Current Psychiatry

Mr. P, age 31, has been using heroin intravenously for 9 years. He smokes 1 pack of cigarettes daily, but denies using other substances, including alcohol. After an unintentional heroin overdose, Mr. P enrolls in a methadone maintenance treatment program (MMTP) that includes primary medical care and addiction medicine and psychiatric specialists, where he undergoes medical evaluation and screening for hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Laboratory data reveal that although Mr. P is HIV negative, he has been exposed to HCV and treatment is indicated.

Among the approximately 3 million people in the United States with chronic HCV—an enveloped, single-stranded RNA virus—there’s a high prevalence of premorbid psychopathology and substance abuse, as well as neuropsychiatric effects caused by HCV treatment.^1-3 Because underdiagnosing and undertreating psychiatric disorders contributes to morbidity and mortality in HCV patients, early identification and prompt treatment is critical.

IV drug use is the most common route for HCV infection, accounting for 65% to 70% of infections.¹ The prevalence of HCV among IV drug users is 28% to 90%.¹ Once exposed to HCV, 75% to 85% of patients do not clear the initial infection and become chronically infected.

This article reviews the pathophysiology, identification, and management of psychiatric manifestations found among HCV patients and provides an understanding of how psychiatric symptoms manifest in HCV patients. This article also discusses HCV treatment and its neuropsychiatric side effects.

Testing for HCV

Chronically infected HCV patients may have few, if any, specific physical complaints, and often are diagnosed during screenings or other routine laboratory evaluations. The presence of risk factors, such as a history of injection drug use or receiving a blood transfusion before 1992,¹ guides the decision to screen for HCV. Normal liver function test results should not preclude testing because many HCV-positive patients have transaminases within the normal range.⁴ Initial screening is via an antibody-mediated immunoassay that is highly specific and sensitive for past exposure to HCV (Table 1).⁴ However, a positive screen does not indicate the presence of active infection. Evidence of the virus via a viral assay will identify active HCV, but does not indicate need for treatment. Liver biopsy confirms the presence of liver injury and quantifies its extent. The severity of liver damage will determine whether treatment is needed. HCV genotyping determines the appropriate duration and dosage of pharmacotherapy.

Table 1

Tests to diagnose and evaluate HCV

CASE CONTINUED: Mood improves, but fatigue persists

As part of pre-HCV treatment evaluation, Mr. P undergoes a psychiatric evaluation. He describes periods of low mood while actively engaged in drug use but has never received psychiatric treatment, experienced suicidal ideation, or attempted suicide. Since starting opioid agonist therapy, he reports improved mood but endorses continued mild fatigue and difficulty falling sleep. The psychiatrist determines Mr. P does not meet criteria for an axis I diagnosis other than a substance use disorder.

Although most HCV patients have few, if any, nonspecific physical symptoms, many have psychiatric symptoms or disorders before the HCV diagnosis is made or treatment is initiated; substance use disorders are most common. Batki et al¹ found that 56% of HCV patients in an MMTP met criteria for a nonsubstance axis I disorder and 82% met criteria for such a disorder during their lifetime. Additionally, 66% of patients were taking psychiatric medications. Table 2^1,5,6 lists the rates of other psychiatric disorders found in patients with untreated HCV.

Table 2

Rates of psychiatric disorders in patients with untreated hepatitis C virus

Many patients with chronic HCV complain of chronic fatigue and deficiencies in attention, concentration, higher executive functions, learning ability, and memory that result in significant reduction in quality of life (Box 1).^7-9 These findings have been found to be independent of the degree of liver disease and are seen in HCV patients with normal liver function.^7,8

Box 1

CASE CONTINUED: Motivated and compliant

Since joining the MMTP 6 months ago, Mr. P has been motivated and compliant with all appointments and treatments. Routine urine toxicology screening supports his claim of abstinence. Mr. P begins HCV treatment while continuing follow-up with addiction medicine and psychiatric clinicians and maintains open communication with all treatment providers.

For many years the standard HCV treatment was pegylated interferon-α (IFN-α) and ribavirin. IFN-α is a proinflammatory cytokine with antiproliferative, antiviral, and immunoregulatory properties. The half-life of IFN-α significantly increases with pegylation, which allows for weekly injections.^10,11 IFN-α usually is combined with ribavirin, which increases its efficacy as measured by the sustained virological response (SVR) compared with IFN-α alone. Depending on the virus genotype, treatment lasts 24 to 48 weeks; SVR rates range from 40% to 82%.^11-13 In 2011, the FDA approved 2 agents—telaprevir and boceprevir—for adjunctive treatment of HCV genotype 1 infection. These 2 agents are protease inhibitors that when added to IFN-α and ribavirin increase the SVR rate in genotype 1 infection from 40% to 50% to approximately 75%.^14,15

Although the neuropsychiatric side effects of telaprevir and boceprevir have not been determined, treating chronic HCV with IFN-α and ribavirin has been associated with multiple psychiatric symptoms, including depression, mania, suicidality, anxiety, and psychosis.^11-14 Psychiatric symptoms are a common reason for discontinuing or reducing HCV treatment. Because of the high frequency of neuropsychiatric complications, some clinicians believe HCV patients with preexisting affective, psychotic, or substance use disorders should be excluded from HCV treatment. This has led to many HCV patients being untreated despite a lack of prospective, controlled data to support this opinion.¹² To improve outcomes and decrease morbidity, providing appropriate psychiatric services appears to be more important than attempting to select lower-risk patients for antiviral therapy.^1,12,16 The goals of psychiatric treatment should be to alleviate symptoms and allow patients to complete IFN-α therapy without interruption.^16,17

Studies of high-risk patients who attend multidisciplinary treatment programs that can monitor adherence and efficacy and control side effects before and during HCV treatment have found psychiatric patients have similar adherence, compliance, and SVR rates and were not at increased risk of worsening depressive or psychotic symptoms compared with patients without a psychiatric history.^12,18 Additionally, HCV patients with a psychiatric history are not at an increased risk of suicide.^13,16 Similar findings have been observed in patients with active IV drug use or those receiving opioid agonist therapy. When HCV and substance use are treated simultaneously, patients can successfully complete HCV treatment with SVR rates comparable to those of patients not receiving opioid agonist therapy.^19-21

CASE CONTINUED: Worsening symptoms

During a psychiatric follow-up 12 weeks after starting HCV treatment, Mr. P reports worsening depressive symptoms with low mood, decreased enjoyment of activities, poor sleep, low appetite, and fatigue. He shows no evidence of psychosis and denies suicidal ideation. We continue his HCV treatment, schedule more frequent psychiatric visits, and initiate citalopram, titrated to 40 mg/d.

Depressive symptoms, the most common neuropsychiatric manifestation of HCV, typically begin early in treatment, usually within the first 12 weeks. Two distinct symptom clusters are noted. A neurovegetative cluster characterized by reduced energy, anorexia, and psychomotor retardation typically begins within the first few months of treatment. Months later, a depression-specific syndrome appears that includes depressed mood, anxiety, and cognitive impairment.²²

Depressive symptoms may occur in up to 60% of patients treated with IFN-α.¹¹ When more rigorous depression measures are used, rates decrease to approximately 20% to 30%.^11,13 Accurate diagnosis and treatment of emerging depressive symptoms is essential because untreated depression can lead to postponing or excluding patients from antiviral treatment.² Screening instruments such as the Beck Depression Inventory-Second Edition (BDI-II) can be used to measure depressive symptoms in HCV patients with high sensitivity. However, because specificity has been low and somatic symptoms of chronic illness and depression often overlap, the BDI-II and other inventories may overestimate depression. Some researchers have suggested that focusing on questions targeting cognitive and affective symptoms rather than somatic ones may be a more valid measure of depression in patients undergoing immunotherapy for HCV.²

The immune system is implicated in IFN-α-induced depression because depressive symptoms share many features with a constellation of somatic and behavioral symptoms termed “sickness behavior.”¹¹ These behaviors can occur when patients are exposed to cytokines that lead to a depressed level of functioning, which may allow the body to devote more energy to fighting illness. IFN-α, a cytokine, stimulates the immune system, which can lead to increases of interleukin (IL)-2, IL-6, and IL-10. Increased circulating levels of these ILs have been correlated with higher depression scores. Additionally, studies have found that patients who develop depression during IFN-α treatment have higher SVR rates, suggesting a more robust immune response.^11,22 For a discussion of how serotonin metabolism and genetic polymorphisms also may help explain the prevalence of depression in patients with HCV, see Box 2.

Box 2

Treating depressed HCV patients

Antidepressants are the treatment of choice for IFN-α-induced depression. Most currently used antidepressants are effective²² and selective serotonin reuptake inhibitors are considered first choice.¹⁶ Antidepressant choice should be guided by principles similar to those used for patients without HCV: using side effects profiles to target specific symptoms and being mindful of pharmacokinetic properties.

Two treatment approaches have been investigated: prophylactic and symptomatic. A 2012 study²³ of 181 HCV patients with no history of mental illness determined escitalopram, 10 mg/d, effectively reduced the incidence and severity of interferon-associated depression. Other studies examining prophylactic treatment of all patients who were to undergo interferon treatment found this approach did not prevent depressive episodes.^24,25 However, antidepressants have been beneficial for patients with subsyndromal depressive symptoms at baseline²⁶ and after clinically significant depressive symptoms emerge.²⁷ Electroconvulsive therapy also has been reported to effectively treat depression in HCV patients undergoing antiviral therapy.²⁸

CASE CONTINUED: Lingering symptoms

Mr. P responds to citalopram with an improvement in mood, anhedonia, and appetite, but he continues to complain of low energy and poor concentration. In an effort to target these symptoms, methylphenidate, titrated to 30 mg/d in divided doses, is added to his regimen, which rapidly improves his symptoms. Insomnia is treated successfully with trazodone, 50 mg/d. Mr. P frequently visits his psychiatrist, who monitors his depressive symptoms using the BDI-II. Mr. P completes HCV treatment without recurrence of depressive symptoms or relapse to heroin use.

Although antidepressants are effective for treating affective and cognitive symptoms, they are not as effective for fatigue and other neurovegetative symptoms.^16,29 The psychostimulants methylphenidate and dextroamphetamine and the nonstimulant modafinil have been studied for treating depressive symptoms in medically ill patients and can be used to treat IFN-α-induced fatigue.^16,22,29

IFN-α’s effect on serotonin metabolism leads to a tryptophan-deficient state because of increased catabolism as a result of activation of indoleamine-2,3-dioxygenase (IDO). This has led to use of tryptophan supplementation, either as augmentation or monotherapy, for managing depressive symptoms in patients treated with IFN-α. Schaefer et al³⁰ reported 3 cases where tryptophan supplementation significantly decreased depressive symptoms. Other researchers have argued that supplementing tryptophan in the context of IDO activation can lead to greater production of kynurenine and quinolinic acid, which have been linked to increased depressive symptoms in patients receiving IFN-α.³¹ They argue that supplementation of 5-HTP, which is available as a dietary supplement without a prescription, can lead to increased serotonin levels and improvement in depressive symptoms.³¹

IFN-α treatment also is associated with mania and psychosis. The incidence, pathophysiology, and management of these treatment-emergent symptoms are not as well studied as IFN-α-induced depression. Mania and hypomania have been reported with interferon treatment, discontinuation of interferon, and use of antidepressants for interferon-induced depression.^29,32 Psychosis, in association with mood symptoms or alone, has been reported to occur in <1% of treated patients.³³ Treatment for mania and psychosis consists of decreasing or discontinuing immunotherapy and adding mood stabilizers and antipsychotics. Once immunotherapy is discontinued, mania and psychosis usually resolve, but prolonged duration of symptoms has been reported.^29,32,33

Related Resources

• Centers for Disease Control and Prevention. Hepatitis C information for health professionals. www.cdc.gov/hepatitis/hcv/index.htm.
• Hep C Connection. www.hepc-connection.org.
• United States Department of Veterans Affairs. Hepatitis C. www.hepatitis.va.gov.

Drug Brand Names

• Boceprevir • Victrelis
• Citalopram • Celexa
• Dextroamphetamine • Dexedrine
• Escitalopram • Lexapro
• Interferon-α • Intron
• Methadone • Dolophine, Methadose
• Methylphenidate • Ritalin, Methylin, others
• Modafinil • Provigil
• Ondansetron • Zofran
• Ribavirin • Copegus, Rebetol, others
• Telaprevir • Incivek
• Trazodone • Desyrel, Oleptro

Disclosure

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

Mr. P, age 31, has been using heroin intravenously for 9 years. He smokes 1 pack of cigarettes daily, but denies using other substances, including alcohol. After an unintentional heroin overdose, Mr. P enrolls in a methadone maintenance treatment program (MMTP) that includes primary medical care and addiction medicine and psychiatric specialists, where he undergoes medical evaluation and screening for hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Laboratory data reveal that although Mr. P is HIV negative, he has been exposed to HCV and treatment is indicated.

Among the approximately 3 million people in the United States with chronic HCV—an enveloped, single-stranded RNA virus—there’s a high prevalence of premorbid psychopathology and substance abuse, as well as neuropsychiatric effects caused by HCV treatment.^1-3 Because underdiagnosing and undertreating psychiatric disorders contributes to morbidity and mortality in HCV patients, early identification and prompt treatment is critical.

IV drug use is the most common route for HCV infection, accounting for 65% to 70% of infections.¹ The prevalence of HCV among IV drug users is 28% to 90%.¹ Once exposed to HCV, 75% to 85% of patients do not clear the initial infection and become chronically infected.

This article reviews the pathophysiology, identification, and management of psychiatric manifestations found among HCV patients and provides an understanding of how psychiatric symptoms manifest in HCV patients. This article also discusses HCV treatment and its neuropsychiatric side effects.

Testing for HCV

Chronically infected HCV patients may have few, if any, specific physical complaints, and often are diagnosed during screenings or other routine laboratory evaluations. The presence of risk factors, such as a history of injection drug use or receiving a blood transfusion before 1992,¹ guides the decision to screen for HCV. Normal liver function test results should not preclude testing because many HCV-positive patients have transaminases within the normal range.⁴ Initial screening is via an antibody-mediated immunoassay that is highly specific and sensitive for past exposure to HCV (Table 1).⁴ However, a positive screen does not indicate the presence of active infection. Evidence of the virus via a viral assay will identify active HCV, but does not indicate need for treatment. Liver biopsy confirms the presence of liver injury and quantifies its extent. The severity of liver damage will determine whether treatment is needed. HCV genotyping determines the appropriate duration and dosage of pharmacotherapy.

Table 1

Tests to diagnose and evaluate HCV

CASE CONTINUED: Mood improves, but fatigue persists

As part of pre-HCV treatment evaluation, Mr. P undergoes a psychiatric evaluation. He describes periods of low mood while actively engaged in drug use but has never received psychiatric treatment, experienced suicidal ideation, or attempted suicide. Since starting opioid agonist therapy, he reports improved mood but endorses continued mild fatigue and difficulty falling sleep. The psychiatrist determines Mr. P does not meet criteria for an axis I diagnosis other than a substance use disorder.

Although most HCV patients have few, if any, nonspecific physical symptoms, many have psychiatric symptoms or disorders before the HCV diagnosis is made or treatment is initiated; substance use disorders are most common. Batki et al¹ found that 56% of HCV patients in an MMTP met criteria for a nonsubstance axis I disorder and 82% met criteria for such a disorder during their lifetime. Additionally, 66% of patients were taking psychiatric medications. Table 2^1,5,6 lists the rates of other psychiatric disorders found in patients with untreated HCV.

Table 2

Rates of psychiatric disorders in patients with untreated hepatitis C virus

Many patients with chronic HCV complain of chronic fatigue and deficiencies in attention, concentration, higher executive functions, learning ability, and memory that result in significant reduction in quality of life (Box 1).^7-9 These findings have been found to be independent of the degree of liver disease and are seen in HCV patients with normal liver function.^7,8

Box 1

CASE CONTINUED: Motivated and compliant

Since joining the MMTP 6 months ago, Mr. P has been motivated and compliant with all appointments and treatments. Routine urine toxicology screening supports his claim of abstinence. Mr. P begins HCV treatment while continuing follow-up with addiction medicine and psychiatric clinicians and maintains open communication with all treatment providers.

For many years the standard HCV treatment was pegylated interferon-α (IFN-α) and ribavirin. IFN-α is a proinflammatory cytokine with antiproliferative, antiviral, and immunoregulatory properties. The half-life of IFN-α significantly increases with pegylation, which allows for weekly injections.^10,11 IFN-α usually is combined with ribavirin, which increases its efficacy as measured by the sustained virological response (SVR) compared with IFN-α alone. Depending on the virus genotype, treatment lasts 24 to 48 weeks; SVR rates range from 40% to 82%.^11-13 In 2011, the FDA approved 2 agents—telaprevir and boceprevir—for adjunctive treatment of HCV genotype 1 infection. These 2 agents are protease inhibitors that when added to IFN-α and ribavirin increase the SVR rate in genotype 1 infection from 40% to 50% to approximately 75%.^14,15

Although the neuropsychiatric side effects of telaprevir and boceprevir have not been determined, treating chronic HCV with IFN-α and ribavirin has been associated with multiple psychiatric symptoms, including depression, mania, suicidality, anxiety, and psychosis.^11-14 Psychiatric symptoms are a common reason for discontinuing or reducing HCV treatment. Because of the high frequency of neuropsychiatric complications, some clinicians believe HCV patients with preexisting affective, psychotic, or substance use disorders should be excluded from HCV treatment. This has led to many HCV patients being untreated despite a lack of prospective, controlled data to support this opinion.¹² To improve outcomes and decrease morbidity, providing appropriate psychiatric services appears to be more important than attempting to select lower-risk patients for antiviral therapy.^1,12,16 The goals of psychiatric treatment should be to alleviate symptoms and allow patients to complete IFN-α therapy without interruption.^16,17

Studies of high-risk patients who attend multidisciplinary treatment programs that can monitor adherence and efficacy and control side effects before and during HCV treatment have found psychiatric patients have similar adherence, compliance, and SVR rates and were not at increased risk of worsening depressive or psychotic symptoms compared with patients without a psychiatric history.^12,18 Additionally, HCV patients with a psychiatric history are not at an increased risk of suicide.^13,16 Similar findings have been observed in patients with active IV drug use or those receiving opioid agonist therapy. When HCV and substance use are treated simultaneously, patients can successfully complete HCV treatment with SVR rates comparable to those of patients not receiving opioid agonist therapy.^19-21

CASE CONTINUED: Worsening symptoms

During a psychiatric follow-up 12 weeks after starting HCV treatment, Mr. P reports worsening depressive symptoms with low mood, decreased enjoyment of activities, poor sleep, low appetite, and fatigue. He shows no evidence of psychosis and denies suicidal ideation. We continue his HCV treatment, schedule more frequent psychiatric visits, and initiate citalopram, titrated to 40 mg/d.

Depressive symptoms, the most common neuropsychiatric manifestation of HCV, typically begin early in treatment, usually within the first 12 weeks. Two distinct symptom clusters are noted. A neurovegetative cluster characterized by reduced energy, anorexia, and psychomotor retardation typically begins within the first few months of treatment. Months later, a depression-specific syndrome appears that includes depressed mood, anxiety, and cognitive impairment.²²

Depressive symptoms may occur in up to 60% of patients treated with IFN-α.¹¹ When more rigorous depression measures are used, rates decrease to approximately 20% to 30%.^11,13 Accurate diagnosis and treatment of emerging depressive symptoms is essential because untreated depression can lead to postponing or excluding patients from antiviral treatment.² Screening instruments such as the Beck Depression Inventory-Second Edition (BDI-II) can be used to measure depressive symptoms in HCV patients with high sensitivity. However, because specificity has been low and somatic symptoms of chronic illness and depression often overlap, the BDI-II and other inventories may overestimate depression. Some researchers have suggested that focusing on questions targeting cognitive and affective symptoms rather than somatic ones may be a more valid measure of depression in patients undergoing immunotherapy for HCV.²

The immune system is implicated in IFN-α-induced depression because depressive symptoms share many features with a constellation of somatic and behavioral symptoms termed “sickness behavior.”¹¹ These behaviors can occur when patients are exposed to cytokines that lead to a depressed level of functioning, which may allow the body to devote more energy to fighting illness. IFN-α, a cytokine, stimulates the immune system, which can lead to increases of interleukin (IL)-2, IL-6, and IL-10. Increased circulating levels of these ILs have been correlated with higher depression scores. Additionally, studies have found that patients who develop depression during IFN-α treatment have higher SVR rates, suggesting a more robust immune response.^11,22 For a discussion of how serotonin metabolism and genetic polymorphisms also may help explain the prevalence of depression in patients with HCV, see Box 2.

Box 2

Treating depressed HCV patients

Antidepressants are the treatment of choice for IFN-α-induced depression. Most currently used antidepressants are effective²² and selective serotonin reuptake inhibitors are considered first choice.¹⁶ Antidepressant choice should be guided by principles similar to those used for patients without HCV: using side effects profiles to target specific symptoms and being mindful of pharmacokinetic properties.

Two treatment approaches have been investigated: prophylactic and symptomatic. A 2012 study²³ of 181 HCV patients with no history of mental illness determined escitalopram, 10 mg/d, effectively reduced the incidence and severity of interferon-associated depression. Other studies examining prophylactic treatment of all patients who were to undergo interferon treatment found this approach did not prevent depressive episodes.^24,25 However, antidepressants have been beneficial for patients with subsyndromal depressive symptoms at baseline²⁶ and after clinically significant depressive symptoms emerge.²⁷ Electroconvulsive therapy also has been reported to effectively treat depression in HCV patients undergoing antiviral therapy.²⁸

CASE CONTINUED: Lingering symptoms

Mr. P responds to citalopram with an improvement in mood, anhedonia, and appetite, but he continues to complain of low energy and poor concentration. In an effort to target these symptoms, methylphenidate, titrated to 30 mg/d in divided doses, is added to his regimen, which rapidly improves his symptoms. Insomnia is treated successfully with trazodone, 50 mg/d. Mr. P frequently visits his psychiatrist, who monitors his depressive symptoms using the BDI-II. Mr. P completes HCV treatment without recurrence of depressive symptoms or relapse to heroin use.

Although antidepressants are effective for treating affective and cognitive symptoms, they are not as effective for fatigue and other neurovegetative symptoms.^16,29 The psychostimulants methylphenidate and dextroamphetamine and the nonstimulant modafinil have been studied for treating depressive symptoms in medically ill patients and can be used to treat IFN-α-induced fatigue.^16,22,29

IFN-α’s effect on serotonin metabolism leads to a tryptophan-deficient state because of increased catabolism as a result of activation of indoleamine-2,3-dioxygenase (IDO). This has led to use of tryptophan supplementation, either as augmentation or monotherapy, for managing depressive symptoms in patients treated with IFN-α. Schaefer et al³⁰ reported 3 cases where tryptophan supplementation significantly decreased depressive symptoms. Other researchers have argued that supplementing tryptophan in the context of IDO activation can lead to greater production of kynurenine and quinolinic acid, which have been linked to increased depressive symptoms in patients receiving IFN-α.³¹ They argue that supplementation of 5-HTP, which is available as a dietary supplement without a prescription, can lead to increased serotonin levels and improvement in depressive symptoms.³¹

IFN-α treatment also is associated with mania and psychosis. The incidence, pathophysiology, and management of these treatment-emergent symptoms are not as well studied as IFN-α-induced depression. Mania and hypomania have been reported with interferon treatment, discontinuation of interferon, and use of antidepressants for interferon-induced depression.^29,32 Psychosis, in association with mood symptoms or alone, has been reported to occur in <1% of treated patients.³³ Treatment for mania and psychosis consists of decreasing or discontinuing immunotherapy and adding mood stabilizers and antipsychotics. Once immunotherapy is discontinued, mania and psychosis usually resolve, but prolonged duration of symptoms has been reported.^29,32,33

Related Resources

• Centers for Disease Control and Prevention. Hepatitis C information for health professionals. www.cdc.gov/hepatitis/hcv/index.htm.
• Hep C Connection. www.hepc-connection.org.
• United States Department of Veterans Affairs. Hepatitis C. www.hepatitis.va.gov.

Drug Brand Names

• Boceprevir • Victrelis
• Citalopram • Celexa
• Dextroamphetamine • Dexedrine
• Escitalopram • Lexapro
• Interferon-α • Intron
• Methadone • Dolophine, Methadose
• Methylphenidate • Ritalin, Methylin, others
• Modafinil • Provigil
• Ondansetron • Zofran
• Ribavirin • Copegus, Rebetol, others
• Telaprevir • Incivek
• Trazodone • Desyrel, Oleptro

Disclosure

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

Mr. P, age 31, has been using heroin intravenously for 9 years. He smokes 1 pack of cigarettes daily, but denies using other substances, including alcohol. After an unintentional heroin overdose, Mr. P enrolls in a methadone maintenance treatment program (MMTP) that includes primary medical care and addiction medicine and psychiatric specialists, where he undergoes medical evaluation and screening for hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Laboratory data reveal that although Mr. P is HIV negative, he has been exposed to HCV and treatment is indicated.

Among the approximately 3 million people in the United States with chronic HCV—an enveloped, single-stranded RNA virus—there’s a high prevalence of premorbid psychopathology and substance abuse, as well as neuropsychiatric effects caused by HCV treatment.^1-3 Because underdiagnosing and undertreating psychiatric disorders contributes to morbidity and mortality in HCV patients, early identification and prompt treatment is critical.

IV drug use is the most common route for HCV infection, accounting for 65% to 70% of infections.¹ The prevalence of HCV among IV drug users is 28% to 90%.¹ Once exposed to HCV, 75% to 85% of patients do not clear the initial infection and become chronically infected.

This article reviews the pathophysiology, identification, and management of psychiatric manifestations found among HCV patients and provides an understanding of how psychiatric symptoms manifest in HCV patients. This article also discusses HCV treatment and its neuropsychiatric side effects.

Testing for HCV

Chronically infected HCV patients may have few, if any, specific physical complaints, and often are diagnosed during screenings or other routine laboratory evaluations. The presence of risk factors, such as a history of injection drug use or receiving a blood transfusion before 1992,¹ guides the decision to screen for HCV. Normal liver function test results should not preclude testing because many HCV-positive patients have transaminases within the normal range.⁴ Initial screening is via an antibody-mediated immunoassay that is highly specific and sensitive for past exposure to HCV (Table 1).⁴ However, a positive screen does not indicate the presence of active infection. Evidence of the virus via a viral assay will identify active HCV, but does not indicate need for treatment. Liver biopsy confirms the presence of liver injury and quantifies its extent. The severity of liver damage will determine whether treatment is needed. HCV genotyping determines the appropriate duration and dosage of pharmacotherapy.

Table 1

Tests to diagnose and evaluate HCV

CASE CONTINUED: Mood improves, but fatigue persists

As part of pre-HCV treatment evaluation, Mr. P undergoes a psychiatric evaluation. He describes periods of low mood while actively engaged in drug use but has never received psychiatric treatment, experienced suicidal ideation, or attempted suicide. Since starting opioid agonist therapy, he reports improved mood but endorses continued mild fatigue and difficulty falling sleep. The psychiatrist determines Mr. P does not meet criteria for an axis I diagnosis other than a substance use disorder.

Although most HCV patients have few, if any, nonspecific physical symptoms, many have psychiatric symptoms or disorders before the HCV diagnosis is made or treatment is initiated; substance use disorders are most common. Batki et al¹ found that 56% of HCV patients in an MMTP met criteria for a nonsubstance axis I disorder and 82% met criteria for such a disorder during their lifetime. Additionally, 66% of patients were taking psychiatric medications. Table 2^1,5,6 lists the rates of other psychiatric disorders found in patients with untreated HCV.

Table 2

Rates of psychiatric disorders in patients with untreated hepatitis C virus

Many patients with chronic HCV complain of chronic fatigue and deficiencies in attention, concentration, higher executive functions, learning ability, and memory that result in significant reduction in quality of life (Box 1).^7-9 These findings have been found to be independent of the degree of liver disease and are seen in HCV patients with normal liver function.^7,8

Box 1

CASE CONTINUED: Motivated and compliant

Since joining the MMTP 6 months ago, Mr. P has been motivated and compliant with all appointments and treatments. Routine urine toxicology screening supports his claim of abstinence. Mr. P begins HCV treatment while continuing follow-up with addiction medicine and psychiatric clinicians and maintains open communication with all treatment providers.

For many years the standard HCV treatment was pegylated interferon-α (IFN-α) and ribavirin. IFN-α is a proinflammatory cytokine with antiproliferative, antiviral, and immunoregulatory properties. The half-life of IFN-α significantly increases with pegylation, which allows for weekly injections.^10,11 IFN-α usually is combined with ribavirin, which increases its efficacy as measured by the sustained virological response (SVR) compared with IFN-α alone. Depending on the virus genotype, treatment lasts 24 to 48 weeks; SVR rates range from 40% to 82%.^11-13 In 2011, the FDA approved 2 agents—telaprevir and boceprevir—for adjunctive treatment of HCV genotype 1 infection. These 2 agents are protease inhibitors that when added to IFN-α and ribavirin increase the SVR rate in genotype 1 infection from 40% to 50% to approximately 75%.^14,15

Although the neuropsychiatric side effects of telaprevir and boceprevir have not been determined, treating chronic HCV with IFN-α and ribavirin has been associated with multiple psychiatric symptoms, including depression, mania, suicidality, anxiety, and psychosis.^11-14 Psychiatric symptoms are a common reason for discontinuing or reducing HCV treatment. Because of the high frequency of neuropsychiatric complications, some clinicians believe HCV patients with preexisting affective, psychotic, or substance use disorders should be excluded from HCV treatment. This has led to many HCV patients being untreated despite a lack of prospective, controlled data to support this opinion.¹² To improve outcomes and decrease morbidity, providing appropriate psychiatric services appears to be more important than attempting to select lower-risk patients for antiviral therapy.^1,12,16 The goals of psychiatric treatment should be to alleviate symptoms and allow patients to complete IFN-α therapy without interruption.^16,17

Studies of high-risk patients who attend multidisciplinary treatment programs that can monitor adherence and efficacy and control side effects before and during HCV treatment have found psychiatric patients have similar adherence, compliance, and SVR rates and were not at increased risk of worsening depressive or psychotic symptoms compared with patients without a psychiatric history.^12,18 Additionally, HCV patients with a psychiatric history are not at an increased risk of suicide.^13,16 Similar findings have been observed in patients with active IV drug use or those receiving opioid agonist therapy. When HCV and substance use are treated simultaneously, patients can successfully complete HCV treatment with SVR rates comparable to those of patients not receiving opioid agonist therapy.^19-21

CASE CONTINUED: Worsening symptoms

During a psychiatric follow-up 12 weeks after starting HCV treatment, Mr. P reports worsening depressive symptoms with low mood, decreased enjoyment of activities, poor sleep, low appetite, and fatigue. He shows no evidence of psychosis and denies suicidal ideation. We continue his HCV treatment, schedule more frequent psychiatric visits, and initiate citalopram, titrated to 40 mg/d.

Depressive symptoms, the most common neuropsychiatric manifestation of HCV, typically begin early in treatment, usually within the first 12 weeks. Two distinct symptom clusters are noted. A neurovegetative cluster characterized by reduced energy, anorexia, and psychomotor retardation typically begins within the first few months of treatment. Months later, a depression-specific syndrome appears that includes depressed mood, anxiety, and cognitive impairment.²²

Depressive symptoms may occur in up to 60% of patients treated with IFN-α.¹¹ When more rigorous depression measures are used, rates decrease to approximately 20% to 30%.^11,13 Accurate diagnosis and treatment of emerging depressive symptoms is essential because untreated depression can lead to postponing or excluding patients from antiviral treatment.² Screening instruments such as the Beck Depression Inventory-Second Edition (BDI-II) can be used to measure depressive symptoms in HCV patients with high sensitivity. However, because specificity has been low and somatic symptoms of chronic illness and depression often overlap, the BDI-II and other inventories may overestimate depression. Some researchers have suggested that focusing on questions targeting cognitive and affective symptoms rather than somatic ones may be a more valid measure of depression in patients undergoing immunotherapy for HCV.²

The immune system is implicated in IFN-α-induced depression because depressive symptoms share many features with a constellation of somatic and behavioral symptoms termed “sickness behavior.”¹¹ These behaviors can occur when patients are exposed to cytokines that lead to a depressed level of functioning, which may allow the body to devote more energy to fighting illness. IFN-α, a cytokine, stimulates the immune system, which can lead to increases of interleukin (IL)-2, IL-6, and IL-10. Increased circulating levels of these ILs have been correlated with higher depression scores. Additionally, studies have found that patients who develop depression during IFN-α treatment have higher SVR rates, suggesting a more robust immune response.^11,22 For a discussion of how serotonin metabolism and genetic polymorphisms also may help explain the prevalence of depression in patients with HCV, see Box 2.

Box 2

Treating depressed HCV patients

Antidepressants are the treatment of choice for IFN-α-induced depression. Most currently used antidepressants are effective²² and selective serotonin reuptake inhibitors are considered first choice.¹⁶ Antidepressant choice should be guided by principles similar to those used for patients without HCV: using side effects profiles to target specific symptoms and being mindful of pharmacokinetic properties.

Two treatment approaches have been investigated: prophylactic and symptomatic. A 2012 study²³ of 181 HCV patients with no history of mental illness determined escitalopram, 10 mg/d, effectively reduced the incidence and severity of interferon-associated depression. Other studies examining prophylactic treatment of all patients who were to undergo interferon treatment found this approach did not prevent depressive episodes.^24,25 However, antidepressants have been beneficial for patients with subsyndromal depressive symptoms at baseline²⁶ and after clinically significant depressive symptoms emerge.²⁷ Electroconvulsive therapy also has been reported to effectively treat depression in HCV patients undergoing antiviral therapy.²⁸

CASE CONTINUED: Lingering symptoms

Mr. P responds to citalopram with an improvement in mood, anhedonia, and appetite, but he continues to complain of low energy and poor concentration. In an effort to target these symptoms, methylphenidate, titrated to 30 mg/d in divided doses, is added to his regimen, which rapidly improves his symptoms. Insomnia is treated successfully with trazodone, 50 mg/d. Mr. P frequently visits his psychiatrist, who monitors his depressive symptoms using the BDI-II. Mr. P completes HCV treatment without recurrence of depressive symptoms or relapse to heroin use.

Although antidepressants are effective for treating affective and cognitive symptoms, they are not as effective for fatigue and other neurovegetative symptoms.^16,29 The psychostimulants methylphenidate and dextroamphetamine and the nonstimulant modafinil have been studied for treating depressive symptoms in medically ill patients and can be used to treat IFN-α-induced fatigue.^16,22,29

IFN-α’s effect on serotonin metabolism leads to a tryptophan-deficient state because of increased catabolism as a result of activation of indoleamine-2,3-dioxygenase (IDO). This has led to use of tryptophan supplementation, either as augmentation or monotherapy, for managing depressive symptoms in patients treated with IFN-α. Schaefer et al³⁰ reported 3 cases where tryptophan supplementation significantly decreased depressive symptoms. Other researchers have argued that supplementing tryptophan in the context of IDO activation can lead to greater production of kynurenine and quinolinic acid, which have been linked to increased depressive symptoms in patients receiving IFN-α.³¹ They argue that supplementation of 5-HTP, which is available as a dietary supplement without a prescription, can lead to increased serotonin levels and improvement in depressive symptoms.³¹

IFN-α treatment also is associated with mania and psychosis. The incidence, pathophysiology, and management of these treatment-emergent symptoms are not as well studied as IFN-α-induced depression. Mania and hypomania have been reported with interferon treatment, discontinuation of interferon, and use of antidepressants for interferon-induced depression.^29,32 Psychosis, in association with mood symptoms or alone, has been reported to occur in <1% of treated patients.³³ Treatment for mania and psychosis consists of decreasing or discontinuing immunotherapy and adding mood stabilizers and antipsychotics. Once immunotherapy is discontinued, mania and psychosis usually resolve, but prolonged duration of symptoms has been reported.^29,32,33

Related Resources

• Centers for Disease Control and Prevention. Hepatitis C information for health professionals. www.cdc.gov/hepatitis/hcv/index.htm.
• Hep C Connection. www.hepc-connection.org.
• United States Department of Veterans Affairs. Hepatitis C. www.hepatitis.va.gov.

Drug Brand Names

• Boceprevir • Victrelis
• Citalopram • Celexa
• Dextroamphetamine • Dexedrine
• Escitalopram • Lexapro
• Interferon-α • Intron
• Methadone • Dolophine, Methadose
• Methylphenidate • Ritalin, Methylin, others
• Modafinil • Provigil
• Ondansetron • Zofran
• Ribavirin • Copegus, Rebetol, others
• Telaprevir • Incivek
• Trazodone • Desyrel, Oleptro

Disclosure

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

In “Pharmacotherapy for comorbid depression and alcohol dependence” (Current Psychiatry, January 2013, p. 24-32; http://bit.ly/1dBavVI), Drs. Gianoli and Petrakis report that the potential benefits of mixing antidepressants and alcohol dependence medications is extremely limited. Their article confirms the general wisdom in addiction psychiatry and is distressing in the short shrift given to the primary avenue physicians have for treating this dual condition—encouraging abstinence.

McLellan et al¹ found that treating alcohol addiction produces outcomes comparable to treating hypertension and diabetes. However, if psychiatry were to bring its current overemphasis on pharmacology and underappreciation of psychotherapy to treating alcohol addiction, it would not produce the effectiveness of current multimodal, multidisciplinary approaches. Under the Affordable Care Act, primary care physicians will be expected to identify high-risk alcohol consumption and encourage reduction of risk, including treatment and recovery. What the authors allude to as “encouraging abstinence” is a complex art and craft that all physicians will need to attend to more than in the past. Drs. Gianoli and Petrakis’ work tells us why this is so: pharmacology does not rule in the treatment of mixed depression and alcohol dependence.

Timmen L. Cermak, MD
Immediate Past President
California Society of Addiction Medicine
Mill Valley, CA

The authors respond

We thank Dr. Cermak for his comments on our article. We wrote a review of the literature on the efficacy of various pharmacologic treatments to treat patients with comorbid depression and alcohol dependence. The purpose of our review was to remind practitioners that efficacy of antidepressants or medications to treat alcohol use disorders may be different in individuals with a comorbid disorder. Studies determining efficacy have been conducted primarily in noncomorbid groups and the results may not be generalizable. Emerging literature is trying to address this shortcoming. This is an important point that we hope we adequately conveyed to Current Psychiatry’s readers.

Our article was not a comprehensive review of all possible treatment options; we mentioned that a review of nonpharmacologic treatments was beyond the scope of our review. This does not mean that psychosocial treatments are not valued or important; they are an important part of any comprehensive treatment plan.

Mayumi Okada Gianoli, PhD
Postdoctoral Fellow
Department of Psychiatry
Yale University School of Medicine

Ismene L. Petrakis, MD
Professor of Psychiatry
Yale University School of Medicine
Chief of Psychiatry Service
Veterans Affairs Connecticut Healthcare Systems
New Haven, CT

In “Pharmacotherapy for comorbid depression and alcohol dependence” (Current Psychiatry, January 2013, p. 24-32; http://bit.ly/1dBavVI), Drs. Gianoli and Petrakis report that the potential benefits of mixing antidepressants and alcohol dependence medications is extremely limited. Their article confirms the general wisdom in addiction psychiatry and is distressing in the short shrift given to the primary avenue physicians have for treating this dual condition—encouraging abstinence.

McLellan et al¹ found that treating alcohol addiction produces outcomes comparable to treating hypertension and diabetes. However, if psychiatry were to bring its current overemphasis on pharmacology and underappreciation of psychotherapy to treating alcohol addiction, it would not produce the effectiveness of current multimodal, multidisciplinary approaches. Under the Affordable Care Act, primary care physicians will be expected to identify high-risk alcohol consumption and encourage reduction of risk, including treatment and recovery. What the authors allude to as “encouraging abstinence” is a complex art and craft that all physicians will need to attend to more than in the past. Drs. Gianoli and Petrakis’ work tells us why this is so: pharmacology does not rule in the treatment of mixed depression and alcohol dependence.

Timmen L. Cermak, MD
Immediate Past President
California Society of Addiction Medicine
Mill Valley, CA

The authors respond

We thank Dr. Cermak for his comments on our article. We wrote a review of the literature on the efficacy of various pharmacologic treatments to treat patients with comorbid depression and alcohol dependence. The purpose of our review was to remind practitioners that efficacy of antidepressants or medications to treat alcohol use disorders may be different in individuals with a comorbid disorder. Studies determining efficacy have been conducted primarily in noncomorbid groups and the results may not be generalizable. Emerging literature is trying to address this shortcoming. This is an important point that we hope we adequately conveyed to Current Psychiatry’s readers.

Our article was not a comprehensive review of all possible treatment options; we mentioned that a review of nonpharmacologic treatments was beyond the scope of our review. This does not mean that psychosocial treatments are not valued or important; they are an important part of any comprehensive treatment plan.

Mayumi Okada Gianoli, PhD
Postdoctoral Fellow
Department of Psychiatry
Yale University School of Medicine

Ismene L. Petrakis, MD
Professor of Psychiatry
Yale University School of Medicine
Chief of Psychiatry Service
Veterans Affairs Connecticut Healthcare Systems
New Haven, CT

In “Pharmacotherapy for comorbid depression and alcohol dependence” (Current Psychiatry, January 2013, p. 24-32; http://bit.ly/1dBavVI), Drs. Gianoli and Petrakis report that the potential benefits of mixing antidepressants and alcohol dependence medications is extremely limited. Their article confirms the general wisdom in addiction psychiatry and is distressing in the short shrift given to the primary avenue physicians have for treating this dual condition—encouraging abstinence.

McLellan et al¹ found that treating alcohol addiction produces outcomes comparable to treating hypertension and diabetes. However, if psychiatry were to bring its current overemphasis on pharmacology and underappreciation of psychotherapy to treating alcohol addiction, it would not produce the effectiveness of current multimodal, multidisciplinary approaches. Under the Affordable Care Act, primary care physicians will be expected to identify high-risk alcohol consumption and encourage reduction of risk, including treatment and recovery. What the authors allude to as “encouraging abstinence” is a complex art and craft that all physicians will need to attend to more than in the past. Drs. Gianoli and Petrakis’ work tells us why this is so: pharmacology does not rule in the treatment of mixed depression and alcohol dependence.

Timmen L. Cermak, MD
Immediate Past President
California Society of Addiction Medicine
Mill Valley, CA

The authors respond

We thank Dr. Cermak for his comments on our article. We wrote a review of the literature on the efficacy of various pharmacologic treatments to treat patients with comorbid depression and alcohol dependence. The purpose of our review was to remind practitioners that efficacy of antidepressants or medications to treat alcohol use disorders may be different in individuals with a comorbid disorder. Studies determining efficacy have been conducted primarily in noncomorbid groups and the results may not be generalizable. Emerging literature is trying to address this shortcoming. This is an important point that we hope we adequately conveyed to Current Psychiatry’s readers.

Our article was not a comprehensive review of all possible treatment options; we mentioned that a review of nonpharmacologic treatments was beyond the scope of our review. This does not mean that psychosocial treatments are not valued or important; they are an important part of any comprehensive treatment plan.

Mayumi Okada Gianoli, PhD
Postdoctoral Fellow
Department of Psychiatry
Yale University School of Medicine

Ismene L. Petrakis, MD
Professor of Psychiatry
Yale University School of Medicine
Chief of Psychiatry Service
Veterans Affairs Connecticut Healthcare Systems
New Haven, CT

The demand for “legal highs”— intoxicating natural or synthetic substances that are not prohibited by law—continues to increase. Young adults may use these substances, which are widely available on the internet, at “head shops,” and at gas stations. Such substances frequently cause adverse medical and psychiatric effects, exemplified by recent reports concerning the dangers of using synthetic cannabinoids (eg, “Spice,” “K2”) and synthetic cathinones (“bath salts”). Although these 2 substances now are illegal in many jurisdictions, other novel substances of misuse remain legal and widely available, including Kratom and methoxetamine.

Because these substances usually are not detectable on standard urine toxicology screens, clinicians need to be aware of them to be able to take an accurate substance use history, consider possible dangerous interactions with prescribed psychotropics, and address medical and psychiatric complications.

Kratom is an herbal product derived from Mitragyna speciosa, a plant native to Southeast Asia. Traditionally used as a medicinal herb, it increasingly is being used for recreational purposes and remains legal and widely available in the United States. Kratom’s leaves contain multiple alkaloids, including mitragynine and 7-hydroxymitragynine, which are believed to act as agonists at the μ-opioid receptor. Mitragynine also may have agonist activity at post-synaptic α2-adrenergic receptors, as well as antagonist activity at 5-HT2A receptors.¹ Mitragynine is 13 times more potent than morphine, and 7-hydroxymitragynine is 4 times more potent than mitragynine.²

Kratom is available as leaves, powdered leaves, or gum. It can be smoked, brewed into tea, or mixed with liquid and ingested. Effects are dose-dependent; lower doses tend to produce a stimulant effect and higher doses produce an opioid effect. A typical dose is 1 to 8 g.³ Users may take Kratom to experience euphoria or analgesia, or to self-treat opioid withdrawal symptoms.³ Kratom withdrawal syndrome shares many features of classic opioid withdrawal—diarrhea, rhinorrhea, cravings, anxiety, tremor, myalgia, sweating, and irritability—but has been reported to be less severe and shorter-lasting.¹ Kratom withdrawal, like opioid withdrawal, may respond to supportive care in combination with opioid-replacement therapy. Airway management and naloxone treatment may be needed on an emergent basis if a user develops respiratory depression.² There have been case reports of seizures occurring following Kratom use.²

Methoxetamine is a ketamine analog originally developed as an alternative to ketamine. It isn’t classified as a controlled substance in the United States and is available on the internet.² Methoxetamine is a white powder typically snorted or taken sublingually, although it can be injected intramuscularly. Because methoxetamine’s structure is similar to ketamine, its mechanism of action is assumed to involve glutamate N-methyl-D-aspartate receptor antagonism and dopamine reuptake inhibition. Doses range from 20 to 100 mg orally and 10 to 50 mg when injected. Effects may not be apparent for 30 to 90 minutes after the drug is snorted, which may cause users to take another dose or ingest a different substance, possibly leading to synergistic adverse effects. Effects may emerge within 5 minutes when injected. The duration of effect generally is 5 to 7 hours—notably longer than ketamine—but as little as 1 hour when injected.

No clinical human or animal studies have been conducted on methoxetamine, which makes it difficult to ascertain the drug’s true clinical and toxic effects; instead, these effects must be surmised from user reports and case studies. Desired effects described by users are similar to those of ketamine: dissociation, short-term mood elevation, visual hallucinations, and alteration of sensory experiences. Reported adverse effects include catatonia, confusion, agitation, and depression.⁴ In addition, methoxetamine may induce sympathomimetic toxicity as evidenced by tachycardia and hypertension. Researchers have suggested that patients who experience methoxetamine toxicity and require emergency treatment be managed with supportive care and benzodiazepines.⁵

Staying current is key

A paucity of clinical research on these substances means their effects are poorly understood, which creates a dangerous situation for users and physicians. In addition, many users assume these substances are safer than illegal substances. New and potentially dangerous substances are being produced so quickly distributors are able to stay ahead of regulatory efforts. When one substance is declared illegal, another related substance quickly is available to take its place. To provide the best care for our patients, it is essential for psychiatrists to stay up-to-date about these novel substances.

Disclosure

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

The demand for “legal highs”— intoxicating natural or synthetic substances that are not prohibited by law—continues to increase. Young adults may use these substances, which are widely available on the internet, at “head shops,” and at gas stations. Such substances frequently cause adverse medical and psychiatric effects, exemplified by recent reports concerning the dangers of using synthetic cannabinoids (eg, “Spice,” “K2”) and synthetic cathinones (“bath salts”). Although these 2 substances now are illegal in many jurisdictions, other novel substances of misuse remain legal and widely available, including Kratom and methoxetamine.

Because these substances usually are not detectable on standard urine toxicology screens, clinicians need to be aware of them to be able to take an accurate substance use history, consider possible dangerous interactions with prescribed psychotropics, and address medical and psychiatric complications.

Kratom is an herbal product derived from Mitragyna speciosa, a plant native to Southeast Asia. Traditionally used as a medicinal herb, it increasingly is being used for recreational purposes and remains legal and widely available in the United States. Kratom’s leaves contain multiple alkaloids, including mitragynine and 7-hydroxymitragynine, which are believed to act as agonists at the μ-opioid receptor. Mitragynine also may have agonist activity at post-synaptic α2-adrenergic receptors, as well as antagonist activity at 5-HT2A receptors.¹ Mitragynine is 13 times more potent than morphine, and 7-hydroxymitragynine is 4 times more potent than mitragynine.²

Kratom is available as leaves, powdered leaves, or gum. It can be smoked, brewed into tea, or mixed with liquid and ingested. Effects are dose-dependent; lower doses tend to produce a stimulant effect and higher doses produce an opioid effect. A typical dose is 1 to 8 g.³ Users may take Kratom to experience euphoria or analgesia, or to self-treat opioid withdrawal symptoms.³ Kratom withdrawal syndrome shares many features of classic opioid withdrawal—diarrhea, rhinorrhea, cravings, anxiety, tremor, myalgia, sweating, and irritability—but has been reported to be less severe and shorter-lasting.¹ Kratom withdrawal, like opioid withdrawal, may respond to supportive care in combination with opioid-replacement therapy. Airway management and naloxone treatment may be needed on an emergent basis if a user develops respiratory depression.² There have been case reports of seizures occurring following Kratom use.²

Methoxetamine is a ketamine analog originally developed as an alternative to ketamine. It isn’t classified as a controlled substance in the United States and is available on the internet.² Methoxetamine is a white powder typically snorted or taken sublingually, although it can be injected intramuscularly. Because methoxetamine’s structure is similar to ketamine, its mechanism of action is assumed to involve glutamate N-methyl-D-aspartate receptor antagonism and dopamine reuptake inhibition. Doses range from 20 to 100 mg orally and 10 to 50 mg when injected. Effects may not be apparent for 30 to 90 minutes after the drug is snorted, which may cause users to take another dose or ingest a different substance, possibly leading to synergistic adverse effects. Effects may emerge within 5 minutes when injected. The duration of effect generally is 5 to 7 hours—notably longer than ketamine—but as little as 1 hour when injected.

No clinical human or animal studies have been conducted on methoxetamine, which makes it difficult to ascertain the drug’s true clinical and toxic effects; instead, these effects must be surmised from user reports and case studies. Desired effects described by users are similar to those of ketamine: dissociation, short-term mood elevation, visual hallucinations, and alteration of sensory experiences. Reported adverse effects include catatonia, confusion, agitation, and depression.⁴ In addition, methoxetamine may induce sympathomimetic toxicity as evidenced by tachycardia and hypertension. Researchers have suggested that patients who experience methoxetamine toxicity and require emergency treatment be managed with supportive care and benzodiazepines.⁵

Staying current is key

A paucity of clinical research on these substances means their effects are poorly understood, which creates a dangerous situation for users and physicians. In addition, many users assume these substances are safer than illegal substances. New and potentially dangerous substances are being produced so quickly distributors are able to stay ahead of regulatory efforts. When one substance is declared illegal, another related substance quickly is available to take its place. To provide the best care for our patients, it is essential for psychiatrists to stay up-to-date about these novel substances.

Disclosure

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

The demand for “legal highs”— intoxicating natural or synthetic substances that are not prohibited by law—continues to increase. Young adults may use these substances, which are widely available on the internet, at “head shops,” and at gas stations. Such substances frequently cause adverse medical and psychiatric effects, exemplified by recent reports concerning the dangers of using synthetic cannabinoids (eg, “Spice,” “K2”) and synthetic cathinones (“bath salts”). Although these 2 substances now are illegal in many jurisdictions, other novel substances of misuse remain legal and widely available, including Kratom and methoxetamine.

Because these substances usually are not detectable on standard urine toxicology screens, clinicians need to be aware of them to be able to take an accurate substance use history, consider possible dangerous interactions with prescribed psychotropics, and address medical and psychiatric complications.

Kratom is an herbal product derived from Mitragyna speciosa, a plant native to Southeast Asia. Traditionally used as a medicinal herb, it increasingly is being used for recreational purposes and remains legal and widely available in the United States. Kratom’s leaves contain multiple alkaloids, including mitragynine and 7-hydroxymitragynine, which are believed to act as agonists at the μ-opioid receptor. Mitragynine also may have agonist activity at post-synaptic α2-adrenergic receptors, as well as antagonist activity at 5-HT2A receptors.¹ Mitragynine is 13 times more potent than morphine, and 7-hydroxymitragynine is 4 times more potent than mitragynine.²

Kratom is available as leaves, powdered leaves, or gum. It can be smoked, brewed into tea, or mixed with liquid and ingested. Effects are dose-dependent; lower doses tend to produce a stimulant effect and higher doses produce an opioid effect. A typical dose is 1 to 8 g.³ Users may take Kratom to experience euphoria or analgesia, or to self-treat opioid withdrawal symptoms.³ Kratom withdrawal syndrome shares many features of classic opioid withdrawal—diarrhea, rhinorrhea, cravings, anxiety, tremor, myalgia, sweating, and irritability—but has been reported to be less severe and shorter-lasting.¹ Kratom withdrawal, like opioid withdrawal, may respond to supportive care in combination with opioid-replacement therapy. Airway management and naloxone treatment may be needed on an emergent basis if a user develops respiratory depression.² There have been case reports of seizures occurring following Kratom use.²

Methoxetamine is a ketamine analog originally developed as an alternative to ketamine. It isn’t classified as a controlled substance in the United States and is available on the internet.² Methoxetamine is a white powder typically snorted or taken sublingually, although it can be injected intramuscularly. Because methoxetamine’s structure is similar to ketamine, its mechanism of action is assumed to involve glutamate N-methyl-D-aspartate receptor antagonism and dopamine reuptake inhibition. Doses range from 20 to 100 mg orally and 10 to 50 mg when injected. Effects may not be apparent for 30 to 90 minutes after the drug is snorted, which may cause users to take another dose or ingest a different substance, possibly leading to synergistic adverse effects. Effects may emerge within 5 minutes when injected. The duration of effect generally is 5 to 7 hours—notably longer than ketamine—but as little as 1 hour when injected.

No clinical human or animal studies have been conducted on methoxetamine, which makes it difficult to ascertain the drug’s true clinical and toxic effects; instead, these effects must be surmised from user reports and case studies. Desired effects described by users are similar to those of ketamine: dissociation, short-term mood elevation, visual hallucinations, and alteration of sensory experiences. Reported adverse effects include catatonia, confusion, agitation, and depression.⁴ In addition, methoxetamine may induce sympathomimetic toxicity as evidenced by tachycardia and hypertension. Researchers have suggested that patients who experience methoxetamine toxicity and require emergency treatment be managed with supportive care and benzodiazepines.⁵

Staying current is key

A paucity of clinical research on these substances means their effects are poorly understood, which creates a dangerous situation for users and physicians. In addition, many users assume these substances are safer than illegal substances. New and potentially dangerous substances are being produced so quickly distributors are able to stay ahead of regulatory efforts. When one substance is declared illegal, another related substance quickly is available to take its place. To provide the best care for our patients, it is essential for psychiatrists to stay up-to-date about these novel substances.

Disclosure

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

The future of psychiatric diagnosis is destined to be reshaped by the rapidly unfolding and disruptive genetic and neuroscience discoveries.

Although it has been slow in coming, the pace clearly is accelerating and new findings are bubbling up at a breathtaking rate. The insights that genetic underpinnings of neuropsychiatric disorders will bring to psychiatry unquestionably will be a disruptive body of scientific knowledge that will drastically change the current descriptive psychiatric diagnostic schema as well as the therapeutic and preventative approaches to psychiatric illness. Pleiotropy—when one gene can influence multiple clinical phenotypic traits—will transform our view of psychiatric disorders into interrelated components of a syndrome. This is not unlike the metabolic syndrome, where ≥1 features (obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension) cluster in the same individual or family, and may be caused by a genetic risk factor.

A study of 33,332 psychiatric patients and 27,888 healthy controls published in February 2013 found a genetic link among 5 major psychiatric disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia.¹ The specific genetic link across those 5 disorders, identified by a commonly used genetic method called a genome-wide association study (GWAS), was a set of 4 risk loci on chromosomes 3 and 10, as well as a single nucleotide polymorphism (SNP) of 2 genes called calcium channel α-1C (CACNA1C) and CACNB2, both of which are involved in neuronal calcium channel signaling. This finding implicates calcium balance in all 5 disorders. Many clinicians may recall that calcium channel blockers have been proposed as a treatment for BD for the past 2 decades.² CACNA1C has been associated with ASD and identified as a gene in common in BD and schizophrenia in prior studies, and even may influence cognition³ and schizotypal personality.⁴

Although these findings may come as a surprise, they shouldn’t. We have observational clinical data in psychiatry that show clustering of ≥2 disorders in the same patient or family. BD often is accompanied by ADHD in childhood and with obsessive-compulsive disorder (OCD), panic disorders, social anxiety, borderline personality disorder, and alcohol abuse in adults. MDD frequently clusters with alcohol abuse, anxiety disorders, cognitive dysfunction, and personality disorders. Studies have established that rates of MDD, substance use, OCD, cognitive deficits, and personality disorders are higher in the families of patients with schizophrenia. Anorexia nervosa patients often manifest body dysmorphic disorder, OCD, depression, or personality disorders. Finally, psychiatric practitioners know all too well that the same medication may exert efficacy in several DSM disorders. Pleiotropy may play a role in all of these clusters and it is only a matter of time before genetic evidence emerges, helping psychiatry connect the observational clinical dots with indisputable genetic evidence. We can hardly wait!

Psychiatrists should start conceptualizing DSM-5 disorders not as freestanding medical conditions but as syndromes—collections of inter-related clinical phenotypes resulting from pleiotropic genes. Given the extensive structural and neurochemical interconnectedness of brain cells, regions, and circuits, it is surprising that we have not approached psychiatric disorders in this fashion long ago, instead of falling in the trap of manufacturing artificially isolated mental disorders and then inventing the concept of “common comorbidity” to explain what we are seeing instead of seeking a genetic linkage between them. It took a century before Syndrome X, later called metabolic syndrome, was recognized as a cluster of several metabolic disorders, and psychiatry may be evolving in the same direction. Further, pleiotropy eventually can help us understand the co-occurrence of disorders of the body with disorders of the brain, explaining why glucose intolerance, dyslipidemia, and hypertension tend to be 2- to 3-fold higher in schizophrenia patients and BD patients even before they are exposed to medications, which can add an iatrogenic exaggeration of those metabolic symptoms. Cognitive impairment observed across major psychiatric disorders may be a product of pleiotropy. In short, many DSM-IV-TR axes I, II, and III disorders that have been eliminated in DSM-5 may one day be shown to have pleiotropic roots and lead to a completely new conceptualization of psychiatric and medical syndromes and novel approaches to treating them.

The plot thickens, and that’s welcome news for the future of psychiatry. We are on the verge of a stunning new era where disease models, diagnostic paradigms, treatment strategies, and prevention approaches will be driven by glorious insights into our patients’ DNA. Biotherapies will be based on unambiguous, genetically (or epigenetically) driven pathophysiologies, which will be confirmed in the lab by various biomarkers, including recognized SNPs and mutations and abnormal proteins produced by specific abnormalities in genetic transcription (for a discussion of potential genetic biomarkers of schizophrenia, see “Genetics of schizophrenia: What do we know? Current Psychiatry, March 2013, p. 24-33; http://bit.ly/1JX9Do8). Our patients will be the beneficiaries of far more rational diagnostic and therapeutic approaches and their outcomes will be far more optimal than what they currently are.

This is why I tell our medical school students there has never been a better time to choose psychiatry as a career.

The future of psychiatric diagnosis is destined to be reshaped by the rapidly unfolding and disruptive genetic and neuroscience discoveries.

Although it has been slow in coming, the pace clearly is accelerating and new findings are bubbling up at a breathtaking rate. The insights that genetic underpinnings of neuropsychiatric disorders will bring to psychiatry unquestionably will be a disruptive body of scientific knowledge that will drastically change the current descriptive psychiatric diagnostic schema as well as the therapeutic and preventative approaches to psychiatric illness. Pleiotropy—when one gene can influence multiple clinical phenotypic traits—will transform our view of psychiatric disorders into interrelated components of a syndrome. This is not unlike the metabolic syndrome, where ≥1 features (obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension) cluster in the same individual or family, and may be caused by a genetic risk factor.

A study of 33,332 psychiatric patients and 27,888 healthy controls published in February 2013 found a genetic link among 5 major psychiatric disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia.¹ The specific genetic link across those 5 disorders, identified by a commonly used genetic method called a genome-wide association study (GWAS), was a set of 4 risk loci on chromosomes 3 and 10, as well as a single nucleotide polymorphism (SNP) of 2 genes called calcium channel α-1C (CACNA1C) and CACNB2, both of which are involved in neuronal calcium channel signaling. This finding implicates calcium balance in all 5 disorders. Many clinicians may recall that calcium channel blockers have been proposed as a treatment for BD for the past 2 decades.² CACNA1C has been associated with ASD and identified as a gene in common in BD and schizophrenia in prior studies, and even may influence cognition³ and schizotypal personality.⁴

Although these findings may come as a surprise, they shouldn’t. We have observational clinical data in psychiatry that show clustering of ≥2 disorders in the same patient or family. BD often is accompanied by ADHD in childhood and with obsessive-compulsive disorder (OCD), panic disorders, social anxiety, borderline personality disorder, and alcohol abuse in adults. MDD frequently clusters with alcohol abuse, anxiety disorders, cognitive dysfunction, and personality disorders. Studies have established that rates of MDD, substance use, OCD, cognitive deficits, and personality disorders are higher in the families of patients with schizophrenia. Anorexia nervosa patients often manifest body dysmorphic disorder, OCD, depression, or personality disorders. Finally, psychiatric practitioners know all too well that the same medication may exert efficacy in several DSM disorders. Pleiotropy may play a role in all of these clusters and it is only a matter of time before genetic evidence emerges, helping psychiatry connect the observational clinical dots with indisputable genetic evidence. We can hardly wait!

Psychiatrists should start conceptualizing DSM-5 disorders not as freestanding medical conditions but as syndromes—collections of inter-related clinical phenotypes resulting from pleiotropic genes. Given the extensive structural and neurochemical interconnectedness of brain cells, regions, and circuits, it is surprising that we have not approached psychiatric disorders in this fashion long ago, instead of falling in the trap of manufacturing artificially isolated mental disorders and then inventing the concept of “common comorbidity” to explain what we are seeing instead of seeking a genetic linkage between them. It took a century before Syndrome X, later called metabolic syndrome, was recognized as a cluster of several metabolic disorders, and psychiatry may be evolving in the same direction. Further, pleiotropy eventually can help us understand the co-occurrence of disorders of the body with disorders of the brain, explaining why glucose intolerance, dyslipidemia, and hypertension tend to be 2- to 3-fold higher in schizophrenia patients and BD patients even before they are exposed to medications, which can add an iatrogenic exaggeration of those metabolic symptoms. Cognitive impairment observed across major psychiatric disorders may be a product of pleiotropy. In short, many DSM-IV-TR axes I, II, and III disorders that have been eliminated in DSM-5 may one day be shown to have pleiotropic roots and lead to a completely new conceptualization of psychiatric and medical syndromes and novel approaches to treating them.

The plot thickens, and that’s welcome news for the future of psychiatry. We are on the verge of a stunning new era where disease models, diagnostic paradigms, treatment strategies, and prevention approaches will be driven by glorious insights into our patients’ DNA. Biotherapies will be based on unambiguous, genetically (or epigenetically) driven pathophysiologies, which will be confirmed in the lab by various biomarkers, including recognized SNPs and mutations and abnormal proteins produced by specific abnormalities in genetic transcription (for a discussion of potential genetic biomarkers of schizophrenia, see “Genetics of schizophrenia: What do we know? Current Psychiatry, March 2013, p. 24-33; http://bit.ly/1JX9Do8). Our patients will be the beneficiaries of far more rational diagnostic and therapeutic approaches and their outcomes will be far more optimal than what they currently are.

This is why I tell our medical school students there has never been a better time to choose psychiatry as a career.

The future of psychiatric diagnosis is destined to be reshaped by the rapidly unfolding and disruptive genetic and neuroscience discoveries.

Although it has been slow in coming, the pace clearly is accelerating and new findings are bubbling up at a breathtaking rate. The insights that genetic underpinnings of neuropsychiatric disorders will bring to psychiatry unquestionably will be a disruptive body of scientific knowledge that will drastically change the current descriptive psychiatric diagnostic schema as well as the therapeutic and preventative approaches to psychiatric illness. Pleiotropy—when one gene can influence multiple clinical phenotypic traits—will transform our view of psychiatric disorders into interrelated components of a syndrome. This is not unlike the metabolic syndrome, where ≥1 features (obesity, insulin resistance, hyperglycemia, dyslipidemia, and hypertension) cluster in the same individual or family, and may be caused by a genetic risk factor.

A study of 33,332 psychiatric patients and 27,888 healthy controls published in February 2013 found a genetic link among 5 major psychiatric disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia.¹ The specific genetic link across those 5 disorders, identified by a commonly used genetic method called a genome-wide association study (GWAS), was a set of 4 risk loci on chromosomes 3 and 10, as well as a single nucleotide polymorphism (SNP) of 2 genes called calcium channel α-1C (CACNA1C) and CACNB2, both of which are involved in neuronal calcium channel signaling. This finding implicates calcium balance in all 5 disorders. Many clinicians may recall that calcium channel blockers have been proposed as a treatment for BD for the past 2 decades.² CACNA1C has been associated with ASD and identified as a gene in common in BD and schizophrenia in prior studies, and even may influence cognition³ and schizotypal personality.⁴

Although these findings may come as a surprise, they shouldn’t. We have observational clinical data in psychiatry that show clustering of ≥2 disorders in the same patient or family. BD often is accompanied by ADHD in childhood and with obsessive-compulsive disorder (OCD), panic disorders, social anxiety, borderline personality disorder, and alcohol abuse in adults. MDD frequently clusters with alcohol abuse, anxiety disorders, cognitive dysfunction, and personality disorders. Studies have established that rates of MDD, substance use, OCD, cognitive deficits, and personality disorders are higher in the families of patients with schizophrenia. Anorexia nervosa patients often manifest body dysmorphic disorder, OCD, depression, or personality disorders. Finally, psychiatric practitioners know all too well that the same medication may exert efficacy in several DSM disorders. Pleiotropy may play a role in all of these clusters and it is only a matter of time before genetic evidence emerges, helping psychiatry connect the observational clinical dots with indisputable genetic evidence. We can hardly wait!

Psychiatrists should start conceptualizing DSM-5 disorders not as freestanding medical conditions but as syndromes—collections of inter-related clinical phenotypes resulting from pleiotropic genes. Given the extensive structural and neurochemical interconnectedness of brain cells, regions, and circuits, it is surprising that we have not approached psychiatric disorders in this fashion long ago, instead of falling in the trap of manufacturing artificially isolated mental disorders and then inventing the concept of “common comorbidity” to explain what we are seeing instead of seeking a genetic linkage between them. It took a century before Syndrome X, later called metabolic syndrome, was recognized as a cluster of several metabolic disorders, and psychiatry may be evolving in the same direction. Further, pleiotropy eventually can help us understand the co-occurrence of disorders of the body with disorders of the brain, explaining why glucose intolerance, dyslipidemia, and hypertension tend to be 2- to 3-fold higher in schizophrenia patients and BD patients even before they are exposed to medications, which can add an iatrogenic exaggeration of those metabolic symptoms. Cognitive impairment observed across major psychiatric disorders may be a product of pleiotropy. In short, many DSM-IV-TR axes I, II, and III disorders that have been eliminated in DSM-5 may one day be shown to have pleiotropic roots and lead to a completely new conceptualization of psychiatric and medical syndromes and novel approaches to treating them.

The plot thickens, and that’s welcome news for the future of psychiatry. We are on the verge of a stunning new era where disease models, diagnostic paradigms, treatment strategies, and prevention approaches will be driven by glorious insights into our patients’ DNA. Biotherapies will be based on unambiguous, genetically (or epigenetically) driven pathophysiologies, which will be confirmed in the lab by various biomarkers, including recognized SNPs and mutations and abnormal proteins produced by specific abnormalities in genetic transcription (for a discussion of potential genetic biomarkers of schizophrenia, see “Genetics of schizophrenia: What do we know? Current Psychiatry, March 2013, p. 24-33; http://bit.ly/1JX9Do8). Our patients will be the beneficiaries of far more rational diagnostic and therapeutic approaches and their outcomes will be far more optimal than what they currently are.

This is why I tell our medical school students there has never been a better time to choose psychiatry as a career.

Discuss this article at www.facebook.com/CurrentPsychiatry

Genetic factors play a major role in the etiology and development of schizophrenia. Genetic linkage studies and twin studies have estimated the heritability of schizophrenia to be 70% to 90%.¹ Research on the genetic underpinnings of schizophrenia has accelerated since the Human Genome Project was completed in 2001, which opened the door to expanding our understanding of molecular mechanisms of human diseases. Experts have hailed the dawn of personalized medicine,² hoping that we will be able to use knowledge of the human genome to tailor individual treatment.

In this article we review some significant recent findings in genetics of schizophrenia. Gene names are italicized and proteins coded by genes are not. The names, functions, and locations of all genes included in this article appear in Table 1. For a glossary of genetic terms, see Table 2.

Table 1

Select genes and their functions

Table 2

Glossary of genetic terms

Focusing on single nucleotide polymorphisms

Genetic research of diseases previously relied on linkage studies, which focus on linking a chromosome region to transmission of a particular trait across multiple familial generations. This approach has identified several genomic regions that may be associated with schizophrenia, but most of these regions contain multiple genes and are not specific to schizophrenia.

Today, many genetic studies examine variations of a single nucleotide in the DNA sequence, ie, a change of 1 letter in a particular location on the DNA chain. Single nucleotide polymorphisms (SNPs)—relatively common DNA variations found in >5% of the population—have been a major focus of psychiatric genetics in the past decade. Technology now allows researchers to simultaneously genotype millions of SNPs across the genome, producing tremendous power to investigate the entire genome in relation to a phenotype (a disease or a trait) in genome-wide association studies (GWAS).³ GWAS do not require an a priori hypothesis regarding which regions or genes may be important, and have yielded many novel genetic variants implicated in schizophrenia.

Susceptibility genes

Genetic researchers initially hoped to find that one or a few genes are responsible for schizophrenia. However, recent research revealed that many genes may be involved in susceptibility to schizophrenia, and that a particular gene may contribute to the risk of not only schizophrenia but also other psychiatric disorders such as bipolar disorder (BD).

Discovery of the DISC1 gene is an example of how our understanding of the complex genetic architecture in psychiatric disorders has evolved. In 2000, a linkage study in a Scottish family cohort found a translocation on chromosome 1, t(1:11), highly correlated with schizophrenia.⁴ Later studies found that this translocation directly disrupts a gene, which researchers named “disrupted in schizophrenia 1.” The protein encoded by DISC1 appears to provide a scaffold to other proteins involved in multiple cellular functions, particularly regulation of brain development and maturation. It is involved in neuronal proliferation, differentiation, and migration via various signaling pathways by interacting with many other proteins.⁵ Disruption of DISC1 results in dysfunction in multiple neurodevelopmental processes, significantly increasing susceptibility not only for schizophrenia but also for BD and depression.

Many common variants of DISC1 slightly alter expression levels of the gene, which may exert subtle but pervasive effects on neural circuitry development. DISC1 knockout mouse models showed close interactions between DISC1 and N-methyl-d-aspartate receptors and dopamine D2 receptors, linking to the glutamate hypothesis of schizophrenia and the common site of action of antipsychotics. Despite advances in understanding the biology of DISC1, large case-control studies have not found a consistent association between DISC1 and schizophrenia.^6,7 It is possible that DISC1 pathology represents one subtype of schizophrenia that is not prevalent among the general population; therefore, large-scale epidemiologic studies could not find evidence to support DISC1’s role in schizophrenia.

DTNBP1 is another schizophrenia susceptibility gene discovered in linkage studies. Originally found in a large Irish cohort, several SNPs of DTNBP1 were significantly associated with schizophrenia.⁸ A meta-analysis of candidate genes identified DTNBP1 as one of 4 genes with the strongest evidence for association with schizophrenia (the other 3 are DRD1, MTHFR, and TPH1).⁹ DTNBP1 is widely expressed in the brain and is present in presynaptic, postsynaptic, and microtubule locations implicated in a number of brain functions, including synaptic transmission and neurite outgrowth in a developing organism. Furthermore, DTNBP1 is associated with cognitive functions in schizophrenia patients¹⁰ as well as in control subjects.¹¹ Cognitive impairment is considered an endophenotype for schizophrenia. Similar to DISC1 and other candidate genes, DTNBP1 has not emerged as a significant hit in later, large-scale GWAS studies.

Since the first schizophrenia GWAS in 2007,¹² >15 GWAS have been published, with increasingly larger samples sizes. GWAS are based on the “common disease/common variant hypothesis” that common disorders such as diabetes, macular degeneration, and schizophrenia are caused by multiple common variants in the genome. Because GWAS can analyze hundreds of thousands of SNPs simultaneously, a stringent criterion (usually P < 5×10^-8) is used to gauge statistical significance to correct for multiple testing. Because most effect sizes associated with genetic markers in psychiatry are fairly small (odds ratios [ORs] are approximately 1.1 to 1.2), large samples are required to detect significant effects. Several international consortia have accumulated large samples. The Psychiatric GWAS Consortium has >17,000 patients with schizophrenia, >11,000 with BD, >16,000 with major depression, and >50,000 healthy controls. This wave of GWAS has implicated several novel genomic regions in schizophrenia pathophysiology, including ZNF804A, the major histocompatibility complex (MHC) region, and MIR137.

ZNF804A was the first gene that reached genome-wide significance in a large GWAS,¹³ and this finding has been replicated. The function of this novel gene largely is unknown. ZNF804A is widely expressed in the brain, especially in the developing hippocampus and the cortex as well as in the adult cerebellum. Recent studies found that ZNF804A is a putative transcription factor, upregulating expression of catechol-O-methyltransferase while downregulating dopamine D2 receptors in animal studies.¹⁴ The minor allele of SNP rs1344706 was associated with impaired brain functional connectivity in a human study.¹⁵ More work is needed to understand how this gene increases schizophrenia susceptibility.

The MHC region on chromosome 6p22.1,1 also was significant in schizophrenia GWAS,^16,17 and this may be the most replicated schizophrenia GWAS finding. This region is a recombination hotspot and harbors many genetic variants. Many immune-related genes previously were associated with autoimmune and infectious disorders, which may suggest that the immunologic system plays a role in schizophrenia pathogenesis. These genes also may involve neurodevelopment, synaptic plasticity, and other neuronal processes.¹⁸ However, the complex gene composition in the region makes it difficult to pinpoint the exact signal to schizophrenia pathophysiology.

The most recent finding from the largest GWAS is MIR137,¹⁹ coding for microRNA 137, which was associated with schizophrenia at P=1.6×10^-11 in 17,836 patients and 33,859 controls. MicroRNAs are small, noncoding RNA fragments that are involved in post-transcriptional regulation of messenger RNAs. MIR137 plays important roles in neuron maturation and adult neurogenesis by acting at the level of dendritic morphogenesis and spine development.²⁰ More interestingly, the other 4 loci achieving genome-wide significance in the same GWAS (TCF4, CACNA1C, CSMD1, and C10orf26) contain predicted target sites of MIR137. This suggests MIR137-mediated dysregulation may be an etiologic mechanism in schizophrenia.

Limitations of these findings. The effect sizes of these genetic variants are small, explaining only 1% to 2% of genetic risks of schizophrenia. However, this is not unique to schizophrenia or psychiatry. “Missing heritability” is puzzling in other branches of medicine.²¹ Future research will focus on gene-environment interactions as well as gene-gene interactions in relation to schizophrenia’s neurodevelopmental processes.

In addition, many top hits in GWAS are SNPs that are not functional or located in intergenic regions with unknown functions. They may be proxies of causal variants that truly play causal roles in pathogenesis of diseases but were not genotyped in those studies. Recently, researchers have grown increasingly interested in copy number variations (CNVs) in the etiology of complex diseases. Compared with SNPs, CNVs usually are much larger changes in the DNA sequence, including deletions and duplications of a large chunk of DNA segments. Disease-causing CNVs are rare but have large effect sizes. Recent studies have examined the role of CNVs in schizophrenia.^22,23

Although genes such as DISC1 and CACNA1C are linked to schizophrenia, they are neither necessary nor sufficient for developing the disorder, and also are linked equally, if not more strongly, to other neuropsychiatric disorders, including BD and autism. Therefore, they are not “schizophrenia genes.” Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia.

Nevertheless, these schizophrenia GWAS findings provide insight into this complex disorder. Much work is needed to move from these association signals to understanding the function and regulation of these genes to turn basic biologic knowledge into targets for new drugs or other interventions.

Antipsychotic pharmacogenetics

Genetic research of schizophrenia also contributes to our knowledge of how to best use existing drugs. Medications for treating schizophrenia often need to be changed because patients experience lack of efficacy or intolerable side effects, which may lead them to discontinue treatment. Clinical predictors of which medication would work for an individual patient are lacking. Pharmacogenetics may be able to fulfill the promise of personalized medicine in psychiatry by using genetic information to guide drug selection to maximize therapeutic efficacy and minimize drug-induced side effects.

Researchers first attempted to find genetic predictors of antipsychotic efficacy in the early 1990s. One replicated finding is that DRD2, the gene coding for dopamine receptor D2, is associated with antipsychotic efficacy. This may not be surprising because D2 receptor antagonism is a common and necessary drug action mechanism for all antipsychotics. One SNP, -141C Ins/Del (rs1799732), represents a deletion (vs insertion) of cytosine at position -141, located in the 5’ promoter region of DRD2. Pre-clinical studies showed that this SNP might modulate DRD2 gene expression and influence D2 receptor density in the brain. Del allele carriers had poor response to clozapine among a treatment-refractory sample²⁴ and took longer to respond to olanzapine and risperidone among first-episode schizophrenia patients.²⁵ A 2010 meta-analysis of approximately 700 patients²⁶ showed that the -141C Ins/Del polymorphism is significantly associated with antipsychotic response. Patients who carry 1 or 2 Del alleles tend to have a less favorable antipsychotic response than patients with the Ins/Ins genotype. Patients with the Ins/Ins genotype are 54% more likely to respond to antipsychotics than those with ≥1 copy of the Del allele.

Researchers have studied other genes in relation to antipsychotic efficacy, but have yielded few consistent findings.²⁷ Some have looked at combining multiple SNPs across several genes to predict antipsychotic efficacy, but these findings have not been replicated. For example, a combination of variants in the HTR2A, HTR2C, and 5-HTTLPR genes and genes coding for H2 receptors was found to correctly predict clozapine response in 76% of patients.²⁸ However, this finding was not replicated in an independent sample.²⁹ A recent GWAS³⁰ found that a combination of 6 genetic markers—NPAS3, XKR4, TNR, GRIA4, GFRA2, and NUDT9P1—predicted treatment response to iloperidone. Although promising, this finding needs to be validated in independent samples.

Predicting adverse drug events

In other branches of medicine, researchers have used pharmacogenetics to successfully identify predictors of drug-induced adverse events. A GWAS found that a specific human leukocyte antigen (HLA) allele markedly increases the risk of liver toxicity from flucloxacillin (OR=80.6).³¹ This HLA marker also is related to hypersensitivity reaction to abacavir, a common medication for treating AIDS, and lamotrigine-induced Stevens-Johnson syndrome.

Clozapine-induced granulocytosis also may be related to genetic variation in the HLA region. Despite superior efficacy, clozapine remains underutilized in part because it carries the risk of potentially fatal agranulocytosis. Identifying a genetic marker for agranulocytosis would lift the burden of weekly blood monitoring. A recent pharmacogenetic study detected a replicated association of an allele at the HLA-DQB1 locus with risk of agranulocytosis in 2 small groups of clozapine-treated schizophrenia patients.³² Effect sizes were extremely high (OR=16.86); nearly 90% of allele carriers developed agranulocytosis. Unfortunately, the overall sensitivity of the marker was 21%, indicating that most individuals who develop agranulocytosis are not carriers of the allele and presumably have other genetic risk factors. A more comprehensive risk profile would be necessary to obviate the need for weekly blood monitoring.

Weight gain and metabolic syndrome are common side effects of antipsychotics, and no clear clinical predictors have been identified. Researchers have examined potential genetic markers in association with antipsychotic-induced weight gain. One consistent finding has been that a single SNP in the promoter region of the HTR2C gene (serotonin receptor 2C), C-759T (rs3813929), affects antipsychotic-induced weight gain. The 5-HT2C receptor is involved in regulating food intake in rodents and is related to late-onset diabetes and obesity in humans. HTR2C knockout mice display chronic hyperphagia that leads to obesity and hyperinsulinemia. Since the original finding in 2002,³³ at least 17 studies have reported on the association between the C-759T SNP in HTR2C and antipsychotic-induced weight gain. A meta-analysis found that the T allele was significantly protective against antipsychotic-induced weight gain.³⁴ The C allele was associated with >2-fold increase of risk for clinically significant weight gain (gaining >7% of baseline body weight).

In a GWAS of antipsychotic-induced weight gain in pediatric patients who were prescribed antipsychotics for the first time, researchers discovered a single top signal at a marginally genome-wide significant level (P=1.6×10^-7).³⁵ This was replicated in 3 other independent samples. The peak signal is located on chromosome 18q21, overlapping a peak identified as a predictor of obesity. This locus is approximately 150 kb downstream from MC4R, the melanocortin 4 receptor gene, which has long been suspected as a candidate for weight-related phenotypes, including antipsychotic-induced weight gain.³⁶ Mutations in this gene are linked with extreme obesity in humans, and MC4R knockout mice develop obesity. MC4R-expressing neurons in the ventromedial hypothalamus are regulated by circulating levels of leptin via pathways in the arcuate nucleus. In turn, MC4R regulates 5-HT2C receptors, which are implicated in weight gain. In the discovery sample, risk allele homozygotes gained twice as much weight as other patients after 12 weeks of treatment, and the genetic effect was not drug-specific. The consistency of HTR2C-MC4R findings poses a possibility that a drug may be developed at these targets to treat or prevent antipsychotic-induced weight gain.

Drug metabolism. Pharmacogenetic studies of antipsychotic drug response also have focused on genes that code for enzymes in drug metabolism, particularly cytochrome (CYP) 450 enzymes, which are responsible for the metabolism of many drugs. CYP2D6 is the main metabolic pathway for several antipsychotics, including risperidone, aripiprazole, haloperidol, and perphenazine. The CYP2D6 gene contains >100 variants, many of which yield nonfunctional or reduced-function enzymes. There are 4 phenotypes of CYP2D6 produced by combinations of various alleles with different degrees of enzymatic activities: poor (PM), intermediate (IM), extensive (EM), and ultrarapid metabolizers (UM). Compared with EMs with normal CYP2D6 enzyme activity, PMs and IMs have minimal or reduced activity, respectively. UMs have duplicate or multiple copies of the gene that result in increased enzyme activity. Approximately 7% to 10% of whites and 1% to 2% of Asians are PMs, who tend to accumulate higher serum drug levels and, theoretically, require lower doses to achieve therapeutic effects. UMs, in contrast, consist of 1% of the population and may require higher doses because of faster drug elimination.³⁷ Therefore, CYP2D6 metabolic status could play an important role in determining patients’ antipsychotic response. So far, no empirical data support the association between CYP2D6 and antipsychotic efficacy, although studies have found significant relationships between PMs and higher rates of drug-induced side effects such as tardive dyskinesia (TD), extrapyramidal symptoms, and weight gain. A meta-analysis³⁸ of 8 studies showed that PMs had a 43% higher risk of developing TD compared with EMs. An FDA-approved pharmacogenetic test, AmpliChip^® CYP450 Test, is available to assess CYP2D6 and CYP2C19 genotypes,³⁹ but its use is limited, perhaps because of clinician concerns about how to interpret test results, paucity of prospective data suggesting that using the test can improve clinical outcomes, and lack of reimbursement.

Implications for clinical practice

Although schizophrenia genetic research has made tremendous progress in the past decade, most findings are at basic science level and clinical applications are limited. It is premature to attempt to use genetic markers to help diagnose schizophrenia or other psychiatric disorders.⁴⁰ Researchers hope that new gene discovery will translate to better understanding of the pathophysiological mechanisms underlying schizophrenia, which in turn lead to finding novel molecular targets for new drug development. Furthermore, pharmacogenetics helps clinicians use existing drugs more efficiently by maximizing efficacy and minimizing side effects. Several institutions have experimented with genotyping CYP450 in routine clinical practice,⁴¹ but prospective pharmacogenetic clinical trials are needed to validate the utility and cost-effectiveness of genetic testing-guided treatment algorithms.⁴²

Bottom Line
Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia. Genome-wide association studies are allowing researchers to gain insight into which patients may have increased susceptibility to the disorder, identify potential molecular targets for new drugs, and expand their knowledge of how to best use medications.

Related Resource

• National Institute of Mental Health Center for Collaborative Genomic Studies on Mental Disorders. Schizophrenia. www.nimhgenetics.org/available_data/schizophrenia.

Drug Brand Names

• Abacavir • Ziagen
• Aripiprazole • Abilify
• Clozapine • Clozaril
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Risperidone • Risperdal

Disclosures

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

Dr. Malhotra is a consultant to Genomind, Inc.

This work was partly supported by a Young Investigator Award from the Brain and Behavior Research Foundation (Dr. Zhang), and by the National Institute of Mental Health (P50MH080173 to Dr. Malhotra and 1K23MH097108 to Dr. Zhang).

Discuss this article at www.facebook.com/CurrentPsychiatry

Genetic factors play a major role in the etiology and development of schizophrenia. Genetic linkage studies and twin studies have estimated the heritability of schizophrenia to be 70% to 90%.¹ Research on the genetic underpinnings of schizophrenia has accelerated since the Human Genome Project was completed in 2001, which opened the door to expanding our understanding of molecular mechanisms of human diseases. Experts have hailed the dawn of personalized medicine,² hoping that we will be able to use knowledge of the human genome to tailor individual treatment.

In this article we review some significant recent findings in genetics of schizophrenia. Gene names are italicized and proteins coded by genes are not. The names, functions, and locations of all genes included in this article appear in Table 1. For a glossary of genetic terms, see Table 2.

Table 1

Select genes and their functions

Table 2

Glossary of genetic terms

Focusing on single nucleotide polymorphisms

Genetic research of diseases previously relied on linkage studies, which focus on linking a chromosome region to transmission of a particular trait across multiple familial generations. This approach has identified several genomic regions that may be associated with schizophrenia, but most of these regions contain multiple genes and are not specific to schizophrenia.

Today, many genetic studies examine variations of a single nucleotide in the DNA sequence, ie, a change of 1 letter in a particular location on the DNA chain. Single nucleotide polymorphisms (SNPs)—relatively common DNA variations found in >5% of the population—have been a major focus of psychiatric genetics in the past decade. Technology now allows researchers to simultaneously genotype millions of SNPs across the genome, producing tremendous power to investigate the entire genome in relation to a phenotype (a disease or a trait) in genome-wide association studies (GWAS).³ GWAS do not require an a priori hypothesis regarding which regions or genes may be important, and have yielded many novel genetic variants implicated in schizophrenia.

Susceptibility genes

Genetic researchers initially hoped to find that one or a few genes are responsible for schizophrenia. However, recent research revealed that many genes may be involved in susceptibility to schizophrenia, and that a particular gene may contribute to the risk of not only schizophrenia but also other psychiatric disorders such as bipolar disorder (BD).

Discovery of the DISC1 gene is an example of how our understanding of the complex genetic architecture in psychiatric disorders has evolved. In 2000, a linkage study in a Scottish family cohort found a translocation on chromosome 1, t(1:11), highly correlated with schizophrenia.⁴ Later studies found that this translocation directly disrupts a gene, which researchers named “disrupted in schizophrenia 1.” The protein encoded by DISC1 appears to provide a scaffold to other proteins involved in multiple cellular functions, particularly regulation of brain development and maturation. It is involved in neuronal proliferation, differentiation, and migration via various signaling pathways by interacting with many other proteins.⁵ Disruption of DISC1 results in dysfunction in multiple neurodevelopmental processes, significantly increasing susceptibility not only for schizophrenia but also for BD and depression.

Many common variants of DISC1 slightly alter expression levels of the gene, which may exert subtle but pervasive effects on neural circuitry development. DISC1 knockout mouse models showed close interactions between DISC1 and N-methyl-d-aspartate receptors and dopamine D2 receptors, linking to the glutamate hypothesis of schizophrenia and the common site of action of antipsychotics. Despite advances in understanding the biology of DISC1, large case-control studies have not found a consistent association between DISC1 and schizophrenia.^6,7 It is possible that DISC1 pathology represents one subtype of schizophrenia that is not prevalent among the general population; therefore, large-scale epidemiologic studies could not find evidence to support DISC1’s role in schizophrenia.

DTNBP1 is another schizophrenia susceptibility gene discovered in linkage studies. Originally found in a large Irish cohort, several SNPs of DTNBP1 were significantly associated with schizophrenia.⁸ A meta-analysis of candidate genes identified DTNBP1 as one of 4 genes with the strongest evidence for association with schizophrenia (the other 3 are DRD1, MTHFR, and TPH1).⁹ DTNBP1 is widely expressed in the brain and is present in presynaptic, postsynaptic, and microtubule locations implicated in a number of brain functions, including synaptic transmission and neurite outgrowth in a developing organism. Furthermore, DTNBP1 is associated with cognitive functions in schizophrenia patients¹⁰ as well as in control subjects.¹¹ Cognitive impairment is considered an endophenotype for schizophrenia. Similar to DISC1 and other candidate genes, DTNBP1 has not emerged as a significant hit in later, large-scale GWAS studies.

Since the first schizophrenia GWAS in 2007,¹² >15 GWAS have been published, with increasingly larger samples sizes. GWAS are based on the “common disease/common variant hypothesis” that common disorders such as diabetes, macular degeneration, and schizophrenia are caused by multiple common variants in the genome. Because GWAS can analyze hundreds of thousands of SNPs simultaneously, a stringent criterion (usually P < 5×10^-8) is used to gauge statistical significance to correct for multiple testing. Because most effect sizes associated with genetic markers in psychiatry are fairly small (odds ratios [ORs] are approximately 1.1 to 1.2), large samples are required to detect significant effects. Several international consortia have accumulated large samples. The Psychiatric GWAS Consortium has >17,000 patients with schizophrenia, >11,000 with BD, >16,000 with major depression, and >50,000 healthy controls. This wave of GWAS has implicated several novel genomic regions in schizophrenia pathophysiology, including ZNF804A, the major histocompatibility complex (MHC) region, and MIR137.

ZNF804A was the first gene that reached genome-wide significance in a large GWAS,¹³ and this finding has been replicated. The function of this novel gene largely is unknown. ZNF804A is widely expressed in the brain, especially in the developing hippocampus and the cortex as well as in the adult cerebellum. Recent studies found that ZNF804A is a putative transcription factor, upregulating expression of catechol-O-methyltransferase while downregulating dopamine D2 receptors in animal studies.¹⁴ The minor allele of SNP rs1344706 was associated with impaired brain functional connectivity in a human study.¹⁵ More work is needed to understand how this gene increases schizophrenia susceptibility.

The MHC region on chromosome 6p22.1,1 also was significant in schizophrenia GWAS,^16,17 and this may be the most replicated schizophrenia GWAS finding. This region is a recombination hotspot and harbors many genetic variants. Many immune-related genes previously were associated with autoimmune and infectious disorders, which may suggest that the immunologic system plays a role in schizophrenia pathogenesis. These genes also may involve neurodevelopment, synaptic plasticity, and other neuronal processes.¹⁸ However, the complex gene composition in the region makes it difficult to pinpoint the exact signal to schizophrenia pathophysiology.

The most recent finding from the largest GWAS is MIR137,¹⁹ coding for microRNA 137, which was associated with schizophrenia at P=1.6×10^-11 in 17,836 patients and 33,859 controls. MicroRNAs are small, noncoding RNA fragments that are involved in post-transcriptional regulation of messenger RNAs. MIR137 plays important roles in neuron maturation and adult neurogenesis by acting at the level of dendritic morphogenesis and spine development.²⁰ More interestingly, the other 4 loci achieving genome-wide significance in the same GWAS (TCF4, CACNA1C, CSMD1, and C10orf26) contain predicted target sites of MIR137. This suggests MIR137-mediated dysregulation may be an etiologic mechanism in schizophrenia.

Limitations of these findings. The effect sizes of these genetic variants are small, explaining only 1% to 2% of genetic risks of schizophrenia. However, this is not unique to schizophrenia or psychiatry. “Missing heritability” is puzzling in other branches of medicine.²¹ Future research will focus on gene-environment interactions as well as gene-gene interactions in relation to schizophrenia’s neurodevelopmental processes.

In addition, many top hits in GWAS are SNPs that are not functional or located in intergenic regions with unknown functions. They may be proxies of causal variants that truly play causal roles in pathogenesis of diseases but were not genotyped in those studies. Recently, researchers have grown increasingly interested in copy number variations (CNVs) in the etiology of complex diseases. Compared with SNPs, CNVs usually are much larger changes in the DNA sequence, including deletions and duplications of a large chunk of DNA segments. Disease-causing CNVs are rare but have large effect sizes. Recent studies have examined the role of CNVs in schizophrenia.^22,23

Although genes such as DISC1 and CACNA1C are linked to schizophrenia, they are neither necessary nor sufficient for developing the disorder, and also are linked equally, if not more strongly, to other neuropsychiatric disorders, including BD and autism. Therefore, they are not “schizophrenia genes.” Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia.

Nevertheless, these schizophrenia GWAS findings provide insight into this complex disorder. Much work is needed to move from these association signals to understanding the function and regulation of these genes to turn basic biologic knowledge into targets for new drugs or other interventions.

Antipsychotic pharmacogenetics

Genetic research of schizophrenia also contributes to our knowledge of how to best use existing drugs. Medications for treating schizophrenia often need to be changed because patients experience lack of efficacy or intolerable side effects, which may lead them to discontinue treatment. Clinical predictors of which medication would work for an individual patient are lacking. Pharmacogenetics may be able to fulfill the promise of personalized medicine in psychiatry by using genetic information to guide drug selection to maximize therapeutic efficacy and minimize drug-induced side effects.

Researchers first attempted to find genetic predictors of antipsychotic efficacy in the early 1990s. One replicated finding is that DRD2, the gene coding for dopamine receptor D2, is associated with antipsychotic efficacy. This may not be surprising because D2 receptor antagonism is a common and necessary drug action mechanism for all antipsychotics. One SNP, -141C Ins/Del (rs1799732), represents a deletion (vs insertion) of cytosine at position -141, located in the 5’ promoter region of DRD2. Pre-clinical studies showed that this SNP might modulate DRD2 gene expression and influence D2 receptor density in the brain. Del allele carriers had poor response to clozapine among a treatment-refractory sample²⁴ and took longer to respond to olanzapine and risperidone among first-episode schizophrenia patients.²⁵ A 2010 meta-analysis of approximately 700 patients²⁶ showed that the -141C Ins/Del polymorphism is significantly associated with antipsychotic response. Patients who carry 1 or 2 Del alleles tend to have a less favorable antipsychotic response than patients with the Ins/Ins genotype. Patients with the Ins/Ins genotype are 54% more likely to respond to antipsychotics than those with ≥1 copy of the Del allele.

Researchers have studied other genes in relation to antipsychotic efficacy, but have yielded few consistent findings.²⁷ Some have looked at combining multiple SNPs across several genes to predict antipsychotic efficacy, but these findings have not been replicated. For example, a combination of variants in the HTR2A, HTR2C, and 5-HTTLPR genes and genes coding for H2 receptors was found to correctly predict clozapine response in 76% of patients.²⁸ However, this finding was not replicated in an independent sample.²⁹ A recent GWAS³⁰ found that a combination of 6 genetic markers—NPAS3, XKR4, TNR, GRIA4, GFRA2, and NUDT9P1—predicted treatment response to iloperidone. Although promising, this finding needs to be validated in independent samples.

Predicting adverse drug events

In other branches of medicine, researchers have used pharmacogenetics to successfully identify predictors of drug-induced adverse events. A GWAS found that a specific human leukocyte antigen (HLA) allele markedly increases the risk of liver toxicity from flucloxacillin (OR=80.6).³¹ This HLA marker also is related to hypersensitivity reaction to abacavir, a common medication for treating AIDS, and lamotrigine-induced Stevens-Johnson syndrome.

Clozapine-induced granulocytosis also may be related to genetic variation in the HLA region. Despite superior efficacy, clozapine remains underutilized in part because it carries the risk of potentially fatal agranulocytosis. Identifying a genetic marker for agranulocytosis would lift the burden of weekly blood monitoring. A recent pharmacogenetic study detected a replicated association of an allele at the HLA-DQB1 locus with risk of agranulocytosis in 2 small groups of clozapine-treated schizophrenia patients.³² Effect sizes were extremely high (OR=16.86); nearly 90% of allele carriers developed agranulocytosis. Unfortunately, the overall sensitivity of the marker was 21%, indicating that most individuals who develop agranulocytosis are not carriers of the allele and presumably have other genetic risk factors. A more comprehensive risk profile would be necessary to obviate the need for weekly blood monitoring.

Weight gain and metabolic syndrome are common side effects of antipsychotics, and no clear clinical predictors have been identified. Researchers have examined potential genetic markers in association with antipsychotic-induced weight gain. One consistent finding has been that a single SNP in the promoter region of the HTR2C gene (serotonin receptor 2C), C-759T (rs3813929), affects antipsychotic-induced weight gain. The 5-HT2C receptor is involved in regulating food intake in rodents and is related to late-onset diabetes and obesity in humans. HTR2C knockout mice display chronic hyperphagia that leads to obesity and hyperinsulinemia. Since the original finding in 2002,³³ at least 17 studies have reported on the association between the C-759T SNP in HTR2C and antipsychotic-induced weight gain. A meta-analysis found that the T allele was significantly protective against antipsychotic-induced weight gain.³⁴ The C allele was associated with >2-fold increase of risk for clinically significant weight gain (gaining >7% of baseline body weight).

In a GWAS of antipsychotic-induced weight gain in pediatric patients who were prescribed antipsychotics for the first time, researchers discovered a single top signal at a marginally genome-wide significant level (P=1.6×10^-7).³⁵ This was replicated in 3 other independent samples. The peak signal is located on chromosome 18q21, overlapping a peak identified as a predictor of obesity. This locus is approximately 150 kb downstream from MC4R, the melanocortin 4 receptor gene, which has long been suspected as a candidate for weight-related phenotypes, including antipsychotic-induced weight gain.³⁶ Mutations in this gene are linked with extreme obesity in humans, and MC4R knockout mice develop obesity. MC4R-expressing neurons in the ventromedial hypothalamus are regulated by circulating levels of leptin via pathways in the arcuate nucleus. In turn, MC4R regulates 5-HT2C receptors, which are implicated in weight gain. In the discovery sample, risk allele homozygotes gained twice as much weight as other patients after 12 weeks of treatment, and the genetic effect was not drug-specific. The consistency of HTR2C-MC4R findings poses a possibility that a drug may be developed at these targets to treat or prevent antipsychotic-induced weight gain.

Drug metabolism. Pharmacogenetic studies of antipsychotic drug response also have focused on genes that code for enzymes in drug metabolism, particularly cytochrome (CYP) 450 enzymes, which are responsible for the metabolism of many drugs. CYP2D6 is the main metabolic pathway for several antipsychotics, including risperidone, aripiprazole, haloperidol, and perphenazine. The CYP2D6 gene contains >100 variants, many of which yield nonfunctional or reduced-function enzymes. There are 4 phenotypes of CYP2D6 produced by combinations of various alleles with different degrees of enzymatic activities: poor (PM), intermediate (IM), extensive (EM), and ultrarapid metabolizers (UM). Compared with EMs with normal CYP2D6 enzyme activity, PMs and IMs have minimal or reduced activity, respectively. UMs have duplicate or multiple copies of the gene that result in increased enzyme activity. Approximately 7% to 10% of whites and 1% to 2% of Asians are PMs, who tend to accumulate higher serum drug levels and, theoretically, require lower doses to achieve therapeutic effects. UMs, in contrast, consist of 1% of the population and may require higher doses because of faster drug elimination.³⁷ Therefore, CYP2D6 metabolic status could play an important role in determining patients’ antipsychotic response. So far, no empirical data support the association between CYP2D6 and antipsychotic efficacy, although studies have found significant relationships between PMs and higher rates of drug-induced side effects such as tardive dyskinesia (TD), extrapyramidal symptoms, and weight gain. A meta-analysis³⁸ of 8 studies showed that PMs had a 43% higher risk of developing TD compared with EMs. An FDA-approved pharmacogenetic test, AmpliChip^® CYP450 Test, is available to assess CYP2D6 and CYP2C19 genotypes,³⁹ but its use is limited, perhaps because of clinician concerns about how to interpret test results, paucity of prospective data suggesting that using the test can improve clinical outcomes, and lack of reimbursement.

Implications for clinical practice

Although schizophrenia genetic research has made tremendous progress in the past decade, most findings are at basic science level and clinical applications are limited. It is premature to attempt to use genetic markers to help diagnose schizophrenia or other psychiatric disorders.⁴⁰ Researchers hope that new gene discovery will translate to better understanding of the pathophysiological mechanisms underlying schizophrenia, which in turn lead to finding novel molecular targets for new drug development. Furthermore, pharmacogenetics helps clinicians use existing drugs more efficiently by maximizing efficacy and minimizing side effects. Several institutions have experimented with genotyping CYP450 in routine clinical practice,⁴¹ but prospective pharmacogenetic clinical trials are needed to validate the utility and cost-effectiveness of genetic testing-guided treatment algorithms.⁴²

Bottom Line
Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia. Genome-wide association studies are allowing researchers to gain insight into which patients may have increased susceptibility to the disorder, identify potential molecular targets for new drugs, and expand their knowledge of how to best use medications.

Related Resource

• National Institute of Mental Health Center for Collaborative Genomic Studies on Mental Disorders. Schizophrenia. www.nimhgenetics.org/available_data/schizophrenia.

Drug Brand Names

• Abacavir • Ziagen
• Aripiprazole • Abilify
• Clozapine • Clozaril
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Risperidone • Risperdal

Disclosures

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

Dr. Malhotra is a consultant to Genomind, Inc.

This work was partly supported by a Young Investigator Award from the Brain and Behavior Research Foundation (Dr. Zhang), and by the National Institute of Mental Health (P50MH080173 to Dr. Malhotra and 1K23MH097108 to Dr. Zhang).

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Genetic factors play a major role in the etiology and development of schizophrenia. Genetic linkage studies and twin studies have estimated the heritability of schizophrenia to be 70% to 90%.¹ Research on the genetic underpinnings of schizophrenia has accelerated since the Human Genome Project was completed in 2001, which opened the door to expanding our understanding of molecular mechanisms of human diseases. Experts have hailed the dawn of personalized medicine,² hoping that we will be able to use knowledge of the human genome to tailor individual treatment.

In this article we review some significant recent findings in genetics of schizophrenia. Gene names are italicized and proteins coded by genes are not. The names, functions, and locations of all genes included in this article appear in Table 1. For a glossary of genetic terms, see Table 2.

Table 1

Select genes and their functions

Table 2

Glossary of genetic terms

Focusing on single nucleotide polymorphisms

Genetic research of diseases previously relied on linkage studies, which focus on linking a chromosome region to transmission of a particular trait across multiple familial generations. This approach has identified several genomic regions that may be associated with schizophrenia, but most of these regions contain multiple genes and are not specific to schizophrenia.

Today, many genetic studies examine variations of a single nucleotide in the DNA sequence, ie, a change of 1 letter in a particular location on the DNA chain. Single nucleotide polymorphisms (SNPs)—relatively common DNA variations found in >5% of the population—have been a major focus of psychiatric genetics in the past decade. Technology now allows researchers to simultaneously genotype millions of SNPs across the genome, producing tremendous power to investigate the entire genome in relation to a phenotype (a disease or a trait) in genome-wide association studies (GWAS).³ GWAS do not require an a priori hypothesis regarding which regions or genes may be important, and have yielded many novel genetic variants implicated in schizophrenia.

Susceptibility genes

Genetic researchers initially hoped to find that one or a few genes are responsible for schizophrenia. However, recent research revealed that many genes may be involved in susceptibility to schizophrenia, and that a particular gene may contribute to the risk of not only schizophrenia but also other psychiatric disorders such as bipolar disorder (BD).

Discovery of the DISC1 gene is an example of how our understanding of the complex genetic architecture in psychiatric disorders has evolved. In 2000, a linkage study in a Scottish family cohort found a translocation on chromosome 1, t(1:11), highly correlated with schizophrenia.⁴ Later studies found that this translocation directly disrupts a gene, which researchers named “disrupted in schizophrenia 1.” The protein encoded by DISC1 appears to provide a scaffold to other proteins involved in multiple cellular functions, particularly regulation of brain development and maturation. It is involved in neuronal proliferation, differentiation, and migration via various signaling pathways by interacting with many other proteins.⁵ Disruption of DISC1 results in dysfunction in multiple neurodevelopmental processes, significantly increasing susceptibility not only for schizophrenia but also for BD and depression.

Many common variants of DISC1 slightly alter expression levels of the gene, which may exert subtle but pervasive effects on neural circuitry development. DISC1 knockout mouse models showed close interactions between DISC1 and N-methyl-d-aspartate receptors and dopamine D2 receptors, linking to the glutamate hypothesis of schizophrenia and the common site of action of antipsychotics. Despite advances in understanding the biology of DISC1, large case-control studies have not found a consistent association between DISC1 and schizophrenia.^6,7 It is possible that DISC1 pathology represents one subtype of schizophrenia that is not prevalent among the general population; therefore, large-scale epidemiologic studies could not find evidence to support DISC1’s role in schizophrenia.

DTNBP1 is another schizophrenia susceptibility gene discovered in linkage studies. Originally found in a large Irish cohort, several SNPs of DTNBP1 were significantly associated with schizophrenia.⁸ A meta-analysis of candidate genes identified DTNBP1 as one of 4 genes with the strongest evidence for association with schizophrenia (the other 3 are DRD1, MTHFR, and TPH1).⁹ DTNBP1 is widely expressed in the brain and is present in presynaptic, postsynaptic, and microtubule locations implicated in a number of brain functions, including synaptic transmission and neurite outgrowth in a developing organism. Furthermore, DTNBP1 is associated with cognitive functions in schizophrenia patients¹⁰ as well as in control subjects.¹¹ Cognitive impairment is considered an endophenotype for schizophrenia. Similar to DISC1 and other candidate genes, DTNBP1 has not emerged as a significant hit in later, large-scale GWAS studies.

Since the first schizophrenia GWAS in 2007,¹² >15 GWAS have been published, with increasingly larger samples sizes. GWAS are based on the “common disease/common variant hypothesis” that common disorders such as diabetes, macular degeneration, and schizophrenia are caused by multiple common variants in the genome. Because GWAS can analyze hundreds of thousands of SNPs simultaneously, a stringent criterion (usually P < 5×10^-8) is used to gauge statistical significance to correct for multiple testing. Because most effect sizes associated with genetic markers in psychiatry are fairly small (odds ratios [ORs] are approximately 1.1 to 1.2), large samples are required to detect significant effects. Several international consortia have accumulated large samples. The Psychiatric GWAS Consortium has >17,000 patients with schizophrenia, >11,000 with BD, >16,000 with major depression, and >50,000 healthy controls. This wave of GWAS has implicated several novel genomic regions in schizophrenia pathophysiology, including ZNF804A, the major histocompatibility complex (MHC) region, and MIR137.

ZNF804A was the first gene that reached genome-wide significance in a large GWAS,¹³ and this finding has been replicated. The function of this novel gene largely is unknown. ZNF804A is widely expressed in the brain, especially in the developing hippocampus and the cortex as well as in the adult cerebellum. Recent studies found that ZNF804A is a putative transcription factor, upregulating expression of catechol-O-methyltransferase while downregulating dopamine D2 receptors in animal studies.¹⁴ The minor allele of SNP rs1344706 was associated with impaired brain functional connectivity in a human study.¹⁵ More work is needed to understand how this gene increases schizophrenia susceptibility.

The MHC region on chromosome 6p22.1,1 also was significant in schizophrenia GWAS,^16,17 and this may be the most replicated schizophrenia GWAS finding. This region is a recombination hotspot and harbors many genetic variants. Many immune-related genes previously were associated with autoimmune and infectious disorders, which may suggest that the immunologic system plays a role in schizophrenia pathogenesis. These genes also may involve neurodevelopment, synaptic plasticity, and other neuronal processes.¹⁸ However, the complex gene composition in the region makes it difficult to pinpoint the exact signal to schizophrenia pathophysiology.

The most recent finding from the largest GWAS is MIR137,¹⁹ coding for microRNA 137, which was associated with schizophrenia at P=1.6×10^-11 in 17,836 patients and 33,859 controls. MicroRNAs are small, noncoding RNA fragments that are involved in post-transcriptional regulation of messenger RNAs. MIR137 plays important roles in neuron maturation and adult neurogenesis by acting at the level of dendritic morphogenesis and spine development.²⁰ More interestingly, the other 4 loci achieving genome-wide significance in the same GWAS (TCF4, CACNA1C, CSMD1, and C10orf26) contain predicted target sites of MIR137. This suggests MIR137-mediated dysregulation may be an etiologic mechanism in schizophrenia.

Limitations of these findings. The effect sizes of these genetic variants are small, explaining only 1% to 2% of genetic risks of schizophrenia. However, this is not unique to schizophrenia or psychiatry. “Missing heritability” is puzzling in other branches of medicine.²¹ Future research will focus on gene-environment interactions as well as gene-gene interactions in relation to schizophrenia’s neurodevelopmental processes.

In addition, many top hits in GWAS are SNPs that are not functional or located in intergenic regions with unknown functions. They may be proxies of causal variants that truly play causal roles in pathogenesis of diseases but were not genotyped in those studies. Recently, researchers have grown increasingly interested in copy number variations (CNVs) in the etiology of complex diseases. Compared with SNPs, CNVs usually are much larger changes in the DNA sequence, including deletions and duplications of a large chunk of DNA segments. Disease-causing CNVs are rare but have large effect sizes. Recent studies have examined the role of CNVs in schizophrenia.^22,23

Although genes such as DISC1 and CACNA1C are linked to schizophrenia, they are neither necessary nor sufficient for developing the disorder, and also are linked equally, if not more strongly, to other neuropsychiatric disorders, including BD and autism. Therefore, they are not “schizophrenia genes.” Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia.

Nevertheless, these schizophrenia GWAS findings provide insight into this complex disorder. Much work is needed to move from these association signals to understanding the function and regulation of these genes to turn basic biologic knowledge into targets for new drugs or other interventions.

Antipsychotic pharmacogenetics

Genetic research of schizophrenia also contributes to our knowledge of how to best use existing drugs. Medications for treating schizophrenia often need to be changed because patients experience lack of efficacy or intolerable side effects, which may lead them to discontinue treatment. Clinical predictors of which medication would work for an individual patient are lacking. Pharmacogenetics may be able to fulfill the promise of personalized medicine in psychiatry by using genetic information to guide drug selection to maximize therapeutic efficacy and minimize drug-induced side effects.

Researchers first attempted to find genetic predictors of antipsychotic efficacy in the early 1990s. One replicated finding is that DRD2, the gene coding for dopamine receptor D2, is associated with antipsychotic efficacy. This may not be surprising because D2 receptor antagonism is a common and necessary drug action mechanism for all antipsychotics. One SNP, -141C Ins/Del (rs1799732), represents a deletion (vs insertion) of cytosine at position -141, located in the 5’ promoter region of DRD2. Pre-clinical studies showed that this SNP might modulate DRD2 gene expression and influence D2 receptor density in the brain. Del allele carriers had poor response to clozapine among a treatment-refractory sample²⁴ and took longer to respond to olanzapine and risperidone among first-episode schizophrenia patients.²⁵ A 2010 meta-analysis of approximately 700 patients²⁶ showed that the -141C Ins/Del polymorphism is significantly associated with antipsychotic response. Patients who carry 1 or 2 Del alleles tend to have a less favorable antipsychotic response than patients with the Ins/Ins genotype. Patients with the Ins/Ins genotype are 54% more likely to respond to antipsychotics than those with ≥1 copy of the Del allele.

Researchers have studied other genes in relation to antipsychotic efficacy, but have yielded few consistent findings.²⁷ Some have looked at combining multiple SNPs across several genes to predict antipsychotic efficacy, but these findings have not been replicated. For example, a combination of variants in the HTR2A, HTR2C, and 5-HTTLPR genes and genes coding for H2 receptors was found to correctly predict clozapine response in 76% of patients.²⁸ However, this finding was not replicated in an independent sample.²⁹ A recent GWAS³⁰ found that a combination of 6 genetic markers—NPAS3, XKR4, TNR, GRIA4, GFRA2, and NUDT9P1—predicted treatment response to iloperidone. Although promising, this finding needs to be validated in independent samples.

Predicting adverse drug events

In other branches of medicine, researchers have used pharmacogenetics to successfully identify predictors of drug-induced adverse events. A GWAS found that a specific human leukocyte antigen (HLA) allele markedly increases the risk of liver toxicity from flucloxacillin (OR=80.6).³¹ This HLA marker also is related to hypersensitivity reaction to abacavir, a common medication for treating AIDS, and lamotrigine-induced Stevens-Johnson syndrome.

Clozapine-induced granulocytosis also may be related to genetic variation in the HLA region. Despite superior efficacy, clozapine remains underutilized in part because it carries the risk of potentially fatal agranulocytosis. Identifying a genetic marker for agranulocytosis would lift the burden of weekly blood monitoring. A recent pharmacogenetic study detected a replicated association of an allele at the HLA-DQB1 locus with risk of agranulocytosis in 2 small groups of clozapine-treated schizophrenia patients.³² Effect sizes were extremely high (OR=16.86); nearly 90% of allele carriers developed agranulocytosis. Unfortunately, the overall sensitivity of the marker was 21%, indicating that most individuals who develop agranulocytosis are not carriers of the allele and presumably have other genetic risk factors. A more comprehensive risk profile would be necessary to obviate the need for weekly blood monitoring.

Weight gain and metabolic syndrome are common side effects of antipsychotics, and no clear clinical predictors have been identified. Researchers have examined potential genetic markers in association with antipsychotic-induced weight gain. One consistent finding has been that a single SNP in the promoter region of the HTR2C gene (serotonin receptor 2C), C-759T (rs3813929), affects antipsychotic-induced weight gain. The 5-HT2C receptor is involved in regulating food intake in rodents and is related to late-onset diabetes and obesity in humans. HTR2C knockout mice display chronic hyperphagia that leads to obesity and hyperinsulinemia. Since the original finding in 2002,³³ at least 17 studies have reported on the association between the C-759T SNP in HTR2C and antipsychotic-induced weight gain. A meta-analysis found that the T allele was significantly protective against antipsychotic-induced weight gain.³⁴ The C allele was associated with >2-fold increase of risk for clinically significant weight gain (gaining >7% of baseline body weight).

In a GWAS of antipsychotic-induced weight gain in pediatric patients who were prescribed antipsychotics for the first time, researchers discovered a single top signal at a marginally genome-wide significant level (P=1.6×10^-7).³⁵ This was replicated in 3 other independent samples. The peak signal is located on chromosome 18q21, overlapping a peak identified as a predictor of obesity. This locus is approximately 150 kb downstream from MC4R, the melanocortin 4 receptor gene, which has long been suspected as a candidate for weight-related phenotypes, including antipsychotic-induced weight gain.³⁶ Mutations in this gene are linked with extreme obesity in humans, and MC4R knockout mice develop obesity. MC4R-expressing neurons in the ventromedial hypothalamus are regulated by circulating levels of leptin via pathways in the arcuate nucleus. In turn, MC4R regulates 5-HT2C receptors, which are implicated in weight gain. In the discovery sample, risk allele homozygotes gained twice as much weight as other patients after 12 weeks of treatment, and the genetic effect was not drug-specific. The consistency of HTR2C-MC4R findings poses a possibility that a drug may be developed at these targets to treat or prevent antipsychotic-induced weight gain.

Drug metabolism. Pharmacogenetic studies of antipsychotic drug response also have focused on genes that code for enzymes in drug metabolism, particularly cytochrome (CYP) 450 enzymes, which are responsible for the metabolism of many drugs. CYP2D6 is the main metabolic pathway for several antipsychotics, including risperidone, aripiprazole, haloperidol, and perphenazine. The CYP2D6 gene contains >100 variants, many of which yield nonfunctional or reduced-function enzymes. There are 4 phenotypes of CYP2D6 produced by combinations of various alleles with different degrees of enzymatic activities: poor (PM), intermediate (IM), extensive (EM), and ultrarapid metabolizers (UM). Compared with EMs with normal CYP2D6 enzyme activity, PMs and IMs have minimal or reduced activity, respectively. UMs have duplicate or multiple copies of the gene that result in increased enzyme activity. Approximately 7% to 10% of whites and 1% to 2% of Asians are PMs, who tend to accumulate higher serum drug levels and, theoretically, require lower doses to achieve therapeutic effects. UMs, in contrast, consist of 1% of the population and may require higher doses because of faster drug elimination.³⁷ Therefore, CYP2D6 metabolic status could play an important role in determining patients’ antipsychotic response. So far, no empirical data support the association between CYP2D6 and antipsychotic efficacy, although studies have found significant relationships between PMs and higher rates of drug-induced side effects such as tardive dyskinesia (TD), extrapyramidal symptoms, and weight gain. A meta-analysis³⁸ of 8 studies showed that PMs had a 43% higher risk of developing TD compared with EMs. An FDA-approved pharmacogenetic test, AmpliChip^® CYP450 Test, is available to assess CYP2D6 and CYP2C19 genotypes,³⁹ but its use is limited, perhaps because of clinician concerns about how to interpret test results, paucity of prospective data suggesting that using the test can improve clinical outcomes, and lack of reimbursement.

Implications for clinical practice

Although schizophrenia genetic research has made tremendous progress in the past decade, most findings are at basic science level and clinical applications are limited. It is premature to attempt to use genetic markers to help diagnose schizophrenia or other psychiatric disorders.⁴⁰ Researchers hope that new gene discovery will translate to better understanding of the pathophysiological mechanisms underlying schizophrenia, which in turn lead to finding novel molecular targets for new drug development. Furthermore, pharmacogenetics helps clinicians use existing drugs more efficiently by maximizing efficacy and minimizing side effects. Several institutions have experimented with genotyping CYP450 in routine clinical practice,⁴¹ but prospective pharmacogenetic clinical trials are needed to validate the utility and cost-effectiveness of genetic testing-guided treatment algorithms.⁴²

Bottom Line
Variations in multiple genes likely cause slight deviations in neurodevelopment that interact with environmental variables and lead to development of schizophrenia. Genome-wide association studies are allowing researchers to gain insight into which patients may have increased susceptibility to the disorder, identify potential molecular targets for new drugs, and expand their knowledge of how to best use medications.

Related Resource

• National Institute of Mental Health Center for Collaborative Genomic Studies on Mental Disorders. Schizophrenia. www.nimhgenetics.org/available_data/schizophrenia.

Drug Brand Names

• Abacavir • Ziagen
• Aripiprazole • Abilify
• Clozapine • Clozaril
• Haloperidol • Haldol
• Iloperidone • Fanapt
• Lamotrigine • Lamictal
• Olanzapine • Zyprexa
• Perphenazine • Trilafon
• Risperidone • Risperdal

Disclosures

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

Dr. Malhotra is a consultant to Genomind, Inc.

This work was partly supported by a Young Investigator Award from the Brain and Behavior Research Foundation (Dr. Zhang), and by the National Institute of Mental Health (P50MH080173 to Dr. Malhotra and 1K23MH097108 to Dr. Zhang).