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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:;

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.

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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).



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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.



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.

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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.

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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.

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

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

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