Meta-analysis backs amisulpride for depression

The second-generation antipsychotic amisulpride performs well in the treatment of depression and associated symptoms in individuals with a major mental health disorder, with efficacy and tolerability profiles similar to those of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), as suggested in a meta-analysis of randomized controlled trials (RCTs).

“Th[e] evidence is stronger for dysthymia and less conclusive for other depressive disorders and depressive episodes in schizophrenia,” the investigators said. “[Amisulpride] use could be evaluated in selected individuals, such as when prioritizing renal excretion over hepatic metabolism.”

The meta-analysis included 11 RCTs evaluating the utility of the second-generation antipsychotic for an acute depressive episode in any major psychiatric disorder. There were 2,065 patients with dysthymia (eight studies), major depression (one study), or schizophrenia (two studies) in total.

The investigators acknowledged that amisulpride was evaluated only for a limited number of mental health disorders and, as such, a systematic evaluation of the transdiagnostic potential of the drug across and beyond diagnoses using the TRANS-D criteria could not be performed.

Pooled data on dysthymia showed that compared with placebo, amisulpride 50 mg/day yielded a larger reduction in depressive symptoms (standardized mean difference [SMD] −0.70, 95 percent confidence interval [CI] −0.92 to −0.49; I², 0.0 percent). The effect was comparable to that of SSRI (SMD −0.08, 95 percent CI −0.23 to 0.06; I², 0.0 percent), amineptine, imipramine, and amitriptyline (three studies, not pooled).  [Hum Psychopharmacol Clin Exp 2021;doi:10.1002/hup.2801]

Results for safety showed a similar pattern, with amisulpride being more favourable than placebo for dysthymia patients (odds ratio [OR] 3.94, 95 percent CI 1.07 to 14.48; I², 0.0 percent) and comparable to SSRIs (OR 0.94, 95 percent CI 0.55 to 1.62; I², 0.0 percent).

Evidence on schizophrenia

In patients with schizophrenia, amisulpride at higher dosages (>400 mg/day) proved to be as good as olanzapine and risperidone (two studies, not pooled).

The investigators acknowledged that the impact of amisulpride on depressive symptoms in schizophrenia is uncertain. “It has been suggested that lower dos[ag]es of amisulpride (<400 mg/day) might be more effective on depressive and negative symptoms, whilst higher dosages for positive symptoms. This apparent discrepancy should be considered in light of the individual response to amisulpride and the gradual activating‐to‐inhibiting transition linked to the pharmacological properties of the drug.” [CNS Drugs 2004;18:933-956]

Regardless of the dosing regimens, the investigators stressed that amisulpride performed better than both olanzapine and risperidone. Furthermore, the tolerability data of the study drug in patients with schizophrenia are consistent with the overall low incidence of extrapyramidal symptoms and limited impact on cognitive function reported in healthy individuals. [Hum Psychopharmacol 2002;17:1-13]

“Commonly reported side effects are weight gain and endocrine dysfunctions due to increase in prolactin levels (eg, galactorrhoea, libido reduction, amenorrhea). Its tolerability profile and the renal excretion make amisulpride suitable as augmentation in patients with complex multipharmacological regimens, or in individuals with significant physical and hepatic comorbidities,” they noted. [PLoS One 2016;11:e0153380]

Currently, amisulpride is indicated for the treatment of acute or chronic schizophrenia disorders in Japan, China, Russia, and multiple countries in Europe. It is approved for use in the US only for managing or prophylaxis against postoperative nausea and vomiting. [tinyurl.com/yj2cb6oz; tinyurl.com/yh5v62xv; tinyurl.com/yj8lzrm9]

The uptake of amisulpride in clinical practice, however, is limited, which is believed to be partly due to the drug not being licensed for treating dysthymia in the majority of the Western countries. [Psychiatria Danubina 2019;31:148-156]

“Leveraging the available—albeit limited—evidence, our findings together with peculiar pharmacodynamic properties (eg, tolerability profile and renal excretion) may support the use of amisulpride for selected individuals with dysthymia, for instance with significant physical and hepatic comorbidities,” they said.

The investigators called for high-quality studies to establish the effect and tolerability of amisulpride as a transdiagnostic agent in the treatment of depressive symptoms.