First Effective Pharmacotherapy Modality for Negative Symptoms in Schizophrenia

Negative Symptoms and Treatment Options

While existing antipsychotic treatments work well on the positive symptoms of schizophrenia (hallucinations, delusions, disorganization), their efficacy on negative symptoms is problematic; improvements are more likely in secondary negative symptoms as a result of treating positive symptoms. There has been a lack of effective treatment for primary negative symptoms until now. Complicating the situation is the fact that negative symptoms are heterogeneous and likely arise from different pathophysiological bases. The main five primary negative symptoms include emotional flattening, alogia, anhedonia, asocial behavior, and loss of motivation.

Cariprazine is a partial agonist of dopamine D₂/D₃ receptors with a preference for D₃ and a partial agonist of serotonin 5-HT_1A receptors. In a prospective study (Németh et al., 2017), cariprazine showed efficacy on positive symptoms of schizophrenia comparable to risperidone, with an added benefit of confirmed efficacy on primary negative symptoms, significantly higher than risperidone. Additionally, cariprazine boasts a very good safety profile—being metabolically neutral, it does not cause weight gain, hyperprolactinemia, and its sedation is comparable to placebo.

Methodology of the Analysis

The authors of the presented work (Fleischhacker et al., 2019) conducted a post hoc analysis and evaluated changes in individual items of the Positive and Negative Syndrome Scale (PANSS) after 26 weeks of medication use. They also processed factor models derived from PANSS, which they assessed using a mixed-effects model for repeated measures (MMRM) in intent-to-treat (ITT) patients (cariprazine n = 227; risperidone n = 227).

Results

From the start to the assessment, changes were significantly different (p < 0.05) in the items of the PANSS-FSNS subscale, where cariprazine showed marked improvement in items N1–N5 (blunted affect, emotional withdrawal, poor relations, passivity, apathy/social withdrawal, difficulty in abstract thinking). These results were not achieved in items N6 (lack of spontaneity/flow of conversation) and N7 (stereotyped thinking).

In all models of negative symptom factors derived from PANSS that were evaluated (PANSS-Factor Score for Negative Symptoms, Liemburg factors, Khan factors, Pentagonal Structure Model Negative Symptom factor), cariprazine demonstrated statistically significant improvement, unlike risperidone (p < 0.01). Small and similar changes in positive/depressive/extrapyramidal symptoms suggest that the improvement in negative symptoms was not pseudo-specific.

Change from baseline was significant for cariprazine compared to risperidone (p < 0.05) also in factors derived from PANSS that evaluated other relevant symptoms (disorganized thoughts, prosocial functions, cognition).

Conclusion

Given that individual symptoms falling under the category of negative symptoms in schizophrenia may have different pathophysiological bases, the significant improvement in most items of the PANSS subscale evaluating negative symptoms and all factors derived from PANSS after cariprazine administration (not risperidone) indicates a broad spectrum of efficacy of cariprazine in treating negative symptoms of schizophrenia.

(mir)

Source: Fleischhacker W., Galderisi S., Laszlovszky I. et al. The efficacy of cariprazine in negative symptoms of schizophrenia: post hoc analyses of PANSS individual items and PANSS-derived factors. Eur Psychiatry 2019; 58: 1–9, doi: 10.1016/j.eurpsy.2019.01.015.