Cognitive Improvement in Schizophrenic Patients does not Require a Serotonergic Mechanism: Randomized Controlled Trial of Olanzapine vs Amisulpride

Abstract

Combined serotonin-2A (5-HT 2A ) and dopamine-2 (D 2 ) receptor blockade has been proposed as a candidate mechanism by which second-generation antipsychotics (SGAs) improve both cognition and negative symptoms in schizophrenic patients, in contrast to antipsychotics of the first generation. The SGA amisulpride, however, only binds to D 2 /D 3 receptors, which makes it an interesting tool to test this assumption. In a randomized controlled trial, 52 schizophrenic patients were allocated to treatment with either olanzapine (10-20 mg/day) or amisulpride (400-800 mg/day). A comprehensive neuropsychological test battery and clinical ratings were used to assess participants at inclusion and after 4 and 8 weeks. Cognitive improvements of moderate size were observed, with effect sizes similar to those obtained in previous studies on the cognitive effects of SGAs. Importantly, amisulpride was not inferior to olanzapine for any cognitive domain. Combined 5-HT 2A /D 2 receptor blockade is probably not necessary for cognitive improvement by SGAs.

The Role of 5-Hydroxytryptamine 7 Receptors in the Phencyclidine-Induced Novel Object Recognition Deficit in Rats

“…APD, has also been reported to improve cognition allegedly by a nonserotonergic mechanism (Wagner et al, 2005). The development of novel adjunctive or stand-alone treatments that can improve some domains of cognition in schizophrenia, accompanied by functional improvement, is a major goal of pharmacologic research (Buchanan et al, 2010).…”

Cognitive function and social abilities in patients with schizophrenia: Relationship with atypical antipsychotics

“…In addition, Wagner et al reported that the atypical antipsychotic amisulpride (which is devoid of 5HT-2A affinity) was as effective at alleviating cognitive deficits as olanzapine (high 5HT-2A affinity). 5 Although this finding in itself does not suggest a cognitive advantage of atypical antipsychotics with no affinity for 5HT-2A receptors, Wagner et al did note stronger effects of amisulpride on attention and executive function and suggested that a similar study with higher statistical power might demonstrate an advantage of amisulpride over risperidone. 5 Certainly, the assertion that serotonin activation impairs learning and memory whereas reduced serotonergic function enhances these processes needs reconsideration.…”

“…5 Although this finding in itself does not suggest a cognitive advantage of atypical antipsychotics with no affinity for 5HT-2A receptors, Wagner et al did note stronger effects of amisulpride on attention and executive function and suggested that a similar study with higher statistical power might demonstrate an advantage of amisulpride over risperidone. 5 Certainly, the assertion that serotonin activation impairs learning and memory whereas reduced serotonergic function enhances these processes needs reconsideration. 37 In addition, our finding of enhanced social abilities for the low-5HT-2A-affinity group suggests that serotonergic mechanisms are important for successful functioning in a social environment.…”

“…The average age of the patients was 38 ± 7.8 years (range 22-52 years), with a mean length of illness of 12 ± 6 years (range, 2 months−25 years). Symptom type and severity was assessed with the Brief Psychiatric Scale (BPRS), 27 which gave a mean total score of 10.2 ± 4.6 (range, [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]. When the BPRS score was broken down according to four symptom dimensions, 28 the ratings were: thinking disturbance, mean 3.6 ± 2.5, range 0-9; withdrawal/retardation, mean 1.8 ± 1.8, range 0-6; hostility/suspiciousness, mean, 1.6 ± 1.4, range 0-4; and anxiety/depression, mean 4.9 ± 3.0, range 1-12.…”

“…[2][3][4] Studies have found that the most widely used atypical antipsychotics, olanzapine, clozapine, risperidone, quetiapine and amisulpride, all have an influence on cognitive function in schizophrenia, and this influence is mostly a positive one. [5][6][7] Nevertheless, it remains unclear precisely how these medications exert their cognitive effects, and an understanding of the biochemical mechanisms involved remains an important goal for researchers and clinicians alike. Candidate neurotransmitter systems primarily include dopamine and serotonin (5HT-2A).…”