems with common psychiatric disorders

Because alcohol problems are common in psychiatric patients, routine screening for alcohol abuse and dependence at the onset of any treatment can be very useful. Thereafter, screening can be done periodically—perhaps annually or more often if the patient’s functioning declines.

CHOOSING A SELF-REPORT MEASURE

Many self-report alcohol screening scales are available,⁴ the most popular being the CAGE⁵ and the Michigan Alcoholism Screening Test (MAST).⁶ Though both instruments can help identify alcohol problems, each has shortcomings:

• The CAGE performs less reliably in women and adolescents than in men, and its validity depends on the patient’s sensitivity to the emotional impacts of alcohol dependence.
• The MAST is long (25 items), concentrates on late-stage alcoholism symptoms, and uses differential weighting—not validated in subsequent studies—of particular items in deriving the score.

Neither addresses drinking behavior or when symptoms occurred and thus may misclassify recovered alcoholics or former problem drinkers.

AUDIT. A more reliable choice is the Alcohol Use Disorders Identification Test (AUDIT).⁷ It was designed by the World Health Organization (WHO) to be valid across gender and culture and to identify even early stage problem drinking. The AUDIT’s 10 items deal with drinking behavior, dependence on alcohol, and adverse consequences of drinking during the past year (Box). The survey takes less than 5 minutes; can be administered orally, in writing, or online; and it retains its validity when given as part of a comprehensive health risk appraisal.⁸

The WHO offers an excellent manual detailing how to administer and interpret the AUDIT (see Related resources). A patient’s score is computed by summing the values associated with his or her responses to each item. A score of 8 or greater indicates excessive alcohol consumption, although some researchers have argued that for women a more accurate threshold might be 6 or 7 points.

Standardized for adults, the AUDIT also appears to accurately gauge drinking behavior in adolescents⁹ and in psychiatric patients, although only three studies have explored its use in the latter population.^10-12 Abbreviated AUDIT versions have been found to be psychometrically sound⁸ and may be useful in an emergency room or busy primary care clinic. In comparisons with other screening tools, the AUDIT almost always has been found to be more valid.^9,13

USING BIOCHEMICAL MEASURES

Self-report screens for alcohol problems, especially the AUDIT, are highly sensitive and specific, though their accuracy depends on the patient's memory, understanding of the questions, and candor. In chronic heavy drinkers, biochemical measures (Table 2) can augment self-reports.¹⁴

Self-report and biochemical screens have different strengths and weaknesses (Table 3). It is important to see them as complementary because each contributes to accurate screening.

CDT. Most biomarkers screen indirectly for alcohol problems by measuring damage to an end organ-typically the liver-caused by chronic excessive alcohol consumption. False positive results are common because of nonalcohol-related organ damage, medications, smoking, obesity, and other confounding factors. An exception appears to be the serum test for carbohydrate-deficient transferrin (CDT), a biomarker for heavy drinking approved in kit form 3 years ago by the Food and Drug Administration.

The value of measuring CDT levels is that few conditions other than excessive alcohol consumption elevate them. For unclear reasons,¹⁵ average daily consumption of >60 grams of alcohol (about five standard drinks) during the previous 2 weeks causes a higher percent of transferrin—a glycoenzyme that transports iron in the body—to lack its usual carbohydrate content.

Bio-Rad Laboratories (www.bio-rad.com) offers a reagent kit (%CDT Turbidimetric Immunoassay). It quantifies CDT as a percent of total serum transferrin, rather than total CDT, thus correcting for individual variations in transferrin levels. CDT values are obtained from a 100-microliter serum sample. The blood is clotted and the serum separated. The sample may be stored at 2 to 8 °C if the test is to be run within 1 week. Samples must be tested at a reference lab (Bio-Rad offers a list of labs). Results are available in a few days.

Patients who deny problem drinking may need convincing to submit to a blood draw. It may help to explain that alcohol use can exacerbate emotional problems and that the test can provide information on possible risky alcohol use.

GGT. Using a second biochemical marker may improve the sensitivity of CDT to detect heavy drinking.^16-18

The most-researched choice for a second marker is gamma glutamyltransferase (GGT). Patients are considered to have tested positive for an alcohol problem if either CDT or GGT levels are elevated. Combining these tests may be especially useful in alcohol-dependent women, in whom the reliability of CDT testing alone has been questioned.

Recommendation. Start with a self-report screening measure. If the patient scores slightly below the threshold for an alcohol problem, follow up with the more costly CDT and GGT tests.

For example, biomarkers might be useful for follow-up in men with AUDIT screening scores of 6 or 7 or women with scores of 5 to 7. Biomarkers also are recommended when you suspect an alcohol problem for another reason or question whether the patient responded accurately to the self-report measure.

Box

Table 2

Biochemical markers of heavy drinking

MONITORING PATIENTS IN TREATMENT

MET. Motivational enhancement therapy (MET) has gained popularity as a means of changing problematic drinking.¹⁹ Project MATCH—a multi-site trial on alcohol abuse treatment—studied MET and two other interventions. MET required fewer sessions but equaled the other interventions in reducing drinking days and aver-age amount of alcohol consumed.²⁰

A key component of MET—and other brief interventions—is to provide patients with empathetic, nonjudgmental feedback.^19-21 Responses to the first three AUDIT items can provide such feedback to patients with drinking problems. Amazingly, heavy drinkers and alcoholics often do not realize how much more they drink than other people. To help them develop this insight, show them their self-report responses in contrast with national normative data.

Biomarker results can be used similarly, in this case comparing the patient’s score with the test’s reference range values. Kristenson et al²² showed that giving men with elevated scores recurrent biomarker information and advice significantly reduced morbidity and mortality and improved their work performance.

Using visual aids can deepen patients’ under-standing of motivational feedback. For example, displaying sequential test results on a timeline can reinforce motivation by showing how their drinking behavior has improved with continuing treatment and sustained effort.

Table 3

Self-report and biochemical measures of drinking: Pros and cons

DETECTING RELAPSE

Although treatment for alcohol problems is often successful,²³ relapse to some level of drinking is not uncommon, especially during the first 3 or 4 months after patients complete treatment.²⁰ Recognizing relapse quickly can help you:

• decrease risk of harm from resumed alcohol use
• reduce the potential for drinking to again become habitual
• identify circumstances and cues that may have triggered the drinking episode, for use in tailoring future interventions.

In clinical practice, relapse is most often revealed via comments from the family, direct observation by the clinician, or voluntary acknowledgment by the patient. Interestingly, CDT has demonstrated a relapse “heralding effect,”²⁴ meaning that it tends to rise well before a patient will admit he or she resumed drinking.^24-26 Although other markers may also rise following relapse, their elevation tends to be delayed and less dramatic.

The sensitivity and specificity of CDT alone and with GGT in identifying relapse have been evaluated. Across male-only studies, CDT’s median sensitivity (percent of relapsed patients with elevated scores) was 0.73, with a specificity (percent of those not relapsed who had low scores) of 0.91. In the two female-only studies, median sensitivity and specificity for CDT were 0.32 and 0.86, respectively. For women, using CDT and GGT in combination substantially raised median sensitivity to 0.62, although specificity fell slightly to 0.80.²⁷

Recommendation. When using biomarkers to identify relapse, examine the temporal pattern of test results to date. Assume that an increase of 30% or more above the lowest observed lab value indicates a relapse.²⁸

Frequent testing—probably biweekly—is recommended during the first 3 or 4 months after patients complete treatment. If there is no indication of relapse, testing frequency could be tapered down.

Related resources

• AUDIT. The Alcohol Use Disorders Identification Test. Guidelines for primary care use. Available at: http://www.who.int/substance_abuse/pubs_alcohol.htm
• Allen JP, Litten RZ. Psychometric and laboratory measures to assist in the treatment of alcoholism. Clin Psychol Rev 1993;13(3):223-39.
• Salaspuro M. Carbohydrate-deficient transferrin as compared to other markers of alcoholism: a systematic review. Alcohol 1999; 19(3):261-71.

Disclosure

Dr. Allen reports that he serves as a consultant to Axis-Shield ASA and Bio-Rad Laboratories, patent holder and U.S. distributor, respectively, of the carbohydrate-deficient transferrin (%CDT) reagent kit.

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

Do you know which of your patients have alcohol problems? Though alcohol use disorders may be difficult to detect, self-report and biochemical measures followed by a thorough face-to-face assessment improve diagnostic accuracy. New tools—such as the serum carbohydrate-deficient transferrin (CDT) test—are changing how psychiatrists screen for alcohol problems, provide motivational feedback, and monitor patients for relapse.

FOUR REASONS TO SCREEN

Screening for excessive alcohol consumption is important in psychiatric practice because:

• Alcohol use disorders coexist with many psychiatric problems, most notably affective and anxiety disorders and—not surprisingly—other substance abuse disorders (Table 1).^1,2
• Patients with psychiatric comorbidity who abuse alcohol have poorer prognoses, are less adherent to treatment, and are more likely to drop out of treatment than are psychiatric patients who do not have alcohol problems.³
• Alcohol interacts with many psychotropics, and chronic heavy drinking can cause pharmacokinetic changes that affect a patient’s response to medications.
• Alcohol-dependent patients are more likely than nondrinkers to become dependent on anxiolytics and sedative-hypnotics.

Table 1

Overlap of alcohol problems with common psychiatric disorders

Because alcohol problems are common in psychiatric patients, routine screening for alcohol abuse and dependence at the onset of any treatment can be very useful. Thereafter, screening can be done periodically—perhaps annually or more often if the patient’s functioning declines.

CHOOSING A SELF-REPORT MEASURE

Many self-report alcohol screening scales are available,⁴ the most popular being the CAGE⁵ and the Michigan Alcoholism Screening Test (MAST).⁶ Though both instruments can help identify alcohol problems, each has shortcomings:

• The CAGE performs less reliably in women and adolescents than in men, and its validity depends on the patient’s sensitivity to the emotional impacts of alcohol dependence.
• The MAST is long (25 items), concentrates on late-stage alcoholism symptoms, and uses differential weighting—not validated in subsequent studies—of particular items in deriving the score.

Neither addresses drinking behavior or when symptoms occurred and thus may misclassify recovered alcoholics or former problem drinkers.

AUDIT. A more reliable choice is the Alcohol Use Disorders Identification Test (AUDIT).⁷ It was designed by the World Health Organization (WHO) to be valid across gender and culture and to identify even early stage problem drinking. The AUDIT’s 10 items deal with drinking behavior, dependence on alcohol, and adverse consequences of drinking during the past year (Box). The survey takes less than 5 minutes; can be administered orally, in writing, or online; and it retains its validity when given as part of a comprehensive health risk appraisal.⁸

The WHO offers an excellent manual detailing how to administer and interpret the AUDIT (see Related resources). A patient’s score is computed by summing the values associated with his or her responses to each item. A score of 8 or greater indicates excessive alcohol consumption, although some researchers have argued that for women a more accurate threshold might be 6 or 7 points.

Standardized for adults, the AUDIT also appears to accurately gauge drinking behavior in adolescents⁹ and in psychiatric patients, although only three studies have explored its use in the latter population.^10-12 Abbreviated AUDIT versions have been found to be psychometrically sound⁸ and may be useful in an emergency room or busy primary care clinic. In comparisons with other screening tools, the AUDIT almost always has been found to be more valid.^9,13

USING BIOCHEMICAL MEASURES

Self-report screens for alcohol problems, especially the AUDIT, are highly sensitive and specific, though their accuracy depends on the patient's memory, understanding of the questions, and candor. In chronic heavy drinkers, biochemical measures (Table 2) can augment self-reports.¹⁴

Self-report and biochemical screens have different strengths and weaknesses (Table 3). It is important to see them as complementary because each contributes to accurate screening.

CDT. Most biomarkers screen indirectly for alcohol problems by measuring damage to an end organ-typically the liver-caused by chronic excessive alcohol consumption. False positive results are common because of nonalcohol-related organ damage, medications, smoking, obesity, and other confounding factors. An exception appears to be the serum test for carbohydrate-deficient transferrin (CDT), a biomarker for heavy drinking approved in kit form 3 years ago by the Food and Drug Administration.

The value of measuring CDT levels is that few conditions other than excessive alcohol consumption elevate them. For unclear reasons,¹⁵ average daily consumption of >60 grams of alcohol (about five standard drinks) during the previous 2 weeks causes a higher percent of transferrin—a glycoenzyme that transports iron in the body—to lack its usual carbohydrate content.

Bio-Rad Laboratories (www.bio-rad.com) offers a reagent kit (%CDT Turbidimetric Immunoassay). It quantifies CDT as a percent of total serum transferrin, rather than total CDT, thus correcting for individual variations in transferrin levels. CDT values are obtained from a 100-microliter serum sample. The blood is clotted and the serum separated. The sample may be stored at 2 to 8 °C if the test is to be run within 1 week. Samples must be tested at a reference lab (Bio-Rad offers a list of labs). Results are available in a few days.

Patients who deny problem drinking may need convincing to submit to a blood draw. It may help to explain that alcohol use can exacerbate emotional problems and that the test can provide information on possible risky alcohol use.

GGT. Using a second biochemical marker may improve the sensitivity of CDT to detect heavy drinking.^16-18

The most-researched choice for a second marker is gamma glutamyltransferase (GGT). Patients are considered to have tested positive for an alcohol problem if either CDT or GGT levels are elevated. Combining these tests may be especially useful in alcohol-dependent women, in whom the reliability of CDT testing alone has been questioned.

Recommendation. Start with a self-report screening measure. If the patient scores slightly below the threshold for an alcohol problem, follow up with the more costly CDT and GGT tests.

For example, biomarkers might be useful for follow-up in men with AUDIT screening scores of 6 or 7 or women with scores of 5 to 7. Biomarkers also are recommended when you suspect an alcohol problem for another reason or question whether the patient responded accurately to the self-report measure.

Box

Table 2

Biochemical markers of heavy drinking

MONITORING PATIENTS IN TREATMENT

MET. Motivational enhancement therapy (MET) has gained popularity as a means of changing problematic drinking.¹⁹ Project MATCH—a multi-site trial on alcohol abuse treatment—studied MET and two other interventions. MET required fewer sessions but equaled the other interventions in reducing drinking days and aver-age amount of alcohol consumed.²⁰

A key component of MET—and other brief interventions—is to provide patients with empathetic, nonjudgmental feedback.^19-21 Responses to the first three AUDIT items can provide such feedback to patients with drinking problems. Amazingly, heavy drinkers and alcoholics often do not realize how much more they drink than other people. To help them develop this insight, show them their self-report responses in contrast with national normative data.

Biomarker results can be used similarly, in this case comparing the patient’s score with the test’s reference range values. Kristenson et al²² showed that giving men with elevated scores recurrent biomarker information and advice significantly reduced morbidity and mortality and improved their work performance.

Using visual aids can deepen patients’ under-standing of motivational feedback. For example, displaying sequential test results on a timeline can reinforce motivation by showing how their drinking behavior has improved with continuing treatment and sustained effort.

Table 3

Self-report and biochemical measures of drinking: Pros and cons

DETECTING RELAPSE

Although treatment for alcohol problems is often successful,²³ relapse to some level of drinking is not uncommon, especially during the first 3 or 4 months after patients complete treatment.²⁰ Recognizing relapse quickly can help you:

• decrease risk of harm from resumed alcohol use
• reduce the potential for drinking to again become habitual
• identify circumstances and cues that may have triggered the drinking episode, for use in tailoring future interventions.

In clinical practice, relapse is most often revealed via comments from the family, direct observation by the clinician, or voluntary acknowledgment by the patient. Interestingly, CDT has demonstrated a relapse “heralding effect,”²⁴ meaning that it tends to rise well before a patient will admit he or she resumed drinking.^24-26 Although other markers may also rise following relapse, their elevation tends to be delayed and less dramatic.

The sensitivity and specificity of CDT alone and with GGT in identifying relapse have been evaluated. Across male-only studies, CDT’s median sensitivity (percent of relapsed patients with elevated scores) was 0.73, with a specificity (percent of those not relapsed who had low scores) of 0.91. In the two female-only studies, median sensitivity and specificity for CDT were 0.32 and 0.86, respectively. For women, using CDT and GGT in combination substantially raised median sensitivity to 0.62, although specificity fell slightly to 0.80.²⁷

Recommendation. When using biomarkers to identify relapse, examine the temporal pattern of test results to date. Assume that an increase of 30% or more above the lowest observed lab value indicates a relapse.²⁸

Frequent testing—probably biweekly—is recommended during the first 3 or 4 months after patients complete treatment. If there is no indication of relapse, testing frequency could be tapered down.

Related resources

• AUDIT. The Alcohol Use Disorders Identification Test. Guidelines for primary care use. Available at: http://www.who.int/substance_abuse/pubs_alcohol.htm
• Allen JP, Litten RZ. Psychometric and laboratory measures to assist in the treatment of alcoholism. Clin Psychol Rev 1993;13(3):223-39.
• Salaspuro M. Carbohydrate-deficient transferrin as compared to other markers of alcoholism: a systematic review. Alcohol 1999; 19(3):261-71.

Disclosure

Dr. Allen reports that he serves as a consultant to Axis-Shield ASA and Bio-Rad Laboratories, patent holder and U.S. distributor, respectively, of the carbohydrate-deficient transferrin (%CDT) reagent kit.

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

Promptly identifying serotonin syndrome and acting decisively can keep side effects at the mild end of the spectrum. Symptoms of this potentially dangerous syndrome range from minimal in patients starting selective serotonin reuptake inhibitors (SSRIs) to fatal in those combining monoamine oxidase inhibitors (MAOIs) with serotonergic agents.

This article presents the latest evidence on how to:

• reduce the risk of serotonin syndrome
• recognize its symptoms
• and treat patients with mild to life-threatening symptoms.

WHAT IS SEROTONIN SYNDROME?

Serotonin syndrome is characterized by changes in autonomic, neuromotor, and cognitive-behavioral function (Table 1) triggered by increased serotonergic stimulation. It typically results from pharmacodynamic and/or pharmacokinetic interactions between drugs that increase serotonin activity.^1,2

Table 1

How to recognize serotonin syndrome

The syndrome was first identified in animal studies, followed by case reports in humans. The first review—with suggested diagnostic criteria— was published in 1991.¹

Since then, case reports have described serotonin syndrome with many drug combinations, including nonpsychotropics and illicit drugs. Using an irreversible MAOI with a serotonergic agent is the most toxic reported combination, but any drug or combination that increases serotonin can, in theory, cause serotonin syndrome (Table 2). A clinical scale³ is being developed to define and identify this potentially dangerous state, but no consensus has emerged on diagnostic criteria.

Pathophysiology. Serotonin syndrome’s symptoms and signs appear to result from stimulation of specific central and peripheral serotonin receptors, especially 5HT1a and 5HT2. Others—such as 5HT3 and 5HT4—may also be involved in causing GI symptoms and may affect dopaminergic transmission.

Damaged vascular or pulmonary endothelium, atherosclerosis, hypertension, or hypercholesterolemia may increase the risk for serotonin syndrome. In patients with these common medical conditions, reduced endothelial MAO-A activity or reduced ability to secrete endothelium-derived nitric oxide may diminish the ability to metabolize serotonin.²

POTENTIALLY DANGEROUS COMBINATIONS

MAOIs. Serotonin syndrome has been reported as a result of interactions between MAOIs— including selegiline and reversible MAO-A inhibitors (RIMAs)—and various serotonergic compounds. These reports have included fatalities,⁴ some of which were preceded by severe hyperthermia with complications such as disseminated intravascular coagulation, rhabdomyolysis, and renal failure. Some cases resulted from overdoses, but others did not.

Most disturbingly, some cases occurred after patients had undergone the traditional 2-week washout from the MAOI and then took a serotonergic agent.^5-7 In one instance,⁸ a patient who had discontinued fluoxetine for 6 weeks developed serotonin syndrome after starting tranylcypromine. These cases remind us to be vigilant when switching patients from irreversible MAOIs to serotonergic antidepressants or vice versa—even when recommended wash-out times are observed—and not to combine these agents acutely.

Selegiline is a relatively selective MAO-B inhibitor when used at 5 to 10 mg/d to treat Parkinson’s disease, though it loses MAO-B selectivity when used at higher dosages to treat depression. In a study⁹ of 4,568 patients with Parkinson’s disease who received selegiline (in dosages selective for MAO-B) plus an antidepressant:

• 11 (0.24%) experienced symptoms “possibly” consistent with serotonin syndrome
• 2 others (0.04%) experienced serious serotonin syndrome symptoms.⁹

Serotonin syndrome has been reported when MAO-B-selective doses of selegiline were combined with meperidine¹⁰ and nortriptyline.¹¹ This underscores the need for caution when combining these agents, especially if transdermal selegiline— which would not be MAO-B-selective—becomes available for treating depression.

Moclobemide is a RIMA used in treating depression and anxiety, with a purported reduced risk of drug and food interactions compared with other MAOIs. Moclobemide is not approved in the United States, but some patients obtain it elsewhere.

Joffe and Bakish reported on safely combining moclobemide with SSRIs,¹² and a review of MAOIs—including RIMAs—indicated that moclobemide was involved in only 9 of 226 cases of adverse effects and 3 of 105 cases of defined serotonin syndrome.¹³ Most moclobemide-SSRI interactions—including fatalities—involved overdoses in suicide attempts, although toxic symptoms have been reported with clomipramine or meperidine taken at normal dosages.^14,15

In one study,¹⁶ 18 healthy controls received fluoxetine, 20 to 40 mg/d, for 23 days, then were given moclobemide, up to 600 mg/d, or placebo and observed for adverse effects. No indication of serotonin syndrome was observed.

Linezolid is an oxazolidinone antibiotic with relatively weak, nonspecific, but reversible MAO inhibition. Cases of potential serotonin syndrome have been reported with linezolid plus paroxetine¹⁷ or sertraline.¹⁸ Patients in each case were medically ill and taking several other medications, which complicates interpretation of these reports. Nonetheless, physicians should be aware of the potential risk of serotonin syndrome if this antibiotic is combined with serotonergic agents.

Table 2

Serotonergic agents and their actions

Atypical antipsychotics. Original diagnostic criteria for serotonin syndrome excluded the addition of, or increase in, an antipsychotic prior to the syndrome’s onset.¹ However, serotonin syndrome has been reported with combinations of risperidone with paroxetine,¹⁹ olanzapine with mirtazapine and tramadol,²⁰ and olanzapine with lithium and citalopram.²¹ The 5HT2 antagonist effect of these atypical antipsychotics may have led indirectly to overactivation of 5HT1a receptors and serotonin syndrome. In each case, neuroleptic malignant syndrome was ruled out.

Table 3

Signs and symptoms that differentiate 5 hyperthermic states

Tramadol is an analgesic with opioid and serotonin-reuptake inhibiting properties that is metabolized by the cytochrome P (CYP)-450 isoenzyme 2D6. Serotonin syndrome has been reported from interactions between tramadol and sertraline²² and fluoxetine.²³ Possible causes include SSRI inhibition of CYP 2D6 metabolism of tramadol, tramadol abuse,²³ and multiple coadministered medications.²²

Sumatriptan is one of the selective 5HT1D agonists used in treating migraine. Gardner and Lynd²⁴ concluded that most patients tolerate sumatriptan with SSRIs or lithium. They felt they could not ensure the safety of sumatriptan with MAOIs, however, because sumatriptan elimination depends on hepatic MAO activity.

Among the 5HT1D agonists, using sumatriptan, zolmitriptan, rizatriptan, or almotriptan with an MAOI or within 2 weeks of discontinuing an MAOI is contraindicated. Naratriptan and frovatriptan appear less likely to interact with MAOIs, based on FDA-approved labeling.

MDMA. 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) is widely used as a recreational drug, especially at crowded dances (“raves”) and with other drugs.²⁵ This illicit amphetamine derivative stimulates the release of serotonin and inhibits its reuptake.

Kaskey reported the rapid onset of serotonin syndrome when a patient taking lithium and phenelzine ingested MDMA.²⁶ Signs and symptoms of serotonin syndrome also may develop when MDMA is used alone, facilitated by the high ambient temperatures on crowded dance floors and the dancers’ relative dehydration.

Fatalities have been blamed on complications including disseminated intravascular coagulation, rhabdomyolysis, and acute hepatic, renal, or cardiac failure.²⁵ Cases are difficult to interpret because of uncertainty about whether the victim ingested MDMA or another agent or combination.

St. John’s wort (Hypericum perforatum) contains numerous constituents, including hypericin and hyperforin, which have been found to inhibit the synaptic uptake of monoamines, including serotonin.²⁷ Which constituents are responsible for its clinical effect is unclear. Adverse effects from monotherapy include GI symptoms, confusion, dry mouth, dizziness, headache, fatigue, allergic skin reactions, photosensitivity, and urinary frequency.²⁷

Several cases of purported serotonin syndrome have been associated with St. John’s wort alone²⁸ or in combination with SSRIs, nefazodone, or fenfluramine.^29,30 GI symptoms and anxiety were the primary complaints and resolved without complications (adjunctive cyproheptadine was prescribed in two cases, though it is not clear that this agent contributed to resolution).

MISCELLANEOUS COMBINATIONS

Antiretroviral therapy. Five cases of serotonin syndrome were reported in HIV-infected patients taking fluoxetine with antiretroviral therapy.³¹ In particular, the use or addition of ritonavir—a potent CYP 2D6 inhibitor—was implicated, though saquinavir, efavirenz, or grapefruit juice (all primarily CYP 3A4 inhibitors) were also used, suggesting that pharmacokinetic interactions increased serotonergic stimulation. All five patients were taking multiple additional medications and had complex medical and/or psychiatric histories. Reducing SSRI dosages by one-half when used with ritonavir has been recommended to minimize adverse effects from a pharmacokinetic interaction.

Erythromycin was reported to induce serotonin syndrome in a 12-year-old boy when added to ongoing treatment with sertraline, an effect believed to be secondary to CYP 3A4 inhibition of sertraline metabolism.³²

Mirtazapine was reported to induce serotonin syndrome in an elderly man 8 days after it was added to a regimen he had been taking for several years to treat chronic obstructive pulmonary disease.³³ Serotonin syndrome also developed in a 12-year-old boy with Ewing’s sarcoma when the 5HT3 antagonist ondansetron was added to mirtazapine and morphine³⁴ and in an 11-year-old girl with acute lymphoblastic leukemia when ondansetron was added to fentanyl. Interestingly, another report³⁵ suggested using mirtazapine to treat serotonin syndrome caused by serotonergic antagonist effects.

Reports have associated the following combinations with serotonin syndrome, perhaps as the result of pharmacodynamic and/or pharmacokinetic interactions:

• paroxetine plus dextromethorphan and pseudoephedrine
• paroxetine plus nefazodone
• fluoxetine plus clomipramine and buspirone
• fluvoxamine plus buspirone
• fluoxetine plus buspirone
• amitriptyline plus meperidine and venlafaxine
• venlafaxine and dextroamphetamine
• fluoxetine plus clomipramine.

Table 4

Clinical signs that distinguish hyperthermic states

HOW TO RECOGNIZE SEROTONIN SYNDROME

Signs and symptoms of serotonin syndrome can overlap with those seen in neuroleptic malignant syndrome, lethal catatonia, malignant hyperthermia, and anticholinergic toxicity (Table 3),^1,36,37 particularly with fever or hyperthermia (>40.5 °C, 105 °F). Fink³⁷ has opined that acute neurotoxic syndromes such as serotonin syndrome and neuroleptic malignant syndrome also meet criteria for catatonia and are therefore subtypes of catatonia. The types of drugs involved and clinical findings can help distinguish the various hyperthermic states (Table 4).

As mentioned above, original diagnostic criteria for serotonin syndrome excluded the addition of, or increase in, an antipsychotic agent. This exclusion was intended to avoid confusion between serotonin syndrome and neuroleptic malignant syndrome. Co-administering antipsychotic and serotonergic agents requires heightened awareness for both neurotoxic syndromes.

TREATING MILD TO SEVERE CASES

If a patient develops serotonin syndrome, immediately discontinue the suspected agent(s) and observe carefully. In most cases, serotonin syndrome will resolve within 24 hours.

In mild cases, lorazepam, 1 to 2 mg slow IV push every 30 minutes until excessive sedation develops, may help. In moderate to severe cases, agents that block serotonin’s action are recommended,² including:

• cyproheptadine (4 mg po every 4 hours as needed, up to 20 mg in 24 hours)
• propranolol (1 to 3 mg IV every 5 minutes, up to 0.1 mg/kg).

Case reports attest to these agents’ potential benefit. Other clinicians have reported using mirtazapine,³⁵ nitroglycerin,³⁸ and chlorpromazine.¹

Serotonin syndrome symptoms resolved within minutes when IV nitroglycerin was used in a patient with serotonin syndrome and cardiac ischemia. The authors hypothesized that nitroglycerin, via nitric acid, provided an “off” signal for serotonin, though they did not advocate this as a routine treatment.³⁸

The rationale for using chlorpromazine is its potential to block serotonin receptors. I would avoid the routine use of any antipsychotic agent in this setting, however, to minimize the risk of neuroleptic malignant syndrome.

Severe cases. Intensive care observation and treatment is required for patients with severe serotonin syndrome, including evidence of hyperthermia, DIC, rhabdomyolysis, renal failure, or aspiration. In cases of hyperthermia, supportive measures and standard treatments include muscle relaxants, cooling, and endotracheal intubation.

Severe complications are most likely with interactions between MAOIs and serotonergic agents, especially in overdose. Therefore, using such combinations requires close observation.

Related resources

• Di Rosa AE, Morgante L, Spina E et al. Epidemiology and pathoetiology of neurological syndromes with hyperthermia. Funct Neurol 1995;10:111-19.
• Radomski, JW, Dursun SM, Reveley MA, et al. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypothesis 2000;55: 218-24.
• Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol 1997;17:208-21.

Drug brand names

• Almotriptan • Axert
• Amitriptyline • Elavil
• Buspirone • Buspar
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clomipramine • Anafranil
• Cyproheptadine • Periactin
• Dextroamphetamine • Dexedrine
• Dextromethorphan • Delsym
• Efavirenz • Sustiva
• Escitalopram • Lexapro
• Fenfluramine • Pondimin
• Fentanyl • Sublimaze
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Frovatriptan • Frova
• Isocarboxazid • Marplan
• Linezolid • Zyvox
• Meperidine • Demerol
• Mirtazapine • Remeron
• Moclobemide • Aurorix
• Nortriptyline • Pamelor
• Naratriptan, • Amerge
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Ondansetron • Zofran
• Paroxetine • Paxil
• Phenelzine • Nardil
• Propranolol • Inderal
• Risperidone • Risperdal
• Ritonavir • Norvir
• Rizatriptan • Maxalt
• Saquinavir • Invirase
• Selegiline • Eldepryl
• Sertraline • Zoloft
• Sumatriptan • Imitrex
• Tramadol • Ultram
• Tranylcypromine • Parnate
• Trazodone • Desyrel
• Venlafaxine • Effexor
• Zolmitriptan • Zomig

Disclosure

Dr. Sternbach receives research grants from Otsuka America Pharmaceuticals and Eli Lilly and Co. and owns stock in Merck & Co., Pfizer Inc., and Johnson & Johnson.

Promptly identifying serotonin syndrome and acting decisively can keep side effects at the mild end of the spectrum. Symptoms of this potentially dangerous syndrome range from minimal in patients starting selective serotonin reuptake inhibitors (SSRIs) to fatal in those combining monoamine oxidase inhibitors (MAOIs) with serotonergic agents.

This article presents the latest evidence on how to:

• reduce the risk of serotonin syndrome
• recognize its symptoms
• and treat patients with mild to life-threatening symptoms.

WHAT IS SEROTONIN SYNDROME?

Serotonin syndrome is characterized by changes in autonomic, neuromotor, and cognitive-behavioral function (Table 1) triggered by increased serotonergic stimulation. It typically results from pharmacodynamic and/or pharmacokinetic interactions between drugs that increase serotonin activity.^1,2

Table 1

How to recognize serotonin syndrome

The syndrome was first identified in animal studies, followed by case reports in humans. The first review—with suggested diagnostic criteria— was published in 1991.¹

Since then, case reports have described serotonin syndrome with many drug combinations, including nonpsychotropics and illicit drugs. Using an irreversible MAOI with a serotonergic agent is the most toxic reported combination, but any drug or combination that increases serotonin can, in theory, cause serotonin syndrome (Table 2). A clinical scale³ is being developed to define and identify this potentially dangerous state, but no consensus has emerged on diagnostic criteria.

Pathophysiology. Serotonin syndrome’s symptoms and signs appear to result from stimulation of specific central and peripheral serotonin receptors, especially 5HT1a and 5HT2. Others—such as 5HT3 and 5HT4—may also be involved in causing GI symptoms and may affect dopaminergic transmission.

Damaged vascular or pulmonary endothelium, atherosclerosis, hypertension, or hypercholesterolemia may increase the risk for serotonin syndrome. In patients with these common medical conditions, reduced endothelial MAO-A activity or reduced ability to secrete endothelium-derived nitric oxide may diminish the ability to metabolize serotonin.²

POTENTIALLY DANGEROUS COMBINATIONS

MAOIs. Serotonin syndrome has been reported as a result of interactions between MAOIs— including selegiline and reversible MAO-A inhibitors (RIMAs)—and various serotonergic compounds. These reports have included fatalities,⁴ some of which were preceded by severe hyperthermia with complications such as disseminated intravascular coagulation, rhabdomyolysis, and renal failure. Some cases resulted from overdoses, but others did not.

Most disturbingly, some cases occurred after patients had undergone the traditional 2-week washout from the MAOI and then took a serotonergic agent.^5-7 In one instance,⁸ a patient who had discontinued fluoxetine for 6 weeks developed serotonin syndrome after starting tranylcypromine. These cases remind us to be vigilant when switching patients from irreversible MAOIs to serotonergic antidepressants or vice versa—even when recommended wash-out times are observed—and not to combine these agents acutely.

Selegiline is a relatively selective MAO-B inhibitor when used at 5 to 10 mg/d to treat Parkinson’s disease, though it loses MAO-B selectivity when used at higher dosages to treat depression. In a study⁹ of 4,568 patients with Parkinson’s disease who received selegiline (in dosages selective for MAO-B) plus an antidepressant:

• 11 (0.24%) experienced symptoms “possibly” consistent with serotonin syndrome
• 2 others (0.04%) experienced serious serotonin syndrome symptoms.⁹

Serotonin syndrome has been reported when MAO-B-selective doses of selegiline were combined with meperidine¹⁰ and nortriptyline.¹¹ This underscores the need for caution when combining these agents, especially if transdermal selegiline— which would not be MAO-B-selective—becomes available for treating depression.

Moclobemide is a RIMA used in treating depression and anxiety, with a purported reduced risk of drug and food interactions compared with other MAOIs. Moclobemide is not approved in the United States, but some patients obtain it elsewhere.

Joffe and Bakish reported on safely combining moclobemide with SSRIs,¹² and a review of MAOIs—including RIMAs—indicated that moclobemide was involved in only 9 of 226 cases of adverse effects and 3 of 105 cases of defined serotonin syndrome.¹³ Most moclobemide-SSRI interactions—including fatalities—involved overdoses in suicide attempts, although toxic symptoms have been reported with clomipramine or meperidine taken at normal dosages.^14,15

In one study,¹⁶ 18 healthy controls received fluoxetine, 20 to 40 mg/d, for 23 days, then were given moclobemide, up to 600 mg/d, or placebo and observed for adverse effects. No indication of serotonin syndrome was observed.

Linezolid is an oxazolidinone antibiotic with relatively weak, nonspecific, but reversible MAO inhibition. Cases of potential serotonin syndrome have been reported with linezolid plus paroxetine¹⁷ or sertraline.¹⁸ Patients in each case were medically ill and taking several other medications, which complicates interpretation of these reports. Nonetheless, physicians should be aware of the potential risk of serotonin syndrome if this antibiotic is combined with serotonergic agents.

Table 2

Serotonergic agents and their actions

Atypical antipsychotics. Original diagnostic criteria for serotonin syndrome excluded the addition of, or increase in, an antipsychotic prior to the syndrome’s onset.¹ However, serotonin syndrome has been reported with combinations of risperidone with paroxetine,¹⁹ olanzapine with mirtazapine and tramadol,²⁰ and olanzapine with lithium and citalopram.²¹ The 5HT2 antagonist effect of these atypical antipsychotics may have led indirectly to overactivation of 5HT1a receptors and serotonin syndrome. In each case, neuroleptic malignant syndrome was ruled out.

Table 3

Signs and symptoms that differentiate 5 hyperthermic states

Tramadol is an analgesic with opioid and serotonin-reuptake inhibiting properties that is metabolized by the cytochrome P (CYP)-450 isoenzyme 2D6. Serotonin syndrome has been reported from interactions between tramadol and sertraline²² and fluoxetine.²³ Possible causes include SSRI inhibition of CYP 2D6 metabolism of tramadol, tramadol abuse,²³ and multiple coadministered medications.²²

Sumatriptan is one of the selective 5HT1D agonists used in treating migraine. Gardner and Lynd²⁴ concluded that most patients tolerate sumatriptan with SSRIs or lithium. They felt they could not ensure the safety of sumatriptan with MAOIs, however, because sumatriptan elimination depends on hepatic MAO activity.

Among the 5HT1D agonists, using sumatriptan, zolmitriptan, rizatriptan, or almotriptan with an MAOI or within 2 weeks of discontinuing an MAOI is contraindicated. Naratriptan and frovatriptan appear less likely to interact with MAOIs, based on FDA-approved labeling.

MDMA. 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) is widely used as a recreational drug, especially at crowded dances (“raves”) and with other drugs.²⁵ This illicit amphetamine derivative stimulates the release of serotonin and inhibits its reuptake.

Kaskey reported the rapid onset of serotonin syndrome when a patient taking lithium and phenelzine ingested MDMA.²⁶ Signs and symptoms of serotonin syndrome also may develop when MDMA is used alone, facilitated by the high ambient temperatures on crowded dance floors and the dancers’ relative dehydration.

Fatalities have been blamed on complications including disseminated intravascular coagulation, rhabdomyolysis, and acute hepatic, renal, or cardiac failure.²⁵ Cases are difficult to interpret because of uncertainty about whether the victim ingested MDMA or another agent or combination.

St. John’s wort (Hypericum perforatum) contains numerous constituents, including hypericin and hyperforin, which have been found to inhibit the synaptic uptake of monoamines, including serotonin.²⁷ Which constituents are responsible for its clinical effect is unclear. Adverse effects from monotherapy include GI symptoms, confusion, dry mouth, dizziness, headache, fatigue, allergic skin reactions, photosensitivity, and urinary frequency.²⁷

Several cases of purported serotonin syndrome have been associated with St. John’s wort alone²⁸ or in combination with SSRIs, nefazodone, or fenfluramine.^29,30 GI symptoms and anxiety were the primary complaints and resolved without complications (adjunctive cyproheptadine was prescribed in two cases, though it is not clear that this agent contributed to resolution).

MISCELLANEOUS COMBINATIONS

Antiretroviral therapy. Five cases of serotonin syndrome were reported in HIV-infected patients taking fluoxetine with antiretroviral therapy.³¹ In particular, the use or addition of ritonavir—a potent CYP 2D6 inhibitor—was implicated, though saquinavir, efavirenz, or grapefruit juice (all primarily CYP 3A4 inhibitors) were also used, suggesting that pharmacokinetic interactions increased serotonergic stimulation. All five patients were taking multiple additional medications and had complex medical and/or psychiatric histories. Reducing SSRI dosages by one-half when used with ritonavir has been recommended to minimize adverse effects from a pharmacokinetic interaction.

Erythromycin was reported to induce serotonin syndrome in a 12-year-old boy when added to ongoing treatment with sertraline, an effect believed to be secondary to CYP 3A4 inhibition of sertraline metabolism.³²

Mirtazapine was reported to induce serotonin syndrome in an elderly man 8 days after it was added to a regimen he had been taking for several years to treat chronic obstructive pulmonary disease.³³ Serotonin syndrome also developed in a 12-year-old boy with Ewing’s sarcoma when the 5HT3 antagonist ondansetron was added to mirtazapine and morphine³⁴ and in an 11-year-old girl with acute lymphoblastic leukemia when ondansetron was added to fentanyl. Interestingly, another report³⁵ suggested using mirtazapine to treat serotonin syndrome caused by serotonergic antagonist effects.

Reports have associated the following combinations with serotonin syndrome, perhaps as the result of pharmacodynamic and/or pharmacokinetic interactions:

• paroxetine plus dextromethorphan and pseudoephedrine
• paroxetine plus nefazodone
• fluoxetine plus clomipramine and buspirone
• fluvoxamine plus buspirone
• fluoxetine plus buspirone
• amitriptyline plus meperidine and venlafaxine
• venlafaxine and dextroamphetamine
• fluoxetine plus clomipramine.

Table 4

Clinical signs that distinguish hyperthermic states

HOW TO RECOGNIZE SEROTONIN SYNDROME

Signs and symptoms of serotonin syndrome can overlap with those seen in neuroleptic malignant syndrome, lethal catatonia, malignant hyperthermia, and anticholinergic toxicity (Table 3),^1,36,37 particularly with fever or hyperthermia (>40.5 °C, 105 °F). Fink³⁷ has opined that acute neurotoxic syndromes such as serotonin syndrome and neuroleptic malignant syndrome also meet criteria for catatonia and are therefore subtypes of catatonia. The types of drugs involved and clinical findings can help distinguish the various hyperthermic states (Table 4).

As mentioned above, original diagnostic criteria for serotonin syndrome excluded the addition of, or increase in, an antipsychotic agent. This exclusion was intended to avoid confusion between serotonin syndrome and neuroleptic malignant syndrome. Co-administering antipsychotic and serotonergic agents requires heightened awareness for both neurotoxic syndromes.

TREATING MILD TO SEVERE CASES

If a patient develops serotonin syndrome, immediately discontinue the suspected agent(s) and observe carefully. In most cases, serotonin syndrome will resolve within 24 hours.

In mild cases, lorazepam, 1 to 2 mg slow IV push every 30 minutes until excessive sedation develops, may help. In moderate to severe cases, agents that block serotonin’s action are recommended,² including:

• cyproheptadine (4 mg po every 4 hours as needed, up to 20 mg in 24 hours)
• propranolol (1 to 3 mg IV every 5 minutes, up to 0.1 mg/kg).

Case reports attest to these agents’ potential benefit. Other clinicians have reported using mirtazapine,³⁵ nitroglycerin,³⁸ and chlorpromazine.¹

Serotonin syndrome symptoms resolved within minutes when IV nitroglycerin was used in a patient with serotonin syndrome and cardiac ischemia. The authors hypothesized that nitroglycerin, via nitric acid, provided an “off” signal for serotonin, though they did not advocate this as a routine treatment.³⁸

The rationale for using chlorpromazine is its potential to block serotonin receptors. I would avoid the routine use of any antipsychotic agent in this setting, however, to minimize the risk of neuroleptic malignant syndrome.

Severe cases. Intensive care observation and treatment is required for patients with severe serotonin syndrome, including evidence of hyperthermia, DIC, rhabdomyolysis, renal failure, or aspiration. In cases of hyperthermia, supportive measures and standard treatments include muscle relaxants, cooling, and endotracheal intubation.

Severe complications are most likely with interactions between MAOIs and serotonergic agents, especially in overdose. Therefore, using such combinations requires close observation.

Related resources

• Di Rosa AE, Morgante L, Spina E et al. Epidemiology and pathoetiology of neurological syndromes with hyperthermia. Funct Neurol 1995;10:111-19.
• Radomski, JW, Dursun SM, Reveley MA, et al. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypothesis 2000;55: 218-24.
• Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol 1997;17:208-21.

Drug brand names

• Almotriptan • Axert
• Amitriptyline • Elavil
• Buspirone • Buspar
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clomipramine • Anafranil
• Cyproheptadine • Periactin
• Dextroamphetamine • Dexedrine
• Dextromethorphan • Delsym
• Efavirenz • Sustiva
• Escitalopram • Lexapro
• Fenfluramine • Pondimin
• Fentanyl • Sublimaze
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Frovatriptan • Frova
• Isocarboxazid • Marplan
• Linezolid • Zyvox
• Meperidine • Demerol
• Mirtazapine • Remeron
• Moclobemide • Aurorix
• Nortriptyline • Pamelor
• Naratriptan, • Amerge
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Ondansetron • Zofran
• Paroxetine • Paxil
• Phenelzine • Nardil
• Propranolol • Inderal
• Risperidone • Risperdal
• Ritonavir • Norvir
• Rizatriptan • Maxalt
• Saquinavir • Invirase
• Selegiline • Eldepryl
• Sertraline • Zoloft
• Sumatriptan • Imitrex
• Tramadol • Ultram
• Tranylcypromine • Parnate
• Trazodone • Desyrel
• Venlafaxine • Effexor
• Zolmitriptan • Zomig

Disclosure

Dr. Sternbach receives research grants from Otsuka America Pharmaceuticals and Eli Lilly and Co. and owns stock in Merck & Co., Pfizer Inc., and Johnson & Johnson.

Promptly identifying serotonin syndrome and acting decisively can keep side effects at the mild end of the spectrum. Symptoms of this potentially dangerous syndrome range from minimal in patients starting selective serotonin reuptake inhibitors (SSRIs) to fatal in those combining monoamine oxidase inhibitors (MAOIs) with serotonergic agents.

This article presents the latest evidence on how to:

• reduce the risk of serotonin syndrome
• recognize its symptoms
• and treat patients with mild to life-threatening symptoms.

WHAT IS SEROTONIN SYNDROME?

Serotonin syndrome is characterized by changes in autonomic, neuromotor, and cognitive-behavioral function (Table 1) triggered by increased serotonergic stimulation. It typically results from pharmacodynamic and/or pharmacokinetic interactions between drugs that increase serotonin activity.^1,2

Table 1

How to recognize serotonin syndrome

The syndrome was first identified in animal studies, followed by case reports in humans. The first review—with suggested diagnostic criteria— was published in 1991.¹

Since then, case reports have described serotonin syndrome with many drug combinations, including nonpsychotropics and illicit drugs. Using an irreversible MAOI with a serotonergic agent is the most toxic reported combination, but any drug or combination that increases serotonin can, in theory, cause serotonin syndrome (Table 2). A clinical scale³ is being developed to define and identify this potentially dangerous state, but no consensus has emerged on diagnostic criteria.

Pathophysiology. Serotonin syndrome’s symptoms and signs appear to result from stimulation of specific central and peripheral serotonin receptors, especially 5HT1a and 5HT2. Others—such as 5HT3 and 5HT4—may also be involved in causing GI symptoms and may affect dopaminergic transmission.

Damaged vascular or pulmonary endothelium, atherosclerosis, hypertension, or hypercholesterolemia may increase the risk for serotonin syndrome. In patients with these common medical conditions, reduced endothelial MAO-A activity or reduced ability to secrete endothelium-derived nitric oxide may diminish the ability to metabolize serotonin.²

POTENTIALLY DANGEROUS COMBINATIONS

MAOIs. Serotonin syndrome has been reported as a result of interactions between MAOIs— including selegiline and reversible MAO-A inhibitors (RIMAs)—and various serotonergic compounds. These reports have included fatalities,⁴ some of which were preceded by severe hyperthermia with complications such as disseminated intravascular coagulation, rhabdomyolysis, and renal failure. Some cases resulted from overdoses, but others did not.

Most disturbingly, some cases occurred after patients had undergone the traditional 2-week washout from the MAOI and then took a serotonergic agent.^5-7 In one instance,⁸ a patient who had discontinued fluoxetine for 6 weeks developed serotonin syndrome after starting tranylcypromine. These cases remind us to be vigilant when switching patients from irreversible MAOIs to serotonergic antidepressants or vice versa—even when recommended wash-out times are observed—and not to combine these agents acutely.

Selegiline is a relatively selective MAO-B inhibitor when used at 5 to 10 mg/d to treat Parkinson’s disease, though it loses MAO-B selectivity when used at higher dosages to treat depression. In a study⁹ of 4,568 patients with Parkinson’s disease who received selegiline (in dosages selective for MAO-B) plus an antidepressant:

• 11 (0.24%) experienced symptoms “possibly” consistent with serotonin syndrome
• 2 others (0.04%) experienced serious serotonin syndrome symptoms.⁹

Serotonin syndrome has been reported when MAO-B-selective doses of selegiline were combined with meperidine¹⁰ and nortriptyline.¹¹ This underscores the need for caution when combining these agents, especially if transdermal selegiline— which would not be MAO-B-selective—becomes available for treating depression.

Moclobemide is a RIMA used in treating depression and anxiety, with a purported reduced risk of drug and food interactions compared with other MAOIs. Moclobemide is not approved in the United States, but some patients obtain it elsewhere.

Joffe and Bakish reported on safely combining moclobemide with SSRIs,¹² and a review of MAOIs—including RIMAs—indicated that moclobemide was involved in only 9 of 226 cases of adverse effects and 3 of 105 cases of defined serotonin syndrome.¹³ Most moclobemide-SSRI interactions—including fatalities—involved overdoses in suicide attempts, although toxic symptoms have been reported with clomipramine or meperidine taken at normal dosages.^14,15

In one study,¹⁶ 18 healthy controls received fluoxetine, 20 to 40 mg/d, for 23 days, then were given moclobemide, up to 600 mg/d, or placebo and observed for adverse effects. No indication of serotonin syndrome was observed.

Linezolid is an oxazolidinone antibiotic with relatively weak, nonspecific, but reversible MAO inhibition. Cases of potential serotonin syndrome have been reported with linezolid plus paroxetine¹⁷ or sertraline.¹⁸ Patients in each case were medically ill and taking several other medications, which complicates interpretation of these reports. Nonetheless, physicians should be aware of the potential risk of serotonin syndrome if this antibiotic is combined with serotonergic agents.

Table 2

Serotonergic agents and their actions

Atypical antipsychotics. Original diagnostic criteria for serotonin syndrome excluded the addition of, or increase in, an antipsychotic prior to the syndrome’s onset.¹ However, serotonin syndrome has been reported with combinations of risperidone with paroxetine,¹⁹ olanzapine with mirtazapine and tramadol,²⁰ and olanzapine with lithium and citalopram.²¹ The 5HT2 antagonist effect of these atypical antipsychotics may have led indirectly to overactivation of 5HT1a receptors and serotonin syndrome. In each case, neuroleptic malignant syndrome was ruled out.

Table 3

Signs and symptoms that differentiate 5 hyperthermic states

Tramadol is an analgesic with opioid and serotonin-reuptake inhibiting properties that is metabolized by the cytochrome P (CYP)-450 isoenzyme 2D6. Serotonin syndrome has been reported from interactions between tramadol and sertraline²² and fluoxetine.²³ Possible causes include SSRI inhibition of CYP 2D6 metabolism of tramadol, tramadol abuse,²³ and multiple coadministered medications.²²

Sumatriptan is one of the selective 5HT1D agonists used in treating migraine. Gardner and Lynd²⁴ concluded that most patients tolerate sumatriptan with SSRIs or lithium. They felt they could not ensure the safety of sumatriptan with MAOIs, however, because sumatriptan elimination depends on hepatic MAO activity.

Among the 5HT1D agonists, using sumatriptan, zolmitriptan, rizatriptan, or almotriptan with an MAOI or within 2 weeks of discontinuing an MAOI is contraindicated. Naratriptan and frovatriptan appear less likely to interact with MAOIs, based on FDA-approved labeling.

MDMA. 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”) is widely used as a recreational drug, especially at crowded dances (“raves”) and with other drugs.²⁵ This illicit amphetamine derivative stimulates the release of serotonin and inhibits its reuptake.

Kaskey reported the rapid onset of serotonin syndrome when a patient taking lithium and phenelzine ingested MDMA.²⁶ Signs and symptoms of serotonin syndrome also may develop when MDMA is used alone, facilitated by the high ambient temperatures on crowded dance floors and the dancers’ relative dehydration.

Fatalities have been blamed on complications including disseminated intravascular coagulation, rhabdomyolysis, and acute hepatic, renal, or cardiac failure.²⁵ Cases are difficult to interpret because of uncertainty about whether the victim ingested MDMA or another agent or combination.

St. John’s wort (Hypericum perforatum) contains numerous constituents, including hypericin and hyperforin, which have been found to inhibit the synaptic uptake of monoamines, including serotonin.²⁷ Which constituents are responsible for its clinical effect is unclear. Adverse effects from monotherapy include GI symptoms, confusion, dry mouth, dizziness, headache, fatigue, allergic skin reactions, photosensitivity, and urinary frequency.²⁷

Several cases of purported serotonin syndrome have been associated with St. John’s wort alone²⁸ or in combination with SSRIs, nefazodone, or fenfluramine.^29,30 GI symptoms and anxiety were the primary complaints and resolved without complications (adjunctive cyproheptadine was prescribed in two cases, though it is not clear that this agent contributed to resolution).

MISCELLANEOUS COMBINATIONS

Antiretroviral therapy. Five cases of serotonin syndrome were reported in HIV-infected patients taking fluoxetine with antiretroviral therapy.³¹ In particular, the use or addition of ritonavir—a potent CYP 2D6 inhibitor—was implicated, though saquinavir, efavirenz, or grapefruit juice (all primarily CYP 3A4 inhibitors) were also used, suggesting that pharmacokinetic interactions increased serotonergic stimulation. All five patients were taking multiple additional medications and had complex medical and/or psychiatric histories. Reducing SSRI dosages by one-half when used with ritonavir has been recommended to minimize adverse effects from a pharmacokinetic interaction.

Erythromycin was reported to induce serotonin syndrome in a 12-year-old boy when added to ongoing treatment with sertraline, an effect believed to be secondary to CYP 3A4 inhibition of sertraline metabolism.³²

Mirtazapine was reported to induce serotonin syndrome in an elderly man 8 days after it was added to a regimen he had been taking for several years to treat chronic obstructive pulmonary disease.³³ Serotonin syndrome also developed in a 12-year-old boy with Ewing’s sarcoma when the 5HT3 antagonist ondansetron was added to mirtazapine and morphine³⁴ and in an 11-year-old girl with acute lymphoblastic leukemia when ondansetron was added to fentanyl. Interestingly, another report³⁵ suggested using mirtazapine to treat serotonin syndrome caused by serotonergic antagonist effects.

Reports have associated the following combinations with serotonin syndrome, perhaps as the result of pharmacodynamic and/or pharmacokinetic interactions:

• paroxetine plus dextromethorphan and pseudoephedrine
• paroxetine plus nefazodone
• fluoxetine plus clomipramine and buspirone
• fluvoxamine plus buspirone
• fluoxetine plus buspirone
• amitriptyline plus meperidine and venlafaxine
• venlafaxine and dextroamphetamine
• fluoxetine plus clomipramine.

Table 4

Clinical signs that distinguish hyperthermic states

HOW TO RECOGNIZE SEROTONIN SYNDROME

Signs and symptoms of serotonin syndrome can overlap with those seen in neuroleptic malignant syndrome, lethal catatonia, malignant hyperthermia, and anticholinergic toxicity (Table 3),^1,36,37 particularly with fever or hyperthermia (>40.5 °C, 105 °F). Fink³⁷ has opined that acute neurotoxic syndromes such as serotonin syndrome and neuroleptic malignant syndrome also meet criteria for catatonia and are therefore subtypes of catatonia. The types of drugs involved and clinical findings can help distinguish the various hyperthermic states (Table 4).

As mentioned above, original diagnostic criteria for serotonin syndrome excluded the addition of, or increase in, an antipsychotic agent. This exclusion was intended to avoid confusion between serotonin syndrome and neuroleptic malignant syndrome. Co-administering antipsychotic and serotonergic agents requires heightened awareness for both neurotoxic syndromes.

TREATING MILD TO SEVERE CASES

If a patient develops serotonin syndrome, immediately discontinue the suspected agent(s) and observe carefully. In most cases, serotonin syndrome will resolve within 24 hours.

In mild cases, lorazepam, 1 to 2 mg slow IV push every 30 minutes until excessive sedation develops, may help. In moderate to severe cases, agents that block serotonin’s action are recommended,² including:

• cyproheptadine (4 mg po every 4 hours as needed, up to 20 mg in 24 hours)
• propranolol (1 to 3 mg IV every 5 minutes, up to 0.1 mg/kg).

Case reports attest to these agents’ potential benefit. Other clinicians have reported using mirtazapine,³⁵ nitroglycerin,³⁸ and chlorpromazine.¹

Serotonin syndrome symptoms resolved within minutes when IV nitroglycerin was used in a patient with serotonin syndrome and cardiac ischemia. The authors hypothesized that nitroglycerin, via nitric acid, provided an “off” signal for serotonin, though they did not advocate this as a routine treatment.³⁸

The rationale for using chlorpromazine is its potential to block serotonin receptors. I would avoid the routine use of any antipsychotic agent in this setting, however, to minimize the risk of neuroleptic malignant syndrome.

Severe cases. Intensive care observation and treatment is required for patients with severe serotonin syndrome, including evidence of hyperthermia, DIC, rhabdomyolysis, renal failure, or aspiration. In cases of hyperthermia, supportive measures and standard treatments include muscle relaxants, cooling, and endotracheal intubation.

Severe complications are most likely with interactions between MAOIs and serotonergic agents, especially in overdose. Therefore, using such combinations requires close observation.

Related resources

• Di Rosa AE, Morgante L, Spina E et al. Epidemiology and pathoetiology of neurological syndromes with hyperthermia. Funct Neurol 1995;10:111-19.
• Radomski, JW, Dursun SM, Reveley MA, et al. An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypothesis 2000;55: 218-24.
• Lane R, Baldwin D. Selective serotonin reuptake inhibitor-induced serotonin syndrome: review. J Clin Psychopharmacol 1997;17:208-21.

Drug brand names

• Almotriptan • Axert
• Amitriptyline • Elavil
• Buspirone • Buspar
• Chlorpromazine • Thorazine
• Citalopram • Celexa
• Clomipramine • Anafranil
• Cyproheptadine • Periactin
• Dextroamphetamine • Dexedrine
• Dextromethorphan • Delsym
• Efavirenz • Sustiva
• Escitalopram • Lexapro
• Fenfluramine • Pondimin
• Fentanyl • Sublimaze
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Frovatriptan • Frova
• Isocarboxazid • Marplan
• Linezolid • Zyvox
• Meperidine • Demerol
• Mirtazapine • Remeron
• Moclobemide • Aurorix
• Nortriptyline • Pamelor
• Naratriptan, • Amerge
• Nefazodone • Serzone
• Olanzapine • Zyprexa
• Ondansetron • Zofran
• Paroxetine • Paxil
• Phenelzine • Nardil
• Propranolol • Inderal
• Risperidone • Risperdal
• Ritonavir • Norvir
• Rizatriptan • Maxalt
• Saquinavir • Invirase
• Selegiline • Eldepryl
• Sertraline • Zoloft
• Sumatriptan • Imitrex
• Tramadol • Ultram
• Tranylcypromine • Parnate
• Trazodone • Desyrel
• Venlafaxine • Effexor
• Zolmitriptan • Zomig

Disclosure

Dr. Sternbach receives research grants from Otsuka America Pharmaceuticals and Eli Lilly and Co. and owns stock in Merck & Co., Pfizer Inc., and Johnson & Johnson.