Psychiatric Annals

Comorbid Substance Abuse Affects Treatment for Bipolar Disorder

William B Lawson, MD, PhD; Walter P Bland, MD

Abstract

1. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results form the Epidemiological Catchement Area (ECA) Study. JAMA. 1990;264(I9):25M-2518.

2. Kessler RC. Crum RM, Warner LA, et al. Lifetime co-occurrence of DSM-IlI-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. Arch Gen Psychiatry. I997;54(4):313-32I.

3. Frye MA, Altshuler LL. McEIroy SL, et al. Gender differences in prevalence, risk, and clinical correlates of alcoholism comorbidity in bipolar disorder. Am J Psychiatry. 2003;160(5):883-889.

4. Winokur G, Turvey C, Akiskal H, et al. Alcoholism and drug abuse in three groups - bipolar 1, unipolare, and their acquaintances. J Affect Disord. 1998;50(2-3):8 1 -89.

5. Brady KT, Lydiard RB. Bipolar affective disorder and substance abuse. J Clin Psychopharmacol. l992;I2(Suppl 1):17S-22S.

6. Tohen M, Greenfield SF, Weiss R, Zarate CA, Vagge LM. The effect of comorbid substance use disorders on the course of bipolar disorder: a review. Harv Rev Psychiatry. I988;6(3):133141.

7. Post RM, Denicoff KD, Leverich GS, et al. Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH life chart method. J CHn Psychiatry. 2003;64(6):680-90.

8. Brady KT. Difficulties in diagnosis and management of bipolar disorder: tbree case presentations. J Clin Psychiatry. 2000:61 (Suppl 13):32-37.

9. Mukherjee S. Shukia S, Woodie J, Rosen AM, Olarte S. Misdiagnosis of schizophrenia in bipolar patients: a multi-ethnic comparison. Am J Psychiatry. 1983;140( 12): 1571-1574.

10. Ghaemi SN, Boiman EE, Goodwin FK. Diagnosing bipolar disorder and the effects of antidepressants: a naturalistic study. J Clin Psychiatry. 2000;61(10):804-808.

11. Dalton EI, Cate-Carter TD. Mundo E, et al. Suicide risk in bipolar patients: the role of comorbid substance use disorders. Bipolar Disord. 2003;5(I):58-61.

12. Potash JB, Kane HS, Chiù YF. et al. Attempted suicide and alcoholism in bipolar disorder: clinical and familial relationships. Am J Psychiatry. 2000;157(12):2048-2050.

13. Dickey B, Normand SL, Weiss RD, Drake RE, Azeni H. Medical morbidity, mental illness, and substance use disorders. Psychiatr Serv. 2002;53(7):861-867.

14. RachBeisel J, Scott J, Dixon L. Co-occuring severe mental illness and substance use disorders: a review of recent research. Psychiatr Serv. 1999:50(1 1):2427-I434.

15. Cruess DG. Evans DL, Repetto MJ, et al. Prevalence, diagnosis , and pharmacological treatment of mood disorders in HTV disease. Biol Psychiatiy. 2O03;54(3):307-316.

16. Solomon DA, Keitner GI, Miller IW, Shea MT, Keller MB. Course of illness and maintenance treatments for patients with bipolar disorder. J Clin Psychiatry. 1995;56(1):5-13.

17. Leverich GS, Nolen WA, Rush AJ, et al. The Stanley Foundation Bipolar Treatment Outcome Network, I: longitudinal methodology. J Affect Disord. 2001;67(l-3):33-44.

18. Geller B, Cooper TB, Sun K, et al. Doubleblind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance abuse dependency. J Am Acad Child Adoles Psychiatry. 1998;37(2):17M78.

19. Brady KT, Sonne SC, Anton R, et al. Valproate in die treamtent of acute bipolar affective episodes complicated by substance abuse: a pilot study. J Clin Psychiatry. 1995;56(3):l 18-121.

20. Bowden CL. Clinical correlates of therapeutic response in bipolar disorder. J Affect Disord. 2001;67(l-3):257-265.

21. Brown ES, Nejtek VA. Perantie DC, Orsulak PJ1 Bobadilla L. Lamotrigine in patients with bipolar disorder and cocaine dependence. J Clin Psychiatry. 2003 ;64(2): 197-201.

22. Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet. 2003;36 1(9370): 1677- 1685.

23. Scheller-Gilkey G, Woolwine BJ, Cooper I, et al. Relationship of clinical symptoms and substance use in schizophrenia patients on conventional versus atypical antipsychotics. Am J Drug Alcohol Abuse. 2003;29(3):553-566.

24. Brown ES. Nejtek VA, Perantie DC, Bobadilla L. Quetiapine in bipolar disorder and cocaine…

Substance abuse is more common in bipolar affective disorder then any other Axis I diagnostic disorder.' Fifty-six percent of all patients with bipolar disorder are substance abusers.

Bipolar disorder is usually divided into two major subtypes. Bipolar I disorder is the diagnosis for patients with mania with or without major depression, while bipolar II is the diagnosis for patients who present with hypomania and major depression but never mania. Patients with the bipolar I subtype have a 61% lifetime prevalence of alcohol or substance abuse, whereas patients with bipolar ? have a 48% lifetime prevalence.

Alcohol abuse is particularly common in bipolar patients. More than one-third of patients with bipolar I and one-fifth of patients with bipolar II have alcohol dependency. Moreover, patients with alcoholism have an odds ratio of 6.2% for co-occurring mania. Substance abuse and alcoholism are more likely in males with bipolar disorder.2 However, females with bipolar are at greater risk than males for alcoholism when compared with the general population.3

Alcohol, cocaine, amphetamines, and marijuana are the most commonly abused drugs. Patients who use one of these drugs probably are more likely than the general population to abuse multiple drugs.3 A popular combination is alcohol, marijuana, and cocaine. The combination of these agents, which individually have unique properties and problems, makes diagnosis of bipolar disorder difficult and finding an effective treatment a formidable task.

EPIDEMIOLOGY

While most studies have focused on the abuser or dependent individual, it is important to remember that dependency norms are based on individuals who otherwise do not have a mental disorder. Bipolar disorder is often associated with impulsivity, and poor compliance. Substance use alone, therefore, has a far greater potential for poor outcomes than in the general population. Unfortunately, there is limited data on the usage pattern of drugs or alcohol in patients with bipolar disorder.

The reason for such a high prevalence of abuse may be multifactorial. Substance abuse probably does not cause bipolar disorder. However, it may help to precipitate the disorder in highrisk individuals. Substance-abusing patients often have an earlier age of onset of bipolar disorder.4 Conversely, the symptoms of bipolar disorder, especially impulsivity, may lead to substance abuse in addiction-prone individuals. Patients may be abusing drugs to self -medicate. Cocaine may help to precipitate hypomania in depressed individuals, and alcohol or sedatives may be used to ameliorate racing thoughts and pressured behavior.5 These agents also may be used to ameliorate the side effects of medication, especially antipsychotic medications. Second-generation antipsychotics do not have the risk for acute dystonia and pseudoparkinsonisra, but they may cause dysphoria and akathisia, which are extremely uncomfortable for many patients.

There may be a common risk factor for both bipolar subtypes, perhaps a similar neurochemical basis and genetic diathesis. Familial clustering of bipolar disorder, substance abuse, and alcoholism have been reported, suggesting a shared heritability.3,6 As noted earlier, substance abuse worsens the course of bipolar disorder; however, a family history of substance abuse also worsens outcome.7

CONSEQUENCES

Misdiagnosis and under-diagnosis are very common for patients with bipolar disorder. Nearly half of those diagnosed with bipolar have received a different diagnosis in the past.8"10 Because similar biochemical systems are often involved, substance abuse can mimic nearly any psychiatric disorder. Stimulant abuse may share many of the features of mania and alcohol, and cocaine withdrawal can mimic depression. As a result, patients in substance abuse programs may have a comorbid bipolar disorder that goes undiagnosed. Unruly individuals may become incarcerated, with limited access to treatment.

Substance abuse worsens the course of illness.7 The onset of illness may be earlier, rapid cycling may be increased, treatment responsiveness may be lessened, rate of hospitalizations may be increased, and intervals between hospitalizations may be decreased. Symptoms of dysphoria, depression, and irritability also may increase.

Substance abuse also may be a contributing factor to the fact that bipolar disorder is associated with the highest risk of suicide attempts of all Axis I disorders.11 Because substance abuse alone is a major risk factor for suicide, it may double the risk in patients with bipolar disorder.12 Bipolar disorder also often is associated with violent behavior; substance abuse may contribute to this behavior by increasing irritability and poor impulse control.

Substance abuse increases the likelihood of missed medical comorbidities.13 Patients who are abusers are less likely to seek mental health and primary-care treatment, keep appointments, and arrange follow-up treatment. They also must negotiate between service providers in the mental health system, substance abuse programs, and primary-care system, which are often in different settings.14 The limited focus of many mental health public-provider networks exacerbate the problem because of an aversion to medicalized treatment systems.

Infectious diseases such as hepatitis C and AIDS are special problems in this population.13 Mentally ill individuals are at a greater risk of developing HTV or hepatitis C, and there is an independent association of substance abuse with these disorders. Concerning ASDS, the increased risk is not simply that of intravenous drug use. Rather, the risk is related to the impuisivity and hedonistic behavior associated with hypomania and mania. Such behavior may include drug use, but may also include unsafe sex practices, including multiple partners, poor partner selection, and indifference to barrier techniques. Moreover, HIV may increase the risk of manic episodes through its effects on the central nervous system.15

TREATMENT

As noted previously, misdiagnosis is common. The problem of misdiagnosis as a result of alcohol use often has been blamed for the lag time of more than a decade between the patient's first verbal report of symptoms and the first treatment intervention.17 When treatment is available, numerous barriers may prevent adequate assessment of services.13

In many public organizational systems, substance abuse is not included in the department of mental health but is instead a part of the department of health. There may be no way to fund services directly for mentally ill individuals with substance abuse problems. The substance abuse treatment community often has difficulty working with mental health providers because they are more likely to discount the mental disorder as crucial for treatment, tend to have difficulty with the psychotropic medical management component, and often include lay people, such as former drug abusers, as active participants in the treatment plan. There is also conflict between substance abuse treatment plans and mental health professionals because mental health professionals tend to be supportive in all circumstances, whereas the substance abuse community emphasizes a policy of not enabling and taking personal responsibility for the addiction.

When psychiatric services are available, they may be presented sequentially, meaning the substance abuse services are only to be presented when the patient is stabilized. Some programs offer concurrent therapy - simultaneous substance abuse and mental health treatment, without any mixing of services. The literature strongly supports integrated therapy - substance abuse and mental health services provided as part of an overall integrated team with co-trained staff and mixed services.14

PHARMACOTHERAPY

Very few studies have investigated the efficacy of pharmacologic agents in substance-abusing, bipolar patients. These patients are often noncompliant and seldom remain in studies. Moreover, large clinical trials, both at the National Institutes of Health and within the industry, generally exclude these patients. Nevertheless, an emerging literature shows some promising factors.

Pharmacologic agents currently in use may have usefulness for substance abusers. Available treatments that are also useful for substance abuse would be especially valuable in a dually diagnosed population. Lithium and valproic acid remain the mainstays of treatment.8 These agents are quite different pharmacologically - lithium is a salt, while valproic acid was originally approved for partial complex seizures. Both have been shown to be efficacious for most of the phases of bipolar disorder, which make them true mood stablizers due to their ability to treat acute mania and depression and provide maintenance coverage by preventing the reemergence of mania or depression without worsening these symptoms. Both also may demonstrate efficacy in treating the substance-abusing, bipolar patient. Lithium may reduce positive urine drug screens for substance-abusing patients.18 Valproic acid has been found to reduce manic and depressive symptoms, as well as drug use.19 Lithium and valproic acid appear to be equally efficacious, but careful data analysis showed substance abusers are less likely to be lithium responders, whereas many of these patients may respond to valproic acid.20

Other anticonvulsants also have shown promise. A recent study found some evidence of efficacy for lamotrigine, an anticonvulsant recently approved for bipolar depression. In an open-label trial, it was found to improve mood in substance-abusing patients and to reduce cocaine cravings.21 Cocaine use declined but did not reach statistical significance.

Topirimate is an anticonvulsant that has shown some antimanic efficacy in open trials but has not been shown to be effective in double-blind studies. In a recent report, however, topirimate was given to alcoholic patients without bipolar disorder. It both reduced craving and drinking behavior.22 It is generally well tolerated in bipolar patients, but additional research is needed with this agent, either alone or as an adjunctive agent with mood stabilizers in patients with bipolar disorder who abuse alcohol.

Antipsychotics are used either as a treatment for acute mania or as the sole agent for maintenance. Older, first-generation antipsychotics actually may increase cravings for drug abuse at high doses. Newer, second-generation, or atypical, antipsychotics have been associated with reduced likelihood of substance abuse in patients with schizophrenia. The newer agents are also associated with somewhat greater efficacy for positive and negative symptoms, fewer depressogenic effects, and fewer acute extrapyramidal symptoms. Consequently, they were thought to reduce the risk of substance abuse because they reduced the need for self-medication. Recent findings suggest, however, that their effects on substance abuse may be through a different mechanism.23 It is not clear if they directly affect substance abuse through a reduced need for drugs of abuse because of fewer side effects or because newer agents effects may simply be more efficacious.

A recent open-label trial examined quetiapine in a small sample of substance-abusing patients with bipolar disorder.24 Craving for cocaine was significandy reduced, and use was reduced but did not reach significance. The promising findings in this study and the encouraging data on substance-abusing patients with schizophrenia support the need for large, double-blind, controlled studies on patients with bipolar disorder.

Several agents have been found to be effective for alcohol abusers and dependent individuals. The opiate antagonist naltrexone is an approved agent with demonstrated efficacy for reducing craving and alcohol use. It was reported to be very effective in a mixed population of patients with Axis I disorders, including bipolar disorder.25 However, it may not be used to its potential in many populations because of biases about using pharmacotherapy to treat alcoholism.26 Another agent, acamprosate, has not yet been approved by the Food and Drug Administration for treatment of alcoholism, but there is evidence of its efficacy. However, there are no reports of this agent for patients with bipolar disorder.

Odensatron, an antiemetic drug and serotonin-3 antagonist, has been found to be effective in reducing alcohol craving and intake. This agent would appear to show promise for substance-abusing patients with bipolar disorder, because it has been shown to reduce the mood disturbances seen in alcohol-dependent patients.

SUMMARY

Bipolar disorder is a chronic, relapsing, psychiatric disorder that is difficult to manage even without comorbidities. The addition of substance abuse clearly affects the diagnosis and treatment of this disorder. This article has examined how substance abuse is an key component of the clinical pathology of this disorder due to its effects on diagnosis, course of illness, and likelihood of medical comorbidities. Promising therapies are beginning to emerge, however, the problems that make this population difficulty to treat also make them unpopular for research protocols. There is a clear-cut societal need for more evidence-based treatment options for this population.

REFERENCES

1. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results form the Epidemiological Catchement Area (ECA) Study. JAMA. 1990;264(I9):25M-2518.

2. Kessler RC. Crum RM, Warner LA, et al. Lifetime co-occurrence of DSM-IlI-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Survey. Arch Gen Psychiatry. I997;54(4):313-32I.

3. Frye MA, Altshuler LL. McEIroy SL, et al. Gender differences in prevalence, risk, and clinical correlates of alcoholism comorbidity in bipolar disorder. Am J Psychiatry. 2003;160(5):883-889.

4. Winokur G, Turvey C, Akiskal H, et al. Alcoholism and drug abuse in three groups - bipolar 1, unipolare, and their acquaintances. J Affect Disord. 1998;50(2-3):8 1 -89.

5. Brady KT, Lydiard RB. Bipolar affective disorder and substance abuse. J Clin Psychopharmacol. l992;I2(Suppl 1):17S-22S.

6. Tohen M, Greenfield SF, Weiss R, Zarate CA, Vagge LM. The effect of comorbid substance use disorders on the course of bipolar disorder: a review. Harv Rev Psychiatry. I988;6(3):133141.

7. Post RM, Denicoff KD, Leverich GS, et al. Morbidity in 258 bipolar outpatients followed for 1 year with daily prospective ratings on the NIMH life chart method. J CHn Psychiatry. 2003;64(6):680-90.

8. Brady KT. Difficulties in diagnosis and management of bipolar disorder: tbree case presentations. J Clin Psychiatry. 2000:61 (Suppl 13):32-37.

9. Mukherjee S. Shukia S, Woodie J, Rosen AM, Olarte S. Misdiagnosis of schizophrenia in bipolar patients: a multi-ethnic comparison. Am J Psychiatry. 1983;140( 12): 1571-1574.

10. Ghaemi SN, Boiman EE, Goodwin FK. Diagnosing bipolar disorder and the effects of antidepressants: a naturalistic study. J Clin Psychiatry. 2000;61(10):804-808.

11. Dalton EI, Cate-Carter TD. Mundo E, et al. Suicide risk in bipolar patients: the role of comorbid substance use disorders. Bipolar Disord. 2003;5(I):58-61.

12. Potash JB, Kane HS, Chiù YF. et al. Attempted suicide and alcoholism in bipolar disorder: clinical and familial relationships. Am J Psychiatry. 2000;157(12):2048-2050.

13. Dickey B, Normand SL, Weiss RD, Drake RE, Azeni H. Medical morbidity, mental illness, and substance use disorders. Psychiatr Serv. 2002;53(7):861-867.

14. RachBeisel J, Scott J, Dixon L. Co-occuring severe mental illness and substance use disorders: a review of recent research. Psychiatr Serv. 1999:50(1 1):2427-I434.

15. Cruess DG. Evans DL, Repetto MJ, et al. Prevalence, diagnosis , and pharmacological treatment of mood disorders in HTV disease. Biol Psychiatiy. 2O03;54(3):307-316.

16. Solomon DA, Keitner GI, Miller IW, Shea MT, Keller MB. Course of illness and maintenance treatments for patients with bipolar disorder. J Clin Psychiatry. 1995;56(1):5-13.

17. Leverich GS, Nolen WA, Rush AJ, et al. The Stanley Foundation Bipolar Treatment Outcome Network, I: longitudinal methodology. J Affect Disord. 2001;67(l-3):33-44.

18. Geller B, Cooper TB, Sun K, et al. Doubleblind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance abuse dependency. J Am Acad Child Adoles Psychiatry. 1998;37(2):17M78.

19. Brady KT, Sonne SC, Anton R, et al. Valproate in die treamtent of acute bipolar affective episodes complicated by substance abuse: a pilot study. J Clin Psychiatry. 1995;56(3):l 18-121.

20. Bowden CL. Clinical correlates of therapeutic response in bipolar disorder. J Affect Disord. 2001;67(l-3):257-265.

21. Brown ES, Nejtek VA. Perantie DC, Orsulak PJ1 Bobadilla L. Lamotrigine in patients with bipolar disorder and cocaine dependence. J Clin Psychiatry. 2003 ;64(2): 197-201.

22. Johnson BA, Ait-Daoud N, Bowden CL, et al. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet. 2003;36 1(9370): 1677- 1685.

23. Scheller-Gilkey G, Woolwine BJ, Cooper I, et al. Relationship of clinical symptoms and substance use in schizophrenia patients on conventional versus atypical antipsychotics. Am J Drug Alcohol Abuse. 2003;29(3):553-566.

24. Brown ES. Nejtek VA, Perantie DC, Bobadilla L. Quetiapine in bipolar disorder and cocaine dependence. Bipolar Disord. 2002;4(6):406411.

25. Maxwell S, Shinderman MS. Use of naltrexone in the treatment of alcohol use disorders in patients wiüi concomitant major mental illness. J Addict Dis. 2000; 19(3):6 1-69.

26. Petrakis IL, Leslie D, Rosenheck R. Use of naltrexone in the treatment of alcoholism nationally in the Department of Veterans Affairs. Alcohol Clin Exp Res. 2003 ;27( 1 1 ): 1 780- 1 784.

27. Johnson BA, Ait-Daoud N, Ma JZ, Wang Y. Ondansetron reduces mood disturbance among biologically predisposed, alcohol-dependent individuals. Alcohol Clin Exp Res. 2003:27(1 0:1773-1779.

10.3928/0048-5713-20040101-09

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