Do psychostimulants help in treating negative symptoms? Schi Research.July.2013


Negative symptoms of schizophrenia (NSS: flattened/blunted affect, alogia, asociality, avolition/amotivation, anergia, and anhedonia ) are particularly difficult to treat. One-third of patients demonstrate persistent negative symptoms, which have not responded to  antipsychotic treatments.

Jean-Pierre Lindenmayer , Henry Nasrallah , Michael Pucci Steven James and Leslie Citrome provide a comprehensive review of the field with focus on therapeutic effects of psychostimulants.

It is clear that D2-receptor antagonism does not   improve negative symptoms and cognitive dysfunction in schizophrenia.Deficits in dopamine transmission at D1 receptors, particularly in the mesocortical DA pathway and PFC are suggested as critical to NSS. ( dopamine deficit in PFC and excess in striatum appears to be the case in schizophrenia) .It is also suggested that optimum D1 function is perhaps crucial for cognitive performance.

Other neurotransmitters also might be playing important modulatory roles.  Hypofunction of NMDA receptors can lead, via reduced GABAergic inhibition, to downstream DA hyperactivity.Hypofunctioning of central noradrenergic systems may result in negative symptoms.

Early studies reported adjunctive use  of stimulants (Modafinil and Armodafinil) as beneficial.However controlled studies have failed to replicate this.A recent study  (Arbabi et al., 2012)  reported significant benefit for a combination of Modafinil (200 mg/d) plus Risperidone (6 mg/d)  .Scoriels et al., 2011 reported that single dose of Modafinil can improve emotional recognition in individuals with schizophrenia. Kane et al’s 2010 study did not show any significant benefit  with stimulant. Lasser et al., 2012  reported significant benefit from  Lisdexamfetamine dimesylate (20 to 70 mg/ d for 14 weeks ) in individuals with schizophrenia on  stable antipsychotic treatment.No evidence of overall positive symptom worsening was observed in that study  though other  trials have reported exacerbation of psychotic symptoms with stimulants.


There is no clear conclusive evidence for psychostimulants efficacy treating NSS.Some evidence suggest that it might be useful.Their benefits possibly result from the DA-enhancing in mesocortical pathways, which are believed to contribute to the negative and cognitive symptoms of schizophrenia. Authors suggest that “clinically stable patients in the non acute phase of illness who are reliably receiving antipsychotic therapy and presenting with minimal positive symptomatology are at a relatively reduced risk for the psychotogenic effects of psychostimulants”.

Summary of the article. 

 systematic review of psychostimulant treatment of negative symptoms of schizophreniaChallenges andtherapeutic opportunities.

Lindenmayer JP, Nasrallah H, Pucci M, James S, Citrome L. Schizophr Res. 2013 Jul;147(2-3):241-52


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