Review
Pharmacological approaches to treating negative symptoms: A review of clinical trials

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Abstract

Clinical trials of pharmacological agents targeting negative symptoms in schizophrenia are reviewed. The focus is on trials that occurred in patients who were stable on an antipsychotic medication at entry to the trial. A small number of trials compared antipsychotics as monotherapy for negative symptoms. Although the data supporting amisulpride for negative symptoms is promising the trials have limitations and it is plausible that the advantages of amisulpride over placebo may result from effects on secondary negative symptoms. Among available agents, antidepressant medications may have effects in negative symptoms. Other promising agents include minocycline, glutamatergic agents, and alpha-7 nicotinic agents. More than 15 active trials are currently underway to evaluate new treatments for negative symptoms.

Introduction

Negative symptoms are an important target for drug development for a number of reasons: (1) negative symptoms are relatively common with a recent study finding that nearly 58% of outpatients had at least one negative symptom (Bobes et al., 2010); (2) negative symptoms are better predictors of functioning than positive symptoms (Rabinowitz et al., 2012); and (3) there are no accepted treatments for primary negative symptoms. With the possible exception of amisulpride in some countries, antipsychotic medications are relatively ineffective for managing negative symptoms in stable patients. This lack of effectiveness is not surprising since complex disorders such as schizophrenia may include families of related disorders. In schizophrenia, patients may have impairments in a number of psychopathological domains including psychotic symptoms, cognitive impairments, and negative symptoms. As a result, it may be unrealistic to expect a single drug to treat all aspects of the disorder (Hyman and Fenton, 2003, Arango et al., 2004, Carpenter and Davis, 2012). Recent attention has focused on the development of pharmacological agents that have specific activity in treating negative symptoms that can be added to an antipsychotic medication (Arango et al., 2004, Kirkpatrick et al., 2006, Marder et al., 2011).

This review will focus on clinical trials of pharmacological agents for treating negative symptoms. We have selected trials that used specific entry criteria for negative symptoms and excluded trials that measured negative symptom change in individuals with acute psychosis. In most cases, the trials fit recent guidelines for negative symptom trials (Marder et al., 2011). That is, negative symptoms were stable and persistent. In addition, other causes of negative symptoms such as depression, extrapyramidal side effects, and psychosis were not sufficiently severe to cause secondary negative symptoms. Studies used different criteria for assuring that persistent positive symptoms such as hallucinations and delusions were not causing negative symptoms such as emotional withdrawal and avolition. These varied from studies requiring that positive symptoms be no greater than mild to studies that permitted moderately severe positive symptoms. This review includes three sections: (1) trials of drugs that are approved for schizophrenia and other illnesses and have also been evaluated for negative symptoms; (2) newer drugs that are not approved and have been evaluated for negative symptoms; and (3) trials of agents for negative symptoms that are currently underway or that have not published results.

Section snippets

Studies with approved agents

This review includes published trials evaluating approved agents in negative symptoms of schizophrenia from 1995 to 2012. Our search found multiple published studies and meta-analyses evaluating monotherapy antipsychotics in patients with prominent or predominant negative symptoms. Most of these studies focused on negative symptom improvement in patients with acute schizophrenia and were not included. As a result, this review is limited to studies of clozapine, amisulpride and asenapine.

Antidepressant drugs

A meta-analysis (Singh et al., 2010) evaluated the efficacy of antidepressant adjunctive to antipsychotic therapy. Although there were many case reports and open label trials where antidepressants were added to an antipsychotic, only trials that used well-described criteria for negative symptoms and used double-blind methods to compare the antidepressant to a placebo were included. This resulted in the inclusion of 23 trials from 22 publications (n = 819 patients). In most studies, mean scores of

Cholinergic

A partial alpha7 nicotinic receptor agonist, 3-(2,4-dimethoxybenzylidene) anabaseine (DMXB-A) was shown to improve negative symptoms as measured by the SANS in 31 stable schizophrenia patients in a double-blind, crossover, add-on study (Freedman et al., 2008). It is interesting to note that the authors developed this study to target cognitive impairment, but found more consistent effects on negative symptoms. Lieberman et al. (2013) recently reported that a partial alpha7 nicotinic receptor

Other approaches

There are a number of other treatment strategies that have been tried in proof of concept studies. Adjunctive intranasal oxytocin for 3 weeks was determined to not be better than placebo for negative symptoms in a small group of 28 subjects (Lee et al., 2013). Ginkgo biloba has also been shown to reduce negative symptoms as compared with placebo in haloperidol treated patients with schizophrenia (Zhang et al., 2001) (Zhang et al., 2001). Recently, 2 mg of folic acid and 400 μg of vitamin B12

Trials that have not reported results

We used the www.clinicaltrials.gov site to document trials that are still recruiting or have not reported results. Trials were located using the search terms negative symptoms and schizophrenia. The table lists the trials along with the proposed mechanism, trial duration, and the instrument used to measure negative symptoms. We only included studies that specified improvement on a negative symptom scale as a primary outcome measure.

AgentSponsorMechanismPhaseAgeDuration (wks)Neg symptom

Discussion

This review indicates that clinicians who are treating negative symptoms in schizophrenia have a number of current options for treating negative symptoms in schizophrenia. These options include selecting amisulpride as an antipsychotic (where it is available), or adding one of a number of adjunctive or co-medications to an antipsychotic. Among promising adjunctive medications, there is some modest evidence suggesting that adding an antidepressant may have some benefit. The evidence for other

Role of funding source

There was no funding source for the work described in this article.

Contributors

Drs. Marder, Arango, and Garibaldi each contributed to the literature review and the conclusions in this article.

Conflict of interests

Dr. Arango has been a consultant to or has received honoraria or grants from Abbot, AMGEN, AstraZeneca, Bristol-Myers Squibb, Caja Navarra, CIBERSAM, Fundación Alicia Koplowitz, Instituto de Salud Carlos III, Janssen Cilag, Lundbeck, Merck, Ministerio de Ciencia e Innovación, Ministerio de Sanidad, Ministerio de Economía y Competitividad, Mutua Madrileña, Otsuka, Pfizer, Roche, Servier, Takeda and Schering Plough.

Stephen R. Marder has consulted for Abbott, Boeheringer Ingelheim, Bristol Meyers

Acknowledgments

None.

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