Safety and tolerability of antipsychotic co-treatment in patients with schizophrenia: results from a systematic review and meta-analysis of randomized controlled trials

ABSTRACT

Introduction: Antipsychotic co-treatment is common in schizophrenia, despite lacking evidence for its efficacy and safety.

Areas: We conducted a systematic search of PubMed/PsycInfo/CJN/WangFan/CBM without language restrictions from database inception until 05/25/2015 for randomized trials comparing antipsychotic monotherapy with antipsychotic co-treatment in ≥20 adults with schizophrenia reporting meta-analyzable adverse events (AEs) data. Meta-analyzing 67 studies (n=4,861, duration=10.3±5.2 weeks), antipsychotic co-treatment was similar to monotherapy regarding intolerability-related discontinuation (risk ratio (RR)=0.84, 95% confidence interval (CI)=0.53-1.33, p=0.455). While incidence of ≥1 AE was lower with antipsychotic co-treatment (RR=0.77, 95%CI=0.66-0.90, p=0.001), these results were solely driven by open-label and efficacy-focused studies. Adjunctive D2-antagonists lead to less nausea (RR=0.220, 95%CI=0.06–0.87, p=0.030) and insomnia (RR=0.26, 95%CI=0.08-0.86, p=0.028), but higher prolactin (SMD=2.20, 95%CI=0.43-3.96, p=0.015). Conversely, adjunctive partial D2-agonists (aripiprazole=100%) resulted in lower electrocardiogram abnormalities (RR=0.43, 95%CI=0.25-0.73, p=0.002), constipation (RR=0.45, 95%CI=0.25-0.79, p=0.006), drooling/hypersalivation (RR=0.14, 95%CI=0.07-0.29, p<0.001), prolactin (SMD=-1.77, 95%CI=-2.38, -1.15, p<0.001), total and LDL-cholesterol (SMD=-0.33, 95%CI=-0.55, -0.11, p=0.003; SMD=-0.33, 95%CI=-0.54, -0.10, p=0.004).

Expert opinion: No double-blind evidence for altered AE burden associated with antipsychotic co-treatment was found. However, AEs were insufficiently and incompletely reported and follow-up duration was modest. Adjunctive partial D2-agonists might be beneficial for counteracting several AEs. High-quality, long-term studies that comprehensively assess AEs are needed.

KEYWORDS:

• Antipsychotics
• augmentation
• cotreatment
• combination
• polypharmacy
• monotherapy
• schizophrenia
• safety
• tolerability
• adverse effects
• metaanalysis

Article highlights

• Although we identified 140 randomized controlled trials comparing antipsychotic monotherapy and co-treatment, only 67 (47.9%, n=4861) of these studies reported on global and/or specific adverse effects (AEs). Frequencies and, especially, severity were insufficiently and incompletely assessed or reported, with only 46/67 (68.6%) AEs being available in at least five studies.

• At least in shorter-term, randomized controlled trials, there is no double-blind evidence for differences in intolerability-related discontinuations or at least one AE associated with antipsychotic co-treatment compared to antipsychotic monotherapy.

• Adjunctive treatment with D2 antagonists was associated with less nausea than monotherapy, whereas adjunctive treatment with partial D2 agonist was associated with significantly lower total cholesterol, low-density lipoprotein (LDL)-cholesterol, and prolactin, as well as less electrocardiogram (EKG) abnormalities, constipation, and hypersalivation.

• However, study results must be interpreted cautiously due to the short follow-up period, apparent reporting bias, and higher incidences of at least one AE with antipsychotic monotherapy in open-label and efficacy-focused studies, suggesting a potential bias in favor of antipsychotic co-treatment.

• Although there is no clear evidence for a higher AE risk with antipsychotic co-treatment, this possibility cannot be ruled out due to limited data. In clinical care, antipsychotic co-treatment should only and very carefully be used if all other treatment options (confirmation of adherence, dose adjustment, switch) have failed. Augmentation with a partial D2 agonist may be considered to counteract metabolic adverse effects and hyperprolactinemia in patients where switching to lower-risk agents or the addition of a non-antipsychotic agent to counter the adverse effect is not an option.

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Declaration of Interest

JM Kane has received honoraria for lectures and/or consulting from Alkermes, Bristol-Myers Squibb, Eli Lilly, Forrest Labs, Forum, Genentech, Intracellular Therapies, Janssen, Johnson and Johnson, Lundbeck, Merck, Novartis, Otsuka, Pfizer, Reviva, Roche, and Sunovion. He has received grant support from Genentech, Johnson and Johnson and Otsuka. He is a shareholder of MedAvante and Vanguard Research Group. He has received grant support from Otsuka and The National Institute of Mental Health. C Correll has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Actavis, Actelion, Alexza; Alkermes, Bristol-Myers Squibb, Cephalon, Eli Lilly, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Janssen/J&J, Lundbeck, Medavante, Medscape, Merck, Otsuka, Pfizer, ProPhase, Reviva, Roche, Sunovion, Supernus, Takeda, Teva, and Vanda. He has received grant support from the American Academy of Child and Adolescent Psychiatry, the Bendheim Foundation, Bristol-Myers Squibb, the National Institute of Mental Health, Novo Nordisk A/S, Otsuka, Takeda and the Thrasher Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.