A systematic review of psychostimulant treatment of negative symptoms of schizophrenia: Challenges and therapeutic opportunities
Background: Primary negative symptoms of schizophrenia (NSS) contribute heavily to functional disability and treatment of these symptoms continues to be a major unmet need even when the positive (psychotic) symptoms are controlled. The modified dopamine (DA) hypothesis posits that positive symptoms are associated with increased DA activity in the mesolimbic tract whereas NSS and cognitive symptoms are associated with decreased DA activity in the mesocortical (frontal) region. Several studies have reported improvement in NSS with DA agonist use, but with varying degrees of risk for triggering psychotic symptoms, especially in the absence of concurrent antipsychotic drug treatment. This article aims to examine older and newer evidence suggesting that psychostimulants may have a potential therapeutic role in the treatment of NSS together with a thorough review of the potential risks and benefits of psychostimulant administration in individuals with schizophrenia. Methods: A systematic search of relevant literature using electronic databases, reference lists, and data presented at recent meetings was conducted. Results: Improvement of NSS after psychostimulant administration is reviewed both in challenge and treatment paradigms with various agents such as methylphenidate, amphetamine, and modafinil or armodafinil. The literature points to evidence that, used adjunctively, DA agonists may improve NSS without worsening of positive symptoms in selected patients who are stable and treated with effective antipsychotic medications. Several areas of inadequate study and limitations are identified including small study samples, single-site trials, varying rigor of bias control, the dose and the duration of adjunctive psychostimulant administration, and the potential for development of tolerance. Conclusion: Large, controlled clinical trials to further characterize effects of psychostimulants on NSS in carefully selected patients are warranted.