ReviewDoes stimulation of 5-HT1A receptors improve cognition in schizophrenia?
Introduction
Cognitive impairment is almost universal in patients with schizophrenia, with over 85% of patients with this disorder showing clinically significant impairment in some but not all domains of cognition, including attention, working memory, declarative memory, speeded motor performance, and executive function [1]. It is well established that this impairment is the strongest determinant of functional outcome in schizophrenia [2]. Typical antipsychotic drugs have minimal benefit on cognition in schizophrenia in most studies (see Ref. [3] for review). Conversely, most, but not all studies have found that atypical antipsychotic drugs, e.g. aripiprazole, clozapine, quetiapine, olanzapine, risperidone, and ziprasidone have greater efficacy to improve cognition than the typical antipsychotic drugs, e.g. haloperidol [4], [5], [6]. These drugs share in common the ability to block serotonin (5-HT)2A receptors and to block dopamine (DA) receptor transmission. With the exception of aripiprazole and the main metabolite of clozapine, N-desmethylclozapine, which are partial DA agonists, they are D2 receptor antagonists, with affinities for the D2 receptor which are weaker than their affinities for the 5-HT2A receptors. We have summarized the evidence concerning differences among the atypical antipsychotic drugs with regard to their ability to improve cognition [4]. Head-to-head comparisons such as a recent study comparing clozapine and ziprasidone [7] sometimes show advantages for one atypical over another but there have been too few such studies to have confidence as to the findings.
There is considerable animal evidence in a variety of paradigms that atypical antipsychotic drugs are more effective than typical antipsychotic drugs in reversing deficits in tasks that involve working memory or long-term memory [8], [9]. In addition to being inverse agonists (antagonists) at 5-HT2A receptors, some atypical antipsychotic drugs, including aripiprazole, bifeprunox, clozapine, perospirone, quetiapine and ziprasidone are serotonin (5-HT)1A partial agonists, while others are inferred to be indirect 5-HT1A agonists in that some of the key actions, including the ability to enhance DA and acetylcholine (ACh) efflux in the medial prefrontal cortex, a region known to be important for cognition, are blocked by the 5-HT1A antagonist (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide (WAY100635) ([10], [11], [12]). However, these results have not been consistently replicated [13]. It has been suggested the 5-HT1A receptor stimulation can improve memory deficits in depression [14]. Some but not all of the atypical antipsychotic drugs are also 5-HT2C, 5-HT6, and 5-HT7 receptor antagonists. These 5-HT receptors, particularly the 5-HT2C and 5-HT6 receptors, may have an important role in cognition, through their ability to modulate the release of cortical and hippocampal DA and acetylcholine [15]. It is beyond the scope of this article to consider the roles of these other types of 5-HT receptors in mediating the action of atypical antipsychotic drugs to improve cognition. As will be discussed below, there is considerable evidence that 5-HT1A and 5-HT2A receptors have a reciprocal relationship on many neurobiological processes, including the activity of pyramidal neurons in cortex and hippocampus. It seems likely that for schizophrenia, the 5-HT2A receptor is more important than the 5-HT1A receptor in terms of both pathophysiology and mechanism of action of antipsychotic drugs, as there is more and more evidence accumulating for an intimate relationship between 5-HT2A receptor function and glutamatergic activity ([16]. Nevertheless, the role of 5-HT1A receptors remains of keen interest. Based upon these and other data to be considered below, there have now been several reviews of the role of 5-HT1A receptors in schizophrenia, including consideration of their importance for cognitive impairment [17], [18].
Section snippets
5-HT1A receptors and 5-HT1A agonist administration in schizophrenia
This background is relevant to understanding studies which have utilized buspirone, a 5-HT1A partial agonist introduced as an anxiolytic, in patients with schizophrenia receiving typical antipsychotic drugs, such as haloperidol [19], [20], [21], [22]. Most studies involving buspirone in doses of 10–100 mg/day, report a beneficial effect on psychotic symptoms or parkinsonism, or both [20], [21], [22]. These findings are supported by a small, randomized, placebo-controlled, double-blind study of
Acknowledgements
Supported, in part, by grants from NARSAD, the Weisman Foundation, Mr. and Mrs. Edward Hintz, and the Prentiss Foundation.
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