Abstract
The relationship between clinically effective antipsychotic drug dosage and binding affinity to cloned dopamine (DA) and serotonin receptor subtypes was analyzed in an effort to elucidate the contribution of individual receptor subtypes to medication response. Clinically effective dose and binding affinity to D2 DA receptor were modestly correlated for typical antipsychotic medications (r=0.54, p=0.046), but surprisingly were not correlated for atypical antipsychotics (r=0.41, p=0.31). For typical antipsychotics, a more robust inverse relationship was observed between medication dose and 5-HT2C affinity (r=−0.68, p=0.021). The strongest correlation for typical antipsychotics was observed between drug dosage and 5-HT2C/D2 binding affinity ratio (r=−0.81, p=0.003). For atypical antipsychotics, no significant correlations were identified between medication dosage and 5-HT2C, 5-HT2A, 5-HT2C/D2, or 5-HT2A/D2 receptor-binding affinities. In contrast, atypical antipsychotic medication dosage was highly correlated with the ratios of D2 (5-HT2A/5-HT1A) (r=0.80, p=0.031), and D2 (5-HT2C/5-HT1A) (r=0.78, p=0.038) binding affinities. These observations demonstrate an interaction between D2 and 5-HT2C receptor effects contributing to positive symptom response for typical antipsychotic medications, suggesting that signaling through 5-HT2C receptors interacts with and improves antipsychotic effects achieved via D2 receptor blockade. This analysis also demonstrates that, in contrast to typical antipsychotics, therapeutic effects of atypical antipsychotic medications are determined by opposing interactions among three different domains: (1) increasing D2 DA receptor-binding affinity enhances antipsychotic potency. (2) Increasing 5-HT2C and 5-HT2A receptor-binding affinities also facilitate antipsychotic efficacy. (3) Increasing 5-HT1A receptor-binding affinity, in contrast, reduces antipsychotic efficacy.
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This work was supported by the Department of Veterans Affairs Medical Research Service, and by a NARSAD Essel Investigator Award (NMR).
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The authors disclose the following relationships, which might potentially bias this work:
Neil M Richtand: Grant support: Janssen, AstraZeneca
Speaker's bureaus: Bristol-Myers Squibb, Pfizer, and Otsuka America Pharmaceutical.
Consultant: Solvay Pharmaceuticals
Stephen M Strakowski: Grant support: Eli Lilly, Janssen, Pfizer, Forrest, AstraZeneca, Bristol-Myers Squibb
Consultant: OrthoMcNeil, Pfizer
Speaker's bureaus: Eli Lilly, Janssen, Pfizer, Forrest, AstraZeneca, Bristol-Myers Squibb, OrthoMcNeil
Paul E Keck Jr: Grant support: principal or co-investigator on research studies sponsored by: Abbott Laboratories, the American Diabetes Association, AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Eli Lilly, Janssen Pharmaceutica, Memory Pharmaceuticals, Merck, National Institute of Mental Health (NIMH), National Institute of Drug Abuse (NIDA), Organon, Ortho-McNeil, Pfizer, the Stanley Medical Research Institute (SMRI), and UCB Pharma.
Dr Keck is a consultant to, or member of the scientific advisory boards of: Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Janssen Pharmceutica, Eli Lilly and Company, Memory Pharmaceuticals, Neurocrine Biosciences, Ortho-McNeil, Pfizer, and Shire.
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Richtand, N., Welge, J., Logue, A. et al. Dopamine and Serotonin Receptor Binding and Antipsychotic Efficacy. Neuropsychopharmacol 32, 1715–1726 (2007). https://doi.org/10.1038/sj.npp.1301305
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DOI: https://doi.org/10.1038/sj.npp.1301305
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