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Optimal Extent of Dopamine D2 Receptor Occupancy by Antipsychotics for Treatment of Dopamine Supersensitivity Psychosis and Late-Onset Psychosis

Iyo, Masaomi MD, PhD*†; Tadokoro, Shigenori MD*; Kanahara, Nobuhisa MD, PhD*; Hashimoto, Tasuku MD, PhD*; Niitsu, Tomihisa MD, PhD; Watanabe, Hiroyuki MD, PhD*; Hashimoto, Kenji PhD

Journal of Clinical Psychopharmacology: June 2013 - Volume 33 - Issue 3 - p 398–404
doi: 10.1097/JCP.0b013e31828ea95c
Review Article

Several studies have proposed an optimal dopamine D2 receptor occupancy by antipsychotics (OOc) to establish optimal pharmacological treatment of schizophrenia. However, there are limitations to the use of the OOc, especially in application to patients with treatment-resistant schizophrenia, including dopamine supersensitivity psychosis (DSP) or late-onset psychosis (LOP). It has been suggested that D2 receptor density is up-regulated by chronic treatment of antipsychotics in DSP, whereas it may be low in LOP owing to age-related reduction. In estimation of the proposed OOc, these alterations have not been taken into account, which may be one of the factors contributing to the limited application of this index. We here hypothesize that there is an optimal range in the number of D2 receptors available for dopamine binding to elicit adequate neurotransmission in the treatment of patients with schizophrenia. We then estimated the OOc under the assumption that the range is constant while D2 density is variable. The results showed that the OOc and plasma level of antipsychotics increase with an increase in the D2 density but decrease with a decrease in the D2 density. That is, if the range of OOc is 65% to 78% in a standard D2 density, it becomes 82% to 89% under 2-fold up-regulated density and 42% to 63% under a 40% reduced density. The results also indicated that the reduction of the plasma antipsychotic level is greater during a given time period in patients with higher D2 density, as they need a higher antipsychotic dose to achieve the raised OOc, which would account for the clinical features of DSP, for example, acute exacerbation after a discontinuation of antipsychotics. On the other hand, in patients with lower D2 density, only a lower antipsychotic dose will achieve the OOc, and a small increase in the dose will result in a greater increase in occupancy and induce extrapyramidal adverse effects more easily. Furthermore, the reduction of the plasma antipsychotic level during the time period is smaller, which prolongs extrapyramidal adverse effects after discontinuation of antipsychotics in LOP. We also attempted to develop a strategy for the prevention and treatment of patients with DSP or LOP by focusing on D2 density.

From the *Department of Psychiatry, Graduate School of Medicine, †Division of Clinical Neuroscience, Center for Forensic Mental Health, and ‡Research Center for Child Mental Development, Graduate School of Medicine, Chiba University, Chiba, Japan.

Received September 28, 2011; accepted after revision October 9, 2012.

Reprints: Masaomi Iyo, MD, PhD, 1-8-1 Inohana, Chiba 260-8670, Japan (e-mail:

© 2013 Lippincott Williams & Wilkins, Inc.