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Severino M, Schubert JJ, Nordio G, Giacomel A, Easmin R, Lao‐Kaim NP, Selvaggi P, Xu Z, Pereira JB, Jauhar S, Piccini P, Howes O, Turkheimer F, Veronese M. Single-Subject Network Analysis of FDOPA PET in Parkinson's Disease and Psychosis Spectrum. Hum Brain Mapp 2025; 46:e70253. [PMID: 40501445 PMCID: PMC12159690 DOI: 10.1002/hbm.70253] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Collaborators] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Revised: 05/12/2025] [Accepted: 05/26/2025] [Indexed: 06/16/2025] Open
Abstract
Greater understanding of individual biological differences is essential for developing more targeted treatment approaches to complex brain disorders. Traditional analysis methods in molecular imaging studies have primarily focused on quantifying tracer binding in specific brain regions, often neglecting inter-regional functional relationships. In this study, we propose a statistical framework that combines molecular imaging data with perturbation covariance analysis to construct single-subject networks and investigate individual patterns of molecular alterations. This framework was tested on [18F]-DOPA PET imaging as a marker of the brain dopamine system in patients with Parkinson's Disease (PD) and schizophrenia to evaluate its ability to classify patients and characterize their disease severity. Our results show that single-subject networks effectively capture molecular alterations, differentiate individuals with heterogeneous conditions, and account for within-group variability. Moreover, the approach successfully distinguishes between preclinical and clinical stages of psychosis and identifies the corresponding molecular connectivity changes in response to antipsychotic medications. Mapping molecular imaging networks presents a new and powerful method for characterizing individualized disease trajectories as well as for evaluating treatment effectiveness in future research.
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Affiliation(s)
- Mario Severino
- Department of Information EngineeringUniversity of PaduaPadovaItaly
| | - Julia J. Schubert
- Department of Neuroimaging, Institute of PsychiatryPsychology & Neuroscience, King's College LondonLondonUK
| | - Giovanna Nordio
- Department of Neuroimaging, Institute of PsychiatryPsychology & Neuroscience, King's College LondonLondonUK
| | - Alessio Giacomel
- Department of Neuroimaging, Institute of PsychiatryPsychology & Neuroscience, King's College LondonLondonUK
| | - Rubaida Easmin
- Department of Neuroimaging, Institute of PsychiatryPsychology & Neuroscience, King's College LondonLondonUK
| | - Nick P. Lao‐Kaim
- Centre for Neurodegeneration and Neuroinflammation, Division of Brain SciencesImperial College LondonLondonUK
| | - Pierluigi Selvaggi
- Department of Neuroimaging, Institute of PsychiatryPsychology & Neuroscience, King's College LondonLondonUK
- Department of Translational Biomedicine and NeuroscienceUniversity of Bari Aldo MoroBariItaly
| | - Zhilei Xu
- Division of Neuro, Department of Clinical NeuroscienceKarolinska InstituteStockholmSweden
| | - Joana B. Pereira
- Division of Neuro, Department of Clinical NeuroscienceKarolinska InstituteStockholmSweden
| | - Sameer Jauhar
- Department of Psychosis Studies, Institute of PsychiatryPsychology & Neuroscience, King's College LondonLondonUK
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith HospitalImperial College LondonLondonUK
| | - Paola Piccini
- Centre for Neurodegeneration and Neuroinflammation, Division of Brain SciencesImperial College LondonLondonUK
| | - Oliver Howes
- Department of Psychosis Studies, Institute of PsychiatryPsychology & Neuroscience, King's College LondonLondonUK
- Psychiatric Imaging Group, MRC London Institute of Medical Sciences, Hammersmith HospitalImperial College LondonLondonUK
- South London and Maudsley NHS Foundation TrustLondonUK
| | - Federico Turkheimer
- Department of Neuroimaging, Institute of PsychiatryPsychology & Neuroscience, King's College LondonLondonUK
| | - Mattia Veronese
- Department of Information EngineeringUniversity of PaduaPadovaItaly
- Department of Neuroimaging, Institute of PsychiatryPsychology & Neuroscience, King's College LondonLondonUK
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Collaborators
Ilinca Angelescu, Micheal Bloomfield, Ilaria Bonoldi, Faith Borgan, Tarik Dahoun, D'Ambrosio Enrico, Arsime Demjaha, Jecek Donocik, Alice Egerton, Stephen Kaar, Euitae Kim, Seoyoung Kim, James Maccabe, Julian Matthews, Robert McCutcheon, Philip McGuire, Chiara Nosarti, Matthew M Nour, Maria Rogdaki, Grazia Rutigliano, Ekaterina Shatalina, Peter S Talbot, Luke Vano,
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Samara MT, Kottmaier E, Helfer B, Leucht C, Christodoulou NG, Huhn M, Rothe PH, Schneider-Thoma J, Leucht S. Switching antipsychotics versus continued current treatment in people with non-responsive schizophrenia. Cochrane Database Syst Rev 2025; 4:CD011885. [PMID: 40214650 PMCID: PMC11988422 DOI: 10.1002/14651858.cd011885.pub2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/14/2025]
Abstract
BACKGROUND Many people with schizophrenia do not respond to an initially prescribed antipsychotic drug. In such cases, one treatment strategy could be to switch to a different antipsychotic drug. OBJECTIVES To examine the effects of switching antipsychotic drugs in treating people with schizophrenia who have not responded to initial antipsychotic treatment. SEARCH METHODS We searched the Cochrane Schizophrenia Group Trials Register (to December 2022). We inspected the references of all included studies for further relevant trials. SELECTION CRITERIA We included all relevant randomised controlled trials (RCTs) comparing switching to a different antipsychotic drug rather than continuing treatment with the same antipsychotic drug for people with schizophrenia who did not respond to their initial antipsychotic treatment. DATA COLLECTION AND ANALYSIS At least two review authors independently extracted data. The primary outcomes were: clinically relevant response as defined by study authors; tolerability (participants leaving the study early due to adverse effects); and quality of life assessed by the change score in the 36-Item Short Form survey. We analysed dichotomous data using the risk ratio (RR) and its 95% confidence interval (CI). We analysed continuous data using mean differences (MD) and corresponding 95% CI. We assessed the risk of bias of the included studies and used GRADE to evaluate the certainty of evidence for the following outcomes: clinically relevant response, tolerability (leaving the study early due to adverse effects), quality of life score change, acceptability (leaving the study early for any reason), general mental state (average change in general mental state scores), duration of hospitalisation, and number of participants experiencing at least one adverse effect. MAIN RESULTS We included 10 RCTs with 997 participants in the review. Nine studies used a parallel design, and one used a cross-over design. Seven studies were double-blind, two were single-blind and one did not provide any detail regarding blinding. All studies included people who were non-responsive to ongoing antipsychotic treatment. The minimum duration of the ongoing antipsychotic treatment ranged from three days to two years. The length of the comparison phase varied from two weeks to six months. The studies were published between 1993 and 2022. In about half of the studies, the methods of randomisation, allocation and blinding were poorly reported. The evidence is very uncertain regarding the effect of switching antipsychotics on clinically relevant response (RR 1.25, 95% CI 0.77 to 2.03; I² = 43%; 7 studies, 693 participants), quality of life (MD -1.30, 95% CI -3.44 to 0.84; 1 study, 188 participants), Positive and Negative Syndrome Scale (PANSS) score change (MD -0.92, 95% CI -4.69 to 2.86; I² = 47%; 6 studies, 777 participants), duration of hospitalisation (in days) (MD 9.19, 95% CI -8.93 to 27.31; I² = 0%; 2 studies, 34 participants) and the number of people experiencing at least one adverse effect (RR 1.29, 95% CI 0.81 to 2.05; I² = 36%; 3 studies, 412 participants). Compared to continuing current treatment, switching antipsychotics may result in little to no difference in tolerability, defined as the number of participants leaving the study early due to adverse effects (RR 0.73, 95% CI 0.24 to 2.26; I² = 31%; 6 studies, 672 participants; low-certainty evidence) and leaving the study early for any reason (RR 0.91, 95% CI 0.71 to 1.17; I² = 0%; 6 studies, 672 participants; low-certainty evidence). AUTHORS' CONCLUSIONS This review synthesises currently available RCT evidence on switching antipsychotics versus continuing the same antipsychotic in individuals with schizophrenia who did not respond to their initial treatment. Overall, the evidence remains highly uncertain regarding the effects of either strategy on efficacy and safety outcomes, and no definitive recommendations can currently be made. There is an urgent need for larger, well-designed trials to identify the optimal treatment strategy for these cases.
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Affiliation(s)
- Myrto T Samara
- Department of Psychiatry and Psychotherapy, School of Medicine and Health, Technical University of Munich, Munich, Germany
- Department of Psychiatry, University of Thessaly, Larissa, Greece
| | - Elisabeth Kottmaier
- Department of Diagnostic and Interventional Neuroradiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Bartosz Helfer
- Institute of Psychology, University of Wroclaw, Wroclaw, Poland
- Meta Research Centre, University of Wroclaw, Wroclaw, Poland
| | | | | | - Maximilian Huhn
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen, Erlangen, Germany
- Department of Psychiatry, Psychotherapy and Psychosomatic Medicine, District Hospital Bayreuth/Psychiatric Health Care Facilities of Upper Franconia, Bayreuth, Germany
| | - Philipp H Rothe
- Kbo-Inn-Salzach-Klinikum, Departement for Psychosis disorders and Personality disorders, Wasserburg (Inn), Germany
| | - Johannes Schneider-Thoma
- Department of Psychiatry and Psychotherapy, School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Stefan Leucht
- Department of Psychiatry and Psychotherapy, School of Medicine and Health, Technical University of Munich, Munich, Germany
- German Center for Mental Health, partner site Munich/Augsburg, Germany
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Giné-Servén E, Boix-Quintana E, Ballesteros A, Daví-Loscos E, Guanyabens N, Casado V, Martínez-Ramírez M, Crespo-Facorro B, Cuesta MJ, Labad J. Bioenergetic markers in cerebrospinal fluid in first-episode psychosis: Are they predictors of early antipsychotic response and 1-year outcomes? Prog Neuropsychopharmacol Biol Psychiatry 2025; 138:111336. [PMID: 40118368 DOI: 10.1016/j.pnpbp.2025.111336] [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: 11/20/2024] [Revised: 02/25/2025] [Accepted: 03/13/2025] [Indexed: 03/23/2025]
Abstract
Psychotic disorders involve complex pathophysiological mechanisms, and identification of biomarkers for treatment response remains a major challenge. We aimed to study whether routine cerebrospinal fluid (CSF) parameters measured at baseline predict poor early response at 2 weeks with optimal antipsychotic treatment doses in patients with first-episode psychosis (FEP). We also explored whether these parameters could predict changes in social functioning and psychopathology over a 1-year follow-up. Ninety-eight inpatients with FEP who had received less than 6 weeks of antipsychotic treatment were included in the study. A lumbar puncture was performed at the index admission to measure CSF parameters (glucose, total protein, and lactate dehydrogenase [LDH]). The Positive and Negative Syndrome Scale (PANSS) was administered. A poor early treatment response at week 2 was defined as a < 20 % reduction in the PANSS positive subscore of a consensus factor. Social functioning was assessed using the Personal and Social Performance Scale (PSP) at baseline and 2, 4, 6, 9, and 12 months. Statistical analyses explored the role of CSF biomarkers in early treatment response using logistic regression and long-term social functioning and psychopathology using mixed linear regression analyses. Eighteen patients with FEP (18.4 %) were nonresponders at week 2. The CSF LDH concentration was a predictor of early treatment nonresponse. Higher CSF LDH concentrations were associated with a reduced improvement in social functioning at month 2, and higher CSF glucose concentrations were associated with lower reductions in the PANSS total scores at all visits. These findings suggest that specific bioenergetic parameters in the CSF, such as LDH and glucose, may serve as prognostic biomarkers for early treatment response and 1-year social and psychopathological outcomes in patients with FEP.
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Affiliation(s)
- Eloi Giné-Servén
- Department of Psychiatry, Hospital Universitario de Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain.
| | - Ester Boix-Quintana
- Department of Mental Health, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain
| | - Alejandro Ballesteros
- Department of Psychiatry, Hospital Universitario de Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Eva Daví-Loscos
- Department of Mental Health, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain
| | - Nicolau Guanyabens
- Department of Neurology, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain
| | - Virginia Casado
- Department of Neurology, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain
| | - María Martínez-Ramírez
- Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain
| | - Benedicto Crespo-Facorro
- University Hospital Virgen del Rocío, IBiS, Department of Psychiatry, University of Sevilla, Sevilla, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain
| | - Manuel J Cuesta
- Department of Psychiatry, Hospital Universitario de Navarra, Pamplona, Spain; IdiSNA, Navarra Institute for Health Research, Pamplona, Spain
| | - Javier Labad
- Department of Mental Health, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain; Translational Neuroscience Research Unit I3PT-INc-UAB, Institut de Innovació i Investigació Parc Taulí (I3PT), Institut de Neurociències, Universitat Autònoma de Barcelona, Spain
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Cao Y, Liang J, Dai B, Shan F, Xia Q. Peripheral blood complement factors C2 and C3 as biomarkers of clinical efficacy in patients with first-episode schizophrenia after aripiprazole treatment. BMC Psychiatry 2024; 24:961. [PMID: 39741241 DOI: 10.1186/s12888-024-06437-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 12/23/2024] [Indexed: 01/02/2025] Open
Abstract
OBJECTIVE The objective of this study was to identify serum complement factor-based biomarkers indicative of clinical efficacy in patients with first-episode schizophrenia (SCZ) following treatment with aripiprazole. METHODS The retrospective study cohort comprised 40 patients diagnosed with first-episode SCZ (SCZ group) and 40 healthy individuals (control group). Quantitative analyses were conducted on five complement factors, namely complement component 1 (C1), C2, C3, C4, and the 50% hemolytic complement (CH50). Baseline serum complement factor levels were compared between the SCZ and control groups. Patients diagnosed with SCZ underwent a 4-week treatment regimen with aripiprazole. The severity of psychiatric symptoms in these patients was assessed using the Positive and Negative Symptom Scale (PANSS) and the Brief Psychiatric Rating Scale-18 Item Version (BPRS). Comparative analyses were conducted on PANSS and BPRS scores, as well as serum complement factor levels, both prior to (pre-treatment group) and following aripiprazole administration (post-treatment group). Pearson's correlation test was employed to evaluate the relationships between changes in serum complement factor levels and the reduction rates of PANSS/BPRS scores. RESULTS At baseline, patients with SCZ exhibited significantly elevated levels of C1, C2, C3, C4, and CH50 compared to the control group (P < 0.05). Moreover, following treatment, there was a significant reduction in the PANSS total score, positive symptom score, negative symptom score, and BPRS score in the post-treatment group compared to the pre-treatment group (P < 0.05). Furthermore, patients in the post-treatment group exhibited a significant reduction in serum levels of C2, C3, and C4, alongside a significant increase in the serum level of CH50 compared to those in the pre-treatment group (P < 0.05). Additionally, the baseline serum C2 levels and the variations in serum C2 levels pre- and post-treatment exhibited a negative correlation with the reduction rate of PANSS/BPRS scores (P < 0.05). Similarly, both the baseline serum C3 levels and the changes in serum C3 levels pre- and post-treatment were negatively correlated with the reduction rate of PANSS/BPRS scores (P < 0.05). CONCLUSION Baseline serum levels of C2 and C3, as well as their variations pre- and post-treatment, may serve as biomarkers for predicting clinical efficacy in patients with first-episode SCZ undergoing treatment with aripiprazole.
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Affiliation(s)
- Yin Cao
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China
- Department of Pharmacy, Hefei Fourth People's Hospital, 316 Huangshan Road, Hefei, 230000, China
- Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China
- Anhui Clinical Research Center for Mental Disorders, Hefei, China
| | - Jun Liang
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China
- Department of Pharmacy, Hefei Fourth People's Hospital, 316 Huangshan Road, Hefei, 230000, China
- Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China
- Anhui Clinical Research Center for Mental Disorders, Hefei, China
| | - Biao Dai
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China
- Department of Pharmacy, Hefei Fourth People's Hospital, 316 Huangshan Road, Hefei, 230000, China
- Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China
- Anhui Clinical Research Center for Mental Disorders, Hefei, China
| | - Feng Shan
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China
- Department of Pharmacy, Hefei Fourth People's Hospital, 316 Huangshan Road, Hefei, 230000, China
- Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China
- Anhui Clinical Research Center for Mental Disorders, Hefei, China
| | - Qingrong Xia
- Affiliated Psychological Hospital of Anhui Medical University, Hefei, China.
- Department of Pharmacy, Hefei Fourth People's Hospital, 316 Huangshan Road, Hefei, 230000, China.
- Psychopharmacology Research Laboratory, Anhui Mental Health Center, Hefei, China.
- Anhui Clinical Research Center for Mental Disorders, Hefei, China.
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5
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Lee R, Griffiths SL, Gkoutos GV, Wood SJ, Bravo-Merodio L, Lalousis PA, Everard L, Jones PB, Fowler D, Hodegkins J, Amos T, Freemantle N, Singh SP, Birchwood M, Upthegrove R. Predicting treatment resistance in positive and negative symptom domains from first episode psychosis: Development of a clinical prediction model. Schizophr Res 2024; 274:66-77. [PMID: 39260340 DOI: 10.1016/j.schres.2024.09.010] [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: 06/07/2024] [Revised: 08/07/2024] [Accepted: 09/06/2024] [Indexed: 09/13/2024]
Abstract
BACKGROUND Treatment resistance (TR) in schizophrenia may be defined by the persistence of positive and/or negative symptoms despite adequate treatment. Whilst previous investigations have focused on positive symptoms, negative symptoms are highly prevalent, impactful, and difficult to treat. In the current study we aimed to develop easily employable prediction models to predict TR in positive and negative symptom domains from first episode psychosis (FEP). METHODS Longitudinal cohort data from 1027 individuals with FEP was utilised. Using a robust definition of TR, n = 51 (4.97 %) participants were treatment resistant in the positive domain and n = 56 (5.46 %) treatment resistant in the negative domain 12 months after first presentation. 20 predictor variables, selected by existing evidence and availability in clinical practice, were entered into two LASSO regression models. We estimated the models using repeated nested cross-validation (NCV) and assessed performance using discrimination and calibration measures. RESULTS The prediction model for TR in the positive domain showed good discrimination (AUC = 0.72). Twelve predictor variables (male gender, cannabis use, age, positive symptom severity, depression and academic and social functioning) were retained by each outer fold of the NCV procedure, indicating importance in prediction of the outcome. However, our negative domain model failed to discriminate those with and without TR, with results only just over chance (AUC = 0.56). CONCLUSIONS Treatment resistance of positive symptoms can be accurately predicted from FEP using routinely collected baseline data, however prediction of negative domain-TR remains a challenge. Detailed negative symptom domains, clinical data, and biomarkers should be considered in future longitudinal studies.
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Affiliation(s)
- Rebecca Lee
- Institute for Mental Health, University of Birmingham, UK; Centre for Youth Mental Health, University of Melbourne, Australia.
| | | | - Georgios V Gkoutos
- Institute of Cancer and Genomic Sciences, Centre for Computational Biology, University of Birmingham, UK; Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, UK; Health Data Research UK, Midlands Site, Birmingham, UK
| | - Stephen J Wood
- Centre for Youth Mental Health, University of Melbourne, Australia; Orygen, Melbourne, Australia; School of Psychology, University of Birmingham, UK
| | - Laura Bravo-Merodio
- Institute of Cancer and Genomic Sciences, Centre for Computational Biology, University of Birmingham, UK; Institute of Translational Medicine, University Hospitals Birmingham NHS Foundation Trust, University of Birmingham, UK
| | - Paris A Lalousis
- Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK
| | - Linda Everard
- Birmingham and Solihull Mental Health Foundation Trust, Birmingham, UK
| | - Peter B Jones
- Department of Psychiatry, University of Cambridge and CAMEO, Cambridge and Peterborough NHS Foundation Trust, Fulbourn, UK
| | - David Fowler
- Department of Psychology, University of Sussex, Brighton, UK
| | | | - Tim Amos
- Academic Unit of Psychiatry, University of Bristol, Bristol, UK
| | - Nick Freemantle
- Institute of Clinical Trials and Methodology, University College London, London, UK
| | - Swaran P Singh
- Coventry and Warwickshire Partnership NHS Trust, UK; Mental Health and Wellbeing Warwick Medical School, University of Warwick, Coventry, UK
| | - Max Birchwood
- Mental Health and Wellbeing Warwick Medical School, University of Warwick, Coventry, UK
| | - Rachel Upthegrove
- Institute for Mental Health, University of Birmingham, UK; Birmingham Early Intervention Service, Birmingham Women's and Children's NHS Foundation Trust, UK
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Stassen HH, Bachmann S, Bridler R, Cattapan K, Hartmann AM, Rujescu D, Seifritz E, Weisbrod M, Scharfetter C. Genetic determinants of antidepressant and antipsychotic drug response. Eur Arch Psychiatry Clin Neurosci 2024:10.1007/s00406-024-01918-5. [PMID: 39379546 DOI: 10.1007/s00406-024-01918-5] [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: 06/07/2024] [Accepted: 09/20/2024] [Indexed: 10/10/2024]
Abstract
Today, more than 90% of inpatients hospitalized with Major Depression or Schizophrenia are treated with psychotropic drugs. Since none of the treatment options is causal, response rates are modest and the course of recovery is very heterogeneous. Genetic studies on the etiology and pathogenesis of major psychiatric disorders over the past decades have been largely unsuccessful. Likewise, genetic studies to predict response to psychopharmacological treatment have also not been particularly successful. In this project we have recruited 902 inpatients with ICD-10 diagnoses of schizophrenic ("F2 patients") or depressive disorders ("F3 patients"). The study assessed today's acute inpatient treatment regimens with up to 8 repeated measurements regarding the time course of recovery and adverse side effects. The genotyping included 100 candidate genes with genotypic patterns computed from 549 Single Nucleotide Polymorphisms (SNPs). To predict response to psychopharmacological treatment, we relied on a multidimensional approach to analyzing genetic diversity in combination with multilayer Neural Nets (NNs). Central to this new method were the "gene vectors" that (1) assessed the multidimensional genotypic patterns observed with genes; and (2) evaluated the correlations between genes. By means of these methods, we searched for combinations of multidimensional genotypic patterns that were characteristic of treatment responders while being rare among non-responders. The chosen method of approach provided a powerful technique to detail the complex structures of SNP data that are not detectable by conventional association methods. Molecular-genetic NNs enabled correct classification of 100% "non-responders", along with 94.7% correctly classified "responders" among the F2 patients, and 82.6% correctly classified "responders" among the F3 patients. The F2 and F3 classifiers were not disjoint but showed an overlap of 29.6% and 35.7% between the diagnostic groups, thus indicating that clinical diagnoses may not constitute etiologic entities. Our results suggested that patients may have an unspecific physical-genetic disposition that enables, facilitates, impedes or prevents recovery from major psychiatric disorders by setting various thresholds for exogenous triggers that initiate improvement ("recovery disposition"). Even though this disposition is not causally linked to recovery, it can nonetheless be clinically used in the sense of a "surrogate". Indeed, clinicians are also interested in reliable tools that can "do the job", despite the fact that etiology and pathogenesis of the treated disorders remain unknown.
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Affiliation(s)
- Hans H Stassen
- Institute for Response-Genetics, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital, Zurich, CH-8032, Switzerland.
- Sanatorium Kilchberg, Alte Landstrasse 70, Kilchberg, CH-8802, Switzerland.
| | - S Bachmann
- Department of Psychiatry, Geneva University Hospitals, Thônex, CH-1226, Switzerland
- Department of Psychiatry, Psychotherapy, and Psychosomatics, University of Halle, Halle, D-06112, Germany
- Clienia AG, Psychiatric Hospital, Littenheid, CH-9573, Switzerland
| | - R Bridler
- Sanatorium Kilchberg, Alte Landstrasse 70, Kilchberg, CH-8802, Switzerland
| | - K Cattapan
- Sanatorium Kilchberg, Alte Landstrasse 70, Kilchberg, CH-8802, Switzerland
- University Hospital of Psychiatry and Psychotherapy, University of Bern, Bern, CH-3012, Switzerland
| | - A M Hartmann
- Clinical Division of General Psychiatry, Medical University of Vienna, Wien, A-1090, Austria
| | - D Rujescu
- Clinical Division of General Psychiatry, Medical University of Vienna, Wien, A-1090, Austria
| | - E Seifritz
- Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital, Zurich, CH-8032, Switzerland
| | - M Weisbrod
- Department of General Psychiatry, Center of Psychosocial Medicine, University of Heidelberg, Heidelberg, D-69115, Germany
- SRH Hospital Karlsbad-Langensteinbach, Karlsbad, D-76307, Germany
| | - Chr Scharfetter
- Institute for Response-Genetics, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital, Zurich, CH-8032, Switzerland
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Tohen M, Yu J, Kramer K, Nguyen HB. Early improvement with cariprazine as a predictor of antidepressant, anxiolytic, and antimanic response in bipolar I mania and depression: A pooled post hoc analysis of randomized cariprazine trials. J Affect Disord 2024; 362:194-200. [PMID: 38942209 DOI: 10.1016/j.jad.2024.06.100] [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: 12/18/2023] [Revised: 06/03/2024] [Accepted: 06/25/2024] [Indexed: 06/30/2024]
Abstract
BACKGROUND Early symptomatic improvement may predict treatment response in bipolar I disorder. Cariprazine has demonstrated early treatment effects in bipolar I depression and mania studies; therefore, we assessed whether early improvement with cariprazine predicts eventual treatment response. METHODS Post hoc analyses used pooled data from randomized, double-blind, placebo-controlled bipolar I depression (NCT02670538, NCT02670551) and mania (NCT00488618, NCT01058096, NCT01058668) trials. In depression studies (cariprazine 1.5 mg/d, 3 mg/d, or placebo), early improvement in Montgomery-Åsberg Depression Rating Scale (MADRS) and Hamilton Anxiety Rating Scale (HAM-A) total scores (≥25 % improvement at day 15) and subsequent depressive/anxiety symptom response status (≥50 % improvement at week 6) were assessed. In mania studies (cariprazine 3-12 mg/d or placebo), early improvement in Young Mania Rating Scale (YMRS) total scores (≥25 % improvement at day 7) and manic symptom response status (≥50 % improvement at week 3) were assessed. RESULTS Patients with bipolar I depression and early MADRS improvement were approximately 4- to 6-times as likely to achieve MADRS or HAM-A response than those without early improvement; patients with early HAM-A improvement were approximately 3- to 4-times as likely to achieve MADRS or HAM-A response. A subset of patients without early improvement with cariprazine 1.5 mg/d (20 %-31 %) subsequently responded following up-titration. Patients with mania and early YMRS improvement were approximately 5 times more likely to have manic symptom response than those without early improvement. LIMITATIONS Post hoc analysis; relatively short study durations; flexible-dosing (mania studies). CONCLUSIONS Early symptom improvement with cariprazine may inform therapeutic decisions for patients with bipolar I disorder.
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Affiliation(s)
- Mauricio Tohen
- Department of Psychiatry and Behavioral Sciences, University of New Mexico School of Medicine, Albuquerque, NM, USA
| | - Jun Yu
- AbbVie, Florham Park, NJ, USA
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Margariti MM, Vlachos II, Mpourazana D, Aristotelidis P, Selakovic M, Ifanti M, Papageorgiou C. Psychotic Arousal and the Psychopathology of Acute Schizophrenia: An Exploratory Study of the Experiential Emotional State in Acute Psychosis. J Clin Med 2024; 13:5477. [PMID: 39336964 PMCID: PMC11432037 DOI: 10.3390/jcm13185477] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Revised: 09/08/2024] [Accepted: 09/13/2024] [Indexed: 09/30/2024] Open
Abstract
Background: Increasing research data suggest that the dysfunction of emotional brain systems may be an important contributor to the pathophysiology of schizophrenia. However, contemporary psychopathology consistently underestimates the role of emotions in the phenomenology of the disease. Psychotic arousal (PA) is a conceptually defined psychopathological construct aiming to portray the experiential emotional state of acute psychosis. The concept provides an explanatory model for the emergence of psychosis, and the formation and maintenance of delusions based on neurobiological models on the formation of core consciousness and subjectivity. This is the first exploratory study of the major assumptions, endorsed in the project summarized as follows: (1) psychotic arousal is a discrete state, eligible for investigation; (2) abnormal experiential feelings are an integral part of this state; and (3) the state is responsive to antipsychotic intervention during the first weeks of treatment. Methods: We developed the Psychotic Arousal Scale (PAS) accordingly, explored its first psychometric properties and tested its relation to other psychopathological measures. Fifty-five acute schizophrenia patients were evaluated with the PAS, the Positive and Negative Syndrome Scale, the Brown Assessment of Beliefs Scale, the Hamilton Anxiety Scale, and the Calgary Depression Scale. Cronbach α coefficients, t-test analysis, correlations and mixed linear regression models were applied for testing the internal reliability of the scale, associations between parameters and sensitivity to change in three time periods during therapeutic intervention. Results: The results of the study support that (PA) is eligible for investigation as a discrete psychopathological state. Abnormal experiential feelings are an integral part of this state, presenting high affinity with other affective measures; their degree of severity relates to the delusions' conviction and are amenable to antipsychotics early in treatment during the acute psychotic episode. Conclusions: The findings of this exploratory study are connotative of the presence of an emotional arousal permeated by abnormal experiential feelings during acute psychosis, largely overlooked by contemporary psychopathology.
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Affiliation(s)
- Maria M Margariti
- 1st Department of Psychiatry, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Ilias I Vlachos
- 1st Department of Psychiatry, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Dimitra Mpourazana
- 1st Department of Psychiatry, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
| | - Panagiotis Aristotelidis
- 2nd Department of Psychiatry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Mirjana Selakovic
- Department of Psychiatry, "Sismanogleio" General Hospital, 15126 Athens, Greece
| | - Maria Ifanti
- 1st Department of Psychiatry, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
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9
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Markota M, Morgan RJ, Leung JG. Updated rationale for the initial antipsychotic selection for patients with schizophrenia. SCHIZOPHRENIA (HEIDELBERG, GERMANY) 2024; 10:74. [PMID: 39223138 PMCID: PMC11369117 DOI: 10.1038/s41537-024-00492-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 07/31/2024] [Indexed: 09/04/2024]
Affiliation(s)
- Matej Markota
- Department of Psychiatry & Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA.
| | - Robert J Morgan
- Department of Psychiatry & Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
| | - Jonathan G Leung
- Department of Psychiatry & Psychology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
- Department of Pharmacy, Mayo Clinic, 200 First Street SW, Rochester, MN, USA
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10
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Mélissa B, Sabrina G, Charles-Edouard G, Hind Z, Consortium S, Kingsada P, Stéphane P, Alexandre D. Clinical characteristics associated with functioning trajectories following admission to a psychiatric institution: A prospective cohort study of individuals with psychosis. Psychiatry Res 2024; 339:116062. [PMID: 38968920 DOI: 10.1016/j.psychres.2024.116062] [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: 02/23/2024] [Revised: 05/26/2024] [Accepted: 06/25/2024] [Indexed: 07/07/2024]
Abstract
Psychotic disorders can be severely enabling, and functional recovery is often difficult to achieve. Admission to a psychiatric unit represents a key opportunity to implement strategies that will improve functional outcomes. In the current literature, there is a lack of consensus on which factors influence functional recovery. Therefore, the present longitudinal cohort study aimed to identify factors associated with functional trajectories following hospital admission for acute psychosis. A sample of 453 individuals with acute psychosis was extracted from the Signature Biobank database. Participants were followed for up to a year following admission. Various clinical indicators were documented over time. Functional trajectories were calculated based on the World Health Organization Disability Assessment Schedule 2.0. Three groups were identified: "improving", "stable", and "worsening" function. Individuals with a more severe symptomatic presentation at baseline were found to have better functional improve more over time. Over time, individuals in the "improving" and "stable" groups had significant improvements in their psychiatric symptoms. Finally, individuals following a "worsening" functional trajectory initially improved in terms of psychotic symptoms, but it did not persist over time. These results highlight the importance of studying function as a key component of recovery rather than solely focusing on relapse prevention.
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Affiliation(s)
- Beaudoin Mélissa
- Department of Psychiatry and Addictology, Faculty of Medicine, University of Montreal. Montreal, QC, Canada; Faculty of Medicine, McGill University. Montreal, QC, Canada; Research center of the Institut universitaire en santé mentale de Montréal. Montreal, QC, Canada.
| | - Giguère Sabrina
- Department of Psychiatry and Addictology, Faculty of Medicine, University of Montreal. Montreal, QC, Canada; Research center of the Institut universitaire en santé mentale de Montréal. Montreal, QC, Canada
| | - Giguère Charles-Edouard
- Research center of the Institut universitaire en santé mentale de Montréal. Montreal, QC, Canada
| | - Ziady Hind
- Department of Psychiatry and Addictology, Faculty of Medicine, University of Montreal. Montreal, QC, Canada; Research center of the Institut universitaire en santé mentale de Montréal. Montreal, QC, Canada
| | - Signature Consortium
- Research center of the Institut universitaire en santé mentale de Montréal. Montreal, QC, Canada
| | - Phraxayavong Kingsada
- Research center of the Institut universitaire en santé mentale de Montréal. Montreal, QC, Canada; Services et recherche psychiatrique AD. Montreal, QC, Canada
| | - Potvin Stéphane
- Department of Psychiatry and Addictology, Faculty of Medicine, University of Montreal. Montreal, QC, Canada; Research center of the Institut universitaire en santé mentale de Montréal. Montreal, QC, Canada
| | - Dumais Alexandre
- Department of Psychiatry and Addictology, Faculty of Medicine, University of Montreal. Montreal, QC, Canada; Research center of the Institut universitaire en santé mentale de Montréal. Montreal, QC, Canada; Services et recherche psychiatrique AD. Montreal, QC, Canada; Institut national de psychiatrie légale Philippe-Pinel. Montreal, QC, Canada.
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11
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Yang JH, Park CHK, Rhee SJ, Kang DH, Kim MJ, Lee HJ, Lee SY, Shim SH, Moon JJ, Cho SJ, Kim SG, Kim MH, Lee J, Kang WS, Yoo J, Lee WY, Ahn YM. Psychotropic Medications Promote Time-Dependent Reduction of Suicidal Ideation in Mood Disorder: A Prospective Cohort Study. J Korean Med Sci 2024; 39:e226. [PMID: 39137811 PMCID: PMC11319105 DOI: 10.3346/jkms.2024.39.e226] [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] [Received: 03/06/2024] [Accepted: 06/24/2024] [Indexed: 08/15/2024] Open
Abstract
BACKGROUND Despite a plethora of research on the topic, there is still no solid evidence that pharmacological treatment actually reduces the risk of suicide in patients with mental illness. In this study, we aimed to assess the effect of psychotropic medications on suicidal ideation in patients with major depressive disorder (MDD) and bipolar disorder (BPD) in two age groups: less than 25 years and 25 years and older. METHODS We analyzed 312 patients with mood disorders with current suicidal thoughts or recent suicide attempts. We followed the participants from baseline for 6 months and assessed changes in suicidal ideation with Columbia-Suicide Severity Rating Scale (C-SSRS). The effect of psychotropic drug administration on suicidal ideation over time was analyzed using a linear mixed model. RESULTS In patients aged 25 years and older with mood disorders, suicidal ideation was more severe when using psychotropic drugs than when not using them. However, suicidal ideation decreased rapidly over time. The time-dependent reduction in suicidal ideation was accelerated when using antidepressants and sedatives/hypnotics in adult MDD, and when using mood stabilizers in adult BPD. However, this effect was not observed in participants aged less than 25 years. CONCLUSION Adequate psychotropic medication may reduce suicidal ideation in patients with mood disorders aged 25 years and older. Additional research on psychotropic drugs is needed to effectively reduce the risk of suicide among children and adolescents with mood disorders.
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Affiliation(s)
- Jeong Hun Yang
- Department of Psychiatry, Chungnam National University Sejong Hospital, Sejong, Korea
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea
| | | | - Sang Jin Rhee
- Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Korea
| | - Dae Hun Kang
- Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Korea
| | - Min Ji Kim
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea
| | - Hyun Jeong Lee
- Cancer Survivorship Branch, National Cancer Control Institute, National Cancer Center, Goyang, Korea
- Department of Psychiatry and Behavioral Science, National Cancer Center, Goyang, Korea
| | - Sang Yeol Lee
- Department of Psychiatry, Wonkwang University Hospital, Iksan, Korea
| | - Se-Hoon Shim
- Department of Psychiatry, Soon Chun Hyang University Cheonan Hospital, Soon Chun Hyang University, Cheonan, Korea
| | - Jung-Joon Moon
- Department of Psychiatry, Busan Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Seong-Jin Cho
- Department of Psychiatry, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Shin Gyeom Kim
- Department of Neuropsychiatry, Soon Chun Hyang University Bucheon Hospital, Bucheon, Korea
| | - Min-Hyuk Kim
- Department of Psychiatry, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jinhee Lee
- Department of Psychiatry, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Won Sub Kang
- Department of Psychiatry, Kyung Hee University Hospital, Seoul, Korea
| | - Jieun Yoo
- College of Social Sciences, Yonsei University, Seoul, Korea
| | - Weon-Young Lee
- Department of Preventive Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Yong Min Ahn
- Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea
- Department of Neuropsychiatry, Seoul National University Hospital, Seoul, Korea
- Institute of Human Behavioral Medicine, Seoul National University Medical Research Center, Seoul, Korea.
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12
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Tandon R, Nasrallah H, Akbarian S, Carpenter WT, DeLisi LE, Gaebel W, Green MF, Gur RE, Heckers S, Kane JM, Malaspina D, Meyer-Lindenberg A, Murray R, Owen M, Smoller JW, Yassin W, Keshavan M. The schizophrenia syndrome, circa 2024: What we know and how that informs its nature. Schizophr Res 2024; 264:1-28. [PMID: 38086109 DOI: 10.1016/j.schres.2023.11.015] [Citation(s) in RCA: 43] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 11/23/2023] [Accepted: 11/29/2023] [Indexed: 03/01/2024]
Abstract
With new data about different aspects of schizophrenia being continually generated, it becomes necessary to periodically revisit exactly what we know. Along with a need to review what we currently know about schizophrenia, there is an equal imperative to evaluate the construct itself. With these objectives, we undertook an iterative, multi-phase process involving fifty international experts in the field, with each step building on learnings from the prior one. This review assembles currently established findings about schizophrenia (construct, etiology, pathophysiology, clinical expression, treatment) and posits what they reveal about its nature. Schizophrenia is a heritable, complex, multi-dimensional syndrome with varying degrees of psychotic, negative, cognitive, mood, and motor manifestations. The illness exhibits a remitting and relapsing course, with varying degrees of recovery among affected individuals with most experiencing significant social and functional impairment. Genetic risk factors likely include thousands of common genetic variants that each have a small impact on an individual's risk and a plethora of rare gene variants that have a larger individual impact on risk. Their biological effects are concentrated in the brain and many of the same variants also increase the risk of other psychiatric disorders such as bipolar disorder, autism, and other neurodevelopmental conditions. Environmental risk factors include but are not limited to urban residence in childhood, migration, older paternal age at birth, cannabis use, childhood trauma, antenatal maternal infection, and perinatal hypoxia. Structural, functional, and neurochemical brain alterations implicate multiple regions and functional circuits. Dopamine D-2 receptor antagonists and partial agonists improve psychotic symptoms and reduce risk of relapse. Certain psychological and psychosocial interventions are beneficial. Early intervention can reduce treatment delay and improve outcomes. Schizophrenia is increasingly considered to be a heterogeneous syndrome and not a singular disease entity. There is no necessary or sufficient etiology, pathology, set of clinical features, or treatment that fully circumscribes this syndrome. A single, common pathophysiological pathway appears unlikely. The boundaries of schizophrenia remain fuzzy, suggesting the absence of a categorical fit and need to reconceptualize it as a broader, multi-dimensional and/or spectrum construct.
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Affiliation(s)
- Rajiv Tandon
- Department of Psychiatry, WMU Homer Stryker School of Medicine, Kalamazoo, MI 49008, United States of America.
| | - Henry Nasrallah
- Department of Psychiatry, University of Cincinnati College of Medicine Cincinnati, OH 45267, United States of America
| | - Schahram Akbarian
- Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, United States of America
| | - William T Carpenter
- Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD 21201, United States of America
| | - Lynn E DeLisi
- Department of Psychiatry, Cambridge Health Alliance and Harvard Medical School, Cambridge, MA 02139, United States of America
| | - Wolfgang Gaebel
- Department of Psychiatry and Psychotherapy, LVR-Klinikum Dusseldorf, Heinrich-Heine University, Dusseldorf, Germany
| | - Michael F Green
- Department of Psychiatry and Biobehavioral Sciences, Jane and Terry Semel Institute of Neuroscience and Human Behavior, UCLA, Los Angeles, CA 90024, United States of America; Greater Los Angeles Veterans' Administration Healthcare System, United States of America
| | - Raquel E Gur
- Department of Psychiatry, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, United States of America
| | - Stephan Heckers
- Department of Psychiatry, Vanderbilt University Medical Center, Nashville, TN 37232, United States of America
| | - John M Kane
- Department of Psychiatry, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Glen Oaks, NY 11004, United States of America
| | - Dolores Malaspina
- Department of Psychiatry, Neuroscience, Genetics, and Genomics, Icahn School of Medicine at Mt. Sinai, New York, NY 10029, United States of America
| | - Andreas Meyer-Lindenberg
- Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Mannhein/Heidelberg University, Mannheim, Germany
| | - Robin Murray
- Institute of Psychiatry, Psychology, and Neuroscience, Kings College, London, UK
| | - Michael Owen
- Centre for Neuropsychiatric Genetics and Genomics, and Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK
| | - Jordan W Smoller
- Center for Precision Psychiatry, Department of Psychiatry, Psychiatric and Neurodevelopmental Unit, Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, United States of America
| | - Walid Yassin
- Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, United States of America
| | - Matcheri Keshavan
- Department of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, United States of America
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13
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Schöttle D, Wiedemann K, Correll CU, Janetzky W, Friede M, Jahn H, Brieden A. Response prediction in treatment of patients with schizophrenia after switching from oral aripiprazole to aripiprazole once-monthly. Schizophr Res 2023; 260:183-190. [PMID: 37683508 DOI: 10.1016/j.schres.2023.08.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 07/12/2023] [Accepted: 08/27/2023] [Indexed: 09/10/2023]
Affiliation(s)
- Daniel Schöttle
- Klinik für Psychiatrie und Psychotherapie, Zentrum für Psychosoziale Medizin, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
| | - Klaus Wiedemann
- Klinik für Psychiatrie und Psychotherapie, Zentrum für Psychosoziale Medizin, Universitätsklinikum Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
| | - 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.
| | | | | | - Holger Jahn
- AMEOS Kliniken Heiligenhafen, AMEOS Krankenhausgesellschaft Holstein mbH, Oldenburg i. H., Preetz, Kiel, Germany.
| | - Andreas Brieden
- Universität der Bundeswehr München, Werner-Heisenberg-Weg 39, D-85577 Neubiberg, Germany.
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14
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Prieto SG, Almeida MC, Silva JCS, Del-Bel E, Echeverry MB. Extrapyramidal Side Effects with Chronic Atypical Antipsychotic Can Be Predicted by Labeling Pattern of FosB and phosphoThr 34-DARPP-32 in Nucleus Accumbens. Biomedicines 2023; 11:2677. [PMID: 37893051 PMCID: PMC10604349 DOI: 10.3390/biomedicines11102677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 09/16/2023] [Accepted: 09/19/2023] [Indexed: 10/29/2023] Open
Abstract
Extrapyramidal side effects (EPS) can be induced by neuroleptics that regulate the expression of transcription factor FosB and dopaminergic mediator DARPP-32 in the striatum. However, the long-term neurobiological changes in striatal projection neurons resulting from a cumulative dosage of typical and atypical antipsychotics are poorly understood. The present study aimed to determine the differential and long-lasting changes in FosB distribution and DARPP-32 phosphorylation in the striatum and nucleus accumbens (NAc) associated with chronic antipsychotic-induced EPS. Male C57Bl/6J mice received daily injections of Olanzapine (Olz, 15 mg/kg), Clozapine (Clz, 20 mg/kg), or Haloperidol (Hal, 1 mg/kg), for a period of 11 weeks with a 4-day withdrawal period before the last dosage. Catalepsy for detection of EPS, along with open-field and rotarod tests, were assessed as behavioral correlates of motor responses. Additionally, FosB and phosphorylated-DARPP-32 immunohistochemistry were examined in striatal regions after treatment. All antipsychotics produced catalepsy and reduced open-field exploration, such as impaired rota-rod performance after Olz and Hal. The washout period was critical for Clz-induced side effects reduction. Both Olz and Clz increased FosB in NAc Shell-region, and phosphoThr34-DARPP-32 in NAc. Only Clz reduced phosphoThr75-DARPP-32 in the dorsal striatum and showed FosB/phosphoThr34-Darpp-32-ir in the NAc Core region. This study provides evidence that atypical antipsychotics such as Olz and Clz also give rise to EPS effects frequently associated with a cumulative dosage of typical neuroleptics such as Hal. Nevertheless, FosB/phosphoThr34-Darpp-32-ir in the NAc Core region is associated with hypokinetic movements inhibition.
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Affiliation(s)
- Sonia G. Prieto
- Center for Mathematics, Computation and Cognition, Federal University of ABC, São Bernardo do Campo 09606-045, SP, Brazil; (S.G.P.); (J.C.S.S.)
| | - Maria Camila Almeida
- Center for Natural and Human Sciences, Federal University of ABC, São Bernardo do Campo 09606-045, SP, Brazil;
| | - João C. S. Silva
- Center for Mathematics, Computation and Cognition, Federal University of ABC, São Bernardo do Campo 09606-045, SP, Brazil; (S.G.P.); (J.C.S.S.)
| | - Elaine Del-Bel
- Department of Morphology, Physiology and Basic Pathology, Dental School of Ribeirão Preto, University of São Paulo, Ribeirão Preto 05508-000, SP, Brazil;
| | - Marcela B. Echeverry
- Center for Mathematics, Computation and Cognition, Federal University of ABC, São Bernardo do Campo 09606-045, SP, Brazil; (S.G.P.); (J.C.S.S.)
- Neuroscience Laboratory, School of Medicine, Universidad de Santander (UDES), Bucaramanga 39006-39005, Santander, Colombia
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15
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Selvaggi P, Jauhar S, Kotoula V, Pepper F, Veronese M, Santangelo B, Zelaya F, Turkheimer FE, Mehta MA, Howes OD. Reduced cortical cerebral blood flow in antipsychotic-free first-episode psychosis and relationship to treatment response. Psychol Med 2023; 53:5235-5245. [PMID: 36004510 PMCID: PMC10476071 DOI: 10.1017/s0033291722002288] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 06/27/2022] [Accepted: 07/04/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND Altered cerebral blood flow (CBF) has been found in people at risk for psychosis, with first-episode psychosis (FEP) and with chronic schizophrenia (SCZ). Studies using arterial spin labelling (ASL) have shown reduction of cortical CBF and increased subcortical CBF in SCZ. Previous studies have investigated CBF using ASL in FEP, reporting increased CBF in striatum and reduced CBF in frontal cortex. However, as these people were taking antipsychotics, it is unclear whether these changes are related to the disorder or antipsychotic treatment and how they relate to treatment response. METHODS We examined CBF in FEP free from antipsychotic medication (N = 21), compared to healthy controls (N = 22). Both absolute and relative-to-global CBF were assessed. We also investigated the association between baseline CBF and treatment response in a partially nested follow-up study (N = 14). RESULTS There was significantly lower absolute CBF in frontal cortex (Cohen's d = 0.84, p = 0.009) and no differences in striatum or hippocampus. Whole brain voxel-wise analysis revealed widespread cortical reductions in absolute CBF in large cortical clusters that encompassed occipital, parietal and frontal cortices (Threshold-Free Cluster Enhancement (TFCE)-corrected <0.05). No differences were found in relative-to-global CBF in the selected region of interests and in voxel-wise analysis. Relative-to-global frontal CBF was correlated with percentage change in total Positive and Negative Syndrome Scale after antipsychotic treatment (r = 0.67, p = 0.008). CONCLUSIONS These results show lower cortical absolute perfusion in FEP prior to starting antipsychotic treatment and suggest relative-to-global frontal CBF as assessed with magnetic resonance imaging could potentially serve as a biomarker for antipsychotic response.
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Affiliation(s)
- Pierluigi Selvaggi
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- Azienda Ospedaliero-Universitaria Consorziale Policlinico di Bari, Bari, Italy
| | - Sameer Jauhar
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- Early Intervention Psychosis Clinical Academic Group, South London & Maudsley NHS Foundation Trust, London, UK
| | - Vasileia Kotoula
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Fiona Pepper
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Mattia Veronese
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Barbara Santangelo
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Fernando Zelaya
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Federico E. Turkheimer
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Mitul A. Mehta
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Oliver D. Howes
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
- MRC London Institute of Medical Sciences, Hammersmith Hospital, London W12 0NN, UK
- Faculty of Medicine, Institute of Clinical Sciences (ICS), Imperial College London, Du Cane Road, London W12 0NN, UK
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16
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Rubio JM, Guinart D, Kane JM, Correll CU. Early Non-Response to Antipsychotic Treatment in Schizophrenia: A Systematic Review and Meta-Analysis of Evidence-Based Management Options. CNS Drugs 2023; 37:499-512. [PMID: 37261669 DOI: 10.1007/s40263-023-01009-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/02/2023] [Indexed: 06/02/2023]
Abstract
BACKGROUND Early non-response is a well-established prognostic marker but evidence-based and consistent recommendations to manage it are limited. The aim of this systematic review and meta-analysis was to generate evidence-based strategies for the management of schizophrenia patients with early non-response to 2 weeks of antipsychotic treatment. METHODS We conducted a systematic review and meta-analysis of randomized trials comparing antipsychotic dose escalation, switch, augmentation and continuation in individuals with study-defined early antipsychotic treatment non-response. Eligibility criteria were (1) clinical trials of primary psychosis treating for at least 2 weeks with antipsychotic monotherapy with study-defined operationalized criteria for early non-response; and (2) randomization to at least two of the following treatment strategies: dose escalation, switch, augmentation, or treatment continuation. Information sources were Pubmed, PsycINFO, and EMBASE, and risk of bias was assessed using Jadad scores. Results were synthesized using random-effects meta-analysis, comparing each intervention with treatment continuation for total symptom change as the primary outcome, generating standardized mean differences (SMDs) and 95% confidence intervals (CIs). Studies meeting the selection criteria but providing insufficient data for a meta-analysis were presented separately. RESULTS We screened 454 records by 1 August 2022, of which 12 individual datasets met the inclusion criteria, representing 947 research participants. Of those studies, five provided data to include in the meta-analysis (four with early non-response at 2 weeks, one at 3 weeks). Early non-response was defined within a timeline of 2 weeks in eight datasets, with the remaining datasets ranging between 3 and 4 weeks. The rates of early non-response ranged between 72.0 and 24.1%, and the endpoint ranged within 4-24 weeks post randomization. Quality was good (i.e., Jadad score of ≥3) in 8 of the 12 datasets. Overall, three studies compared antipsychotic switch versus continuation and two compared antipsychotic switch versus augmentation, in both cases without significant pooled between-group differences for total symptom severity (n = 149, SMD 0.18, 95% CI -0.14 to 0.5). Individually, two relatively large studies for antipsychotic switch versus continuation found small advantages for switching antipsychotics for total symptom severity (n = 149, SMD -0.49, 95% CI -1.05 to -0.06). One relatively large study found an advantage for dose escalation, although this finding has not been replicated and was not included in the meta-analysis. None of the alternatives included antipsychotic switch to clozapine. CONCLUSIONS Despite robust accuracy of early antipsychotic non-response predicting ultimate response, the evidence for treatment strategies that should be used for early non-response after 2-3 weeks is limited. While meta-analytic findings were non-significant, some individual studies suggest advantages of antipsychotic switch or dose escalation. Therefore, any conclusions should be interpreted carefully, given the insufficient high-quality evidence.
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Affiliation(s)
- Jose M Rubio
- The Zucker Hillside Hospital, Division of Psychiatry Research, Northwell Health, Glen Oaks, NY, USA
- Institute of Behavioral Science, The Feinstein Institute for Medical Research, Manhasset, NY, USA
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Daniel Guinart
- The Zucker Hillside Hospital, Division of Psychiatry Research, Northwell Health, Glen Oaks, NY, USA
- Institute of Behavioral Science, The Feinstein Institute for Medical Research, Manhasset, NY, USA
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut de Neuropsiquiatria i Addiccions (INAD), Hospital del Mar, Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona, Spain
| | - John M Kane
- The Zucker Hillside Hospital, Division of Psychiatry Research, Northwell Health, Glen Oaks, NY, USA
- Institute of Behavioral Science, The Feinstein Institute for Medical Research, Manhasset, NY, USA
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Christoph U Correll
- The Zucker Hillside Hospital, Division of Psychiatry Research, Northwell Health, Glen Oaks, NY, USA.
- Institute of Behavioral Science, The Feinstein Institute for Medical Research, Manhasset, NY, USA.
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
- Department of Child and Adolescent Psychiatry, Charité-Universitätsmedizin Berlin, Berlin, Germany.
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17
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Tang Y, Wu Y, Li X, Hao Q, Deng W, Yue W, Yan H, Zhang Y, Tan L, Chen Q, Yang G, Lu T, Wang L, Yang F, Zhang F, Yang J, Li K, Lv L, Tan Q, Zhang H, Ma X, Li L, Wang C, Ma X, Zhang D, Yu H, Zhao L, Ren H, Wang Y, Zhang G, Li C, Du X, Hu X, Li T, Wang Q. Early Efficacy of Antipsychotic Medications at Week 2 Predicts Subsequent Responses at Week 6 in a Large-scale Randomized Controlled Trial. Curr Neuropharmacol 2023; 21:424-436. [PMID: 36411567 PMCID: PMC10190139 DOI: 10.2174/1570159x21666221118164612] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/25/2022] [Accepted: 10/18/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Since the early clinical efficacy of antipsychotics has not yet been well perceived, this study sought to decide whether the efficacy of antipsychotics at week 2 can predict subsequent responses at week 6 and identify how such predictive capacities vary among different antipsychotics and psychotic symptoms. METHODS A total of 3010 patients with schizophrenia enrolled in a randomized controlled trial (RCT) and received a 6-week treatment with one antipsychotic drug randomly chosen from five atypical antipsychotics (risperidone 2-6 mg/d, olanzapine 5-20 mg/d, quetiapine 400-750 mg/d, aripiprazole 10-30 mg/d, and ziprasidone 80-160 mg/d) and two typical antipsychotics (perphenazine 20-60 mg/d and haloperidol 6-20 mg/d). Early efficacy was defined as the reduction rate using the Positive and Negative Syndrome Scale (PANSS) total score at week 2. With cut-offs at 50% reduction, logistic regression, receiver operating characteristic (ROC) and random forests were adopted. RESULTS The reduction rate of PANSS total score and improvement of psychotic symptoms at week 2 enabled subsequent responses to 7 antipsychotics to be predicted, in which improvements in delusions, lack of judgment and insight, unusual thought content, and suspiciousness/ persecution were endowed with the greatest weight. CONCLUSION It is robust enough to clinically predict treatment responses to antipsychotics at week 6 using the reduction rate of PANSS total score and symptom relief at week 2. Psychiatric clinicians had better determine whether to switch the treatment plan by the first 2 weeks.
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Affiliation(s)
- Yiguo Tang
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, China
| | - Yulu Wu
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, China
| | - Xiaojing Li
- Department of Neurobiology, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - QinJian Hao
- The Center of Gerontology and Geriatrics, West China Hospital of Sichuan University, Chengdu, China
| | - Wei Deng
- Department of Neurobiology, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Weihua Yue
- Peking University Sixth Hospital, Institute of Mental Health, Beijing, China
- National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China
| | - Hao Yan
- Peking University Sixth Hospital, Institute of Mental Health, Beijing, China
- National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China
| | - Yamin Zhang
- Department of Neurobiology, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Liwen Tan
- Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qi Chen
- Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Guigang Yang
- Beijing Anding Hospital, Institute for Brain Disorders, Capital Medical University, Beijing, China
| | - Tianlan Lu
- Peking University Sixth Hospital, Institute of Mental Health, Beijing, China
- National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China
| | - Lifang Wang
- Peking University Sixth Hospital, Institute of Mental Health, Beijing, China
- National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China
| | - Fude Yang
- Beijing HuiLongGuan Hospital, Beijing, China
| | - Fuquan Zhang
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
| | - Jianli Yang
- Institute of Mental Health, Tianjin Anding Hospital, Tianjin, China
- Tianjin Medical University General Hospital, Tianjin Medical University, Tianjin, China
| | - Keqing Li
- Hebei Mental Health Center, Baoding, Hebei, China
| | - Luxian Lv
- Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, Henan, China
| | - Qingrong Tan
- Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi, China
| | - Hongyan Zhang
- Wuxi Mental Health Center, Nanjing Medical University, Wuxi, China
| | - Xin Ma
- Beijing Anding Hospital, Institute for Brain Disorders, Capital Medical University, Beijing, China
| | - Lingjiang Li
- Department of Psychiatry, and National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Chuanyue Wang
- Beijing Anding Hospital, Institute for Brain Disorders, Capital Medical University, Beijing, China
| | - Xiaohong Ma
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, China
| | - Dai Zhang
- Peking University Sixth Hospital, Institute of Mental Health, Beijing, China
- National Clinical Research Center for Mental Disorders and Key Laboratory of Mental Health, Ministry of Health (Peking University), Beijing, China
| | - Hao Yu
- Department of Psychiatry, Jining Medical University, Jining, China
| | - Liansheng Zhao
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, China
| | - Hongyan Ren
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, China
| | - Yingcheng Wang
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, China
| | - Guangya Zhang
- Department of Psychiatry, Suzhou Psychiatric Hospital, Suzhou, China
- The Affiliated Guangji Hospital of Soochow University, Suzhou, China
| | - Chuanwei Li
- Department of Psychiatry, Suzhou Psychiatric Hospital, Suzhou, China
- The Affiliated Guangji Hospital of Soochow University, Suzhou, China
| | - Xiangdong Du
- Department of Psychiatry, Suzhou Psychiatric Hospital, Suzhou, China
- The Affiliated Guangji Hospital of Soochow University, Suzhou, China
| | - Xun Hu
- The Clinical Research Center and the Department of Pathology, Affiliated Second Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Tao Li
- Department of Neurobiology, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Qiang Wang
- Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China
- Sichuan Clinical Medical Research Center for Mental Disorders, Chengdu, China
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18
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Meyer R, Skov K, Dhillon IK, Olsson E, Graudal NA, Baandrup L, Jürgens G. Onset of Action of Selected Second-Generation Antipsychotics (Pines)-A Systematic Review and Meta-Analyses. Biomedicines 2022; 11:82. [PMID: 36672589 PMCID: PMC9855925 DOI: 10.3390/biomedicines11010082] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/23/2022] [Accepted: 12/24/2022] [Indexed: 12/30/2022] Open
Abstract
Recommendations for duration of treatment with antipsychotics before considering a switch vary from 2 to 8 weeks, although several studies suggest a rapid onset of action. The objective of this review was to estimate time to onset of action and time to maximum antipsychotic effect of asenapine, olanzapine, quetiapine, and zotepine (pines). We searched bibliographic databases for randomized, placebo-controlled trials in adults with schizophrenia estimating the antipsychotic effect of pines over time. Thirty-five studies including 6331 patients diagnosed with chronic schizophrenia were included. We estimated the standardized mean differences (SMD) of changes in symptom score from baseline to follow-up between intervention and placebo groups across studies using meta-analysis techniques. The summarized effect across all included pines administered as immediate-release formulations showed a statistically significant effect at week 1 (SMD, -0.20 [CI95% -0.28, -0.13]), which increased until week 3 (SMD, -0.42 [CI95% -0.50, -0.34]), after which the effect leveled off (week 6: SMD, -0.53 [CI95% -0.62, -0.44]). The sensitivity analyses of the individual pines confirm this finding, although data sparsity increases variability and limits conclusiveness of these analyses.
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Affiliation(s)
- Rikke Meyer
- Clinical Pharmacology Unit, Zealand University Hospital, Roskilde, Sygehusvej 10, 4000 Roskilde, Denmark
| | - Kenneth Skov
- Clinical Pharmacology Unit, Zealand University Hospital, Roskilde, Sygehusvej 10, 4000 Roskilde, Denmark
- Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | | | - Emilie Olsson
- Clinical Pharmacology Unit, Zealand University Hospital, Roskilde, Sygehusvej 10, 4000 Roskilde, Denmark
| | - Niels Albert Graudal
- Lupus and Vasculitis Clinic VRR4242, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen, Denmark
| | - Lone Baandrup
- Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
- Mental Health Center Copenhagen, Gentofte Hospitalsvej 15, Hellerup, 2900 Copenhagen, Denmark
| | - Gesche Jürgens
- Clinical Pharmacology Unit, Zealand University Hospital, Roskilde, Sygehusvej 10, 4000 Roskilde, Denmark
- Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
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19
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Kwee CMB, van Gerven JMA, Bongaerts FLP, Cath DC, Jacobs G, Baas JMP, Groenink L. Cannabidiol in clinical and preclinical anxiety research. A systematic review into concentration-effect relations using the IB-de-risk tool. J Psychopharmacol 2022; 36:1299-1314. [PMID: 36239014 PMCID: PMC9716490 DOI: 10.1177/02698811221124792] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Preclinical research suggests that cannabidiol (CBD) may have therapeutic potential in pathological anxiety. Dosing guidelines to inform future human studies are however lacking. AIM We aimed to predict the therapeutic window for anxiety-reducing effects of CBD in humans based on preclinical models. METHODS We conducted two systematic searches in PubMed and Embase up to August 2021, into pharmacokinetic (PK) and pharmacodynamic (PD) data of systemic CBD exposure in humans and animals, which includes anxiety-reducing and potential side effects. Risk of bias was assessed with SYRCLE's RoB tool and Cochrane RoB 2.0. A control group was an inclusion criterion in outcome studies. In human outcome studies, randomisation was required. We excluded studies that co-administered other substances. We used the IB-de-risk tool for a translational integration of outcomes. RESULTS We synthesised data from 87 studies. For most observations (70.3%), CBD had no effect on anxiety outcomes. There was no identifiable relation between anxiety outcomes and drug levels across species. In all species (humans, mice, rats), anxiety-reducing effects seemed to be clustered in certain concentration ranges, which differed between species. DISCUSSION A straightforward dosing recommendation was not possible, given variable concentration-effect relations across species, and no consistent linear effect of CBD on anxiety reduction. Currently, these results raise questions about the broad use as a drug for anxiety. Meta-analytic studies are needed to quantitatively investigate drug efficacy, including aspects of anxiety symptomatology. Acute and (sub)chronic dosing studies with integrated PK and PD outcomes are required for substantiated dose recommendations.
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Affiliation(s)
- Caroline MB Kwee
- Department of Experimental Psychology and Helmholtz Institute, Faculty of Social and Behavioural Sciences, Utrecht University, Utrecht, The Netherlands,Altrecht Academic Anxiety Centre, Utrecht, The Netherlands,Caroline MB Kwee, Department of Experimental Psychology and Helmholtz Institute, Faculty of Social and Behavioural Sciences, Utrecht University, Heidelberglaan 1, Utrecht 3584 CS, The Netherlands.
| | | | - Fleur LP Bongaerts
- Department of Experimental Psychology and Helmholtz Institute, Faculty of Social and Behavioural Sciences, Utrecht University, Utrecht, The Netherlands
| | - Danielle C Cath
- University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands,Department of Specialist Trainings, GGZ Drenthe, Assen, The Netherlands
| | | | - Johanna MP Baas
- Department of Experimental Psychology and Helmholtz Institute, Faculty of Social and Behavioural Sciences, Utrecht University, Utrecht, The Netherlands
| | - Lucianne Groenink
- Department of Pharmaceutical Sciences, Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
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20
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Maramis MM, Sofyan Almahdy M, Atika A, Bagus Jaya Lesmana C, Gerick Pantouw J. The biopsychosocial-spiritual factors influencing relapse of patients with schizophrenia. Int J Soc Psychiatry 2022; 68:1824-1833. [PMID: 34961376 DOI: 10.1177/00207640211065678] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE High relapse rate of patients with schizophrenia has a large impact on patients and their families that can be reviewed from biopsychosocial and spiritual factors. Determining all the potential risk factors of relapse in schizophrenia can help increase awareness of physicians, patients, and families. Physicians are the ones who examine patients and have responsibility to manage and educate them and expect to prevent relaps. This study analyze various biopsychosocial and spiritual factors affecting relapse occurrence in patients with schizophrenia. METHODS Cross sectional observational analytic study on 226 subjects with schizophrenia in three places in East Java, Indonesia, namely Soetomo Academic Hospital Surabaya (33.2%), Menur Hospital Surabaya (32.7%), and Radjiman Wediodiningrat Mental Hospital Lawang (34.1%) that met the inclusion and exclusion criteria. Data collection including 33 biopsychosocial and spiritual factors and were analyzed using bivariate and multivariate logistic regression. RESULTS Relapse rate within 1 year was 59.73%. There were 12 factors significantly affected the relapse of schizophrenia, namely history of physical disease of mothers during pregnancy (p < .001; B = 27.31; 95% CI 3.96-188.52), presence of trigger (p < .000; B = 6.25; 95% CI 2.61-14.96), negative beliefs (p < .000; B = 4.94; 95% CI 2.10-11.61), hereditary factors (p < .001; B = 4.84; 95% CI 1.93-12.10), insight (p < .003; B = 4.27; 95% CI 1.62-11.27), 1-year GAF Scale (p < .015; B = 3.79; 95% CI 1.30-11.09), response to treatment (p < .006; B = 3.68; 95% CI 1.45-9.36), family knowledge (p < .011; B = 3.23; 95% CI 1.31-7.93), history of head trauma (p < .029; B = 3.13; 95% CI 1.13-8.69), medication side effects (p < .028; B = 2.92; 95% CI 1.12-7.61), substance use history (p < .031; B = 2.86; 95% CI 1.10-7.45), and occupation (p < .040; B = 2.40; 95% CI 1.04-5.52). CONCLUSIONS The 12 factors of biopsychosocial-spiritual are determinant to predict the risk of relapse in patients with schizophrenia. These factors should be emphasized in psychoeducation for patients and their families to enable intervention and relapse prevention.
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Affiliation(s)
- Margarita M Maramis
- Department of Psychiatry, Faculty of Medicine, Dr. Soetomo General Academic Hospital, Universitas Airlangga, Surabaya, Indonesia
| | - Muhammad Sofyan Almahdy
- Department of Psychiatry, Faculty of Medicine, Dr. Soetomo General Academic Hospital, Universitas Airlangga, Surabaya, Indonesia
| | - Atika Atika
- Department of Public Health and Preventive Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | | | - Jakobus Gerick Pantouw
- Department of Psychiatry, Faculty of Medicine, Widya Mandala Catholic University Surabaya, Surabaya, Indonesia
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21
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Margariti MM, Vlachos II. The concept of psychotic arousal and its relevance to abnormal subjective experiences in schizophrenia. A hypothesis for the formation of primary delusions. Med Hypotheses 2022. [DOI: 10.1016/j.mehy.2022.110915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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22
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Zahid U, McCutcheon RA, Borgan F, Jauhar S, Pepper F, Nour MM, Rogdaki M, Osugo M, Murray GK, Hathway P, Murray RM, Egerton A, Howes OD. The effect of antipsychotics on glutamate levels in the anterior cingulate cortex and clinical response: A 1H-MRS study in first-episode psychosis patients. Front Psychiatry 2022; 13:967941. [PMID: 36032237 PMCID: PMC9403834 DOI: 10.3389/fpsyt.2022.967941] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 07/19/2022] [Indexed: 11/14/2022] Open
Abstract
Introduction Glutamatergic dysfunction is implicated in the pathophysiology of schizophrenia. It is unclear whether glutamatergic dysfunction predicts response to treatment or if antipsychotic treatment influences glutamate levels. We investigated the effect of antipsychotic treatment on glutamatergic levels in the anterior cingulate cortex (ACC), and whether there is a relationship between baseline glutamatergic levels and clinical response after antipsychotic treatment in people with first episode psychosis (FEP). Materials and methods The sample comprised 25 FEP patients; 22 completed magnetic resonance spectroscopy scans at both timepoints. Symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Results There was no significant change in glutamate [baseline 13.23 ± 2.33; follow-up 13.89 ± 1.74; t(21) = -1.158, p = 0.260], or Glx levels [baseline 19.64 ± 3.26; follow-up 19.66 ± 2.65; t(21) = -0.034, p = 0.973]. There was no significant association between glutamate or Glx levels at baseline and the change in PANSS positive (Glu r = 0.061, p = 0.777, Glx r = -0.152, p = 0.477), negative (Glu r = 0.144, p = 0.502, Glx r = 0.052, p = 0.811), general (Glu r = 0.110, p = 0.607, Glx r = -0.212, p = 0.320), or total scores (Glu r = 0.078, p = 0.719 Glx r = -0.155, p = 0.470). Conclusion These findings indicate that treatment response is unlikely to be associated with baseline glutamatergic metabolites prior to antipsychotic treatment, and there is no major effect of antipsychotic treatment on glutamatergic metabolites in the ACC.
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Affiliation(s)
- Uzma Zahid
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Robert A. McCutcheon
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Faith Borgan
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Sameer Jauhar
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Fiona Pepper
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
- Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
- Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London Centre, London, United Kingdom
| | - Matthew M. Nour
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
- Max Planck University College London Centre for Computational Psychiatry and Ageing Research, London, United Kingdom
- Wellcome Trust Centre for Neuroimaging, University College London, London, United Kingdom
| | - Maria Rogdaki
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
- Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Martin Osugo
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Graham K. Murray
- Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom
| | - Pamela Hathway
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Robin M. Murray
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Alice Egerton
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
| | - Oliver D. Howes
- Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, United Kingdom
- Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London, United Kingdom
- H. Lundbeck UK, Valby, Denmark
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23
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Early Antipsychotic Nonresponse as a Predictor of Nonresponse and Nonremission in Adolescents With Psychosis Treated With Aripiprazole or Quetiapine: Results From the TEA Trial. J Am Acad Child Adolesc Psychiatry 2022; 61:997-1009. [PMID: 35026408 DOI: 10.1016/j.jaac.2021.11.032] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 11/14/2021] [Accepted: 01/03/2022] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To evaluate 1) whether early nonresponse to antipsychotics predicts nonresponse and nonremission, 2) patient and illness characteristics as outcome predictors, and 3) response prediction of 30-item Positive and Negative Syndrome Scale (PANSS-30) compared with 6-item PANSS (PANSS-6) and Clinical Global Impressions-Improvement Scale (CGI-I) in youths with first-episode psychosis. METHOD Post hoc analysis from a 12-week, double-blinded, randomized trial of aripiprazole vs extended-release quetiapine in adolescents (age 12-17 years) with first-episode psychosis was performed. Early nonresponse (week 2 or week 4) was defined as <20% symptom reduction (PANSS-30) (or <20% symptom reduction [PANSS-6] or CGI-I score 4-7 [less than "minimally improved"]). Nonresponse (week 12) was defined as <50% symptom reduction (PANSS-30). Nonremission (week 12) was defined as a score of >3 on 8 selected PANSS-items. Positive/negative predictive values (PPV/NPV) and receiver operating characteristics, binary logistic regression models, and PPV/NPV using PANSS-6 and CGI-I were analyzed. RESULTS Of 113 randomized patients, 84 were included in post hoc analysis (mean [SD] age = 15.7 [1.3] years; 28.6% male). The 12-week symptom decrease was 31.9% [27.9%], most pronounced within the first 2 weeks (61.1% of total PANSS reduction). Response (27.4%) and remission (22.6%) rates were low. Results indicated that early nonresponse reliably predicted 12-week nonresponse (PPV: week 2, 82.2%; week 4, 90.0%) and nonremission (PPV: week 2, 80.0%; week 4, 90.0%); early nonresponse at week 4 was a statistically significant baseline predictor for 12-week nonresponse; and PANSS-6 had similar predictive significance as PANSS-30. However, outcomes were heterogeneous using CGI-I. CONCLUSION In youths with first-episode psychosis showing early nonresponse to aripiprazole or extended-release quetiapine, switching antipsychotic drug should be considered. PANSS-6 is a feasible and clinically relevant alternative to PANSS-30 to predict 12-week nonresponse/nonremission. CLINICAL TRIAL REGISTRATION INFORMATION Tolerance and Effect of Antipsychotics in Children and Adolescents With Psychosis; https://www. CLINICALTRIALS gov/; NCT01119014.
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24
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Sodium nitroprusside enhances the antipsychotic-like effect of olanzapine but not clozapine in the conditioned avoidance response test in rats. Eur Neuropsychopharmacol 2022; 60:48-54. [PMID: 35635996 DOI: 10.1016/j.euroneuro.2022.05.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 04/29/2022] [Accepted: 05/01/2022] [Indexed: 01/02/2023]
Abstract
The nitric oxide (NO)-donor, sodium nitroprusside (SNP) has been proposed as an adjunct treatment to enhance the effect of antipsychotic drugs (APDs). As NO constitutes an important downstream signaling molecule of N-methyl-D-aspartate receptors, SNP may alleviate symptoms of schizophrenia by modulating glutamatergic signaling. We previously showed that SNP enhances the antipsychotic-like effect of a sub-effective dose of risperidone in the conditioned avoidance response (CAR) test, indicating that adjunct SNP may be used to lower the dose of risperidone and in this way reduce the risk of side effects. By using the CAR test, we here investigated if SNP also enhances the antipsychotic-like effect of olanzapine or clozapine. Importantly, SNP (1.5 mg/kg) significantly enhanced the antipsychotic-like effect of olanzapine (1.25 and 2.5mg/kg) to a clinically relevant level, supporting the potential clinical use of SNP as an adjunct treatment to improve the effect of APDs. However, SNP (1.5 mg/kg) did not increase the antipsychotic-like effect of clozapine (5 and 6 mg/kg). Moreover, we found that the rats developed tolerance towards clozapine after repeated administrations. Thus, our study motivates further investigation using different preclinical models to assess the effect of adjunct treatment of SNP to APDs, also targeting the negative symptoms and cognitive deficits seen in schizophrenia.
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Canazei M, Weninger J, Pohl W, Marksteiner J, Weiss EM. Effects of dynamic bedroom lighting on measures of sleep and circadian rest-activity rhythm in inpatients with major depressive disorder. Sci Rep 2022; 12:6137. [PMID: 35414714 PMCID: PMC9005730 DOI: 10.1038/s41598-022-10161-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 04/01/2022] [Indexed: 11/08/2022] Open
Abstract
Bright light therapy is an effective treatment option for seasonal and non-seasonal affective disorders. However up to now, no study has investigated effects of dynamic bedroom lighting in hospitalized patients with major depression. A bedroom lighting system, which automatically delivered artificial dawn and dusk and blue-depleted nighttime lighting (DD-N lighting) was installed in a psychiatric ward. Patients with moderate to severe depression were randomly assigned to stay in bedrooms with the new lighting or standard lighting system. Patients wore wrist actimeters during the first two treatment weeks. Additionally, hospitalization duration and daily psychotropic medication were retrieved from patients' medical charts. Data from thirty patients, recorded over a period of two weeks, were analyzed. Patients under DD-N lighting generally woke up earlier (+ 20 min), slept longer (week 1: + 11 min; week 2: + 27 min) and showed higher sleep efficiency (+ 2.4%) and shorter periods of nighttime awakenings (- 15 min). In the second treatment week, patients started sleep and the most active 10-h period earlier (- 33 min and - 64 min, respectively). This pilot study gives first evidence that depressed patients' sleep and circadian rest/activity system may benefit from bedroom lighting when starting inpatient treatment.
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Affiliation(s)
- Markus Canazei
- Department of Psychology, University of Innsbruck, Innrain 52f, 6020, Innsbruck, Austria.
| | - Johannes Weninger
- Research Department, Bartenbach GmbH, Rinnerstrasse 14, 6071, Aldrans, Austria
| | - Wilfried Pohl
- Research Department, Bartenbach GmbH, Rinnerstrasse 14, 6071, Aldrans, Austria
| | - Josef Marksteiner
- Abteilung Psychiatrie und Psychotherapie A, Regional Psychiatric Hospital, 6060, Hall in Tirol, Austria
| | - Elisabeth M Weiss
- Department of Psychology, University of Innsbruck, Innrain 52f, 6020, Innsbruck, Austria
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Early Markers in Resistant Schizophrenia: Effect of the First Antipsychotic Drug. Diagnostics (Basel) 2022; 12:diagnostics12040803. [PMID: 35453850 PMCID: PMC9030295 DOI: 10.3390/diagnostics12040803] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/23/2022] [Accepted: 03/23/2022] [Indexed: 11/25/2022] Open
Abstract
Background: Schizophrenia is a mental illness with a multifactorial etiology and clinical presentation. Treatment is mainly with antipsychotic drugs. Despite the increasing number of antipsychotic drugs, there has been no significant change in the percentage of resistant cases. These data gave us reason to look for a link between the effect of the first individually selected antipsychotic drug and the established resistance to therapy. Method: An assessment has been made of 105 patients with chronic schizophrenia with consecutive psychotic episodes. The choice of antipsychotic has been made on the basis of clinical features, history of efficacy of previously used neuroleptics, anthropometric features, as well as somatic comorbidities. Accidental use of benzodiazepines in anxiety conditions as well as correctors in indications for extrapyramidal problems have been reported. Assessment was made based on clinical observation as well as on changes in PANSS score. Results: Of the 105 observed patients, the effectiveness of the first antipsychotic effect was found in 46.7% of patients. Follow-up of patients for a period of 12 weeks revealed that 45 (42.8%) of them had resistant schizophrenia, while the remaining 60 (57.2%) achieved clinical remission and initial functional recovery. The effect of the first antipsychotic drug was established in 9 (20%) of the patients with resistant schizophrenia and in 40 (66.57%) of the patients in clinical remission. Conclusion: The evaluation of the first antipsychotic medication is significant for the prognosis of patients with schizophrenia. Its lack of effectiveness indicates a high probability of resistance and can be a good indicator of earlier change and a possible search for more “aggressive” measures to prevent future resistance and possible disability.
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Piccinelli MP, Bortolaso P, Wilkinson GD. Rethinking hospital psychiatry in Italy in light of COVID-19 experience. World J Virol 2022; 11:73-81. [PMID: 35117972 PMCID: PMC8788211 DOI: 10.5501/wjv.v11.i1.73] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 08/13/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Italy retains a distinctive organization of mental health services according to a community-based model of care with a multidisciplinary team serving a well-defined catchment area under the coordination of the local department of mental health. The coronavirus disease 2019 (COVID-19) pandemic is forcing Italian mental health services to develop new organizational strategies at all levels of care in order to face the associated challenges.
AIM To explore factors associated with changes in psychiatric admissions to an inpatient psychiatric unit located in Lombardia Region, Italy.
METHODS All hospital admissions (n = 44) were recorded to an inpatient psychiatric unit during a three month national lockdown in Italy in 2020 and compared with those occurring over the same time period in 2019 (n = 71). For each admission, a 20-item checklist was completed to identify factors leading to admission. Statistical analyses were performed using Statistical Package for Social Sciences for Windows, release 11.0. Chi-square test (or Fisher’s exact test) and Mann-Whitney U-test were applied, where appropriate.
RESULTS Hospital admissions dropped by 38% during the COVID-19 pandemic. No significant differences were found in demographics, clinical variables associated with hospital admissions and length of stay between 2019 and 2020. Compared with 2019, a significantly greater proportion of hospital admissions in 2020 were related to difficulties in organizing care programs outside the hospital (chi-square = 4.91, df 1, one-way P = 0.035) and in patients’ family contexts (chi-square = 3.71, df 1, one-way P = 0.049). On the other hand, logistic and communication difficulties pertaining to residential facilities and programs were significantly more common in 2019 than in 2020 (chi-square = 4.38, df 1, one-way P = 0.032).
CONCLUSION Admissions to the inpatient psychiatric unit dropped significantly during the COVID-19 pandemic in 2020, with difficulties in organizing care programs outside the hospital and in patients’ family contexts occurring more frequently compared with 2019.
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Affiliation(s)
- Marco P Piccinelli
- Psychiatric Unit Verbano, Department of Mental Health and Substance Abuse, Cittiglio 21033, Varese, Italy
| | - Paola Bortolaso
- Psychiatric Unit Verbano, Department of Mental Health and Substance Abuse, Cittiglio 21033, Varese, Italy
| | - Greg D Wilkinson
- Liverpool University Hospitals NHS Trust, Liverpool University, Liverpool 2170, United Kingdom
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Japanese Society of Neuropsychopharmacology. Japanese Society of Neuropsychopharmacology: "Guideline for Pharmacological Therapy of Schizophrenia". Neuropsychopharmacol Rep 2021; 41:266-324. [PMID: 34390232 PMCID: PMC8411321 DOI: 10.1002/npr2.12193] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 06/27/2021] [Indexed: 12/01/2022] Open
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Gómez-Revuelta M, Pelayo-Terán JM, Vázquez-Bourgon J, Ortiz-García de la Foz V, Mayoral-van Son J, Ayesa-Arriola R, Crespo-Facorro B. Aripiprazole vs Risperidone for the acute-phase treatment of first-episode psychosis: A 6-week randomized, flexible-dose, open-label clinical trial. Eur Neuropsychopharmacol 2021; 47:74-85. [PMID: 33678469 DOI: 10.1016/j.euroneuro.2021.02.009] [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: 10/07/2020] [Revised: 02/14/2021] [Accepted: 02/17/2021] [Indexed: 12/25/2022]
Abstract
Selecting the first antipsychotic agent for the acute phase of a first episode of psychosis (FEP) is a critical task that may impact on the long-term outcome. Despite that, there is a lack of research comparing head-to-head different second-generation antipsychotics at this stage. The aim of this study was to compare the effectiveness of aripiprazole and risperidone in the treatment of the acute phase after a FEP. For that purpose, from February 2011 to October 2018, a prospective, randomized, open-label study was undertaken. Two hundred-sixty-six first-episode, drug-naïve patients were randomly assigned to aripiprazole (n = 136), or risperidone (n = 130) and followed-up for 6-weeks. The primary effectiveness measure was all-cause treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted to assess clinical efficacy. The overall dropout rate at 6-week reached 19.5%. Effectiveness measures were similar between both treatment groups as treatment discontinuation rates (χ2 = 1.863; p = 0.172) and mean time until all-cause discontinuation (log rank = 1.421; p = 0.233) showed no statistically significant differences. In terms of clinical efficacy, risperidone proved a statistically significant better performance according to BPRS mean change between baseline and 6-week total score (t = 3.187; p = 0.002). Patients under risperidone treatment were significantly more likely to suffer sex-related adverse events. In conclusion, no differences regarding effectiveness were found between aripiprazole and risperidone for the acute-phase treatment of FEP. Despite the importance of efficacy during this phase of treatment, selecting the most effective treatment for the long-term outcome, requires addressing safety and patient´s preferences.
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Affiliation(s)
- Marcos Gómez-Revuelta
- University Hospital Marqués de Valdecilla-IDIVAL, Department of Psychiatry, School of Medicine, University of Cantabria, Avda. Valdecilla n 25, 39008, SANTANDER, Cantabria, Santander, Spain.
| | - José María Pelayo-Terán
- University Hospital Marqués de Valdecilla-IDIVAL, Department of Psychiatry, School of Medicine, University of Cantabria, Avda. Valdecilla n 25, 39008, SANTANDER, Cantabria, Santander, Spain; CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain; Servicio de Psiquiatría y Salud Mental, Hospital El Bierzo, GASBI, Servicio de Salud de Castilla y León (SACYL), Ponferrada (León), Spain
| | - Javier Vázquez-Bourgon
- University Hospital Marqués de Valdecilla-IDIVAL, Department of Psychiatry, School of Medicine, University of Cantabria, Avda. Valdecilla n 25, 39008, SANTANDER, Cantabria, Santander, Spain; CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain
| | - Víctor Ortiz-García de la Foz
- University Hospital Marqués de Valdecilla-IDIVAL, Department of Psychiatry, School of Medicine, University of Cantabria, Avda. Valdecilla n 25, 39008, SANTANDER, Cantabria, Santander, Spain; CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain
| | - Jacqueline Mayoral-van Son
- University Hospital Marqués de Valdecilla-IDIVAL, Department of Psychiatry, School of Medicine, University of Cantabria, Avda. Valdecilla n 25, 39008, SANTANDER, Cantabria, Santander, Spain; CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain; Hospital Universitario Virgen del Rocío, Department of Psychiatry, Universidad de Sevilla, Sevilla, Spain. Instituto de Investigacion Sanitaria de Sevilla, IBiS Spain
| | - Rosa Ayesa-Arriola
- University Hospital Marqués de Valdecilla-IDIVAL, Department of Psychiatry, School of Medicine, University of Cantabria, Avda. Valdecilla n 25, 39008, SANTANDER, Cantabria, Santander, Spain; CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain
| | - Benedicto Crespo-Facorro
- University Hospital Marqués de Valdecilla-IDIVAL, Department of Psychiatry, School of Medicine, University of Cantabria, Avda. Valdecilla n 25, 39008, SANTANDER, Cantabria, Santander, Spain; CIBERSAM, Centro Investigación Biomédica en Red Salud Mental, Madrid, Spain; Hospital Universitario Virgen del Rocío, Department of Psychiatry, Universidad de Sevilla, Sevilla, Spain. Instituto de Investigacion Sanitaria de Sevilla, IBiS Spain
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Hua LL, Alderman EM, Chung RJ, Grubb LK, Lee J, Powers ME, Upadhya KK, Wallace SB. Collaborative Care in the Identification and Management of Psychosis in Adolescents and Young Adults. Pediatrics 2021; 147:peds.2021-051486. [PMID: 34031232 DOI: 10.1542/peds.2021-051486] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Pediatricians are often the first physicians to encounter adolescents and young adults presenting with psychotic symptoms. Although pediatricians would ideally be able to refer these patients immediately into psychiatric care, the shortage of child and adolescent psychiatry services may sometimes require pediatricians to make an initial assessment or continue care after recommendations are made by a specialist. Knowing how to identify and further evaluate these symptoms in pediatric patients and how to collaborate with and refer to specialty care is critical in helping to minimize the duration of untreated psychosis and to optimize outcomes. Because not all patients presenting with psychotic-like symptoms will convert to a psychotic disorder, pediatricians should avoid prematurely assigning a diagnosis when possible. Other contributing factors, such as co-occurring substance abuse or trauma, should also be considered. This clinical report describes psychotic and psychotic-like symptoms in the pediatric age group as well as etiology, risk factors, and recommendations for pediatricians, who may be among the first health care providers to identify youth at risk.
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Affiliation(s)
- Liwei L. Hua
- Catholic Charities of Baltimore, Baltimore, Maryland
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Honer WG. Better Evidence for Pharmacological Maintenance Treatment in Nonaffective Psychoses: Implications for Relapse Prevention. Am J Psychiatry 2021; 178:369-371. [PMID: 33979537 DOI: 10.1176/appi.ajp.2021.21030281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- William G Honer
- Department of Psychiatry, University of British Columbia, and British Columbia Mental Health and Substance Use Services Research Institute, Vancouver, Canada
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Chestnykh DA, Amato D, Kornhuber J, Müller CP. Pharmacotherapy of schizophrenia: Mechanisms of antipsychotic accumulation, therapeutic action and failure. Behav Brain Res 2021; 403:113144. [PMID: 33515642 DOI: 10.1016/j.bbr.2021.113144] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 12/13/2022]
Abstract
Schizophrenia is a multi-dimensional disorder with a complex and mostly unknown etiology, leading to a severe decline in life quality. Antipsychotic drugs (APDs) remain beneficial interventions in the treatment of the disorder, but vary significantly in binding profile, clinical effects and adverse reactions. The present review summarizes the main principles of APD mechanisms of action with a particular focus on recent findings in APD accumulation and its role in the therapeutic efficacy and treatment failure. High and low doses of APDs were shown to be effective in different dimensions of antipsychotic-like behaviour in rodent models. Efficacy of the APDs correlates with high dopamine D2 receptor occupancy, which occurs quickly after drug administration. However, onset and peak of action are delayed up to several days or weeks. APD accumulation via acidic trapping in synaptic vesicles is considered to underlie the time course of APD action. Use-dependent exocytosis, co-release with dopamine and serotonin and inhibition of ion channels impact on the neuronal transmission and determine effects of APDs. Disruption in accumulating properties leads to diminished APD effects. In addition, long-term APD administration at therapeutic doses leads to treatment failure both in animal models and in humans. APD failure was associated with treatment induced neuroadaptations, including a decline in extracellular dopamine levels, dopamine transporter upregulation, and altered neuronal firing. However, enhanced synaptic vesicle release has also been reported. APD loss of efficacy may be reversed through inhibition of the dopamine transporter or switching the administration regimen from continuous to intermittent. Thus, manipulating the accumulation properties of APDs, changes in the administration regimen and doses, or co-administration with dopamine transporter inhibitors may be considered to yield benefits in the development of new effective strategies in the treatment of schizophrenia.
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Affiliation(s)
- Daria A Chestnykh
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany
| | - Davide Amato
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany; Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany
| | - Christian P Müller
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054, Erlangen, Germany.
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Uzuneser TC, Weiss EM, Dahlmanns J, Kalinichenko LS, Amato D, Kornhuber J, Alzheimer C, Hellmann J, Kaindl J, Hübner H, Löber S, Gmeiner P, Grömer TW, Müller CP. Presynaptic vesicular accumulation is required for antipsychotic efficacy in psychotic-like rats. J Psychopharmacol 2021; 35:65-77. [PMID: 33274688 PMCID: PMC7770212 DOI: 10.1177/0269881120965908] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
BACKGROUND The therapeutic effects of antipsychotic drugs (APDs) are mainly attributed to their postsynaptic inhibitory functions on the dopamine D2 receptor, which, however, cannot explain the delayed onset of full therapeutic efficacy. It was previously shown that APDs accumulate in presynaptic vesicles during chronic treatment and are released like neurotransmitters in an activity-dependent manner triggering an auto-inhibitory feedback mechanism. Although closely mirroring therapeutic action onset, the functional consequence of the APD accumulation process remained unclear. AIMS Here we tested whether the accumulation of the APD haloperidol (HAL) is required for full therapeutic action in psychotic-like rats. METHODS We designed a HAL analog compound (HAL-F), which lacks the accumulation property of HAL, but retains its postsynaptic inhibitory action on dopamine D2 receptors. RESULTS/OUTCOMES By perfusing LysoTracker fluorophore-stained cultured hippocampal neurons, we confirmed the accumulation of HAL and the non-accumulation of HAL-F. In an amphetamine hypersensitization psychosis-like model in rats, we found that subchronic intracerebroventricularly delivered HAL (0.1 mg/kg/day), but not HAL-F (0.3-1.5 mg/kg/day), attenuates psychotic-like behavior in rats. CONCLUSIONS/INTERPRETATION These findings suggest the presynaptic accumulation of HAL may serve as an essential prerequisite for its full antipsychotic action and may explain the time course of APD action. Targeting accumulation properties of APDs may, thus, become a new strategy to improve APD action.
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Affiliation(s)
- Taygun C Uzuneser
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany,Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada
| | - Eva-Maria Weiss
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Jana Dahlmanns
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Liubov S Kalinichenko
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Davide Amato
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany,Department of Neuroscience, Medical University of South Carolina, Charleston, USA
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Christian Alzheimer
- Institute of Physiology and Pathophysiology, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Jan Hellmann
- Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Jonas Kaindl
- Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Harald Hübner
- Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Stefan Löber
- Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Peter Gmeiner
- Department of Chemistry and Pharmacy, Medicinal Chemistry, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Teja W Grömer
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany
| | - Christian P Müller
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany,Christian P Müller, Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander University of Erlangen-Nuremberg, Schwabachanlage 6, Erlangen 91054, Germany.
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Oh H, Lee J, Kim S, Rufino KA, Fonagy P, Oldham JM, Schanzer B, Patriquin MA. Time in treatment: Examining mental illness trajectories across inpatient psychiatric treatment. J Psychiatr Res 2020; 130:22-30. [PMID: 32768710 DOI: 10.1016/j.jpsychires.2020.07.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 06/03/2020] [Accepted: 07/01/2020] [Indexed: 12/12/2022]
Abstract
Early discharge or reduced length of stay for inpatient psychiatric patients is related to increased readmission rates and worse clinical outcomes including increased risk for suicide. Trajectories of mental illness outcomes have been identified as an important method for predicting the optimal length of stay but the distinguishing factors that separate trajectories remain unclear. We sought to identify the distinct classes of patients who demonstrated similar trajectories of mental illness over the course of inpatient treatment, and we explore the patient characteristics associated with these mental illness trajectories. We used data (N = 3406) from an inpatient psychiatric hospital with intermediate lengths of stay. Using growth mixture modeling, latent mental illness scores were derived from six mental illness indicators: psychological flexibility, emotion regulation problems, anxiety, depression, suicidal ideation, and disability. The patients were grouped into three distinct trajectory classes: (1) High-Risk, Rapid Improvement (HR-RI); (2) Low-Risk, Gradual Improvement (LR-GI); and (3) High-Risk, Gradual Improvement (HR-GI). The HR-GI was significantly younger than the other two classes. The HR-GI had significantly more female patients than males, while the LR-GI had more male patients than females. Our findings indicated that younger females had more severe mental illness at admission and only gradual improvement during the inpatient treatment period, and they remained in treatment for longer lengths of stay, than older males.
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Affiliation(s)
- Hyuntaek Oh
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, 1977 Butler Blvd., Houston, TX, 77030, USA; The Menninger Clinic, 12301 S Main St, Houston, TX, 77035, USA.
| | - Jaehoon Lee
- Department of Educational Psychology and Leadership, College of Education, Texas Tech University, 3002 18th Street, Lubbock, TX, 79409, USA
| | - Seungman Kim
- Department of Educational Psychology and Leadership, College of Education, Texas Tech University, 3002 18th Street, Lubbock, TX, 79409, USA
| | - Katrina A Rufino
- The Menninger Clinic, 12301 S Main St, Houston, TX, 77035, USA; Department of Social Sciences, University of Houston - Downtown, One Main St, Houston, TX, 77002, USA
| | - Peter Fonagy
- Research Department of Clinical, Educational and Health Psychology, University College London, UK
| | - John M Oldham
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, 1977 Butler Blvd., Houston, TX, 77030, USA; The Menninger Clinic, 12301 S Main St, Houston, TX, 77035, USA
| | - Bella Schanzer
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, 1977 Butler Blvd., Houston, TX, 77030, USA; The Menninger Clinic, 12301 S Main St, Houston, TX, 77035, USA
| | - Michelle A Patriquin
- Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, 1977 Butler Blvd., Houston, TX, 77030, USA; The Menninger Clinic, 12301 S Main St, Houston, TX, 77035, USA
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Abstract
Introduction: Psychosis is a multifaceted clinical phenomenon in which the various symptoms may show a differential response to treatment. Important information may be lost when heterogeneous symptoms are grouped together in global sum scores when studying treatment effects.Aims: The aim of this study was to compare the level and rate of change in the two separate symptoms hallucinations and delusions during the acute psychotic phase, and to explore whether potential temporal differences depend on diagnosis or patients being previously medicated with antipsychotics or not.Method: Patients admitted with active symptoms of schizophrenia or related psychotic disorders were included in the Bergen Psychosis Project (BPP) (N = 226), a prospective, pragmatic, study of four second-generation antipsychotics. The Positive and Negative Syndrome Scale were assessed at baseline, one, three and six months.Results: Over the total follow-up period, latent growth curve models showed greater reductions in delusions than in hallucinations. However, the percentage of the total reduction was found to be larger in hallucinations than that of delusions in the first interval (91% vs. 64%). The levels and changes in these variables were dependent on diagnosis and whether or not patients had a life-time history of antipsychotic use.Conclusion: Focusing on separate symptoms rather than general symptom clusters could offer clinicians a useful approach when evaluating the early response of antipsychotics.ClinicalTrials.gov ID: NCT00932529; URL: http://www.clinicaltrials.gov/.
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Younis IR, Gopalakrishnan M, Mathis M, Mehta M, Uppoor R, Zhu H, Farchione T. Association of End Point Definition and Randomized Clinical Trial Duration in Clinical Trials of Schizophrenia Medications. JAMA Psychiatry 2020; 77:1064-1071. [PMID: 32609294 PMCID: PMC7330825 DOI: 10.1001/jamapsychiatry.2020.1596] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
IMPORTANCE Facilitating the development of safe and effective medications for schizophrenia is a public health imperative. OBJECTIVES To evaluate the association of shortening randomized clinical trial (RCT) duration with the modification of the Positive and Negative Syndrome Scale (PANSS) for the design of RCTs of medications for schizophrenia and to offer perspective on an alternative regulatory pathway to the historically accepted trial duration and response assessment. DATA SOURCES A database was created consisting of clinical trial data from 32 placebo-controlled RCTs of 8 atypical antipsychotic drugs approved by the US Food and Drug Administration (FDA) between January 1, 2001, and December 31, 2015. The database included information on total and individual PANSS item ratings, demographic characteristics, disposition, and adverse events (AEs). STUDY SELECTION All clinical trials submitted to 8 new drug applications of atypical antipsychotic drugs were selected. DATA EXTRACTION AND SYNTHESIS Quality control checks were performed to ensure that the collected data were consistent with the reported results of each trial. Data were collected from March 15, 2015, to September 30, 2015. Data analysis was conducted from October 1, 2015, to June 20, 2016. MAIN OUTCOMES AND MEASURES The following analyses were performed: (1) longitudinal assessment of mean change from baseline in total PANSS score, (2) correlation analyses between change from baseline in total PANSS score at week 6 and earlier time points, (3) concordance analyses of outcomes across trials between week 6 and earlier time points using total PANSS and modified PANSS, and (4) analyses of time course of treatment-emergent AEs. RESULTS The final database contained data from 14 219 participants enrolled in 32 drug trials; 9805 of 14 219 participants (69.0%) were male and were either white (7183 [50.5%]) or black (4346 [30.6%]) individuals. The mean (SD) age during treatment was 38.9 (10.9) years, and the mean (SD) age at schizophrenia diagnosis was 25 (8.5) years. Statistically significant separation between treatment response and placebo response was observed after 1 week of treatment. The overall concordance rate across treatment groups steadily increased from week 1 to week 4 (68.0% for week 1, 74.0% for week 2, 83.0% for week 3, and 93.0% for week 4). Trends in AE occurrence were evident by week 1 and percentage of AEs were similar across weeks 3, 4, and 6. The overall concordance rate between change from baseline in the modified PANSS score and change from baseline in the total PANSS score was 93.0% (80 of 86 treatment groups) at week 4 and 97.7% (84 of 86 treatment groups) at week 6. Shortening the trial duration to 4 weeks increased the required sample size to 502 participants. Using the modified PANSS as the end point, the sample size for a 4-week trial was 402 participants and 296 participants for a 6-week trial. CONCLUSIONS AND RELEVANCE Findings from this analysis suggest that there is the potential to streamline the design of schizophrenia drug clinical trials. Trial sponsors may consider incorporating these strategies and are encouraged to consult with the FDA early in the drug development process.
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Affiliation(s)
- Islam R. Younis
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Mathangi Gopalakrishnan
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland,Center for Translational Medicine, University of Maryland, Baltimore
| | - Mitchell Mathis
- Division of Psychiatry Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Mehul Mehta
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Ramana Uppoor
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Hao Zhu
- Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
| | - Tiffany Farchione
- Division of Psychiatry Products, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland
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Gattaz WF, Saracco-Alvarez R, Daltio CS, Van de Bilt MT, Ortegón JJ, Villaseñor-Bayardo SJ, Louzã M, Elkis H, Soares B, Cabrera Jaramillo P, Lawson F, Díaz-Galvis L. Treatment of Patients with Recently Exacerbated Schizophrenia with Paliperidone Palmitate: A Pilot Study of Efficacy and Tolerability. Neuropsychiatr Dis Treat 2020; 16:2063-2072. [PMID: 32982245 PMCID: PMC7490440 DOI: 10.2147/ndt.s233537] [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: 10/08/2019] [Accepted: 08/04/2020] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Paliperidone palmitate is a long-acting, second-generation antipsychotic (SGA) indicated for the treatment of acute exacerbations and maintenance treatment of adults with schizophrenia. This study addressed the response to paliperidone palmitate in Latin American patients with acute symptoms and recently diagnosed schizophrenia. OBJECTIVE Explore the efficacy and tolerability of paliperidone palmitate administered once a month for 4 months in patients with acute phase and recent diagnosis (within 1-6 years) of schizophrenia in 3 Latin American countries. METHODS This was a non-randomized, open-label, multicenter study with paliperidone palmitate injected intramuscularly in the deltoid muscle at an initial loading dose of 150 mg eq. (234 mg) on day 1 and 100 mg eq. (156 mg) on day 8 (± 4 days). The recommended maintenance dose was 75 mg eq. (117 mg) from day 36 to day 92. Efficacy was evaluated with PANSS and CGI-S. The last observation carried forward (LOCF) was used for efficacy analysis for imputation of missing data; no adjustments were made for multiplicity. Adverse events were evaluated during treatment. RESULTS The patient retention rate was 84.0% (144 patients received study drug; 121 finished the study). The percentage of patients with a reduction of at least 30% in PANSS total score compared to baseline gradually increased during the study, and at the end, 78.4% of patients showed response. The PANSS total score and CGI-S scores decreased significantly from baseline to LOCF endpoint (P <0.0001 for both); significant reduction in PANSS total score was observed at day 8 and persisted to the end of the study. Most common adverse events were muscle rigidity (11.8%), akathisia (11.1%), injection-site pain (7.6%), weight gain (7.6%), and insomnia (7.6%). CONCLUSION Paliperidone palmitate was efficacious in Latin American patients studied with an acute exacerbation and recent diagnosis of schizophrenia, and no new safety signals were identified.
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Affiliation(s)
- Wagner F Gattaz
- Laboratory of Neuroscience (LIM27), Instituto de Psiquiatria do Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | | | | | - Martinus T Van de Bilt
- Laboratory of Neuroscience (LIM27), Instituto de Psiquiatria do Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Jose Julian Ortegón
- Centro de Investigaciones del Sistema Nervioso, Grupo Cisne, Bogotá, Colombia
| | - Sergio J Villaseñor-Bayardo
- University of Guadalajara, Mexico, Hospital Civil de Guadalajara, “Fray Antonio Alcalde”, Guadalajara, Mexico
| | - Mario Louzã
- Instituto de Psiquiatria do HCFMUSP, São Paulo, Brazil
| | - Helio Elkis
- Instituto de Psiquiatria do HCFMUSP, São Paulo, Brazil
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Subeesh V, Maheswari E, Singh H, Saraswathy GR, Reddy N, Chiranjeevi P. Early prediction of clinical response in first episode schizophrenia (FES) patients receiving olanzapine. Int J Psychiatry Clin Pract 2020; 24:309-314. [PMID: 32338556 DOI: 10.1080/13651501.2020.1757118] [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] [Indexed: 10/24/2022]
Abstract
Background: At present, schizophrenia guidelines recommend waiting for 8 weeks before considering a patient as non-responder. This study aims to detect the optimal early response threshold that best predict the final outcome of olanzapine.Methods: The study was conducted for 8-week, four points follow up (week 2,3,4, and 8) prospective observational study. A reduction of 20, 25, 30% in Positive and Negative Syndrome Scale (PANSS) score from the base line at week 2,3, and 4 respectively were considered as early response. A reduction of 50% at week 8 was considered as responders. Receiver Operating Characteristics (ROC) curves were performed to detect the optimal threshold.Results: Mean total baseline PANSS score was 106.66(95% CI; 100.4, 112.9). Week 2 (AUC = 50.5%, p > 0.964) and week 3 (AUC = 64.9, p > 0.13) responses failed to predict the 8th week response. Week 4 response (AUC = 92%, p < 0.001) can be taken for the prediction of 8th week response (specificity = 72%, sensitivity = 100%, Positive Predictive Value = 61.1%, Negative Predictive Value = 100% and Optimum Early Response (OER) = 29.4%). 25 patients (69%) achieved more than 50% reduction (responders) in PANSS score after 8 weeks of treatment.Conclusions: Our study suggests that patients with early response at week 4 are likely to achieve positive response after 8 weeks. This may help in appropriate clinical decision making for early non-responders.Key PointsThe early response can forecast the outcome at the endpoint for the treatment of FESA reduction of baseline PANSS score by 30% or more after four weeks are likely to have remission after week 8 with olanzapine therapy.
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Affiliation(s)
- Viswam Subeesh
- Department of Pharmacy Practice, Faculty of Pharmacy, M S Ramaiah University of Applied Sciences, Bengaluru, India
| | - Eswaran Maheswari
- Department of Pharmacy Practice, Faculty of Pharmacy, M S Ramaiah University of Applied Sciences, Bengaluru, India
| | - Hemendra Singh
- Department of Psychiatry, Ramaiah Medical College, Bengaluru, India
| | | | - Neha Reddy
- Department of Pharmacy Practice, Faculty of Pharmacy, M S Ramaiah University of Applied Sciences, Bengaluru, India
| | - Pudi Chiranjeevi
- Department of Pharmacy Practice, Faculty of Pharmacy, M S Ramaiah University of Applied Sciences, Bengaluru, India
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Siafis S, Çıray O, Schneider-Thoma J, Bighelli I, Krause M, Rodolico A, Ceraso A, Deste G, Huhn M, Fraguas D, Mavridis D, Charman T, Murphy DG, Parellada M, Arango C, Leucht S. Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis. Mol Autism 2020; 11:66. [PMID: 32847616 PMCID: PMC7448339 DOI: 10.1186/s13229-020-00372-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 08/14/2020] [Indexed: 12/16/2022] Open
Abstract
Background Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms. Methods We searched ClinicalTrials.gov, CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317. Results Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8–12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = − 0.32, 95% CI [− 0.39, − 0.25], in repetitive behaviors − 0.23[− 0.32, − 0.15] and in scales measuring overall core symptoms − 0.36 [− 0.46, − 0.26]. Overall, 19%, 95% CI [16–22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain. Limitations About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers. Conclusions Placebo response in ASD was substantial and predicted by design- and participant-related factors, which could inform the design of future trials in order to improve the detection of efficacy in core symptoms. Potential solutions could be the minimization and careful selection of study sites as well as rigorous participant enrollment and the use of measurements of change not solely dependent on caregivers.
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Affiliation(s)
- Spyridon Siafis
- Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Ismaningerstr. 22, 81675, Munich, Germany.
| | - Oğulcan Çıray
- Department of Child and Adolescent Psychiatry, School of Medicine, Balçova Dokuz Eylul University, İzmir, Turkey
| | - Johannes Schneider-Thoma
- Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Ismaningerstr. 22, 81675, Munich, Germany
| | - Irene Bighelli
- Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Ismaningerstr. 22, 81675, Munich, Germany
| | - Marc Krause
- Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Ismaningerstr. 22, 81675, Munich, Germany
| | - Alessandro Rodolico
- Department of Experimental and Clinical Medicine, Psychiatric Clinic University Hospital 'Gaspare Rodolico', University of Catania, Catania, Italy
| | - Anna Ceraso
- Department of Psychiatry, Spedali Civili Hospital, Brescia, Italy
| | - Giacomo Deste
- Department of Psychiatry, Spedali Civili Hospital, Brescia, Italy
| | - Maximilian Huhn
- Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Ismaningerstr. 22, 81675, Munich, Germany.,Department of Psychiatry, Psychosomatic Medicine and Psychotherapy Social Foundation Bamberg, Teaching Hospital of the University of Erlangen, Erlangen, Germany
| | - David Fraguas
- Department of Child and Adolescent Psychiatry, Hospital General Universitario Gregorio Marañón, Institute of Psychiatry and Mental Health, IiSGM, CIBERSAM, Madrid, Spain.,School of Medicine, Universidad Complutense, Madrid, Spain
| | - Dimitris Mavridis
- Department of Primary Education, University of Ioannina, Ioannina, Greece.,Faculté de Médecine, Université Paris Descartes, Paris, France
| | - Tony Charman
- Department of Psychology, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Declan G Murphy
- Department of Forensic and Neurodevelopmental Sciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Mara Parellada
- Department of Primary Education, University of Ioannina, Ioannina, Greece.,Faculté de Médecine, Université Paris Descartes, Paris, France
| | - Celso Arango
- Department of Primary Education, University of Ioannina, Ioannina, Greece.,Faculté de Médecine, Université Paris Descartes, Paris, France
| | - Stefan Leucht
- Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Ismaningerstr. 22, 81675, Munich, Germany
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JUSTUS UCHENNA ONU, OHAERI JUDEUZOMA. Using data from schizophrenia outcome study to estimate the time to treatment outcome and the early-response cut-off score that predicts outcome at week 16. ARCH CLIN PSYCHIAT 2020. [DOI: 10.1590/0101-60830000000234] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Maffioletti E, Valsecchi P, Minelli A, Magri C, Bonvicini C, Barlati S, Sacchetti E, Vita A, Gennarelli M. Association study betweenHTR2Ars6313 polymorphism and early response to risperidone and olanzapine in schizophrenia patients. Drug Dev Res 2020; 81:754-761. [DOI: 10.1002/ddr.21686] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Revised: 04/16/2020] [Accepted: 05/01/2020] [Indexed: 12/17/2022]
Affiliation(s)
| | - Paolo Valsecchi
- Department of Mental Health and Addiction ServicesASST Spedali Civili Brescia Italy
- Department of Clinical and Experimental SciencesUniversity of Brescia Brescia Italy
| | - Alessandra Minelli
- Department of Molecular and Translational MedicineUniversity of Brescia Brescia Italy
| | - Chiara Magri
- Department of Molecular and Translational MedicineUniversity of Brescia Brescia Italy
| | - Cristian Bonvicini
- Genetics UnitIRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli Brescia Italy
| | - Stefano Barlati
- Department of Mental Health and Addiction ServicesASST Spedali Civili Brescia Italy
- Department of Clinical and Experimental SciencesUniversity of Brescia Brescia Italy
| | - Emilio Sacchetti
- Department of Mental Health and Addiction ServicesASST Spedali Civili Brescia Italy
- Department of Clinical and Experimental SciencesUniversity of Brescia Brescia Italy
| | - Antonio Vita
- Department of Mental Health and Addiction ServicesASST Spedali Civili Brescia Italy
- Department of Clinical and Experimental SciencesUniversity of Brescia Brescia Italy
| | - Massimo Gennarelli
- Department of Molecular and Translational MedicineUniversity of Brescia Brescia Italy
- Genetics UnitIRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli Brescia Italy
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Biancosino B, Rocchi D, Donà S, Kotrotsiou V, Marmai L, Grassi L. Efficacy of a short-term psychoeducational intervention for persistent non-organic insomnia in severely mentally ill patients. A pilot study. Eur Psychiatry 2020; 21:460-2. [PMID: 15964745 DOI: 10.1016/j.eurpsy.2005.03.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2004] [Accepted: 03/21/2005] [Indexed: 11/16/2022] Open
Abstract
AbstractInsomnia in psychiatric patients is frequently underestimated in clinical practice. Usually drugs are prescribed for the treatment of this disorder but non-pharmacological intervention can be successfully used. The present study aimed at evaluating the efficacy of a two-session psychoeducational intervention in improving persistent non-organic insomnia and reducing the administration of PRN therapy in severely mentally ill patients.A pre-post study was performed on 36 psychiatric patients admitted to a residential psychiatric unit. The Nocturnal Sleep Onset Scale (NSOS) and Daytime Sleepiness Scale (DSS), the sleep onset latency, the time awake after sleep onset and the numbers of awakenings were gathered 2 weeks before the intervention (T0), immediately prior the intervention (T1), 2 weeks after the last session of the intervention (T2) and a 3-month follow-up (T3). The total number of administrations of PRN therapy from T0 toT1 and from T1 to T2 were also examined. A significant reduction was shown on the NSOS, the sleep onset latency and in the time awake after sleep onset from T1 to T2 and from T1 to T3, while no significant difference was found between T0 and T1. A significant decrease on the mean number of administrations of PRN therapy was also found between 15 days before the intervention (T0–T1) and 15 days after intervention (T1–T2). The initial results of this study seems to suggest the possible efficacy of a short-term psychoeducational intervention on improving persistent non-organic insomnia in severely mentally ill patients. Further control studies are necessary to confirm these findings.
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Affiliation(s)
- Bruno Biancosino
- Section of Psychiatry, Department of Medical Sciences of Communication and Behavior, University of Ferrara, Corso Giovecca 203, 44100 Ferrara, Italy
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Fusar-Poli P, Allen P, McGuire P. Neuroimaging studies of the early stages of psychosis: A critical review. Eur Psychiatry 2020; 23:237-44. [DOI: 10.1016/j.eurpsy.2008.03.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2006] [Revised: 01/15/2008] [Accepted: 01/17/2008] [Indexed: 11/26/2022] Open
Abstract
AbstractPsychiatric imaging, in particular functional imaging techniques such as functional magnetic resonance imaging (fMRI) are potentially powerful tools to explore the neurophysiological basis of the early stages of psychosis. Despite this impressive growth, neuroimaging has yet to become an established as diagnostic instrument this area, partly as a result of significant heterogeneity across the findings from research studies. The present review aims to: (i) assess the determinants of inconsistencies in the results from neuroimaging studies of the early stages of psychosis; and (ii) suggest approaches for future imaging research in this field that may reduce methodological differences between studies.
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Early improvement as a predictor of remission and response in schizophrenia: Results from a naturalistic study. Eur Psychiatry 2020; 24:501-6. [DOI: 10.1016/j.eurpsy.2009.02.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2009] [Accepted: 02/20/2009] [Indexed: 11/19/2022] Open
Abstract
AbstractObjectiveTo examine the predictive validity of early improvement in a naturalistic sample of inpatients and to identify the criterion that best defines early improvement.MethodsTwo hundred and forty-seven inpatients who fulfilled ICD-10 criteria for schizophrenia were assessed with the Positive And Negative Syndrome Scale (PANSS) at admission and at biweekly intervals until discharge from hospital. Remission was defined according to the recently proposed consensus criteria, response as a reduction of at least 40% in the PANNS total score from admission to discharge.ResultsReceiver operating characteristic (ROC) analyses showed that early improvement (reduction of the PANSS total score within the first 2 weeks of treatment) predicts remission (AUC = 0.659) and response (AUC = 0.737) at discharge. A 20% reduction in the PANSS total score within the first 2 weeks was the most accurate cut-off for the prediction of remission (total accuracy: 65%; sensitivity: 53%; specificity: 76%), and a 30% reduction the most accurate cut-off for the prediction of response (total accuracy: 76%; sensitivity: 47%; specificity: 90%).ConclusionThe findings of clinical drug trials that early improvement is a predictor of subsequent treatment response were replicated in a naturalistic sample. Further studies should examine whether patients without early improvement benefit from an early change of antipsychotic medication.
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Sustained antipsychotic effect of metacognitive training in psychosis: A randomized-controlled study. Eur Psychiatry 2020; 29:275-81. [DOI: 10.1016/j.eurpsy.2013.08.003] [Citation(s) in RCA: 66] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Revised: 07/04/2013] [Accepted: 08/26/2013] [Indexed: 11/19/2022] Open
Abstract
AbstractPersistent psychotic symptoms represent a major challenge for psychiatric care. Basic research has shown that psychotic symptoms are associated with cognitive biases. Metacognitive training (MCT) aims at helping patients to become aware of these biases and to improve problem-solving. Fifty-two participants fulfilling diagnostic criteria of schizophrenia or schizoaffective disorders and persistent delusions and stabilized antipsychotic medication were enrolled in this study. Following baseline assessment patients were randomized either to treatment as usual (TAU) conditions or TAU + MCT. The intervention consisted of eight weekly 1-hour sessions (maximum: 8 hours). Participants were assessed at 8 weeks and 6-months later by blind assessors. Participants were assessed with the Psychotic Symptoms Rating Scales (PSYRATS) and the positive subscale of the PANSS. Between-group differences in post- and pre-test values were significant at a medium effect size in favor of the MCT for the PSYRATS delusion scale and the positive scale of the PANSS both at post and follow-up. The results of this study indicate that MCT training has a surplus antipsychotic effect for patients suffering from schizophrenia-related disorders who demonstrate only a partial response to antipsychotic treatment and that the effect of the intervention persists for at least 6 months after the intervention.
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Ogyu K, Noda Y, Yoshida K, Kurose S, Masuda F, Mimura Y, Nishida H, Plitman E, Tarumi R, Tsugawa S, Wada M, Miyazaki T, Uchida H, Graff-Guerrero A, Mimura M, Nakajima S. Early improvements of individual symptoms as a predictor of treatment response to asenapine in patients with schizophrenia. Neuropsychopharmacol Rep 2020; 40:138-149. [PMID: 32180369 PMCID: PMC7722672 DOI: 10.1002/npr2.12103] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 01/02/2020] [Accepted: 01/06/2020] [Indexed: 12/11/2022] Open
Abstract
Aim It is well accepted that early improvement with antipsychotics predicts subsequent response in patients with schizophrenia. However, no study has examined the contribution of individual symptoms rather than overall symptom severity as the predictors. Thus, we aimed to detect individual symptoms whose improvements could predict subsequent response in patients with schizophrenia during treatment with asenapine and examine whether a prediction model with individual symptoms would be superior to a model using overall symptom severity. Methods This study analyzed a dataset including 532 patients with schizophrenia enrolled in a 6‐week double‐blind, placebo‐controlled, randomized trial of asenapine. Response to asenapine was defined as a ≥30% decrease in Positive and Negative Syndrome Scale (PANSS) total score from baseline to week 6. Stepwise logistic regression analyses were performed to investigate the associations among response and PANSS total/individual item score improvements at week 1 or week 2. Results Response was associated with early improvement in the following PANSS items: disturbance of volition, active social avoidance, poor impulse control at week 1; and active social avoidance, poor attention, lack of judgment and insight at week 2. Prediction accuracy was almost compatible between the model with individual symptoms and the model with PANSS total score both at weeks 1 and 2 (Nagelkerke R2: .51, .42 and .55, .54, respectively). Conclusion Early improvement in negative symptoms, poor attention and impulse control, and lack of insight, in particular predicted subsequent treatment response in patients with schizophrenia during treatment with asenapine as accurately as prediction based on overall symptom severity. This study found that treatment response to asenapine was predicted by early improvements of individual symptoms such as negative symptoms, poor attention and impulse control, and lack of insight in patients with schizophrenia. In addition, prediction accuracy was almost comparable between the model with individual symptoms and the model with the PANSS total score, supporting the importance to assess both individual symptoms and the whole severity in the clinical settings.![]()
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Affiliation(s)
- Kamiyu Ogyu
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Yoshihiro Noda
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Kazunari Yoshida
- Pharmacogenetic Research Clinic, Centre for Addiction and Mental Health, Toronto, ON, Canada
| | - Shin Kurose
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Fumi Masuda
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Yu Mimura
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Hana Nishida
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Eric Plitman
- Cerebral Imaging Centre, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada
| | - Ryosuke Tarumi
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Sakiko Tsugawa
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Masataka Wada
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Takahiro Miyazaki
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Hiroyuki Uchida
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Ariel Graff-Guerrero
- Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
| | - Masaru Mimura
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan
| | - Shinichiro Nakajima
- Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.,Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada
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Neurometabolic correlates of 6 and 16 weeks of treatment with risperidone in medication-naive first-episode psychosis patients. Transl Psychiatry 2020; 10:15. [PMID: 32066680 PMCID: PMC7026447 DOI: 10.1038/s41398-020-0700-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 11/25/2019] [Accepted: 12/08/2019] [Indexed: 02/06/2023] Open
Abstract
Antipsychotic medications are the cornerstone of treatment in schizophrenia spectrum disorders. In first-episode psychosis, the recommended time for an antipsychotic medication trial is up to 16 weeks, but the biological correlates of shorter and longer antipsychotic treatment trials in these cohorts remain largely unknown. We enrolled 29 medication-naive first-episode patients (FEP) and 22 matched healthy controls (HC) in this magnetic resonance spectroscopy (MRS) study, examining the levels of combined glutamate and glutamine (commonly referred to as Glx) in the bilateral medial prefrontal cortex (MPFC) with a PRESS sequence (TR/TE = 2000/80 ms) before initiation of antipsychotic treatment, after 6 and 16 weeks of treatment with risperidone. Data were quantified in 18 HC and 20 FEP at baseline, for 19 HC and 15 FEP at week 6, and for 14 HC and 16 FEP at week 16. At baseline, none of the metabolites differed between groups. Metabolite levels did not change after 6 or 16 weeks of treatment in patients. Our data suggest that metabolite levels do not change after 6 or 16 weeks of treatment with risperidone in FEP. It is possible that our choice of sequence parameters and the limited sample size contributed to negative findings reported here. On the other hand, longer follow-up may be needed to detect treatment-related metabolic changes with MRS. In summary, our study adds to the efforts in better understanding glutamatergic neurometabolism in schizophrenia, especially as it relates to antipsychotic exposure.
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Barnes TR, Drake R, Paton C, Cooper SJ, Deakin B, Ferrier IN, Gregory CJ, Haddad PM, Howes OD, Jones I, Joyce EM, Lewis S, Lingford-Hughes A, MacCabe JH, Owens DC, Patel MX, Sinclair JM, Stone JM, Talbot PS, Upthegrove R, Wieck A, Yung AR. Evidence-based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2020; 34:3-78. [PMID: 31829775 DOI: 10.1177/0269881119889296] [Citation(s) in RCA: 173] [Impact Index Per Article: 34.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
These updated guidelines from the British Association for Psychopharmacology replace the original version published in 2011. They address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting was held in 2017, involving experts in schizophrenia and its treatment. They were asked to review key areas and consider the strength of the evidence on the risk-benefit balance of pharmacological interventions and the clinical implications, with an emphasis on meta-analyses, systematic reviews and randomised controlled trials where available, plus updates on current clinical practice. The guidelines cover the pharmacological management and treatment of schizophrenia across the various stages of the illness, including first-episode, relapse prevention, and illness that has proved refractory to standard treatment. It is hoped that the practice recommendations presented will support clinical decision making for practitioners, serve as a source of information for patients and carers, and inform quality improvement.
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Affiliation(s)
- Thomas Re Barnes
- Emeritus Professor of Clinical Psychiatry, Division of Psychiatry, Imperial College London, and Joint-head of the Prescribing Observatory for Mental Health, Centre for Quality Improvement, Royal College of Psychiatrists, London, UK
| | - Richard Drake
- Clinical Lead for Mental Health in Working Age Adults, Health Innovation Manchester, University of Manchester and Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK
| | - Carol Paton
- Joint-head of the Prescribing Observatory for Mental Health, Centre for Quality Improvement, Royal College of Psychiatrists, London, UK
| | - Stephen J Cooper
- Emeritus Professor of Psychiatry, School of Medicine, Queen's University Belfast, Belfast, UK
| | - Bill Deakin
- Professor of Psychiatry, Neuroscience & Psychiatry Unit, University of Manchester and Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK
| | - I Nicol Ferrier
- Emeritus Professor of Psychiatry, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| | - Catherine J Gregory
- Honorary Clinical Research Fellow, University of Manchester and Higher Trainee in Child and Adolescent Psychiatry, Manchester University NHS Foundation Trust, Manchester, UK
| | - Peter M Haddad
- Honorary Professor of Psychiatry, Division of Psychology and Mental Health, University of Manchester, UK and Senior Consultant Psychiatrist, Department of Psychiatry, Hamad Medical Corporation, Doha, Qatar
| | - Oliver D Howes
- Professor of Molecular Psychiatry, Imperial College London and Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
| | - Ian Jones
- Professor of Psychiatry and Director, National Centre of Mental Health, Cardiff University, Cardiff, UK
| | - Eileen M Joyce
- Professor of Neuropsychiatry, UCL Queen Square Institute of Neurology, London, UK
| | - Shôn Lewis
- Professor of Adult Psychiatry, Faculty of Biology, Medicine and Health, The University of Manchester, UK, and Mental Health Academic Lead, Health Innovation Manchester, Manchester, UK
| | - Anne Lingford-Hughes
- Professor of Addiction Biology and Honorary Consultant Psychiatrist, Imperial College London and Central North West London NHS Foundation Trust, London, UK
| | - James H MacCabe
- Professor of Epidemiology and Therapeutics, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, and Honorary Consultant Psychiatrist, National Psychosis Service, South London and Maudsley NHS Foundation Trust, Beckenham, UK
| | - David Cunningham Owens
- Professor of Clinical Psychiatry, University of Edinburgh. Honorary Consultant Psychiatrist, Royal Edinburgh Hospital, Edinburgh, UK
| | - Maxine X Patel
- Honorary Clinical Senior Lecturer, King's College London, Institute of Psychiatry, Psychology and Neuroscience and Consultant Psychiatrist, Oxleas NHS Foundation Trust, London, UK
| | - Julia Ma Sinclair
- Professor of Addiction Psychiatry, Faculty of Medicine, University of Southampton, Southampton, UK
| | - James M Stone
- Clinical Senior Lecturer and Honorary Consultant Psychiatrist, King's College London, Institute of Psychiatry, Psychology and Neuroscience and South London and Maudsley NHS Trust, London, UK
| | - Peter S Talbot
- Senior Lecturer and Honorary Consultant Psychiatrist, University of Manchester and Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK
| | - Rachel Upthegrove
- Professor of Psychiatry and Youth Mental Health, University of Birmingham and Consultant Psychiatrist, Birmingham Early Intervention Service, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK
| | - Angelika Wieck
- Honorary Consultant in Perinatal Psychiatry, Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK
| | - Alison R Yung
- Professor of Psychiatry, University of Manchester, School of Health Sciences, Manchester, UK and Centre for Youth Mental Health, University of Melbourne, Australia, and Honorary Consultant Psychiatrist, Greater Manchester Mental Health NHS Foundation Trust, Manchester, UK
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Palaniyappan L. Inefficient neural system stabilization: a theory of spontaneous resolutions and recurrent relapses in psychosis. J Psychiatry Neurosci 2019; 44:367-383. [PMID: 31245961 PMCID: PMC6821513 DOI: 10.1503/jpn.180038] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Revised: 02/07/2019] [Accepted: 03/05/2019] [Indexed: 12/21/2022] Open
Abstract
A striking feature of psychosis is its heterogeneity. Presentations of psychosis vary from transient symptoms with no functional consequence in the general population to a tenacious illness at the other extreme, with a wide range of variable trajectories in between. Even among patients with schizophrenia, who are diagnosed on the basis of persistent deterioration, marked variation is seen in response to treatment, frequency of relapses and degree of eventual recovery. Existing theoretical accounts of psychosis focus almost exclusively on how symptoms are initially formed, with much less emphasis on explaining their variable course. In this review, I present an account that links several existing notions of the biology of psychosis with the variant clinical trajectories. My aim is to incorporate perspectives of systems neuroscience in a staging framework to explain the individual variations in illness course that follow the onset of psychosis.
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Affiliation(s)
- Lena Palaniyappan
- From the Department of Psychiatry and Robarts Research Institute, University of Western Ontario and Lawson Health Research Institute, London, Ont., Canada
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50
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Arceo S, Ulloa RE. Early Response in Adolescents with Schizophrenia is not Associated with Remission at Six Months. JOURNAL OF THE CANADIAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY = JOURNAL DE L'ACADEMIE CANADIENNE DE PSYCHIATRIE DE L'ENFANT ET DE L'ADOLESCENT 2019; 28:91-93. [PMID: 31447907 PMCID: PMC6691793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 03/26/2019] [Indexed: 06/10/2023]
Abstract
OBJECTIVE The objectives of present study were to determine the frequency of early response (ER), defined as a 20% decrease in total baseline PANSS score at three weeks and to compare the rate of symptomatic and functional remission between schizophrenic adolescents with and without ER. METHODS The sample included 61 patients (65% males) with a mean age of 15 (+ 1.54) y.o., 88.5% on their first episode of psychosis who were evaluated with PANSS and PSP scales y. They were evaluated with PANSS at week three and with PANSS and PSP at month six. RESULTS Twenty-three patients (37.7%) showed ER. There were no significant differences in the rate of symptomatic or functional remission at month six between responders and non-responders. CONCLUSIONS Early response to antipsychotic treatment can be observed in adolescent patients, however, it is not associated with remission at six months.
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Affiliation(s)
- Sadot Arceo
- Child Psychiatric Hospital Dr. Juan N Navarro, Mexico City, Mexico
| | - Rosa Elena Ulloa
- Child Psychiatric Hospital Dr. Juan N Navarro, Mexico City, Mexico
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