Efficacy of 42 Pharmacologic Cotreatment Strategies Added to Antipsychotic Monotherapy in Schizophrenia

Abstract

Meta-analyses of 21 interventions fully or partially recommended their use, with recommendations being positively correlated with the effect sizes of the pooled intervention. However, the effect sizes were inversely correlated with meta-analyzed study quality, reducing confidence in these recommendations. Higher-quality trials and patient-based meta-analyses are needed to determine whether subpopulations might benefit from combination treatment, as no single strategy can be recommended for patients with schizophrenia based on the current meta-analytic literature.

Polypharmacy in schizophrenia

“…Selective serotonin reuptake inhibitors (SSRIs) and mirtazapine (a noradrenergic, specific serotonergic agent) are the compounds that have been most often investigated. As regards effect specifically on negative symptoms, the latest meta‐regression found a small therapeutic effect of SSRIs (SMD −0.26; 95% CI −0.50 to −0.02; N = 922) and a larger effect of serotonergic and noradrenergic reuptake inhibitors (SNRIs) (SMD −1.40; 95% CI −2.44 to −0.36; N = 40), but no effect of mirtazapine . Limitations of the current studies include small sample size, short trial duration and failure to control for change in secondary negative symptoms.…”

“…The meta‐analyses published after 2009 have generally not been able to replicate the positive findings for augmenting clozapine treatment with an additional antipsychotic compound, but results are mixed . The most recent meta‐analysis indicates a potential therapeutic effect on negative symptoms only when augmenting with aripiprazole (a partial dopamine D2 agonist) compared with antipsychotic monotherapy (standardized mean difference [SMD] −0.41; 95% confidence interval [CI] −0.79 to −0.03; N = 532) . If choosing to combine two antipsychotic compounds with the aim of obtaining supplementary efficacy, the rational choice will be to combine two compounds with different receptor profiles (cf.…”

“…Recent meta‐analyses indicate that there is some evidence of a small to moderate effect of combining an antidepressant with antipsychotic treatment for total symptom score improvement . Selective serotonin reuptake inhibitors (SSRIs) and mirtazapine (a noradrenergic, specific serotonergic agent) are the compounds that have been most often investigated.…”

“…Augmenting antipsychotic treatment with an antiepileptic (or mood stabilizer) stems from clinical practice where this has been considered an option in a subgroup of patients with the aim of reducing aggression or stabilizing mood outside the licensed indication of bipolar disorder. Regarding the latter use, especially patients diagnosed with schizoaffective disorder are in the clinical target group for combined treatment with an antipsychotic and a mood stabilizer although there is no firm evidence base to support this clinical practice . Theoretically, antiepileptic drugs may reduce aggression by reducing neuronal hyper‐excitability associated with aggression, but the current evidence is not convincing .…”

“…Theoretically, antiepileptic drugs may reduce aggression by reducing neuronal hyper‐excitability associated with aggression, but the current evidence is not convincing . The clinical practice of combining an antipsychotic with an antiepileptic in patients with schizophrenia has been the subject of several smaller clinical trials with the latest meta‐regression results indicating that lamotrigine might be associated with a therapeutic effect regarding total psychopathology score (SMD −0.73; 95% CI −1.26 to −0.20; N = 98) as well as psychotic (SMD −0.69; 95% CI −1.20 to −0.18; N = 67) and negative symptom score (SMD −0.96; 95% CI −1.40 to −0.52; N = 98), whereas carbamazepine had no effect. When specifically addressing clozapine combination treatment, a systematic review and meta‐analysis reported that lamotrigine was superior to placebo augmentation in both total psychopathology score (SMD 0.57; 95% CI 0.25‐0.89; N = 161), psychotic symptoms (SMD 0.34; 95% CI 0.02‐0.65) and negative symptoms (SMD 0.43; 95% CI 0.11‐0.75) .…”