Evidence-Based Reviews

Psychiatric patients—especially those with substance abuse disorders—are at high risk for HIV infection, which puts psychiatrists on the AIDS pandemic’s front lines.

In the wake of last month’s International AIDS Conference in Thailand, this article supplements American Psychiatric Association guidelines for managing patients with HIV/AIDS.¹ Here is updated information on:

• who is at greatest risk for HIV infection today
• neuropsychiatric side effects of HIV medications
• in-office assessment of HIV-associated cognitive changes
• how to avoid psychotropic/antiretroviral interactions.

HIV and psychiatric patients

Psychiatric patients are among those at highest risk for HIV (Box).^2-4 Cournos and McKinnon⁵ found that HIV seroprevalence among persons with severe mental illness was 4% to 23%compared with 0.4% in the general population.⁶ They defined severe mental illness as schizophrenia, schizoaffective disorder, major depression, or bipolar disorder accompanied by significant functional impairment, disruption of normal life tasks, periods of hospitalization, and need for psychotropics.

Infection rates varied with HIV geographic concentration, presence of comorbid substance use disorders, age, and ethnicity, but not psychiatric diagnosis. Unsafe sex and drug use (including noninjection) were associated with infection, and women were as likely to be infected as men.

Side effects and interactions

‘Triple therapy.’ Combining three antiretroviral agents—highly-active antiretroviral therapy (HAART) or “triple therapy”—is standard treatment for HIV infection in the United States. Initially, HAART was recommended for all patients with early-stage HIV, even if asymptomatic. This changed as antiretrovirals’ side effects—such as peripheral neuropathy with didanosine— and drug resistance from suboptimal adherence became apparent. Viral resistance develops if patients are <95% adherent to antiretroviral regimens.⁷

Antiretroviral therapy is usually started when:

• CD4 lymphocyte count is <200 cells/mm3 or abruptly decreasing
• plasma viral load is >55,000 copies/mL or abruptly increasing
• symptomatic AIDS emerges.

Psychiatric side effects. Psychiatric symptoms—such as depression, anxiety, confusion, psychosis, hallucinations, insomnia, and mania—are common side effects of antiretrovirals and other drugs used to treat HIV and its opportunistic infections and cancers (Table 1).⁸ Two antiretrovirals are of particular interest to psychiatrists:

Efavirenz is a non-nucleoside reverse transcriptase inhibitor that causes vivid dreams, especially when initiated.

Box

Ritonavir is a protease inhibitor that may inhibit psychotropics metabolized by cytochrome P450 3A4 and 2D6 isoenzymes.

Other HIV medications increase or decrease psychotropic blood levels via inhibition or induction of CYP isoenzymes (Table 2).⁹ When a patient is taking ritonavir or another protease inhibitor, reduced starting dosages of selective serotonin reuptake inhibitors (SSRIs) may be appropriate. Benzodiazepine dosages may need to be increased because of ritonavir induction of the enzyme glucuronosyltransferase.

Table 1

Psychiatric side effects of common HIV medications

Table 2

Psychotropic/HIV drug interactions, by cytochrome P-450 isoenzyme

The FDA approved enfuvirtide—the first of the new fusion inhibitor class of antiretroviral agents—in March 2003. Enfuvirtide prevents HIV from entering the target CD4 lymphocyte in patients who show continued viral replication despite ongoing antiretroviral therapy. This agent requires twice-daily subcutaneous injections. Because enfuvirtide can be viewed as a medication of last resort, nonresponse may be especially disheartening to an AIDS patient.

Substances of abuse also interact with HIV medications. A lethal overdose of the street drug MDMA (“Ecstasy”) has been reported in a patient treated with ritonavir.¹⁰ MDMA is metabolized primarily via CYP 2D6. Other substances of abuse metabolized by CYP 2D6 or 3A4—such as amphetamines, ketamine, heroin, cocaine, and gamma-hydroxybutyrate—may cause toxic reactions in patients being treated with protease inhibitors.

Because substance abuse is a common comorbidity of HIV infection, warn patients that using recreational drugs with antiretroviral medications can cause adverse reactions. Extensive drug interaction lists are available on patient education and physician Web sites (see Related Resources).

Table 3

Diagnostic criteria for HIV-associated minor cognitive motor disorder

Lipid and hyperglycemic side effects. Antivirals— especially protease inhibitors —appear to be associated with HIV lipodystrophy, which is associated with cosmetic and serum lipid changes as well as hyperglycemia.¹¹ Facial wasting, buffalo humps, and central intra-abdominal obesity may occur, and elevated serum cholesterol and triglycerides often require treatment with cholesterollowering “statin” drugs.

Though it is unclear whether HIV lipodystrophy increases cardiovascular disease risk, carefully consider the potential effects of psychotropics associated with weight gain, hyper-glycemia, and elevated lipids in patients receiving antiretroviral therapy.

Hepatitis. Patients at risk for HIV infection are also at risk for viral hepatitis. One-quarter of persons with HIV are coinfected with hepatitis C, primarily through IV drug use.¹² Alpha-interferon treatment of hepatitis B and C has been associated with depression. SSRI treatment—such as paroxetine, 20 mg/d—can ease depressive symptoms.¹³

HIV-associated cognitive changes

Minor cognitive-motor disorder(Table 3) and HIV-associated dementia (Table 4) ¹⁴ are typically seen in late-stage HIV infections and are diagnoses of exclusion. Physical or neurologic examination in a patient with HIV/AIDS and altered mental status may show:

• focal deficits indicating a space-occupying lesion (eg, CNS lymphoma or toxoplasmosis)
• sensory changes that may indicate peripheral neuropathy
• ataxia or gait changes that may indicate myelopathy.

Useful neuropsychological tests include the HIV Dementia Rating Scale,¹⁵ Halstead finger-tapping test for motor speed,¹⁶ and the Trailmaking Test, which assesses psychomotor speed and sequencing ability.¹⁷

Antiretroviral therapy appears to reduce the risk of HIV-associated dementia. In a trial conducted at 42 AIDS Clinical Trials Group sites and 7 National Hemophilia Foundation sites, combination reverse transcriptase inhibitors helped preserve or improve neurologic function.¹⁸

Psychostimulants appear to improve HIV-induced brain impairment.¹⁹ Immune modulators—such as tumor necrosis factor-alpha blockers (eg, pentoxifylline)²⁰ and interleukin-1 receptor blockers²¹ —have also been studied for possible beneficial effects on HIV brain disease.

HIV prevention

Because unprotected sex and IV substance use are the primary HIV transmission routes in the United States, assessing psychiatric patients’ sexual and substance use behaviors may help you prevent HIV infection. The CDC offers guidelines for HIV testing, counseling, and referral (see Related Resources).

To identify persons at risk for HIV infection, the CDC recommends asking open-ended questions about risk behaviors, such as: “What are you doing now or what have you done in the past that you think may put you at risk for HIV infection?”²²

The shift of new HIV infection disproportionately into African-American and Hispanic populations suggests the need for more-intensive prevention and education in those communities. CDC guidelines emphasize the importance of using culturally sensitive language when asking about risk behavior. Some individuals may engage in same-sex behaviors but do not identify themselves as “homosexual” or “gay.” In some African-American communities, for example, being “on the down low” is used to describe men—oftentimes married—who have sex with men.

To incorporate HIV-prevention messages and brief behavioral interventions into clinical visits:

• speak with patients about sexual and drug use behaviors in simple, everyday language
• learn about interventions shown to be effective
• become familiar with community resources that address HIV risk reduction.²³

Training. The CDC and Health Resources and Services Administration of the U.S. Department of Health and Human Services offer free training on risk screening and prevention, as well as opportunities for continuing medical education (see Related Resources).

Table 4

Diagnostic criteria for HIV-associated dementia

Advances in antibody testing

Psychiatrists play an important supportive role in encouraging HIV screening of at-risk patients of unknown serostatus and in counseling such patients before, during, and after test results are known.

Rapid lab tests. In 2002, the FDA approved a rapid, highly accurate HIV-1 screening test for serum specimens and in March 2004 approved the same test for screening oral fluid specimens. Test results with serum or an oral swab are available from a laboratory in approximately 20 minutes. In clinical studies submitted to the FDA, the OraQuick oral fluid test correctly identified 99.3% of persons infected with HIV-1 (sensitivity) and 99.9% of those not infected (specificity).

CDC guidelines for HIV counseling and testing have been revised to include rapid testing. Screening tests are most accurate at least 3 months after an HIV exposure—the time required for antibodies to develop. When counseling patients after a reactive test result, emphasize that the result is preliminary and further testing is needed to confirm the result. Counsel patients who have a negative result within 3 months of possible infection to be retested to guard against a possible false-negative result.

Home test kits. An FDA-approved consumer-controlled test kit—Home Access HIV-1 Test System²⁴ —is sold at drug stores without a prescription. The customer pricks a finger with a special device, places drops of blood on a specially treated card, and mails the card to a licensed laboratory. Anonymous identification numbers are used when phoning for the results.

Customers may speak to a counselor before taking the test, while awaiting results, and when results are given. All individuals with a reactive test result are referred for a more-specific test and receive information and resources on treatment and support services.

Counseling the HIV patient

The psychological impact of positive HIV antibody test results on psychiatric patients has not been studied. Persons without psychiatric disorders commonly experience anxiety and depression immediately after learning of a positive result. Unless the patient has HIV-related physical symptoms, these psychological sequelae often return to baseline—similar to when the blood sample was drawn—within 2 weeks.²⁵

Patients need to know that a positive HIV test result is no longer associated with death within 2 to 3 years. During a 2-year period, for example, disease progression from HIV infection to AIDS decreased 7-fold among patients who started antiretroviral therapy with a CD4+ T-cell count >350 cells/mm3, compared with others who were monitored without therapy.²⁶ This may be especially important to reinforce with newly-diagnosed patients unfamiliar with advances in HAART.

Medication adherence. To increase patients’ adherence to antiretroviral therapy:

• express interest that they are taking their medications
• use psychotherapy to help them solve problems that interfere with adherence.

Suicide risk. In the 1980s, significantly increased suicide rates were reported among HIV-infected persons. For example, the suicide rate in 1985 for New York City men ages 20 to 59 living with an AIDS diagnosis was 36 times higher than that of similar men without AIDS.²⁷ A later study of HIV infection in New York male suicide victims from 1991 to 1993 suggested that HIV serostatus was associated with a modest increase—at most—in suicide risk. That study considered the interplay of other suicide risk factors, such as substance abuse.²⁸

Related resources

• Guidelines for HIV counseling, testing, and referral. Centers for Disease Control and Prevention. www.cdc.gov/mmwr/preview/mmwrhtml/rr5019a1.htm
• Training in HIV prevention and counseling. National Network of STD/HIV Prevention Training Centers (http://depts.washington.edu/nnptc) and AIDS Education and Training Centers National Resource Center (http://www.aids-ed.org)
• Rapid HIV testing. Centers for Disease Control and Prevention. http://www.cdc.gov/hiv/rapid_testing/
• Cytochrome P450 drug interaction table. Indiana University School of Medicine. Division of Clinical Pharmacology. www.drug-interactions.com

Drug brand names

• Buspirone • BuSpar
• Carbamazepine • Carbatrol
• Citalopram • Celexa
• Clomipramine • Anafranil
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Imipramine • Tofranil
• Mirtazapine • Remeron
• Paroxetine • Paxil
• Sertraline • Zoloft
• Trazodone • Desyrel
• Venlafaxine • Effexor

Disclosure

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

Psychiatric patients—especially those with substance abuse disorders—are at high risk for HIV infection, which puts psychiatrists on the AIDS pandemic’s front lines.

In the wake of last month’s International AIDS Conference in Thailand, this article supplements American Psychiatric Association guidelines for managing patients with HIV/AIDS.¹ Here is updated information on:

• who is at greatest risk for HIV infection today
• neuropsychiatric side effects of HIV medications
• in-office assessment of HIV-associated cognitive changes
• how to avoid psychotropic/antiretroviral interactions.

HIV and psychiatric patients

Psychiatric patients are among those at highest risk for HIV (Box).^2-4 Cournos and McKinnon⁵ found that HIV seroprevalence among persons with severe mental illness was 4% to 23%compared with 0.4% in the general population.⁶ They defined severe mental illness as schizophrenia, schizoaffective disorder, major depression, or bipolar disorder accompanied by significant functional impairment, disruption of normal life tasks, periods of hospitalization, and need for psychotropics.

Infection rates varied with HIV geographic concentration, presence of comorbid substance use disorders, age, and ethnicity, but not psychiatric diagnosis. Unsafe sex and drug use (including noninjection) were associated with infection, and women were as likely to be infected as men.

Side effects and interactions

‘Triple therapy.’ Combining three antiretroviral agents—highly-active antiretroviral therapy (HAART) or “triple therapy”—is standard treatment for HIV infection in the United States. Initially, HAART was recommended for all patients with early-stage HIV, even if asymptomatic. This changed as antiretrovirals’ side effects—such as peripheral neuropathy with didanosine— and drug resistance from suboptimal adherence became apparent. Viral resistance develops if patients are <95% adherent to antiretroviral regimens.⁷

Antiretroviral therapy is usually started when:

• CD4 lymphocyte count is <200 cells/mm3 or abruptly decreasing
• plasma viral load is >55,000 copies/mL or abruptly increasing
• symptomatic AIDS emerges.

Psychiatric side effects. Psychiatric symptoms—such as depression, anxiety, confusion, psychosis, hallucinations, insomnia, and mania—are common side effects of antiretrovirals and other drugs used to treat HIV and its opportunistic infections and cancers (Table 1).⁸ Two antiretrovirals are of particular interest to psychiatrists:

Efavirenz is a non-nucleoside reverse transcriptase inhibitor that causes vivid dreams, especially when initiated.

Box

Ritonavir is a protease inhibitor that may inhibit psychotropics metabolized by cytochrome P450 3A4 and 2D6 isoenzymes.

Other HIV medications increase or decrease psychotropic blood levels via inhibition or induction of CYP isoenzymes (Table 2).⁹ When a patient is taking ritonavir or another protease inhibitor, reduced starting dosages of selective serotonin reuptake inhibitors (SSRIs) may be appropriate. Benzodiazepine dosages may need to be increased because of ritonavir induction of the enzyme glucuronosyltransferase.

Table 1

Psychiatric side effects of common HIV medications

Table 2

Psychotropic/HIV drug interactions, by cytochrome P-450 isoenzyme

The FDA approved enfuvirtide—the first of the new fusion inhibitor class of antiretroviral agents—in March 2003. Enfuvirtide prevents HIV from entering the target CD4 lymphocyte in patients who show continued viral replication despite ongoing antiretroviral therapy. This agent requires twice-daily subcutaneous injections. Because enfuvirtide can be viewed as a medication of last resort, nonresponse may be especially disheartening to an AIDS patient.

Substances of abuse also interact with HIV medications. A lethal overdose of the street drug MDMA (“Ecstasy”) has been reported in a patient treated with ritonavir.¹⁰ MDMA is metabolized primarily via CYP 2D6. Other substances of abuse metabolized by CYP 2D6 or 3A4—such as amphetamines, ketamine, heroin, cocaine, and gamma-hydroxybutyrate—may cause toxic reactions in patients being treated with protease inhibitors.

Because substance abuse is a common comorbidity of HIV infection, warn patients that using recreational drugs with antiretroviral medications can cause adverse reactions. Extensive drug interaction lists are available on patient education and physician Web sites (see Related Resources).

Table 3

Diagnostic criteria for HIV-associated minor cognitive motor disorder

Lipid and hyperglycemic side effects. Antivirals— especially protease inhibitors —appear to be associated with HIV lipodystrophy, which is associated with cosmetic and serum lipid changes as well as hyperglycemia.¹¹ Facial wasting, buffalo humps, and central intra-abdominal obesity may occur, and elevated serum cholesterol and triglycerides often require treatment with cholesterollowering “statin” drugs.

Though it is unclear whether HIV lipodystrophy increases cardiovascular disease risk, carefully consider the potential effects of psychotropics associated with weight gain, hyper-glycemia, and elevated lipids in patients receiving antiretroviral therapy.

Hepatitis. Patients at risk for HIV infection are also at risk for viral hepatitis. One-quarter of persons with HIV are coinfected with hepatitis C, primarily through IV drug use.¹² Alpha-interferon treatment of hepatitis B and C has been associated with depression. SSRI treatment—such as paroxetine, 20 mg/d—can ease depressive symptoms.¹³

HIV-associated cognitive changes

Minor cognitive-motor disorder(Table 3) and HIV-associated dementia (Table 4) ¹⁴ are typically seen in late-stage HIV infections and are diagnoses of exclusion. Physical or neurologic examination in a patient with HIV/AIDS and altered mental status may show:

• focal deficits indicating a space-occupying lesion (eg, CNS lymphoma or toxoplasmosis)
• sensory changes that may indicate peripheral neuropathy
• ataxia or gait changes that may indicate myelopathy.

Useful neuropsychological tests include the HIV Dementia Rating Scale,¹⁵ Halstead finger-tapping test for motor speed,¹⁶ and the Trailmaking Test, which assesses psychomotor speed and sequencing ability.¹⁷

Antiretroviral therapy appears to reduce the risk of HIV-associated dementia. In a trial conducted at 42 AIDS Clinical Trials Group sites and 7 National Hemophilia Foundation sites, combination reverse transcriptase inhibitors helped preserve or improve neurologic function.¹⁸

Psychostimulants appear to improve HIV-induced brain impairment.¹⁹ Immune modulators—such as tumor necrosis factor-alpha blockers (eg, pentoxifylline)²⁰ and interleukin-1 receptor blockers²¹ —have also been studied for possible beneficial effects on HIV brain disease.

HIV prevention

Because unprotected sex and IV substance use are the primary HIV transmission routes in the United States, assessing psychiatric patients’ sexual and substance use behaviors may help you prevent HIV infection. The CDC offers guidelines for HIV testing, counseling, and referral (see Related Resources).

To identify persons at risk for HIV infection, the CDC recommends asking open-ended questions about risk behaviors, such as: “What are you doing now or what have you done in the past that you think may put you at risk for HIV infection?”²²

The shift of new HIV infection disproportionately into African-American and Hispanic populations suggests the need for more-intensive prevention and education in those communities. CDC guidelines emphasize the importance of using culturally sensitive language when asking about risk behavior. Some individuals may engage in same-sex behaviors but do not identify themselves as “homosexual” or “gay.” In some African-American communities, for example, being “on the down low” is used to describe men—oftentimes married—who have sex with men.

To incorporate HIV-prevention messages and brief behavioral interventions into clinical visits:

• speak with patients about sexual and drug use behaviors in simple, everyday language
• learn about interventions shown to be effective
• become familiar with community resources that address HIV risk reduction.²³

Training. The CDC and Health Resources and Services Administration of the U.S. Department of Health and Human Services offer free training on risk screening and prevention, as well as opportunities for continuing medical education (see Related Resources).

Table 4

Diagnostic criteria for HIV-associated dementia

Advances in antibody testing

Psychiatrists play an important supportive role in encouraging HIV screening of at-risk patients of unknown serostatus and in counseling such patients before, during, and after test results are known.

Rapid lab tests. In 2002, the FDA approved a rapid, highly accurate HIV-1 screening test for serum specimens and in March 2004 approved the same test for screening oral fluid specimens. Test results with serum or an oral swab are available from a laboratory in approximately 20 minutes. In clinical studies submitted to the FDA, the OraQuick oral fluid test correctly identified 99.3% of persons infected with HIV-1 (sensitivity) and 99.9% of those not infected (specificity).

CDC guidelines for HIV counseling and testing have been revised to include rapid testing. Screening tests are most accurate at least 3 months after an HIV exposure—the time required for antibodies to develop. When counseling patients after a reactive test result, emphasize that the result is preliminary and further testing is needed to confirm the result. Counsel patients who have a negative result within 3 months of possible infection to be retested to guard against a possible false-negative result.

Home test kits. An FDA-approved consumer-controlled test kit—Home Access HIV-1 Test System²⁴ —is sold at drug stores without a prescription. The customer pricks a finger with a special device, places drops of blood on a specially treated card, and mails the card to a licensed laboratory. Anonymous identification numbers are used when phoning for the results.

Customers may speak to a counselor before taking the test, while awaiting results, and when results are given. All individuals with a reactive test result are referred for a more-specific test and receive information and resources on treatment and support services.

Counseling the HIV patient

The psychological impact of positive HIV antibody test results on psychiatric patients has not been studied. Persons without psychiatric disorders commonly experience anxiety and depression immediately after learning of a positive result. Unless the patient has HIV-related physical symptoms, these psychological sequelae often return to baseline—similar to when the blood sample was drawn—within 2 weeks.²⁵

Patients need to know that a positive HIV test result is no longer associated with death within 2 to 3 years. During a 2-year period, for example, disease progression from HIV infection to AIDS decreased 7-fold among patients who started antiretroviral therapy with a CD4+ T-cell count >350 cells/mm3, compared with others who were monitored without therapy.²⁶ This may be especially important to reinforce with newly-diagnosed patients unfamiliar with advances in HAART.

Medication adherence. To increase patients’ adherence to antiretroviral therapy:

• express interest that they are taking their medications
• use psychotherapy to help them solve problems that interfere with adherence.

Suicide risk. In the 1980s, significantly increased suicide rates were reported among HIV-infected persons. For example, the suicide rate in 1985 for New York City men ages 20 to 59 living with an AIDS diagnosis was 36 times higher than that of similar men without AIDS.²⁷ A later study of HIV infection in New York male suicide victims from 1991 to 1993 suggested that HIV serostatus was associated with a modest increase—at most—in suicide risk. That study considered the interplay of other suicide risk factors, such as substance abuse.²⁸

Related resources

• Guidelines for HIV counseling, testing, and referral. Centers for Disease Control and Prevention. www.cdc.gov/mmwr/preview/mmwrhtml/rr5019a1.htm
• Training in HIV prevention and counseling. National Network of STD/HIV Prevention Training Centers (http://depts.washington.edu/nnptc) and AIDS Education and Training Centers National Resource Center (http://www.aids-ed.org)
• Rapid HIV testing. Centers for Disease Control and Prevention. http://www.cdc.gov/hiv/rapid_testing/
• Cytochrome P450 drug interaction table. Indiana University School of Medicine. Division of Clinical Pharmacology. www.drug-interactions.com

Drug brand names

• Buspirone • BuSpar
• Carbamazepine • Carbatrol
• Citalopram • Celexa
• Clomipramine • Anafranil
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Imipramine • Tofranil
• Mirtazapine • Remeron
• Paroxetine • Paxil
• Sertraline • Zoloft
• Trazodone • Desyrel
• Venlafaxine • Effexor

Disclosure

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

Psychiatric patients—especially those with substance abuse disorders—are at high risk for HIV infection, which puts psychiatrists on the AIDS pandemic’s front lines.

In the wake of last month’s International AIDS Conference in Thailand, this article supplements American Psychiatric Association guidelines for managing patients with HIV/AIDS.¹ Here is updated information on:

• who is at greatest risk for HIV infection today
• neuropsychiatric side effects of HIV medications
• in-office assessment of HIV-associated cognitive changes
• how to avoid psychotropic/antiretroviral interactions.

HIV and psychiatric patients

Psychiatric patients are among those at highest risk for HIV (Box).^2-4 Cournos and McKinnon⁵ found that HIV seroprevalence among persons with severe mental illness was 4% to 23%compared with 0.4% in the general population.⁶ They defined severe mental illness as schizophrenia, schizoaffective disorder, major depression, or bipolar disorder accompanied by significant functional impairment, disruption of normal life tasks, periods of hospitalization, and need for psychotropics.

Infection rates varied with HIV geographic concentration, presence of comorbid substance use disorders, age, and ethnicity, but not psychiatric diagnosis. Unsafe sex and drug use (including noninjection) were associated with infection, and women were as likely to be infected as men.

Side effects and interactions

‘Triple therapy.’ Combining three antiretroviral agents—highly-active antiretroviral therapy (HAART) or “triple therapy”—is standard treatment for HIV infection in the United States. Initially, HAART was recommended for all patients with early-stage HIV, even if asymptomatic. This changed as antiretrovirals’ side effects—such as peripheral neuropathy with didanosine— and drug resistance from suboptimal adherence became apparent. Viral resistance develops if patients are <95% adherent to antiretroviral regimens.⁷

Antiretroviral therapy is usually started when:

• CD4 lymphocyte count is <200 cells/mm3 or abruptly decreasing
• plasma viral load is >55,000 copies/mL or abruptly increasing
• symptomatic AIDS emerges.

Psychiatric side effects. Psychiatric symptoms—such as depression, anxiety, confusion, psychosis, hallucinations, insomnia, and mania—are common side effects of antiretrovirals and other drugs used to treat HIV and its opportunistic infections and cancers (Table 1).⁸ Two antiretrovirals are of particular interest to psychiatrists:

Efavirenz is a non-nucleoside reverse transcriptase inhibitor that causes vivid dreams, especially when initiated.

Box

Ritonavir is a protease inhibitor that may inhibit psychotropics metabolized by cytochrome P450 3A4 and 2D6 isoenzymes.

Other HIV medications increase or decrease psychotropic blood levels via inhibition or induction of CYP isoenzymes (Table 2).⁹ When a patient is taking ritonavir or another protease inhibitor, reduced starting dosages of selective serotonin reuptake inhibitors (SSRIs) may be appropriate. Benzodiazepine dosages may need to be increased because of ritonavir induction of the enzyme glucuronosyltransferase.

Table 1

Psychiatric side effects of common HIV medications

Table 2

Psychotropic/HIV drug interactions, by cytochrome P-450 isoenzyme

The FDA approved enfuvirtide—the first of the new fusion inhibitor class of antiretroviral agents—in March 2003. Enfuvirtide prevents HIV from entering the target CD4 lymphocyte in patients who show continued viral replication despite ongoing antiretroviral therapy. This agent requires twice-daily subcutaneous injections. Because enfuvirtide can be viewed as a medication of last resort, nonresponse may be especially disheartening to an AIDS patient.

Substances of abuse also interact with HIV medications. A lethal overdose of the street drug MDMA (“Ecstasy”) has been reported in a patient treated with ritonavir.¹⁰ MDMA is metabolized primarily via CYP 2D6. Other substances of abuse metabolized by CYP 2D6 or 3A4—such as amphetamines, ketamine, heroin, cocaine, and gamma-hydroxybutyrate—may cause toxic reactions in patients being treated with protease inhibitors.

Because substance abuse is a common comorbidity of HIV infection, warn patients that using recreational drugs with antiretroviral medications can cause adverse reactions. Extensive drug interaction lists are available on patient education and physician Web sites (see Related Resources).

Table 3

Diagnostic criteria for HIV-associated minor cognitive motor disorder

Lipid and hyperglycemic side effects. Antivirals— especially protease inhibitors —appear to be associated with HIV lipodystrophy, which is associated with cosmetic and serum lipid changes as well as hyperglycemia.¹¹ Facial wasting, buffalo humps, and central intra-abdominal obesity may occur, and elevated serum cholesterol and triglycerides often require treatment with cholesterollowering “statin” drugs.

Though it is unclear whether HIV lipodystrophy increases cardiovascular disease risk, carefully consider the potential effects of psychotropics associated with weight gain, hyper-glycemia, and elevated lipids in patients receiving antiretroviral therapy.

Hepatitis. Patients at risk for HIV infection are also at risk for viral hepatitis. One-quarter of persons with HIV are coinfected with hepatitis C, primarily through IV drug use.¹² Alpha-interferon treatment of hepatitis B and C has been associated with depression. SSRI treatment—such as paroxetine, 20 mg/d—can ease depressive symptoms.¹³

HIV-associated cognitive changes

Minor cognitive-motor disorder(Table 3) and HIV-associated dementia (Table 4) ¹⁴ are typically seen in late-stage HIV infections and are diagnoses of exclusion. Physical or neurologic examination in a patient with HIV/AIDS and altered mental status may show:

• focal deficits indicating a space-occupying lesion (eg, CNS lymphoma or toxoplasmosis)
• sensory changes that may indicate peripheral neuropathy
• ataxia or gait changes that may indicate myelopathy.

Useful neuropsychological tests include the HIV Dementia Rating Scale,¹⁵ Halstead finger-tapping test for motor speed,¹⁶ and the Trailmaking Test, which assesses psychomotor speed and sequencing ability.¹⁷

Antiretroviral therapy appears to reduce the risk of HIV-associated dementia. In a trial conducted at 42 AIDS Clinical Trials Group sites and 7 National Hemophilia Foundation sites, combination reverse transcriptase inhibitors helped preserve or improve neurologic function.¹⁸

Psychostimulants appear to improve HIV-induced brain impairment.¹⁹ Immune modulators—such as tumor necrosis factor-alpha blockers (eg, pentoxifylline)²⁰ and interleukin-1 receptor blockers²¹ —have also been studied for possible beneficial effects on HIV brain disease.

HIV prevention

Because unprotected sex and IV substance use are the primary HIV transmission routes in the United States, assessing psychiatric patients’ sexual and substance use behaviors may help you prevent HIV infection. The CDC offers guidelines for HIV testing, counseling, and referral (see Related Resources).

To identify persons at risk for HIV infection, the CDC recommends asking open-ended questions about risk behaviors, such as: “What are you doing now or what have you done in the past that you think may put you at risk for HIV infection?”²²

The shift of new HIV infection disproportionately into African-American and Hispanic populations suggests the need for more-intensive prevention and education in those communities. CDC guidelines emphasize the importance of using culturally sensitive language when asking about risk behavior. Some individuals may engage in same-sex behaviors but do not identify themselves as “homosexual” or “gay.” In some African-American communities, for example, being “on the down low” is used to describe men—oftentimes married—who have sex with men.

To incorporate HIV-prevention messages and brief behavioral interventions into clinical visits:

• speak with patients about sexual and drug use behaviors in simple, everyday language
• learn about interventions shown to be effective
• become familiar with community resources that address HIV risk reduction.²³

Training. The CDC and Health Resources and Services Administration of the U.S. Department of Health and Human Services offer free training on risk screening and prevention, as well as opportunities for continuing medical education (see Related Resources).

Table 4

Diagnostic criteria for HIV-associated dementia

Advances in antibody testing

Psychiatrists play an important supportive role in encouraging HIV screening of at-risk patients of unknown serostatus and in counseling such patients before, during, and after test results are known.

Rapid lab tests. In 2002, the FDA approved a rapid, highly accurate HIV-1 screening test for serum specimens and in March 2004 approved the same test for screening oral fluid specimens. Test results with serum or an oral swab are available from a laboratory in approximately 20 minutes. In clinical studies submitted to the FDA, the OraQuick oral fluid test correctly identified 99.3% of persons infected with HIV-1 (sensitivity) and 99.9% of those not infected (specificity).

CDC guidelines for HIV counseling and testing have been revised to include rapid testing. Screening tests are most accurate at least 3 months after an HIV exposure—the time required for antibodies to develop. When counseling patients after a reactive test result, emphasize that the result is preliminary and further testing is needed to confirm the result. Counsel patients who have a negative result within 3 months of possible infection to be retested to guard against a possible false-negative result.

Home test kits. An FDA-approved consumer-controlled test kit—Home Access HIV-1 Test System²⁴ —is sold at drug stores without a prescription. The customer pricks a finger with a special device, places drops of blood on a specially treated card, and mails the card to a licensed laboratory. Anonymous identification numbers are used when phoning for the results.

Customers may speak to a counselor before taking the test, while awaiting results, and when results are given. All individuals with a reactive test result are referred for a more-specific test and receive information and resources on treatment and support services.

Counseling the HIV patient

The psychological impact of positive HIV antibody test results on psychiatric patients has not been studied. Persons without psychiatric disorders commonly experience anxiety and depression immediately after learning of a positive result. Unless the patient has HIV-related physical symptoms, these psychological sequelae often return to baseline—similar to when the blood sample was drawn—within 2 weeks.²⁵

Patients need to know that a positive HIV test result is no longer associated with death within 2 to 3 years. During a 2-year period, for example, disease progression from HIV infection to AIDS decreased 7-fold among patients who started antiretroviral therapy with a CD4+ T-cell count >350 cells/mm3, compared with others who were monitored without therapy.²⁶ This may be especially important to reinforce with newly-diagnosed patients unfamiliar with advances in HAART.

Medication adherence. To increase patients’ adherence to antiretroviral therapy:

• express interest that they are taking their medications
• use psychotherapy to help them solve problems that interfere with adherence.

Suicide risk. In the 1980s, significantly increased suicide rates were reported among HIV-infected persons. For example, the suicide rate in 1985 for New York City men ages 20 to 59 living with an AIDS diagnosis was 36 times higher than that of similar men without AIDS.²⁷ A later study of HIV infection in New York male suicide victims from 1991 to 1993 suggested that HIV serostatus was associated with a modest increase—at most—in suicide risk. That study considered the interplay of other suicide risk factors, such as substance abuse.²⁸

Related resources

• Guidelines for HIV counseling, testing, and referral. Centers for Disease Control and Prevention. www.cdc.gov/mmwr/preview/mmwrhtml/rr5019a1.htm
• Training in HIV prevention and counseling. National Network of STD/HIV Prevention Training Centers (http://depts.washington.edu/nnptc) and AIDS Education and Training Centers National Resource Center (http://www.aids-ed.org)
• Rapid HIV testing. Centers for Disease Control and Prevention. http://www.cdc.gov/hiv/rapid_testing/
• Cytochrome P450 drug interaction table. Indiana University School of Medicine. Division of Clinical Pharmacology. www.drug-interactions.com

Drug brand names

• Buspirone • BuSpar
• Carbamazepine • Carbatrol
• Citalopram • Celexa
• Clomipramine • Anafranil
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Imipramine • Tofranil
• Mirtazapine • Remeron
• Paroxetine • Paxil
• Sertraline • Zoloft
• Trazodone • Desyrel
• Venlafaxine • Effexor

Disclosure

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

Bedside psychotherapy is not only possible but invaluable for some medical-surgical patients, despite hospitals’ distractions, lack of privacy, and short stays. If you are asked to evaluate a hospitalized patient, a 5-step strategy can help you:

• identify acute psychiatric problems that psychotherapy can help
• watch for common psychodynamic themes
• choose a beneficial psychotherapy
• integrate drug/psychotherapy, as needed
• quickly establish rapport by using an effective bedside manner.

Case report: A deeply wounded patient

Ms. T, age 45, was admitted to the trauma unit with gunshot wounds. Her estranged husband shot her during an argument and killed her 14-year-old son, who tried to help her.

She underwent multiple surgeries to repair internal organs and endured intense pain. She was medically stable after 10 days, and the surgical team called on the psychiatric consultation-liaison (C-L) service to evaluate her “depression.”

Table 1

5 steps to bedside psychotherapy

Ms. T told the psychiatrist she was having nightmares and re-experiencing the shootings. She felt overwhelming guilt and blamed herself for her son’s death. She reported hyperarousal, muscle tension, and palpitations. She also worried about facing her son’s killer in court.

The C-L psychiatrist felt Ms. T would benefit from medication and psychotherapy for anxiety while hospitalized.

Obstacles to bedside psychotherapy

Hospitalized patients do not usually seek psychiatric consultation but are referred by their physicians. Pain and injuries, medications, and illness can limit patients’ energy and motivation to participate in therapy, as well as their concentration and cognition. Moreover, bedside psychotherapy sessions are likely to be interrupted for blood draws, medical rounds, investigations, and procedures.

Despite these obstacles, medical patients are often receptive to psychiatric care.¹ An alliance often develops within minutes, and the psychiatrist can achieve effective psychotherapy during a single bedside visit.²

The Academy of Psychosomatic Medicine considers psychotherapy a required skill for anyone who evaluates and treats psychiatric disorders in general medical settings.³

How to overcome obstacles

STEP 1. Identify when psychotherapy may help. Not every problem or patient benefits from bedside psychotherapy. The C-L psychiatrist’s first task is to identify:

• Problems that warrant psychotherapy. These may include depression, bereavement, adjustment disorder, maladaptive coping, anxiety related to medical procedures, acute stress disorder, posttraumatic stress disorder (PTSD), and demoralization.
• Patients likely to benefit. Look for evidence of ego strength, ability to interact in the first session, psychological-mindedness, ability to experience feeling, and absence of severe cognitive deficit.²

These patient traits are not prerequisites, however, and clinical judgment applies on a case-by-case basis.

Demoralization is the most common reason for psychiatric evaluation of medically-ill patients, though their physicians typically request a “depression” evaluation.⁴ Demoralization is an understandable response to serious illness or disabling, agonizing, or deforming treatment.⁵ Symptoms include anxiety, guilt, shame, depression, diminished self-worth, and possibly somatic complaints or preoccupation.⁶

Ms. T was experiencing survivor guilt—she blamed herself for her son’s death—and she described herself as feeling “lost.” Four strategies can treat demoralization (Table 2).

STEP 2. Watch for common psychodynamic themes, such as denial of illness, loss of control, dependency and regression, fear of abandonment, loss of identity, and fear of death.⁷ Other issues include survivor guilt, anger at the treatment team or family, and knowing someone who had a negative experience with the same illness or treatment.

Identifying these themes and integrating them into the treatment plan can improve outcomes. For example:

• Giving an empathic validation can help overcome fear of abandonment.
• Letting the patient choose the time when blood is drawn increases feelings of control.

Table 2

4 bedside strategies to treat demoralization

STEP 3. Select appropriate psychotherapy. The psychiatrist’s challenge is to know:

• when to use which approach
• when to combine approaches
• what problems each approach targets.

A hospitalized medical patient often has a fluctuating course and may require more than one approach—or even a different approach at each visit. Thus, flexibility and creativity are keys to successful bedside psychotherapy.

STEP 4. Integrate psychotherapy with medication, as needed. Consider target symptoms for using psychotropics and how medication may help the patient attain treatment goals. Does the patient require medication to allow psychotherapy to occur?

STEP 5. Combine steps 1 to 4 with a good bedside manner. An empathetic approach will help most patients, no matter which psychotherapy model you use (Box 1).^4,8,9

Case continued: First aid for the ego

The C-L psychiatrist diagnosed Ms. T as having acute stress disorder and identified four target symptoms: bereavement, demoralization, anxiety, and hyperarousal. During the initial interview, Ms. T appeared to be psychologically-minded and open to psychiatric intervention.

The psychiatrist considered her at high risk for PTSD and prescribed citalopram, 20 mg/d, because selective serotonin reuptake inhibitors may prevent PTSD. Ms. T was also given clonazepam, 0.25 mg as needed, for severe anxiety.

The psychiatrist visited her 20 to 30 minutes daily. Initial psychotherapy focused on supporting Ms. T’s ego. Resilience-building interviews—using questions to counter feelings of despair, meaninglessness, and sorrow—addressed her demoralization and grief. She regained some sense of meaning and hope by focusing on caring for her other son and on her family’s love. She also found a sense of peace through prayer and by visualizing her lost son safe in God’s hands.

The psychiatrist also taught her relaxation skills to manage her anxiety symptoms. These included abdominal breathing and guided imagery (picturing herself in a safe, comforting place).

Box 1

Psychotherapeutic options

Three psychotherapeutic approaches are particularly useful at bedside—supportive therapy and resilience-building, cognitive-behavioral therapy (CBT), and psychodynamic therapy.

Supportive therapy and resilience-building is the most common bedside model. Supportive therapy’s goal is to strengthen coping skills, thereby reducing anxiety and enhancing well-being, self-esteem, and function.

Fostering a good working relationship is the first priority.¹⁰ The therapist works to contain the patient’s anxiety and provide an “auxiliary ego” to supplement his or her reality testing, planning and judgment, and sense of self.^2,10 Supportive techniques include suggestion, clarification, limit-setting, reinforcement, reassurance, and empathic listening.

Much of the work relies on positive transference to build the supportive relationship.^8,10 Transference is interpreted only when negative transference disrupts treatment; the therapeutic goal is to decrease the patient’s anxiety. Resilience-building questions (Box 2)^4,11 help identify the patient’s skills and competencies and mobilize his or her internal resources.

CBT attempts to identify, challenge, and correct a patient’s inaccurate or dysfunctional beliefs about illness, treatment, or self-image. For example:

• a patient with second-degree burns may be convinced she is the world’s ugliest person
• a patient facing an operation may believe he will be permanently disabled, as was his father after a similar procedure.

CBT can also help dispel beliefs that psychiatric treatment is for “crazy” people.

Behavioral therapy can help patients manage distress related to their medical care, such as shortness of breath while being weaned from a ventilator or arousal and anxiety related to procedures. Techniques that work in office settings—systematic desensitization, in vivo exposure, breathing exercises, progressive muscle relaxation, guided imagery, meditation, and hypnosis—also can be effective at bedside.¹²

Psychodynamic therapy. Patients can develop insight through psychodynamic therapy, even in brief therapeutic relationships. Useful bedside techniques include clarification, confrontation, and interpretation of behavior, conflict, and transference.

For example, a patient who survived heart surgery later developed depression and suicidal ideation. Psychiatric interview revealed she was experiencing survivor guilt because her mother had died from a heart attack. Emphatic clarification and validation of feelings often can help lift such a patient’s mood and allow a dialogue to begin.

A “psychodynamic life-narrative” approach¹ can help treat depression in medically ill patients. The therapist first asks the patient to describe the illness’ meaning in his or her lifespan, then formulates a statement (the “narrative”) of its meaning at the moment. The narrative is intended to:

• create a new perspective
• increase self-esteem by emphasizing the patient’s strengths
• support coping mechanisms that worked in the past.

This approach also can help the patient understand that a psychiatric symptom is an understandable response when a previously successful adaptive method cannot be used.

Choosing a psychotherapy

Three factors—patient characteristics, therapist characteristics, and evidence—determine the psychotherapeutic approach.

Patient characteristics include ego functioning level and maturity, object relationship stability,¹³ history and experience of psychotherapeutic treatment, personality and coping style, and physical condition. For example:

• CBT and education may be effective for patients who cope through analytical thinking, controlling emotional expression, and managing situations.
• Psychodynamic methods may help those who cope through expressing feelings, self-reflection, and a wish to be understood.

Therapist characteristics include experience, preference, and degree of comfort in conducting each therapeutic approach, as well as time and schedule.

Box 2

Evidence of efficacy. Psychiatric literature supports using CBT for depressive cognition in major depression,¹⁴ resilience-building interviews for demoralization,⁴ and behavioral therapy and relaxation for anxiety related to medical procedures.¹²

Case continued: Coming home

As Ms. T’s medical condition improved over several days and her discharge was planned, the psychiatrist began to emphasize practical issues, such as:

• limiting visitation to allow her time to grieve
• addressing her anxieties about outpatient treatment and moving in with her parents.

At discharge, Ms. T was taking citalopram, 40 mg/d, and clonazepam, 0.25 mg as needed. With this regimen, her nightmares and re-experiencing had decreased. The psychiatrist had treated Ms. T in the hospital for 21 days. She continued psychiatric care for acute stress disorder at a local outpatient center.

Related resources

• Academy of Psychosomatic Medicine. www.apm.org
• American Psychosomatic Society. www.psychosomatic.org
• Griffith JL, Griffith ME. Encountering the sacred in psychotherapy: how to talk with people about their spiritual lives. New York: Guilford Press, 2002.
• Dewan MJ, Steenbarger BN, Greenberg RP (eds). The art and science of brief psychotherapies: a practitioner’s guide. Washington, DC: American Psychiatric Publishing, 2004

Drug brand names

• Citalopram • Celexa
• Clonazepam • Klonopin

Disclosure

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

Acknowledgments

The author thanks James Griffith, MD, and Thomas Wise, MD, for their valuable contributions to this article.

Bedside psychotherapy is not only possible but invaluable for some medical-surgical patients, despite hospitals’ distractions, lack of privacy, and short stays. If you are asked to evaluate a hospitalized patient, a 5-step strategy can help you:

• identify acute psychiatric problems that psychotherapy can help
• watch for common psychodynamic themes
• choose a beneficial psychotherapy
• integrate drug/psychotherapy, as needed
• quickly establish rapport by using an effective bedside manner.

Case report: A deeply wounded patient

Ms. T, age 45, was admitted to the trauma unit with gunshot wounds. Her estranged husband shot her during an argument and killed her 14-year-old son, who tried to help her.

She underwent multiple surgeries to repair internal organs and endured intense pain. She was medically stable after 10 days, and the surgical team called on the psychiatric consultation-liaison (C-L) service to evaluate her “depression.”

Table 1

5 steps to bedside psychotherapy

Ms. T told the psychiatrist she was having nightmares and re-experiencing the shootings. She felt overwhelming guilt and blamed herself for her son’s death. She reported hyperarousal, muscle tension, and palpitations. She also worried about facing her son’s killer in court.

The C-L psychiatrist felt Ms. T would benefit from medication and psychotherapy for anxiety while hospitalized.

Obstacles to bedside psychotherapy

Hospitalized patients do not usually seek psychiatric consultation but are referred by their physicians. Pain and injuries, medications, and illness can limit patients’ energy and motivation to participate in therapy, as well as their concentration and cognition. Moreover, bedside psychotherapy sessions are likely to be interrupted for blood draws, medical rounds, investigations, and procedures.

Despite these obstacles, medical patients are often receptive to psychiatric care.¹ An alliance often develops within minutes, and the psychiatrist can achieve effective psychotherapy during a single bedside visit.²

The Academy of Psychosomatic Medicine considers psychotherapy a required skill for anyone who evaluates and treats psychiatric disorders in general medical settings.³

How to overcome obstacles

STEP 1. Identify when psychotherapy may help. Not every problem or patient benefits from bedside psychotherapy. The C-L psychiatrist’s first task is to identify:

• Problems that warrant psychotherapy. These may include depression, bereavement, adjustment disorder, maladaptive coping, anxiety related to medical procedures, acute stress disorder, posttraumatic stress disorder (PTSD), and demoralization.
• Patients likely to benefit. Look for evidence of ego strength, ability to interact in the first session, psychological-mindedness, ability to experience feeling, and absence of severe cognitive deficit.²

These patient traits are not prerequisites, however, and clinical judgment applies on a case-by-case basis.

Demoralization is the most common reason for psychiatric evaluation of medically-ill patients, though their physicians typically request a “depression” evaluation.⁴ Demoralization is an understandable response to serious illness or disabling, agonizing, or deforming treatment.⁵ Symptoms include anxiety, guilt, shame, depression, diminished self-worth, and possibly somatic complaints or preoccupation.⁶

Ms. T was experiencing survivor guilt—she blamed herself for her son’s death—and she described herself as feeling “lost.” Four strategies can treat demoralization (Table 2).

STEP 2. Watch for common psychodynamic themes, such as denial of illness, loss of control, dependency and regression, fear of abandonment, loss of identity, and fear of death.⁷ Other issues include survivor guilt, anger at the treatment team or family, and knowing someone who had a negative experience with the same illness or treatment.

Identifying these themes and integrating them into the treatment plan can improve outcomes. For example:

• Giving an empathic validation can help overcome fear of abandonment.
• Letting the patient choose the time when blood is drawn increases feelings of control.

Table 2

4 bedside strategies to treat demoralization

STEP 3. Select appropriate psychotherapy. The psychiatrist’s challenge is to know:

• when to use which approach
• when to combine approaches
• what problems each approach targets.

A hospitalized medical patient often has a fluctuating course and may require more than one approach—or even a different approach at each visit. Thus, flexibility and creativity are keys to successful bedside psychotherapy.

STEP 4. Integrate psychotherapy with medication, as needed. Consider target symptoms for using psychotropics and how medication may help the patient attain treatment goals. Does the patient require medication to allow psychotherapy to occur?

STEP 5. Combine steps 1 to 4 with a good bedside manner. An empathetic approach will help most patients, no matter which psychotherapy model you use (Box 1).^4,8,9

Case continued: First aid for the ego

The C-L psychiatrist diagnosed Ms. T as having acute stress disorder and identified four target symptoms: bereavement, demoralization, anxiety, and hyperarousal. During the initial interview, Ms. T appeared to be psychologically-minded and open to psychiatric intervention.

The psychiatrist considered her at high risk for PTSD and prescribed citalopram, 20 mg/d, because selective serotonin reuptake inhibitors may prevent PTSD. Ms. T was also given clonazepam, 0.25 mg as needed, for severe anxiety.

The psychiatrist visited her 20 to 30 minutes daily. Initial psychotherapy focused on supporting Ms. T’s ego. Resilience-building interviews—using questions to counter feelings of despair, meaninglessness, and sorrow—addressed her demoralization and grief. She regained some sense of meaning and hope by focusing on caring for her other son and on her family’s love. She also found a sense of peace through prayer and by visualizing her lost son safe in God’s hands.

The psychiatrist also taught her relaxation skills to manage her anxiety symptoms. These included abdominal breathing and guided imagery (picturing herself in a safe, comforting place).

Box 1

Psychotherapeutic options

Three psychotherapeutic approaches are particularly useful at bedside—supportive therapy and resilience-building, cognitive-behavioral therapy (CBT), and psychodynamic therapy.

Supportive therapy and resilience-building is the most common bedside model. Supportive therapy’s goal is to strengthen coping skills, thereby reducing anxiety and enhancing well-being, self-esteem, and function.

Fostering a good working relationship is the first priority.¹⁰ The therapist works to contain the patient’s anxiety and provide an “auxiliary ego” to supplement his or her reality testing, planning and judgment, and sense of self.^2,10 Supportive techniques include suggestion, clarification, limit-setting, reinforcement, reassurance, and empathic listening.

Much of the work relies on positive transference to build the supportive relationship.^8,10 Transference is interpreted only when negative transference disrupts treatment; the therapeutic goal is to decrease the patient’s anxiety. Resilience-building questions (Box 2)^4,11 help identify the patient’s skills and competencies and mobilize his or her internal resources.

CBT attempts to identify, challenge, and correct a patient’s inaccurate or dysfunctional beliefs about illness, treatment, or self-image. For example:

• a patient with second-degree burns may be convinced she is the world’s ugliest person
• a patient facing an operation may believe he will be permanently disabled, as was his father after a similar procedure.

CBT can also help dispel beliefs that psychiatric treatment is for “crazy” people.

Behavioral therapy can help patients manage distress related to their medical care, such as shortness of breath while being weaned from a ventilator or arousal and anxiety related to procedures. Techniques that work in office settings—systematic desensitization, in vivo exposure, breathing exercises, progressive muscle relaxation, guided imagery, meditation, and hypnosis—also can be effective at bedside.¹²

Psychodynamic therapy. Patients can develop insight through psychodynamic therapy, even in brief therapeutic relationships. Useful bedside techniques include clarification, confrontation, and interpretation of behavior, conflict, and transference.

For example, a patient who survived heart surgery later developed depression and suicidal ideation. Psychiatric interview revealed she was experiencing survivor guilt because her mother had died from a heart attack. Emphatic clarification and validation of feelings often can help lift such a patient’s mood and allow a dialogue to begin.

A “psychodynamic life-narrative” approach¹ can help treat depression in medically ill patients. The therapist first asks the patient to describe the illness’ meaning in his or her lifespan, then formulates a statement (the “narrative”) of its meaning at the moment. The narrative is intended to:

• create a new perspective
• increase self-esteem by emphasizing the patient’s strengths
• support coping mechanisms that worked in the past.

This approach also can help the patient understand that a psychiatric symptom is an understandable response when a previously successful adaptive method cannot be used.

Choosing a psychotherapy

Three factors—patient characteristics, therapist characteristics, and evidence—determine the psychotherapeutic approach.

Patient characteristics include ego functioning level and maturity, object relationship stability,¹³ history and experience of psychotherapeutic treatment, personality and coping style, and physical condition. For example:

• CBT and education may be effective for patients who cope through analytical thinking, controlling emotional expression, and managing situations.
• Psychodynamic methods may help those who cope through expressing feelings, self-reflection, and a wish to be understood.

Therapist characteristics include experience, preference, and degree of comfort in conducting each therapeutic approach, as well as time and schedule.

Box 2

Evidence of efficacy. Psychiatric literature supports using CBT for depressive cognition in major depression,¹⁴ resilience-building interviews for demoralization,⁴ and behavioral therapy and relaxation for anxiety related to medical procedures.¹²

Case continued: Coming home

As Ms. T’s medical condition improved over several days and her discharge was planned, the psychiatrist began to emphasize practical issues, such as:

• limiting visitation to allow her time to grieve
• addressing her anxieties about outpatient treatment and moving in with her parents.

At discharge, Ms. T was taking citalopram, 40 mg/d, and clonazepam, 0.25 mg as needed. With this regimen, her nightmares and re-experiencing had decreased. The psychiatrist had treated Ms. T in the hospital for 21 days. She continued psychiatric care for acute stress disorder at a local outpatient center.

Related resources

• Academy of Psychosomatic Medicine. www.apm.org
• American Psychosomatic Society. www.psychosomatic.org
• Griffith JL, Griffith ME. Encountering the sacred in psychotherapy: how to talk with people about their spiritual lives. New York: Guilford Press, 2002.
• Dewan MJ, Steenbarger BN, Greenberg RP (eds). The art and science of brief psychotherapies: a practitioner’s guide. Washington, DC: American Psychiatric Publishing, 2004

Drug brand names

• Citalopram • Celexa
• Clonazepam • Klonopin

Disclosure

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

Acknowledgments

The author thanks James Griffith, MD, and Thomas Wise, MD, for their valuable contributions to this article.

Bedside psychotherapy is not only possible but invaluable for some medical-surgical patients, despite hospitals’ distractions, lack of privacy, and short stays. If you are asked to evaluate a hospitalized patient, a 5-step strategy can help you:

• identify acute psychiatric problems that psychotherapy can help
• watch for common psychodynamic themes
• choose a beneficial psychotherapy
• integrate drug/psychotherapy, as needed
• quickly establish rapport by using an effective bedside manner.

Case report: A deeply wounded patient

Ms. T, age 45, was admitted to the trauma unit with gunshot wounds. Her estranged husband shot her during an argument and killed her 14-year-old son, who tried to help her.

She underwent multiple surgeries to repair internal organs and endured intense pain. She was medically stable after 10 days, and the surgical team called on the psychiatric consultation-liaison (C-L) service to evaluate her “depression.”

Table 1

5 steps to bedside psychotherapy

Ms. T told the psychiatrist she was having nightmares and re-experiencing the shootings. She felt overwhelming guilt and blamed herself for her son’s death. She reported hyperarousal, muscle tension, and palpitations. She also worried about facing her son’s killer in court.

The C-L psychiatrist felt Ms. T would benefit from medication and psychotherapy for anxiety while hospitalized.

Obstacles to bedside psychotherapy

Hospitalized patients do not usually seek psychiatric consultation but are referred by their physicians. Pain and injuries, medications, and illness can limit patients’ energy and motivation to participate in therapy, as well as their concentration and cognition. Moreover, bedside psychotherapy sessions are likely to be interrupted for blood draws, medical rounds, investigations, and procedures.

Despite these obstacles, medical patients are often receptive to psychiatric care.¹ An alliance often develops within minutes, and the psychiatrist can achieve effective psychotherapy during a single bedside visit.²

The Academy of Psychosomatic Medicine considers psychotherapy a required skill for anyone who evaluates and treats psychiatric disorders in general medical settings.³

How to overcome obstacles

STEP 1. Identify when psychotherapy may help. Not every problem or patient benefits from bedside psychotherapy. The C-L psychiatrist’s first task is to identify:

• Problems that warrant psychotherapy. These may include depression, bereavement, adjustment disorder, maladaptive coping, anxiety related to medical procedures, acute stress disorder, posttraumatic stress disorder (PTSD), and demoralization.
• Patients likely to benefit. Look for evidence of ego strength, ability to interact in the first session, psychological-mindedness, ability to experience feeling, and absence of severe cognitive deficit.²

These patient traits are not prerequisites, however, and clinical judgment applies on a case-by-case basis.

Demoralization is the most common reason for psychiatric evaluation of medically-ill patients, though their physicians typically request a “depression” evaluation.⁴ Demoralization is an understandable response to serious illness or disabling, agonizing, or deforming treatment.⁵ Symptoms include anxiety, guilt, shame, depression, diminished self-worth, and possibly somatic complaints or preoccupation.⁶

Ms. T was experiencing survivor guilt—she blamed herself for her son’s death—and she described herself as feeling “lost.” Four strategies can treat demoralization (Table 2).

STEP 2. Watch for common psychodynamic themes, such as denial of illness, loss of control, dependency and regression, fear of abandonment, loss of identity, and fear of death.⁷ Other issues include survivor guilt, anger at the treatment team or family, and knowing someone who had a negative experience with the same illness or treatment.

Identifying these themes and integrating them into the treatment plan can improve outcomes. For example:

• Giving an empathic validation can help overcome fear of abandonment.
• Letting the patient choose the time when blood is drawn increases feelings of control.

Table 2

4 bedside strategies to treat demoralization

STEP 3. Select appropriate psychotherapy. The psychiatrist’s challenge is to know:

• when to use which approach
• when to combine approaches
• what problems each approach targets.

A hospitalized medical patient often has a fluctuating course and may require more than one approach—or even a different approach at each visit. Thus, flexibility and creativity are keys to successful bedside psychotherapy.

STEP 4. Integrate psychotherapy with medication, as needed. Consider target symptoms for using psychotropics and how medication may help the patient attain treatment goals. Does the patient require medication to allow psychotherapy to occur?

STEP 5. Combine steps 1 to 4 with a good bedside manner. An empathetic approach will help most patients, no matter which psychotherapy model you use (Box 1).^4,8,9

Case continued: First aid for the ego

The C-L psychiatrist diagnosed Ms. T as having acute stress disorder and identified four target symptoms: bereavement, demoralization, anxiety, and hyperarousal. During the initial interview, Ms. T appeared to be psychologically-minded and open to psychiatric intervention.

The psychiatrist considered her at high risk for PTSD and prescribed citalopram, 20 mg/d, because selective serotonin reuptake inhibitors may prevent PTSD. Ms. T was also given clonazepam, 0.25 mg as needed, for severe anxiety.

The psychiatrist visited her 20 to 30 minutes daily. Initial psychotherapy focused on supporting Ms. T’s ego. Resilience-building interviews—using questions to counter feelings of despair, meaninglessness, and sorrow—addressed her demoralization and grief. She regained some sense of meaning and hope by focusing on caring for her other son and on her family’s love. She also found a sense of peace through prayer and by visualizing her lost son safe in God’s hands.

The psychiatrist also taught her relaxation skills to manage her anxiety symptoms. These included abdominal breathing and guided imagery (picturing herself in a safe, comforting place).

Box 1

Psychotherapeutic options

Three psychotherapeutic approaches are particularly useful at bedside—supportive therapy and resilience-building, cognitive-behavioral therapy (CBT), and psychodynamic therapy.

Supportive therapy and resilience-building is the most common bedside model. Supportive therapy’s goal is to strengthen coping skills, thereby reducing anxiety and enhancing well-being, self-esteem, and function.

Fostering a good working relationship is the first priority.¹⁰ The therapist works to contain the patient’s anxiety and provide an “auxiliary ego” to supplement his or her reality testing, planning and judgment, and sense of self.^2,10 Supportive techniques include suggestion, clarification, limit-setting, reinforcement, reassurance, and empathic listening.

Much of the work relies on positive transference to build the supportive relationship.^8,10 Transference is interpreted only when negative transference disrupts treatment; the therapeutic goal is to decrease the patient’s anxiety. Resilience-building questions (Box 2)^4,11 help identify the patient’s skills and competencies and mobilize his or her internal resources.

CBT attempts to identify, challenge, and correct a patient’s inaccurate or dysfunctional beliefs about illness, treatment, or self-image. For example:

• a patient with second-degree burns may be convinced she is the world’s ugliest person
• a patient facing an operation may believe he will be permanently disabled, as was his father after a similar procedure.

CBT can also help dispel beliefs that psychiatric treatment is for “crazy” people.

Behavioral therapy can help patients manage distress related to their medical care, such as shortness of breath while being weaned from a ventilator or arousal and anxiety related to procedures. Techniques that work in office settings—systematic desensitization, in vivo exposure, breathing exercises, progressive muscle relaxation, guided imagery, meditation, and hypnosis—also can be effective at bedside.¹²

Psychodynamic therapy. Patients can develop insight through psychodynamic therapy, even in brief therapeutic relationships. Useful bedside techniques include clarification, confrontation, and interpretation of behavior, conflict, and transference.

For example, a patient who survived heart surgery later developed depression and suicidal ideation. Psychiatric interview revealed she was experiencing survivor guilt because her mother had died from a heart attack. Emphatic clarification and validation of feelings often can help lift such a patient’s mood and allow a dialogue to begin.

A “psychodynamic life-narrative” approach¹ can help treat depression in medically ill patients. The therapist first asks the patient to describe the illness’ meaning in his or her lifespan, then formulates a statement (the “narrative”) of its meaning at the moment. The narrative is intended to:

• create a new perspective
• increase self-esteem by emphasizing the patient’s strengths
• support coping mechanisms that worked in the past.

This approach also can help the patient understand that a psychiatric symptom is an understandable response when a previously successful adaptive method cannot be used.

Choosing a psychotherapy

Three factors—patient characteristics, therapist characteristics, and evidence—determine the psychotherapeutic approach.

Patient characteristics include ego functioning level and maturity, object relationship stability,¹³ history and experience of psychotherapeutic treatment, personality and coping style, and physical condition. For example:

• CBT and education may be effective for patients who cope through analytical thinking, controlling emotional expression, and managing situations.
• Psychodynamic methods may help those who cope through expressing feelings, self-reflection, and a wish to be understood.

Therapist characteristics include experience, preference, and degree of comfort in conducting each therapeutic approach, as well as time and schedule.

Box 2

Evidence of efficacy. Psychiatric literature supports using CBT for depressive cognition in major depression,¹⁴ resilience-building interviews for demoralization,⁴ and behavioral therapy and relaxation for anxiety related to medical procedures.¹²

Case continued: Coming home

As Ms. T’s medical condition improved over several days and her discharge was planned, the psychiatrist began to emphasize practical issues, such as:

• limiting visitation to allow her time to grieve
• addressing her anxieties about outpatient treatment and moving in with her parents.

At discharge, Ms. T was taking citalopram, 40 mg/d, and clonazepam, 0.25 mg as needed. With this regimen, her nightmares and re-experiencing had decreased. The psychiatrist had treated Ms. T in the hospital for 21 days. She continued psychiatric care for acute stress disorder at a local outpatient center.

Related resources

• Academy of Psychosomatic Medicine. www.apm.org
• American Psychosomatic Society. www.psychosomatic.org
• Griffith JL, Griffith ME. Encountering the sacred in psychotherapy: how to talk with people about their spiritual lives. New York: Guilford Press, 2002.
• Dewan MJ, Steenbarger BN, Greenberg RP (eds). The art and science of brief psychotherapies: a practitioner’s guide. Washington, DC: American Psychiatric Publishing, 2004

Drug brand names

• Citalopram • Celexa
• Clonazepam • Klonopin

Disclosure

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

Acknowledgments

The author thanks James Griffith, MD, and Thomas Wise, MD, for their valuable contributions to this article.

When nothing else works, desperate clinicians are resorting to progressively more-tenuous and unpredictable treatments, trying to improve the lives of patients with refractory schizophrenia. High-dose antipsychotics is a common strategy.

Does boosting antipsychotic doses beyond the recommended range—but short of the neuroleptic threshold—enhance efficacy? This article attempts to answer that question by presenting the evidence on higher-than-recommended doses of atypical antipsychotics.

Lessons from neuroleptics

Up to 30% of patients with schizophrenia do not respond to antipsychotics and are considered “treatment refractory.”¹ Even among those who do respond, improving symptoms by 20%—as research defines “treatment response”—does not necessarily yield clinical or functional improvement. Clozapine is the only atypical antipsychotic with well-established efficacy in these chronically ill patients,² but its daunting side effects greatly curtail its use.

Before atypical antipsychotics, patients who did not respond to usual dosages of the typical neuroleptics were treated with higher dosages or switched to another drug class. Although many clinicians embraced high-dose neuroleptics, subsequent research discredited “rapid neuroleptization” in any clinical circumstance and showed that exceeding an antipsychotic’s neuroleptic threshold—the dose at which extrapyramidal side effects (EPS) occur—reduces its efficacy (Figure 1).^3-5 In some instances, reducing neuroleptic dosages improves treatment-resistant patients’ symptoms and reduces druginduced side effects.⁶

Figure 1 Typical antipsychotics’ dose-response curve

Narrow therapeutic window between antipsychotic effect and neuroleptic threshold. Dotted line indicates declining efficacy.

Figure 2 Atypical antipsychotics’ dose-response curve

Wider therapeutic window with atypicals, compared with typical antipsychotics, as neuroleptic threshold (dotted line) moves right.Atypical antipsychotics are defined by their relative lack of EPS at recommended dosages (Figure 2). Because these agents can cause EPS if dosed too high, however, our historical habit of testing this dose limit risks losing “atypicality” and encountering other untoward events (Figure 3).

What is the safest, most effective dosage? Consider the evidence for each atypical antipsychotic.

Risperidone

Recommended dosage too high? When using atypicals at recommended doses, you are most likely to encounter the neuroleptic threshold with risperidone, with EPS risk increasing substantially at >6 mg/d.⁷ Post-approval studies set the most effective and safest dosage at approximately 4 mg/d, though this dosage was not studied in North American pre-approval trials. Dosages of 2 to 4 mg/d have been associated with more-favorable outcomes, suggesting that the initial recommendation to titrate to 6 mg/d within the first 3 days was ill-advised.⁸

In our study of patients with treatment-refractory schizophrenia,⁹ those treated with risperidone, 6 mg/d, improved significantly more after 4 weeks than did those receiving haloperidol, 15 mg/d, based on Brief Psychiatric Rating Scale (BPRS) scores. No additional benefit was seen after risperidone was increased to >6 mg/d at 8 weeks. Akathisia and tardive dyskinesia occurred significantly more often in the haloperidol group.

Conclusion. Some patients respond to higher-dose risperidone, but emerging EPS suggest the need to reduce the dosage rather than add an antiparkinsonian agent.

Figure 3 Unknown effects of high-dose atypical antipsychotic therapy

Dotted line indicates potential for greater antipsychotic effect with increasing dose.

Olanzapine

Mixed results. Case reports suggest that some patients who did not respond to previous antipsychotic trials or olanzapine, 20 mg/d, improved sig-nificantly—without substanial side effects—when olanzapine was increased up to 60 mg/d.^10-14 Other case studies, however, report EPS, increased heart rate, increased transaminases, hyperprolactinemia, and prolonged QTc interval with high-dose olanzapine.^14-16

In an open-label trial,¹⁷ 43 patients with schizophrenia received olanzapine, up to 40 mg/d, after inadequate response to neuroleptics and risperidone or clozapine. Olanzapine was titrated to 20 mg/d by week 4 and increased 5 mg every 2 weeks if symptoms did not improve. After 14 weeks, improvement was modest and only 17% of patients met response criteria. However, >20 mg/d reduced symptoms more than did <20 mg/d, suggesting that high-dose olanzapine was more effective.

In a randomized trial,¹⁸ patients who did not respond to at least one atypical antipsychotic then received 8 weeks of fixed, standard-dose treatment with (mean dosages):

• haloperidol, 18.9 mg/d
• risperidone, 7.9 mg/d
• olanzapine, 19.6 mg/d
• clozapine, 401.6 mg/d.

Flexible dosing was then allowed for 6 weeks, and mean dosages were:

• haloperidol, 25.7 mg/d
• risperidone, 11.6 mg/d
• olanzapine, 30.4 mg/d
• clozapine, 526.6 mg/d.

Symptoms improved modestly at best for all medications, although patients taking olanzapine or clozapine improved significantly more than those treated with haloperidol as shown by mean changes in total Positive and Negative Syndrome Scale (PANSS) scores.

PANSS scores for olanzapine-treated patients showed additional improvement at week 14—when higher dosages were used—compared with week 8. This was not the case for the other medications, for which response plateaued. These findings suggest that high-dose risperidone and haloperidol are incrementally ineffective, but high-dose olanzapine could help some patients with refractory symptoms.

Results were different in a randomized, double-blind, 16-week, crossover study,¹⁹ when 13 patients with inadequate response to neuroleptics, risperidone, or conventional-dose olanzapine then received olanzapine, 50 mg/d, or clozapine, 450 mg/d. No olanzapine-treated patients and 20% of clozapine-treated patients met criteria for treatment response (20% improvement in BPRS score and final BPRS score <35 or 1-point improvement on Clinical Global Impressions-Severity of Illness scale).

Box

Subjects switching from clozapine to olanzapine tended to worsen, whereas those switching from olanzapine to clozapine tended to improve. Olanzapine-treated patients experienced more anticholinergic side effects and more weight gain than did clozapine-treated subjects.²⁰

Conclusion. These mixed findings on high-dose olanzapine suggest questionable efficacy in patients with treatment-resistant schizophrenia and an uncertain risk of increased toxicity.

Quetiapine

Early placebo-controlled studies of quetiapine in schizophrenia concluded that statistically significant improvement begins at 150 mg/d and falls off after 600 mg/d.²¹ Although few high-dose quetiapine cases have been presented, clinical opinion holds that:

• most patients with chronic schizophrenia require 400 to 800 mg/d
• some treatment-refractory patients might benefit from >800 mg/d.

One patient responded to quetiapine, 1,600 mg/d, after not responding to olanzapine, 40 mg/d, and quetiapine, 800 mg/d. Constipation was the only reported side effect.²²

Our group²³ reported a series of 7 patients who responded (by clinician report) to quetiapine, 1,200 to 2,400 mg/d, after not responding to quetiapine, 800 mg/d, or to neuroleptics, risperidone, or olanzapine. Six responded to high-dose quetiapine and 1 to high-dose quetiapine plus risperidone, 2 mg/d; 4 received adjunctive dival-proex sodium, 1,500 to 3,000 mg/d. Psychopathology, violence, and behavioral disturbances were reduced throughout 5 to 14 months of monitoring. Side effects included sedation, orthostasis, and dysphagia.

When Nelson et al²⁴ treated 13 subjects for 14 weeks with quetiapine, 1,000 to 1,400 mg/d, mean weight, glucose, total cholesterol, prolactin, and QTc interval duration did not change significantly. Heart rate increased significantly (though not to tachycardia), and headache, constipation, and lethargy were the most frequent side effects.

Summary. Although encouraging, these reports are preliminary, unpublished, and lack peer review. Controlled trials of high-dose quetiapine’s efficacy and safety are needed.

Ziprasidone and aripiprazole

No studies of high-dose ziprasidone or aripiprazole have been published. In premarketing trials:

• ziprasidone was studied at 200 mg/d and released with a maximum recommended dosage of 160 mg/d
• aripiprazole, 30 mg/d, was not more effective than 15 mg/d.²⁵

Deutschman et al²⁶ reviewed the charts of 31 patients who received ziprasidone, 240 to 320 mg/d, after an “incomplete” response to 160 mg/d. At the higher dosing:

• psychosis, affective symptoms, or anxiety improved in nearly one-half of patients
• 15% reported sedation, but most reported no side effects
• none developed QTc intervals >500 msec.

Caveats and precautions

These uncontrolled case reports and open-label studies do not “prove” efficacy or safety but reflect clinical practice. More than anything, they show that we need controlled trials to gauge high-dose antipsychotic therapy’s efficacy and safety and to curb our collective habit of relying on anecdotal experience and idiosyncratic beliefs.

Despite its side-effect profile, clozapine remains the treatment of choice for refractory schizophrenia. Given high-dose antipsychotic therapy’s uncertain efficacy and unknown risks, the evidence supports a clozapine trial before higher-than-recommended dosing is attempted.

Because educated guesswork plays a role in premarketing dosing studies, a medication’s optimal dose may be:

• overestimated (as with risperidone)
• underestimated (as perhaps with olanzapine and quetiapine).

Keep in mind some important caveats when you consider giving a patient high-dose antipsychotic therapy (Box).²⁷ Of course, nonadherence is often the cause of apparent medication nonresponse. Increasing the dosage of a medication a patient is not taking rarely improves adherence. Interventions to enhance adherence—careful assessment, psychoeducation, and using longacting intramuscular medication—may be useful.

Related resources

• Marder SR, Essock SM, Miller AL, et al. The Mount Sinai Conference on the pharmacotherapy of schizophrenia. Schizophrenia Bull 2002;28:5-16.
• Practice guideline for the treatment of patients with schizophrenia (2nd ed). Am J Psychiatry 2004;161(suppl):1-56.
• Texas Medication Algorithm Project antipsychotic algorithm. http://www.mhmr.state.tx.us/centraloffice/medicaldirector/timascz1algo.pdf

Drug brand names

• Aripiprazole • Abilify
• Clozapine • Clozaril
• Divalproex • Depakote
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Pierre receives research support from Cephalon Inc., and is a consultant to and/or speaker for Pfizer Inc., Bristol-Myers Squibb Co., AstraZeneca Pharmaceuticals, and Janssen Pharmaceutica.

Dr. Donna Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, AstraZeneca Pharmaceuticals, and Abbott Laboratories.

Dr. William Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, and AstraZeneca Pharmaceuticals.

When nothing else works, desperate clinicians are resorting to progressively more-tenuous and unpredictable treatments, trying to improve the lives of patients with refractory schizophrenia. High-dose antipsychotics is a common strategy.

Does boosting antipsychotic doses beyond the recommended range—but short of the neuroleptic threshold—enhance efficacy? This article attempts to answer that question by presenting the evidence on higher-than-recommended doses of atypical antipsychotics.

Lessons from neuroleptics

Up to 30% of patients with schizophrenia do not respond to antipsychotics and are considered “treatment refractory.”¹ Even among those who do respond, improving symptoms by 20%—as research defines “treatment response”—does not necessarily yield clinical or functional improvement. Clozapine is the only atypical antipsychotic with well-established efficacy in these chronically ill patients,² but its daunting side effects greatly curtail its use.

Before atypical antipsychotics, patients who did not respond to usual dosages of the typical neuroleptics were treated with higher dosages or switched to another drug class. Although many clinicians embraced high-dose neuroleptics, subsequent research discredited “rapid neuroleptization” in any clinical circumstance and showed that exceeding an antipsychotic’s neuroleptic threshold—the dose at which extrapyramidal side effects (EPS) occur—reduces its efficacy (Figure 1).^3-5 In some instances, reducing neuroleptic dosages improves treatment-resistant patients’ symptoms and reduces druginduced side effects.⁶

Figure 1 Typical antipsychotics’ dose-response curve

Narrow therapeutic window between antipsychotic effect and neuroleptic threshold. Dotted line indicates declining efficacy.

Figure 2 Atypical antipsychotics’ dose-response curve

Wider therapeutic window with atypicals, compared with typical antipsychotics, as neuroleptic threshold (dotted line) moves right.Atypical antipsychotics are defined by their relative lack of EPS at recommended dosages (Figure 2). Because these agents can cause EPS if dosed too high, however, our historical habit of testing this dose limit risks losing “atypicality” and encountering other untoward events (Figure 3).

What is the safest, most effective dosage? Consider the evidence for each atypical antipsychotic.

Risperidone

Recommended dosage too high? When using atypicals at recommended doses, you are most likely to encounter the neuroleptic threshold with risperidone, with EPS risk increasing substantially at >6 mg/d.⁷ Post-approval studies set the most effective and safest dosage at approximately 4 mg/d, though this dosage was not studied in North American pre-approval trials. Dosages of 2 to 4 mg/d have been associated with more-favorable outcomes, suggesting that the initial recommendation to titrate to 6 mg/d within the first 3 days was ill-advised.⁸

In our study of patients with treatment-refractory schizophrenia,⁹ those treated with risperidone, 6 mg/d, improved significantly more after 4 weeks than did those receiving haloperidol, 15 mg/d, based on Brief Psychiatric Rating Scale (BPRS) scores. No additional benefit was seen after risperidone was increased to >6 mg/d at 8 weeks. Akathisia and tardive dyskinesia occurred significantly more often in the haloperidol group.

Conclusion. Some patients respond to higher-dose risperidone, but emerging EPS suggest the need to reduce the dosage rather than add an antiparkinsonian agent.

Figure 3 Unknown effects of high-dose atypical antipsychotic therapy

Dotted line indicates potential for greater antipsychotic effect with increasing dose.

Olanzapine

Mixed results. Case reports suggest that some patients who did not respond to previous antipsychotic trials or olanzapine, 20 mg/d, improved sig-nificantly—without substanial side effects—when olanzapine was increased up to 60 mg/d.^10-14 Other case studies, however, report EPS, increased heart rate, increased transaminases, hyperprolactinemia, and prolonged QTc interval with high-dose olanzapine.^14-16

In an open-label trial,¹⁷ 43 patients with schizophrenia received olanzapine, up to 40 mg/d, after inadequate response to neuroleptics and risperidone or clozapine. Olanzapine was titrated to 20 mg/d by week 4 and increased 5 mg every 2 weeks if symptoms did not improve. After 14 weeks, improvement was modest and only 17% of patients met response criteria. However, >20 mg/d reduced symptoms more than did <20 mg/d, suggesting that high-dose olanzapine was more effective.

In a randomized trial,¹⁸ patients who did not respond to at least one atypical antipsychotic then received 8 weeks of fixed, standard-dose treatment with (mean dosages):

• haloperidol, 18.9 mg/d
• risperidone, 7.9 mg/d
• olanzapine, 19.6 mg/d
• clozapine, 401.6 mg/d.

Flexible dosing was then allowed for 6 weeks, and mean dosages were:

• haloperidol, 25.7 mg/d
• risperidone, 11.6 mg/d
• olanzapine, 30.4 mg/d
• clozapine, 526.6 mg/d.

Symptoms improved modestly at best for all medications, although patients taking olanzapine or clozapine improved significantly more than those treated with haloperidol as shown by mean changes in total Positive and Negative Syndrome Scale (PANSS) scores.

PANSS scores for olanzapine-treated patients showed additional improvement at week 14—when higher dosages were used—compared with week 8. This was not the case for the other medications, for which response plateaued. These findings suggest that high-dose risperidone and haloperidol are incrementally ineffective, but high-dose olanzapine could help some patients with refractory symptoms.

Results were different in a randomized, double-blind, 16-week, crossover study,¹⁹ when 13 patients with inadequate response to neuroleptics, risperidone, or conventional-dose olanzapine then received olanzapine, 50 mg/d, or clozapine, 450 mg/d. No olanzapine-treated patients and 20% of clozapine-treated patients met criteria for treatment response (20% improvement in BPRS score and final BPRS score <35 or 1-point improvement on Clinical Global Impressions-Severity of Illness scale).

Box

Subjects switching from clozapine to olanzapine tended to worsen, whereas those switching from olanzapine to clozapine tended to improve. Olanzapine-treated patients experienced more anticholinergic side effects and more weight gain than did clozapine-treated subjects.²⁰

Conclusion. These mixed findings on high-dose olanzapine suggest questionable efficacy in patients with treatment-resistant schizophrenia and an uncertain risk of increased toxicity.

Quetiapine

Early placebo-controlled studies of quetiapine in schizophrenia concluded that statistically significant improvement begins at 150 mg/d and falls off after 600 mg/d.²¹ Although few high-dose quetiapine cases have been presented, clinical opinion holds that:

• most patients with chronic schizophrenia require 400 to 800 mg/d
• some treatment-refractory patients might benefit from >800 mg/d.

One patient responded to quetiapine, 1,600 mg/d, after not responding to olanzapine, 40 mg/d, and quetiapine, 800 mg/d. Constipation was the only reported side effect.²²

Our group²³ reported a series of 7 patients who responded (by clinician report) to quetiapine, 1,200 to 2,400 mg/d, after not responding to quetiapine, 800 mg/d, or to neuroleptics, risperidone, or olanzapine. Six responded to high-dose quetiapine and 1 to high-dose quetiapine plus risperidone, 2 mg/d; 4 received adjunctive dival-proex sodium, 1,500 to 3,000 mg/d. Psychopathology, violence, and behavioral disturbances were reduced throughout 5 to 14 months of monitoring. Side effects included sedation, orthostasis, and dysphagia.

When Nelson et al²⁴ treated 13 subjects for 14 weeks with quetiapine, 1,000 to 1,400 mg/d, mean weight, glucose, total cholesterol, prolactin, and QTc interval duration did not change significantly. Heart rate increased significantly (though not to tachycardia), and headache, constipation, and lethargy were the most frequent side effects.

Summary. Although encouraging, these reports are preliminary, unpublished, and lack peer review. Controlled trials of high-dose quetiapine’s efficacy and safety are needed.

Ziprasidone and aripiprazole

No studies of high-dose ziprasidone or aripiprazole have been published. In premarketing trials:

• ziprasidone was studied at 200 mg/d and released with a maximum recommended dosage of 160 mg/d
• aripiprazole, 30 mg/d, was not more effective than 15 mg/d.²⁵

Deutschman et al²⁶ reviewed the charts of 31 patients who received ziprasidone, 240 to 320 mg/d, after an “incomplete” response to 160 mg/d. At the higher dosing:

• psychosis, affective symptoms, or anxiety improved in nearly one-half of patients
• 15% reported sedation, but most reported no side effects
• none developed QTc intervals >500 msec.

Caveats and precautions

These uncontrolled case reports and open-label studies do not “prove” efficacy or safety but reflect clinical practice. More than anything, they show that we need controlled trials to gauge high-dose antipsychotic therapy’s efficacy and safety and to curb our collective habit of relying on anecdotal experience and idiosyncratic beliefs.

Despite its side-effect profile, clozapine remains the treatment of choice for refractory schizophrenia. Given high-dose antipsychotic therapy’s uncertain efficacy and unknown risks, the evidence supports a clozapine trial before higher-than-recommended dosing is attempted.

Because educated guesswork plays a role in premarketing dosing studies, a medication’s optimal dose may be:

• overestimated (as with risperidone)
• underestimated (as perhaps with olanzapine and quetiapine).

Keep in mind some important caveats when you consider giving a patient high-dose antipsychotic therapy (Box).²⁷ Of course, nonadherence is often the cause of apparent medication nonresponse. Increasing the dosage of a medication a patient is not taking rarely improves adherence. Interventions to enhance adherence—careful assessment, psychoeducation, and using longacting intramuscular medication—may be useful.

Related resources

• Marder SR, Essock SM, Miller AL, et al. The Mount Sinai Conference on the pharmacotherapy of schizophrenia. Schizophrenia Bull 2002;28:5-16.
• Practice guideline for the treatment of patients with schizophrenia (2nd ed). Am J Psychiatry 2004;161(suppl):1-56.
• Texas Medication Algorithm Project antipsychotic algorithm. http://www.mhmr.state.tx.us/centraloffice/medicaldirector/timascz1algo.pdf

Drug brand names

• Aripiprazole • Abilify
• Clozapine • Clozaril
• Divalproex • Depakote
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Pierre receives research support from Cephalon Inc., and is a consultant to and/or speaker for Pfizer Inc., Bristol-Myers Squibb Co., AstraZeneca Pharmaceuticals, and Janssen Pharmaceutica.

Dr. Donna Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, AstraZeneca Pharmaceuticals, and Abbott Laboratories.

Dr. William Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, and AstraZeneca Pharmaceuticals.

When nothing else works, desperate clinicians are resorting to progressively more-tenuous and unpredictable treatments, trying to improve the lives of patients with refractory schizophrenia. High-dose antipsychotics is a common strategy.

Does boosting antipsychotic doses beyond the recommended range—but short of the neuroleptic threshold—enhance efficacy? This article attempts to answer that question by presenting the evidence on higher-than-recommended doses of atypical antipsychotics.

Lessons from neuroleptics

Up to 30% of patients with schizophrenia do not respond to antipsychotics and are considered “treatment refractory.”¹ Even among those who do respond, improving symptoms by 20%—as research defines “treatment response”—does not necessarily yield clinical or functional improvement. Clozapine is the only atypical antipsychotic with well-established efficacy in these chronically ill patients,² but its daunting side effects greatly curtail its use.

Before atypical antipsychotics, patients who did not respond to usual dosages of the typical neuroleptics were treated with higher dosages or switched to another drug class. Although many clinicians embraced high-dose neuroleptics, subsequent research discredited “rapid neuroleptization” in any clinical circumstance and showed that exceeding an antipsychotic’s neuroleptic threshold—the dose at which extrapyramidal side effects (EPS) occur—reduces its efficacy (Figure 1).^3-5 In some instances, reducing neuroleptic dosages improves treatment-resistant patients’ symptoms and reduces druginduced side effects.⁶

Figure 1 Typical antipsychotics’ dose-response curve

Narrow therapeutic window between antipsychotic effect and neuroleptic threshold. Dotted line indicates declining efficacy.

Figure 2 Atypical antipsychotics’ dose-response curve

Wider therapeutic window with atypicals, compared with typical antipsychotics, as neuroleptic threshold (dotted line) moves right.Atypical antipsychotics are defined by their relative lack of EPS at recommended dosages (Figure 2). Because these agents can cause EPS if dosed too high, however, our historical habit of testing this dose limit risks losing “atypicality” and encountering other untoward events (Figure 3).

What is the safest, most effective dosage? Consider the evidence for each atypical antipsychotic.

Risperidone

Recommended dosage too high? When using atypicals at recommended doses, you are most likely to encounter the neuroleptic threshold with risperidone, with EPS risk increasing substantially at >6 mg/d.⁷ Post-approval studies set the most effective and safest dosage at approximately 4 mg/d, though this dosage was not studied in North American pre-approval trials. Dosages of 2 to 4 mg/d have been associated with more-favorable outcomes, suggesting that the initial recommendation to titrate to 6 mg/d within the first 3 days was ill-advised.⁸

In our study of patients with treatment-refractory schizophrenia,⁹ those treated with risperidone, 6 mg/d, improved significantly more after 4 weeks than did those receiving haloperidol, 15 mg/d, based on Brief Psychiatric Rating Scale (BPRS) scores. No additional benefit was seen after risperidone was increased to >6 mg/d at 8 weeks. Akathisia and tardive dyskinesia occurred significantly more often in the haloperidol group.

Conclusion. Some patients respond to higher-dose risperidone, but emerging EPS suggest the need to reduce the dosage rather than add an antiparkinsonian agent.

Figure 3 Unknown effects of high-dose atypical antipsychotic therapy

Dotted line indicates potential for greater antipsychotic effect with increasing dose.

Olanzapine

Mixed results. Case reports suggest that some patients who did not respond to previous antipsychotic trials or olanzapine, 20 mg/d, improved sig-nificantly—without substanial side effects—when olanzapine was increased up to 60 mg/d.^10-14 Other case studies, however, report EPS, increased heart rate, increased transaminases, hyperprolactinemia, and prolonged QTc interval with high-dose olanzapine.^14-16

In an open-label trial,¹⁷ 43 patients with schizophrenia received olanzapine, up to 40 mg/d, after inadequate response to neuroleptics and risperidone or clozapine. Olanzapine was titrated to 20 mg/d by week 4 and increased 5 mg every 2 weeks if symptoms did not improve. After 14 weeks, improvement was modest and only 17% of patients met response criteria. However, >20 mg/d reduced symptoms more than did <20 mg/d, suggesting that high-dose olanzapine was more effective.

In a randomized trial,¹⁸ patients who did not respond to at least one atypical antipsychotic then received 8 weeks of fixed, standard-dose treatment with (mean dosages):

• haloperidol, 18.9 mg/d
• risperidone, 7.9 mg/d
• olanzapine, 19.6 mg/d
• clozapine, 401.6 mg/d.

Flexible dosing was then allowed for 6 weeks, and mean dosages were:

• haloperidol, 25.7 mg/d
• risperidone, 11.6 mg/d
• olanzapine, 30.4 mg/d
• clozapine, 526.6 mg/d.

Symptoms improved modestly at best for all medications, although patients taking olanzapine or clozapine improved significantly more than those treated with haloperidol as shown by mean changes in total Positive and Negative Syndrome Scale (PANSS) scores.

PANSS scores for olanzapine-treated patients showed additional improvement at week 14—when higher dosages were used—compared with week 8. This was not the case for the other medications, for which response plateaued. These findings suggest that high-dose risperidone and haloperidol are incrementally ineffective, but high-dose olanzapine could help some patients with refractory symptoms.

Results were different in a randomized, double-blind, 16-week, crossover study,¹⁹ when 13 patients with inadequate response to neuroleptics, risperidone, or conventional-dose olanzapine then received olanzapine, 50 mg/d, or clozapine, 450 mg/d. No olanzapine-treated patients and 20% of clozapine-treated patients met criteria for treatment response (20% improvement in BPRS score and final BPRS score <35 or 1-point improvement on Clinical Global Impressions-Severity of Illness scale).

Box

Subjects switching from clozapine to olanzapine tended to worsen, whereas those switching from olanzapine to clozapine tended to improve. Olanzapine-treated patients experienced more anticholinergic side effects and more weight gain than did clozapine-treated subjects.²⁰

Conclusion. These mixed findings on high-dose olanzapine suggest questionable efficacy in patients with treatment-resistant schizophrenia and an uncertain risk of increased toxicity.

Quetiapine

Early placebo-controlled studies of quetiapine in schizophrenia concluded that statistically significant improvement begins at 150 mg/d and falls off after 600 mg/d.²¹ Although few high-dose quetiapine cases have been presented, clinical opinion holds that:

• most patients with chronic schizophrenia require 400 to 800 mg/d
• some treatment-refractory patients might benefit from >800 mg/d.

One patient responded to quetiapine, 1,600 mg/d, after not responding to olanzapine, 40 mg/d, and quetiapine, 800 mg/d. Constipation was the only reported side effect.²²

Our group²³ reported a series of 7 patients who responded (by clinician report) to quetiapine, 1,200 to 2,400 mg/d, after not responding to quetiapine, 800 mg/d, or to neuroleptics, risperidone, or olanzapine. Six responded to high-dose quetiapine and 1 to high-dose quetiapine plus risperidone, 2 mg/d; 4 received adjunctive dival-proex sodium, 1,500 to 3,000 mg/d. Psychopathology, violence, and behavioral disturbances were reduced throughout 5 to 14 months of monitoring. Side effects included sedation, orthostasis, and dysphagia.

When Nelson et al²⁴ treated 13 subjects for 14 weeks with quetiapine, 1,000 to 1,400 mg/d, mean weight, glucose, total cholesterol, prolactin, and QTc interval duration did not change significantly. Heart rate increased significantly (though not to tachycardia), and headache, constipation, and lethargy were the most frequent side effects.

Summary. Although encouraging, these reports are preliminary, unpublished, and lack peer review. Controlled trials of high-dose quetiapine’s efficacy and safety are needed.

Ziprasidone and aripiprazole

No studies of high-dose ziprasidone or aripiprazole have been published. In premarketing trials:

• ziprasidone was studied at 200 mg/d and released with a maximum recommended dosage of 160 mg/d
• aripiprazole, 30 mg/d, was not more effective than 15 mg/d.²⁵

Deutschman et al²⁶ reviewed the charts of 31 patients who received ziprasidone, 240 to 320 mg/d, after an “incomplete” response to 160 mg/d. At the higher dosing:

• psychosis, affective symptoms, or anxiety improved in nearly one-half of patients
• 15% reported sedation, but most reported no side effects
• none developed QTc intervals >500 msec.

Caveats and precautions

These uncontrolled case reports and open-label studies do not “prove” efficacy or safety but reflect clinical practice. More than anything, they show that we need controlled trials to gauge high-dose antipsychotic therapy’s efficacy and safety and to curb our collective habit of relying on anecdotal experience and idiosyncratic beliefs.

Despite its side-effect profile, clozapine remains the treatment of choice for refractory schizophrenia. Given high-dose antipsychotic therapy’s uncertain efficacy and unknown risks, the evidence supports a clozapine trial before higher-than-recommended dosing is attempted.

Because educated guesswork plays a role in premarketing dosing studies, a medication’s optimal dose may be:

• overestimated (as with risperidone)
• underestimated (as perhaps with olanzapine and quetiapine).

Keep in mind some important caveats when you consider giving a patient high-dose antipsychotic therapy (Box).²⁷ Of course, nonadherence is often the cause of apparent medication nonresponse. Increasing the dosage of a medication a patient is not taking rarely improves adherence. Interventions to enhance adherence—careful assessment, psychoeducation, and using longacting intramuscular medication—may be useful.

Related resources

• Marder SR, Essock SM, Miller AL, et al. The Mount Sinai Conference on the pharmacotherapy of schizophrenia. Schizophrenia Bull 2002;28:5-16.
• Practice guideline for the treatment of patients with schizophrenia (2nd ed). Am J Psychiatry 2004;161(suppl):1-56.
• Texas Medication Algorithm Project antipsychotic algorithm. http://www.mhmr.state.tx.us/centraloffice/medicaldirector/timascz1algo.pdf

Drug brand names

• Aripiprazole • Abilify
• Clozapine • Clozaril
• Divalproex • Depakote
• Fluphenazine • Prolixin
• Haloperidol • Haldol
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Pierre receives research support from Cephalon Inc., and is a consultant to and/or speaker for Pfizer Inc., Bristol-Myers Squibb Co., AstraZeneca Pharmaceuticals, and Janssen Pharmaceutica.

Dr. Donna Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, AstraZeneca Pharmaceuticals, and Abbott Laboratories.

Dr. William Wirshing receives research support from, is a consultant to, and/or is a speaker for Bristol-Myers Squibb Co., Pfizer Inc., Eli Lilly & Co., Janssen Pharmaceutica, and AstraZeneca Pharmaceuticals.

One of the most perplexing and shocking aspects of human behavior is the cruelty we can inflict on one another. Infamous events such as the Spanish Inquisition, slavery, lynching, conquest of the native Americans, and Nazi concentration camps are so sickening that many of us can barely tolerate hearing about them. How can people behave this way?

Recently, we’ve been shocked by photographs from the Abu Ghraib military prison in Iraq. American soldiers with unremarkable backgrounds—not Saddam’s henchmen—were shown humiliating and abusing Iraqi prisoners. Most remarkable was the joy on the Americans’ faces (Figure 1).

‘Good’ people, ‘bad’ circumstances

In experiments with college students, psychologists have shown that “regular” people can become sadistic under the right (or wrong) circumstances.¹ One explanation is that it’s not just psychopaths who perpetrate crimes against humanity. Somehow, the psychopath within us all becomes unleashed.

Artificial situations such as the Stanford Prison Experiment (www.prisonexp.org) show that normal people can dissolve into cruelty but don’t explain why. A recent neuroscience experiment suggests a mechanism for this kind of aggression.

Figure 1 Deriving pleasure from abuse?

American soldiers appearing to enjoy themselves as they humiliate Iraqi prisoners in the Abu Ghraib military prison.

Source: Reprinted with permission of The New Yorker, which first published this photo.

Dopamine and aggression

The nucleus accumbens has been called the brain’s “pleasure center,” and dopamine is the neurotransmitter that activates it.² Activities and substances that stimulate dopamine release include sex, gambling, and smoking as well as cocaine and alcohol. The good feeling a person gets from these activities/substances reinforces the behavior that produced the feeling. In some cases, problems develop when people cannot resist the urge for more.

Ferrari et al³ placed micropipettes in rats’ nucleus accumbens to measure extracellular dopamine before, during, and after an aggressive confrontation. When the rats were confronted with an intruder rat for 10 minutes, they attacked and bit the intruder an average of 5 times, despite being implanted, tethered, and sampled. During and after the fight, dopamine was increased in the rats’ nucleus accumbens (Figure 2). Clearly, fighting gave them a “squirt” of pleasure that lasted almost 2 hours.

If we can extrapolate from this study to humans, we may understand why people become aggressive. At some level, they enjoy it. The bully on the playground, the wife beater, the mean boss—they get pleasure from being aggressive. It’s not just serial killers.

It is important to acknowledge that other variables such as poor supervision and too much power affected the actions of American soldiers working as prison guards in Iraq. However, the neuroscientific studies show us that aggression can be pleasurable, and people often have a hard time resisting what feels good. This knowledge may help us treat war veterans struggling not only with traumatic memories of violence but also with socially and personally unacceptable feelings of pleasure.

Figure 2 A ‘squirt’ of dopamine during violence

A 10-minute fight increased extracellular dopamine levels in rats’ nucleus accumbens for approximately 2 hours, suggesting that aggressive behavior produced pleasure.

Source: Adapted and reprinted with permission from reference 3. Copyright 2003, Blackwell Publishing.

One of the most perplexing and shocking aspects of human behavior is the cruelty we can inflict on one another. Infamous events such as the Spanish Inquisition, slavery, lynching, conquest of the native Americans, and Nazi concentration camps are so sickening that many of us can barely tolerate hearing about them. How can people behave this way?

Recently, we’ve been shocked by photographs from the Abu Ghraib military prison in Iraq. American soldiers with unremarkable backgrounds—not Saddam’s henchmen—were shown humiliating and abusing Iraqi prisoners. Most remarkable was the joy on the Americans’ faces (Figure 1).

‘Good’ people, ‘bad’ circumstances

In experiments with college students, psychologists have shown that “regular” people can become sadistic under the right (or wrong) circumstances.¹ One explanation is that it’s not just psychopaths who perpetrate crimes against humanity. Somehow, the psychopath within us all becomes unleashed.

Artificial situations such as the Stanford Prison Experiment (www.prisonexp.org) show that normal people can dissolve into cruelty but don’t explain why. A recent neuroscience experiment suggests a mechanism for this kind of aggression.

Figure 1 Deriving pleasure from abuse?

American soldiers appearing to enjoy themselves as they humiliate Iraqi prisoners in the Abu Ghraib military prison.

Source: Reprinted with permission of The New Yorker, which first published this photo.

Dopamine and aggression

The nucleus accumbens has been called the brain’s “pleasure center,” and dopamine is the neurotransmitter that activates it.² Activities and substances that stimulate dopamine release include sex, gambling, and smoking as well as cocaine and alcohol. The good feeling a person gets from these activities/substances reinforces the behavior that produced the feeling. In some cases, problems develop when people cannot resist the urge for more.

Ferrari et al³ placed micropipettes in rats’ nucleus accumbens to measure extracellular dopamine before, during, and after an aggressive confrontation. When the rats were confronted with an intruder rat for 10 minutes, they attacked and bit the intruder an average of 5 times, despite being implanted, tethered, and sampled. During and after the fight, dopamine was increased in the rats’ nucleus accumbens (Figure 2). Clearly, fighting gave them a “squirt” of pleasure that lasted almost 2 hours.

If we can extrapolate from this study to humans, we may understand why people become aggressive. At some level, they enjoy it. The bully on the playground, the wife beater, the mean boss—they get pleasure from being aggressive. It’s not just serial killers.

It is important to acknowledge that other variables such as poor supervision and too much power affected the actions of American soldiers working as prison guards in Iraq. However, the neuroscientific studies show us that aggression can be pleasurable, and people often have a hard time resisting what feels good. This knowledge may help us treat war veterans struggling not only with traumatic memories of violence but also with socially and personally unacceptable feelings of pleasure.

Figure 2 A ‘squirt’ of dopamine during violence

A 10-minute fight increased extracellular dopamine levels in rats’ nucleus accumbens for approximately 2 hours, suggesting that aggressive behavior produced pleasure.

Source: Adapted and reprinted with permission from reference 3. Copyright 2003, Blackwell Publishing.

One of the most perplexing and shocking aspects of human behavior is the cruelty we can inflict on one another. Infamous events such as the Spanish Inquisition, slavery, lynching, conquest of the native Americans, and Nazi concentration camps are so sickening that many of us can barely tolerate hearing about them. How can people behave this way?

Recently, we’ve been shocked by photographs from the Abu Ghraib military prison in Iraq. American soldiers with unremarkable backgrounds—not Saddam’s henchmen—were shown humiliating and abusing Iraqi prisoners. Most remarkable was the joy on the Americans’ faces (Figure 1).

‘Good’ people, ‘bad’ circumstances

In experiments with college students, psychologists have shown that “regular” people can become sadistic under the right (or wrong) circumstances.¹ One explanation is that it’s not just psychopaths who perpetrate crimes against humanity. Somehow, the psychopath within us all becomes unleashed.

Artificial situations such as the Stanford Prison Experiment (www.prisonexp.org) show that normal people can dissolve into cruelty but don’t explain why. A recent neuroscience experiment suggests a mechanism for this kind of aggression.

Figure 1 Deriving pleasure from abuse?

American soldiers appearing to enjoy themselves as they humiliate Iraqi prisoners in the Abu Ghraib military prison.

Source: Reprinted with permission of The New Yorker, which first published this photo.

Dopamine and aggression

The nucleus accumbens has been called the brain’s “pleasure center,” and dopamine is the neurotransmitter that activates it.² Activities and substances that stimulate dopamine release include sex, gambling, and smoking as well as cocaine and alcohol. The good feeling a person gets from these activities/substances reinforces the behavior that produced the feeling. In some cases, problems develop when people cannot resist the urge for more.

Ferrari et al³ placed micropipettes in rats’ nucleus accumbens to measure extracellular dopamine before, during, and after an aggressive confrontation. When the rats were confronted with an intruder rat for 10 minutes, they attacked and bit the intruder an average of 5 times, despite being implanted, tethered, and sampled. During and after the fight, dopamine was increased in the rats’ nucleus accumbens (Figure 2). Clearly, fighting gave them a “squirt” of pleasure that lasted almost 2 hours.

If we can extrapolate from this study to humans, we may understand why people become aggressive. At some level, they enjoy it. The bully on the playground, the wife beater, the mean boss—they get pleasure from being aggressive. It’s not just serial killers.

It is important to acknowledge that other variables such as poor supervision and too much power affected the actions of American soldiers working as prison guards in Iraq. However, the neuroscientific studies show us that aggression can be pleasurable, and people often have a hard time resisting what feels good. This knowledge may help us treat war veterans struggling not only with traumatic memories of violence but also with socially and personally unacceptable feelings of pleasure.

Figure 2 A ‘squirt’ of dopamine during violence

A 10-minute fight increased extracellular dopamine levels in rats’ nucleus accumbens for approximately 2 hours, suggesting that aggressive behavior produced pleasure.

Source: Adapted and reprinted with permission from reference 3. Copyright 2003, Blackwell Publishing.

Is it realistic for patients with schizophrenia to believe they can recover? Recent observational studies show that some do,¹ even though all DSM editions have defined schizophrenia as a chronic disease with a poor outcome.²

Our understanding of schizophrenia is changing as we gain new insights into:

• mechanism of recovery
• efficacy of combined psychotherapeutic, psychosocial, and drug therapies for sustaining remission and recovery
• the value of long-term aftercare. This article examines evidence on:
• achieving recovery from schizophrenia
• factors associated with remission
• treatments that may help prevent relapse and lead to stable, lasting recovery.

What is ‘recovery’?

Diagnostic criteria. Recovery from schizophrenia has social, occupational, symptomatic, and psychostructural dimensions. For clinical practice, Liberman et al³ developed a useful set of 10 criteria for recovery (Table 1) by analyzing the literature and cases of 23 schizophrenia patients who returned to work or school with their symptoms under control.

Table 1

Recovery from schizophrenia: 10 clinical criteria

Recovery is not a smooth, linear progression. Even when patients attain remission, they often find it hard to make up for “lost life” during years of disability.⁴ Recovery also can be defined as social, emotional, and biological maturation. This definition considers recovery not as an end-state or cure but as a process of personal growth.⁵

Several groups proposed recently that recovery from schizophrenia includes four processes:

• finding hope
• re-establishing identity
• taking responsibility for recovery
• finding meaning⁶ and “getting on with life”⁷ (Box).

Long-tem vs short-term

Recovery has been studied in many populations, but the evidence is difficult to compare. Data quality is compromised by poorly-defined cohorts, weak study designs, and lack of clear definitions of recovery and its diagnostic criteria. Moreover, empirical evidence is lacking on recovery’s multidimensional nature, including psychosocial, biochemical, genetic, environmental, cultural, and ethnic correlates.

Long-term recovery. Recently, three studies of American populations diagnosed with schizophrenia detected trends toward long-term (>5 years) recovery.

U.S. populations. Modestin et al⁸ in 2003 re-evaluated diagnoses of 208 patients in Swiss psychiatrist Manfred Bleuler’s influential 1972 study on schizophrenia’s long-term course. Using DSM-III-R, DSM-IV, and International Statistical Classification of Diseases and Related Health Problems (ICD-10) criteria, the authors excluded about 30% of the original patients (most rediagnosed with schizoaffective disorder). Among those remaining, 12% to 15% showed long-term recovery and one-half had an undulating course with remissions.

In 1997, Stephens et al⁹ examined hospital records from 1913 to 1940 of 484 patients, mean age 27, hospitalized with schizophrenia. Using >5 years of follow-up data and DSM-IV criteria, the authors rated 13% as recovered and 58% unimproved.

Also in 1997, Harrow et al¹⁰ evaluated 74 patients diagnosed with schizophrenia by DSM-IV criteria at 2, 4.5, and 7.5 years. In this longitudinal study, one-third (32%) showed complete remission at one follow-up session, compared with 5% at all three evaluations.

This study suggested that schizophrenia patients show relatively poor functioning, compared with other psychotic patients. Over time, however, the likelihood of long-term remission appeared to increase. A similar pattern was seen in a sample of 658 Americans age >65 with schizophrenia diagnosed by DSM-III criteria. As these patients aged, 15% developed long-lasting remission.¹¹

Elsewhere, empirical findings across 15 years from three Norwegian studies indicate that lasting recovery from schizophrenia—with symptom improvement and psychosocial adjustment—is rare (3% to 5% of patients).³ Similarly, only 4% of a Scandinavian sample of 301 patients attained complete, long-term remission during 3 to 39 years of follow-up.¹²

Across cultures, an international study¹³ evaluated 15- and 25-year outcomes in 1,633 patients diagnosed with schizophrenia. Approximately 50% had favorable outcomes—stable work, independent from support, no imprisonment, no substance abuse, no rehospitalization, improved social life—but heterogeneity was marked.

Box

Table 2

Psychosocial interventions for patients in recovery from schizophrenia*

Short-term course predicted long-term outcome, and local environment played a significant role in determining symptoms and social disability. The authors concluded that adequate early treatment and an optimum environment might lead to favorable long-term outcome.

In the United Kingdom, 14% of a sample of patients diagnosed by ICD-10 criteria achieved remission across a mean 8.5 years.¹⁴ In a study of Czechoslovakian patients (70 men, 50 women) with early-onset schizophrenia diagnosed by DSM-III-R criteria, 10% recovered during 13 to 42 years of follow-up.¹⁵

Short-term recovery. The McLean-Harvard first-episode project examined outcomes 6 months after schizophrenia diagnosis in 102 patients (55 men, 47 women). Sixty-five percent attained syndromal recovery (significant reduction of diagnostic features), whereas only 33% achieved functional recovery (increased social-emotional, vocational, and coping abilities).¹⁶

In Japan, 62 patients (33 men, 29 women; mean age 25) were followed for 13 years after a first hospitalization for schizophrenia. The authors reported an undulating course with recovery or a mild end-state in 53%, and a simple course of recovery and a moderate or severe end-state in 28%.¹⁷

Conclusions. The evidence suggests that early and lasting treatment of schizophrenic symptoms—even in recovered patients—might prevent frequent rehospitalizations. Thus, patients with schizophrenia must be followed carefully during and after recovery. Health care professionals, colleagues, friends, and relatives can help patients sustain recovery by watching for the earliest signs of deterioration and intervening before relapse occurs.

Strategies for recovery

Therapeutic factors. Many studies suggest psychosocial interventions (Table 2), psychotherapy, and medication are most effective in combination for stabilizing patients with schizophrenia and continuing their recovery. Other patient factors that may contribute to recovery include:

• quality of relationships with family, friends, and professional caregivers
• ability and motivation to use resources and take responsibility for one’s life
• spiritual and religious activities
• awareness that recovery is possible.

Sells et al¹⁸ noted that attempting to make new contacts outside of their former spheres (“positive withdrawal”) may allow schizophrenia patients to reconsider and ultimately recover a durable sense of self.

We at the W. Kahn Institute¹⁹ find that all these treatment strategies may be useful and even necessary to continue and stabilize recovery from schizophrenia. We feel they merit the attention of all professionals involved in recovered patients’ aftercare and guidance.

Table 3

Suggested antipsychotic dosages during schizophrenia recovery*

Social/vocational network. Family, friends, neighbors, and social workers play an important role in the patient’s development during recovery. They provide positive stimulation (such as physical activities and social or vocational engagements) and support.

To equip the patient’s network for this responsible task, provide them with training (such as in acceptance, empathy, feedback, and communication), education, and guidance. Support groups can enhance the social networks of patients whose own networks are too small to prevent social isolation or overburdening of members.

Vocational training and mediation also may be stabilizing. Religious activities are central to self-understanding and recovery for many psychiatric patients and may improve outcomes.²⁰

Patient skills. To achieve stabilization and continue their recovery, patients must develop social interaction skills and coping strategies. Conversation training, for example, seems to help improve social interaction. Patients in remission must learn to:

• find or create low-stress, positively stimulating environments in which their recovery can flourish
• tolerate discomfort and stress
• overcome internalized stigma about recovery.

Patients also need to learn when and how to withdraw from hectic, stressful environments and from people who are overly emotional, patronizing, or hold unrealistic expectations about them.

Pharmacotherapy. Sound pharmacotherapy underlies rehabilitation and psychosocial treatment of patients in remission from schizophrenia.²¹ Healthy neurobiological functioning and equilibrium may help normalize social-emotional behavior and create opportunities to improve all life dimensions via psychotherapy, psychosocial guidance, education, and training.

Dosages often can be reduced during recovery, titrating gradually downward to reduce the risk of relapse. Suggested antipsychotic dosages during recovery are listed in Table 3. Be patient and consistent when adjusting dosages, guided by information in package inserts, from clinical trials, and in recent articles on specific medications. When introducing a medication, start with the lowest dosage and increase in small steps until symptoms are reduced and side effects are minimal.

Discontinuing antipsychotics. Is it therapeutically reasonable to discontinue antipsychotics after recovery? Probably not.

Relapse rates in unmedicated patients with schizophrenia appear extremely high—perhaps 8 or 9 out of 10 cases—even during remission. By comparison, relapse rates appear very low—perhaps 3 or 4 out of 10 cases—for remitted patients who remain on antipsychotics. Atypical antipsychotics or low doses of conventional agents are generally well-tolerated and safe in the long term.²²

Patient monitoring. Patients in remission from schizophrenia benefit from:

• 24-hour phone lines to call for guidance, treatment, and quick interventions
• central, alert treatment coordination among psychiatrists, psychologists, social workers, therapists, vocational experts, and activity counselors.

Psychiatrists in solo or small-group settings may need to seek out these resources in their communities. The goal of this team approach—in cooperation with the patient’s social network—is to help the patient develop employment and social activities appropriate to his or her needs and capabilities.

Related resources

• Ascher-Svanuw H, Kraus A. Psychoeducational groups for patients with schizophrenia: a guide for practitioners. Gaithersburg, MD: Aspen Publishers, 1991.
• Suzuki T, Uchida H, Tanaka KF, et al. Revising polypharmacy to a single antipsychotic regimen for patients with chronic schizophrenia. Int J Neuropsychopharmacol 2004;7(2):133-42.
• American Psychiatric Association. Schizophrenia (patient/family information). www.psych.org/public_info/schizo.cfm
• Schizophrenia.com. Nonprofit Web community providing information, support, and education. www.schizophrenia.com

Drug brand names

• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

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

Is it realistic for patients with schizophrenia to believe they can recover? Recent observational studies show that some do,¹ even though all DSM editions have defined schizophrenia as a chronic disease with a poor outcome.²

Our understanding of schizophrenia is changing as we gain new insights into:

• mechanism of recovery
• efficacy of combined psychotherapeutic, psychosocial, and drug therapies for sustaining remission and recovery
• the value of long-term aftercare. This article examines evidence on:
• achieving recovery from schizophrenia
• factors associated with remission
• treatments that may help prevent relapse and lead to stable, lasting recovery.

What is ‘recovery’?

Diagnostic criteria. Recovery from schizophrenia has social, occupational, symptomatic, and psychostructural dimensions. For clinical practice, Liberman et al³ developed a useful set of 10 criteria for recovery (Table 1) by analyzing the literature and cases of 23 schizophrenia patients who returned to work or school with their symptoms under control.

Table 1

Recovery from schizophrenia: 10 clinical criteria

Recovery is not a smooth, linear progression. Even when patients attain remission, they often find it hard to make up for “lost life” during years of disability.⁴ Recovery also can be defined as social, emotional, and biological maturation. This definition considers recovery not as an end-state or cure but as a process of personal growth.⁵

Several groups proposed recently that recovery from schizophrenia includes four processes:

• finding hope
• re-establishing identity
• taking responsibility for recovery
• finding meaning⁶ and “getting on with life”⁷ (Box).

Long-tem vs short-term

Recovery has been studied in many populations, but the evidence is difficult to compare. Data quality is compromised by poorly-defined cohorts, weak study designs, and lack of clear definitions of recovery and its diagnostic criteria. Moreover, empirical evidence is lacking on recovery’s multidimensional nature, including psychosocial, biochemical, genetic, environmental, cultural, and ethnic correlates.

Long-term recovery. Recently, three studies of American populations diagnosed with schizophrenia detected trends toward long-term (>5 years) recovery.

U.S. populations. Modestin et al⁸ in 2003 re-evaluated diagnoses of 208 patients in Swiss psychiatrist Manfred Bleuler’s influential 1972 study on schizophrenia’s long-term course. Using DSM-III-R, DSM-IV, and International Statistical Classification of Diseases and Related Health Problems (ICD-10) criteria, the authors excluded about 30% of the original patients (most rediagnosed with schizoaffective disorder). Among those remaining, 12% to 15% showed long-term recovery and one-half had an undulating course with remissions.

In 1997, Stephens et al⁹ examined hospital records from 1913 to 1940 of 484 patients, mean age 27, hospitalized with schizophrenia. Using >5 years of follow-up data and DSM-IV criteria, the authors rated 13% as recovered and 58% unimproved.

Also in 1997, Harrow et al¹⁰ evaluated 74 patients diagnosed with schizophrenia by DSM-IV criteria at 2, 4.5, and 7.5 years. In this longitudinal study, one-third (32%) showed complete remission at one follow-up session, compared with 5% at all three evaluations.

This study suggested that schizophrenia patients show relatively poor functioning, compared with other psychotic patients. Over time, however, the likelihood of long-term remission appeared to increase. A similar pattern was seen in a sample of 658 Americans age >65 with schizophrenia diagnosed by DSM-III criteria. As these patients aged, 15% developed long-lasting remission.¹¹

Elsewhere, empirical findings across 15 years from three Norwegian studies indicate that lasting recovery from schizophrenia—with symptom improvement and psychosocial adjustment—is rare (3% to 5% of patients).³ Similarly, only 4% of a Scandinavian sample of 301 patients attained complete, long-term remission during 3 to 39 years of follow-up.¹²

Across cultures, an international study¹³ evaluated 15- and 25-year outcomes in 1,633 patients diagnosed with schizophrenia. Approximately 50% had favorable outcomes—stable work, independent from support, no imprisonment, no substance abuse, no rehospitalization, improved social life—but heterogeneity was marked.

Box

Table 2

Psychosocial interventions for patients in recovery from schizophrenia*

Short-term course predicted long-term outcome, and local environment played a significant role in determining symptoms and social disability. The authors concluded that adequate early treatment and an optimum environment might lead to favorable long-term outcome.

In the United Kingdom, 14% of a sample of patients diagnosed by ICD-10 criteria achieved remission across a mean 8.5 years.¹⁴ In a study of Czechoslovakian patients (70 men, 50 women) with early-onset schizophrenia diagnosed by DSM-III-R criteria, 10% recovered during 13 to 42 years of follow-up.¹⁵

Short-term recovery. The McLean-Harvard first-episode project examined outcomes 6 months after schizophrenia diagnosis in 102 patients (55 men, 47 women). Sixty-five percent attained syndromal recovery (significant reduction of diagnostic features), whereas only 33% achieved functional recovery (increased social-emotional, vocational, and coping abilities).¹⁶

In Japan, 62 patients (33 men, 29 women; mean age 25) were followed for 13 years after a first hospitalization for schizophrenia. The authors reported an undulating course with recovery or a mild end-state in 53%, and a simple course of recovery and a moderate or severe end-state in 28%.¹⁷

Conclusions. The evidence suggests that early and lasting treatment of schizophrenic symptoms—even in recovered patients—might prevent frequent rehospitalizations. Thus, patients with schizophrenia must be followed carefully during and after recovery. Health care professionals, colleagues, friends, and relatives can help patients sustain recovery by watching for the earliest signs of deterioration and intervening before relapse occurs.

Strategies for recovery

Therapeutic factors. Many studies suggest psychosocial interventions (Table 2), psychotherapy, and medication are most effective in combination for stabilizing patients with schizophrenia and continuing their recovery. Other patient factors that may contribute to recovery include:

• quality of relationships with family, friends, and professional caregivers
• ability and motivation to use resources and take responsibility for one’s life
• spiritual and religious activities
• awareness that recovery is possible.

Sells et al¹⁸ noted that attempting to make new contacts outside of their former spheres (“positive withdrawal”) may allow schizophrenia patients to reconsider and ultimately recover a durable sense of self.

We at the W. Kahn Institute¹⁹ find that all these treatment strategies may be useful and even necessary to continue and stabilize recovery from schizophrenia. We feel they merit the attention of all professionals involved in recovered patients’ aftercare and guidance.

Table 3

Suggested antipsychotic dosages during schizophrenia recovery*

Social/vocational network. Family, friends, neighbors, and social workers play an important role in the patient’s development during recovery. They provide positive stimulation (such as physical activities and social or vocational engagements) and support.

To equip the patient’s network for this responsible task, provide them with training (such as in acceptance, empathy, feedback, and communication), education, and guidance. Support groups can enhance the social networks of patients whose own networks are too small to prevent social isolation or overburdening of members.

Vocational training and mediation also may be stabilizing. Religious activities are central to self-understanding and recovery for many psychiatric patients and may improve outcomes.²⁰

Patient skills. To achieve stabilization and continue their recovery, patients must develop social interaction skills and coping strategies. Conversation training, for example, seems to help improve social interaction. Patients in remission must learn to:

• find or create low-stress, positively stimulating environments in which their recovery can flourish
• tolerate discomfort and stress
• overcome internalized stigma about recovery.

Patients also need to learn when and how to withdraw from hectic, stressful environments and from people who are overly emotional, patronizing, or hold unrealistic expectations about them.

Pharmacotherapy. Sound pharmacotherapy underlies rehabilitation and psychosocial treatment of patients in remission from schizophrenia.²¹ Healthy neurobiological functioning and equilibrium may help normalize social-emotional behavior and create opportunities to improve all life dimensions via psychotherapy, psychosocial guidance, education, and training.

Dosages often can be reduced during recovery, titrating gradually downward to reduce the risk of relapse. Suggested antipsychotic dosages during recovery are listed in Table 3. Be patient and consistent when adjusting dosages, guided by information in package inserts, from clinical trials, and in recent articles on specific medications. When introducing a medication, start with the lowest dosage and increase in small steps until symptoms are reduced and side effects are minimal.

Discontinuing antipsychotics. Is it therapeutically reasonable to discontinue antipsychotics after recovery? Probably not.

Relapse rates in unmedicated patients with schizophrenia appear extremely high—perhaps 8 or 9 out of 10 cases—even during remission. By comparison, relapse rates appear very low—perhaps 3 or 4 out of 10 cases—for remitted patients who remain on antipsychotics. Atypical antipsychotics or low doses of conventional agents are generally well-tolerated and safe in the long term.²²

Patient monitoring. Patients in remission from schizophrenia benefit from:

• 24-hour phone lines to call for guidance, treatment, and quick interventions
• central, alert treatment coordination among psychiatrists, psychologists, social workers, therapists, vocational experts, and activity counselors.

Psychiatrists in solo or small-group settings may need to seek out these resources in their communities. The goal of this team approach—in cooperation with the patient’s social network—is to help the patient develop employment and social activities appropriate to his or her needs and capabilities.

Related resources

• Ascher-Svanuw H, Kraus A. Psychoeducational groups for patients with schizophrenia: a guide for practitioners. Gaithersburg, MD: Aspen Publishers, 1991.
• Suzuki T, Uchida H, Tanaka KF, et al. Revising polypharmacy to a single antipsychotic regimen for patients with chronic schizophrenia. Int J Neuropsychopharmacol 2004;7(2):133-42.
• American Psychiatric Association. Schizophrenia (patient/family information). www.psych.org/public_info/schizo.cfm
• Schizophrenia.com. Nonprofit Web community providing information, support, and education. www.schizophrenia.com

Drug brand names

• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

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

Is it realistic for patients with schizophrenia to believe they can recover? Recent observational studies show that some do,¹ even though all DSM editions have defined schizophrenia as a chronic disease with a poor outcome.²

Our understanding of schizophrenia is changing as we gain new insights into:

• mechanism of recovery
• efficacy of combined psychotherapeutic, psychosocial, and drug therapies for sustaining remission and recovery
• the value of long-term aftercare. This article examines evidence on:
• achieving recovery from schizophrenia
• factors associated with remission
• treatments that may help prevent relapse and lead to stable, lasting recovery.

What is ‘recovery’?

Diagnostic criteria. Recovery from schizophrenia has social, occupational, symptomatic, and psychostructural dimensions. For clinical practice, Liberman et al³ developed a useful set of 10 criteria for recovery (Table 1) by analyzing the literature and cases of 23 schizophrenia patients who returned to work or school with their symptoms under control.

Table 1

Recovery from schizophrenia: 10 clinical criteria

Recovery is not a smooth, linear progression. Even when patients attain remission, they often find it hard to make up for “lost life” during years of disability.⁴ Recovery also can be defined as social, emotional, and biological maturation. This definition considers recovery not as an end-state or cure but as a process of personal growth.⁵

Several groups proposed recently that recovery from schizophrenia includes four processes:

• finding hope
• re-establishing identity
• taking responsibility for recovery
• finding meaning⁶ and “getting on with life”⁷ (Box).

Long-tem vs short-term

Recovery has been studied in many populations, but the evidence is difficult to compare. Data quality is compromised by poorly-defined cohorts, weak study designs, and lack of clear definitions of recovery and its diagnostic criteria. Moreover, empirical evidence is lacking on recovery’s multidimensional nature, including psychosocial, biochemical, genetic, environmental, cultural, and ethnic correlates.

Long-term recovery. Recently, three studies of American populations diagnosed with schizophrenia detected trends toward long-term (>5 years) recovery.

U.S. populations. Modestin et al⁸ in 2003 re-evaluated diagnoses of 208 patients in Swiss psychiatrist Manfred Bleuler’s influential 1972 study on schizophrenia’s long-term course. Using DSM-III-R, DSM-IV, and International Statistical Classification of Diseases and Related Health Problems (ICD-10) criteria, the authors excluded about 30% of the original patients (most rediagnosed with schizoaffective disorder). Among those remaining, 12% to 15% showed long-term recovery and one-half had an undulating course with remissions.

In 1997, Stephens et al⁹ examined hospital records from 1913 to 1940 of 484 patients, mean age 27, hospitalized with schizophrenia. Using >5 years of follow-up data and DSM-IV criteria, the authors rated 13% as recovered and 58% unimproved.

Also in 1997, Harrow et al¹⁰ evaluated 74 patients diagnosed with schizophrenia by DSM-IV criteria at 2, 4.5, and 7.5 years. In this longitudinal study, one-third (32%) showed complete remission at one follow-up session, compared with 5% at all three evaluations.

This study suggested that schizophrenia patients show relatively poor functioning, compared with other psychotic patients. Over time, however, the likelihood of long-term remission appeared to increase. A similar pattern was seen in a sample of 658 Americans age >65 with schizophrenia diagnosed by DSM-III criteria. As these patients aged, 15% developed long-lasting remission.¹¹

Elsewhere, empirical findings across 15 years from three Norwegian studies indicate that lasting recovery from schizophrenia—with symptom improvement and psychosocial adjustment—is rare (3% to 5% of patients).³ Similarly, only 4% of a Scandinavian sample of 301 patients attained complete, long-term remission during 3 to 39 years of follow-up.¹²

Across cultures, an international study¹³ evaluated 15- and 25-year outcomes in 1,633 patients diagnosed with schizophrenia. Approximately 50% had favorable outcomes—stable work, independent from support, no imprisonment, no substance abuse, no rehospitalization, improved social life—but heterogeneity was marked.

Box

Table 2

Psychosocial interventions for patients in recovery from schizophrenia*

Short-term course predicted long-term outcome, and local environment played a significant role in determining symptoms and social disability. The authors concluded that adequate early treatment and an optimum environment might lead to favorable long-term outcome.

In the United Kingdom, 14% of a sample of patients diagnosed by ICD-10 criteria achieved remission across a mean 8.5 years.¹⁴ In a study of Czechoslovakian patients (70 men, 50 women) with early-onset schizophrenia diagnosed by DSM-III-R criteria, 10% recovered during 13 to 42 years of follow-up.¹⁵

Short-term recovery. The McLean-Harvard first-episode project examined outcomes 6 months after schizophrenia diagnosis in 102 patients (55 men, 47 women). Sixty-five percent attained syndromal recovery (significant reduction of diagnostic features), whereas only 33% achieved functional recovery (increased social-emotional, vocational, and coping abilities).¹⁶

In Japan, 62 patients (33 men, 29 women; mean age 25) were followed for 13 years after a first hospitalization for schizophrenia. The authors reported an undulating course with recovery or a mild end-state in 53%, and a simple course of recovery and a moderate or severe end-state in 28%.¹⁷

Conclusions. The evidence suggests that early and lasting treatment of schizophrenic symptoms—even in recovered patients—might prevent frequent rehospitalizations. Thus, patients with schizophrenia must be followed carefully during and after recovery. Health care professionals, colleagues, friends, and relatives can help patients sustain recovery by watching for the earliest signs of deterioration and intervening before relapse occurs.

Strategies for recovery

Therapeutic factors. Many studies suggest psychosocial interventions (Table 2), psychotherapy, and medication are most effective in combination for stabilizing patients with schizophrenia and continuing their recovery. Other patient factors that may contribute to recovery include:

• quality of relationships with family, friends, and professional caregivers
• ability and motivation to use resources and take responsibility for one’s life
• spiritual and religious activities
• awareness that recovery is possible.

Sells et al¹⁸ noted that attempting to make new contacts outside of their former spheres (“positive withdrawal”) may allow schizophrenia patients to reconsider and ultimately recover a durable sense of self.

We at the W. Kahn Institute¹⁹ find that all these treatment strategies may be useful and even necessary to continue and stabilize recovery from schizophrenia. We feel they merit the attention of all professionals involved in recovered patients’ aftercare and guidance.

Table 3

Suggested antipsychotic dosages during schizophrenia recovery*

Social/vocational network. Family, friends, neighbors, and social workers play an important role in the patient’s development during recovery. They provide positive stimulation (such as physical activities and social or vocational engagements) and support.

To equip the patient’s network for this responsible task, provide them with training (such as in acceptance, empathy, feedback, and communication), education, and guidance. Support groups can enhance the social networks of patients whose own networks are too small to prevent social isolation or overburdening of members.

Vocational training and mediation also may be stabilizing. Religious activities are central to self-understanding and recovery for many psychiatric patients and may improve outcomes.²⁰

Patient skills. To achieve stabilization and continue their recovery, patients must develop social interaction skills and coping strategies. Conversation training, for example, seems to help improve social interaction. Patients in remission must learn to:

• find or create low-stress, positively stimulating environments in which their recovery can flourish
• tolerate discomfort and stress
• overcome internalized stigma about recovery.

Patients also need to learn when and how to withdraw from hectic, stressful environments and from people who are overly emotional, patronizing, or hold unrealistic expectations about them.

Pharmacotherapy. Sound pharmacotherapy underlies rehabilitation and psychosocial treatment of patients in remission from schizophrenia.²¹ Healthy neurobiological functioning and equilibrium may help normalize social-emotional behavior and create opportunities to improve all life dimensions via psychotherapy, psychosocial guidance, education, and training.

Dosages often can be reduced during recovery, titrating gradually downward to reduce the risk of relapse. Suggested antipsychotic dosages during recovery are listed in Table 3. Be patient and consistent when adjusting dosages, guided by information in package inserts, from clinical trials, and in recent articles on specific medications. When introducing a medication, start with the lowest dosage and increase in small steps until symptoms are reduced and side effects are minimal.

Discontinuing antipsychotics. Is it therapeutically reasonable to discontinue antipsychotics after recovery? Probably not.

Relapse rates in unmedicated patients with schizophrenia appear extremely high—perhaps 8 or 9 out of 10 cases—even during remission. By comparison, relapse rates appear very low—perhaps 3 or 4 out of 10 cases—for remitted patients who remain on antipsychotics. Atypical antipsychotics or low doses of conventional agents are generally well-tolerated and safe in the long term.²²

Patient monitoring. Patients in remission from schizophrenia benefit from:

• 24-hour phone lines to call for guidance, treatment, and quick interventions
• central, alert treatment coordination among psychiatrists, psychologists, social workers, therapists, vocational experts, and activity counselors.

Psychiatrists in solo or small-group settings may need to seek out these resources in their communities. The goal of this team approach—in cooperation with the patient’s social network—is to help the patient develop employment and social activities appropriate to his or her needs and capabilities.

Related resources

• Ascher-Svanuw H, Kraus A. Psychoeducational groups for patients with schizophrenia: a guide for practitioners. Gaithersburg, MD: Aspen Publishers, 1991.
• Suzuki T, Uchida H, Tanaka KF, et al. Revising polypharmacy to a single antipsychotic regimen for patients with chronic schizophrenia. Int J Neuropsychopharmacol 2004;7(2):133-42.
• American Psychiatric Association. Schizophrenia (patient/family information). www.psych.org/public_info/schizo.cfm
• Schizophrenia.com. Nonprofit Web community providing information, support, and education. www.schizophrenia.com

Drug brand names

• Aripiprazole • Abilify
• Carbamazepine • Tegretol
• Clozapine • Clozaril
• Haloperidol • Haldol
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosure

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

Psychiatrists in the trenches are not alone in being unsure how to treat breakthrough bipolar depression. No panelist or other expert attending a recent American College of Neuropsychopharmacology symposium could definitively recommend:

• when to add an antidepressant to mood-stabilizer therapy
• whether to discontinue antidepressants after bipolar depression is stabilized.

Until controlled trials address these issues, we must use limited evidence to treat patients with bipolar depression. To help you meet this challenge, this article offers provisional suggestions based on recent published and unpublished reports.

Evidence for continuing

No published, randomized studies have examined how long to continue antidepressants after bipolar depression has stabilized. Until recently, conventional wisdom has been to discontinue antidepressants as soon as possible because of worries about antidepressant-induced mania. Then two case-controlled studies—one retrospective and one prospective—challenged that assumption.

Figure Reduced relapse rates in patients whose antidepressants were continued

In a prospective case-controlled study, patients with bipolar disorder who continued antidepressant treatment for 6 to 12 months or >12 months after depressive episode remission had lower relapse rates than those who discontinued antidepressants within 6 months.

Source: Reprinted with permission from reference 2. Copyright 2003. American Psychiatric AssociationUsing similar methodologies, Altshuler et al^1,2 examined bipolar patients who remained in remission for 6 weeks on mood stabilizers plus adjunctive antidepressants. Those who continued the antidepressants were less likely to relapse into depression (without an increase in manic episodes) than those whose antidepressants were discontinued (Figure).

Relapse rates in the first study¹ were 35% at 1 year in those who continued antidepressants and 68% in those who did not. In the second study,² 36% and 70% of patients, respectively, had relapsed at 1 year. In the latter study, those who continued to take antidepressants for at least 6 months—instead of at least 12 months—had intermediate depressive relapse rates (53% for 6 months vs. 24% for 12 months).

When interpreting these data, keep several caveats in mind. For one, patients were not randomly assigned to continue or discontinue antidepressants but were designated by patient and clinician choice. When comparing the two patient groups, however, the authors found no inherent differences in illness characteristics that might have biased the results.

More importantly, few patients initially treated with antidepressant augmentation responded well and remained in remission. In the prospective study, 549 of 1,078 patients in the Stanley Foundation Bipolar Network received an antidepressant for breakthrough depressive symptoms.² Only 189 remained on antidepressants for 2 months, and only 84 (15%) of the original population remained in remission for 2 months.

Summary. A small subgroup of patients appears to respond well to antidepressants and sustains this response for 6 to 8 weeks. For this subset, continuing antidepressant therapy would appear to be an appropriate strategy, based on:

• a significantly reduced risk for depressive relapse
• no increased risk of switching to mania, which is the usual reason to terminate antidepressants early.

Subsequent evidence

One needs to assess these observations in light of an interim analysis reported halfway through a small, open, randomized study. Ghaemi et al³ found no significant difference in outcomes—regardless of rapid-cycling status—among 14 bipolar patients who remained on antidepressants and 19 who discontinued across an average 60 and 50 weeks, respectively.

Table

Evidence on continuing antidepressants in breakthrough bipolar depression

A survival analysis initially suggested some benefit for continuing antidepressants, but this disappeared when the authors adjusted for potential confounding factors—which was not done in the Altshuler et al studies. Patients receiving short-term or long-term antidepressants had a similar number of depressive episodes per year (1.00 vs. 0.75 episodes/year, respectively). For some reason, nonrapid-cycling patients showed greater depressive morbidity than those with rapid cycling.

Rapid cyclers comprised 30% of patients who continued antidepressants and 37% of those who discontinued. This may explain the 50% relapse rate within 20 weeks in both groups. By comparison, the Altshuler et al studies included no rapid cyclers.^1,2 More details on this unpublished data are expected.

Are antidepressants the answer?

The high relapse rate in patients taking mood stabilizers—with or without an antidepressant—and the Ghaemi et al data³ suggest that we need alternate antidepressant approaches to bipolar depression. Potential regimens—anticonvulsants, atypical antipsychotics, and other agents—merit further study. So far the evidence is mixed, and the most effective approaches are not well-delineated.

Anticonvulsants. Sachs et al⁴ reported that adding lamotrigine or lamotrigine plus an antidepressant to mood stabilizer therapy did not appear more effective in treating bipolar depression than simply maintaining the mood stabilizers.

Similarly, a small randomized, double-blind study in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was stopped early because of low total response. Adjunctive lamotrigine (24%) and inositol (17%) appeared more effective than risperidone (5%) for refractory bipolar depression.

Antipsychotics. In an 8-week randomized trial by Tohen et al,⁵ 833 patients with moderate to severe bipolar I depression were treated with olanzapine, olanzapine plus fluoxetine, or placebo. Core depression symptoms improved significantly more with olanzapine alone or with fluoxetine compared with placebo, as measured by mean changes in the Montgomery-Asberg Depression Rating Scale.

In a 6-month open trial, 192 patients whose bipolar I depression remitted with any of the three treatments⁶ continued olanzapine and then, if needed after the first week, the olanzapine/fluoxetine combination (OFC). Nearly two-thirds of patients (62%) remained without a depressive recurrence, and 94% remained without a manic recurrence while taking the OFC. These unpublished data indicate that the OFC provided greater prophylactic antimanic than antidepressant effects.

Calabrese et al⁷ recently presented unpublished data comparing the effects of quetiapine monotherapy, 300 or 600 mg/d, with placebo in patients with bipolar depression. Beginning in the first week of treatment, both quetiapine dosages produced significantly greater antidepressant, antianxiety, and anti-insomnia effects than placebo (P < 0.001). Remission rates with both dosages were >50%.

Summary. These first controlled studies of atypical antipsychotics in bipolar depression suggest that this drug class may have antidepressant as well as their demonstrated antimanic effects.

Recommendations—for now

Controlled clinical trials have not been conducted, and the evidence on using adjunctive antidepressants in bipolar depression is ambiguous.^8-11 As a result, it is unclear when or how long to use antidepressants, and many of the inferences and suggestions in this paper remain highly provisional.

Initiating antidepressants. My personal treatment guidelines—and those of many other clinicians—are to use the unimodal antidepressants to augment mood stabilizers in bipolar patients experiencing breakthrough depression, as long as they have not had:

• ultra-rapid cycling (>4 episodes/week)
• antidepressant-induced cycle acceleration
• or multiple episodes of antidepressant-induced mania, despite co-treatment with mood stabilizers.

If any of these variables is present, I would instead add another mood stabilizer or an atypical antipsychotic.

Continuing antidepressants. If the patient remains stable for 2 months after the antidepressant is added—with no depression or manic occurrence—I would continue the antidepressant indefinitely, based on the Altshuler et al data.¹²

Mood charting.I also recommend that clinicians help patients develop an individual method for mood charting, such as that used in the National Institute of Mental Health Life Chart Method (NIMH-LCM)^12,13 or the STEP-BD program.¹⁴ Goals of the 5-year STEP-BD are to:

• determine the most effective treatments and relapse prevention strategies for bipolar disorder
• evaluate the psychotropic benefit of anticonvulsants, atypical antipsychotics, cholinesterase inhibitors, and neurotransmitter precursors
• determine the benefit of psychotropic combinations.

Mood charts can provide a retrospective and prospective overview of a patient’s illness course and response to medications. Compared with patient recall, mood charts help clinicians evaluate more precisely the risk of switching and the risks and benefits of starting, continuing, or discontinuing antidepressants. Mood charts may be your most effective tool for managing a patient’s bipolar depression and achieving and maintaining long-term remission.

Summary. In the absence of consensus or guidelines for treating bipolar depression, I suggest:

• a conservative approach—ie, no changes in medication—when the patient remains well on a given regimen
• an aggressive—if not radical—series of treatments and revisions when the illness course remains problematic.

Many medication classes and adjunctive strategies are available for treating bipolar illness.^15-18 I recommend that you continue to systematically explore adjunctive treatments and combinations until the patient improves or—even better—attains remission. Good response can be achieved—even in treatment-refractory patients ill for long periods or with recurrent bipolar depression—although complex combination therapy is often required.

Related resources

• National Institute of Mental Health-Life Chart Method. Retrospective and prospective mood-tracking charts for patients with bipolar disorder. www.bipolarnews.org
• Systematic Treatment Enhancement Program for Bipolar Depression (STEP-BD). National Institute of Mental Health. www.stepbd.org/research/

Drug brand names

• Fluoxetine • Prozac
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Olanzapine/fluoxetine • Symbyax
• Quetiapine • Seroquel
• Risperidone • Risperdal

Disclosure

Dr. Post is a consultant to Abbott Laboratories, Astra-Zeneca Pharmaceuticals, Bristol-Myers Squibb Co., Elan Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, Novartis Pharmaceuticals Corp., Shire Pharmaceuticals, and UCB Pharma.

Psychiatrists in the trenches are not alone in being unsure how to treat breakthrough bipolar depression. No panelist or other expert attending a recent American College of Neuropsychopharmacology symposium could definitively recommend:

• when to add an antidepressant to mood-stabilizer therapy
• whether to discontinue antidepressants after bipolar depression is stabilized.

Until controlled trials address these issues, we must use limited evidence to treat patients with bipolar depression. To help you meet this challenge, this article offers provisional suggestions based on recent published and unpublished reports.

Evidence for continuing

No published, randomized studies have examined how long to continue antidepressants after bipolar depression has stabilized. Until recently, conventional wisdom has been to discontinue antidepressants as soon as possible because of worries about antidepressant-induced mania. Then two case-controlled studies—one retrospective and one prospective—challenged that assumption.

Figure Reduced relapse rates in patients whose antidepressants were continued

In a prospective case-controlled study, patients with bipolar disorder who continued antidepressant treatment for 6 to 12 months or >12 months after depressive episode remission had lower relapse rates than those who discontinued antidepressants within 6 months.

Source: Reprinted with permission from reference 2. Copyright 2003. American Psychiatric AssociationUsing similar methodologies, Altshuler et al^1,2 examined bipolar patients who remained in remission for 6 weeks on mood stabilizers plus adjunctive antidepressants. Those who continued the antidepressants were less likely to relapse into depression (without an increase in manic episodes) than those whose antidepressants were discontinued (Figure).

Relapse rates in the first study¹ were 35% at 1 year in those who continued antidepressants and 68% in those who did not. In the second study,² 36% and 70% of patients, respectively, had relapsed at 1 year. In the latter study, those who continued to take antidepressants for at least 6 months—instead of at least 12 months—had intermediate depressive relapse rates (53% for 6 months vs. 24% for 12 months).

When interpreting these data, keep several caveats in mind. For one, patients were not randomly assigned to continue or discontinue antidepressants but were designated by patient and clinician choice. When comparing the two patient groups, however, the authors found no inherent differences in illness characteristics that might have biased the results.

More importantly, few patients initially treated with antidepressant augmentation responded well and remained in remission. In the prospective study, 549 of 1,078 patients in the Stanley Foundation Bipolar Network received an antidepressant for breakthrough depressive symptoms.² Only 189 remained on antidepressants for 2 months, and only 84 (15%) of the original population remained in remission for 2 months.

Summary. A small subgroup of patients appears to respond well to antidepressants and sustains this response for 6 to 8 weeks. For this subset, continuing antidepressant therapy would appear to be an appropriate strategy, based on:

• a significantly reduced risk for depressive relapse
• no increased risk of switching to mania, which is the usual reason to terminate antidepressants early.

Subsequent evidence

One needs to assess these observations in light of an interim analysis reported halfway through a small, open, randomized study. Ghaemi et al³ found no significant difference in outcomes—regardless of rapid-cycling status—among 14 bipolar patients who remained on antidepressants and 19 who discontinued across an average 60 and 50 weeks, respectively.

Table

Evidence on continuing antidepressants in breakthrough bipolar depression

A survival analysis initially suggested some benefit for continuing antidepressants, but this disappeared when the authors adjusted for potential confounding factors—which was not done in the Altshuler et al studies. Patients receiving short-term or long-term antidepressants had a similar number of depressive episodes per year (1.00 vs. 0.75 episodes/year, respectively). For some reason, nonrapid-cycling patients showed greater depressive morbidity than those with rapid cycling.

Rapid cyclers comprised 30% of patients who continued antidepressants and 37% of those who discontinued. This may explain the 50% relapse rate within 20 weeks in both groups. By comparison, the Altshuler et al studies included no rapid cyclers.^1,2 More details on this unpublished data are expected.

Are antidepressants the answer?

The high relapse rate in patients taking mood stabilizers—with or without an antidepressant—and the Ghaemi et al data³ suggest that we need alternate antidepressant approaches to bipolar depression. Potential regimens—anticonvulsants, atypical antipsychotics, and other agents—merit further study. So far the evidence is mixed, and the most effective approaches are not well-delineated.