Secondary Logo

Share this article on:

Efficacy and Safety of Atypical Antipsychotics in Bipolar Disorder With Comorbid Substance Dependence: A Systematic Review

Sepede, Gianna, MD, PhD*; Lorusso, Marco, MD*; Spano, Maria Chiara, MD*; Di Nanno, Piero, MD*; Di Iorio, Giuseppe, MD, PhD*†; Di Giannantonio, Massimo, MD*†

doi: 10.1097/WNF.0000000000000297
Review Article

Objectives Bipolar disorder (BD) patients with a comorbid substance use disorder (SUD) are notoriously difficult to treat. Atypical antipsychotics (AAPs) are widely prescribed in BD, but their efficacy in patients with comorbid SUD is still debated. The aim of the present article is to systematically review the literature findings on the efficacy and safety of AAPs in BD patients with comorbid SUD.

Methods We searched PubMed to identify original studies focused on the treatment of dual diagnosed BD with AAPs.

Results Ten articles met our inclusion/exclusion criteria, involving a total of 969 subjects, 906 affected by BD and 793 with comorbid SUD: 4 were randomized controlled trials, 4 were open label trials and 2 were observational studies, published between 2002 and 2017. The most commonly abused substances were alcohol and cocaine. The AAPs used to treat patients were quetiapine (n = 337), asenapine (n = 119), olanzapine (n = 80), risperidone (n = 62), and aripiprazole (n = 48). In terms of safety, AAPs were usually well tolerated. Atypical antipsychotics were usually efficacious on acute mood symptoms, whereas their impact on substance-related issues was reported only in those studies without a placebo comparison.

Conclusions According to our results, even though AAPs are widely used and efficacious in treating the clinical symptoms of BD, there are not enough data to suggest their adjunctive benefit on craving and substance consumption.

*Department of Neuroscience, Imaging and Clinical Science, “G. d’Annunzio” University of Chieti; and

Department of Mental Health, National Health Trust, Chieti, Italy.

Address correspondence and reprint requests to Gianna Sepede, MD, PhD, Universita degli Studi di Chieti, Chieti, Italy; E-mail: g.sepede@unich.it; gsepede@libero.it

M.L. and M.C.S. equally contributed.

Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare.

A substance use disorder (SUD) is reported in almost half of patients affected by a bipolar disorder (BD),1–4 with alcohol, cannabis, and cocaine as the most involved substances.5–8

Strakowski et al.9 proposed different hypotheses to explain the complex association between SUD and BD, taking into account the temporal correlation between the 2 issues: (a) SUD as a symptom of BD; (b) SUD as a self-medication attempt for mood symptoms; (c) SUD as a cause of BD in at-risk subjects; (d) SUD and BD as a result of a common vulnerability factor. Even though each of the abovementioned hypotheses was supported by data, none of them could explain all cases, so the authors concluded that all of these 4 mechanisms could play a role in clarifying the link between SUD and BD.

The clinical consequences of a comorbid SUD in BD are usually severe: dual diagnosis patients are characterized by earlier illness onset and poorer prognosis,10,11 and they present more acute episodes, violent conducts, and suicidal behaviors with respect to BD patients without SUD.12 Moreover, they often do not respond adequately to standard therapeutic strategies,13,14 and therefore combined treatments are required to achieve an improvement in acute mood symptoms.15–17

Due to its dramatic impact on functional outcome and quality of life,18,19 the treatment of dual diagnosis is nowadays an interesting topic for both researchers and clinical psychiatrists.

In the last decades, atypical antipsychotics (AAPs) have largely replaced typical antipsychotics (TAPs) in the treatment of BD,20,21 but we still do not have an answer for an extremely relevant clinical question: could AAPs, that are frequently prescribed for the management of the acute phases of BD (especially in manic or mixed episodes,4 but also in depressive episodes with mixed features22), reduce craving and promote abstinence for comorbid SUD?

The aim of the present article was therefore to systematically review the literature findings of the efficacy and safety of AAPs in patients affected by BD with comorbid SUD.

Back to Top | Article Outline

METHODS

We searched PubMed to identify the studies pertaining the treatment of dual diagnosed BD patients with AAP agents.

The following search words were used, both alone and in combination: bipolar disorder, substance abuse, atypical antipsychotics, dual diagnosis, comorbidity, depression, mania.

The search was conducted on March 24, 2017, and yielded 229 records. Moreover, we manually checked the reference lists of the identified articles, and we found 6 more potential studies, for a total number of 235 records. Inclusion criteria were the following: original articles (open-label trials [OLTs] or double-blind trials, and prospective or retrospective observational studies) written in English, patients 18 years or older, patients affected by BD with comorbid SUD, treatment with AAPs. Animal studies, reviews, commentaries, case reports, studies not enrolling dual diagnosed BD patients or not including a treatment arm with an AAP were excluded.

By reading titles and abstracts, we excluded 216 records. By reading the full texts of the 19 remaining articles, we found 10 articles meeting our inclusion/exclusion criteria, which were therefore included in the qualitative synthesis (Fig. 1).

FIGURE 1

FIGURE 1

Back to Top | Article Outline

RESULTS

We included 10 articles in our qualitative synthesis, for a total number of 969 tested subjects, 906 of which affected by BD. The studies were 4 double-blind randomized controlled trials (DB-RCT) (3 with a placebo arm, and one with an active treatment as a comparison), 4 OLTs and 2 observational (1 prospective, 1 retrospective) reports, published between 2002 and 2017.23–32

In 3 of the studies, a few subjects diagnosed with other disorders, such as Schizoaffective Disorder (SCA) (N = 3),27,24 major depression (N = 6), anxiety disorders (N = 5)25 or borderline personality disorder (N = 10)27 were enrolled. The study duration ranged from to 4 to 20 weeks in the clinical trials. In 8 studies, all participants were dual diagnosed, whereas in the papers by Sani et al30 and De Filippis et al,32 a group of BD without comorbid SUD was also included. Among the total 906 BD patients, 793 presented a comorbid SUD. The characteristic of the groups and the results of the studies are synthetized in Table 1, and reviewed below.

TABLE 1

TABLE 1

Dual diagnosed BD patients (N = 793) were more frequently male (n = 381, 57.8%), and the mean age ranged from 32 to 43 years. Eight studies reported a distinction between the type of BD, with BD type I (BD-I) (n = 616, 88.4%) being much more represented than BD type II (BD-II) (n = 81, 11.6%). In 6 studies, the clinical phase of the illness was also specified: patients were usually enrolled during manic/mixed (n = 170, 42.4%) or depressive (n = 220, 54.9%) episodes, with only a few euthymic subjects (n = 11, 2.7%).

The substances used by the patients were specified in 9 studies: the most represented were alcohol (n = 668), cocaine (n = 108), amphetamines (n = 39), cannabis (n = 23). Other substances, such as opiates (n = 8) and hallucinogens (n = 1), were rarely reported.

The completion rate of the reviewed studies was reported in 8 articles, and it ranged from 15% to 97.5%.

The AAPs used in the reviewed studies were quetiapine (QUE) (N = 337), asenapine (ASE) (N = 119), olanzapine (OLA) (N = 80), risperidone (RIS) (N = 62), and aripiprazole (ARI) (N = 48).

In 3 studies,28,29,31 an AAP (QUE) was compared with placebo (PLA); in 1 study, 2 AAPs (QUE and RIS)26 were compared with one another, and in the remaining 6 studies, a single AAP was tested, without any comparison group: QUE,23,27 RIS,25 ASE,32 ARI24 and OLA.30 None of the reviewed articles used TAPs as comparisons.

In terms of safety, AAPs were usually well tolerated: drop-outs due to medication side effects ranged from 0% to 23.9%.

Quetiapine was tested in 6 studies, 4 RCTs and 2 OLTs. In the 3 placebo-controlled QUE-RCTs, almost the totality of the enrolled patients had alcohol use disorder, but the results varied among studies. In the study by Stedman et al,29 no statistically significant differences emerged between treatments, for both substance use patterns and depressive symptoms. In the study by Brown et al,31 a statistical trend favoring QUE versus PLA was noted with regard to depressive symptoms (IDS-SR30). On the contrary, in a previous study published by the same author,28 QUE was significantly more effective than placebo in reducing HAM-D scores, even though the difference had small clinical relevance (QUE = −10.1; PLA = −9.0 points). No significant effect on drinking habits was found.

In the RCT by Nejtek et al,26 QUE was compared with RIS, and both medications were equally effective in improving mood symptoms and reducing drug use and drug craving. When considering the 2 QUE OLT studies,23,27 conducted on a small number of patients with BD, a good efficacy of the drug was reported for both mood and craving.

In the OLT by Brown et al,24 ARI was compared with AAPs previously used by the patients, and resulted more efficacious in improving both mood and drug craving.

Asenapine was used in the OLT by De Filippis et al.32 in 2 subgroups of BD patients, with (N = 47) or without (N = 72) a comorbid SUD. The authors found out that, in terms of psychiatric symptoms, SUD-BD patients improved significantly less than NSUD-BD patients after ASE treatment.

Sani et al30 tested 80 manic/mixed BD-I inpatients, 40 with a comorbid SUD and 40 without SUD, administering OLA (5–20 mg/d) as an add-on therapy. At the end of the study, both SUD and non-SUD patients improved in terms of mood symptoms, and almost half of the patients (SUD, N = 19 [47.5%]; non-SUD, N = 20 [50%]) experienced a full remission. In the SUD group, a significant reduction of drug craving and drug use was also observed.

In the study published by Albanese and Suh,25 the authors tested RIS in a residential substance abuse program setting, enrolling 16 male patients with cocaine use disorder (9 of them affected by BD, the others by MDD and PTSD), and reported a reduction in cocaine craving in more than 80% of the participants.

Back to Top | Article Outline

DISCUSSION

It is well known that bipolar disorder (BD) is characterized by different phases of illness with several symptoms and comorbidities that may lead to different therapeutic approaches and outcomes. Even though AAPs are widely used and effective in the treatment of the clinical symptoms of BD, less is known for both primary SUD-AUD and BD with comorbid SUD-AUD.

Alcohol and drugs consumption significantly contributes to physical and psychiatric morbidity and mortality. Unfortunately, there are not clear data on effective therapies for patients affected by dual diagnosis, and dedicated guidelines are still lacking.56,57

The efficacy of AAPs in the treatment of the acute phases of BD is well documented.22 In the meta-analysis by Muralidharan et al,58 BD patients in manic or mixed state treated with AAPs had a significant general improvement when compared with placebo-treated patients. When analyzing the different phases of the illness, Derry and Moore59 observed that QUE showed a better efficacy compared with OLA (5 studies reviewed), whereas during manic-mixed states, all AAPs resulted significantly better than placebo (25 studies reviewed).

Literature findings are less concordant in case of SUD patients without psychiatric comorbidities. Kishi et al60 performed a meta-analysis on 13 DB-RCTs of antipsychotics in 1593 patients with primary alcohol dependence. The RCTs included treatments with amisulpride (1 study), ARI (2 studies), flupenthixol decanoate (1 study), OLA (2 studies), QUE (4 studies), tiapride (3 studies). As a result, Kishi et al60 failed to find a significant superiority of AAPs in comparison to placebo in reducing drinking or craving in patients with primary alcohol dependence.

Brunetti et al61 reviewed the scientific literature to assess the efficacy of ARI in alcohol, cocaine, amphetamine, methamphetamine, and nicotine dependence. The authors reported a good efficacy of ARI on alcohol and nicotine use, and controversial results for the other substances, thus concluding that ARI could have potential for the treatment of SUD.

Rae et al62 conducted a 12-week double blind placebo-controlled trial on heavy alcohol users without other comorbid psychiatric conditions. Participants (N = 129) were randomly assigned to either OLA (2.5 mg or 5 mg/d), or placebo, and a dose-dependent effectiveness of OLA on alcohol craving was found.

With regard to BD with comorbid SUD, the results of our systematic review seem to evidence that AAPs are effective on mood symptoms, but not equally efficacious on SUD. We also observed a better efficacy for OLTs, with respect to DB-RCTs.

To explain our findings, we can consider several aspects:

(1) other pharmacological treatments allowed: 9 of 10 studies allowed treatment with benzodiazepines (BDZs), mood stabilizers (MSs) or antidepressants (ADs). All the abovementioned drugs were found to actively modify the course of comorbid SUD in BD patients (see Tolliver et al. for a review),56 so it may be possible that the AAPs add-on did not make the difference.

(2) Different temporal patterns between BD and SUD: in the reviewed studies, there is no mention of the type of comorbid condition (SUD preceding or following BD). Patients with previous BD onset were found to have a more severe clinical condition when compared to patients with previous SUD onset.17 Our controversial results may be therefore explained by heterogenic study samples.

(3) Epidemiological variables and other psychiatric conditions affecting the course of BD with comorbid SUD: the efficacy of pharmacological therapy could be linked to other factors, such as psychotic features of BD, acute phases of the illness (manic versus depressive episode), type of BD (BD-I vs BD-II), unrecognized early stages of illness with consequent delay in treatment or even peculiar basal temperament characteristics.57,63 Another important prognostic factor could be other comorbidities, such as personality disorders57,64–68 and anxiety disorders.69 Moreover, those bipolar patients with comorbid substance use and personality disorder70 are at augmented risk for suicide and crimes.71 Furthermore, childhood trauma, especially sexual abuse, is often correlated with diagnoses of mood disorder, substance-induced mood disorder, and SUDs.72 A strong relationship between early traumas and impulsive behavior was found among a large group of female adolescents that was partially mediated through substance abuse.73

To summarize our results, we may affirm that, despite the large use of AAPs in BD, we found a paucity of data to support their beneficial effects on substance-related symptoms in patients with dual diagnosis. Moreover, the few published studies were not properly designed to take into account important confounding factors, such as other treatments, concomitant pathologies, and temporal relations between BD and SUD.

Back to Top | Article Outline

CONCLUSIONS

Based on our results, even though AAPs are widely used and efficacious in treating the clinical symptoms of BD (especially manic and psychotic features), in case of comorbid SUD, there are not enough data to suggest their adjunctive benefit on craving and substance consumption.

Back to Top | Article Outline

ACKNOWLEDGMENTS

The authors thank Dr Rita Santacroce for kindly editing the language.

Back to Top | Article Outline

REFERENCES

1. Schaffer A, Cairney J, Veldhuizen S, et al. A population-based analysis of distinguishers of bipolar disorder from major depressive disorder. J Affect Disord 2010;125(1–3):103–110.
2. Cerullo MA, Strakowski SM. The prevalence and significance of substance use disorders in bipolar type I and II disorder. Subst Abuse Treat Prev Policy 2007;2:29.
3. Beaulieu S, Saury S, Sareen J, et al. The Canadian Network for Mood and Anxiety Treatments (CANMAT) task force recommendations for the management of patients with mood disorders and comorbid substance use disorders. Ann Clin Psychiatry 2012;24(1):38–55.
4. Yatham LN, Beaulieu S, Schaffer A, et al. Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: a CANMAT randomized double-blind trial. Mol Psychiatry 2016;21(8):1050–1056.
5. Cassidy F, Ahearn EP, Carroll BJ. Substance abuse in bipolar disorder. Bipolar Disord 2001;3:181–188.
6. Grant BF, Stinson FS, Hasin DS, et al. Prevalence, correlates, and comorbidity of bipolar I disorder and axis I and II disorders: results from the National Epidemiologic Survey on alcohol and related conditions. J Clin Psychiatry 2005;66(10):1205–1215.
7. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) study. JAMA 1990;264(19):2511–2518.
8. Maremmani AG, Bacciardi S, Gehring ND, et al. The impact of mood symptomatology on pattern of substance use among homeless. J Affect Disord 2015;176:164–170. doi: 10.1016/j.jad.2015.01.059.
9. Strakowski SM, Del Bello MP. The co-occurrence of bipolar and substance use disorders. Clin Psychol Rev 2000;20(2):191–206.
10. Goldstein BI, Bukstein OG. Comorbid substance use disorders among youth with bipolar disorder: opportunities for early identification and prevention. J Clin Psychiatry 2010;71(3):348–358.
11. Kessler U, Schoeyen HK, Andreassen OA, et al. Neurocognitive profiles in treatment-resistant bipolar I and bipolar II disorder depression. BMC Psychiatry 2013;13:105.
12. Swann AC. Mechanisms of impulsivity in bipolar disorder and related illness. Epidemiol Psichiatr Soc 2010;19(2):120–130.
13. Sharma V, Mazmanian D, Persad E, et al. A comparison of comorbid patterns in treatment-resistant unipolar and bipolar depression. Can J Psychiatry 1995;40(5):270–274.
14. Goldberg JF, Garno JL, Leon AC, et al. A history of substance abuse complicates remission from acute mania in bipolar disorder. J Clin Psychiatry 1999;60(11):733–740.
15. Vincenti A, Ventriglio A, Baldessarini RJ, et al. Characteristics and clinical changes during hospitalization in bipolar and psychotic disorder patients with versus without substance-use disorders. Pharmacopsychiatry 2010;43(6):225–232.
16. Pettinati HM, O'Brien CP, Dundon WD. Current status of co-occurring mood and substance use disorders: a new therapeutic target. Am J Psychiatry 2013;170(1):23–30.
17. Sepede G, Di lorio G, Lupi M, et al. Bupropion as an add-on therapy in depressed bipolar disorder type I patients with comorbid cocaine dependence. Clin Neuropharmacol 2014;37(1):17–21.
18. Benaiges I, Prat G, Adan A. Health-related quality of life in patients with dual diagnosis: clinical correlates. Health Qual Life Outcomes 2012;10:106.
19. Najt P, Fusar-Poli P, Brambilla P. Co-occurring mental and substance abuse disorders: a review on the potential predictors and clinical outcomes. Psychiatry Res 2011;186(2–3):159–164.
20. Vieta E, Valentí M. Pharmacological management of bipolar depression: acute treatment, maintenance, and prophylaxis. CNS Drugs 2013;27(7):515–529.
21. Malhi GS, Bargh DM, McIntyre R, et al. Balanced efficacy, safety, and tolerability recommendations for the clinical management of bipolar disorder. Bipolar Disord 2012;14(Suppl 2):1–21.
22. Fornaro M, Stubbs B, De Berardis D, et al. Atypical antipsychotics in the treatment of acute bipolar depression with mixed features: a systematic review and exploratory meta-analysis of placebo-controlled clinical trials. Int J Mol Sci 2016;17(2):241.
23. Brown ES, Nejtek VA, Perantie DC, et al. Quetiapine in bipolar disorder and cocaine dependence. Bipolar Disord 2002;4(6):406–411.
24. Brown ES, Jeffress J, Liggin JD, et al. Switching outpatients with bipolar or schizoaffective disorders and substance abuse from their current antipsychotic to aripiprazole. J Clin Psychiatry 2005;66(6):756–760.
25. Albanese MJ, Suh JJ. Risperidone in cocaine-dependent patients with comorbid psychiatric disorders. J Psychiatr Pract 2006;12(5):306–311.
26. Nejtek VA, Avila M, Chen LA, et al. Do atypical antipsychotics effectively treat co-occurring bipolar disorder and stimulant dependence? A randomized, double-blind trial. J Clin Psychiatry 2008;69(8):1257–1266.
27. Martinotti G, Andreoli S, Di Nicola M, et al. Quetiapine decreases alcohol consumption, craving, and psychiatric symptoms in dually diagnosed alcoholics. Hum Psychopharmacol 2008;23(5):417–424.
28. Brown ES, Garza M, Carmody TJ. A randomized, double-blind, placebo-controlled add-on trial of quetiapine in outpatients with bipolar disorder and alcohol use disorders. J Clin Psychiatry 2008;69(5):701–705.
29. Stedman M, Pettinati HM, Brown ES, et al. A double-blind, placebo-controlled study with quetiapine as adjunct therapy with lithium or divalproex in bipolar I patients with coexisting alcohol dependence. Alcohol Clin Exp Res 2010;34(10):1822–1831.
30. Sani G, Kotzalidis GD, Vöhringer P, et al. Effectiveness of short-term olanzapine in patients with bipolar I disorder, with or without comorbidity with substance use disorder. J Clin Psychopharmacol 2013;33(2):231–235.
31. Brown ES, Davila D, Nakamura A, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in patients with bipolar disorder, mixed or depressed phase, and alcohol dependence. Alcohol Clin Exp Res 2014;38:2113–2118.
32. De Filippis S, Cuomo I, Kotzalidis GD, et al. Does the efficacy of asenapine in bipolar disorder increase in the presence of comorbidity with a substance use disorder? A naturalistic study. Ther Adv Psychopharmacol 2017;7(2):67–77. doi: 10.1177/2045125316674698. Epub 2016 Oct 28.
33. Tiffany ST, Singleton E, Haertzen CA, et al. The development of a cocaine craving questionnaire. Drug Alcohol Depend 1993;34:19–28.
    34. Young RC, Biggs JT, Ziegler VE, et al. A rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978;133:429–435.
      35. Shipley WC, Burlingame CD. A convenient self-administering scale for measuring intellectual impairment in psychotics. Amer J Psychiat 1941;97:1313–1325.
        36. Thase ME, Fava M, Halbreich U, et al. A placebo-controlled, randomized clinical trial comparing sertraline and imipramine for the treatment of dysthymia. Arch Gen Psychiatry 1996;53(9):777–784.
          37. Rush AJ, Gullion CM, Basco MR, et al. The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med 1996;26(3):477–486.
            38. Folstein MF, Folstein SE, McHugh PR. “Mini-mental status”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12(3):189–198.
              39. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry. 1960;23:56–62.
                40. Flannery BA, Volpicelli JR, Pettinati HM. Psychometric properties of the Penn Alcohol Craving Scale. Alcohol Clin Exp Res 1999;23:1287–1288.
                  41. Psychopharmacology Research Branch National Institute of Mental Health. Abnormal InvoluntaryMovement Scale (AIMS). In: Guy W, eds. ECDEU Assessment Manual for Psychopharmacology. Rev. ed. US Dept Health Education and Welfare Publication (ADM) 76–338. Rockville, MD: National Institute of Mental Health; 1976:534–537.
                    42. Simpson GM, Angus JW. A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970;45(Suppl 212):11–19.
                      43. Barnes TRE. A rating scale for drug-induced akathisia. Br J Psychiatry 1989;154:672–676.
                        44. Maxwell C. Sensitivity and accuracy of the visual analogue scale: a psycho-physical classroom experiment. Br J Clin Pharmacol 1978;6(1):15–24.
                          45. Anton RF, Moak DH, Latham P. The Obsessive Compulsive Drinking Scale: A self-rated instrument for the quantification of thoughts about alcohol and drinking behavior. Alcohol Clin Exp Res 1995;19:92–99.
                            46. Reoux JP, Miller K. Routine hospital alcohol detoxification practice compared to symptom triggered management with an objective withdrawal scale (CIWA-Ar). Am J Addict 2000;9(2):135–144.
                              47. First MB, Spitzer RL, Gibbon M, et al. Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Research Version, Patient Edition (SCID-I/P). New York: Biometrics Research, New York State Psychiatric Institute; 2002.
                                48. First MB, Gibbon M, Spitzer RL, et al. Structured Clinical Interview for DSM-IVAxis II Personality Disorders, (SCID-II). Washington, DC: American Psychiatric Press, Inc.; 1997.
                                  49. McLellan TA, Kushner H, Metzger D, et al. The 5th edition of the Addiction Severity Index. J Subst Abuse Treat 1992;9(3):199–213.
                                    50. Guy W. “Clinical Global Impressions”. ECDEU Assessment Manual for Psychopharmacology—Revised. Rockville, MD: U.S. Department of Health, Education, and Welfare; Public Health Service, Alcohol; Drug Abuse, and Mental Health Administration; National Institute of Mental Health; Psychopharmacology Research Branch; Division of Extramural Research Programs; 1976:218–222 OCLC 2344751. DHEW Publ No ADM 76–338—via Internet Archive.
                                      51. Sobell LC, Sobell MB. Timeline follow-back: A technique for assessing self-reported alcohol consumption. In: Littenand RZ, Allen JP, eds. Measuring alcohol consumption: Psychosocial and biological methods. Totowa, NJ: Humana Press: 1992:41–72.
                                        52. Endicott J, Nee J, Harrison W, et al. Quality of Life Enjoyment and Satisfaction Questionnaire: a new measure. Psychopharmacol Bull 1993;29(2):321–326.
                                          53. Sheehan DV. The Anxiety Disease. New York: Charles Scribner and Sons; 1983.
                                            54. Somoza E, Dyrenforth S, Goldsmith J, et al. In search of a universal drug craving scale. Paper presented at the Annual Meeting of the American Psychiatric Association, Miami Florida; 1995.
                                              55. Hall RC. Global assessment of functioning. A modified scale. Psychosomatics 1995;36(3):267–275.
                                                56. Tolliver BK, Anton RF. Assessment and treatment of mood disorders in the context of substance abuse. Dialogues Clin Neurosci 2015;17(2):181–190.
                                                57. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2016;30(6):495–553.
                                                58. Muralidharan K, Ali M, Silveira LE, et al. Efficacy of second generation antipsychotics in treating acute mixed episodes in bipolar disorder: a meta-analysis of placebo-controlled trials. J Affect Disord 2013;150(2):408–414. doi: 10.1016/j.jad.2013.04.032. Epub 2013 Jun 2.
                                                59. Derry S, Moore RA. Atypical antipsychotics in bipolar disorder: systematic review of randomised trials. BMC Psychiatry 2007;7:40.
                                                60. Kishi T, Sevy S, Chekuri R, et al. Antipsychotics for primary alcohol dependence: a systematic review and meta-analysis of placebo-controlled trials. J Clin Psychiatry 2013;74(7):e642–e654.
                                                61. Brunetti M, Di Tizio L, Dezi S, et al. Aripiprazole alcohol and substance abuse: a review. Eur Rev Med Pharmacol Sci 2012;16(10):1346–1354.
                                                62. Littlewood RA, Claus ED, Arenella P, et al. Dose specific effects of olanzapine in the treatment of alcohol dependence. Psychopharmacology (Berl) 2015;232(7):1261–1268.
                                                63. Iasevoli F, Valchera A, Di Giovambattista E, et al. Affective temperaments are associated with specific clusters of symptoms and psychopathology: a cross-sectional study on bipolar disorder inpatients in acute manic, mixed, or depressive relapse. J Affect Disord 2013;540–550.
                                                64. Bieling PJ, MacQueen GM, Marriot MJ, et al. Longitudinal outcome in patients with bipolar disorder assessed by life-charting is influenced by DSM-IV personality disorder symptoms. Bipolar Disord 2003;5(1):14–21.
                                                65. George EL, Miklowitz DJ, Richards JA, et al. The comorbidity of bipolar disorder and axis II personality disorders: prevalence and clinical correlates. Bipolar Disord 2003;5:115–122.
                                                66. Colom F, Vieta E, Martinez-Aran A, et al. Clinical factors associated with treatment noncompliance in euthymic bipolar patients. J Clin Psychiatry 2000;61:549–555.
                                                67. Lembke A, Miklowitz DJ, Otto MW, et al. Psychosocial service utilization by patients with bipolar disorders: data from the first 500 participants in the systematic treatment enhancement program. J Psychiatr Pract 2004;10(2):81–87.
                                                68. Kay JH, Altshuler LL, Ventura J, et al. Impact of axis II comorbidity on the course of bipolar illness in men: a retrospective chart review. Bipolar Disord 2002;4:237–242.
                                                69. Pavlova B, Perlis RH, Alda M, et al. Lifetime prevalence of anxiety disorders in people with bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry 2015;2:710–717.
                                                70. Leverich GS, Altshuler LL, Frye MA, et al. Factors associated with suicide attempts in 648 patients with bipolar disorder in the Stanley Foundation Bipolar Network. J Clin Psychiatry 2003;64:506–515.
                                                71. Webb RT, Lichtenstein P, Larsson H, et al. Suicide, hospital-presenting suicide attempts, and criminality in bipolar disorder: examination of risk for multiple adverse outcomes. J Clin Psychiatry 2014;75:e809–e816.
                                                72. Parsaik AK, Abdelgawad N, Chotalia JK, et al. Early-life trauma in hospitalized patients with mood disorders and its association with clinical outcomes. J Psychiatr Pract 2017;23(1):36–43. doi: 10.1097/PRA.0000000000000202.
                                                73. Clements-Nolle K, Larson S, Buttar A, et al. Childhood maltreatment and unprotected sex among female juvenile offenders: evidence of mediation by substance abuse and psychological distress. Womens Health Issues 2017;27(2):188–195. doi: 10.1016/j.whi.2016.12.004.
                                                Keywords:

                                                bipolar disorder; substance use disorder; dual diagnosis; atypical antipsychotics; comorbidity

                                                Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.