Alpha-2 receptor antagonist add-on therapy in the treatment of schizophrenia; a meta-analysis

Reduced dopaminergic activity in the pre-frontal cortex may partially explain the negative symptoms of schizophrenia. Animal models have shown that adding an alpha-2 adrenergic receptor antagonist to a D2 antagonist can efflux dopamine into the frontal cortex increasing dopaminergic activity. Trials of alpha-2 antagonist add-on therapy in humans have been limited by small sample sizes. Therefore, a meta-analysis was conducted to determine if adding an alpha-2 antagonist to a D2 antagonist improves schizophrenia treatment by reducing negative symptoms.

Randomized, placebo-controlled trials of the addition of an alpha-2 antagonist to a D2 antagonist were identified through a PubMed search. Treatment effects were measured using schizophrenia rating scales and meta-analyzed as standardized mean differences using random effects models.

Eight unique studies were identified, each including 18 to 41 patients and lasting four to eight weeks. The overall effect size of add-on alpha-2 therapy across the eight trials was an improvement of 0.16 (95% C.I., -.30 to 0.62) for positive symptoms, 0.84 (95% C.I., .17 to 1.51) for negative symptoms, 0.28 (95% C.I., -.08 to 0.64) for general symptoms, and .80 (95% C.I., .15 to 1.46) for symptoms overall. Negative symptom improvements were independent of improvements in depressive symptoms, measured using the Hamilton depression rating scale, for 3 of the 5 studies.

Add-on agents with alpha-2 antagonist activity appear to improve the efficacy of D2 antagonists for the treatment of schizophrenia by reducing negative symptoms. These results support conducting a more definitive confirmatory clinical trial.