Antipsychotic-induced dopamine supersensitivity (DS) psychosis in schizophrenia was first reported by Guy Chouinard in 1978. With the advent of clozapine in the USA in 1990, concerns about this disease abated somewhat within the psychiatric community. However, in Japan, clozapine was introduced in 2009, a full 19 years after the introduction in the USA, and Japan is known to have extremely long psychiatric hospitalizations with very high doses of antipsychotic drugs. Therefore, we started to research treatment-resistant schizophrenia (TRS), with a focus on DS psychosis, in 2010. Currently, the importance of DS psychosis in antipsychotic treatment is again being recognized worldwide (see the Figure below; Harrow M, et al., Psychol Med. 2021; Kane JM, et al., J Clin Psychiatry 2019; Yin J, et al., Curr Neuropharmacol. 2017; Murray R, et al., Br J Psychiatry 2016; Lally J, et al., Psychol Med. 2016).

We found that chronic haloperidol administration increased dopamine D2 receptor (DRD2) density and dopamine supersensitivity (DS) behavior, whereas aripiprazole (ARP), a dopamine partial agonist (DPA), induced no change in DRD2 density or DS behavior in rats (1). We concluded that DS could be developed by excessive blockade of DRD2 and dopamine depletion due to haloperidol-induced depolarization block. Furthermore, we found that chronic administration of ARP to haloperidol-induced DS rats reduced DRD2 density and DS behavior (1), meaning that ARP administration even at a dose that did not change the DRD2 density in normal rats resulted in an excessive enhancement of dopamine signals via DRD2 in DS rats, and thereby a downregulation of DRD2 density. We also suggest that DS psychosis is difficult to treat with conventional antipsychotic treatment and should be categorized into TRS.

Based on these results, we proposed the following hypothesis about DS psychosis in 2013 (2): Maintaining an optimal occupancy of DRD2 by antipsychotics is important in the treatment of schizophrenia, because excessive blocking of DRD2 increases DRD2 density, leading to DS psychosis and TRS; the optimal DRD2 occupancy is higher in the DS state, which is associated with susceptibility to recurrence and instability of psychotic symptoms; stable blocking within the increased optimal occupancy by antipsychotics improves unstable DS psychosis; DPAs and electroconvulsive therapy (ECT) lead to DRD2 downregulation, resulting in release from the DS state; and clozapine is useful as a therapeutic drug.

We have been conducting clinical and basic research and have reported data in support of the above-described hypothesis and related reviews. The topics of these studies are as follows:

1) elucidating the mechanisms (1-5)
2) the prevalence of DS psychosis in TRS (6, 7) [about 70% of TRS is DS psychosis in Japan]
3) efficacy of long-acting injectable antipsychotics for DS psychosis (8-10)
4) efficacy of high-lipophilic second generation for DS psychosis (11, 12)
5) clozapine for DS psychosis (13, 14)
6) aripiprazole and DS psychosis (15-18)
7) downregulation of DRD2 density and extinction of DS behavior by ECT (19).
8) studies on gene polymorphisms associated with DS psychosis (20-23).
9) review and concept of DS psychosis (24-28)
The figure below shows the time course of the number of publications related to supersensitivity psychosis based on a PubMed search as of 23 June 2021; our contribution to the present wave of interest in DS psychosis is shown in red. Today, DS psychosis has once again garnered attention worldwide and is being widely researched from the viewpoint of better antipsychotic treatments. Our DS psychosis research has also influenced the development of new antipsychotic drugs by pharmaceutical companies.

References

1. Tadokoro S, Okamura N, Sekine Y, Kanahara N, Hashimoto K, Iyo M. Chronic treatment with aripiprazole prevents development of dopamine supersensitivity and potentially supersensitivity psychosis. Schizophr Bull. 2012 Sep;38(5):1012-20.
2. Iyo M, Tadokoro S, Kanahara N, Hashimoto T, Niitsu T, Watanabe H, Hashimoto K. Optimal extent of dopamine D2 receptor occupancy by antipsychotics for treatment of dopamine supersensitivity psychosis and late-onset psychosis. J Clin Psychopharmacol. 2013 Jun;33(3):398-404.
3. Oda Y, Fujita Y, Oishi K, Nakata Y, Takase M, Niitsu T, Kanahara N, Shirayama Y, Hashimoto K, Iyo M.　Alterations in glutamatergic signaling in the brain of dopamine supersensitivity psychosis and non-supersensitivity psychosis model rats.　Psychopharmacology (Berl). 2017 Oct;234(20):3027-3036.
4. Oda Y, Tadokoro S, Takase M, Kanahara N, Watanabe H, Shirayama Y, Hashimoto K, Iyo M.　G protein-coupled receptor kinase 6/beta-arrestin 2 system in a rat model of dopamine supersensitivity psychosis.　J Psychopharmacol. 2015 Dec;29(12):1308-13.
5. Kimura M, Oda Y, Kimura H, Nangaku M, Hirose Y, Niitsu T, Kanahara N, Shirayama Y, Hashimoto K, Iyo M.　Reduction of dopamine and glycogen synthase kinase-3 signaling in rat striatum after continuous administration of haloperidol.　Pharmacol Biochem Behav. 2021 Mar;202:173114.
6. Suzuki T, Kanahara N, Yamanaka H, Takase M, Kimura H, Watanabe H, Iyo M. Dopamine supersensitivity psychosis as a pivotal factor in treatment-resistant schizophrenia. Psychiatry Res. 2015 Jun 30;227(2-3):278-82.
7. Yamanaka H, Kanahara N, Suzuki T, Takase M, Moriyama T, Watanabe H, Hirata T, Asano M, Iyo M. Impact of dopamine supersensitivity psychosis in treatment-resistant schizophrenia: An analysis of multi-factors predicting long-term prognosis. Schizophr Res. 2016 Feb;170(2-3):252-8.
8. Kimura H, Kanahara N, Watanabe H, Iyo M. Potential treatment strategy of risperidone in long-acting injectable form for schizophrenia with dopamine supersensitivity psychosis. Schizophr Res. 2013 Apr;145(1-3):130-1.
9. Kimura H, Kanahara N, Komatsu N, Ishige M, Muneoka K, Yoshimura M, Yamanaka H, Suzuki T, Komatsu H, Sasaki T, Hashimoto T, Hasegawa T, Shiina A, Ishikawa M, Sekine Y, Shiraishi T, Watanabe H, Shimizu E, Hashimoto K, Iyo M. A prospective comparative study of risperidone long-acting injectable for treatment-resistant schizophrenia with dopamine supersensitivity psychosis. Schizophr Res. 2014 May;155(1-3):52-8.
10. Kimura H, Kanahara N, Sasaki T, Komatsu N, Ishige M, Muneoka K, Ino H, Yoshimura K, Yamanaka H, Suzuki T, Komatsu H, Watanabe H, Shimizu E, Iyo M. Risperidone long-acting injectable in the treatment of treatment-resistant schizophrenia with dopamine supersensitivity psychosis: Results of a 2-year prospective study, including an additional 1-year follow-up. J Psychopharmacol. 2016 Aug;30(8):795-802.
11. Tachibana M, Niitsu T, Watanabe M, Hashimoto T, Kanahara N, Ishikawa M, Iyo M. Effectiveness of blonanserin for patients with drug treatment-resistant schizophrenia and dopamine supersensitivity: A retrospective analysis. Asian J Psychiatr. 2016 Dec;24:28-32.
12. Niitsu T, Hata T, Nishimoto M, Hosoda Y, Kimura A, Oda Y, Suzuki M, Takase N, Seki R, Fujita K, Endo M, Yoshida T, Inoue M, Hattori N, Murakami T, Imamura Y, Ogawa K, Fukami G, Sato T, Kawasaki Y, Hashimoto T, Ishikawa M, Shiina A, Kanahara N, Iyo M; ROADS Study Group. A randomized-controlled trial of blonanserin and olanzapine as adjunct to antipsychotics in the treatment of patients with schizophrenia and dopamine supersensitivity psychosis: The ROADS study. Asian J Psychiatr. 2020 Oct;53:102369.
13. Nakata Y, Kanahara N, Kimura H, Watanabe H, Iyo M. Efficacy of clozapine on dopamine supersensitivity psychosis in schizophrenia. Int Clin Psychopharmacol. 2017 May;32(3):169-173.
14. Kobayashi R, Oda Y, Hayatsu R, Ohki N, Akutsu M, Oiwa T, Komatsu H, Niitsu T, Sasaki T, Iyo M. Successful rechallenge with paliperidone after clozapine treatment for a patient with dopamine supersensitivity psychosis. SAGE Open Med Case Rep. 2020 Jun 7;8:2050313X20929561.
15. Takase M, Kanahara N, Oda Y, Kimura H, Watanabe H, Iyo M. Dopamine supersensitivity psychosis and dopamine partial agonist: a retrospective survey of failure of switching to aripiprazole in schizophrenia. J Psychopharmacol. 2015 Apr;29(4):383-9.
16. Tadokoro S, Nonomura N, Kanahara N, Hashimoto K, Iyo M. Reduction of Severity of Recurrent Psychotic Episode by Sustained Treatment with Aripiprazole in a Schizophrenic Patient with Dopamine Supersensitivity: A Case Report. Clin Psychopharmacol Neurosci. 2017 Feb 28;15(1):79-81.
17. Kanahara N, Hirabayashi M, Mamada T, Nishimoto M, Iyo M. Combination therapy of electroconvulsive therapy and aripiprazole for dopamine supersensitivity psychosis. Schizophr Res. 2018 Dec;202:398-400.
18. Kanahara N, Takase M, Sasaki T, Honma M, Fujita Y, Tadokoro S, Suzuki H, Yamanaka H, Noda S, Yanahashi S, Saiga T, Komatsu N, Simoyama T, Iyo M. The effectiveness of very slow switching to aripiprazole in schizophrenia patients with dopamine supersensitivity psychosis: a case series from an open study. Int Clin Psychopharmacol. 2020 Nov;35(6):338-344. doi: 10.1097/YIC.0000000000000322.
19. Kimura M, Oda Y, Oishi K, Yoshino K, Kimura H, Niitsu T, Kanahara N, Shirayama Y, Hashimoto K, Iyo M. Effects of repeated electroconvulsive shocks on dopamine supersensitivity psychosis model rats. Schizophr Res. 2021 Feb;228:1-6.
20. Oda Y, Kanahara N, Kimura H, Watanabe H, Hashimoto K, Iyo M. Genetic association between G protein-coupled receptor kinase 6/beta-arrestin 2 and dopamine supersensitivity psychosis in schizophrenia. Neuropsychiatr Dis Treat. 2015 Jul 29;11:1845-51.
21. Takase M, Kanahara N, Oda Y, Niitsu T, Watanabe H, Iyo M. The impacts of dopamine D2 receptor polymorphism and antipsychotic dosage on dopamine supersensitivity psychosis in schizophrenia. Schizophr Res. 2017 Dec;190:182-183.
22. Oishi K, Kanahara N, Takase M, Oda Y, Nakata Y, Niitsu T, Ishikawa M, Sato Y, Iyo M. Vulnerable combinations of functional dopaminergic polymorphisms to late-onset treatment resistant schizophrenia. PLoS One. 2018 Nov 8;13(11):e0207133.
23. Kanahara N, Yoshimura K, Nakamura M, Oda Y, Watanabe M, Iyo M. Metabolism of risperidone by CYP2D6 and the presence of drug-induced dopamine supersensitivity psychosis in patients with schizophrenia. Int Clin Psychopharmacol. 2019 May;34(3):124-130.
24. Oda Y, Kanahara N, Iyo M. Alterations of Dopamine D2 Receptors and Related Receptor-Interacting Proteins in Schizophrenia: The Pivotal Position of Dopamine Supersensitivity Psychosis in Treatment-Resistant Schizophrenia. Int J Mol Sci. 2015 Dec 17;16(12):30144-63.
25. Chouinard G, Samaha AN, Chouinard VA, Peretti CS, Kanahara N, Takase M, Iyo M. Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy. Psychother Psychosom. 2017;86(4):189-219.
26. Nakata Y, Kanahara N, Iyo M. Dopamine supersensitivity psychosis in schizophrenia: Concepts and implications in clinical practice. J Psychopharmacol. 2017 Dec;31(12):1511-1518.
27. Kimura H, Kanahara N, Iyo M. Rationale and neurobiological effects of treatment with antipsychotics in patients with chronic schizophrenia considering dopamine supersensitivity. Behav Brain Res. 2021 Apr 9;403:113126.
28. Kanahara N, Kimura H, Oda Y, Ito F, Iyo M. Recent discussions on dopamine supersensitivity psychosis: Eight points to consider when diagnosing treatment-resistant schizophrenia. Curr Neuropharmacol. 2021 Jan 25.