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      Brexpiprazole has a low risk of dopamine D 2 receptor sensitization and inhibits rebound phenomena related to D 2 and serotonin 5‐HT 2A receptors in rats

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          Abstract

          Background

          Long‐term antipsychotic treatment in patients with schizophrenia can induce supersensitivity psychosis and tardive dyskinesia which is thought to be caused by dopamine D 2 receptor sensitization. We evaluated the effects of brexpiprazole on D 2 receptor sensitivity after subchronic treatment in rats. We also evaluated whether brexpiprazole could suppress enhanced response to D 2 receptors in rats subchronically dosed with another atypical antipsychotic.

          Methods

          The maximum D 2 receptor density ( B max) and apomorphine (a D 2 receptor agonist)‐induced stereotypy were measured in rats orally dosed with vehicle, haloperidol (1 mg/kg), or brexpiprazole (4 or 30 mg/kg for B max, 6 or 30 mg/kg for stereotypy) for 21 days. Then, effects of oral administrations of brexpiprazole (3 mg/kg), aripiprazole (10 mg/kg), and olanzapine (3 mg/kg) against increases in apomorphine‐induced hyperlocomotion and (±)‐2,5‐dimethoxy‐4‐iodoamphetamine hydrochloride (DOI: a 5‐HT 2A receptor agonist)‐induced head twitches were evaluated in rats subcutaneously treated with risperidone (1.5 mg/kg/d) via minipumps for 21 days.

          Results

          Haloperidol and brexpiprazole (30 mg/kg: approximately tenfold ED 50 of anti‐apomorphine‐induced stereotypy) but not brexpiprazole (4 or 6 mg/kg) significantly increased the B max and apomorphine‐induced stereotypy. Brexpiprazole (3 mg/kg) and olanzapine (3 mg/kg) significantly suppressed both increases in apomorphine‐induced hyperlocomotion and also DOI‐induced head twitches in rats subchronically treated with risperidone, but aripiprazole (10 mg/kg) significantly suppressed only apomorphine‐induced hyperlocomotion.

          Conclusion

          Brexpiprazole has a low risk of D 2 receptor sensitization after a repeated administration and suppresses the rebound phenomena related to D 2 and 5‐HT 2A receptors after a repeated administration of risperidone.

          Abstract

          Brexpiprazole has less potential to evoke dopamine D2 receptor supersensitivity in rats after repeated administration compared to haloperidol. In addition, brexpiprazole may have a lower risk for producing rebound symptoms associated with D2 receptor, 5‐HT2A receptor sensitization when switching from other antipsychotics such as risperidone.

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          Rethinking schizophrenia.

          Thomas Insel (2010)
          How will we view schizophrenia in 2030? Schizophrenia today is a chronic, frequently disabling mental disorder that affects about one per cent of the world's population. After a century of studying schizophrenia, the cause of the disorder remains unknown. Treatments, especially pharmacological treatments, have been in wide use for nearly half a century, yet there is little evidence that these treatments have substantially improved outcomes for most people with schizophrenia. These current unsatisfactory outcomes may change as we approach schizophrenia as a neurodevelopmental disorder with psychosis as a late, potentially preventable stage of the illness. This 'rethinking' of schizophrenia as a neurodevelopmental disorder, which is profoundly different from the way we have seen this illness for the past century, yields new hope for prevention and cure over the next two decades.
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            Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.

            Stefan Leucht, Andrea Cipriani, Loukia Spineli … (2013)
            The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs. We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation. We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73-1·03; amisulpride 0·66, 0·53-0·78; olanzapine 0·59, 0·53-0·65; risperidone 0·56, 0·50-0·63; paliperidone 0·50, 0·39-0·60; zotepine 0·49, 0·31-0·66; haloperidol 0·45, 0·39-0·51; quetiapine 0·44, 0·35-0·52; aripiprazole 0·43, 0·34-0·52; sertindole 0·39, 0·26-0·52; ziprasidone 0·39, 0·30-0·49; chlorpromazine 0·38, 0·23-0·54; asenapine 0·38, 0·25-0·51; lurasidone 0·33, 0·21-0·45; and iloperidone 0·33, 0·22-0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from -0·09 for the best drug (haloperidol) to -0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to -1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to -0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses. Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines. None. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.

              Jeffrey A Lieberman, T. Stroup, Joseph P. McEvoy … (2005)
              The relative effectiveness of second-generation (atypical) antipsychotic drugs as compared with that of older agents has been incompletely addressed, though newer agents are currently used far more commonly. We compared a first-generation antipsychotic, perphenazine, with several newer drugs in a double-blind study. A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and randomly assigned to receive olanzapine (7.5 to 30 mg per day), perphenazine (8 to 32 mg per day), quetiapine (200 to 800 mg per day), or risperidone (1.5 to 6.0 mg per day) for up to 18 months. Ziprasidone (40 to 160 mg per day) was included after its approval by the Food and Drug Administration. The primary aim was to delineate differences in the overall effectiveness of these five treatments. Overall, 74 percent of patients discontinued the study medication before 18 months (1061 of the 1432 patients who received at least one dose): 64 percent of those assigned to olanzapine, 75 percent of those assigned to perphenazine, 82 percent of those assigned to quetiapine, 74 percent of those assigned to risperidone, and 79 percent of those assigned to ziprasidone. The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine (P<0.001) or risperidone (P=0.002) group, but not in the perphenazine (P=0.021) or ziprasidone (P=0.028) group. The times to discontinuation because of intolerable side effects were similar among the groups, but the rates differed (P=0.04); olanzapine was associated with more discontinuation for weight gain or metabolic effects, and perphenazine was associated with more discontinuation for extrapyramidal effects. The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons. Olanzapine was the most effective in terms of the rates of discontinuation, and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine, risperidone, and ziprasidone. Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism. Copyright 2005 Massachusetts Medical Society.
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                Author and article information

                Contributors
                Naoki Amada:
                ORCID: https://orcid.org/0000-0002-9625-6240
                amada.naoki@otsuka.jp
                Journal
                Journal ID (nlm-ta): Neuropsychopharmacol Rep
                Journal ID (iso-abbrev): Neuropsychopharmacol Rep
                Journal ID (doi): 10.1002/(ISSN)2574-173X
                Journal ID (publisher-id): NPR2
                Title: Neuropsychopharmacology Reports
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Electronic): 2574-173X
                Publication date (Electronic): 05 September 2019
                Publication date Collection: December 2019
                Volume: 39
                Issue: 4 ( doiID: 10.1002/npr2.v39.4 )
                Pages: 279-288
                Affiliations
                [ 1 ] Department of CNS Research Otsuka Pharmaceutical Co., Ltd. Tokushima Japan
                [ 2 ] Department of Lead Discovery Research Otsuka Pharmaceutical Co., Ltd. Tokushima Japan
                [ 3 ] Global Business Development Otsuka Pharmaceutical Development and Commercialization, Ltd. Princeton New Jersey
                [ 4 ] Global CNS Business Otsuka Pharmaceutical Development and Commercialization, Ltd. Princeton New Jersey
                [ 5 ] Pharmaceutical Division Otsuka Pharmaceutical Co., Ltd. Tokushima Japan
                Author notes
                [*] [* ] Correspondence

                Naoki Amada, Department of CNS Research, Otsuka Pharmaceutical Co., Ltd., 463‐10 Kagasuno, Kawauchi‐cho, Tokushima, 771‐0192, Japan.

                Email: amada.naoki@ 123456otsuka.jp

                Author information
                https://orcid.org/0000-0002-9625-6240
                Article
                Publisher ID: NPR212076
                DOI: 10.1002/npr2.12076
                PMC ID: 7292306
                PubMed ID: 31487433
                SO-VID: 5289ba0d-e0f6-4bd1-a077-f75747283fd2
                Copyright © © 2019 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of NeuropsychoPharmacology.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                Date received : 05 June 2019
                Date revision received : 24 July 2019
                Date accepted : 02 August 2019
                Page count
                Figures: 4, Tables: 3, Pages: 10, Words: 7047
                Funding
                Funded by: Otsuka Pharmaceutical , open-funder-registry 10.13039/501100007132;
                Categories
                Subject: Original Article
                Subject: Original Articles
                Custom metadata
                source-schema-version-number 2.0
                cover-date December 2019
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.4 mode:remove_FC converted:11.06.2020

                Keywords: antipsychotic drug,brexpiprazole,d2 receptor partial agonist,rebound symptoms,receptor sensitization
                Data availability:
                Keywords: antipsychotic drug, brexpiprazole, d2 receptor partial agonist, rebound symptoms, receptor sensitization

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