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Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties. (REVIEW)

Newman-Tancredi A., Kleven M.S.

Psychopharmacology (Berl). 2011 Mar 11. [Epub ahead of print].


RATIONALE: There is increasing interest in antipsychotics intended to manage positive symptoms via D2 receptor blockade and improve negative symptoms and cognitive deficits via 5-HT1A activation. Such a strategy reduces side-effects such as the extrapyramidal syndrome (EPS), weight gain, and autonomic disturbance liability.

OBJECTIVE: This study aims to review pharmacological literature on compounds interacting at both 5-HT1A and D2 receptors (as well as at other receptors), including aripiprazole, perospirone, ziprasidone, bifeprunox, lurasidone and cariprazine, PF-217830, adoprazine, SSR181507, and F15063.

METHODS: We examine data on in vitro binding and agonism and in vivo tests related to (1) positive symptoms (e.g., psychostimulant-induced hyperactivity or prepulse inhibition deficit), (2) negative symptoms (e.g., phencyclidine-induced social interaction deficits and cortical dopamine release), and (3) cognitive deficits (e.g., phencyclidine or scopolamine-induced memory deficits). EPS liability is assessed by measuring catalepsy and neuroendocrine impact by determining plasma prolactin, glucose, and corticosterone levels.

RESULTS: Compounds possessing "balanced" 5-HT1A receptor agonism and D2 antagonism (or weak partial agonism) and, in some cases, combined with other beneficial properties, such as 5-HT2A receptor antagonism, are efficacious in a broad range of rodent pharmacological models yet have a lower propensity to elicit EPS or metabolic dysfunction.

CONCLUSIONS: Recent compounds exhibiting combined 5-HT1A/D2 properties may be effective in treating a broader range of symptoms of schizophrenia and be better tolerated than existing antipsychotics. Nevertheless, further investigations are necessary to evaluate recent compounds, notably in view of their differing levels of 5-HT1A affinity and efficacy, which can markedly influence activity and side-effect profiles.