Neural Basis for the Ability of Atypical Antipsychotic Drugs to Improve Cognition in Schizophrenia

Abstract

Cognitive impairments are considered to largely affect functional outcome in patients with schizophrenia, other psychotic illnesses, or mood disorders. Specifically, there is much attention to the role of psychotropic compounds acting on serotonin (5-HT) receptors in ameliorating cognitive deficits of schizophrenia. It is noteworthy that atypical antipsychotic drugs (AAPDs), e.g., clozapine, melperone, risperidone, olanzapine, quetiapine, aripiprazole, perospirone, blonanserin, and lurasidone, have variable affinities for these receptors. Among the 5-HT receptor subtypes, the 5-HT1A receptor is attracting particular interests as a potential target for enhancing cognition, based on preclinical and clinical evidence. The neural network underlying the ability of 5-HT1A agonists to treat cognitive impairments of schizophrenia likely includes dopamine, glutamate, and gamma-aminobutyric acid neurons. A novel strategy for cognitive enhancement in psychosis may be benefited by focusing on energy metabolism in the brain. In this context, lactate plays a major role, and has been shown to protect neurons against oxidative and other stressors. In particular, our data indicate chronic treatment with tandospirone, a partial 5-HT1A agonist, recover stress-induced lactate production in the prefrontal cortex of a rat model of schizophrenia. Recent advances of electrophysiological measures, e.g., event-related potentials, and their imaging have provided insights into facilitative effects on cognition of some AAPDs acting directly or indirectly on 5-HT1A receptors. These findings are expected to promote the development of novel therapeutics for the improvement of functional outcome in people with schizophrenia.

Improvement of dizocilpine-induced social recognition deficits in mice by brexpiprazole, a novel serotonin–dopamine activity modulator

“…Further studies of the effects of 5-HT 1A receptor agonists and antagonists on social recognition are needed. Previously, Sumiyoshi et al (2001aSumiyoshi et al ( , 2001bSumiyoshi et al ( , 2007 reported that treatment with tandospirone (or buspirone), 5-HT 1A receptor agonists, improved cognition including executive function and verbal learning in patients with schizophrenia, indicating a key role of 5-HT 1A receptor in cognition in patients (Meltzer and Sumiyoshi, 2008;Sumiyoshi et al, 2013). Taken together, it seems that brexpiprazole can ameliorate cognitive deficits associated with NMDA receptor dysfunction, via its 5-HT 1A agonistic activity.…”

Glutamatergic agents for schizophrenia: current evidence and perspectives

“…Similarly, the add-on treatment with APZ might be interesting because this SGA combines partial 5HT 1A agonism with complex effects on GABAergic and glutamatergic neurotransmission [72,174,175]. Agonism at 5HT 1A [176,177] as well as antagonistic effects at 5HT 6 and 5HT 7 receptors, as seen with asenapine and lurasidone, may exert pro-cognitive effects [178]. A third mode of augmentation might be add-on treatment trials to enhance psychotherapy because pro-glutamatergic substances might stimulate learning processes.…”

Design and synthesis of new homo and hetero bis-piperazinyl-1-propanone derivatives as 5-HT7R selective ligands over 5-HT1AR

“…Several studies of various classes of ligands with an arylpiperazine moiety in their structure have been reported and these efforts have led to successful drugs such as buspirone, perospirone, ziprasidone, and aripiprazole. [1][2][3][4] Generally, CNS agents with arylpiperazine-based template are characterized by three structural moieties (i.e. aryl group linked to the piperazine, alkyl chain with different length, heterocyclic terminal fragment), which can be modified to modulate specific properties such as pharmacokinetic, affinity, and selectivity for different targets (Fig.1).…”