Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders

Abstract

Current treatments for schizophrenia adequately treat the positive symptoms of schizophrenia but only modestly improve cognitive deficits. This review provides evidence for and against the use of selective 5-HT receptor drugs as cognition enhancing agents for schizophrenia and other disorders. Pre-clinical and clinical literature concerned with the role of the serotonergic system in cognition and memory as it relates to schizophrenia is reviewed. Individual 5-HT receptor subtypes for which selective drugs are available that are likely to improve cognition are reviewed. Recommendations for clinical testing are proposed. Four 5-HT receptor systems (5-HT_1A, 5-HT_2A, 5-HT₄, 5-HT₆) are highlighted as suitable targets for enhancing cognition and memory. Because many clinically available antipsychotic drugs already target 5-HT_1A, 5-HT_2A and 5-HT₆ receptors, design of clinical trials will need to take into account the serotonergic pharmacology of concurrently administered antipsychotic medications. 5-HT_1A partial agonists and 5-HT_2A antagonists have shown modest effectiveness in improving cognition in schizophrenia. 5-HT₆-selective compounds for cognition enhancement are in late-stage clinical trials, while 5-HT₄ compounds have not yet been tested in humans for cognition enhancement. For stand-alone therapy for enhancing cognition, 5-HT_1A partial agonists, 5-HT_2A antagonists, 5-HT₄ partial agonists and 5-HT₆ antagonists are all likely to induce at least modest improvement in cognition in schizophrenia. If “add-on therapy” is contemplated, antipsychotic drugs with weak affinities for serotonin receptors should be used to avoid confounds. It is likely that serotonergic drugs will soon be available as cognition enhancing medications for disorders other than schizophrenia (e.g. dementia).