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

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Abstract

Rationale

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.

Methods

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.

Results and conclusions

Four 5-HT receptor systems (5-HT1A, 5-HT2A, 5-HT4, 5-HT6) are highlighted as suitable targets for enhancing cognition and memory. Because many clinically available antipsychotic drugs already target 5-HT1A, 5-HT2A and 5-HT6 receptors, design of clinical trials will need to take into account the serotonergic pharmacology of concurrently administered antipsychotic medications. 5-HT1A partial agonists and 5-HT2A 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.

Recommendations

For stand-alone therapy for enhancing cognition, 5-HT1A partial agonists, 5-HT2A 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).

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Acknowledgements

This work was supported by the NIMH Psychoactive Drug Screening Program (NO1MH80005) and KO2MH01366 to B.L.R.

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  1. Departments of Biochemistry, Psychiatry and Neurosciences and NIMH Psychoactive Drug Screening Program, Case Western Reserve University Medical School, 2109 Adelbert Road, Cleveland, OH, 44106, USA

    Bryan L. Roth, S. Mohammad Hanizavareh & Andrew E. Blum

  2. Department of Biochemistry, Case Western Reserve University Medical School, 2109 Adelbert Road, Cleveland, OH, 44106, USA

    Bryan L. Roth

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Roth, B.L., Hanizavareh, S.M. & Blum, A.E. Serotonin receptors represent highly favorable molecular targets for cognitive enhancement in schizophrenia and other disorders. Psychopharmacology 174, 17–24 (2004). https://doi.org/10.1007/s00213-003-1683-8

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