Amisulpride May Be Most Effective Antipsychotic for Negative Symptoms in Schizophrenia

white round pills
white round pills
There has been a question of whether antipsychotic medications are truly acting upon "primary" negative symptoms, or whether they are instead improving "secondary" negative symptoms via improvement in positive or depressive symptoms.

A systematic literature review and meta-analysis of antipsychotic use in patients with schizophrenia with predominant or prominent negative symptoms revealed that amisulpride was the only medication found to be superior to placebo for those with predominant negative symptoms. For prominent negative symptoms, no studies were found that supported a specific antipsychotic compared with placebo. However, for both categories of negative symptoms, other head-to-head comparisons did demonstrate an advantage of certain agents over others. These findings were published in the European Archives of Psychiatry and Clinical Neuroscience.

Although negative symptoms lie at the heart of schizophrenia, it is unclear how effective antipsychotic medications are at treating them. When such agents have proved efficacious for negative symptoms, there has also been a question of whether they are truly acting on “primary” negative symptoms or whether they are instead improving “secondary” negative symptoms via improvement in positive or depressive symptoms. The investigators aimed to answer these questions as well as determine the appropriateness of merely prominent symptoms (vs predominant) being used in studies. This analysis appears to be the first to study this specific population while separating the patients into predominant and prominent negative symptoms groups.

Researchers reviewed a total of 21 blinded, randomized controlled drug trials evaluating 34 different antipsychotics involving 3451 participants published from 1989 to 2017. Separate analyses were carried out for predominant and prominent negative symptoms, with the primary outcome being change in negative symptoms, as measured by the Positive and Negative Syndrome Scale and the Scale for the Assessment of Negative Symptoms. Secondary outcomes included depressive or positive symptoms, as well as extrapyramidal adverse effects.

As noted earlier, in those with predominant negative symptoms, only amisulpride was found to be significantly better than placebo for negative symptoms (N=4; n=590; standardized mean difference [SMD], 0.47; 95% CI, 0.23-0.71) and depression (N=4; n=345; SMD, 0.35; 95% CI, 0.02-0.68). When comparing antipsychotics with each other in the predominant group, cariprazine was superior to risperidone (N=1; n=456; SMD, −0.29; 95% CI, −0.48 to −0.11), whereas a small study saw olanzapine outperform haloperidol (N=1; n=35; SMD, 0.75; 95% CI, 0.06-1.44) in reducing negative symptoms. There were no significant differences between medications when analyzing for positive symptoms or depression.

For subjects with prominent negative symptoms, no placebo-controlled studies were included, meaning efficacy vs placebo could not be reported in the review. In direct comparisons between 2 drugs, amisulpride proved superior to fluphenazine only in the depressive symptom category (N=1; n=48; SMD, -0.78; 95% CI, -1.37 to -0.19). However, in 1 study, olanzapine showed greater efficacy vs risperidone for both negative symptoms (N=1; n=235; SMD, -0.30; 95% CI, -0.04 to -0.56) and positive symptoms (N=1; n=235; SMD, -0.32; 95% CI, -0.06 to -0.57). In addition, another single study saw quetiapine outperform risperidone for negative symptoms (N=1; n=44; SMD, -1.34; 95% CI, -2.00 to -0.68). 

It is worth noting that the authors suspected a larger confounding influence (via secondary effects) in these studies vs those examining predominant negative symptoms, making prominent negative symptoms somewhat less suited for evaluation.

Related Articles

Limitations included a relatively small number of controlled studies focused on negative symptoms, a lack of information in the original studies regarding secondary outcomes, difficulty interpreting scores for the Positive and Negative Syndrome Scale and Scale for the Assessment of Negative Symptoms, and a reliance on less scientific measures to separate subtypes of negative symptoms.

With respect to the last issue, the researchers suggest using scientifically developed definitions such as the “deficit syndrome” and “persistent negative symptoms” for these purposes in future trials. Finding methods to tease apart the effect on actual negative symptoms from those related to secondary effects via reduction of positive symptoms and depression will be an important direction for future studies.

For the time being, particularly for patients with predominant negative symptoms, amisulpride appears best able to help mitigate the considerable burden of negative symptoms in schizophrenia, although the exact nature of these associations needs to be investigated further.

Disclosures: In the last 3 years, Stefan Leucht has received honoraria for consulting from LB Pharma, Lundbeck, Otsuka, Teva Pharmaceutical Industries Ltd, LTS Lohmann, Geodon Richter, Recordati, and Boehringer Ingelheim, and for lectures from Janssen, Lilly, Lundbeck, Otsuka, Sanofi Aventis, and Servier.


Krause M, Zhu Y, Huhn M, et al. Antipsychotic drugs for patients with schizophrenia and predominant or prominent negative symptoms: a systematic review and meta-analysis [published online January 24, 2018]Eur Arch Psychiatry Clin Neurosci. doi:10.1007/s00406-018-0869-3