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Comorbid and substance abuse: Evidence-based options

Medication selection may vary based on which substance patients abuse

mong DSM axis I diagnoses, bipolar disorder (BD) has the highest rates of comorbid sub- Astance use disorders (SUDs).1-3 Approximately 60% of patients with have a lifetime diagnosis of an SUD.1 Excluding tobacco, is the substance most often abused by BD patients, followed by , amphetamines, and .1-3 BD patients with comorbid SUD usually exhibit more severe clinical presentations and poorer outcomes than their counterparts without SUDs. Compared with pa- tients with BD alone, those with BD and SUD comorbidi- ty (BD-SUD) experience earlier onset of mood symptoms; higher rates of anxiety disorders, attempts, acci- dents, hospitalizations, and rapid cycling; more depres- sive episodes; and lower treatment compliance.4-9 © IMAGES.COM/CORBIS Several treatment options are available for patients with BD-SUD, including psychotherapy modalities, Fabiano G. Nery, MD, PhD primarily used to treat BD, and medica- Instructor, Mood and Anxiety Inpatient Unit Institute of Psychiatry and Bipolar tions primarily used to treat SUDs. Evidence-based Disorder Program support for these treatments remains limited, and no Department of Psychiatry treatment of choice has emerged. This article reviews University of São Paulo Medical School São Paulo, Brazil evidence on the longer-term treatment of BD-SUD, including general strategies and specific psychosocial Jair C. Soares,MD Professor and Chair and pharmacologic interventions. Short-term treat- Department of Psychiatry and Behavioral Sciences ment strategies, such as pharmacotherapy for detoxifi- University of Texas Medical School at Houston cation, are outside the scope of this review. Houston, TX

General strategies The causes of BD-SUD are complex. Evidence suggests Current Psychiatry that the presence of affective symptoms is associated Vol. 10, No. 4 57 Table 1 for BD patients with substance use disorders Substance Study Intervention Design use disorder Results Geller et al, Lithium vs Double-blind, Alcohol and cannabis Decreased positive drug 199813 placebo placebo-controlled use disorders screen results Comorbid BD Nunes et al, Lithium Open label Cocaine abuse Nonsignificant decrease 199014 in cocaine use and SUDs BD: bipolar disorder

with an increased risk for substance mis- induced .11 Therefore, antidepres- use. This should be kept in mind when sants should be prescribed cautiously for treating a patient with BD-SUD because patients with BD-SUD. controlling mood symptoms probably will help control substance abuse. However, Clinical Point evidence also shows that SUDs may be Integrated psychosocial therapy Treating only mood independent of mood episodes. Therefore, BD-SUD patients may benefit from attend- symptoms in the treating only mood symptoms in the hope ing self-help programs such as Alcoholics that doing so will control substance abuse Anonymous and Narcotics Anonymous, hope that doing may not be enough. provided their mood is stable enough to so will control Because the negative impact of SUDs on allow them to participate. Other forms of substance abuse BD outcome is well documented, inform psychotherapy for BD-SUD patients in- may not be enough patients that limiting their use of alcohol clude standard group drug counseling and and/or drugs is vital to control their mood integrated group therapy that simultane- disorder. Efforts to educate, stimulate, and ously addresses both conditions. support patients to moderate or stop their Integrated group therapy is based on alcohol and/or drug use are likely to re- the premise that changing maladaptive sult in positive changes.10 Therefore, treat- mood cognitions and behaviors will fa- ment for BD-SUD should follow, in part, cilitate recovery from SUDs, and chang- the same recommendations for treatment ing maladaptive substance use cognitions of SUDs in patients with no comorbid axis and behaviors will facilitate recovery from I disorders: mood disorders.12 In a recent randomized • identify the problem (ie, the existence controlled trial, 62 BD-SUD patients were of a comorbid SUD) blindly assigned to integrated group thera- • share your concerns with your patient py or standard group drug counseling and • offer appropriate and specific treat- followed for 3 months.12 Pharmacotherapy ments, such as detoxification and/or was prescribed as usual. Substance use self-help and counseling programs.10 decreased for both groups. However, Because SUDs usually are chronic and compared with patients in the drug coun- relapsing conditions, periods of drug and/ seling group, those who participated in in- or alcohol use should be expected and not tegrated group therapy spent fewer days considered a sign of treatment failure. In ad- using substances in general and alcohol ONLINE ONLY dition, integrating treatment for both condi- in particular, fewer days using alcohol to tions probably is better than managing each intoxication, and had a shorter time from Visit this article at separately. Therefore, targeting BD symp- treatment initiation to the first abstinent CurrentPsychiatry.com for a table that summarizes toms with mood-stabilizing medications month. There were no differences between medications used to treat and substance abuse with nonpharmaco- groups in number of weeks in a mood BD-SUD logic modalities such as drug counseling episode. likely will bring about the best results. Compared with BD patients without Pharmacotherapy options comorbid SUD, BD-SUD patients have a For a table that summarizes the dosages Current Psychiatry 58 April 2011 7-fold increased risk of antidepressant- and indications of the medications used Table 2 Studies suggest may reduce alcohol, cocaine use in BD patients

Substance Study Intervention Design use disorder Results Salloum Divalproex Double-blind, Alcohol Decreased number of drinking et al, 200516 sodium plus placebo-controlled dependence days and number of drinks lithium vs placebo per day and increased time plus lithium of abstinence Salloum Divalproex Open label Cocaine Increased cocaine-abstinent et al, 200717 sodium dependence days and decreased money spent on cocaine and cocaine use severity index Brady et al,* Double-blind, Cocaine Decreased cocaine craving 200218 vs placebo placebo-controlled dependence and cocaine use Brown et al, Lamotrigine Open label Cocaine Decreased cocaine craving 19 2006 dependence and money spent on cocaine Clinical Point *Sample included, but was not limited to, patients with BD BD: bipolar disorder In alcohol- dependent BD to treat BD-SUD that are described below, Anticonvulsants. In a double-blind, placebo- patients, lithium plus visit this article at CurrentPsychiatry.com. controlled study of 59 alcohol-dependent divalproex sodium bipolar I disorder patients, lithium plus di- increased abstinence Lithium. Given its well-documented mood valproex sodium was superior to lithium stabilizing effect, lithium would seem to plus placebo in decreasing number of drink- be a reasonable option to treat BD-SUD ing days and number of drinks per day and patients, but scant evidence supports its in increasing periods of abstinence (Table role as an anti-alcohol or anti-drug medi- 2).16-19 Divalproex sodium was well toler- cation (Table 1).13,14 Lithium’s efficacy was ated and function improved in the evaluated in a study of 25 adolescents suf- divalproex sodium group compared with fering from mood disorders (mostly BD) the placebo group, which probably was a and comorbid SUDs (mostly alcohol and benefit of decreased alcohol consumption. cannabis) randomized to receive lithium In addition, there was a strong association or placebo for 6 weeks.13 Lithium was between mood symptoms and alcohol use, well tolerated and improved psychiatric which suggests that maximizing mood symptoms. At week 3, patients receiving symptom treatment may decrease alcohol lithium produced fewer positive results on use. However, the divalproex sodium and randomly administered drug screens placebo groups did not differ in measures of than those receiving placebo. mood symptoms, which implies that dival- However, lithium seems to have little proex sodium might exhibit a positive effect efficacy in reducing cocaine use in cocaine- on drinking regardless of its mood-stabiliz- dependent patients with bipolar spectrum ing properties. disorders.14 In an open-label study, 10 pa- Divalproex sodium also has been used tients with a history of or cy- to treat BD comorbid with cocaine depen- clothymia received lithium monotherapy dence. In a small open-label study, 15 pa- for 12 weeks. Although patients experi- tients receiving divalproex sodium plus enced improved mood symptoms and de- counseling for mood and substance use creased cocaine use, the mean decrease was disorders were followed for 6 weeks.17 transitory and not statistically significant. The 7 patients who completed the trial Another factor that may limit lithium’s use had significantly more cocaine-abstinent for BD-SUD patients is that these patients days, spent less money on cocaine, and are more likely to comply with experienced fewer manic and depressive Current Psychiatry treatment than with lithium.15 symptoms. However, divalproex sodium’s Vol. 10, No. 4 59 continued on page 63 continued from page 59

Table 3 Evidence of efficacy for for BD patients with SUDs

Substance Study Intervention Design use disorder Results Martinotti Open label Alcohol Decreased alcohol et al,* 200820 dependence consumption and alcohol craving Brown et al, Quetiapine Double-blind, Alcohol No difference between 200821 vs placebo placebo- dependence quetiapine and placebo in controlled decreasing alcohol use and alcohol craving Brown et al, Quetiapine Open label Cocaine Decreased cocaine use 200222 dependence and cocaine craving Nejtek et al, Open label Cocaine Decreased drug use and 200823 vs quetiapine dependence and drug craving amphetamine dependence Clinical Point Brown et al, Open label Alcohol and cocaine Decreased alcohol and 200524 dependence cocaine craving and money In a placebo- spent on alcohol *Sample included, but was not limited to, patients with BD controlled trial, BD: bipolar disorder; SUDs: substance use disorders carbamazepine modestly reduced positive drug screens effect on cocaine use cannot be determined safety and tolerability profile in BD patients in cocaine-dependent solely from this study because there was make it an interesting option for those with no placebo control group. co-occurring alcohol dependence. BD patients Despite its widespread use as a and potential use in alcohol Atypical antipsychotics. In an open-label detoxification, carbamazepine scarcely study, 16 weeks of quetiapine monothera- has been studied in BD-SUD patients. A py effectively decreased alcohol consump- double-blind, placebo-controlled study of tion, alcohol craving, and psychotic and 139 cocaine-dependent patients with BD affective symptoms in 28 alcoholics with or other affective disorders found that pa- a variety of psychiatric diagnoses, includ- tients taking carbamazepine for 12 weeks ing BD, , and bor- experienced modest reductions in positive derline personality disorder (Table 3).20-24 urine drug screens and increased time to However, in a double-blind study of aug- cocaine use.18 They also reported less co- mentation with quetiapine or placebo for caine craving than patients taking placebo, 102 alcohol-dependent BD patients, no and mood symptoms (mostly depressive) significant differences in alcohol use were improved. found between groups.21 An open-label study used lamotrigine Quetiapine may be effective for treat- as adjunctive therapy or monotherapy ing BD patients with comorbid cocaine for 62 cocaine-dependent BD patients fol- dependence. In an open-label study, 12 lowed for 36 weeks.19 There was some de- weeks of quetiapine augmentation in 17 crease in cocaine craving, money spent on cocaine-dependent BD patients was asso- cocaine, and rate of depressive and manic ciated with decreased cocaine craving and symptoms, but no effect on cocaine use. improvement in depressive symptoms.22 A placebo-controlled trial is necessary to In another open-label study, 80 BD patients confirm these modest effects. with comorbid cocaine or amphetamine No studies have evaluated the potential dependence were randomly assigned to role of in treating BD-SUD, de- receive quetiapine or risperidone as ad- spite its FDA-approved indication for alco- junctive therapy or monotherapy for 20 Current Psychiatry holism treatment. Topiramate’s well-known weeks.23 Both groups showed significantly Vol. 10, No. 4 63 Table 4 Naltrexone and disulfiram for BD patients with alcohol dependence

Substance Study Intervention Design use disorder Results Brown et al, Naltrexone Open label Alcohol Decreased alcohol use 200626 dependence and craving Brown et al, Naltrexone vs Double-blind, Alcohol Nonsignificant decrease in Comorbid BD 27 and SUDs 2009 placebo placebo-controlled dependence alcohol consumption Petrakis et Naltrexone alone Double-blind, Alcohol More time in abstinence al, 200528 vs disulfiram alone randomized, dependence and decreased craving for and 200729 vs naltrexone plus placebo-controlled both compounds disulfiram BD: bipolar disorder

decreased drug use and drug craving and of alcohol use decrease and alcohol crav- Clinical Point improved mood. This study suggests that ing were moderate to large compared with Open-label studies risperidone also may be an option for BD placebo, which suggests that naltrexone suggest quetiapine patients with comorbid cocaine or stimu- may be effective for treating alcoholism in lant dependence. these patients. may be effective for A 20-week, open-label study of 20 BD- Two other studies evaluated naltrexone treating cocaine- SUD patients found that switching pa- and disulfiram in patients with BD or oth- dependent BD tients from their previous to er mood disorders.28,29 Naltrexone was well patients aripiprazole resulted in less cocaine crav- tolerated, caused no serious adverse side ing, less alcohol craving, and less money effects, and was significantly more effec- spent on alcohol.24 tive than placebo in decreasing drinking has not been systematically rates and increasing the number of absti- studied in BD-SUD patients. Some case nent days.28,29 Disulfiram was as effective reports suggest that olanzapine may de- as naltrexone, but the combination of both crease cocaine craving and use in patients offered no advantage over use of either with schizoaffective disorder (bipolar type) drug separately. and alcohol craving and use in BD patients There are reports of a new-onset manic with comorbid alcohol dependence.25 episode associated with naltrexone use in a patient with dependence, and a SUD medications. Little evidence guides manic episode triggered by naltrexone in using medications indicated for treating a patient with BD with comorbid alcohol SUDs—such as naltrexone, acamprosate, dependence.30,31 At both low and high dos- and disulfiram—as treatment for BD pa- es, disulfiram is associated with induction tients (Table 4).26-29 In an open-label trial of of psychotic mania in alcoholic patients 34 BD patients with alcohol dependence, without a personal or family history of naltrexone was well tolerated and associ- BD.32,33 ated with decreased alcohol craving and We found no studies that evaluated use and modest improvement in manic treating BD patients who abused other ONLINE ONLY and depressive symptoms.26 substances, such as cannabis or opiates. In a double-blind, placebo-controlled We recommend that BD patients with Discuss this article at study, 50 alcohol-dependent BD patients these substance use disorders should be www.facebook.com/ CurrentPsychiatry treated with standard mood-stabilizing referred to treatment modalities that are therapy and cognitive-behavioral therapy condition-specific, such as psychotherapy were randomized to receive add-on nal- for cannabis use disorders or trexone, 50 mg/d, or placebo.27 Patients or naltrexone treatment for opiate depen- receiving naltrexone showed decreased al- dence. More severe cases of comorbid SUD cohol consumption, although no measures probably would benefit from a referral to Current Psychiatry 64 April 2011 were statistically significant. Effect sizes or consultation with a SUD specialist. References 1. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from Related Resource the Epidemiologic Catchment Area (ECA) Study. JAMA. • Tolliver BK. Bipolar disorder and substance abuse: 1990;264(19):2511-2518. Overcome the challenges of ‘dual diagnosis’ patients. 2. Kessler RC, Crum RM, Warner LA, et al. Lifetime co- Current Psychiatry. 2010;9(8):32-38. occurrence of DSM-III-R alcohol abuse and dependence with other psychiatric disorders in the National Comorbidity Drug Brand Names Survey. Arch Gen Psychiatry. 1997;54(4):313-321. Acamprosate • Campral Lithium • Eskalith, Lithobid 3. Grant BF, Stinson FS, Hasin DS, et al. Prevalence, correlates, Aripiprazole • Abilify Methadone • Dolophine and comorbidity of bipolar I disorder and axis I and II Carbamazepine • Carbatrol, Naltrexone • ReVia, Vivitrol disorders: results from the National Epidemiologic Survey Equetro, others Quetiapine • Seroquel on Alcohol and Related Conditions. J Clin Psychiatry. 2005;66(10):1205-1215. Disulfiram • Antabuse Risperidone • Risperdal Divalproex sodium • Depakote, Topiramate • Topamax 4. Feinman JA, Dunner DL. The effect of alcohol and substance abuse on the course of bipolar affective disorder. J Affect Depakote ER Valproate • Depacon Disord. 1996;37(1):43-49. Lamotrigine • Lamictal 5. Cassidy F, Ahearn EP, Carroll BJ. Substance abuse in bipolar Disclosures disorder. Bipolar Disord. 2001;3(4):181-188. 6. Frye MA, Altshuler LL, McElroy SL, et al. Gender Dr. Nery held a temporary work contract as a clinical research differences in prevalence, risk, and clinical correlates of physician with Eli Lilly and Company Brazil from May 2009 to alcoholism comorbidity in bipolar disorder. Am J Psychiatry. November 2009. 2003;160(5):883-889. Dr. Soares was partly supported by National Institute of Health 7. Khalsa HM, Salvatore P, Hennen J, et al. Suicidal events and grants MH 68766, MH 69774, and RR 20571. He receives accidents in 215 first-episode bipolar I disorder patients: grant/research support from Bristol-Myers Squibb, Cephalon, Clinical Point predictive factors. J Affect Disord. 2008;106(1-2):179-184. GlaxoSmithKline, and Sunovion. 8. Baldessarini RJ, Perry R, Pike J. Factors associated with In 2 trials, naltrexone treatment nonadherence among US bipolar disorder patients. Hum Psychopharmacol. 2008;23(2):95-105. and disulfiram 9. Cardoso BM, Kauer Sant’Anna M, Dias VV, et al. The impact of co-morbid alcohol use disorder in bipolar patients. bipolar disorder: a preliminary study. J Clin Psychiatry. 2002; reduced drinking in Alcohol. 2008;42(6):451-457. 63:791-795. 10. Schuckit MA. Alcohol-use disorders. Lancet. 2009;373 12. Weiss RD, Griffin ML, Kolodziej ME, et al. A randomized patients with mood (9662):492-501. trial of integrated group therapy versus group drug 11. Goldberg JF, Whiteside JE. The association between counseling for patients with bipolar disorder and substance disorders substance abuse and antidepressant-induced mania in dependence. Am J Psychiatry. 2007;164(1):100-107. continued

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Also available at CurrentPsychiatry.com Introduction by Click on Supplements/CME Philip G. Janicak, MD • Rush University Medical Center, Chicago, Illinois This supplement was sponsored by Neuronetics and was peer reviewed by Current Psychiatry. 13. Geller B, Cooper TB, Sun K, et al. Double-blind and placebo- and stimulant dependence? A randomized, double-blind controlled study of lithium for adolescent bipolar disorders trial. J Clin Psychiatry. 2008;69(8):1257-1266. with secondary substance dependency. J Am Acad Child 24. Brown ES, Jeffress J, Liggin JD, et al. Switching outpatients Adolesc Psychiatry. 1998;37:171-178. with bipolar or schizoaffective disorders and substance 14. Nunes EV, McGrath PJ, Wager S, et al. Lithium treatment abuse from their current antipsychotic to aripiprazole. J Clin for cocaine abusers with bipolar spectrum disorders. Am J Psychiatry. 2005;66:756-760. Psychiatry. 1990;147:655-657. 25. Sattar SP, Grant K, Bhatia S, et al. Potential use of olanzapine 15. Weiss RD, Greenfield SF, Najavits LM, et al. Medication in treatment of substance dependence disorders. J Clin compliance among patients with bipolar disorder Psychopharmacol. 2003;23:413-415. and substance use disorder. J Clin Psychiatry. 1998;59: 26. Brown ES, Beard L, Dobbs L, et al. Naltrexone in patients 172-174. with bipolar disorder and alcohol dependence. Depress Comorbid BD 16. Salloum IM, Cornelius JR, Daley DC, et al. Efficacy of Anxiety. 2006;23(8):492-495. and SUDs valproate maintenance in patients with bipolar disorder and 27. Brown ES, Carmody TJ, Schmitz JM, et al. A randomized, alcoholism: a double-blind placebo-controlled study. Arch double-blind, placebo-controlled pilot study of naltrexone in Gen Psychiatry. 2005;62(1):37-45. outpatients with bipolar disorder and alcohol dependence. 17. Salloum IM, Douaihy A, Cornelius JR, et al. Divalproex Alcohol Clin Exp Res. 2009;33:1863-1869. utility in bipolar disorder with co-occurring cocaine 28. Petrakis IL, Poling J, Levinson C, et al, and the VA New dependence: a pilot study. Addict Behav. 2007;32(2): England VISN I MIRECC Study Group. Naltrexone 410-405. and disulfiram in patients with alcohol dependence 18. Brady KT, Sonne SC, Malcolm RJ, et al. Carbamazepine in and comorbid psychiatric disorders. Biol Psychiatry. the treatment of : subtyping by affective 2005;57(10):1128-1137. disorder. Exp Clin Psychopharmacol. 2002;10:276-285. 29. Petrakis I, Ralevski E, Nich C, et al, and the VA VISN 19. Brown ES, Perantie DC, Dhanani N, et al. Lamotrigine I MIRECC Study Group. Naltrexone and disulfiram for bipolar disorder and comorbid cocaine dependence: a in patients with alcohol dependence and current Clinical Point replication and extension study. J Affect Disord. 2006;93(1- depression. J Clin Psychopharmacol. 2007;27(2):160-165. 3):219-222. 30. Sullivan MA, Nunes EV. New-onset mania and 20. Martinotti G, Andreoli S, Di Nicola M, et al. Quetiapine following heroin detoxification and naltrexone maintenance. In case reports, decreases alcohol consumption, craving, and psychiatric Am J Addict. 2005;14(5):486-487. naltrexone triggered symptoms in dually diagnosed alcoholics. Hum 31. Sonne SC, Brady KT. Naltrexone for individuals with Psychopharmacol. 2008;23(5):417-424. comorbid bipolar disorder and alcohol dependence. J Clin mania in BD patients 21. Brown ES, Garza M, Carmody TJ. A randomized, double- Psychopharmacol. 2000;20(1):114-115. blind, placebo-controlled add-on trial of quetiapine in 32. Ceylan ME, Turkcan A, Mutlu E, et al. Manic episode who were alcohol- or outpatients with bipolar disorder and alcohol use disorders. with psychotic symptoms associated with high dose J Clin Psychiatry. 2008;69(5):701-705. of disulfiram: a case report. J Clin Psychopharmacol. cocaine-dependent 22. Brown ES, Nejtek VA, Perantie DC, et al. Quetiapine in 2007;27(2):224-225. bipolar disorder and cocaine dependence. Bipolar Disord. 33. Li MY, Shen YC. Manic episode with psychosis 2002;4(6):406-411. following a lower than recommended dosage regimen of 23. Nejtek VA, Avila M, Chen LA, et al. Do atypical disulfiram. Prog Neuropsychopharmacol Biol Psychiatry. antipsychotics effectively treat co-occurring bipolar disorder 2008;32(1):311-312.

Bottom Line Evidence suggests that lithium and divalproex sodium are options for treating bipolar disorder (BD) patients with comorbid alcohol use disorders; naltrexone and disulfiram also may be reasonable. For cocaine-dependent BD patients, carbamazepine has a modest effect on cocaine use; divalproex sodium, lamotrigine, quetiapine, and risperidone may be considered. Psychosocial treatments for Current Psychiatry 66 April 2011 substance use disorders always should be part of the treatment plan. ONLINE-ONLY TABLE

Table Medications used to treat substance use disorders in bipolar disorder patients*

Drug Dosages FDA-approved indication(s) Acamprosate 1,998 mg/d Maintenance of abstinence from alcohol in patients with alcohol dependence Aripiprazole 15 to 45 mg/d Acute manic or mixed episode of bipolar disorder; augmentation therapy for major depressive disorder Carbamazepine 400 to 1,200 mg/d Manic and mixed episodes associated with bipolar disorder Disulfiram 250 to 500 mg/d Enforced sobriety in abstinent alcohol- dependence patients Divalproex Initial dose: 750 mg/d Manic episodes associated with bipolar sodium Maximum dose: 60 mg/kg/d† disorder Lamotrigine 200 mg/d Maintenance treatment of bipolar I disorder Lithium 900 to 1,800 mg/d for Manic episodes associated with bipolar acute episodes disorder; maintenance treatment of bipolar 900 mg to 1,200 mg/d disorder for maintenance‡ Naltrexone 50 mg/d Alcohol dependence 380 mg/month Quetiapine 300 mg/d for bipolar depression Depressive and acute manic episodes 400 to 800 mg/d for bipolar mania associated with bipolar I disorder; maintenance treatment of bipolar I disorder 400 to 800 mg/d for maintenance treatment of bipolar disorder Risperidone 1 to 6 mg/d Acute manic or mixed episodes associated with bipolar I disorder *None of the medications cited in this table or the text have been specifically approved by the FDA for treating alcohol/drug abuse/dependence co-occurring with bipolar disorder †Dose should correspond to valproic acid therapeutic levels between 50 and 100 µg/mL ‡Dose should correspond to lithium therapeutic levels between 0.8 and 1.2 mEq/L for acute manic episode treatment and 0.6 and 1.0 mEq/L for maintenance treatment

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