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Home , Cyclothymia

and Alcoholism

Susan C. Sonne, PharmD, and Kathleen T. Brady, M.D., Ph.D.

Bipolar disorder and alcoholism commonly co-occur. Multiple explanations for the relationship between these conditions have been proposed, but this relationship remains poorly understood. Some evidence suggests a genetic link. This comorbidity also has implications for diagnosis and treatment. Alcohol use may worsen the clinical course of bipolar disorder, making it harder to treat. There has been little research on the appropriate treatment for comorbid patients. Some studies have evaluated the effects of , , and naltrexone, as well as psychosocial interventions, in treating alcoholic bipolar patients, but further research is needed. KEY WORDS: comorbidity; manic-depressive ; AODD (alcohol and other drug dependence); alcoholic beverage; prevalence; genetic linkage; onset; disease course; diagnosis; drug therapy; lithium; valproate; naltrexone; patient compliance; psychosocial treatment method; literature review

ipolar disorder and alcoholism between the onset of illness and diag­ least 4 days in a row and is not severe co-occur at higher than expected nosis and treatment (Lish et al. 1994). enough to require hospitalization. Brates. That is, they co-occur more Bipolar disorder affects approximately is interspersed with depres­ often than would be expected by chance 1 to 2 percent of the population and sive episodes that last at least 14 days. and they co-occur more often than do often starts in early adulthood. People with bipolar II disorder often alcoholism and unipolar . There are a number of disorders in enjoy being hypomanic (due to ele­ This article will explore the relationship the bipolar spectrum, including bipolar vated and inflated self-esteem) between these disorders, focusing on I disorder, bipolar II disorder, and and are more likely to seek treatment the prevalence of this comorbidity, poten­ cyclothymia. is the during a depressive episode than a tial theoretical explanations for the high most severe; it is characterized by manic manic episode. Cyclothymia is a disor­ rates of comorbidity, effects of comorbid episodes that last for at least a week der in the bipolar spectrum that is alcoholism on the course and features and depressive episodes that last for at characterized by frequent low-level of bipolar disorder, diagnostic issues, least 2 weeks. Patients who are fully mood fluctuations that range from and treatment of comorbid patients. manic often require hospitalization to hypomania to low-level depression, Bipolar disorder, often called manic decrease the risk of harming themselves with symptoms existing for at least 2 depression, is a that is or others. People can also have symptoms years (American Psychiatric Association characterized by extreme fluctuations of both depression and at the [APA] 1994). in mood from euphoria to severe depres­ same time. This mixed mania, as it is sion, interspersed with periods of normal called, appears to be accompanied by a mood (i.e., ). Bipolar disorder greater risk of and is more diffi­ SUSAN C. SONNE, PHARMD, is a research represents a significant public health cult to treat. Patients with 4 or more assistant professor of and behav­ problem, which often goes undiagnosed mood episodes within the same 12 ioral sciences and clinical assistant profes­ and untreated for lengthy periods. In a months are considered to have rapid sor of pharmacy practice, and KATHLEEN survey of 500 bipolar patients, 48 per- cycling bipolar disorder, which is a pre­ T. BRADY, M.D., PH.D., is a professor of cent consulted 5 or more health care dictor of poor response to some medi­ psychiatry and behavioral sciences, both professionals before finally receiving a cations. Bipolar II disorder is character­ at the Medical University of South diagnosis of bipolar disorder, and 35 ized by episodes of hypomania, a less Carolina, Center for Drug and Alcohol percent spent an average of 10 years severe form of mania, which lasts for at Programs, Charleston, South Carolina.

Vol. 26, No. 2, 2002 103 Alcohol dependence, also known as alcoholism, is characterized by a craving for alcohol, possible Comorbid Mood Disorders* and on alcohol, an inability to control one’s drinking on any given occasion, and an Any substance abuse Alcohol Alcohol increasing tolerance to alcohol’s effects or dependence (%) dependence (%) abuse (%) (APA 1994). Approximately 14 percent Any Mood Disorder 32.0 4.9 6.9 of people experience alcohol dependence Any Bipolar Disorder 56.1 27.6 16.1 at some time during their lives (Kessler Bipolar I 60.7 31.5 14.7 et al. 1997). It often starts in early adult- Bipolar II 48.1 20.8 18.4 hood. Criteria for a diagnosis of alcohol Unipolar Depression 27.2 11.6 5.0 abuse, on the other hand, do not include the craving and lack of control over NOTES: *Mood disorders include depression and bipolar disorder. Bipolar disorder, or manic depression, is characterized by extreme mood swings. drinking that are characteristic of alco­ Bipolar I disorder is the most severe bipolar disorder. holism. Rather, alcohol abuse is defined Bipolar II disorder is less severe. as a pattern of drinking that results in Unipolar depression is depression without manic episodes. SOURCE: Data reported in the table are based on findings of the Epidemiologic Catchment Area study (Regier the failure to fulfill responsibilities at et al. 1990). work, school, or home; drinking in dangerous situations; and having recur- ring alcohol-related legal problems and the table, alcohol dependence was twice drawal may trigger bipolar symptoms. relationship problems that are caused as likely to co-occur in people with bipo­ Still other studies have suggested that or worsened by drinking (APA 1994). lar spectrum disorders than in those people with bipolar disorder may use The lifetime prevalence of alcohol abuse with unipolar depression (i.e., depression alcohol during manic episodes in an is approximately 10 percent (Kessler et without mania). It is also noteworthy attempt at self-, either to al. 1997). Alcohol abuse often occurs in that bipolar disorder was more likely prolong their pleasurable state or to early adulthood and is usually a precur­ to occur with alcohol dependence than sedate the agitation of mania. Finally, sor to alcohol dependence (APA 1994). with alcohol abuse (see table). As part other researchers have suggested that of the ECA study, Helzer and Przybeck alcohol use and withdrawal may affect (1988) found that mania (i.e., bipolar I the same brain chemicals (i.e., neuro­ Prevalence of Comorbidity disorder) and alcohol use disorders are transmitters) involved in bipolar illness, far more likely to occur together (i.e., thereby allowing one disorder to change Several studies have reported an associ­ 6.2 times more likely) than would be the clinical course of the other. In other ation between alcoholism and mood expected by chance. Of all other psy­ words, alcohol use or withdrawal may disorders. To date, there have been two chiatric diagnoses investigated in this “prompt” bipolar disorder symptoms large epidemiological studies of psychi­ study, only antisocial (Tohen et al. 1998). It remains unclear atric disorders: the National Institute of was more likely to be related to alco­ which if any of these potential mecha­ ’s Epidemiologic Catchment holism than mania. The findings of nisms is responsible for the strong asso­ Area (ECA) study (Regier et al. 1990) the NCS with regard to the comorbid­ ciation between alcoholism and bipolar and the National Comorbidity Survey ity of mood disorders and alcoholism disorder. It is very likely that this relation- (NCS) (Kessler et al. 1996). The ECA were very similar. ship is not simply a reflection of cause study (Regier et al. 1990) revealed that and effect but rather that it is complex 60.7 percent of people with bipolar I and bidirectional. Genetic factors may disorder had a lifetime diagnosis of a Possible Explanations also play a role, as described below. (i.e., an alcohol for Comorbidity or other drug use disorder); 46.2 percent Familial Risk of Bipolar of those with bipolar I disorder had an Although researchers have proposed Disorder and Alcoholism alcohol use disorder; and 40.7 percent explanations for the strong association had a drug abuse or dependence diagno­ between alcoholism and bipolar disorder, The role of genetic factors in psychiatric sis (the percentages of people with alco­ the exact relationship between these disorders has received much attention hol use disorders and drug abuse disor­ disorders is not well understood. One recently. Some evidence is available to ders do not add to 100 due to overlap). proposed explanation is that certain support the possibility of familial trans- Forty-eight percent of people with bipo­ psychiatric disorders (such as bipolar mission of both bipolar disorder and lar II disorder had a substance use dis­ disorder) may be risk factors for sub- alcoholism (Merikangas and Gelernter order, 39.2 percent had an alcohol use stance use. Alternatively, symptoms of 1990; Berrettini et al. 1997). Common disorder, and 21 percent had a drug abuse bipolar disorder may emerge during the genetic factors may play a role in the or dependence diagnosis (these figures course of chronic alcohol intoxication or development of this comorbidity, but reflect overlap, as above.) As shown in withdrawal. For example, alcohol with­ this relationship is complex (Tohen et

104 Alcohol Research & Health Bipolar Disorder and Alcoholism

al. 1998). Preisig and colleagues (2001) essarily indicate that alcoholism worsens patients with bipolar disorder can have conducted a family study of mood disor­ bipolar symptoms, it does point out the remission of their alcoholism. ders and alcoholism by evaluating 226 relationship between them. A compari­ people with alcoholism with and with- son of patients with bipolar disorder Order of Onset out a mood disorder as well as family and a coexisting substance use disorder members of those people. The researchers with others who had bipolar disorder An important factor in studying the found that there was a greater familial alone found that those with comorbid influence of one comorbid disorder on association between alcoholism and substance use disorders had an earlier another is the order of onset of the two bipolar disorder (odds ratio of 14.5) age of onset for their mood disorder, disorders. A mood disorder that occurs than between alcoholism and unipolar were more likely to be male, had more prior to the onset of another psychiatric depression (odds ratio of 1.7). These comorbid psychiatric disorders in addi­ disorder is called a primary affective findings have implications for prevention tion to bipolar disorder, and were sig­ disorder. Secondary affective disorders and treatment. A positive family his- nificantly more likely to have mixed occur after the onset of other psychi­ tory of bipolar disorder or alcoholism is mania at the time of interview (Sonne atric disorders. Feinman and Dunner an important risk factor for offspring. and Brady 1999b). (1996) conducted a retrospective chart Although research suggests that alco­ review of three groups of patients: hol and other drug abuse may worsen 1. Those with primary bipolar disor­ Issues Surrounding the course of bipolar disorder, some der with no history of substance abuse the Treatment of data indicate that patients with bipolar (primary group), with 103 patients Comorbid Bipolar disorder and alcoholism do better in 2. Those with primary bipolar dis­ Disorder and Alcoholism substance abuse treatment than alcoholic order complicated by substance abuse, patients with other mood disorders. which began after the onset of bipolar This section examines some of the O’Sullivan and colleagues (1988) found disorder (complicated group), with 35 issues to consider in treating comorbid that alcoholics with bipolar disorder patients patients, and a subsequent section functioned better during a 2-year fol­ 3. Those with bipolar disorder that reviews pharmacologic and psychother­ lowup period than did primary alcoholics came after the onset of substance abuse apeutic treatment approaches. (i.e., those without comorbid mood (secondary group), with 50 patients. disorders) or alcoholics with unipolar The researchers found that patients Alcoholism’s Effect on Comorbid depression. This suggests that bipolar in the complicated group had a signifi­ Bipolar Disorder patients may use alcohol primarily as a cantly earlier age of onset of bipolar means to medicate their affective symp­ disorder than the other groups. They A growing number of studies have shown toms, and if their bipolar symptoms are also found that the complicated and that substance abuse, including alco­ adequately treated, they are able to stop secondary groups had higher rates of holism, may worsen the clinical course abusing alcohol. Hasin and colleagues suicide attempts than did the primary of bipolar disorder. Sonne and colleagues (1989) found that patients with bipolar group. Preisig and colleagues (2001) (1994) evaluated the course and features II disorder were likely to have an earlier also reported that the onset of bipolar of bipolar disorder in patients with and remission from alcoholism compared disorder tended to precede that of without a lifetime substance use disor­ with patients with schizoaffective disor­ alcoholism. They concluded that this der. They found that compared to non- der or bipolar I disorder. Researchers finding is in accordance with results of substance abusers, substance-abusing have also proposed that the presence clinical studies that suggest alcoholism bipolar patients were more likely to of mania may precipitate or exacerbate is often a of bipolar disor­ have frequent hospitalizations for affec­ alcoholism (Hasin et al. 1985). der rather than a risk factor for it. tive symptoms, earlier onset of bipolar In conclusion, it appears that alco­ In a 5-year followup study, Winokur disorder, more rapid cycling, and more holism may adversely affect the course and colleagues (1995) evaluated a group mixed mania (the latter two considered and prognosis of bipolar disorder, lead­ of bipolar patients with and without to be the most severe, treatment-resistant ing to more frequent hospitalizations. alcoholism. In the alcoholic patients, forms of bipolar disorder). Keller and In addition, patients with more treatment- bipolar illness and alcoholism were colleagues (1986) compared patients resistant symptoms (i.e., rapid cycling, categorized as being either primary or who had pure depression or pure mania mixed mania) are more likely to have secondary. The patients with primary with patients who had mixed or rapid comorbid alcoholism than patients with alcoholism had significantly fewer cycling bipolar disorder and found that less severe bipolar symptoms. If left episodes of mood disorder at followup, a higher percentage of patients with untreated, alcohol dependence and which may suggest that these patients mixed or rapid cycling bipolar disorder withdrawal are likely to worsen mood had a less severe form of bipolar illness. had concurrent alcoholism (13 percent) symptoms, thereby forming a vicious Thus, there is growing evidence that and that these patients had a slower cycle of alcohol use and mood instability. the presence of a concomitant alcohol recovery from the bipolar disorder. However, some data indicate that with use disorder may adversely affect the Although this association does not nec­ effective treatment of mood symptoms, course of bipolar disorder, and the order

Vol. 26, No. 2, 2002 105 of onset of the two disorders has prog­ mood problems leading to substance substance abusers, alcoholics appear to nostic implications. Specifically, bipolar use, which leads to a worsening of be at greater risk for developing mixed patients with secondary alcoholism mood symptoms, which in turn may mania and rapid cycling. Researchers may be better able to stop drinking if worsen the substance abuse, leading to have found that patients with mixed their bipolar illness is adequately treated; even worse mood symptoms. mania respond less well to lithium than and, conversely, bipolar patients with As a general rule, it seems appropriate patients with the nonmixed form of primary alcoholism (alcoholism occurs to diagnose bipolar disorder if the symp­ the disorder (Prien et al. 1988). This first) may be better able to control their toms clearly occur before the onset of suggests that lithium may not be the mood symptoms if they are able to the alcoholism or if they persist during best choice for a substance-abusing stop drinking. periods of sustained abstinence. The bipolar patient. However, in a 6-week adequate amount of abstinence for diag­ trial of lithium versus placebo in 25 Comorbidity and Diagnostic Issues nostic purposes has not been clearly adolescents with bipolar disorder and defined. Family history and severity of secondary , Almost every alcoholic will report having symptoms should also factor into diag­ Geller and colleagues (1998) found a mood swings. It is very important to nostic considerations. Given that bipo­ significant reduction in positive urine distinguish these alcohol-induced lar disorder and substance abuse co­ tests for substances of abuse and signifi­ symptoms from actual bipolar disorder. occur so frequently, it also makes sense cant improvement in psychiatric symp­ However, diagnosing bipolar disorder to screen for substance abuse in people toms. This suggests that lithium may in the face of alcohol abuse can be dif­ seeking treatment for bipolar disorder. be a good choice for adolescent sub- ficult because alcohol use and with­ stance abusers. The presence of bipolar drawal, particularly with chronic use, subtypes was not addressed in this can mimic nearly any psychiatric disor­ Treatment of Comorbid study, so it is not clear if these adoles­ der. Alcohol intoxication can produce a Bipolar Disorder and cents had the subtypes of bipolar illness syndrome indistinguishable from mania Alcoholism that are more difficult to treat. or hypomania, characterized by eupho­ ria, increased energy, decreased appetite, In spite of the significant prevalence of Valproate grandiosity, and sometimes . comorbid alcoholism and bipolar disor­ However, these alcohol-induced manic der, there is little published data on In 1998, the Depakote® symptoms generally occur only during specific pharmacologic and psychother­ (also called divalproex sodium, or val­ active alcohol intoxication, which makes apeutic treatments for bipolar disorder proate) was approved by the Food and them fairly easy to differentiate from in the presence of alcoholism. The Drug Administration (FDA) for the mania associated with bipolar I disorder. most frequently used for initial treatment of manic episodes asso­ Still, alcoholic patients going through treating bipolar disorder are the mood ciated with bipolar disorder. Numerous alcohol withdrawal may appear to have stabilizers lithium and valproate. As studies have concluded that patients depression. Depression is a key symptom stated previously, preliminary evidence with mixed or rapid cycling bipolar of withdrawal from several substances suggests that alcoholic bipolar patients disorder are more likely to respond to of abuse, and studies have demonstrated may have more rapid cycling and more anticonvulsant medications than to that symptoms of withdrawal-related mixed mania than other bipolar patients. lithium (Bowden 1995). Because, as depression may persist for 2 to 4 weeks There is also evidence to suggest that stated previously, bipolar patients with (Brown and Schuckit 1988). Because these subtypes of bipolar disorder have concomitant alcoholism appear to have of this phenomenon, it is likely that different responses to medications more mixed or rapid cycling bipolar observation during lengthier periods of (Prien et al. 1988), which would help disorder than do bipolar patients who abstinence (i.e., continued observation provide a rationale for the choice of are not alcoholic, alcoholic bipolar following the withdrawal stage) is impor­ agents in the alcoholic bipolar patient. patients may also respond better to tant for the diagnosis of depression as Available research on the use of lithium, anticonvulsant medications (e.g., val­ compared with mania. valproate, and naltrexone for comorbid proate) than to lithium therapy. In fact, Bipolar II disorder and cyclothymia patients is reviewed below. in an open-label study (i.e., a study in are even more difficult to reliably diag­ which all participants receive the exper­ nose because of the more subtle nature Lithium imental treatment), Brady and colleagues of the psychiatric symptoms. Because (1995) found valproate to be safe and of the diagnostic difficulties, it may be Lithium has been the standard treatment effective in nine mixed-manic bipolar that this diagnostic group is often over- for bipolar disorder for several decades. patients with concurrent substance looked. Although these less severe forms Unfortunately, several studies have dependence (primarily alcohol depen­ of bipolar disorder may not be as dis­ reported that substance abuse is a pre­ dence) who previously had either not ruptive as bipolar I disorder, it is still dictor of poor response of bipolar dis­ tolerated lithium or not responded to important to recognize and treat them order to lithium. More specifically, as it. Similarly, Albanese and coworkers in order to break the potential cycle of stated previously, compared to non- (2000) reported on 20 patients treated

106 Alcohol Research & Health Bipolar Disorder and Alcoholism

with divalproex sodium and found that Compliance as a result of being assigned to it by the even at fairly low doses divalproex researchers. Potential study participants Medication compliance is an important effectively treated the mood symptoms, were told that the investigators were issue to consider when assessing the and based on self-report, all patients interested in better understanding the remained abstinent during the trial. effectiveness of medications. One study relationship between bipolar disorder Both valproate and alcohol con­ of the lifetime medication compliance and substance abuse and therefore wished sumption are known to cause tempo­ of lithium and valproate in 44 alcohol to see them monthly for 6 months. rary elevations in liver function tests, and other drug-abusing bipolar patients The investigators found that psychother­ and in rare cases, fatal liver failure found that patients were significantly apy and Alcoholics Anonymous (AA) (Sussman and McLain 1979; Lieber more likely to take valproate (50 percent attendance decreased over time and and Leo 1992). Therefore, the safety compliant) compared with lithium (21 that substance use tended to increase of valproate in the alcoholic population percent compliant). Side effects, includ­ from month 1 to month 6. The focus has been questioned because of the ing lethargy, weight gain, and tremors, of the study participants’ potential for hepatotoxicity in patients were listed as the main reason for non- also changed, with less emphasis on who are already at risk for this compli­ compliance with lithium (Weiss et al. their specific disorders and more empha­ cation. However, recent preliminary 1998). However, it is also important sis on family, school, work, and other evidence suggests that liver enzymes do to note that prescription bottles for personal issues. Although differences in not dramatically increase in alcoholic lithium usually have a warning label on mood or substance use between months patients who are receiving valproate, them not to drink alcohol while taking 1 and 6 were not statistically significant, even if they are actively drinking (Sonne the medication. Thus, if an alcoholic there was a trend for increased substance and Brady 1999a). Thus, valproate has the choice between taking lithium use. If the study participants had con­ appears to be a safe and effective medi­ or drinking alcohol, it is very likely the tinued with AA and if psychotherapy cation for alcoholic bipolar patients. alcoholic will not be compliant with had continued to focus on bipolar dis­ lithium. Increased medication compli­ order and alcoholism, the patients’ sub- ance with valproate may be an impor­ Naltrexone stance use might have improved. Given tant factor in selecting a mood stabi­ the generally poor prognosis associated Because evidence suggests that active lizer for alcoholic bipolar patients. with bipolar disorder and alcoholism, drinking may worsen bipolar symptoms, it is particularly important to continu­ it makes sense that medications designed Psychosocial Interventions ously educate patients concerning the to decrease alcohol consumption may relationship between these two disorders. be useful in bipolar alcoholics. Naltrexone Psychosocial interventions have often The authors concluded that the devel­ (ReVia™ ) is an FDA-approved medication been considered the mainstays of treat­ opment of dually focused psychosocial designed to decrease cravings for alco­ ment for alcoholism and other sub- treatments for this population may hol. Maxwell and Shinderman (2000) stance use disorders. Several studies help improve substance use and affec­ reviewed the use of naltrexone in the have demonstrated success with cognitive tive outcomes. treatment of alcoholism in 72 patients behavioral therapy in treating alcoholism with major mental disorders, including (Project MATCH Research Group bipolar disorder and major depression. 1998). Many of the principles of cog­ Conclusion Eighty-two percent of patients stayed on nitive behavioral therapy are commonly naltrexone for at least 8 weeks, 11 per- applied in the treatment of both mood Bipolar disorder and alcoholism com­ cent discontinued the medication disorders and alcoholism. Weiss and monly co-occur. In two epidemiologic because of side effects, and the remaining colleagues (1999) have developed a survey studies, alcohol dependence was 7 percent discontinued for other rea­ relapse prevention group therapy using more likely to occur with bipolar disor­ sons. The authors concluded that nal­ cognitive behavioral therapy techniques der than with all other psychiatric dis­ trexone was useful in treating patients for treating patients with comorbid orders except antisocial personality with comorbid psychiatric and alcohol bipolar disorder and substance use dis­ disorder. The nature of the relationship problems. However, Sonne and Brady order. This therapy uses an integrated between alcoholism and bipolar disorder (2000) reported on two cases of bipolar approach; participants discuss topics is complex and not well understood. It women (both actively hypomanic) who that are relevant to both disorders, such appears that alcohol use may worsen received naltrexone for alcohol cravings, as , emphasizing common the clinical course of bipolar disorder, and both had significant side effects aspects of recovery and relapse. making it harder to treat. There is also similar to those of opiate withdrawal. Interestingly, the same investigators evidence for a genetic link between the Given that there is only preliminary (Weiss et al. 2000) evaluated the progress two conditions. Bipolar disorder com­ data on the use of naltrexone in bipolar of a group of substance abusers with plicated by alcoholism is associated alcoholics to date, naltrexone should be comorbid bipolar spectrum disorders with an increased number of hospital­ used with caution in patients who have who were pursuing psychosocial treat­ izations, more mixed mania, earlier age been actively hypomanic. ment independently, rather than of onset of bipolar disorder, and more

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108 Alcohol Research & Health