Perspectives on the role of serotonergic mechanisms in the pharmacology of schizophrenia

Abstract

In recent years, a number of research findings has renewed interest in the possible role of serotonin (5-HT) in the pharmacology of schizophrenia. Atypical antipsychotics that potently block 5-HT receptors have been shown to be at least as effective as classical antipsychotics as well as producing fewer extrapyramidal side-effects. In addition, molecular biological studies have suggested that allelic variations of 5-HT receptor genes may affect both susceptibility to schizophrenia and clinical response to atypical antipsychotics. Building on these findings, this article proposes that 5-HT receptors are critical sites of antipsychotic action, and examines the implications of this to the treatment and pathophysiology of schizophrenia. Possible pharmacological mechanisms underlying the clinical efficacy of 5-HT blocking antipsychotics are discussed, and the potential of functional neuroimaging techniques to further elucidate these mechanisms is emphasized.

Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence

“…Thus, 5-HT 2 receptor blockade is most probably insufficient for antipsychotic activity but may well contribute to the overall efficacy and side effect profile, e.g., effects on negative symptoms or to a lower EPS potential, (e.g., Meltzer and Nash 1991;Busatto and Kerwin 1997). arAdrenoceptors. Unfortunately, no ligand is available for the study of a 1 -adrenoceptor occupancy by APDs.…”

Atypical antipsychotics in persons with developmental disabilities

“…Considerably more serotonin than dopamine receptor subtypes have been identified. A number of these receptors comprise the 5-HT1 and 5-HT2 families [Busatto and Kerwin, 1997]. Subtypes 5-HT3 through 5-HT7 complete the list of receptors identified to date (Table 1).…”

“…These findings have encouraged others to hypothesize that such augmentation occurring in the prefrontal cortex may be related to atypical neuroleptic effects on negative symptoms [Richelson, 1996]. By contrast, a recent review of serotonergic mechanisms in schizophrenia by Busatto and Kerwin [1997] described the possibility of a ''5-HT2 hypersensitivity,'' with alleviation of negative symptoms being more a direct consequence of serotonin receptor blockade. The authors go on to report, however, that later postmortem and other types of studies dispute this idea.…”

Serotonin Receptors Modulate GABAAReceptor Channels through Activation of Anchored Protein Kinase C in Prefrontal Cortical Neurons

“…Dysfunction of serotonergic neurotransmission has long been implicated in the pathogenesis of neuropsychiatric disorders, including schizophrenia, depression, and anxiety (Breier, 1995;Dubovsky and Thomas, 1995;Abi-Dargham et al, 1997;Stockmeier, 1997). Many effective drugs for these disorders act primarily on the serotonin system (Fuxe et al, 1983;Deakin, 1988;Griebel, 1995;Meltzer, 1995;Kapur and Remington, 1996;Busatto and Kerwin, 1997;Lieberman et al, 1998). One of the main target structures of the serotonergic system is prefrontal cortex (PFC), a brain region associated with high-level, "executive" processes needed for complicated goal-directed behavior (Goldman-Rakic, 1995;Miller, 1999).…”