The Clinical Challenge of Comorbid Bipolar Disorder and Substance Use Disorder

August 1, 2006

Bipolar disorder I and II have the highest association with substance use disorder, compared with any other major psychiatric disorder. Treatment requires an integrated approach that includes specific psychotherapy as well as the use of medication.

August 2006, Vol. XXIII, No. 9

Bipolar disorder (BD) is among the top causes of disability worldwide and is the fourth leading mental illness as a source of disease burden in established market economies.1 BD complicated by alcoholism and substance use disorder (SUD) represents a serious public health problem and a major challenge to treatment providers. Several large epidemiologic surveys during the past 20 years have confirmed a high association between BD and SUD.2-4 The Epidemiological Catchment Area Study, completed in the 1980s, found that BD I and BD II had the highest association with SUD, compared with any other major psychiatric disorder.4 The study reported that the prevalence of lifetime alcohol abuse or dependence in persons with BD I and BD II was 46% and 39.2%, respectively. Similarly, the National Comorbidity Survey found that respondents with mania were 8 to 9 times more likely than the general population to have an additional lifetime disorder of drug or alcohol dependence.3

The largest and most recent epidemiologic study to date, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), surveyed a representative sample of over 42,000 respondents in the United States. The researchers found that mania and hypomania were associated with very high rates of SUD.5 Respondents with mania were 6 times more likely to have alcohol dependence and, strikingly, 14 times more likely to have drug dependence during the previous 12 months.

The lifetime prevalence of mania in respondents with drug use disorders in the NESARC study ranged from 8.9% to 33.4%, while that of hypomania ranged from 3.7% to 13.4%. These rates are much higher than those reported for the general population in that sample, which was 3.31% for mania and 2.33% for hypomania.6

Furthermore, more than 68% of persons with BD are current cigarette smokers and more than 82% are lifetime smokers, making tobacco dependence the most frequent, and perhaps the least addressed, SUD in this population.7

Clinical challenges and issues

Comorbidity of BD and SUD is characterized by a complicated course with multiple recurrences of bipolar episodes and increased hospitalizations. Patients also have a high frequency of other comorbid disorders, including physical conditions and additional psychiatric comorbidities, such as anxiety and polysubstance dependence disorders. Medical comorbidities are heightened in this group of patients by vulnerabilities to metabolic disorders8 and added risk of morbidities associated with alcoholism and SUD, such as chronic viral hepatitis B and C, HIV/AIDS, and the risk of injury and violence.

Furthermore, the suicide attempt rate for patients with BD is more than 50%,9 and the risk of suicide attempt is significantly higher when associated with SUD.10,11 In addition, BD is associated with pervasive social, family, and employment dysfunction.9

Another complicating factor is the variegated and changing clinical picture characteristic of the course of BD.12 The variability in the clinical symptoms during a treatment episode is often exacerbated and confounded by the use of psychoactive substances and may lead to polypharmacy.

Poor treatment adherence in this population is also a serious clinical challenge that significantly impacts treatment response and outcome. Thus, the reported increased mortality in patients with comorbid psychiatric SUD is not surprising.13

Reciprocal negative impact

The association between BD and alcoholism and/or SUD negatively affects the manifestations and course of each disorder. Substance abuse appears to increase the symptom burden in BD.14 Patients presenting in an acute manic episode with alcoholism had significantly increased mood lability, impulsiveness, violent behavior, other drug use, and overall symptom severity as compared with those presenting with mania but without alcoholism.15 Compared with men, women with BD appeared to have a significantly higher risk for alcoholism16 and had more symptoms of sad mood, lowself-esteem, increased anxiety, and increased libido than women who had BD without alcoholism or men with BD and alcoholism.17 Furthermore, SUD reportedly led to an earlier age of BD onset and contributed to late recovery and more frequent bipolar episodes.14

BD, on the other hand, was found to predate the onset of SUD. Adolescent-onset BD has been shown to be a risk factor for SUD. For example, Wilens and colleagues18 found that adolescents with an onset of BD at age 13 or older were 5 times more likely to develop SUD. A striking finding of their study was that most of these adolescents also had multiple comorbid psychiatric disorders in addition to substance use and BD and 21% of them were smokers.18

Strakowski and colleagues19 completed a prospective study of a sample of patients with BD and comorbid alcoholism. They found that patients who had BD onset before substance abuse onset reported longer periods of mood episodes and alcohol use than those patients whose alcohol abuse began before the onset of BD.

Mood states have also been found to correlate with increased alcohol and drug use. One study found that participants who were in the manic phase reported drinking almost 3 times as much alcohol as those in the depressive phase, with those in the mixed state falling in between.20

Impulsivity, a common symptom of BD, has also been linked to the risk of developing alcoholism and SUD. Impulsivity appears to be significantly higher in persons with acute mania and alcoholism than in those with either acute mania or alcoholism alone.15Furthermore, unstable bipolar illness severely impairs coping skills, contributing to substance use relapse or impeding efforts at sobriety (Table 1).

Multiple recurrences Frequent hospitalizations Multiple morbidities (psychiatric and medical) Heightened suicide, violence, and mortality Poor treatment adherence Comorbidity with reciprocal negative impact SUDs increase symptom burden, worsen outcome, and interfere with treatment adherence BD increases vulnerability to SUDs Active mood symptoms impair coping skills and SUD recovery efforts
BD, bipolar disorder; SUD, substance use disorder.

Developing an appropriate and effective treatment approach

An integrated approach is the recommended treatment model for this population. Such an approach should include simultaneous treatment for both BD and SUD in the same setting. However, the concept of treatment integration should be considered in a broader context to fully address the treatment needs for these complex conditions (Table 2). Integration should be considered at the health care delivery system level to ensure appropriate financing and access to treatment and at the provider level to ensure appropriate training and commitment to competently deliver care under these challenging conditions.

An obvious need for integration is at the specific intervention level. There is an urgent need to identify effective pharmacologic agents and psychosocial interventions to optimize treatment response for this population. Another important aspect of the integration model is to enhance the recognition of the deleterious relationship between these dual diagnoses in persons with these disorders.

Diagnostic considerations

Misdiagnosis and underdiagnosis of BD have been noted to commonly occur, with an estimated 10-year lag between symptom onset and full recognition of the BD.21,22 The presence of an SUD can obscure the diagnosis of BD, because intoxication by or withdrawal from a number of substances can mimic manic and depressive symptoms. Most notoriously, stimulant intoxication can mimic manic or manic paranoid states. On the other hand, depressant intoxication and withdrawal can mimic depressive agitated and anxious states.

It is generally suggested that symptoms must persist for a period of 4 weeks in a drug-free state before declaring a primary psychiatric disorder. This is likely an oversimplified statement, because it employs 1 rule-waiting a period of 4 weeks-for a disparate number of psychoactive substances with different pharmacodynamic and pharmacokinetic profiles. This 4-week period is also highly impractical in the current system of care. More research is needed to clarify the validity and duration of psychoactive-induced disorders. Significant mood symptoms persisting beyond the expected intoxicating or withdrawal effects of a specific psychoactive substance would most likely require treatment. For example, several clinical trials in patients with concomitant major depressive disorder and alcohol dependence have noted that depressive symptoms showed modest improvement in the placebo group beyond the 1 to 2 weeks of detoxification and treatment.23-25 These findings suggest that a shorter period of time may be sufficient to confirm and initiate treatment for the depressive disorder

Treatment considerations

BD, alcoholism, and SUD are chronic relapsing disorders that require a longterm treatment approach to ensure continuity of treatment between episodes. It is important to emphasize preventive and recovery issues. Self-help activities, including participation in dual-diagnosis self-help groups and consumer advocacy groups, such as the Depression and Bipolar Support Alliance (, should be considered.

What role does psychotherapy play in the treatment process?

Psychotherapy has a crucial role in the overall treatment of patients who present with multiple psychosocial needs and dysfunctions. Psychotherapy also has an essential role in cementing the therapeutic alliance, enhancing treatment and medication adherence, and addressing relapse prevention and recovery issues.

To date, only 1 form of integrated group therapy has been developed specifically for comorbid BD and addictive disorder.26 Weiss and colleagues27 developed integrated group therapy, a weekly group therapy for patients with BD and SUD that addresses similarities and common themes involved in the recovery process of both disorders. Specific individual counseling for these patients is being developed.28

The use of simple education material also has been found to be helpful. For example, we found the use of the Personal Calendar, published by the Depression and Bipolar Support Alliance, to be very helpful in the selfmanagement of bipolar symptoms by allowing for mood charting. Education to recognize early warning signs of mania and depression and to identify effective coping strategies to avoid deterioration into full episodes was found to be effective in preventing hospitalization.29

System integration From financing to access
Provider factors Training and commitment
Interventions/ integration Targeted pharmacotherapy and psychosocial interventions
Consumer factors Recognition of interrelationship of the 2 disorders

Pharmacotherapy options

Effective pharmacotherapy for comorbid BD and SUD is still limited. Currently, there are 2 published double-blind placebo-controlled studies, 1 in adult patients with BD I and alcohol dependence and 1 pilot study in adolescents with bipolar spectrum disorder and substance use.20,30 A number of openlabel trials of various medications also have been published (Table 3).20, 30-40 Geller and colleagues30 conducted a 6-week, double-blind, placebo-controlled trial of lithium in 25 adolescents with BD I, BD II, and SUD. Patients treated with lithium had significantly fewer positive urine drug screens (mostly for marijuana) and showed more improvement on the Clinical Global Impression scale. To date, there has been no replication or confirmation of these promising results by larger and more definitive trials.

The other placebo-controlled trial evaluated the efficacy of valproate maintenance in patients with BD and alcoholism. In that study, 59 patients with BD and alcohol dependence were randomly selected to receive placebo or valproate in addition to treatment as usual, which consisted of lithium and weekly psychosocial counseling.20 The results showed an advantage of valproate over placebo in decreasing heavy drinking, as well as in preventing relapse to heavy drinking. Furthermore, in those patients who were more compliant, there was a significant decrease in the number of drinks per drinking day (ie, those receiving valproate on average drank half as much as those receiving placebo). The medication was well tolerated and there were no serious adverse events.

Another double-blind placebo-controlled study evaluated carbamazepine for cocaine dependence.32Although carbamazepine was not effective in participants with only cocaine dependence, there was a trend toward an advantage over placebo on cocaine-positive urine in a subgroup of patients with a history of affective disorder, including BD.

A recent study found significantly decreased cocaine use among patients receiving valproate compared with placebo in a subgroup of 15 patients with BD, alcoholism, and cocaine abuse.31 Other studies have suggested that anticonvulsants compared with lithium may be better tolerated in patients with comorbid BD and SUD.41

Thus, from the current available evidence, it appears that certain anticonvulsants may provide a beneficial effect for comorbid BD and SUD. There is more information available for valproate than carbamazepine.

Some atypical antipsychotic medications, such as clozapine, aripiprazole, and quetiapine, may have a role in treat-ing comorbid BD and SUD. However, there are no published double-blind, placebo-controlled studies to support their efficacy in this population.

Another promising approach is the use of medications found to be effective for addictive disorders in combination with those indicated for BD.34 For example, 3 agents (disulfiram, naltrexone [oral and monthly intramuscular injection], and acamprosate) are approved by the FDA for alcoholism. In awell-conducted clinical trial, topiramate, which is not approved for alcoholism by the FDA, was found to decrease alcohol use.42


BD with comorbid substance abuse represents a complex clinical condition with difficult treatment challenges. Treatment for BD requires an integrated approach that includes specific psychotherapy as well as the use of medication that targets comorbid BD and SUD. Such treatment should be done in a long-term continuum-of-care model, with a focus on episode prevention and health recovery.

There is still scant empiric evidence for effective pharmacotherapeutic and psychotherapeutic treatment interventions, although certain anticonvulsants have shown the most promise to date. The vulnerability of adolescent-onset BD in leading to SUD calls for vigorous screening and preventive strategies for this high-risk population.

 MedicationNo. of participantsType of abuseConclusion 
Divalproex59AlcoholDecreased heavy drinking 
Lithium25SUDs, mostly THCDecreased SUD 
Divalproex15Alcohol and cocaineDecreased cocaine use 
Carbamazepine57CocaineTrend to decreased cocaine use 
Divalproex15CocaineDecreased cocaine and SUD 
Divalproex and naltrexone21AlcoholDecreased alcohol use 
Aripiprazole20Alcohol and cocaineDecreased alcohol use 
Lamotrigine30CocaineDecreased craving; trend to decreased cocaine use 
Quetiapine17CocaineDecreased craving; no change in cocaine use 
Divalproex20SUDs, alcoholRemained abstinent 
Divalproex23SUDsDecreased SUD 
Lithium10CocaineNo effect on SUD 
BD, bipolar disorder; SUD, substance use disorder; THC, tetrahydrocannabinol.

Dr Salloum is associate professor of psychiatry at the Western Psychiatric Institute and Clinic of UPMC at the University of Pittsburgh School of Medicine. He reports that he has received research support from AstraZeneca, Abbott Laboratories, Ortho-McNeil Pharmaceutical, Drug Abuse Sciences, Inc, Alkermese, Inc, Oy Contral Pharma, and Lipha Pharma. He is a consultant for Abbott Laboratories, Forest Laboratories, Cephalon, and AstraZeneca, and he is on the speakers' bureau for Abbott Laboratories.

Drugs Mentioned in This Article

Acamprosate (Campral)
Aripiprazole (Abilify)
Carbamazepine (Carbatrol, Tegretol, others)
Clozapine (Clozaril)
Disulfiram (Antabuse)
Naltrexone (Depade, ReVia)
Naltrexone intramuscular injection (Vivitrol)
Quetiapine (Seroquel)
Topiramate (Topamax)
Valproate/Valproic acid (Depakote, others)


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Evidence-based References

  • Strakowski SM, DelBello MP, Fleck DE, et al. Effects of co-occurring alcohol abuse on the course of bipolar disorder following a first hospitalization for mania. Arch Gen Psychiatry. 2005;62:851-858.

  • Salloum IM, Cornelius JR, Daley DC, et al. Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study. Arch Gen Psychiatry. 2005;62:37-45.