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Kim E, Kim S, Kim SW, Nam BW, Lee KU, Lee BJ, Won SH, Lee CH, Jung SW, In Kim S, Cho SJ, Chung YC, Choi TK, Cheon EJ, Baek JH, Correll CU, Kwon JS. Stability of psychotic symptoms and safety in switching to aripiprazole once-monthly according to prior oral antipsychotic drugs. Schizophr Res 2025; 281:180-190. [PMID: 40382834 DOI: 10.1016/j.schres.2025.04.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2024] [Revised: 04/17/2025] [Accepted: 04/28/2025] [Indexed: 05/20/2025]
Abstract
Long-acting injectable aripiprazole has substantiated safety and efficacy in treating schizophrenia. However, interindividual variability in clinical response to aripiprazole, possibly linked to its D2 partial agonism and D2 upregulation due to prior antipsychotics, has been reported. This study assessed whether there would be symptomatic aggravations or adverse events in clinically stable patients with schizophrenia when switching from oral antipsychotics to aripiprazole once-monthly (AOM), considering prior antipsychotics: oral aripiprazole (Group I) or other D2 antagonists (Group II). This was a 20-week, prospective, open-label, multicenter trial. Clinically stable patients with schizophrenia were assigned to two groups based on their oral antipsychotic medication and received AOM every 4 weeks. The primary endpoint was a change from baseline in the total Positive and Negative Syndrome Scale (PANSS) score. Treatment-emergent adverse events (TEAEs) were monitored. Altogether, 100 patients in Group I and 101 in Group II completed the study. The mean changes (±SD) from baseline in PANSS total score after switching to AOM were - 9.43 ± 9.79 in Group I (p < 0.0001) and - 4.04 ± 8.72 in Group II (p = 0.0102). Compared to Group I, in Group II, more sleep disturbance (p = 0.0243) and psychotic symptoms (p = 0.0042) TEAE emerged after AOM initiation, with both TEAEs resolving during the study. Psychotic symptoms TEAE was associated with faster tapering of the prior oral antipsychotics (p = 0.0269). Initiating AOM did not aggravate symptoms. Furthermore, AOM ameliorated psychotic symptoms without any significant adverse effect, regardless of their prior oral antipsychotics. However, patients previously treated with D2 antagonists may experience transient psychiatric TEAEs that can be minimized with longer cross-titration.
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Affiliation(s)
- Euitae Kim
- Department of Psychiatry, College of Medicine, Seoul National University, Seoul, Republic of Korea; Department of Brain & Cognitive Sciences, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea; Department of Neuropsychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea
| | - Seoyoung Kim
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea
| | - Sung-Wan Kim
- Department of Psychiatry, Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Beom-Woo Nam
- Department of Psychiatry, Konkuk University School of Medicine, Konkuk University Chungju Hospital, Chungju, Republic of Korea
| | - Kyoung-Uk Lee
- Department of Psychiatry, The Catholic University of Korea Uijeongbu St. Mary's Hospital, Uijeongbu, Republic of Korea
| | - Bong Ju Lee
- Department of Psychiatry, Inje University Haeundae Paik Hospital, Inje University College of Medicine, Busan, Republic of Korea
| | - Seung-Hee Won
- Department of Psychiatry, Kyungpook National University School of Medicine, Daegu, Republic of Korea
| | - Chang Hwa Lee
- Department of Psychiatry, Eulji University School of Medicine, Eulji University Hospital, Daejeon, Republic of Korea
| | - Sung Won Jung
- Department of Psychiatry, Keimyung University Dongsan Medical Center, Daegu, Republic of Korea
| | - Soo In Kim
- Department of Psychiatry, Ewha Womans University College of Medicine, Seoul, Republic of Korea
| | - Sung Joon Cho
- Department of Psychiatry, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young-Chul Chung
- Department of Psychiatry, Jeonbuk National University Medical School, Jeonju, Republic of Korea
| | - Tai Kiu Choi
- Department of Psychiatry, CHA Bundang Medical Center, CHA University, Gyeonggi-do, Republic of Korea
| | - Eun-Jin Cheon
- Department of Psychiatry, Yeungnam University College of Medicine, Yeungnam University Medical Center, Daegu, Republic of Korea
| | - Ji Hyun Baek
- Department of Psychiatry, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Christoph U Correll
- Department of Psychiatry, The Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY, USA; Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA; Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin Berlin, Berlin, Germany; German Center for Mental Health (DZPG), partner site Berlin, Germany
| | - Jun Soo Kwon
- Institute of Human Behavioral Science, Seoul National University-Medical Research Center, Seoul, Republic of Korea; Department of Psychiatry, Hanyang University Hospital, Seoul, Republic of Korea.
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Shoae-Hagh P, Razavi BM, Sadeghnia HR, Mehri S, Karimi G, Hosseinzadeh H. Molecular and Behavioral Neuroprotective Effects of Clavulanic Acid and Crocin in Haloperidol-Induced Tardive Dyskinesia in Rats. Mol Neurobiol 2025; 62:5156-5182. [PMID: 39520654 DOI: 10.1007/s12035-024-04566-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Accepted: 10/18/2024] [Indexed: 11/16/2024]
Abstract
Clavulanic acid (ClvA), a beta-lactamase inhibitor, is being explored for its significant neuroprotective potential. The effects of ClvA were assessed both individually and in combination with crocin (Cr), an antioxidant derived from saffron, in the context of tardive dyskinesia (TD). In rat haloperidol (Hp)-induced-TD (1 mg/kg, i.p. 21 days), the effects of ClvA (50, 100, 150 mg/kg) and Cr (10, 20, 40 mg/kg) were assessed via vacuous chewing movements (VCM) and tongue protrusion (TP). Striatal malondialdehyde (MDA) and glutathione (GSH) were measured spectrophotometrically. Based on the results, ClvA (100 mg/kg) and Cr (10 mg/kg) were determined with sub-effective doses. Glutamate transporter-subtype1 (GLT1), dopamine active transporter (DAT), vesicular monoamine transporter-type2 (VMAT2), Bax/Bcl2, cleaved Caspase3, phosphorylated AKT/AKT, IL1β, and TNFα levels were quantified using western blotting in sub-effective doses and their combination. The behavioral results of catalepsy and orofacial dyskinesia demonstrated model establishment. Hp decreased GLT1 (p < 0.05), DAT (p < 0.01), VMAT2 (p < 0.001), GSH and pAKT/AKT (p < 0.0001); increased TNFα (p < 0.05), IL1β, cleaved Caspase3 (p < 0.001); MDA and Bax/Bcl2 (p < 0.0001). ClvA 100 mg/kg reversed the decreased GLT1 and VMAT2 (p < 0.01), alongside the increased MDA (p < 0.0001) and VCM (p < 0.05). It also increased AKT phosphorylation (p < 0.05). No effects were noted on DAT, GSH, Bax/Bcl2, or inflammatory factors. However, the combination with Cr at 10 mg/kg influenced ClvA on DAT (p < 0.01) and resulted in a significant increase in GSH (p < 0.0001). Additionally, there was a marked decrease in TNFα (p < 0.0001) and IL1β (p < 0.001), enhancing its effects on reducing MDA and increasing pAKT/AKT (p < 0.0001). The combination adversely affected GLT1. ClvA protects against TD via GLT1 and VMAT2; combined with Cr, it enhances antioxidant effects, improves DAT, and requires dose optimization for GLT1 disruption.
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Affiliation(s)
- Parisa Shoae-Hagh
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bibi Marjan Razavi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Hamid Reza Sadeghnia
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Division of Neurocognitive Sciences, Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Soghra Mehri
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Centre, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gholamreza Karimi
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Centre, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
- Pharmaceutical Research Centre, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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Tiihonen J, Tanskanen A, Solmi M, Rubio JM, Correll CU, Kane JM, Taipale H. Continuous Dopamine D 2 Receptor Blockade and Long-Term Outcome in First-Episode Schizophrenia. Am J Psychiatry 2025; 182:341-348. [PMID: 39967411 DOI: 10.1176/appi.ajp.20240321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/20/2025]
Abstract
OBJECTIVE It is not known what proportion of patients experience relapse in first-episode schizophrenia despite continuous dopamine D2 receptor blockade and whether breakthrough psychosis is attributable to long-term use of D2-blocking antipsychotics. Using data from a Finnish nationwide cohort, the authors sought to test the hypothesis that the incidence of breakthrough psychosis is accelerated among previously relapse-free patients receiving continuous D2 antagonist treatment beyond 5 years. METHODS All persons age 45 years or younger with first-episode schizophrenia were identified from the nationwide registry of inpatient care for the years 1996-2014. The primary outcome was a severe relapse leading to hospitalization among those treated continuously with long-acting injectable (LAI) antipsychotics. The secondary outcome was the incidence rate ratio (IRR) of relapse during years 2-10, using year 1 as the reference. RESULTS A total of 305 patients initiated ensured LAI use during the first 30 days of follow-up. Kaplan-Meier analysis showed that during the 10-year follow-up, their cumulative probability of relapse was 45% (95% CI=35-57). The annual relapse incidence per person-year decreased from 0.26 (95% CI=0.20-0.35) during the first year to 0.05 (95% CI=0.01-0.19) during the fifth year, corresponding to an IRR of 0.18 (95% CI=0.04-0.74). During years 6-10, only four relapses occurred during 128 person-years, corresponding to an IRR of 0.12 (95% CI=0.03-0.33) compared with year 1. CONCLUSIONS About 40%-50% of patients with first-episode schizophrenia will relapse despite continuous D2 blockade, apparently due to non-dopaminergic elements of the pathophysiology of the illness, as the results show that long-term dopamine receptor blockade is not associated with an increased risk of breakthrough psychosis.
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Affiliation(s)
- Jari Tiihonen
- Department of Forensic Psychiatry, University of Eastern Finland, and Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Tiihonen, Tanskanen, Taipale); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen, Tanskanen, Taipale); SCIENCES Lab and Department of Psychiatry, University of Ottawa, Ottawa (Solmi); On Track: The Champlain First Episode Psychosis Program, and Regional Centre for the Treatment of Eating Disorders, Department of Mental Health, Ottawa Hospital, Ottawa (Solmi); Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa (Solmi); Department of Child and Adolescent Psychiatry, Charité-Universitätsmedizin Berlin, Berlin (Solmi, Correll); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY (Rubio, Correll, Kane); Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY (Rubio, Correll, Kane); Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY (Rubio, Kane); German Center for Mental Health, partner site Berlin (Correll); School of Pharmacy, University of Eastern Finland, Kuopio (Taipale)
| | - Antti Tanskanen
- Department of Forensic Psychiatry, University of Eastern Finland, and Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Tiihonen, Tanskanen, Taipale); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen, Tanskanen, Taipale); SCIENCES Lab and Department of Psychiatry, University of Ottawa, Ottawa (Solmi); On Track: The Champlain First Episode Psychosis Program, and Regional Centre for the Treatment of Eating Disorders, Department of Mental Health, Ottawa Hospital, Ottawa (Solmi); Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa (Solmi); Department of Child and Adolescent Psychiatry, Charité-Universitätsmedizin Berlin, Berlin (Solmi, Correll); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY (Rubio, Correll, Kane); Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY (Rubio, Correll, Kane); Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY (Rubio, Kane); German Center for Mental Health, partner site Berlin (Correll); School of Pharmacy, University of Eastern Finland, Kuopio (Taipale)
| | - Marco Solmi
- Department of Forensic Psychiatry, University of Eastern Finland, and Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Tiihonen, Tanskanen, Taipale); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen, Tanskanen, Taipale); SCIENCES Lab and Department of Psychiatry, University of Ottawa, Ottawa (Solmi); On Track: The Champlain First Episode Psychosis Program, and Regional Centre for the Treatment of Eating Disorders, Department of Mental Health, Ottawa Hospital, Ottawa (Solmi); Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa (Solmi); Department of Child and Adolescent Psychiatry, Charité-Universitätsmedizin Berlin, Berlin (Solmi, Correll); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY (Rubio, Correll, Kane); Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY (Rubio, Correll, Kane); Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY (Rubio, Kane); German Center for Mental Health, partner site Berlin (Correll); School of Pharmacy, University of Eastern Finland, Kuopio (Taipale)
| | - Jose M Rubio
- Department of Forensic Psychiatry, University of Eastern Finland, and Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Tiihonen, Tanskanen, Taipale); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen, Tanskanen, Taipale); SCIENCES Lab and Department of Psychiatry, University of Ottawa, Ottawa (Solmi); On Track: The Champlain First Episode Psychosis Program, and Regional Centre for the Treatment of Eating Disorders, Department of Mental Health, Ottawa Hospital, Ottawa (Solmi); Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa (Solmi); Department of Child and Adolescent Psychiatry, Charité-Universitätsmedizin Berlin, Berlin (Solmi, Correll); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY (Rubio, Correll, Kane); Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY (Rubio, Correll, Kane); Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY (Rubio, Kane); German Center for Mental Health, partner site Berlin (Correll); School of Pharmacy, University of Eastern Finland, Kuopio (Taipale)
| | - Christoph U Correll
- Department of Forensic Psychiatry, University of Eastern Finland, and Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Tiihonen, Tanskanen, Taipale); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen, Tanskanen, Taipale); SCIENCES Lab and Department of Psychiatry, University of Ottawa, Ottawa (Solmi); On Track: The Champlain First Episode Psychosis Program, and Regional Centre for the Treatment of Eating Disorders, Department of Mental Health, Ottawa Hospital, Ottawa (Solmi); Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa (Solmi); Department of Child and Adolescent Psychiatry, Charité-Universitätsmedizin Berlin, Berlin (Solmi, Correll); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY (Rubio, Correll, Kane); Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY (Rubio, Correll, Kane); Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY (Rubio, Kane); German Center for Mental Health, partner site Berlin (Correll); School of Pharmacy, University of Eastern Finland, Kuopio (Taipale)
| | - John M Kane
- Department of Forensic Psychiatry, University of Eastern Finland, and Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Tiihonen, Tanskanen, Taipale); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen, Tanskanen, Taipale); SCIENCES Lab and Department of Psychiatry, University of Ottawa, Ottawa (Solmi); On Track: The Champlain First Episode Psychosis Program, and Regional Centre for the Treatment of Eating Disorders, Department of Mental Health, Ottawa Hospital, Ottawa (Solmi); Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa (Solmi); Department of Child and Adolescent Psychiatry, Charité-Universitätsmedizin Berlin, Berlin (Solmi, Correll); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY (Rubio, Correll, Kane); Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY (Rubio, Correll, Kane); Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY (Rubio, Kane); German Center for Mental Health, partner site Berlin (Correll); School of Pharmacy, University of Eastern Finland, Kuopio (Taipale)
| | - Heidi Taipale
- Department of Forensic Psychiatry, University of Eastern Finland, and Niuvanniemi Hospital, Kuopio, Finland (Tiihonen, Tanskanen, Taipale); Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Tiihonen, Tanskanen, Taipale); Center for Psychiatry Research, Stockholm City Council, Stockholm (Tiihonen, Tanskanen, Taipale); SCIENCES Lab and Department of Psychiatry, University of Ottawa, Ottawa (Solmi); On Track: The Champlain First Episode Psychosis Program, and Regional Centre for the Treatment of Eating Disorders, Department of Mental Health, Ottawa Hospital, Ottawa (Solmi); Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa (Solmi); Department of Child and Adolescent Psychiatry, Charité-Universitätsmedizin Berlin, Berlin (Solmi, Correll); Department of Psychiatry, Zucker Hillside Hospital, Northwell Health, Glen Oaks, NY (Rubio, Correll, Kane); Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY (Rubio, Correll, Kane); Institute for Behavioral Science, Feinstein Institutes for Medical Research, Manhasset, NY (Rubio, Kane); German Center for Mental Health, partner site Berlin (Correll); School of Pharmacy, University of Eastern Finland, Kuopio (Taipale)
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Kinoshita I, Nishijima H, Nakamura T, Kon T, Shimoyama S, Hikichi H, Suzuki C, Tomiyama M. Co-Expression of Tardive Dyskinesia and Drug-Induced Parkinsonism in Rats Chronically Treated With Haloperidol. Neuropsychopharmacol Rep 2025; 45:e12524. [PMID: 39789385 PMCID: PMC11717661 DOI: 10.1002/npr2.12524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Revised: 11/28/2024] [Accepted: 12/16/2024] [Indexed: 01/30/2025] Open
Abstract
AIM We aimed to create a rat model of drug-induced parkinsonism and tardive dyskinesia by chronic administration of haloperidol and examine the expression of direct and indirect pathway markers in the striatum of the model rats. METHODS We treated 21 rats, 14 with haloperidol decanoate and 7 with placebo. The number of vacuous chewing movements per 2 min was counted, and haloperidol-treated rats were classified into two groups: mild and severe tardive dyskinesia. Other behavioral analyses were also conducted. After a 6-month treatment period, rat brains were removed, and protein expression was evaluated by Western blotting. RESULTS All haloperidol-treated rats exhibited vacuous chewing movements. The frequency of exploratory behavior and rotarod test performance was lower in the mild and severe tardive dyskinesia groups. The number of vacuous chewing movements and frequency of exploratory behavior were positively correlated in haloperidol-treated rats. The expression of dynorphin, a direct pathway marker, decreased in the severe tardive dyskinesia group. The expression of enkephalin, an indirect pathway marker, decreased both in the mild and severe tardive dyskinesia groups. The expression of dopamine D1 and D2 receptors also decreased with haloperidol treatment. CONCLUSION Both direct and indirect pathways are involved in haloperidol-induced movement disorders.
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Affiliation(s)
- Iku Kinoshita
- Department of NeurologyHirosaki University Graduate School of MedicineHirosakiJapan
- Department of NeurologyHirosaki University HospitalHirosakiJapan
| | - Haruo Nishijima
- Department of NeurologyHirosaki University Graduate School of MedicineHirosakiJapan
- Department of NeurologyHirosaki University HospitalHirosakiJapan
| | - Takashi Nakamura
- Department of NeurologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Tomoya Kon
- Department of NeurologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Shuji Shimoyama
- Department of NeurophysiologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Hiroki Hikichi
- Department of NeurologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Chieko Suzuki
- Department of NeurologyHirosaki University Graduate School of MedicineHirosakiJapan
| | - Masahiko Tomiyama
- Department of NeurologyHirosaki University Graduate School of MedicineHirosakiJapan
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Ponciano R, Hallak JEC, Crippa JA, Guimarães FS, Bel EAD. Cannabigerol Mitigates Haloperidol-Induced Vacuous Chewing Movements in Mice. Neurotox Res 2024; 43:2. [PMID: 39699828 DOI: 10.1007/s12640-024-00724-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/10/2024] [Accepted: 12/11/2024] [Indexed: 12/20/2024]
Abstract
Chronic use of typical antipsychotics can lead to varying motor effects depending on the timing of analysis. Acute treatment typically induces hypokinesia, resembling parkinsonism, while repeated use can result in tardive dyskinesia, a hyperkinetic syndrome marked by involuntary orofacial movements, such as vacuous chewing movements in mice. Tardive dyskinesia is particularly concerning due to its potential irreversibility and associated motor discomfort. One prevailing theory suggests that tardive dyskinesia arises from hypersensitivity of D2-type dopaminergic receptors caused by continuous blockade from typical antipsychotics like haloperidol. Additionally, increased inflammation, oxidative stress, and elevated FosB protein expression in the dorsolateral striatum are implicated in its pathophysiology. Current treatments for tardive dyskinesia often lack clear efficacy and may lead to significant side effects. Cannabigerol, a non-psychotomimetic cannabinoid with antioxidant and anti-inflammatory properties, has been investigated for its potential antidyskinetic effects. In this study, mice were treated with cannabigerol at doses of 3 and 10 mg/kg to evaluate its ability to prevent, ameliorate, or reverse haloperidol-induced vacuous chewing movements. Cannabigerol successfully reduced vacuous chewing movements without affecting normal motor activity, exacerbating haloperidol-induced hypokinesia, or inducing dyskinetic effects on its own. However, no significant reversal of the haloperidol-induced motor effects was observed under the current protocol. Furthermore, cannabigerol did not alter FosB expression or microglia morphology. These findings underscore the need for further research to explore cannabigerol's therapeutic potential and contribute to our understanding of its possible clinical applications in managing tardive dyskinesia.
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Affiliation(s)
- R Ponciano
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - J E C Hallak
- Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - J A Crippa
- Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - F S Guimarães
- Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - Elaine Ap Del Bel
- Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
- Department of Neurosciences and Behavioral Sciences, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
- Department of Basic and Oral Biology, School of Dentistry of Ribeirão Preto, University of São Paulo, Av. Do Café s/n, Ribeirão Preto, São Paulo, Ribeirão Preto, SP, 14049-900, Brazil.
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Detanac M, Williams C, Dragovic M, Shymko G, John AP. Prevalence of treatment-resistant schizophrenia among people with early psychosis and its clinical and demographic correlates. Aust N Z J Psychiatry 2024; 58:1080-1089. [PMID: 39198966 PMCID: PMC11585183 DOI: 10.1177/00048674241274314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/01/2024]
Abstract
OBJECTIVE The prevalence of treatment-resistant schizophrenia (TRS) among people with first-episode schizophrenia (FES) has been sub-optimally researched in Australia and internationally. We evaluated the prevalence of TRS among a cohort of FES patients and compared their sociodemographic and clinical characteristics to those with FES who were treatment responsive. METHODS Over 2 years, we collated demographic, clinical and treatment-related data of all patients with ICD-10 (International Classification of Diseases, Tenth revision) diagnosis of schizophrenia who were active in October 2020 at four early psychosis intervention services (EPIS) in Western Australia. We used a modified version of Suzuki et al. criteria to diagnose TRS. The data were analysed utilising descriptive statistics, the Mann-Whitney U test, Student's t-test and the False-Discovery Rate method. RESULTS The prevalence of TRS among the 167 patients diagnosed with FES was 41.3%, and the rates did not differ significantly between the services (p = 0.955). Those in the TRS group were less independent (p = 0.011), had more prolonged unemployment (p = 0.014) and were more likely to be on disability pension (p = 0.011) compared to the treatment responsive group. Furthermore, they had greater severity of symptoms (p = 0.002), longer duration of psychiatric symptoms (p = 0.019), more hospitalisations (p = 0.002) and longer cumulative admission durations (p = 0.002). CONCLUSIONS Our study revealed that treatment resistance to antipsychotics is prevalent among people with FES managed at EPIS. Notably, it establishes an association between TRS and heightened clinical severity and psychosocial and treatment burden. These findings highlight the imperative for early detection of treatment resistance and timely and specialised interventions for this condition in mental health services.
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Affiliation(s)
- Mirza Detanac
- Graylands Hospital, Mental Health, North Metropolitan Health Service, Perth, WA, Australia
| | | | - Milan Dragovic
- Graylands Hospital, Mental Health, North Metropolitan Health Service, Perth, WA, Australia
- Division of Psychiatry, Medical School, The University of Western Australia, Crawley, WA, Australia
- Clinical Research Centre, Graylands Hospital, Perth, WA, Australia
| | - Gordon Shymko
- headspace Early Psychosis, Osborne Park, WA, Australia
- Mental Health, Peel and Rockingham Kwinana Mental Health Service, Perth, WA, Australia
| | - Alexander Panickacheril John
- Division of Psychiatry, Medical School, The University of Western Australia, Crawley, WA, Australia
- Mental Health, Royal Perth Bentley Group, Perth, WA, Australia
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Shakir M, van Harten PN, Hoogendoorn AW, Willems AE, Tenback DE. Switching a combination of first- and second-generation antipsychotic polypharmacy to antipsychotic monotherapy in long-term inpatients with schizophrenia and related disorders. The SwAP trial II: Results on side effects. Schizophr Res 2024; 274:105-112. [PMID: 39288473 DOI: 10.1016/j.schres.2024.09.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Revised: 08/23/2024] [Accepted: 09/03/2024] [Indexed: 09/19/2024]
Abstract
OBJECTIVE This study examined the effects of switching antipsychotic polypharmacy (APP) to antipsychotic monotherapy (APM) on various side effects in inpatients with schizophrenia. Side effects of interest included psychic, autonomic, and sexual symptoms, as well as metabolic side effects and movement disorders. METHOD A 9-month parallel randomized open-label clinical trial was conducted involving 136 chronic inpatients from two psychiatric hospitals in the Netherlands. Participants were randomly assigned to either a STAY or a SWITCH group. The SWITCH group underwent a 3-month tapering-off period in which either first-generation or second-generation antipsychotic medication was discontinued, followed by APM. Patients were assessed at baseline and at follow-up assessments at 3, 6, and 9 months. Psychic, neurological, autonomic, and sexual side effects were evaluated using the UKU Rating Scale, while movement disorders were measured with the St. Hans Rating Scale. Various metabolic parameters were also recorded. RESULTS In the STAY group, side effects remained generally stable over time, except for a slight reduction in sexual desire. In contrast, the SWITCH group experienced significant reductions in psychic and autonomic symptoms, as well as improvements in akathisia, parkinsonism, and dyskinesia. There were no changes in dystonia, paresthesia, epilepsy, or sexual symptoms for this group. Notably, the SWITCH group also showed significant reductions in BMI and body weight. CONCLUSION Switching APP to APM in long-term inpatients reduces the severity of various side effects, including movement disorders and metabolic side effects.
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Affiliation(s)
- Mushde Shakir
- Veldzicht Center for Transcultural Psychiatry, Custodial Institutions Agency (DJI), Ministry of Justice and Security, Balkbrug, the Netherlands; Parnassia Group Mental Health Service, Den Haag, the Netherlands; Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Faculty Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands.
| | - Peter N van Harten
- Department of Psychiatry & Neuropsychology, School for Mental Health and Neuroscience, Faculty Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands; GGZ Centraal Mental Health Service, Amersfoort, the Netherlands
| | - Adriaan W Hoogendoorn
- Department of Psychiatry, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands; Amsterdam Public Health Research Institute, Amsterdam, the Netherlands
| | | | - Diederik E Tenback
- Veldzicht Center for Transcultural Psychiatry, Custodial Institutions Agency (DJI), Ministry of Justice and Security, Balkbrug, the Netherlands; FPC de Oostvaarderskliniek, Custodial Institutions Agency (DJI), Ministry of Justice and Security, Almere, the Netherlands
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8
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Hart XM, Gründer G, Ansermot N, Conca A, Corruble E, Crettol S, Cumming P, Frajerman A, Hefner G, Howes O, Jukic MM, Kim E, Kim S, Maniscalco I, Moriguchi S, Müller DJ, Nakajima S, Osugo M, Paulzen M, Ruhe HG, Scherf-Clavel M, Schoretsanitis G, Serretti A, Spina E, Spigset O, Steimer W, Süzen SH, Uchida H, Unterecker S, Vandenberghe F, Verstuyft C, Zernig G, Hiemke C, Eap CB. Optimisation of pharmacotherapy in psychiatry through therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests: Focus on antipsychotics. World J Biol Psychiatry 2024; 25:451-536. [PMID: 38913780 DOI: 10.1080/15622975.2024.2366235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 05/12/2024] [Accepted: 06/06/2024] [Indexed: 06/26/2024]
Abstract
BACKGROUND For psychotic disorders (i.e. schizophrenia), pharmacotherapy plays a key role in controlling acute and long-term symptoms. To find the optimal individual dose and dosage strategy, specialised tools are used. Three tools have been proven useful to personalise drug treatments: therapeutic drug monitoring (TDM) of drug levels, pharmacogenetic testing (PG), and molecular neuroimaging. METHODS In these Guidelines, we provide an in-depth review of pharmacokinetics, pharmacodynamics, and pharmacogenetics for 45 antipsychotics. Over 30 international experts in psychiatry selected studies that have measured drug concentrations in the blood (TDM), gene polymorphisms of enzymes involved in drug metabolism, or receptor/transporter occupancies in the brain (positron emission tomography (PET)). RESULTS Study results strongly support the use of TDM and the cytochrome P450 (CYP) genotyping and/or phenotyping to guide drug therapies. Evidence-based target ranges are available for titrating drug doses that are often supported by PET findings. CONCLUSION All three tools discussed in these Guidelines are essential for drug treatment. TDM goes well beyond typical indications such as unclear compliance and polypharmacy. Despite its enormous potential to optimise treatment effects, minimise side effects and ultimately reduce the global burden of diseases, personalised drug treatment has not yet become the standard of care in psychiatry.
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Affiliation(s)
- Xenia Marlene Hart
- Department of Molecular Neuroimaging, Medical Faculty Mannheim, Central Institute of Mental Health, University of Heidelberg, Mannheim, Germany
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Gerhard Gründer
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
- German Center for Mental Health (DZPG), Partner Site Mannheim, Heidelberg, Germany
| | - Nicolas Ansermot
- Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neuroscience, Lausanne University Hospital, Prilly, Switzerland
| | - Andreas Conca
- Dipartimento di Psichiatria, Comprensorio Sanitario di Bolzano, Bolzano, Italy
| | - Emmanuelle Corruble
- Service Hospitalo-Universitaire de Psychiatrie, Hôpital de Bicêtre, Université Paris-Saclay, AP-HP, Le Kremlin-Bicêtre, France
- Equipe MOODS, Inserm U1018, CESP (Centre de Recherche en Epidémiologie et Sante des Populations), Le Kremlin-Bicêtre, France
| | - Severine Crettol
- Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neuroscience, Lausanne University Hospital, Prilly, Switzerland
| | - Paul Cumming
- Department of Nuclear Medicine, Bern University Hospital, Bern, Switzerland
- School of Psychology and Counseling, Queensland University of Technology, Brisbane, Australia
| | - Ariel Frajerman
- Service Hospitalo-Universitaire de Psychiatrie, Hôpital de Bicêtre, Université Paris-Saclay, AP-HP, Le Kremlin-Bicêtre, France
- Equipe MOODS, Inserm U1018, CESP (Centre de Recherche en Epidémiologie et Sante des Populations), Le Kremlin-Bicêtre, France
| | - Gudrun Hefner
- Forensic Psychiatry, Vitos Clinic for Forensic Psychiatry, Eltville, Germany
| | - Oliver Howes
- Department of Psychosis Studies, IoPPN, King's College London, London, UK
- Faculty of Medicine, Institute of Clinical Sciences (ICS), Imperial College London, London, UK
| | - Marin M Jukic
- Department of Physiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia
- Pharmacogenetics Section, Department of Physiology and Pharmacology, Karolinska Institutet, Solna, Sweden
| | - Euitae Kim
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Seoyoung Kim
- Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Ignazio Maniscalco
- Dipartimento di Psichiatria, Comprensorio Sanitario di Bolzano, Bolzano, Italy
| | - Sho Moriguchi
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Daniel J Müller
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
- Pharmacogenetics Research Clinic, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario, Canada
- Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
| | - Shinichiro Nakajima
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Martin Osugo
- Department of Psychosis Studies, IoPPN, King's College London, London, UK
- Faculty of Medicine, Institute of Clinical Sciences (ICS), Imperial College London, London, UK
| | - Michael Paulzen
- Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany
- JARA - Translational Brain Medicine, Alexianer Center for Mental Health, Aachen, Germany
| | - Henricus Gerardus Ruhe
- Department of Psychiatry, Radboudumc, Nijmegen, Netherlands
- Donders Institute for Brain, Cognition and Behavior, Radboud University, Nijmegen, Netherlands
| | - Maike Scherf-Clavel
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
| | - Georgios Schoretsanitis
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland
| | | | - Edoardo Spina
- Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
| | - Olav Spigset
- Department of Clinical Pharmacology, St. Olav University Hospital, Trondheim, Norway
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
| | - Werner Steimer
- Institute of Clinical Chemistry and Pathobiochemistry, Technical University Munich, Munich, Germany
| | - Sinan H Süzen
- Department of Pharmaceutic Toxicology, Faculty of Pharmacy, Ankara University, Ankara, Turkey
| | - Hiroyuki Uchida
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Stefan Unterecker
- Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital of Würzburg, Würzburg, Germany
| | - Frederik Vandenberghe
- Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neuroscience, Lausanne University Hospital, Prilly, Switzerland
| | - Celine Verstuyft
- Equipe MOODS, Inserm U1018, CESP (Centre de Recherche en Epidémiologie et Sante des Populations), Le Kremlin-Bicêtre, France
- Department of Molecular Genetics, Pharmacogenetics and Hormonology, Bicêtre University Hospital Paris-Saclay, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Gerald Zernig
- Department of Pharmacology, Medical University Innsbruck, Hall in Tirol, Austria
- Private Practice for Psychotherapy and Court-Certified Witness, Hall in Tirol, Austria
| | - Christoph Hiemke
- Department of Psychiatry and Psychotherapy and Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Mainz, Germany
| | - Chin B Eap
- Department of Psychiatry, Unit of Pharmacogenetics and Clinical Psychopharmacology, Center for Psychiatric Neuroscience, Lausanne University Hospital, Prilly, Switzerland
- School of Pharmaceutical Sciences, University of Geneva, University of Lausanne, Geneva, Switzerland
- Center for Research and Innovation in Clinical Pharmaceutical Sciences, University of Lausanne, Lausanne, Switzerland
- Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, University of Lausanne, Lausanne, Switzerland
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Horowitz MA, Moncrieff J. Gradually tapering off antipsychotics: lessons for practice from case studies and neurobiological principles. Curr Opin Psychiatry 2024; 37:320-330. [PMID: 38726815 PMCID: PMC11139239 DOI: 10.1097/yco.0000000000000940] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/01/2024]
Abstract
PURPOSE OF REVIEW There has been an increasing focus on deprescribing in psychiatry recently, particularly of antipsychotic medication, with recognition that not all patients with psychotic disorders require lifelong medication. We summarize some empirical and theoretical papers, and examine case studies to provide instruction on this topic. RECENT FINDINGS Recent studies have found that slower tapering (over months or longer) of antipsychotics is associated with a lower relapse rate than quicker tapering (weeks). Case studies presented suggest that the process of reduction is associated with the precipitation or exacerbation of psychotic symptoms and that a slower process of reduction may minimize this effect. This may be because faster reductions cause greater disruption of homeostatic equilibria, provoking psychotic symptoms either as direct withdrawal symptoms or consequences of nonpsychotic withdrawal symptoms (e.g. insomnia) - although not all patients will experience withdrawal symptoms. This suggests that smaller dose reductions, especially at lower doses, made very gradually, may minimize the risk of psychotic symptoms. SUMMARY Slower tapering of antipsychotics may provide time for adaptations made to the presence of the medications to resolve, thus reducing the disruption to homeostatic equilibrium caused by dose reduction, potentially reducing the risk of relapse. Exacerbation of psychotic symptoms on antipsychotic reduction may not represent evidence of the need for a higher dose of antipsychotic on a long-term basis but may indicate the need for more gradual reduction. Gradual reduction of antipsychotics, especially after long-term use in clinical practice is prudent.
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Affiliation(s)
- Mark A. Horowitz
- Division of Psychiatry, University College London, Maple House, Fitzrovia, London
- North East London Foundation Trust, Goodmayes Hospital, Goodmayes, Ilford, UK
| | - Joanna Moncrieff
- Division of Psychiatry, University College London, Maple House, Fitzrovia, London
- North East London Foundation Trust, Goodmayes Hospital, Goodmayes, Ilford, UK
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10
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Panov G, Panova P. Neurobiochemical Disturbances in Psychosis and their Implications for Therapeutic Intervention. Curr Top Med Chem 2024; 24:1784-1798. [PMID: 38265370 DOI: 10.2174/0115680266282773240116073618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 12/17/2023] [Accepted: 12/19/2023] [Indexed: 01/25/2024]
Abstract
Psychosis, marked by the emergence of psychotic symptoms, delves into the intricate dance of neurotransmitter dynamics, prominently featuring dopamine as a key orchestrator. In individuals living with psychotic conditions, the finely tuned balance of dopamine becomes disrupted, setting off a cascade of perceptual distortions and the manifestation of psychotic symptoms. A lot of factors can impact dopamine metabolism, further complicating its effects. From genetic predispositions to environmental stressors and inflammation, the delicate equilibrium is susceptible to various influences. The sensorium, the origin of incoming information, loses its intrinsic valence in this complex interplay. The concept of the "signal-to-noise ratio" encapsulates dopamine's role as a molecular switch in neural networks, influencing the flow of information serving the basic biological functions. This nuanced modulation acts as a cognitive prism, shaping how the world is perceived. However, in psychosis, this balance is disrupted, steering individuals away from a shared reality. Understanding dopamine's centrality requires acknowledging its unique status among neurotransmitters. Unlike strictly excitatory or inhibitory counterparts, dopamine's versatility allows it to toggle between roles and act as a cognitive director in the neural orchestra. Disruptions in dopamine synthesis, exchange, and receptor representation set off a chain reaction, impacting the delivery of biologically crucial information. The essence of psychosis is intricately woven into the delicate biochemical ballet choreographed by dopamine. The disruption of this neurotransmitter not only distorts reality but fundamentally reshapes the cognitive and behavioral field of our experience. Recognizing dopamine's role as a cognitive prism provides vital insights into the multifaceted nature of psychotic conditions, offering avenues for targeted therapeutic interventions aimed at restoring this delicate neurotransmitter balance.
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Affiliation(s)
- Georgi Panov
- Psychiatric Clinic, University Hospital for Active Treatment "Prof. Dr. Stoyan Kirkovich," Trakia University, Stara Zagora, 6000, Bulgaria
- Department "Neurology, Psychiatry, Psychology," Medical Faculty of University "Prof. Dr. Asen Zlatarov," Burgas, 8000, Bulgaria
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11
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Valle-León M, Casajuana-Martin N, Del Torrent CL, Argerich J, Gómez-Acero L, Sahlholm K, Ferré S, Pardo L, Ciruela F. Unique effect of clozapine on adenosine A 2A-dopamine D 2 receptor heteromerization. Biomed Pharmacother 2023; 160:114327. [PMID: 36736280 PMCID: PMC11959194 DOI: 10.1016/j.biopha.2023.114327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 01/21/2023] [Accepted: 01/26/2023] [Indexed: 02/04/2023] Open
Abstract
The striatal dopamine D2 receptor (D2R) is generally accepted to be involved in positive symptoms of schizophrenia and is a main target for clinically used antipsychotics. D2R are highly expressed in the striatum, where they form heteromers with the adenosine A2A receptor (A2AR). Changes in the density of A2AR-D2R heteromers have been reported in postmortem tissue from patients with schizophrenia, but the degree to which A2R are involved in schizophrenia and the effect of antipsychotic drugs is unknown. Here, we examine the effect of exposure to three prototypical antipsychotic drugs on A2AR-D2R heteromerization in mammalian cells using a NanoBiT assay. After 16 h of exposure, a significant increase in the density of A2AR-D2R heteromers was found with haloperidol and aripiprazole, but not with clozapine. On the other hand, clozapine, but not haloperidol or aripiprazole, was associated with a significant decrease in A2AR-D2R heteromerization after 2 h of treatment. Computational binding models of these compounds revealed distinctive molecular signatures that explain their different influence on heteromerization. The bulky tricyclic moiety of clozapine displaces TM 5 of D2R, inducing a clash with A2AR, while the extended binding mode of haloperidol and aripiprazole stabilizes a specific conformation of the second extracellular loop of D2R that enhances the interaction with A2AR. It is proposed that an increase in A2AR-D2R heteromerization is involved in the extrapyramidal side effects (EPS) of antipsychotics and that the specific clozapine-mediated destabilization of A2AR-D2R heteromerization can explain its low EPS liability.
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Affiliation(s)
- Marta Valle-León
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain
| | - Nil Casajuana-Martin
- Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autònoma Barcelona, Bellaterra, 08193 Barcelona, Spain
| | - Claudia Llinas Del Torrent
- Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autònoma Barcelona, Bellaterra, 08193 Barcelona, Spain
| | - Josep Argerich
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain
| | - Laura Gómez-Acero
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain
| | - Kristoffer Sahlholm
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain; Department of Integrative Medical Biology, Wallenberg Centre for Molecular Medicine, Umeå University, 907 87 Umeå, Sweden; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Sergi Ferré
- Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.
| | - Leonardo Pardo
- Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autònoma Barcelona, Bellaterra, 08193 Barcelona, Spain.
| | - Francisco Ciruela
- Pharmacology Unit, Department of Pathology and Experimental Therapeutics, School of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08907 L'Hospitalet de Llobregat, Spain; Neuropharmacology and Pain Group, Neuroscience Program, Institut d'Investigació Biomèdica de Bellvitge, IDIBELL, 08907 L'Hospitalet de Llobregat, Spain.
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Dopamine Dynamics and Neurobiology of Non-Response to Antipsychotics, Relevance for Treatment Resistant Schizophrenia: A Systematic Review and Critical Appraisal. Biomedicines 2023; 11:biomedicines11030895. [PMID: 36979877 PMCID: PMC10046109 DOI: 10.3390/biomedicines11030895] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/08/2023] [Accepted: 03/12/2023] [Indexed: 03/17/2023] Open
Abstract
Treatment resistant schizophrenia (TRS) is characterized by a lack of, or suboptimal response to, antipsychotic agents. The biological underpinnings of this clinical condition are still scarcely understood. Since all antipsychotics block dopamine D2 receptors (D2R), dopamine-related mechanisms should be considered the main candidates in the neurobiology of antipsychotic non-response, although other neurotransmitter systems play a role. The aims of this review are: (i) to recapitulate and critically appraise the relevant literature on dopamine-related mechanisms of TRS; (ii) to discuss the methodological limitations of the studies so far conducted and delineate a theoretical framework on dopamine mechanisms of TRS; and (iii) to highlight future perspectives of research and unmet needs. Dopamine-related neurobiological mechanisms of TRS may be multiple and putatively subdivided into three biological points: (1) D2R-related, including increased D2R levels; increased density of D2Rs in the high-affinity state; aberrant D2R dimer or heteromer formation; imbalance between D2R short and long variants; extrastriatal D2Rs; (2) presynaptic dopamine, including low or normal dopamine synthesis and/or release compared to responder patients; and (3) exaggerated postsynaptic D2R-mediated neurotransmission. Future points to be addressed are: (i) a more neurobiologically-oriented phenotypic categorization of TRS; (ii) implementation of neurobiological studies by directly comparing treatment resistant vs. treatment responder patients; (iii) development of a reliable animal model of non-response to antipsychotics.
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Cookson J, Pimm J, Reynolds G. Partial agonists of dopamine receptors: clinical effects and dopamine receptor interactions in combining aripiprazole with a full antagonist in treating psychosis. BJPSYCH ADVANCES 2023. [DOI: 10.1192/bja.2022.86] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
SUMMARY
Partial agonists of dopamine receptors are used in combination with full antagonists in treating psychosis, either to mitigate side-effects or in the hope of increasing effectiveness. We examine how combinations may affect the occupancy of D2/D3 dopamine receptors and explore how these can explain the outcomes in the light of the dopamine hypothesis of psychosis. The combinations considered here are from published studies combining aripiprazole with amisulpride, with risperidone in people with hyperprolactinaemia and with olanzapine to mitigate weight gain. We discuss possible worsening of symptoms by the addition of a partial agonist or switching. We also examine the potentially adverse interaction with a full antagonist such as haloperidol given during a subsequent relapse to control severe agitation.
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Lippi M, Fanelli G, Fabbri C, De Ronchi D, Serretti A. The dilemma of polypharmacy in psychosis: is it worth combining partial and full dopamine modulation? Int Clin Psychopharmacol 2022; 37:263-275. [PMID: 35815937 PMCID: PMC9521590 DOI: 10.1097/yic.0000000000000417] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 05/16/2022] [Indexed: 02/04/2023]
Abstract
Antipsychotic polypharmacy in psychotic disorders is widespread despite international guidelines favoring monotherapy. Previous evidence indicates the utility of low-dose partial dopamine agonist (PDAs) add-ons to mitigate antipsychotic-induced metabolic adverse effects or hyperprolactinemia. However, clinicians are often concerned about using PDAs combined with high-potency, full dopaminergic antagonists (FDAs) due to the risk of psychosis relapse. We, therefore, conducted a literature review to find studies investigating the effects of combined treatment with PDAs (i.e. aripiprazole, cariprazine and brexpiprazole) and FDAs having a strong D 2 receptor binding affinity. Twenty studies examining the combination aripiprazole - high-potency FDAs were included, while no study was available on combinations with cariprazine or brexpiprazole. Studies reporting clinical improvement suggested that this may require a relatively long time (~11 weeks), while studies that found symptom worsening observed this happening in a shorter timeframe (~3 weeks). Patients with longer illness duration who received add-on aripiprazole on ongoing FDA monotherapy may be at greater risk for symptomatologic worsening. Especially in these cases, close clinical monitoring is therefore recommended during the first few weeks of combined treatment. These indications may be beneficial to psychiatrists who consider using this treatment strategy. Well-powered randomized clinical trials are needed to derive more solid clinical recommendations.
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Affiliation(s)
- Matteo Lippi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Giuseppe Fanelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands
| | - Chiara Fabbri
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
- Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
| | - Diana De Ronchi
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Alessandro Serretti
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
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Takeuchi H, Mori Y, Tsutsumi Y. Pathophysiology, prognosis and treatment of tardive dyskinesia. Ther Adv Psychopharmacol 2022; 12:20451253221117313. [PMID: 36312846 PMCID: PMC9597038 DOI: 10.1177/20451253221117313] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 07/15/2022] [Indexed: 11/06/2022] Open
Abstract
Tardive dyskinesia (TD), a movement disorder associated with antipsychotics, most frequently affects the lower face and jaw muscles, but can also affect walking, breathing and use of the hands and limbs. Knowledge of TD among physicians may be limited, and the pathophysiology of TD is poorly understood. We conducted this review to summarise the current knowledge surrounding the pathophysiology of TD and present recommendations for prevention and treatment based on a literature search and roundtable discussion attended by psychiatrists in Japan. It has been suggested that dopamine hypersensitivity, damaged gamma-aminobutyric acidergic neurons and/or increased production of reactive oxygen species may contribute to development of TD. Symptoms can profoundly affect everyday life; patients who develop TD have poorer prognoses, worse health-related quality of life, greater social withdrawal and higher mortality than patients without TD. Traditional treatment options include dietary supplements, although evidence for their effectiveness is low. Among pharmaceutical interventions, there is moderate evidence that switching to the second-generation antipsychotic clozapine, which has a lower affinity for dopamine D2 receptors than other antipsychotics, may improve symptoms. Vesicular monoamine transporter 2 (VMAT-2) inhibitors, which oppose the increased dopaminergic activity associated with prolonged antipsychotic use by interfering with dopamine uptake and storage, have the strongest evidence for efficacy. VMAT-2 inhibitors are approved in the United States for the treatment of TD, and the first VMAT-2 inhibitor was approved in Japan for this indication in March 2022. Most guidelines recommend treating TD by first reducing the dose of antipsychotics or switching to clozapine or other second-generation antipsychotics, which have a lower association with TD than first-generation antipsychotics. We recommend focusing on prevention and monitoring for TD when prescribing antipsychotics, given that TD is often irreversible. Physicians should treat with antipsychotics only when necessary and at the lowest effective dose, and frequently monitor for TD symptoms. Plain Language Summary Plain Language Summary (In Japanese). Visual Summary Visual Summary (In Japanese).
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Affiliation(s)
- Hiroyoshi Takeuchi
- Department of Neuropsychiatry, School of
Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582,
Japan
| | - Yasuhiro Mori
- Department of Psychiatry, Aichi Medical
University, Aichi, Japan
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Abler V, Brain C, Ballard C, Berrio A, Coate B, Espay AJ. Motor- and cognition-related safety of pimavanserin in patients with Parkinson's disease psychosis. Front Neurol 2022; 13:919778. [PMID: 36277907 PMCID: PMC9580496 DOI: 10.3389/fneur.2022.919778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 09/07/2022] [Indexed: 12/01/2022] Open
Abstract
Background Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, is the only treatment approved by the US Food and Drug Administration for hallucinations and delusions associated with Parkinson's disease (PD) psychosis. Aim We aimed to evaluate motor- and cognition-related safety in pimavanserin-treated patients with PD psychosis. Methods This analysis included patients with PD psychosis treated with pimavanserin 34 mg from a pooled analysis of 3 randomized, double-blind, placebo-controlled, 6-week studies [NCT00477672 (study ACP-103-012), NCT00658567 (study ACP-103-014), and NCT01174004 (study ACP-103-020)] and a subgroup of patients with PD dementia with psychosis from HARMONY (NCT03325556), a randomized discontinuation study that included a 12-week open-label period followed by a randomized double-blind period of up to 26 weeks. Motor- and cognition-related safety were examined. Results The pooled analysis included 433 randomized patients (pimavanserin, 202; placebo, 231). Least squares mean (standard error [SE]) change from baseline to week 6 Unified Parkinson's Disease Rating Scale (UPDRS) II + III score was similar for pimavanserin [−2.4 (0.69)] and placebo [−2.3 (0.60)] (95% Confidence Interval [CI]:−1.9, 1.6). The change from baseline to week 6 for UPDRS II and UPDRS III scores was similar between groups. In the HARMONY open-label period, 49 patients with PD dementia with psychosis were treated with pimavanserin 34 mg, 36 of whom were randomized in the double-blind period (pimavanserin, 16; placebo, 20). In the open-label period, the mean (SE) change from baseline to week 12 (n = 39) Extra-Pyramidal Symptom Rating Scale (ESRS-A) score was −1.7 (0.74); in the double-blind period, the results were generally comparable between the pimavanserin and placebo arms. The change from baseline in Mini-Mental State Examination (MMSE) score was also comparable between pimavanserin- and placebo-treated patients in HARMONY [open-label (n = 37): mean (SE) change from baseline to week 12, 0.3 (0.66)]. Rates of motor- and cognition-related adverse events were similar between pimavanserin and placebo in both analyses. Conclusions Pimavanserin 34 mg was well tolerated and did not yield a negative impact on motor- or cognition-related function in patients with PD psychosis.
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Affiliation(s)
- Victor Abler
- Acadia Pharmaceuticals Inc, San Diego, CA, United States
| | - Cecilia Brain
- Acadia Pharmaceuticals Inc, San Diego, CA, United States
| | - Clive Ballard
- University of Exeter Medical School, Exeter, United Kingdom
| | - Ana Berrio
- Acadia Pharmaceuticals Inc, San Diego, CA, United States
| | - Bruce Coate
- Acadia Pharmaceuticals Inc, San Diego, CA, United States
| | - Alberto J. Espay
- Gardner Family Center for Parkinson's Disease and Movement Disorders, Department of Neurology, University of Cincinnati, Cincinnati, OH, United States
- *Correspondence: Alberto J. Espay
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17
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de Bartolomeis A, Vellucci L, Barone A, Manchia M, De Luca V, Iasevoli F, Correll CU. Clozapine's multiple cellular mechanisms: What do we know after more than fifty years? A systematic review and critical assessment of translational mechanisms relevant for innovative strategies in treatment-resistant schizophrenia. Pharmacol Ther 2022; 236:108236. [PMID: 35764175 DOI: 10.1016/j.pharmthera.2022.108236] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/21/2022] [Accepted: 06/21/2022] [Indexed: 12/21/2022]
Abstract
Almost fifty years after its first introduction into clinical care, clozapine remains the only evidence-based pharmacological option for treatment-resistant schizophrenia (TRS), which affects approximately 30% of patients with schizophrenia. Despite the long-time experience with clozapine, the specific mechanism of action (MOA) responsible for its superior efficacy among antipsychotics is still elusive, both at the receptor and intracellular signaling level. This systematic review is aimed at critically assessing the role and specific relevance of clozapine's multimodal actions, dissecting those mechanisms that under a translational perspective could shed light on molecular targets worth to be considered for further innovative antipsychotic development. In vivo and in vitro preclinical findings, supported by innovative techniques and methods, together with pharmacogenomic and in vivo functional studies, point to multiple and possibly overlapping MOAs. To better explore this crucial issue, the specific affinity for 5-HT2R, D1R, α2c, and muscarinic receptors, the relatively low occupancy at dopamine D2R, the interaction with receptor dimers, as well as the potential confounder effects resulting in biased ligand action, and lastly, the role of the moiety responsible for lipophilic and alkaline features of clozapine are highlighted. Finally, the role of transcription and protein changes at the synaptic level, and the possibility that clozapine can directly impact synaptic architecture are addressed. Although clozapine's exact MOAs that contribute to its unique efficacy and some of its severe adverse effects have not been fully understood, relevant information can be gleaned from recent mechanistic understandings that may help design much needed additional therapeutic strategies for TRS.
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Affiliation(s)
- Andrea de Bartolomeis
- Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry and Unit of Treatment Resistant Psychosis, Department of Neuroscience, Reproductive Science and Dentistry, University Medical School of Naples "Federico II", Naples, Italy.
| | - Licia Vellucci
- Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry and Unit of Treatment Resistant Psychosis, Department of Neuroscience, Reproductive Science and Dentistry, University Medical School of Naples "Federico II", Naples, Italy
| | - Annarita Barone
- Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry and Unit of Treatment Resistant Psychosis, Department of Neuroscience, Reproductive Science and Dentistry, University Medical School of Naples "Federico II", Naples, Italy
| | - Mirko Manchia
- Section of Psychiatry, Department of Medical Sciences and Public Health, University of Cagliari, Cagliari, Italy; Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
| | | | - Felice Iasevoli
- Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry and Unit of Treatment Resistant Psychosis, Department of Neuroscience, Reproductive Science and Dentistry, University Medical School of Naples "Federico II", Naples, Italy
| | - Christoph U Correll
- The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; Charité Universitätsmedizin Berlin, Department of Child and Adolescent Psychiatry, Berlin, Germany
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18
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Grant CE, Flis A, Ryan BM. Understanding the Role of Dopamine in Cancer: Past, Present, and Future. Carcinogenesis 2022; 43:517-527. [PMID: 35616105 DOI: 10.1093/carcin/bgac045] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 05/12/2022] [Accepted: 05/23/2022] [Indexed: 11/14/2022] Open
Abstract
Dopamine (DA, 3-hydroxytyramine) is member of the catecholamine family and is classically characterized according to its role in the central nervous system as a neurotransmitter. In recent decades, many novel and intriguing discoveries have been made about the peripheral expression of DA receptors (DRs) and the role of DA signaling in both normal and pathological processes. Drawing from decades of evidence suggesting a link between DA and cancer, the DA pathway (DAP) has recently emerged as a potential target in antitumor therapies. Due to the onerous, expensive, and frequently unsuccessful nature of drug development, the repurposing of dopaminergic drugs for cancer therapy has the potential to greatly benefit patients and drug developers alike. However, the lack of clear mechanistic data supporting the direct involvement of DRs and their downstream signaling components in cancer represents an ongoing challenge that has limited the translation of these drugs to the clinic. Despite this, the breadth of evidence linking DA to cancer and non-tumor cells in the tumor microenvironment (TME) justifies further inquiry into the potential applications of this treatment modality in cancer. Herein, we review the literature characterizing the interplay between the DA signaling axis and cancer, highlighting key findings, and then propose rational lines of investigation to follow.
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Affiliation(s)
- Christopher E Grant
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Amy Flis
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD
| | - Bríd M Ryan
- Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, MD
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19
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Lugg W. Antipsychotic-induced supersensitivity - A reappraisal. Aust N Z J Psychiatry 2022; 56:437-444. [PMID: 34144649 DOI: 10.1177/00048674211025694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVES Tardive dyskinesia, psychotic relapse and treatment-refractory psychosis have long been associated. A common underlying mechanism involving antipsychotic-induced 'supersensitivity', albeit in different brain pathways, was proposed as early as 1978. This piece seeks to reappraise the concept and potential implications of antipsychotic-induced supersensitivity. CONCLUSIONS Evidence increasingly suggests that chronic antipsychotic exposure induces neuroadaptive physiological changes in dopaminergic, and other, neurotransmitter systems that may render some individuals more vulnerable to psychotic relapse - including those receiving continuous antipsychotic treatment. It is possible that in treating every episode of psychosis with prolonged or indefinite antipsychotic therapy, we paradoxically increase the risk of psychotic relapse in a significant proportion of people. A greater appreciation of supersensitivity may allow us to optimise any potential benefits of antipsychotics while minimising the risk of inadvertent iatrogenic harms. More research is needed to improve our understanding of the underlying neurophysiology of supersensitivity and to better identify which individuals are most vulnerable to its development. It is time we paid more attention to the concept, emerging evidence and potential implications of antipsychotic-induced supersensitivity and, where appropriate, adjusted our practice accordingly.
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Affiliation(s)
- William Lugg
- Department of Psychiatry, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
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20
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den Boer JA, de Vries EJ, Borra RJ, Waarde AV, Lammertsma AA, Dierckx RA. Role of Brain Imaging in Drug Development for Psychiatry. Curr Rev Clin Exp Pharmacol 2022; 17:46-71. [DOI: 10.2174/1574884716666210322143458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 12/17/2020] [Accepted: 01/06/2021] [Indexed: 11/22/2022]
Abstract
Background:
Over the last decades, many brain imaging studies have contributed to
new insights in the pathogenesis of psychiatric disease. However, in spite of these developments,
progress in the development of novel therapeutic drugs for prevalent psychiatric health conditions
has been limited.
Objective:
In this review, we discuss translational, diagnostic and methodological issues that have
hampered drug development in CNS disorders with a particular focus on psychiatry. The role of
preclinical models is critically reviewed and opportunities for brain imaging in early stages of drug
development using PET and fMRI are discussed. The role of PET and fMRI in drug development
is reviewed emphasizing the need to engage in collaborations between industry, academia and
phase I units.
Conclusion:
Brain imaging technology has revolutionized the study of psychiatric illnesses, and
during the last decade, neuroimaging has provided valuable insights at different levels of analysis
and brain organization, such as effective connectivity (anatomical), functional connectivity patterns
and neurochemical information that may support both preclinical and clinical drug development.
Since there is no unifying pathophysiological theory of individual psychiatric syndromes and since
many symptoms cut across diagnostic boundaries, a new theoretical framework has been proposed
that may help in defining new targets for treatment and thus enhance drug development in CNS diseases.
In addition, it is argued that new proposals for data-mining and mathematical modelling as
well as freely available databanks for neural network and neurochemical models of rodents combined
with revised psychiatric classification will lead to new validated targets for drug development.
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Affiliation(s)
| | - Erik J.F. de Vries
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Ronald J.H. Borra
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Aren van Waarde
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Adriaan A. Lammertsma
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Rudi A. Dierckx
- Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
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21
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Ma CH, Chan HY, Hsieh MH, Liu CC, Liu CM, Hwu HG, Kuo CH, Chen WJ, Hwang TJ. Identifying dopamine supersensitivity through a randomized controlled study of switching to aripiprazole from other antipsychotic agents in patients with schizophrenia. Ther Adv Psychopharmacol 2022; 12:20451253211064396. [PMID: 35111295 PMCID: PMC8801645 DOI: 10.1177/20451253211064396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 11/16/2021] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND Aripiprazole has been reported to worsen psychotic symptoms when switching from other antipsychotics, possibly due to dopamine supersensitivity psychosis. OBJECTIVE This study aimed to explore the predictors and possible underlying mechanisms of aripiprazole-related psychotic exacerbation. METHODS We conducted an 8-week, open-label, randomized controlled study from October 2007 to September 2009, assigning patients with a primary diagnosis of schizophrenia or schizoaffective disorder to switch from other antipsychotics to aripiprazole with 2-week dual administration, and then to taper off the original agents in fast (n = 38, within 1 week) or slow (n = 41, within 4 weeks) strategies. Positive and Negative Syndrome Scale (PANSS) was examined at day 0, 7, 14, 28, 56. Aripiprazole-related exacerbation (ARE) was defined positive as a 2-point increase in delusion/hallucination dimension score within 28 days compared with baseline. Baseline demographic, clinical and intervention-related variables were compared between the ARE+ and ARE- groups. RESULTS Of the 79 randomized patients, 21 fulfilled the criteria of ARE+ , and 46 were classified as ARE-. Fourteen patients in the ARE+ group had worsening psychotic symptoms in the first and second weeks. Compared with the ARE- group, the ARE+ group had a higher baseline chlorpromazine equivalent dose (405.8 ± 225.8 mg vs 268.1 ± 165.4 mg, p = 0.007) and was associated with prescription of first-generation antipsychotics (p = 0.038). CONCLUSIONS A higher dose of original antipsychotics and prescription of first-generation antipsychotics may be associated with a higher risk of ARE. The underlying mechanism might be covert dopamine supersensitivity psychosis. These findings may help to identify high-risk patients and guide appropriate treatment strategies. TRIAL REGISTRATION ClinicalTrials.gov, identifier: NCT00545467.
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Affiliation(s)
- Chia-Hao Ma
- Department of Psychiatry, National Taiwan University Hospital Yunlin Branch, Douliu City
| | - Hung-Yu Chan
- Department of General Psychiatry, Taoyuan Psychiatric Center, Taoyuan, Taiwan
| | - Ming H Hsieh
- Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Chen-Chung Liu
- Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Chih-Min Liu
- Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Hai-Gwo Hwu
- Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan
| | - Ching-Hua Kuo
- School of Pharmacy, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Wei J Chen
- Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Tzung-Jeng Hwang
- Department of Psychiatry, National Taiwan University Hospital and College of Medicine, No. 7, Chung-Shan South Road, Taipei 10002
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22
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Thalamic dopamine D2-receptor availability in schizophrenia: a study on antipsychotic-naive patients with first-episode psychosis and a meta-analysis. Mol Psychiatry 2022; 27:1233-1240. [PMID: 34759359 PMCID: PMC9054658 DOI: 10.1038/s41380-021-01349-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 09/24/2021] [Accepted: 10/04/2021] [Indexed: 12/16/2022]
Abstract
Pharmacological and genetic evidence support a role for an involvement of the dopamine D2-receptor (D2-R) in the pathophysiology of schizophrenia. Previous molecular imaging studies have suggested lower levels of D2-R in thalamus, but results are inconclusive. The objective of the present study was to use improved methodology to compare D2-R density in whole thalamus and thalamic subregions between first-episode psychosis patients and healthy controls. Differences in thalamocortical connectivity was explored based on the D2-R results. 19 antipsychotic-naive first-episode psychosis patients and 19 age- and sex-matched healthy controls were examined using high-resolution Positron Emission Tomography (PET) and the high-affinity D2-R radioligand [11C]FLB457. The main outcome was D2-R binding potential (BPND) in thalamus, and it was predicted that patients would have lower binding. Diffusion tensor imaging (DTI) was performed in a subgroup of 11 patients and 15 controls. D2-R binding in whole thalamus was lower in patients compared with controls (Cohen's dz = -0.479, p = 0.026, Bayes Factor (BF) > 4). Among subregions, lower BPND was observed in the ROI representing thalamic connectivity to the frontal cortex (Cohen's dz = -0.527, p = 0.017, BF > 6). A meta-analysis, including the sample of this study, confirmed significantly lower thalamic D2-R availability in patients. Exploratory analyses suggested that patients had lower fractional anisotropy values compared with controls (Cohen's d = -0.692, p = 0.036) in the inferior thalamic radiation. The findings support the hypothesis of a dysregulation of thalamic dopaminergic neurotransmission in schizophrenia, and it is hypothesized that this could underlie a disturbance of thalamocortical connectivity.
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23
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Ferraiolo M, Atik H, Ponthot R, Belo do Nascimento I, Beckers P, Stove C, Hermans E. Receptor density influences ligand-induced dopamine D 2L receptor homodimerization. Eur J Pharmacol 2021; 911:174557. [PMID: 34626593 DOI: 10.1016/j.ejphar.2021.174557] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 09/03/2021] [Accepted: 09/10/2021] [Indexed: 01/23/2023]
Abstract
Chronic treatments with dopamine D2 receptor ligands induce fluctuations in D2 receptor density. Since D2 receptors tend to assemble as homodimers, we hypothesized that receptor density might influence constitutive and ligand-induced homodimerization. Using a nanoluciferase-based complementation assay to monitor dopamine D2L receptor homodimerization in a cellular model enabling the tetracycline-controlled expression of dopamine D2L receptors, we observed that increasing receptor density promoted constitutive dopamine D2L receptor homodimerization. Receptor full agonists promoted homodimerization, while antagonists and partial agonists disrupted dopamine D2L receptor homodimers. High receptor densities enhanced this inhibitory effect only for receptor antagonists. Taken together, our findings indicate that both receptor density and receptor ligands influence dopamine D2L receptor homodimerization, albeit excluding any strict correlation with ligands' intrinsic activity and highlighting further complexity to dopaminergic pharmacology.
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Affiliation(s)
- Mattia Ferraiolo
- Neuropharmacology Laboratory, Institute of Neuroscience, UCLouvain, Brussels, Belgium
| | - Hicham Atik
- Neuropharmacology Laboratory, Institute of Neuroscience, UCLouvain, Brussels, Belgium
| | - Romane Ponthot
- Neuropharmacology Laboratory, Institute of Neuroscience, UCLouvain, Brussels, Belgium
| | | | - Pauline Beckers
- Neuropharmacology Laboratory, Institute of Neuroscience, UCLouvain, Brussels, Belgium
| | - Christophe Stove
- Laboratory of Toxicology, Department of Bioanalysis, Ghent University, Ghent, Belgium
| | - Emmanuel Hermans
- Neuropharmacology Laboratory, Institute of Neuroscience, UCLouvain, Brussels, Belgium.
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24
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Kruyer A, Parrilla-Carrero J, Powell C, Brandt L, Gutwinski S, Angelis A, Chalhoub RM, Jhou TC, Kalivas PW, Amato D. Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity. Mol Psychiatry 2021; 26:6159-6169. [PMID: 34349226 PMCID: PMC8760070 DOI: 10.1038/s41380-021-01235-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 07/05/2021] [Accepted: 07/07/2021] [Indexed: 02/07/2023]
Abstract
Antipsychotic-induced dopamine supersensitivity, or behavioral supersensitivity, is a problematic consequence of long-term antipsychotic treatment characterized by the emergence of motor abnormalities, refractory symptoms, and rebound psychosis. The underlying mechanisms are unclear and no approaches exist to prevent or reverse these unwanted effects of antipsychotic treatment. Here we demonstrate that behavioral supersensitivity stems from long-lasting pre, post and perisynaptic plasticity, including insertion of Ca2+-permeable AMPA receptors and loss of D2 receptor-dependent inhibitory postsynaptic currents (IPSCs) in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). The resulting hyperexcitability, prominent in a subpopulation of D2-MSNs (21%), caused locomotor sensitization to cocaine and was associated with behavioral endophenotypes of antipsychotic treatment resistance and substance use disorder, including disrupted extinction learning and augmented cue-induced cocaine-seeking behavior. Chemogenetic restoration of IPSCs in D2-MSNs in the NAcore was sufficient to prevent antipsychotic-induced supersensitivity, pointing to an entirely novel therapeutic direction for overcoming this condition.
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Affiliation(s)
- Anna Kruyer
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA
| | | | - Courtney Powell
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA
| | - Lasse Brandt
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Stefan Gutwinski
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Ariana Angelis
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA
| | - Reda M Chalhoub
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA
| | - Thomas C Jhou
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA
| | - Peter W Kalivas
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA
| | - Davide Amato
- Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
- Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany.
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25
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Kimura M, Oda Y, Hirose Y, Kimura H, Yoshino K, Niitsu T, Kanahara N, Shirayama Y, Hashimoto K, Iyo M. Upregulation of heat-shock protein HSP-70 and glutamate transporter-1/glutamine synthetase in the striatum and hippocampus in haloperidol-induced dopamine-supersensitivity-state rats. Pharmacol Biochem Behav 2021; 211:173288. [PMID: 34653399 DOI: 10.1016/j.pbb.2021.173288] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 10/07/2021] [Accepted: 10/07/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND The excessive blockade of dopamine D2 receptors (DRD2s) with long-term antipsychotic treatment is known to induce a dopamine supersensitivity state (DSS). The mechanism of DSS is speculated to be a compensatory up-regulation of DRD2s, but an excess blockade of DRD2s can also cause glutamatergic neuronal damage. Herein, we investigated whether antipsychotic-induced neuronal damage plays a role in the development of DSS. METHODS Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. Haloperidol-treated rats were divided into groups of DSS rats and non-DSS rats based on their voluntary locomotion data. We then determined the tissue levels of glutamate transporter-1 (GLT-1)/glutamine synthetase (GS) and heat shock protein-70 (HSP-70) in the rats' brain regions. RESULTS The levels of HSP-70 in the striatum and CA-3 region of the DSS rats were significantly higher than those of the control and non-DSS rats, whereas the dentate gyrus HSP-70 levels in both the DSS and non-DSS rats were increased versus the controls. The levels of GLT-1/GS in the CA-3 and nucleus accumbens were increased in the DSS rats. CONCLUSIONS These results suggest that the DSS rats experienced striatal neuronal damage and indicate that a HAL-induced upregulation of HSP-70 and the GLT-1/GS system in the CA3 may be involved in the development of DSS. It remains unknown why the non-DSS rats did not suffer neuronal damage. In view of the need for therapeutic strategies for treatment-resistant schizophrenia, dopamine supersensitivity psychosis, and tardive dyskinesia, further investigations of our findings are warranted.
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Affiliation(s)
- Makoto Kimura
- Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan
| | - Yasunori Oda
- Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan.
| | - Yuki Hirose
- Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan
| | - Hiroshi Kimura
- Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan; Department of Psychiatry, School of Medicine, International University of Health and Welfare, 4-3 Kozunomori, Narita, Chiba 286-8686, Japan
| | - Kouhei Yoshino
- Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan
| | - Tomihisa Niitsu
- Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan
| | - Nobuhisa Kanahara
- Division of Medical Treatment and Rehabilitation, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan
| | - Yukihiko Shirayama
- Department of Psychiatry, Teikyo University Chiba Medical Center, 3426-3 Anesaki, Ichihara, Chiba 290-0111, Japan
| | - Kenji Hashimoto
- Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan
| | - Masaomi Iyo
- Department of Psychiatry, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba, Chiba 260-8670, Japan
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26
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Horowitz MA, Jauhar S, Natesan S, Murray RM, Taylor D. A Method for Tapering Antipsychotic Treatment That May Minimize the Risk of Relapse. Schizophr Bull 2021; 47:1116-1129. [PMID: 33754644 PMCID: PMC8266572 DOI: 10.1093/schbul/sbab017] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The process of stopping antipsychotics may be causally related to relapse, potentially linked to neuroadaptations that persist after cessation, including dopaminergic hypersensitivity. Therefore, the risk of relapse on cessation of antipsychotics may be minimized by more gradual tapering. There is converging evidence that suggests that adaptations to antipsychotic exposure can persist for months or years after stopping the medication-from animal studies, observation of tardive dyskinesia in patients, and the clustering of relapses in this time period after the cessation of antipsychotics. Furthermore, PET imaging demonstrates a hyperbolic relationship between doses of antipsychotic and D2 receptor blockade. We, therefore, suggest that when antipsychotics are reduced, it should be done gradually (over months or years) and in a hyperbolic manner (to reduce D2 blockade "evenly"): ie, reducing by one quarter (or one half) of the most recent dose of antipsychotic, equivalent approximately to a reduction of 5 (or 10) percentage points of its D2 blockade, sequentially (so that reductions become smaller and smaller in size as total dose decreases), at intervals of 3-6 months, titrated to individual tolerance. Some patients may prefer to taper at 10% or less of their most recent dose each month. This process might allow underlying adaptations time to resolve, possibly reducing the risk of relapse on discontinuation. Final doses before complete cessation may need to be as small as 1/40th a therapeutic dose to prevent a large decrease in D2 blockade when stopped. This proposal should be tested in randomized controlled trials.
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Affiliation(s)
- Mark Abie Horowitz
- Division of Psychiatry, University College London, Maple House, 149 Tottenham Court Road, Fitzrovia, London W1T 7BN, UK
- North East London Foundation Trust. Goodmayes Hospital, 157 Barley Lane, Goodmayes, Ilford IG3 8XJ, UK
| | - Sameer Jauhar
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, Camberwell, London SE5 8AF, UK
| | - Sridhar Natesan
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, Camberwell, London SE5 8AF, UK
| | - Robin M Murray
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, Camberwell, London SE5 8AF, UK
| | - David Taylor
- Institute of Psychiatry, Psychology and Neuroscience, King’s College London, 16 De Crespigny Park, Camberwell, London SE5 8AF, UK
- Pharmacy Department, South London and Maudsley NHS Foundation Trust, London SE5 8AZ, UK
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Characterization of dopamine D 2 receptor coupling to G proteins in postmortem brain of subjects with schizophrenia. Pharmacol Rep 2021; 73:1136-1146. [PMID: 34196951 PMCID: PMC8413194 DOI: 10.1007/s43440-021-00305-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 06/16/2021] [Accepted: 06/24/2021] [Indexed: 11/04/2022]
Abstract
Background Alterations of dopamine D1 (D1R) and D2 receptor (D2R) are proposed in schizophrenia but brain neuroimaging and postmortem studies have shown controversial results in relation to D1R and D2R density. Besides, scarce information on the functionality of brain D1R and D2R is available. The present study characterized G-protein activation by D1R and D2R agonists in postmortem human brain. Furthermore, D2R functional status was compared between schizophrenia and control subjects. Methods G-protein receptor coupling was assessed in control caudate nucleus and frontal cortex by [35S]GTPγS-binding stimulation induced by increasing concentrations (10–10–10–3 M) of dopamine, and the selective dopaminergic agonists SKF38393 (D1R) and NPA (D2R). Concentration–response curves to NPA stimulation of [35S]GTPγS binding were analyzed in antipsychotic-free (n = 10) and antipsychotic-treated (n = 7) schizophrenia subjects and matched controls (n = 17). Results In caudate, [35S]GTPγS-binding responses to agonists were compatible with the existence of functional D2R. In contrast, stimulations in cortex showed responses that did not correspond to D1R or D2R. [35S]GTPγS-binding activation by NPA in caudate displayed biphasic curves with similar profile in schizophrenia (EC50H = 7.94 nM; EC50L = 7.08 μM) and control (EC50H = 7.24 nM; EC50L = 15.14 μM) subjects. The presence or absence of antipsychotic medication did not influence the pharmacological parameters. Conclusions Feasibility of functional evaluation of dopamine receptors in postmortem human brain by conventional [35S]GTPγS-binding assays appears to be restricted to signalling through inhibitory Gi/o proteins. These findings provide functional information about brain D2R status in subjects with schizophrenia and do not support the existence of D2R supersensitive in this mental disorder. Supplementary Information The online version contains supplementary material available at 10.1007/s43440-021-00305-4.
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Stämpfli D, Weiler S, Burden AM. Movement disorders and use of risperidone and methylphenidate: a review of case reports and an analysis of the WHO database in pharmacovigilance. Eur Child Adolesc Psychiatry 2021; 30:1047-1058. [PMID: 32621088 DOI: 10.1007/s00787-020-01589-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 06/26/2020] [Indexed: 11/30/2022]
Abstract
For patients with attention deficit hyperactivity disorder and comorbid conduct-dissocial disorder, a combination therapy of the psychostimulant methylphenidate and the antipsychotic risperidone may be prescribed. Case reports describe the occurrence of movement disorders under this combination therapy, but clinical trials had limited power to detect these events. This study aimed (1) to summarise published case reports and (2) to analyse pharmacovigilance data consisting of adverse drug event reports to elucidate these reactions. PubMed, Embase, and APA PsycInfo were used to retrieve case reports. For the pharmacovigilance data, aggregated information on individual case safety reports (ICSRs) within the database of suspected adverse drug events by the WHO were analysed. ICSRs were assessed for disproportionality in reporting. Thirteen published case reports (62% male) on movement disorders were identified, with ages between 5 and 15 years. Seven reports (54%) described incidents when risperidone was tapered down or switched to methylphenidate. From the WHO, we identified 25,556 ICSRs (16,118 for methylphenidate, 8,614 for risperidone, and 824 for both). Of these, 953 (5.9%), 1356 (15.7%), and 159 (19.3%) ICSRs reported movement disorders in association with methylphenidate, risperidone or both, respectively. The analyses on disproportionality showed an increased number of ICSRs with movement disorders when the two drugs were coded in combination. The potential of movement disorders as adverse effects might be amplified when methylphenidate and risperidone are used in combination. The results from the literature underline the necessity of caution and patient monitoring when risperidone dosing is modified during methylphenidate therapy.
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Affiliation(s)
- Dominik Stämpfli
- Pharmacoepidemiology, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland.
| | - Stefan Weiler
- Pharmacoepidemiology, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland.,National Poisons Information Centre, Tox Info Suisse, Associated Institute of the University of Zurich, Zurich, Switzerland
| | - Andrea M Burden
- Pharmacoepidemiology, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland
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Cope ZA, Kenton JA, Minassian A, Martin MV, Perry W, Bundgaard C, Arnt J, van Enkhuizen J, Geyer MA, Young JW. Chronic antipsychotic treatment exerts limited effects on the mania-like behavior of dopamine transporter knockdown mice. Behav Brain Res 2021; 405:113167. [PMID: 33577882 PMCID: PMC10729608 DOI: 10.1016/j.bbr.2021.113167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 11/26/2022]
Abstract
BACKGROUND Bipolar disorder is a life-threatening disorder linked to dopamine transporter (DAT) polymorphisms, with reduced DAT levels seen in positron emission tomography and postmortem brains. AIMS The purpose of this study was to examine the effects of approved antipsychotics on DAT dysfunction-mediated mania behavior in mice. METHODS DAT knockdown mice received either D2-family receptor antagonist risperidone or asenapine and mania-related behaviors were assessed in the clinically-relevant behavioral pattern monitor to assess spontaneous exploration. RESULTS Chronic risperidone did not reverse mania-like behavior in DAT knockdown mice. Chronic asenapine reduced mania behavior but this effect was more pronounced in wild-type littermates than in DAT knockdown mice. CONCLUSION Taken together, these findings suggest that while acute antipsychotic treatment may be beneficial in management of bipolar mania, more targeted therapeutics may be necessary for long-term treatment. Specific investigation into DAT-targeting drugs could improve future treatment of bipolar mania.
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Affiliation(s)
- Zackary A Cope
- Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, United States
| | - Johnny A Kenton
- Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, United States
| | - Arpi Minassian
- Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, United States; Center of Excellence for Stress and Mental Health and Research Service, VA San Diego Healthcare System, United States
| | - Maureen V Martin
- Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, United States
| | - William Perry
- Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, United States
| | - Christoffer Bundgaard
- H. Lundbeck A/S. Neuroscience Research, Ottiliavej 9, DK-2500, Copenhagen, Valby, Denmark
| | - Jørn Arnt
- Sunred Pharma Consulting, Solrød Strand, Denmark
| | - Jordy van Enkhuizen
- Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, United States
| | - Mark A Geyer
- Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, United States; Research Service, VA San Diego Healthcare System, San Diego, CA, United States
| | - Jared W Young
- Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, United States; Research Service, VA San Diego Healthcare System, San Diego, CA, United States.
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Mitelman SA, Buchsbaum MS, Christian BT, Merrill BM, Buchsbaum BR, Mukherjee J, Lehrer DS. Dopamine receptor density and white mater integrity: 18F-fallypride positron emission tomography and diffusion tensor imaging study in healthy and schizophrenia subjects. Brain Imaging Behav 2021; 14:736-752. [PMID: 30523488 DOI: 10.1007/s11682-018-0012-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Dopaminergic dysfunction and changes in white matter integrity are among the most replicated findings in schizophrenia. A modulating role of dopamine in myelin formation has been proposed in animal models and healthy human brain, but has not yet been systematically explored in schizophrenia. We used diffusion tensor imaging and 18F-fallypride positron emission tomography in 19 healthy and 25 schizophrenia subjects to assess the relationship between gray matter dopamine D2/D3 receptor density and white matter fractional anisotropy in each diagnostic group. AFNI regions of interest were acquired for 42 cortical Brodmann areas and subcortical gray matter structures as well as stereotaxically placed in representative white matter areas implicated in schizophrenia neuroimaging literature. Welch's t-test with permutation-based p value adjustment was used to compare means of z-transformed correlations between fractional anisotropy and 18F-fallypride binding potentials in hypothesis-driven regions of interest in the diagnostic groups. Healthy subjects displayed an extensive pattern of predominantly negative correlations between 18F-fallypride binding across a range of cortical and subcortical gray matter regions and fractional anisotropy in rostral white matter regions (internal capsule, frontal lobe, anterior corpus callosum). These patterns were disrupted in subjects with schizophrenia, who displayed significantly weaker overall correlations as well as comparatively scant numbers of significant correlations with the internal capsule and frontal (but not temporal) white matter, especially for dopamine receptor density in thalamic nuclei. Dopamine D2/D3 receptor density and white matter integrity appear to be interrelated, and their decreases in schizophrenia may stem from hyperdopaminergia with dysregulation of dopaminergic impact on axonal myelination.
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Affiliation(s)
- Serge A Mitelman
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA. .,Department of Psychiatry, Division of Child and Adolescent Psychiatry, Elmhurst Hospital Center, 79-01 Broadway, Elmhurst, NY, 11373, USA.
| | - Monte S Buchsbaum
- Departments of Psychiatry and Radiology, University of California, San Diego, 11388 Sorrento Valley Road, San Diego, CA, 92121, USA.,Department of Psychiatry and Human Behavior, Irvine School of Medicine, University of California, 101 The City Dr. S, Orange, CA, 92868, USA
| | - Bradley T Christian
- Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, 1500 Highland Avenue, Room T231, Madison, WI, 53705, USA
| | - Brian M Merrill
- Department of Psychiatry, Boonshoft School of Medicine, Wright State University, East Medical Plaza, Dayton, OH, 45408, USA
| | - Bradley R Buchsbaum
- The Rotman Research Institute, Baycrest Centre for Geriatric Care and Department of Psychiatry, University of Toronto, 3560 Bathurst St, Toronto, ON, M6A 2E1, Canada
| | - Jogeshwar Mukherjee
- Department of Radiological Sciences, Preclinical Imaging, Irvine School of Medicine, University of California, Irvine, CA, 92697, USA
| | - Douglas S Lehrer
- Department of Psychiatry, Boonshoft School of Medicine, Wright State University, East Medical Plaza, Dayton, OH, 45408, USA
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Takao N, Murai T, Fujiwara H. Treatment-resistant schizophrenia characterised by dopamine supersensitivity psychosis and efficacy of asenapine. BMJ Case Rep 2021; 14:e242495. [PMID: 33849886 PMCID: PMC8051386 DOI: 10.1136/bcr-2021-242495] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/30/2021] [Indexed: 11/21/2022] Open
Abstract
Dopamine supersensitivity psychosis (DSP) frequently arises with long-term antipsychotic treatment and accounts for a significant proportion of treatment-resistant schizophrenia. The mechanism underlying DSP is thought to be a compensatory increase in dopamine receptor density in the striatum caused by long-term antipsychotic treatment. Previous animal studies have reported that antipsychotics increase serotonin 5-HT2A receptor density in the striatum and that 5-HT2A receptor blockers suppress dopamine-sensitive psychomotor activity, which may be linked to the pathophysiology of DSP. In this paper, we describe a patient who was hospitalised with treatment-resistant schizophrenia. Following treatment with high-dose antipsychotic polypharmacy for 10 weeks, the patient experienced worsening of psychotic and extrapyramidal symptoms. The patient was then started on second-generation antipsychotic asenapine while other antipsychotics were tapered off, resulting in improvement of these symptoms. Retrospectively, we presumed that the high-dose antipsychotic polypharmacy caused DSP, which was effectively treated by the potent 5-HT2A receptor antagonism of asenapine.
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Affiliation(s)
- Nagara Takao
- Psychiatry, Kyoto University Hospital, Kyoto, Japan
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32
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Effects of repeated electroconvulsive shocks on dopamine supersensitivity psychosis model rats. Schizophr Res 2021; 228:1-6. [PMID: 33429150 DOI: 10.1016/j.schres.2020.11.062] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 08/26/2020] [Accepted: 11/27/2020] [Indexed: 01/08/2023]
Abstract
While the long-term administration of antipsychotics is known to cause dopamine supersensitivity psychosis (DSP), recent studies revealed that DSP helps form the foundation of treatment resistance. Electroconvulsive shock (ES) is one of the more effective treatments for treatment-resistant schizophrenia. The objective of this study was to examine whether repeated ES can release rats from dopamine supersensitivity states such as striatal dopamine D2 receptor (DRD2) up-regulation and voluntary hyperlocomotion following chronic administration of haloperidol (HAL). HAL (0.75 mg/kg/day) was administered for 14 days via mini-pumps implanted in rats, and DRD2 density and voluntary locomotion were measured one day after drug cessation to confirm the development of dopamine supersensitivity. The rats with or without dopamine supersensitivity received repeated ES or sham treatments, and then DRD2 density was assessed and a voluntary locomotion test was performed. Chronic treatment with HAL led to the up-regulation of striatal DRD2 and hyperlocomotion in the rats one day after drug cessation. We thus confirmed that these rats experienced a dopamine supersensitivity state. Moreover, after repeated ES, locomotor activity and DRD2 density in the DSP model rats fell to the control level, while an ES sham operation had no effect on the dopamine supersensitivity state. The present study suggests that repeated ES could release DSP model rats from dopamine supersensitivity states. ES may be helpful for patients with DSP.
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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; 403:113126. [PMID: 33460681 DOI: 10.1016/j.bbr.2021.113126] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/29/2020] [Accepted: 01/04/2021] [Indexed: 12/12/2022]
Abstract
The long-term treatment of patients with schizophrenia often involves the management of relapses for most patients and the development of treatment resistance in some patients. To stabilize the clinical course and allow as many patients as possible to recover, clinicians need to recognize dopamine supersensitivity, which can be provoked by administration of high dosages of antipsychotics, and deal with it properly. However, no treatment guidelines have addressed this issue. The present review summarized the characteristics of long-acting injectable antipsychotics, dopamine partial agonists, and clozapine in relation to dopamine supersensitivity from the viewpoints of receptor profiles and pharmacokinetics. The potential merits and limitations of these medicines are discussed, as well as the risks of treating patients with established dopamine supersensitivity with these classes of drugs. Finally, the review discussed the biological influence of antipsychotic treatment on the human brain based on findings regarding the relationship between the hippocampus and antipsychotics.
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Affiliation(s)
- Hiroshi Kimura
- Department of Psychiatry, School of Medicine, International University of Health and Welfare, Chiba, Japan; Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Department of Psychiatry, Gakuji-kai Kimura Hospital, Chiba, Japan.
| | - Nobuhisa Kanahara
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Division of Medical Treatment and Rehabilitation, Chiba University Center for Forensic Mental Health, Chiba, Japan
| | - Masaomi Iyo
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
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Rubio JM, Malhotra AK, Kane JM. Towards a framework to develop neuroimaging biomarkers of relapse in schizophrenia. Behav Brain Res 2021; 402:113099. [PMID: 33417996 DOI: 10.1016/j.bbr.2020.113099] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 12/16/2020] [Accepted: 12/27/2020] [Indexed: 12/31/2022]
Abstract
Schizophrenia is a chronic disorder that often requires long-term relapse-prevention treatment. This treatment is effective for most individuals, yet approximately 20-30 % of them may still relapse despite confirmed adherence. Alternatively, for about 15 % it may be safe to discontinue medications over the long term, but since there are no means to identify who those individuals will be, the recommendation is that all individuals receive long-term relapse-prevention treatment with antipsychotic maintenance. Thus, the current approach to prevent relapse in schizophrenia may be suboptimal for over one third of individuals, either by being insufficient to protect against relapse, or by unnecessarily exposing them to medication side effects. There is great need to identify biomarkers of relapse in schizophrenia to stratify treatment according to the risk and develop therapeutics targeting its pathophysiology. In order to develop a line of research that meets those needs, it is necessary to create a framework by identifying the challenges to this type of study as well as potential areas for biomarker identification and development. In this manuscript we review the literature to create such a framework.
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Affiliation(s)
- Jose M Rubio
- The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Manhasset, NY, USA.
| | - Anil K Malhotra
- The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Manhasset, NY, USA
| | - John M Kane
- The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Manhasset, NY, USA
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Emsley R, Asmal L, Rubio JM, Correll CU, Kane JM. Predictors of psychosis breakthrough during 24 months of long-acting antipsychotic maintenance treatment in first episode schizophrenia. Schizophr Res 2020; 225:55-62. [PMID: 31767510 DOI: 10.1016/j.schres.2019.11.025] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2019] [Revised: 11/11/2019] [Accepted: 11/13/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Some patients develop breakthrough psychotic symptoms on antipsychotic maintenance medication (BAMM), despite receiving therapeutic antipsychotic doses to which they previously responded. METHODS We examined the occurrence of BAMM in previously minimally treated first-episode patients with schizophrenia-spectrum disorders who were treated according to a standard protocol with a long-acting injectable antipsychotic and regularly assessed over 24 months. RESULTS Of 99 patients (age = 24.1 ± 6.5 years, male = 73.7%) who received treatment for ≥6 months (mean follow-up = 20.0 ± 6.5 months) and had responded well to treatment, 21 (21.2%) developed BAMM using operationally defined criteria, after a mean of 17.4 ± 6.1 months. Baseline risk factors for BAMM included lower baseline Positive and Negative Syndrome Scale positive symptoms, poorer quality of life in social relationships and higher blood - high-density lipoprotein-cholesterol. Regarding intra-treatment-factors, BAMM was independently predicted by an increase in low-density lipoprotein-cholesterol and current cannabis use. We did not find a relationship between BAMM and cumulative antipsychotic exposure or dose escalation. While symptoms of the BAMM episode were less severe than during the first episode, the post-BAMM treatment response was poorer than that for the first psychotic episode, suggesting a relationship between BAMM and emergent treatment refractoriness. CONCLUSIONS About one in five patients with first-episode schizophrenia developed BAMM during the first two years of treatment, despite assured antipsychotic LAI treatment, indicating that this phenomenon is not restricted to the chronic stages of illness. The role of cannabis use and a possible link between BAMM and blood lipids should be further explored.
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Affiliation(s)
- Robin Emsley
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, 8000 Cape Town, South Africa.
| | - Laila Asmal
- Department of Psychiatry, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, 8000 Cape Town, South Africa
| | - Jose M Rubio
- The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Manhasset, NY, USA
| | - Christoph U Correll
- The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Manhasset, NY, USA; Charité Universitätsmedizin Berlin, Department of Child and Adolescent Psychiatry, Berlin, Germany
| | - John M Kane
- The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Manhasset, NY, USA
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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; 35:338-344. [PMID: 32868522 DOI: 10.1097/yic.0000000000000322] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Dopamine supersensitivity psychosis (DSP) in patients with schizophrenia is induced by treatment with a high dosage of antipsychotics for a long time period, and it is characterized by unstable psychotic symptoms. The upregulation of dopamine D2 receptor (DRD2) provoked by antipsychotics underlies DSP. Aripiprazole does not cause an excessive blockade of DRD2 and is less likely to upregulate DRD2 by aripiprazole's dopamine partial agonistic profile. Aripiprazole; however, has a potential risk of inducing severe rebound psychosis in patients who have already developed dopamine supersensitivity. Recently, an animal model study suggested that aripiprazole could attenuate established dopamine supersensitivity. The present study was conducted to examine whether very slowly switching to aripiprazole could help patients with schizophrenia with dopamine supersensitivity while avoiding rebound psychosis. This study was a single-armed and open-labeled study in which patients were observed over a period of 2 years. Only 11 patients were ultimately recruited. Five patients were successfully switched to a sufficient dose of aripiprazole and completed the study protocol. These five patients did not present with severe DSP over the study period, but only one patient showed a large improvement in psychopathology. Five patients dropped out of the study, and one of these five showed a severe worsening of psychosis. The present study indicated that the introduction of aripiprazole in patients with DSP was difficult, but suggested that aripiprazole could contribute to attaining a stable state in psychosis if it was applied with careful observation.
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The mGluR2/3 agonist pomaglumetad methionil normalizes aberrant dopamine neuron activity via action in the ventral hippocampus. Neuropsychopharmacology 2020; 45:2106-2113. [PMID: 32663839 PMCID: PMC7547679 DOI: 10.1038/s41386-020-0764-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 05/27/2020] [Accepted: 07/08/2020] [Indexed: 11/09/2022]
Abstract
The group 2 metabotropic glutamate receptor (mGluR2/3) agonist, pomaglumetad methionil (POM), showed promise as a novel antipsychotic in preclinical research but failed to show efficacy in clinical trials, though it has been suggested that it may be effective in certain patient populations. Although previous studies have shown that mGluR2/3 agonists have no effect on dopamine (DA) in wild type rats, we used the methylzoxymethanol acetate (MAM) model to determine whether POM may indirectly normalize DA neuron activity in a model representative of the hyperdopaminergic state thought to underlie psychosis, compared to SAL rats, using in vivo, anesthetized, electrophysiological recordings. POM dose-dependently reduced the number of spontaneously active DA neurons in the VTA of MAM rats to control levels without affecting DA firing in SAL rats, which persisted following 14d repeated treatment with POM. In female MAM rats, POM significantly reduced DA neuron population activity only during proestrous and estrous stages. MAM rats also demonstrated dose-dependent improvement in novel object recognition following acute POM, which was not observed in SAL rats. Similar to the MAM rats, DA neuron population activity was increased in a hippocampal-dependent manner following acute restraint stress. Administration of POM prior to 2 h restraint stress prevented the restraint-induced increase in DA neuron population activity, and this effect was blocked by pretreatment with an mGluR2/3 antagonist. Thus, the ability of POM to reduce the hyperdopaminergic activity in both MAM rats and in wild type rats following restraint stress suggests that it can indirectly regulate DA neuron activity, which may underlie its potential therapeutic effects.
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Abstract
Tardive dyskinesia (TD) is a delayed and potentially irreversible motor complication following chronic exposure to centrally acting dopamine receptor antagonists, mainly of the class of antipsychotics drugs. New generations of antipsychotic drugs reduced its mean prevalence to 20%, but it continues to mar the drug experience and social integration in a significant fraction of patients. The underlying molecular cascade remains elusive, explaining in part why TD management is so often difficult. Protocol variations between experimental laboratories and inter-species differences in the biological response to antipsychotic drugs have added layers of complexity. The traditional dopamine D2 receptor supersensitivity hypothesis was revisited in an experimental nonhuman primate model. Findings in the striatum revealed a strong upregulation of D3, not D2, receptors specific to dyskinetic animals, and indirect evidence suggestive of a link between overactivation of glycogen synthase kinase-3β signaling and TD. New effective vesicular monoamine transporter type 2 inhibitors alleviating TD have been approved in the USA. They were integrated to an emerging stepwise treatment algorithm for troublesome TD, which also includes consideration for changes in the current antipsychotic drug regimen and recognition of potentially aggravating factors such as anticholinergic co-medications. These advances may benefit TD.
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Hui CLM, Lam BST, Lee EHM, Chan SKW, Chang WC, Suen YN, Chen EYH. Perspective on medication decisions following remission from first-episode psychosis. Schizophr Res 2020; 225:82-89. [PMID: 32115314 DOI: 10.1016/j.schres.2020.02.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 02/13/2020] [Accepted: 02/15/2020] [Indexed: 10/24/2022]
Abstract
While antipsychotics (APs) could provide rapid relief of positive symptoms in psychotic disorders, their usage is often associated with side effects, stigma and inconveniences. For these and other reasons, many psychosis patients, particularly those of first-episode psychosis (FEP) in remission, wish to discontinue maintenance treatment. The current review aims to discuss the strategies of AP treatment following remission from FEP, with particular emphasis on the evaluation of outcomes following AP discontinuation. Upon review of relevant literature, three potential strategies are put forth for treatment-responsive, remitted FEP patients: a) life-long maintenance treatment, b) AP discontinuation during second year of treatment, or c) AP discontinuation after three years of treatment. In theory, the first strategy presents the safest option for maximal symptom control. However, a rigorous RCT indicates that if AP discontinuation is to be attempted, the third strategy best prevents poor long-term clinical outcomes. Further data is needed to address the costs and benefits of each treatment strategy, compare AP-free patients with those on different types of APs, as well as explore even longer-term outcomes.
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Affiliation(s)
- Christy L M Hui
- Department of Psychiatry, University of Hong Kong, Hong Kong, China.
| | - Bertha S T Lam
- Department of Psychiatry, University of Hong Kong, Hong Kong, China
| | - Edwin H M Lee
- Department of Psychiatry, University of Hong Kong, Hong Kong, China
| | - Sherry K W Chan
- Department of Psychiatry, University of Hong Kong, Hong Kong, China; State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, China
| | - W C Chang
- Department of Psychiatry, University of Hong Kong, Hong Kong, China; State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, China
| | - Y N Suen
- Department of Psychiatry, University of Hong Kong, Hong Kong, China
| | - Eric Y H Chen
- Department of Psychiatry, University of Hong Kong, Hong Kong, China; State Key Laboratory of Brain and Cognitive Sciences, University of Hong Kong, Hong Kong, China
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Abstract
Tardive syndrome (TS) is an iatrogenic, often persistent movement disorder caused by drugs that block dopamine receptors. It has a broad phenotype including movement (orobuccolingual stereotypy, dystonia, tics, and others) and nonmotor features (akathisia and pain). TS has garnered increased attention of late because of the Food and Drug Administration approval of the first therapeutic agents developed specifically for this purpose. This paper will begin with a discussion on pathogenesis, clinical features, and epidemiology. However, the main focus will be treatment options currently available for TS including a suggested algorithm based on current evidence. Recently, there have been significant advances in TS therapy, particularly with the development of 2 new vesicular monoamine transporter type 2 inhibitors for TS and with new data on the efficacy of deep brain stimulation. The discussion will start with switching antipsychotics and the use of clozapine monotherapy which, despite the lack of higher-level evidence, should be considered for the treatment of psychosis and TS. Anti-dyskinetic drugs are separated into 3 tiers: 1) vesicular monoamine transporter type 2 inhibitors, which have level A evidence, are approved for use in TS and are recommended first-choice agents; 2) drugs with lower level of evidence for efficacy including clonazepam, Ginkgo biloba, and amantadine; and 3) drugs that have the potential to be beneficial, but currently have insufficient evidence including levetiracetam, piracetam, vitamin B6, melatonin, baclofen, propranolol, zolpidem, and zonisamide. Finally, the roles of botulinum toxin and surgical therapy will be examined. Current therapies, though improved, are symptomatic. Next steps should focus on the prevention and reversal of the pathogenic process.
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Affiliation(s)
- Stewart A Factor
- Jean and Paul Amos Parkinson's Disease and Movement Disorder Program, Emory University School of Medicine, 12 Executive Park Drive Northeast, Atlanta, Georgia, 30329, USA.
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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. 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; 53:102369. [PMID: 32920492 DOI: 10.1016/j.ajp.2020.102369] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 08/13/2020] [Accepted: 08/23/2020] [Indexed: 12/14/2022]
Abstract
Dopamine supersensitivity psychosis (DSP) is a key factor contributing to the development of antipsychotic treatment-resistant schizophrenia. We examined the efficacy and safety of blonanserin (BNS) and olanzapine (OLZ) as adjuncts to prior antipsychotic treatment in patients with schizophrenia and DSP in a 24-week, multicenter (17 sites), randomized, rater-blinded study with two parallel groups (BNS and OLZ add-on treatments) in patients with schizophrenia and DSP: the ROADS Study. The primary outcome was the change in the Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 24. Secondary outcomes were changes in the PANSS subscale scores, Clinical Global Impressions, and Extrapyramidal Symptom Rating Scale (ESRS), and changes in antipsychotic doses. The 61 assessed patients were allocated into a BNS group (n = 26) and an OLZ group (n = 29). The PANSS total scores were reduced in both groups (mean ± SD: -14.8 ± 24.0, p = 0.0042; -10.5 ± 12.9, p = 0.0003; respectively) with no significant between-group difference (mean, -4.3, 95 %CI 15.1-6.4, p = 0.42). The BNS group showed significant reductions from week 4; the OLZ group showed significant reductions from week 8. The ESRS scores were reduced in the BNS group and the others were reduced in both groups. The antipsychotic monotherapy rates at the endpoint were 26.3 % (n = 6) for BNS and 23.8 % (n = 5) for OLZ. The concomitant antipsychotic doses were reduced in both groups with good tolerability. Our results suggest that augmentations with BNS and OLZ are antipsychotic treatment options for DSP patients, and BNS may be favorable for DSP based on the relatively quick responses to BNS observed herein.
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Affiliation(s)
- Tomihisa Niitsu
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.
| | - Tatsuki Hata
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Fujita Hospital, Sosa, Chiba, Japan
| | | | - Yutaka Hosoda
- Fujita Hospital, Sosa, Chiba, Japan; Child Psychiatry, Chiba University Hospital, Chiba, Japan
| | - Atsushi Kimura
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Yasunori Oda
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
| | | | | | - Ryota Seki
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Chiba Hospital, Funabashi, Chiba, Japan
| | - Kiyoshi Fujita
- Okehazama Hospital Fujita Kokoro Care Center, Toyoake, Aichi, Japan
| | | | | | | | | | | | - Yukitsugu Imamura
- Department of Neuropsychiatry, Asahi General Hospital, Asahi, Chiba, Japan
| | - Kohei Ogawa
- Yowa Hospital, Tokyo, Japan; Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan
| | - Goro Fukami
- Chiba Psychiatric Medical Center, Chiba, Japan
| | - Takatoshi Sato
- Project Leader Office, Clinical Research Center, Chiba University Hospital, Chiba, Japan
| | - Yohei Kawasaki
- Biostatistics Section, Clinical Research Center, Chiba University Hospital, Chiba, Japan
| | - Tasuku Hashimoto
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Sodegaura-Satsukidai Hospital, Sodegaura, Chiba, Japan
| | - Masatomo Ishikawa
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Akihiro Shiina
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Division of Medical Treatment and Rehabilitation, Center for Forensic Mental Health, Chiba University, Chiba, Japan
| | - Nobuhisa Kanahara
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Division of Medical Treatment and Rehabilitation, Center for Forensic Mental Health, Chiba University, Chiba, Japan
| | - Masaomi Iyo
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan; Child Psychiatry, Chiba University Hospital, Chiba, Japan; Division of Medical Treatment and Rehabilitation, Center for Forensic Mental Health, Chiba University, Chiba, Japan
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43
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Hakimi Y, Petitpain N, Pinzani V, Montastruc JL, Bagheri H. Paradoxical adverse drug reactions: descriptive analysis of French reports. Eur J Clin Pharmacol 2020; 76:1169-1174. [DOI: 10.1007/s00228-020-02892-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 05/06/2020] [Indexed: 01/20/2023]
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Mitelman SA, Buchsbaum MS, Christian BT, Merrill BM, Buchsbaum BR, Mukherjee J, Lehrer DS. Positive association between cerebral grey matter metabolism and dopamine D 2/D 3 receptor availability in healthy and schizophrenia subjects: An 18F-fluorodeoxyglucose and 18F-fallypride positron emission tomography study. World J Biol Psychiatry 2020; 21:368-382. [PMID: 31552783 DOI: 10.1080/15622975.2019.1671609] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Objectives: Overlapping decreases in extrastriatal dopamine D2/D3-receptor availability and glucose metabolism have been reported in subjects with schizophrenia. It remains unknown whether these findings are physiologically related or coincidental.Methods: To ascertain this, we used two consecutive 18F-fluorodeoxyglucose and 18F-fallypride positron emission tomography scans in 19 healthy and 25 unmedicated schizophrenia subjects. Matrices of correlations between 18F-fluorodeoxyglucose uptake and 18F-fallypride binding in voxels at the same xyz location and AFNI-generated regions of interest were evaluated in both diagnostic groups.Results:18F-fluorodeoxyglucose uptake and 18F-fallypride binding potential were predominantly positively correlated across the striatal and extrastriatal grey matter in both healthy and schizophrenia subjects. In comparison to healthy subjects, significantly weaker correlations in subjects with schizophrenia were confirmed in the right cingulate gyrus and thalamus, including the mediodorsal, lateral dorsal, anterior, and midline nuclei. Schizophrenia subjects showed decreased D2/D3-receptor availability in the hypothalamus, mamillary bodies, thalamus and several thalamic nuclei, and increased glucose uptake in three lobules of the cerebellar vermis.Conclusions: Dopaminergic system may be involved in modulation of grey matter metabolism and neurometabolic coupling in both healthy human brain and psychopathology. Hyperdopaminergic state in untreated schizophrenia may at least partly account for the corresponding decreases in grey matter metabolism.
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Affiliation(s)
- Serge A Mitelman
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York City,NY, USA.,Department of Psychiatry, Division of Child and Adolescent Psychiatry, Elmhurst Hospital Center, Elmhurst, IL, USA
| | - Monte S Buchsbaum
- Departments of Psychiatry and Radiology, University of California, San Diego, CA, USA.,Department of Psychiatry and Human Behavior, University of California, Irvine School of Medicine, Orange, CA, USA
| | - Bradley T Christian
- Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison, Madison, WI, USA
| | - Brian M Merrill
- Department of Psychiatry, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA
| | - Bradley R Buchsbaum
- The Rotman Research Institute, Baycrest Centre for Geriatric Care and Department of Psychiatry, University of Toronto, Toronto, Canada
| | - Jogeshwar Mukherjee
- Department of Radiological Sciences, Preclinical Imaging, University of California, Irvine School of Medicine, Irvine, CA, USA
| | - Douglas S Lehrer
- Department of Psychiatry, Boonshoft School of Medicine, Wright State University, Dayton, OH, USA
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Kious BM, Bakian AV. Evidence of new-onset depression among persons with migraine after discontinuing antidepressants. Psychiatry Res 2020; 288:112990. [PMID: 32353695 DOI: 10.1016/j.psychres.2020.112990] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/05/2020] [Accepted: 04/06/2020] [Indexed: 10/24/2022]
Abstract
Antidepressants have been hypothesized to cause tardive dysphoria-the delayed development of negative emotional symptoms. We assessed the risk of tardive dysphoria in a cohort of persons with migraine taking anti-migraine antidepressants with no known diagnosis of any mood or anxiety disorder. We included all outpatient encounters in a university hospital system for migraine from January 2008 through October 2018, excluding subjects with prior psychiatric diagnoses. Kaplan-Meier survival curves and multivariable Cox proportional hazards analyses were conducted. 13,048 subjects were included; 1191 took an antidepressant; 402 discontinued an antidepressant. In multivariable analyses examining the first year after exposure, antidepressant use was not significantly associated with risk of a depression, any mood disorder (including depression, mania, and other mood disorders), or anxiety. Antidepressant discontinuation was significantly associated with increased risk of depression, but not any mood disorder or anxiety. Among persons with migraine with no known psychiatric diagnosis, antidepressants did not appear to be associated with indicators of tardive dysphoria. Antidepressant discontinuation, however, was associated with increased risk of a depression diagnosis.
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Affiliation(s)
- Brent M Kious
- Department of Psychiatry, University of Utah, Salt Lake City, Utah, United States.
| | - Amanda V Bakian
- Department of Psychiatry, University of Utah, Salt Lake City, Utah, United States
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Takase M, Kimura H, Kanahara N, Nakata Y, Iyo M. Plasma monoamines change under dopamine supersensitivity psychosis in patients with schizophrenia: A comparison with first-episode psychosis. J Psychopharmacol 2020; 34:540-547. [PMID: 31961236 DOI: 10.1177/0269881119900982] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Patients with first-episode psychosis respond well to initial antipsychotic treatment, but among patients experiencing a relapse of psychosis, the response rate falls to approximately 30%. The mechanism of this discrepancy has not been clarified, but the development of dopamine supersensitivity psychosis with the underlying up-regulation of post-synaptic dopamine D2 receptors could be involved in this lesser response. It is uncertain whether elevated dopamine synthesis and release occurs in patients with dopamine supersensitivity psychosis, in contrast to those with first-episode psychosis. PATIENTS AND METHODS We examined a first-episode psychosis group (n=6) and a chronic schizophrenia group, i.e. patients experiencing relapse (n=23) including those who relapsed due to dopamine supersensitivity psychosis (n=18). Following the initiation of treatment, we measured the patients' blood concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylglycol at two weeks and four weeks after the baseline measurements. RESULTS The first-episode psychosis group tended to show decreased homovanillic acid, accompanied by an improvement of symptoms. The chronic schizophrenia group showed no alteration of homovanillic acid or 3-methoxy-4-hydroxyphenylglycol over the treatment period. These results were the same in the dopamine supersensitivity psychosis patients alone. CONCLUSIONS Our findings suggest that unlike first-episode psychosis, the release of dopamine from presynaptic neurons did not increase in relapse episodes in the patients with dopamine supersensitivity psychosis. This indirectly indicates that the development of supersensitivity of post-synapse dopamine D2 receptor is involved in relapse in dopamine supersensitivity psychosis patients.
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Affiliation(s)
- Masayuki Takase
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Hisoshi Kimura
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.,Department of Psychiatry, Gakuji-kai Kimura Hospital, Chiba, Japan
| | - Nobuhisa Kanahara
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan.,Center for Forensic Mental Health, Chiba University, Chiba, Japan
| | - Yusuke Nakata
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
| | - Masaomi Iyo
- Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan
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Abstract
PURPOSE OF REVIEW Recently, it has been questioned whether the re-emergence of psychotic symptoms following antipsychotic discontinuation or dose reduction is attributable to underlying psychotic vulnerability or to rebound effects of chronic use of antipsychotic medication. It was repeatedly shown that relapse rates are high after discontinuation of maintenance treatment. A potential contributing factor could be the increase in density of postsynaptic dopamine D2 receptors in the striatum and the higher affinity of D2 receptors for dopamine after chronic blockade. RECENT FINDINGS To date, little clinical evidence is available for the mechanisms involved in postsynaptic striatal D2 receptor up-regulation after use of antipsychotic medication, and most knowledge comes from animal studies. SUMMARY Further research is needed to investigate whether antipsychotic medication causes neuroadaptations leading to a dopamine supersensitive state in humans, how long such hypersensitive states may last and what differences exist between high and low D2 affinity antipsychotic drugs. Further, information is needed on discontinuation schedules that provide optimal protection for relapse during hypersensitive periods.
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González-Rodríguez A, Guàrdia A, Palao DJ, Labad J, Seeman MV. Moderators and mediators of antipsychotic response in delusional disorder: Further steps are needed. World J Psychiatry 2020; 10:34-45. [PMID: 32399397 PMCID: PMC7203082 DOI: 10.5498/wjp.v10.i4.34] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/04/2020] [Accepted: 03/22/2020] [Indexed: 02/05/2023] Open
Abstract
Delusional disorder (DD) has been traditionally considered a relatively rare and treatment-resistant psychotic disorder. In the last decade, increasing attention has focused on therapeutic outcomes of individuals affected by this disorder. The aim of this paper is to provide a synthesis of the literature addressing two very important questions arising from DD research: (1) For which patients with DD do antipsychotic medications work best (the moderators of response); and (2) What variables best explain the relationship between such treatments and their effectiveness (the mediators of response). We searched PubMed and Google Scholar databases for English, German, French and Spanish language papers published since 2000. We also included a few classic earlier papers addressing this topic. Variables potentially moderating antipsychotic response in DD are gender, reproductive status, age, duration of illness, the presence of comorbidity (especially psychiatric comorbidity) and its treatment, brain structure, and genetics of neurochemical receptors and drug metabolizing enzymes. Antipsychotic and hormonal blood levels during treatment, as well as functional brain changes, are potential mediating variables. Some, but not all, patients with DD benefit from antipsychotic treatment. Understanding the circumstances under which treatment works best can serve to guide optimal management.
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Affiliation(s)
- Alexandre González-Rodríguez
- Department of Mental Health, Parc Taulí University Hospital, Autonomous University of Barcelona, Sabadell 08280, Spain
| | - Armand Guàrdia
- Department of Mental Health, Parc Taulí University Hospital, Autonomous University of Barcelona, Sabadell 08280, Spain
| | - Diego José Palao
- Department of Mental Health, Parc Taulí University Hospital, Autonomous University of Barcelona, Sabadell 08280, Spain
| | - Javier Labad
- Department of Mental Health, Parc Taulí University Hospital, Autonomous University of Barcelona, Sabadell 08280, Spain
| | - Mary V Seeman
- Department of Psychiatry, University of Toronto, Toronto, ON M5P 3L6, Canada
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Ali Z, Roque A, El-Mallakh RS. A unifying theory for the pathoetiologic mechanism of tardive dyskinesia. Med Hypotheses 2020; 140:109682. [PMID: 32200182 DOI: 10.1016/j.mehy.2020.109682] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/06/2020] [Accepted: 03/15/2020] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Chronic treatment with dopamine D2 receptor antagonists has been proposed to lead to dopamine receptor supersensitivity. Frequently, this is conceptualized as upregulation or changes in the structure or function of the post-synaptic D2 receptor. However, the measured 1.4-fold increase in D2 receptor density and the lack of actual receptor supersensitivity are probably inadequate to explain outcomes such as tardive dyskinesia (TD) and dopamine supersensitivity psychosis. HYPOTHESIS Recent data suggest that TD may result from a combination of presynaptic, synaptic, and postsynaptic changes. DISCUSSION Presynaptic increase in dopamine release occurs when super-therapeutic blockade of postsynaptic D2 receptors results in excess synaptic unbound dopamine which ultimately ends up being reuptaken by the presynaptic neuron through the dopamine transporter. The increased availability of recycled dopamine results in higher vesicular dopamine concentrations. Since the quantity of neurotransmitter released (known as quanta) is determined by the number of presynaptic neurotransmitter vesicles, the increase in the number (concentration) of dopamine molecules in the vesicles results in a higher concentration of synaptic dopamine with successive depolarization events. Synaptic changes such as the appearance of perforated synapses which is an early step in new synapse formation have been shown in animal models of TD. Finally, postsynaptic increases in D2 receptor expression without demonstration of increased sensitivity or potency has been demonstrated. CONCLUSION TD likely develops due to changes across the synapse and terminology such as 'dopamine receptor supersensitivity' can be misleading. 'Synaptic upregulation' may be a more correct term.
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Affiliation(s)
- Ziad Ali
- Mood Disorders Research Program, Depression Center, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY, United States.
| | - Autumn Roque
- Center for Mindfulness and CBT, 10845 Olive Blvd, St. Louis, MO 63141, United States.
| | - Rif S El-Mallakh
- Mood Disorders Research Program, Depression Center, Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, Louisville, KY, United States
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50
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Blanchet PJ, Lévesque D. Time for a New Slate in Tardive Dyskinesia Research. Mov Disord 2020; 35:752-755. [PMID: 32067258 DOI: 10.1002/mds.28003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Revised: 01/28/2020] [Accepted: 02/02/2020] [Indexed: 12/26/2022] Open
Affiliation(s)
- Pierre J Blanchet
- Department of Stomatology, Faculty of Dental Medicine, University of Montreal, Montreal, QC, Canada.,Department of Medicine, University of Montreal Hospital Centre (CHU Montreal), Montreal, QC, Canada
| | - Daniel Lévesque
- Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada
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