|
1
|
Lawrence C, Roberts C, Galides C, Chamberlain SR, Hou R. Antipsychotic polypharmacy and high-dose antipsychotic therapy compared to antipsychotic monotherapy at standard doses in schizophrenia - a systematic review. J Psychopharmacol 2025; 39:132-140. [PMID: 39655766 PMCID: PMC11831860 DOI: 10.1177/02698811241303652] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/18/2025]
Abstract
BACKGROUND Schizophrenia is considered to have a lifetime prevalence of around 1%. Up to 30% of patients diagnosed with schizophrenia are subsequently categorised as treatment resistant. Current guidelines advise against the use of antipsychotic polypharmacy (APP) or high-dose antipsychotic therapy (HDAT) in the treatment of schizophrenia; however, these treatment approaches continue to be used in up to 25% of cases. AIMS This review was to evaluate the evidence for the efficacy and tolerability of APP and HDAT as an alternative to antipsychotic monotherapy at standard doses in the treatment of schizophrenia. METHODS This is a systematic review. We searched PubMed, EMBASE and PsycINFO, for eligible trials published prior to 24 March 2023. The protocol was registered on PROSPERO (CRD42023408785). Quality assessment was conducted using the Revised Cochrane risk-of-bias tool for randomised trials. RESULTS A total of 14 studies were included in this review. Two studies demonstrated clinically significant improvement with APP compared to standard treatment. There was no clear evidence that APP or HDAT is definitively less tolerable than antipsychotic monotherapy at a standard dose. CONCLUSIONS This review found limited evidence for the efficacy of APP and HDAT in the treatment of schizophrenia over the use of antipsychotic monotherapy at a standard dose. The relative tolerability was unclear. Management of treatment-resistant schizophrenia remains a prominent clinical issue and further research, including high-quality large-scale Randomised Controlled Trials (RCTs) of APP and HDAT in patients who have been unresponsive to clozapine, would be of significant benefit to the field of psychiatry.
Collapse
Affiliation(s)
- Christopher Lawrence
- Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, UK
- Hampshire and Isle of Wight Healthcare NHS Foundation Trust, Southampton, UK
| | - Chloe Roberts
- Dorset Healthcare University Foundation Trust, Poole, Dorset, UK
| | - Chloe Galides
- Hampshire and Isle of Wight Healthcare NHS Foundation Trust, Southampton, UK
| | - Samuel R Chamberlain
- Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, UK
- Hampshire and Isle of Wight Healthcare NHS Foundation Trust, Southampton, UK
| | - Ruihua Hou
- Faculty of Medicine, Clinical and Experimental Sciences, University of Southampton, Southampton, UK
| |
Collapse
|
|
2
|
Rodrigues T, Bressan GN, Juliani PZ, da Silva MEB, Fachinetto R. Ketamine impairs the performance of male mice in novel recognition object test and reduces the immunoreactivity of GAD 67 in the hippocampus: Role of pioglitazone. Pharmacol Biochem Behav 2025; 247:173950. [PMID: 39725040 DOI: 10.1016/j.pbb.2024.173950] [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: 09/11/2024] [Revised: 12/09/2024] [Accepted: 12/17/2024] [Indexed: 12/28/2024]
Abstract
Schizophrenia is a mental disorder characterized by positive, negative, and cognitive symptoms which is treated with antipsychotics. However, these drugs present several side effects and, some schizophrenia symptoms, like cognitive, are difficult to treat. The peroxisome proliferator-activated receptors-gamma (PPAR-γ) are expressed in dopaminergic neurons of the midbrain participating in the modulation of dopamine-mediated behavior . We investigated the effects of pioglitazone, an agonist of PPAR-γ, on the behavioral alterations induced by ketamine and, whether alterations in monoamine oxidase (MAO) activity, glutamic acid decarboxylase (GAD67), PPAR-γ or tyrosine hydroxylase (TH) immunoreactivity in brain tissues are involved in these effects. Male mice received ketamine (30 mg/kg), intraperitoneally, for 14 consecutive days, and pioglitazone (3 or 9 mg/kg), by gavage (day 8 up to day 14). Ketamine decreased nail-biting increasing the time exploring the center of the open field on day 8 and the number of rearing evaluated 30 min after its administration on day 14. Furthermore, ketamine decreased the percentage of investigation in the NOR test and the immunoreactivity of GAD67 in the hippocampus. No significant changes were found in other behavioral and biochemical tests. Pioglitazone attenuated the effects of ketamine on rearing and GAD67 immunoreactivity in the hippocampus, recovering the ketamine effects on NOR test. At a dose of 9 mg/kg, pioglitazone alone reduced the immunoreactivity of GAD67 in the hippocampus. Pioglitazone at both doses recovered the cognitive symptoms induced by ketamine an effect that seems to involve the modulation of GAD67 immunoreactivity in the hippocampus. In conclusion, pioglitazone improved the effects of ketamine on the NOR test which was, at least in part, associated with the modulation of GAD67 immunoreactivity in the hippocampus suggesting its beneficial role in cognitive symptoms.
Collapse
Affiliation(s)
- Talita Rodrigues
- Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, RS, Brazil
| | - Getulio Nicola Bressan
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, RS, Brazil
| | - Patrícia Zorzi Juliani
- Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, RS, Brazil
| | | | - Roselei Fachinetto
- Programa de Pós-Graduação em Farmacologia, Universidade Federal de Santa Maria, RS, Brazil.
| |
Collapse
|
|
3
|
Shih YJ, Lin CH, Chou LS. The factors associated with clozapine polypharmacy for schizophrenia patients discharged from a large public psychiatric hospital in Taiwan, 2006-2021. Medicine (Baltimore) 2024; 103:e40897. [PMID: 39705447 DOI: 10.1097/md.0000000000040897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2024] Open
Abstract
Clozapine treatment continues to be recognized as the gold standard for managing treatment-resistant schizophrenia. Combining clozapine with other antipsychotics (i.e., clozapine polypharmacy) has emerged as an option for clozapine-resistant schizophrenia. We aimed to investigate the factors associated with clozapine polypharmacy in schizophrenia patients discharged on clozapine from a public psychiatric hospital. The analysis included patients with schizophrenia who were discharged between 2006 and 2021 and prescribed clozapine upon discharge. All patients were divided into 2 groups: clozapine monotherapy and clozapine polypharmacy. Multivariate logistic regression was used to identify factors associated with clozapine polypharmacy. A total of 1396 (42.7%) schizophrenia patients discharged on clozapine polypharmacy. In a multivariate logistic regression model, the clozapine polypharmacy was more likely to be male gender, to be younger, to be earlier age of onset, to have a greater number of previous hospitalizations, to have a shorter length of hospital stay, and to have a lower clozapine daily dose. The prevalence of clozapine significantly increased from 22.4% in 2006 to 50% in 2021. Compared with clozapine monotherapy, clozapine polypharmacy was associated with male gender, younger, earlier age of onset, a greater number of previous hospitalizations, shorter length of hospital stay, and lower clozapine daily dose. The utilization of clozapine polypharmacy has seen a significant increase over time. Further research is necessary to clarify its efficacy, safety, and overall risk/benefit ratio.
Collapse
Affiliation(s)
- Yu-Ju Shih
- Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan
| | - Ching-Hua Lin
- Department of Psychiatry, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Sun Yat-Sen University, Kaohsiung, Taiwan
| | - Li-Shiu Chou
- Kaohsiung Municipal Kai-Syuan Psychiatric Hospital, Kaohsiung, Taiwan
- Department of Psychiatry, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| |
Collapse
|
|
4
|
Lochmann van Bennekom MWH, IntHout J, Gijsman HJ, Akdede BBK, Yağcıoğlu AEA, Barnes TRE, Galling B, Gueorguieva R, Kasper S, Kreinin A, Nielsen J, Nielsen RE, Remington G, Repo-Tiihonen E, Schmidt-Kraepelin C, Shafti SS, Xiao L, Correll CU, Verkes RJ. Efficacy and tolerability of antipsychotic polypharmacy for schizophrenia spectrum disorders. A systematic review and meta-analysis of individual patient data. Schizophr Res 2024; 272:1-11. [PMID: 39142215 DOI: 10.1016/j.schres.2024.07.035] [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: 12/10/2023] [Revised: 07/14/2024] [Accepted: 07/15/2024] [Indexed: 08/16/2024]
Abstract
BACKGROUND Antipsychotic polypharmacy (APP) is frequently prescribed for schizophrenia-spectrum disorders. Despite the inconsistent findings on efficacy, APP may be beneficial for subgroups of psychotic patients. This meta-analysis of individual patient data investigated moderators of efficacy and tolerability of APP in adult patients with schizophrenia-spectrum disorders. DESIGN We searched PubMed, EMBASE, and the Cochrane Central Register of Randomized Trials until September 1, 2022, for randomized controlled trials comparing APP with antipsychotic monotherapy. We estimated the effects with a one-stage approach for patient-level moderators and a two-stage approach for study-level moderators, using (generalized) linear mixed-effects models. Primary outcome was treatment response, defined as a reduction of 25 % or more in the Positive and Negative Syndrome Scale (PANSS) score. Secondary outcomes were study discontinuation, and changes from baseline on the PANSS total score, its positive and negative symptom subscale scores, the Clinical Global Impressions Scale (CGI), and adverse effects. RESULTS We obtained individual patient data from 10 studies (602 patients; 31 % of all possible patients) and included 599 patients in our analysis. A higher baseline PANSS total score increased the chance of a response to APP (OR = 1.41, 95 % CI 1.02; 1.94, p = 0.037 per 10-point increase in baseline PANSS total), mainly driven by baseline positive symptoms. The same applied to changes on the PANSS positive symptom subscale and the CGI severity scale. Extrapyramidal side effects increased significantly where first and second-generation antipsychotics were co-prescribed. Study discontinuation was comparable between both treatment arms. CONCLUSIONS APP was effective in severely psychotic patients with high baseline PANSS total scores and predominantly positive symptoms. This effect must be weighed against potential adverse effects.
Collapse
Affiliation(s)
- Marc W H Lochmann van Bennekom
- Pro Persona Mental Health Care, Expertise Center for Depression, Nijmeegsebaan 61, 6525 DX Nijmegen, the Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Radboud University, Nijmegen, the Netherlands.
| | - Joanna IntHout
- Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands
| | | | - Berna B K Akdede
- Dokuz Eylul University Faculty of Medicine, Department of Psychiatry, Balçova, İzmir, Turkey
| | - A Elif Anıl Yağcıoğlu
- Hacettepe University Faculty of Medicine, Department of Psychiatry, Sıhhiye, Ankara, Turkey
| | | | - Britta Galling
- Department of Child and Adolescent Psychiatry and Psychotherapy, Centre for Integrative Psychiatry, School of Medicine, Kiel, Germany
| | | | - Siegfried Kasper
- Medical University of Vienna, Center for Brain Research, Department of Molecular Neuroscience, Vienna, Austria
| | | | - Jimmi Nielsen
- Department of Clinical Medicine, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark; Mental health Centre Glostrup, Mental health service Capital Region Denmark, Copenhagen, Denmark
| | - René Ernst Nielsen
- Psychiatry, Aalborg University Hospital, Aalborg, Denmark; Aalborg University, Department of Clinical Medicine, Aalborg, Denmark
| | - Gary Remington
- Schizophrenia Division, Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, Ontario, Canada
| | | | - Christian Schmidt-Kraepelin
- Kaiserswerther Diakonie, Florence-Nightingale-Hospital, Department of Psychiatry and Psychotherapy, Düsseldorf, Germany; LVR-Clinic Düsseldorf, Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine-University, Duesseldorf, Germany
| | - Saeed S Shafti
- University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Le Xiao
- The National Clinical Research Center for Mental Disorders, Mood Disorders Center, Beijing Anding Hospital Capital Medical University, Beijing, China
| | - Christoph U Correll
- The Zucker Hillside Hospital, Department of Psychiatry, Northwell Health, Glen Oaks, NY, USA; Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, NY, USA; The Feinstein Institute for Medical Research, Center for Psychiatric Neuroscience, Northwell Health, New Hyde Park, NY, USA; Charité - Universitätsmedizin Berlin, Department of Child and Adolescent Psychiatry, Berlin, Germany; DZPG, German Center for Mental Health, Partner Site Berlin, Germany
| | - Robbert-Jan Verkes
- Department of Psychiatry, Radboud University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Radboud University, Nijmegen, the Netherlands
| |
Collapse
|
|
5
|
Lappin JM, Davies K, O'Donnell M, Walpola IC. Underuse of recommended treatments among people living with treatment-resistant psychosis. Front Psychiatry 2022; 13:987468. [PMID: 36147973 PMCID: PMC9485552 DOI: 10.3389/fpsyt.2022.987468] [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: 07/06/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND International guidelines recommend that individuals with treatment-resistant psychosis must be treated with clozapine. ECT has also been reported to improve symptom profiles. Identification of clozapine and/or ECT use in real-world practice enables understanding of the extent to which this evidence-base is implemented. SETTING Statewide public health tertiary referral service, the Tertiary Referral Service for Psychosis (TRSP), NSW, Australia. OBJECTIVES To (i) describe clinical characteristics of individuals with treatment-resistant psychosis and to detail the proportion who had received a trial of clozapine or ECT at any point during their illness course; (ii) describe the characteristics of the treatment trials in both those currently on clozapine and those previously on clozapine; (iii) document reasons in relevant individuals why clozapine had never been used. METHODS All TRSP clients who met the criteria for treatment resistance (TR) were included. A detailed casenote review was conducted to examine whether clozapine and/or ECT had ever been prescribed. Characteristics of clozapine and ECT trials were documented. Tertiary service treatment recommendations are described. FINDINGS Thirty-six of 48 individuals had TR. They had marked clinical and functional impairment. A minority were currently receiving clozapine (n = 14/36). Most had received a clozapine trial at some point (n = 32/36). Most experienced persistent clinical symptoms while on clozapine (n = 29/32). Clozapine plasma levels were very rarely reported (4/32). Augmentation and antipsychotic polypharmacy were common among those currently on clozapine. The median clozapine trial duration was 4.0 (IQR: 3.0-20.3) months in individuals previously prescribed clozapine. Reasons for clozapine discontinuation included intolerable side effects (n = 10/18) and poor adherence (n = 7/18). One-quarter of TR individuals had trialed ECT (n = 9/36). Tertiary service recommendations included routine plasma monitoring to optimize dose among people currently on clozapine; clozapine retrial in those previously treated; and clozapine initiation for those who had never received clozapine. ECT was recommended to augment clozapine and as an alternative where clozapine trial/retrial was not feasible. CONCLUSION Among people with TR referred to a tertiary service, clozapine and ECT were underutilized. Clozapine trials are typically terminated without an adequate trial. Strategies to optimize the use of clozapine therapy and ECT in clinical settings are needed to increase the therapeutic effectiveness of evidence-based therapies for treatment-resistant psychosis.
Collapse
Affiliation(s)
- Julia M Lappin
- The Tertiary Referral Service for Psychosis (TRSP), South Eastern Sydney Local Health District, Randwick, NSW, Australia.,Discipline of Psychiatry and Mental Health, School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Kensington, NSW, Australia
| | - Kimberley Davies
- The Tertiary Referral Service for Psychosis (TRSP), South Eastern Sydney Local Health District, Randwick, NSW, Australia.,Discipline of Psychiatry and Mental Health, School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Kensington, NSW, Australia
| | - Maryanne O'Donnell
- The Tertiary Referral Service for Psychosis (TRSP), South Eastern Sydney Local Health District, Randwick, NSW, Australia.,Discipline of Psychiatry and Mental Health, School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Kensington, NSW, Australia
| | - Ishan C Walpola
- The Tertiary Referral Service for Psychosis (TRSP), South Eastern Sydney Local Health District, Randwick, NSW, Australia.,Discipline of Psychiatry and Mental Health, School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Kensington, NSW, Australia
| |
Collapse
|
|
6
|
Kim JJ, Pae CU, Han C, Bahk WM, Lee SJ, Patkar AA, Masand PS. Exploring Hidden Issues in the Use of Antipsychotic Polypharmacy in the Treatment of Schizophrenia. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2021; 19:600-609. [PMID: 34690115 PMCID: PMC8553537 DOI: 10.9758/cpn.2021.19.4.600] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 01/13/2021] [Accepted: 02/02/2021] [Indexed: 12/23/2022]
Abstract
The mainstay of schizophrenia treatment is pharmacological therapy using various antipsychotics including first- and second-generation antipsychotics which have different pharmacokinetic and pharmacodynamic property leading to differential presentation of adverse events (AEs) and treatment effects such as negative symptoms, cognitive symptoms and cormorbid symptoms. Major treatment guidelines suggest the use of antipsychotic monotherapy (APM) as a gold standard in the treatment of schizophrenia. However, the effects of APM is inadequate and less potent to achieve symptom remission as well as functional recovery in real practice which has been consistently reported in numerous controlled clinical trials, large practical trials, independent small studies and systematic reviews till today. Therefore anti-psychotic polypharmacy (APP) regardless of the class of antipsychotics has been also commonly utilized for many reasons in real world practice. However, APP has also crucial pitfalls including increase of total psychotics including antipsychotics, high-doses of antipsychotics used, poor compliance, drug-drug interaction and risks for developing AEs, all of which are paradoxically related to poor clinical outcomes, whereas APP has also substantial advantages in reduction of re-hospitalization, severe psychopathology and targeted control of concurrent symptoms. Given currently limited therapeutic options, it is also important to properly utilize APP in order to maximize its clinical utility and minimize its risk for better treatment outcomes for patients with schizophrenia, based on risk/benefit with full understanding of pharmacological and clinical issues on APP. The present paper intends to address intriguing and important issues in the use of APP in real world practice.
Collapse
Affiliation(s)
- Jung-Jin Kim
- Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Chi-Un Pae
- Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Korea.,Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Changsu Han
- Department of Psychiatry, Korea University College of Medicine, Seoul, Korea
| | - Won-Myong Bahk
- Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Soo-Jung Lee
- Department of Psychiatry, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ashwin A Patkar
- Department of Psychiatry and Behavioral Sciences, Rush University Medical Center, Chicago, IL, USA
| | | |
Collapse
|
|
7
|
Ali T, Sisay M, Tariku M, Mekuria AN, Desalew A. Antipsychotic-induced extrapyramidal side effects: A systematic review and meta-analysis of observational studies. PLoS One 2021; 16:e0257129. [PMID: 34506552 PMCID: PMC8432767 DOI: 10.1371/journal.pone.0257129] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2020] [Accepted: 08/24/2021] [Indexed: 11/19/2022] Open
Abstract
Background Antipsychotic agents are the basis for the pharmacological management of acute and chronic schizophrenia, bipolar disorders, mood disorders with psychotic feature, and other psychotic disorders. Antipsychotic medication use is frequently associated with unfavorable adverse effects such as extrapyramidal side effects (EPSEs). Hence, this systematic review and meta-analysis was aimed to determine the magnitude of antipsychotic-induced EPSEs. Method A literature search was conducted using legitimate databases, indexing services, and directories including PubMed/MEDLINE (Ovid®), EMBASE (Ovid®), google scholar and WorldCat to retrieve studies. Following screening and eligibility, the relevant data were extracted from the included studies using an Excel sheet and exported to STATA 15.0 software for analyses. The Random effects pooling model was used to analyze outcome measures at a 95% confidence interval. Besides, publication bias analysis was conducted. The protocol has been registered on PROSPERO with ID: CRD42020175168. Result In total, 15 original articles were included for the systematic review and meta-analysis. The pooled prevalence of antipsychotic-induced EPSEs among patient taking antipsychotic medications was 37% (95% CI: 18–55%, before sensitivity) and 31% (95% CI: 19–44%, after sensitivity). The prevalence of antipsychotic-induced parkinsonism, akathisia, and tardive dyskinesia was 20% (95% CI: 11–28%), 11% (95% CI: 6–17%), and 7% (95% CI: 4–9%), respectively. To confirm a small-study effect, Egger’s regression test accompanied by funnel plot asymmetry demonstrated that there was a sort of publication bias in studies reporting akathisia and tardive dyskinesia. Conclusion The prevalence of antipsychotic-induced EPSEs was considerably high. One in five and more than one in ten patients experienced parkinsonism and akathisia, respectively. Appropriate prevention and early management of these effects can enhance the net benefits of antipsychotics.
Collapse
Affiliation(s)
- Tilahun Ali
- Department of Psychiatry, School of Nursing and Midwifery, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
- * E-mail:
| | - Mekonnen Sisay
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Mandaras Tariku
- Department of Psychiatry, School of Nursing and Midwifery, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Abraham Nigussie Mekuria
- Department of Pharmacology and Toxicology, School of Pharmacy, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| | - Assefa Desalew
- School of Nursing and Midwifery, College of Health and Medical Sciences, Haramaya University, Harar, Ethiopia
| |
Collapse
|
|
8
|
Chakrabarti S. Clozapine resistant schizophrenia: Newer avenues of management. World J Psychiatry 2021; 11:429-448. [PMID: 34513606 PMCID: PMC8394694 DOI: 10.5498/wjp.v11.i8.429] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/12/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
About 40%-70% of the patients with treatment-resistant schizophrenia have a poor response to adequate treatment with clozapine. The impact of clozapine-resistant schizophrenia (CRS) is even greater than that of treatment resistance in terms of severe and persistent symptoms, relapses and hospitalizations, poorer quality of life, and healthcare costs. Such serious consequences often compel clinicians to try different augmentation strategies to enhance the inadequate clozapine response in CRS. Unfortunately, a large body of evidence has shown that antipsychotics, antidepressants, mood stabilizers, electroconvulsive therapy, and cognitive-behavioural therapy are mostly ineffective in augmenting clozapine response. When beneficial effects of augmentation have been found, they are usually small and of doubtful clinical significance or based on low-quality evidence. Therefore, newer treatment approaches that go beyond the evidence are needed. The options proposed include developing a clinical consensus about the augmentation strategies that are most likely to be effective and using them sequentially in patients with CRS. Secondly, newer approaches such as augmentation with long-acting antipsychotic injections or multi-component psychosocial interventions could be considered. Lastly, perhaps the most effective way to deal with CRS would be to optimize clozapine treatment, which might prevent clozapine resistance from developing. Personalized dosing, adequate treatment durations, management of side effects and non-adherence, collaboration with patients and caregivers, and addressing clinician barriers to clozapine use are the principal ways of ensuring optimal clozapine treatment. At present, these three options could the best way to manage CRS until research provides more firm directions about the effective options for augmenting clozapine response.
Collapse
Affiliation(s)
- Subho Chakrabarti
- Department of Psychiatry, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India
| |
Collapse
|
|
9
|
Lähteenvuo M, Tiihonen J. Antipsychotic Polypharmacy for the Management of Schizophrenia: Evidence and Recommendations. Drugs 2021; 81:1273-1284. [PMID: 34196945 PMCID: PMC8318953 DOI: 10.1007/s40265-021-01556-4] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2021] [Indexed: 12/13/2022]
Abstract
Schizophrenia is a debilitating illness with a lifetime prevalence estimate of 0.6% and consists of symptoms from the positive, negative, and cognitive domains. Social support, therapy, psychoeducation, and overall case management are very important aspects of the treatment of schizophrenia. However, as abnormalities in neurotransmission are one of the key findings of schizophrenia pathology, pharmacotherapies are cornerstones of the management of schizophrenia. Antipsychotics have been used as the primary pharmacological treatment of schizophrenia. These agents often have a good effect on reducing positive symptoms, but may not markedly improve negative symptoms or cognitive defects. However, at least 20% of individuals with schizophrenia do not experience a substantial response from monotherapy with antipsychotics. Further, despite evolving treatment protocols and advances in early recognition of the disorder, 70% of patients with schizophrenia require long-term, even lifetime, medication to control their symptoms and do not achieve complete recovery. To address these shortcomings, clinicians and research scientists have explored different combinations of treatments, polypharmacy, to improve the treatment of patients. Antipsychotic polypharmacy has been shown to cause more side effects than monotherapy, which is the main reason why most treatment guidelines caution against it. Antipsychotic monotherapy should be strived for and clozapine should be tried at the latest if two monotherapy trials with other antipsychotics have failed and no absolute contraindications exist. If residual symptoms exist despite trials of adequate dose and duration, other reasons that may reduce treatment effect should be ruled out. Long-acting injectables or blood concentration measurements should be considered to affirm compliance and proper serum levels. Antipsychotic polypharmacy should be considered and discussed with patients from whom the aforementioned procedures do not produce a satisfactory treatment result. In some cases, antipsychotic polypharmacy may produce better results than other forms of treatment augmentation, such as benzodiazepines. In particular, combining aripiprazole with clozapine may be effective in reducing treatment side effects or residual symptoms, and this is likely to hold true for combining other partial dopamine D2 agonists with clozapine as well, although currently scant data exist. More research is needed, both in controlled but also real-world settings, to define optimal antipsychotic polypharmacy and/or other psychotropic treatment augmentation strategies for specific patient groups and situations.
Collapse
Affiliation(s)
- Markku Lähteenvuo
- Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Niuvankuja 65, 70240, Kuopio, Finland.
| | - Jari Tiihonen
- Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Eastern Finland, Niuvankuja 65, 70240, Kuopio, Finland
- Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Center for Psychiatry Research, Stockholm City Council, Stockholm, Sweden
| |
Collapse
|
|
10
|
Kang SG, Cho SE, Na KS, Pae CU, Cho SJ. Clinical Usefulness of Amisulpride Add-on Therapy in Schizophrenia Patients without Treatment Response to Second-generation Antipsychotics. CLINICAL PSYCHOPHARMACOLOGY AND NEUROSCIENCE 2021; 19:117-124. [PMID: 33508795 PMCID: PMC7851466 DOI: 10.9758/cpn.2021.19.1.117] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 07/10/2020] [Accepted: 07/13/2020] [Indexed: 01/09/2023]
Abstract
Objective The response to antipsychotics in patients with schizophrenia is still unsatisfactory. Therefore, augmentation with other antipsychotics is common in clinical situations. The purpose of this study was to evaluate the improvement of psychiatric symptoms and side effects after amisulpride add-on therapy. Methods Forty patients with schizophrenia or schizoaffective disorder without treatment response to second-generation antipsychotics were included in this study. Psychotic symptoms were evaluated using the Positive and Negative Syndrome Scale (PANSS) and the Korean version of Calgary Depression Scale for Schizophrenia (CDSS) at baseline, 4 weeks, and 8 weeks after the addition of amisulpride. Results Among the 29 subjects who completed the 8-week study, 34.5% were responders according to PANSS total score. At week 8, the mean positive (p < 0.001), negative (p < 0.001), general (p < 0.001), and total (p < 0.001) PANSS scores and CDSS scores (p = 0.002) showed significant improvement compared to baseline. There was no increase in extrapyramidal side effects according to Simpson Angus Scale (p = 0.379) and Barnes Akathisia Rating Scale (p = 0.070) and no weight gain (p = 0.308) after the add-on treatment. Conclusion The addition of amisulpride for schizophrenia patients without therapeutic response to second-generation antipsychotics is considered an effective and safe treatment. This study's results suggested that augmentation of second-generation antipsychotics with amisulpride could be a useful option for patients with schizophrenia unresponsive to second-generation antipsychotics. Further studies investigating the efficacy of amisulpride add-on therapy using placebo control are necessary to confirm these results.
Collapse
Affiliation(s)
- Seung-Gul Kang
- Department of Psychiatry, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Seo-Eun Cho
- Department of Psychiatry, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Kyoung-Sae Na
- Department of Psychiatry, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Chi-Un Pae
- Department of Psychiatry, Bucheon St. Mary's Hospital, Bucheon, Korea.,Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, Bucheon, Korea
| | - Seong-Jin Cho
- Department of Psychiatry, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| |
Collapse
|
|
11
|
Ijaz S, Blanca Bolea, Davies S, Savović J, Richards A, Sullivan S, Moran P. Antipsychotic Polypharmacy and Metabolic Syndrome in Schizophrenia: A Review of Systematic Reviews. FOCUS: JOURNAL OF LIFE LONG LEARNING IN PSYCHIATRY 2020; 18:482-492. [PMID: 33343261 DOI: 10.1176/appi.focus.18307] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
(Reprinted with permission from BMC Psychiatry (2018) 18:275).
Collapse
|
|
12
|
Azorin JM, Simon N. Antipsychotic polypharmacy in schizophrenia: evolving evidence and rationale. Expert Opin Drug Metab Toxicol 2020; 16:1175-1186. [DOI: 10.1080/17425255.2020.1821646] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Affiliation(s)
| | - Nicolas Simon
- Department of Clinical Pharmacology, Aix Marseille University, INSERM, IRD, SESSTIM, Marseille, France
| |
Collapse
|
|
13
|
Baandrup L. Polypharmacy in schizophrenia. Basic Clin Pharmacol Toxicol 2020; 126:183-192. [PMID: 31908124 DOI: 10.1111/bcpt.13384] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/26/2019] [Accepted: 12/27/2019] [Indexed: 12/16/2022]
Abstract
Schizophrenia is a severe mental disorder characterized by a heterogeneous symptom profile which comprises a clinical platform for widespread use of polypharmacy even though antipsychotic monotherapy is the recommended treatment regimen. This narrative review provides a summary of the current gap between evidence and practice for use of antipsychotic combination therapy in patients with schizophrenia. Antipsychotic polypharmacy is frequently prescribed instead of following international consensus of clozapine monotherapy in treatment-resistant patients. Antipsychotic-benzodiazepine combination therapy clearly has a role in the treatment of acute agitation whereas there is no evidence to support an effect on core schizophrenia symptoms when chronically prescribed. Antidepressants are typically added to antipsychotic treatment in case of persistent negative symptoms. Available evidence suggests that antidepressants may improve negative symptom control in schizophrenia. Combining an antipsychotic with an antiepileptic is not supported by any firm evidence, but individual mood stabilizers have come out positively in single trials. Generally, the evidence base for polypharmacy in schizophrenia maintenance treatment is sparse but may be warranted in certain clinical situations. Therapeutic benefits and side effects should be carefully monitored and considered to ensure a beneficial risk-benefit ratio if prescribing polypharmacy for specific clinical indications.
Collapse
Affiliation(s)
- Lone Baandrup
- Centre for Neuropsychiatric Schizophrenia Research (CNSR), Mental Health Centre Glostrup, Glostrup, Denmark.,Mental Health Centre Copenhagen, Hellerup, Denmark
| |
Collapse
|
|
14
|
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: 162] [Impact Index Per Article: 32.4] [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.
Collapse
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
| |
Collapse
|
|
15
|
Wagner E, Löhrs L, Siskind D, Honer WG, Falkai P, Hasan A. Clozapine augmentation strategies - a systematic meta-review of available evidence. Treatment options for clozapine resistance. J Psychopharmacol 2019; 33:423-435. [PMID: 30696332 DOI: 10.1177/0269881118822171] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND Treatment options for clozapine resistance are diverse whereas, in contrast, the evidence for augmentation or combination strategies is sparse. AIMS We aimed to extract levels of evidence from available data and extrapolate recommendations for clinical practice. METHODS We conducted a systematic literature search in the PubMed/MEDLINE database and in the Cochrane database. Included meta-analyses were assessed using Scottish Intercollegiate Guidelines Network criteria, with symptom improvement as the endpoint, in order to develop a recommendation grade for each clinical strategy identified. RESULTS Our search identified 21 meta-analyses of clozapine combination or augmentation strategies. No strategies met Grade A criteria. Strategies meeting Grade B included combinations with first- or second-generation antipsychotics, augmentation with electroconvulsive therapy for persistent positive symptoms, and combination with certain antidepressants (fluoxetine, duloxetine, citalopram) for persistent negative symptoms. Augmentation strategies with mood-stabilisers, anticonvulsants, glutamatergics, repetitive transcranial magnetic stimulation, transcranial direct current stimulation or cognitive behavioural therapy met Grades C-D criteria only. CONCLUSION More high-quality clinical trials are needed to evaluate the efficacy of add-on treatments for symptom improvement in patients with clozapine resistance. Applying definitions of clozapine resistance would improve the reporting of future clinical trials. Augmentation with second-generation antipsychotics and first-generation antipsychotics can be beneficial, but the supporting evidence is from low-quality studies. Electroconvulsive therapy may be effective for clozapine-resistant positive symptoms.
Collapse
Affiliation(s)
- Elias Wagner
- 1 Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Germany
| | - Lisa Löhrs
- 1 Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Germany
| | - Dan Siskind
- 2 School of Medicine, University of Queensland, Brisbane, QLD, Australia.,3 Metro South Addiction and Mental Health Service, Brisbane, QLD, Australia
| | - William G Honer
- 4 Department of Psychiatry, The University of British Columbia, Vancouver, BC, Canada
| | - Peter Falkai
- 1 Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Germany
| | - Alkomiet Hasan
- 1 Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Germany
| |
Collapse
|
|
16
|
Tréhout M, Zhang N, Blouet M, Borha A, Dollfus S. Dandy-Walker Malformation-Like Condition Revealed by Refractory Schizophrenia: A Case Report and Literature Review. Neuropsychobiology 2019; 77:59-66. [PMID: 30448844 DOI: 10.1159/000494695] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Accepted: 10/17/2018] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Dandy-Walker malformation is a rare congenital malformation involving cystic dilatation of the fourth ventricle, enlarged posterior fossa, complete or partial agenesis of the cerebellar vermis, elevated tentorium cerebelli, and hydrocephalus. Previous research highlighted a possible role for the cerebellum in schizophrenia as well as the contribution of underlying brain malformations to treatment resistance. Here, we present a case of a Dandy-Walker malformation-like condition revealed by a refractory schizophrenia in a 24-year-old male patient. We also conduct a literature review of all previously published case reports or case series of co-occurring posterior fossa abnormalities and schizophrenia or psychosis using a PubMed search query to better understand the potential link between these two disorders. CASE PRESENTATION A 9-month hospital stay was needed to address the treatment-resistant psychotic symptoms, and the patient continued to experience moderate symptoms despite the prescription of various antipsychotic and antidepressant medications. After an irregular initial medical follow-up, the patient is currently treated with 350 mg daily clozapine and 20 mg daily prazepam and still exhibits moderate anxiety without delirious thoughts, however allowing him to re-enroll at the university. Regarding the literature, 24 cases published between 1996 and 2017 were identified, reviewed and compared to the present case report. DISCUSSION This case report and literature review further illuminates the pathophysiology of psychotic disorders including the potential role of the cerebellum, reinforces the importance of a multidisciplinary approach for the neurological and psychiatric management of patients with schizophrenia, and highlights optimal pharmacological management strategies for treatment-resistant schizophrenia.
Collapse
Affiliation(s)
- Maxime Tréhout
- Service de Psychiatrie, CHU de Caen, Caen, France, .,UFR de Médecine, UNICAEN, Normandie Université, Caen, France, .,ISTS, UNICAEN, Normandie Université, Caen, France,
| | | | - Marie Blouet
- Service de Radiologie, CHU de Caen, Caen, France
| | - Alin Borha
- Service de Neurochirurgie, CHU de Caen, Caen, France
| | - Sonia Dollfus
- Service de Psychiatrie, CHU de Caen, Caen, France.,UFR de Médecine, UNICAEN, Normandie Université, Caen, France.,ISTS, UNICAEN, Normandie Université, Caen, France
| |
Collapse
|
|
17
|
Ijaz S, Bolea B, Davies S, Savović J, Richards A, Sullivan S, Moran P. Antipsychotic polypharmacy and metabolic syndrome in schizophrenia: a review of systematic reviews. BMC Psychiatry 2018; 18:275. [PMID: 30176844 PMCID: PMC6122457 DOI: 10.1186/s12888-018-1848-y] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2018] [Accepted: 08/13/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND There is conflicting evidence on the association between antipsychotic polypharmacy and metabolic syndrome in schizophrenia. We conducted a review of published systematic reviews to evaluate evidence on the association between metabolic syndrome (diabetes, hypertension, and hyperlipidaemia) and exposure to antipsychotic polypharmacy in schizophrenia. METHODS We searched five electronic databases, complemented by reference screening, to find systematic reviews that investigated the association of antipsychotic polypharmacy in schizophrenia with hypertension, diabetes, or hyperlipidaemia. Selection of reviews, data extraction and review quality were conducted independently by two people and disagreements resolved by discussion. Results were synthesised narratively. RESULTS We included 12 systematic reviews, which reported heterogeneous results, mostly with narrative syntheses and without pooled data. The evidence was rated as low quality. There was some indication of a possible protective effect of drug combinations including aripiprazole for diabetes and hyperlipidaemias, compared to other combinations and/or monotherapy. Only one review reported the association between APP and hypertension. The most frequently reported combinations of medication included clozapine, possibly representing a sample of patients with treatment resistant illness. No included review reported results separately by setting (primary or secondary care). CONCLUSIONS Further robust studies are needed to elucidate the possible protective effect of aripiprazole. Long-term prospective studies are required for accurate appraisal of diabetes risk, hypertension and hyperlipidaemia in patients exposed to antipsychotic polypharmacy.
Collapse
Affiliation(s)
- Sharea Ijaz
- Bristol Medical School, University of Bristol, Bristol, UK. .,National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) West, 9th floor, Whitefriars, Lewins Mead, Bristol, BS1 2NT, UK.
| | - Blanca Bolea
- 0000 0001 2157 2938grid.17063.33Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, Canada
| | - Simon Davies
- 0000 0001 2157 2938grid.17063.33Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, Canada
| | - Jelena Savović
- 0000 0004 1936 7603grid.5337.2Bristol Medical School, University of Bristol, Bristol, UK ,National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) West, 9th floor, Whitefriars, Lewins Mead, Bristol, BS1 2NT UK
| | - Alison Richards
- 0000 0004 1936 7603grid.5337.2Bristol Medical School, University of Bristol, Bristol, UK ,National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) West, 9th floor, Whitefriars, Lewins Mead, Bristol, BS1 2NT UK
| | - Sarah Sullivan
- 0000 0004 1936 7603grid.5337.2Bristol Medical School, University of Bristol, Bristol, UK
| | - Paul Moran
- 0000 0004 1936 7603grid.5337.2Bristol Medical School, University of Bristol, Bristol, UK
| |
Collapse
|
|
18
|
Barnes TR, Leeson V, Paton C, Marston L, Osborn DP, Kumar R, Keown P, Zafar R, Iqbal K, Singh V, Fridrich P, Fitzgerald Z, Bagalkote H, Haddad PM, Husni M, Amos T. Amisulpride augmentation of clozapine for treatment-refractory schizophrenia: a double-blind, placebo-controlled trial. Ther Adv Psychopharmacol 2018; 8:185-197. [PMID: 29977519 PMCID: PMC6022882 DOI: 10.1177/2045125318762365] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Accepted: 12/01/2017] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND A second antipsychotic is commonly added to clozapine to treat refractory schizophrenia, notwithstanding the limited evidence to support such practice. METHODS The efficacy and adverse effects of this pharmacological strategy were examined in a double-blind, placebo-controlled, 12-week randomized trial of clozapine augmentation with amisulpride, involving 68 adults with treatment-resistant schizophrenia and persistent symptoms despite a predefined trial of clozapine. RESULTS There were no statistically significant differences between the amisulpride and placebo groups on the primary outcome measure (clinical response defined as a 20% reduction in total Positive and Negative Syndrome Scale score) or other mental state measures. However, the trial under recruited and was therefore underpowered to detect differences in the primary outcome, meaning that acceptance of the null hypothesis carries an increased risk of type II error. The findings suggested that amisulpride-treated participants were more likely to fulfil the clinical response criterion, odds ratio 1.17 (95% confidence interval 0.40-3.42) and have a greater reduction in negative symptoms, but these numerical differences were not statistically significant and only evident at 12 weeks. A significantly higher proportion of participants in the amisulpride group had at least one adverse event compared with the control group (p = 0.014), and these were more likely to be cardiac symptoms. CONCLUSIONS Treatment for more than 6 weeks may be required for an adequate trial of clozapine augmentation with amisulpride. The greater side-effect burden associated with this treatment strategy highlights the need for safety and tolerability monitoring, including vigilance for indicators of cardiac abnormalities, when it is used in either a clinical or research setting.
Collapse
Affiliation(s)
- Thomas R.E. Barnes
- Centre for Psychiatry, Hammersmith Hospital Campus, Imperial College London, 7th Floor Commonwealth Building, Du Cane Road, London W12 0NN, UK
| | | | - Carol Paton
- Centre for Psychiatry, Imperial College London, UK
- Oxleas NHS Foundation Trust, UK
| | - Louise Marston
- Department of Primary Care and Population Health, University College London, UK
- PRIMENT Clinical Trials Unit, University College London, UK
| | - David P. Osborn
- Division of Psychiatry, University College London, UK
- Camden and Islington NHS Foundation Trust, London, UK
| | - Raj Kumar
- Tees, Esk and Wear Valley NHS Foundation Trust, Billingham, UK
| | - Patrick Keown
- Northumberland Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, UK
- Newcastle University, Newcastle-upon-Tyne, UK
| | - Rameez Zafar
- Lincolnshire Partnership NHS Foundation Trust, Lincoln, UK
| | | | - Vineet Singh
- Derbyshire Healthcare NHS Foundation Trust, Derby, UK
| | - Pavel Fridrich
- North Essex Partnership University NHS Foundation Trust, Harlow, UK
| | | | | | - Peter M. Haddad
- Greater Manchester West Mental Health NHS Foundation Trust, Manchester, UK
- University of Manchester, Manchester, UK
| | - Mariwan Husni
- Central and North West London NHS Foundation Trust, London, UK
- Northern Ontario School of Medicine, Ontario, Canada
| | - Tim Amos
- Avon and Wiltshire Mental Health Partnership NHS Trust, Bristol, UK
- School of Social and Community Medicine, University of Bristol, Bristol, UK
| |
Collapse
|
|
19
|
Barnes TR, Leeson VC, Paton C, Marston L, Davies L, Whittaker W, Osborn D, Kumar R, Keown P, Zafar R, Iqbal K, Singh V, Fridrich P, Fitzgerald Z, Bagalkote H, Haddad PM, Husni M, Amos T. Amisulpride augmentation in clozapine-unresponsive schizophrenia (AMICUS): a double-blind, placebo-controlled, randomised trial of clinical effectiveness and cost-effectiveness. Health Technol Assess 2018; 21:1-56. [PMID: 28869006 DOI: 10.3310/hta21490] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND When treatment-refractory schizophrenia shows an insufficient response to a trial of clozapine, clinicians commonly add a second antipsychotic, despite the lack of robust evidence to justify this practice. OBJECTIVES The main objectives of the study were to establish the clinical effectiveness and cost-effectiveness of augmentation of clozapine medication with a second antipsychotic, amisulpride, for the management of treatment-resistant schizophrenia. DESIGN The study was a multicentre, double-blind, individually randomised, placebo-controlled trial with follow-up at 12 weeks. SETTINGS The study was set in NHS multidisciplinary teams in adult psychiatry. PARTICIPANTS Eligible participants were people aged 18-65 years with treatment-resistant schizophrenia unresponsive, at a criterion level of persistent symptom severity and impaired social function, to an adequate trial of clozapine monotherapy. INTERVENTIONS Interventions comprised clozapine augmentation over 12 weeks with amisulpride or placebo. Participants received 400 mg of amisulpride or two matching placebo capsules for the first 4 weeks, after which there was a clinical option to titrate the dosage of amisulpride up to 800 mg or four matching placebo capsules for the remaining 8 weeks. MAIN OUTCOME MEASURES The primary outcome measure was the proportion of 'responders', using a criterion response threshold of a 20% reduction in total score on the Positive and Negative Syndrome Scale. RESULTS A total of 68 participants were randomised. Compared with the participants assigned to placebo, those receiving amisulpride had a greater chance of being a responder by the 12-week follow-up (odds ratio 1.17, 95% confidence interval 0.40 to 3.42) and a greater improvement in negative symptoms, although neither finding had been present at 6-week follow-up and neither was statistically significant. Amisulpride was associated with a greater side effect burden, including cardiac side effects. Economic analyses indicated that amisulpride augmentation has the potential to be cost-effective in the short term [net saving of between £329 and £2011; no difference in quality-adjusted life-years (QALYs)] and possibly in the longer term. LIMITATIONS The trial under-recruited and, therefore, the power of statistical analysis to detect significant differences between the active and placebo groups was limited. The economic analyses indicated high uncertainty because of the short duration and relatively small number of participants. CONCLUSIONS The risk-benefit of amisulpride augmentation of clozapine for schizophrenia that has shown an insufficient response to a trial of clozapine monotherapy is worthy of further investigation in larger studies. The size and extent of the side effect burden identified for the amisulpride-clozapine combination may partly reflect the comprehensive assessment of side effects in this study. The design of future trials of such a treatment strategy should take into account that a clinical response may be not be evident within the 4- to 6-week follow-up period usually considered adequate in studies of antipsychotic treatment of acute psychotic episodes. Economic evaluation indicated the need for larger, longer-term studies to address uncertainty about the extent of savings because of amisulpride and impact on QALYs. The extent and nature of the side effect burden identified for the amisulpride-clozapine combination has implications for the nature and frequency of safety and tolerability monitoring of clozapine augmentation with a second antipsychotic in both clinical and research settings. TRIAL REGISTRATION EudraCT number 2010-018963-40 and Current Controlled Trials ISRCTN68824876. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 49. See the NIHR Journals Library website for further project information.
Collapse
Affiliation(s)
- Thomas Re Barnes
- Centre for Mental Health, Imperial College London, London, UK.,West London Mental Health NHS Trust, London, UK
| | - Verity C Leeson
- Centre for Mental Health, Imperial College London, London, UK
| | - Carol Paton
- Centre for Mental Health, Imperial College London, London, UK.,Oxleas NHS Foundation Trust, London, UK
| | - Louise Marston
- Department of Primary Care and Population Health, University College London, London, UK.,PRIMENT Clinical Trials Unit, University College London, London, UK
| | - Linda Davies
- Centre for Health Economics, Institute of Population Health, University of Manchester, Manchester, UK
| | - William Whittaker
- Centre for Health Economics, Institute of Population Health, University of Manchester, Manchester, UK
| | - David Osborn
- Division of Psychiatry, University College London, London, UK.,Camden and Islington NHS Foundation Trust, London, UK
| | - Raj Kumar
- Tees, Esk and Wear Valley NHS Foundation Trust, Billingham, UK
| | - Patrick Keown
- Northumberland Tyne and Wear NHS Foundation Trust, Newcastle upon Tyne, UK.,Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK
| | - Rameez Zafar
- Lincolnshire Partnership NHS Foundation Trust, Lincoln, UK
| | | | - Vineet Singh
- Derbyshire Healthcare NHS Foundation Trust, Derby, UK
| | - Pavel Fridrich
- North Essex Partnership University NHS Foundation Trust, Chelmsford, UK
| | | | | | - Peter M Haddad
- Greater Manchester West Mental Health NHS Foundation Trust, Manchester, UK.,Institute of Brain, Behaviour and Mental Health, University of Manchester, Manchester, UK
| | - Mariwan Husni
- Central and North West London NHS Foundation Trust, London, UK.,Northern Ontario School of Medicine, Sudbury, ON, Canada
| | - Tim Amos
- Avon and Wiltshire Mental Health Partnership NHS Trust, Bristol, UK.,School of Social and Community Medicine, University of Bristol, Bristol, UK
| |
Collapse
|
|
20
|
Tungaraza TE, Zahid U, Venkataramaiah B. Polypharmacy and high-dose antipsychotics at the time of discharge from acute psychiatric wards. ACTA ACUST UNITED AC 2018. [DOI: 10.1192/pb.bp.110.033167] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Aims and methodTo determine the extent of prescribed antipsychotic polypharmacy and high-dose antipsychotics at the time of discharge from an acute psychiatric ward. Copies of discharge summaries for patients between the ages of 18 and 65 were examined; only those that had antipsychotic medications at the time of discharge were included. Names and doses of antipsychotics and all other medications concurrently prescribed were recorded.ResultsA total of 651 discharge summaries were included in the study. Nearly a quarter of individuals were discharged on one antipsychotic as the only medication to take home; only 6.8% were discharged on a high-dose antipsychotic and of those on combinations 59.6% were on depot medications. Combining antipsychotics significantly predicted the use of high dose.Clinical implicationsMost patients were discharged on doses of antipsychotics within the British National Formulary limits; however, a small proportion is still sent home on high doses of antipsychotics. Combining antipsychotics remains the strongest predictor of high-dose antipsychotic use; clinicians need to be aware of this.
Collapse
|
|
21
|
Marcinkowska M, Kołaczkowski M, Kamiński K, Bucki A, Pawłowski M, Siwek A, Karcz T, Starowicz G, Słoczyńska K, Pękala E, Wesołowska A, Samochowiec J, Mierzejewski P, Bienkowski P. 3-Aminomethyl Derivatives of 2-Phenylimidazo[1,2-a]-pyridine as Positive Allosteric Modulators of GABA A Receptor with Potential Antipsychotic Activity. ACS Chem Neurosci 2017; 8:1291-1298. [PMID: 28211669 DOI: 10.1021/acschemneuro.6b00432] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Schizophrenia is a mental illness characterized by behavioral changes as well as anatomical and neurochemical abnormalities. There has been remarkable progress in the drug discovery for schizophrenia; however, antipsychotics that act through molecular targets, other than monoaminergic receptors, have not been developed. One of the hypotheses of schizophrenia states that GABAergic dysfunction might be implemented in the pathophysiology of this disease. Our recent findings and previous clinical observations have suggested that modulation of GABAergic system through α1-GABAA receptors would represent an original approach for the treatment of schizophrenia. This study presents the synthesis and biological evaluation of a series of fluorinated 3-aminomethyl derivatives of 2-phenylimidazo[1,2-a]-pyridine as potential antipsychotic agents. Compound 7 has a high affinity for GABAA receptor (Ki = 27.2 nM), high in vitro metabolic stability, and antipsychotic-like activity in amphetamine-induced hyperlocomotion test in rats (MED = 10 mg/kg). Compound 7 represents a promising point of entry in the course of development of antipsychotic agents with a nondopaminergic mechanism of action.
Collapse
Affiliation(s)
- Monika Marcinkowska
- Faculty
of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland
| | - Marcin Kołaczkowski
- Faculty
of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland
| | - Krzysztof Kamiński
- Faculty
of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland
| | - Adam Bucki
- Faculty
of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland
| | - Maciej Pawłowski
- Faculty
of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland
| | - Agata Siwek
- Faculty
of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland
| | - Tadeusz Karcz
- Faculty
of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland
| | - Gabriela Starowicz
- Faculty
of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland
| | - Karolina Słoczyńska
- Faculty
of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland
| | - Elżbieta Pękala
- Faculty
of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland
| | - Anna Wesołowska
- Faculty
of Pharmacy, Jagiellonian University Medical College, 9 Medyczna St., 30-688 Krakow, Poland
| | - Jerzy Samochowiec
- Department
of Psychiatry, Pomeranian Medical University, 1 Rybacka St., 70-204 Szczecin, Poland
| | - Paweł Mierzejewski
- Department
of Pharmacology, Institute of Psychiatry and Neurology, 9 Sobieskiego
St. 02-957 Warsaw, Poland
| | - Przemyslaw Bienkowski
- Department
of Psychiatry, Medical University of Warsaw, ul. Nowowiejska 27, 00-665 Warsaw, Poland
| |
Collapse
|
|
22
|
MacKay M, Cetin M, Baker G, Dursun S. Modulation of Central Nitric Oxide as a Therapeutic Strategy for Schizophrenia. ACTA ACUST UNITED AC 2016. [DOI: 10.1080/10177833.2010.11790644] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- Marnie MacKay
- Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Canada, Centre for Psychiatric Assessment and Therapeutics, Alberta Hospital Edmonton, Alberta Health Services, Edmonton, Canada
| | - Mesut Cetin
- GATA Haydarpasa Training Hospital, Department of Psychiatry, Istanbul-Turkey
| | - Glen Baker
- Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Canada, Centre for Psychiatric Assessment and Therapeutics, Alberta Hospital Edmonton, Alberta Health Services, Edmonton, Canada
| | - Serdar Dursun
- Neurochemical Research Unit, Department of Psychiatry, University of Alberta, Edmonton, Canada, Centre for Psychiatric Assessment and Therapeutics, Alberta Hospital Edmonton, Alberta Health Services, Edmonton, Canada
| |
Collapse
|
|
23
|
Design, synthesis, and biological evaluation of fluorinated imidazo[1,2- a ]pyridine derivatives with potential antipsychotic activity. Eur J Med Chem 2016; 124:456-467. [DOI: 10.1016/j.ejmech.2016.08.059] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/23/2016] [Accepted: 08/24/2016] [Indexed: 10/21/2022]
|
|
24
|
Grover S, Balachander S, Chakarabarti S, Avasthi A. Prescription practices and attitude of psychiatrists towards clozapine: A survey of psychiatrists from India. Asian J Psychiatr 2015; 18:57-65. [PMID: 26498722 DOI: 10.1016/j.ajp.2015.09.013] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 09/20/2015] [Accepted: 09/28/2015] [Indexed: 01/17/2023]
Abstract
AIM To assess the attitude of psychiatrists towards clozapine and also to evaluate the prescription practices of psychiatrists for clozapine. METHODOLOGY An email survey was sent to 3381 psychiatrists from India, of whom 548 (16.2%) responded. RESULTS Mean number of years in clinical practice was 12.59 (SD-10.1) for participating psychiatrists. Majority of the participants rated their knowledge about clozapine to be good (61.5%)/very good (34.5%). The primary indication for use of clozapine for almost all the participants was treatment resistance and most of the psychiatrists initiated clozapine either in the dose of 25mg OD (44.3%) or 12.5mg OD (37%). Half (51.8%) of the psychiatrists preferred to use clozapine as BD dosing schedule, and median doses required to stabilize the patients ranged from 137.5 to 400mg/day. Once the clozapine dose had been stabilized, about half (51%) of the psychiatrists advised blood monitoring at monthly intervals. Almost all psychiatrists rated effectiveness of clozapine to be better than other antipsychotics. In terms of tolerability, 45.3% of the psychiatrists rated it as 'same as other antipsychotics' and 15.9% rated it as better than other antipsychotics. Most common patient and therapist related factors associated with reluctance to start clozapine were history of poor medication compliance and need for monitoring, respectively. Upon reviewing the prescription of other psychiatrists, participating psychiatrists reported that in about 28.46% of patients clozapine was not prescribed though indicated. CONCLUSIONS This survey suggests that clozapine is underused in India, although psychiatrists have adequate knowledge about the drug but many psychiatrists have negative attitude towards clozapine.
Collapse
Affiliation(s)
- Sandeep Grover
- Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India.
| | - Srinivas Balachander
- Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Subho Chakarabarti
- Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| | - Ajit Avasthi
- Department of Psychiatry, Post Graduate Institute of Medical Education and Research, Chandigarh 160012, India
| |
Collapse
|
|
25
|
Murphy PM, Iles A, Sreedharan S. High-dose antipsychotics: addressing patients' resistance to physical health monitoring. BJPSYCH ADVANCES 2015. [DOI: 10.1192/apt.bp.113.011833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
SummaryHigh-dose antipsychotics are sometimes used in clinical practice when patients fail to respond to treatment at standard doses. Owing to the potential physical complications associated with this, strict adherence to physical health monitoring is essential. Challenges arise for clinicians when patients refuse to cooperate with this monitoring. We discuss different interventions to overcome this problem, many of which are coercive in nature, and consider their professional, ethical and legal implications. We include a flow diagram to assist clinicians in their documentation and decision-making in these circumstances as well as case vignettes showing when monitoring under restraint is and is not justifiable.
Collapse
|
|
26
|
Abstract
Antipsychotic polypharmacy remains prevalent; it has probably increased for the treatment of schizophrenia in real-world clinical settings. The current evidence suggests some clinical benefits of antipsychotic polypharmacy, such as better symptom control with clozapine plus another antipsychotic, and a reversal of metabolic side-effects with a concomitant use of aripiprazole. On the other hand, the interpretation of findings in the literature should be made conservatively in light of the paucity of good studies and potentially serious side-effects. Also, although the available data are still limited, two smaller-scale clinical trials provide preliminary evidence that converting antipsychotic polypharmacy to monotherapy could be a valid and reasonable treatment option. Several studies have explored strategies to change physicians' antipsychotic polypharmacy prescribing behaviours. These have revealed that, while the impact of purely educational interventions may be limited, more aggressive procedures such as directly notifying physicians by letters or phone calls can be more effective in reducing antipsychotic polypharmacy. In conclusion, antipsychotic polypharmacy can work for some clinically difficult conditions; however, it should be the exception rather than the rule and may be avoidable in many patients. More importantly, the paucity of the data clearly emphasizes the need for further investigations on not only advantages and disadvantages of antipsychotic polypharmacy, but also regarding effective interventions in already prescribed polypharmacy regimens.
Collapse
|
|
27
|
Park T, Kuntz KM. Cost-effectiveness of second-generation antipsychotics for the treatment of schizophrenia. VALUE IN HEALTH : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH 2014; 17:310-319. [PMID: 24968989 DOI: 10.1016/j.jval.2014.02.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Revised: 02/18/2014] [Accepted: 02/20/2014] [Indexed: 06/03/2023]
Abstract
OBJECTIVE To compare the cost-effectiveness of alternate treatment strategies using second-generation antipsychotics (SGAs) for patients with schizophrenia. METHODS We developed a Markov model to estimate the costs and quality-adjusted life-years (QALYs) for different sequences of treatments for 40-year-old patients with schizophrenia. We considered first-line treatment with one of the four SGAs: olanzapine (OLZ), risperidone (RSP), quetiapine (QTP), and ziprasidone (ZSD). Patients could switch to another of these antipsychotics as second-line therapy, and only clozapine (CLZ) was allowed as third-line treatment. We derived parameter estimates from the Clinical Antipsychotic Trial of Intervention Effectiveness (CATIE) study and published sources. RESULTS The ZSD-QTP strategy (first-line treatment with ZSD, change to QTP if ZSD is discontinued, and switch to CLZ if QTP is discontinued) was most costly while yielding the greatest QALYs, with an incremental cost-effective ratio (ICER) of $542,500 per QALY gained compared with the ZSD-RSP strategy. However, the ZSD-RSP strategy had an ICER of $5,200/QALY gained versus the RSP-ZSD strategy and had the greatest probability of being cost-effective given a willingness-to-pay threshold between $50,000 and $100,000 per QALY. All other treatment strategies were more costly and less effective than another strategy or combination of other strategies. Results varied by different time horizons adopted. CONCLUSIONS The ZSD-RSP strategy was most cost-effective at a willingness-to-pay threshold between $5,200 and $542,500 per QALY. Our results should be interpreted with caution because they are based largely on the CATIE trial with potentially limited generalizability to all patient populations and doses of SGAs used in practice.
Collapse
Affiliation(s)
- Taehwan Park
- College of Pharmacy, University of Minnesota, Minneapolis, MN
| | - Karen M Kuntz
- School of Public Health, University of Minnesota, Minneapolis, MN.
| |
Collapse
|
|
28
|
|
|
29
|
Eryılmaz G, Hızlı Sayar G, Ozten E, Gögcegöz Gül I, Karamustafalıoğlu O. Aripirazole augmentation in clozapine-associated obsessive-compulsive symptoms in schizophrenia. Ann Gen Psychiatry 2013; 12:40. [PMID: 24330737 PMCID: PMC3874630 DOI: 10.1186/1744-859x-12-40] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 12/03/2013] [Indexed: 12/03/2022] Open
Abstract
OBJECTIVE Patients with schizophrenia often experience comorbid obsessive-compulsive symptoms. Within these patients, a significant subgroup developed secondary obsessive-compulsive symptoms during treatment with clozapine. METHOD In this paper, we report on four cases in which adjunctive therapy with aripiprazole was tested to alleviate obsessive-compulsive symptoms in schizophrenia. RESULTS All four patients had a significant improvement in obsessive-compulsive symptoms. The combination of clozapine and aripiprazole was well tolerated. CONCLUSION This case series demonstrates the clinical efficacy of aripiprazole adjunctive therapy with clozapine in schizophrenic patients with comorbid obsessive-compulsive symptoms. Larger-sampled and controlled studies are required in order to test and confirm these observations.
Collapse
Affiliation(s)
| | - Gökben Hızlı Sayar
- Department of Psychiatry, Uskudar University, Neuropsychiatry Istanbul Hospital, Alemdag Caddesi Site Yolu No:29, Umraniye, Istanbul, Turkey.
| | | | | | | |
Collapse
|
|
30
|
Aripiprazole versus haloperidol in combination with clozapine for treatment-resistant schizophrenia: a 12-month, randomized, naturalistic trial. J Clin Psychopharmacol 2013; 33:533-7. [PMID: 23775051 DOI: 10.1097/jcp.0b013e318296884f] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
BACKGROUND Long-term studies for patients with resistant schizophrenia are necessary to assess the effectiveness of combination strategies on persisting positive symptoms. AIMS AND METHODS This multicenter, naturalistic, randomized, superiority study (ClinicalTrials.gov identifier: NCT00395915) aimed to compare clinical efficacy and tolerability of haloperidol versus aripiprazole as combination treatment with clozapine in patients with resistant schizophrenia. RESULTS One hundred six patients were followed up for 12 months. After 12 months, the proportion of patients who discontinued treatment was not significantly different between aripiprazole and haloperidol (37% vs 28%, respectively; P = 0.431). The change in the Brief Psychiatric Rating Scale score was similar in the aripiprazole and haloperidol groups (-7.0 vs -7.9, respectively; P = 0.389), whereas the tolerability total score decreased significantly more in the aripiprazole group (-7.2 vs -2.3; P = 0.008). CONCLUSIONS While the effectiveness of clozapine augmentation with a second antipsychotic agent is not clearly demonstrated yet, results from this study suggest that augmentation with aripiprazole offers no substantial benefit over haloperidol in efficacy. Aripiprazole was perceived more tolerable than haloperidol, but it is uncertain how this finding may translate into the real world of clinical practice.
Collapse
|
|
31
|
Lochmann van Bennekom MWH, Gijsman HJ, Zitman FG. Antipsychotic polypharmacy in psychotic disorders: a critical review of neurobiology, efficacy, tolerability and cost effectiveness. J Psychopharmacol 2013; 27:327-36. [PMID: 23413275 DOI: 10.1177/0269881113477709] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE The purpose of this study was to review the scientific evidence for neurobiological rationale, efficacy, tolerability and cost effectiveness of antipsychotic polypharmacy (APP). DATA SOURCES A systematic literature search of Medline, Embase, Ovid and the Cochrane Database of Systematic Reviews until April 2012 was carried out. RESULTS Theories behind APP have only modest pre-clinical and clinical evidence. We found limited statistical evidence supporting modest efficacy of APP in patients with psychotic symptoms refractory to clozapine. APP is associated with increased mortality, metabolic syndrome, decreased cognitive functioning, high dose prescription and non-adherence. It brings up extra costs, lacking evidence for cost-effectiveness. CONCLUSIONS Pre-clinical studies underpinning neurobiological hypotheses in APP are lacking. Evidence supporting efficacy of APP is limited with modest beneficial clinical relevance. APP is associated with several serious adverse effects and increased health costs. In the absence of more convincing pre-clinical support and clinical evidence we advise adherence to existing guidelines and limiting combinations of antipsychotics (in consideration with other pharmacotherapeutic, somatic and psychotherapeutic options) to patients with clozapine-refractory psychosis in well-evaluated individual trials that might need 10 weeks or more.
Collapse
|
|
32
|
Lamotrigine augmentation in patients with schizophrenia who show partial response to clozapine treatment. Schizophr Res 2013; 143:207-14. [PMID: 23217729 DOI: 10.1016/j.schres.2012.11.006] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2012] [Revised: 10/18/2012] [Accepted: 11/01/2012] [Indexed: 01/03/2023]
Abstract
BACKGROUND Several placebo controlled studies investigating lamotrigine augmentation of clozapine in schizophrenia patients with partial response have shown varying results. The aim of this study was to further investigate the efficacy and safety of this augmentation strategy, and its effect on the glutamatergic system through utilizing mismatch negativity (MMN) component of auditory event related potentials. METHODS The study was designed to evaluate the efficacy and safety of lamotrigine augmentation of clozapine in a 12-week, double-blind, placebo-controlled, prospective, randomized design. Thirty-four patients diagnosed according to DSM-IV schizophrenia criteria and with partial response to clozapine were included. Patients were randomized to 25mg/day of lamotrigine or placebo, gradually increasing up to 200mg/day on the 6th week. The change in psychopathology was assessed with Positive and Negative Syndrome (PANSS), Calgary Depression (CDS) and Clinical Global Impression-Severity (CGI-S) scales. A neuropsychological test battery was administered and MMN measurements were also obtained at baseline and endpoint. Safety evaluation included physical examination, UKU Side Effect Rating Scale (UKU) assessment and serum drug level measurements. RESULTS No significant differences were found between the two treatment groups in PANSS Positive and General Psychopathology, CDS, neurocognitive test and UKU scores, as well as MMN measurements. PANSS Total, Negative and CGI-S scores showed significant improvement compared to lamotrigine in the placebo group. CONCLUSION This study did not show any benefit of augmentation of clozapine with lamotrigine in schizophrenia patients with partial response. The need for further investigation of other augmentation strategies of clozapine in partially responsive schizophrenia patients is evident.
Collapse
|
|
33
|
Sommer IE, Begemann MJH, Temmerman A, Leucht S. Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. Schizophr Bull 2012; 38:1003-11. [PMID: 21422107 PMCID: PMC3446238 DOI: 10.1093/schbul/sbr004] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND When schizophrenia patients have insufficient response to clozapine, pharmacological augmentation is often applied. This meta-analysis summarizes available evidence on efficacy of pharmacological augmentation of clozapine treatment in schizophrenia spectrum disorder. METHODS Only double-blind randomized controlled studies were included. Primary outcome measure was total symptom severity, and secondary outcome measures were subscores for positive and negative symptoms. Effect sizes were calculated from individual studies and combined to standardized mean differences (Hedges's g). RESULTS Twenty-nine studies reporting on 15 different augmentations were included. Significant better efficacy than placebo on total symptom severity was observed for lamotrigine, citalopram, sulpiride, and CX516 (a glutamatergic agonist). The positive effect of lamotrigine disappeared after outlier removal. The other positive findings were based on single studies. Significantly better efficacy on positive symptom severity was observed for topiramate and sulpiride. The effect of topiramate disappeared after outlier removal. Results for sulpiride were based on a single randomized controlled trial. Citalopram, sulpiride, and CX516 showed better efficacy for negative symptoms than placebo, all based on single studies. CONCLUSIONS Evidence for efficacy of clozapine augmentation is currently scarce. Efficacy of lamotrigine and topiramate were both dependent on single studies with deviating findings. The effect of citalopram, sulpiride, and CX516 were based on single studies. Thus, despite their popularity, pharmacological augmentations of clozapine are not (yet) demonstrated to be superior to placebo.
Collapse
Affiliation(s)
- Iris E. Sommer
- Neuroscience Department of the University Medical Center Utrecht & Rudolf Magnus Institute for Neuroscience, Utrecht, the Netherlands,To whom correspondence should be addressed; tel: +31-88-7556370, fax: +31-88-7555443, e-mail:
| | - Marieke J. H. Begemann
- Neuroscience Department of the University Medical Center Utrecht & Rudolf Magnus Institute for Neuroscience, Utrecht, the Netherlands
| | - Anke Temmerman
- Neuroscience Department of the University Medical Center Utrecht & Rudolf Magnus Institute for Neuroscience, Utrecht, the Netherlands
| | - Stefan Leucht
- Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany
| |
Collapse
|
|
34
|
Abstract
INTRODUCTION Despite considerable progress in the pharmacological treatment of schizophrenia, about 30% of patients are minimally responsive to antipsychotics and there is still an excessively high rate of mortality in schizophrenia patients. Clozapine , a D(2)-5HT(2) antagonist, was the first antipsychotic to demonstrate efficacy in treatment-resistant patients, and to be associated with the lowest risk of death. AREAS COVERED The pharmacodynamics, pharmacokinetics, clinical efficacy, safety and cost-effectiveness of clozapine are covered in this article, based on a literature review (PubMed) from 1975 to 2012. Pivotal, as well as supporting, randomized controlled trials are reviewed, along with observational and/or naturalistic safety studies. This review of clozapine will allow the reader to determine the place for clozapine in the schizophrenia treatment landscape. EXPERT OPINION Studies conducted so far suggest that clozapine is the treatment of choice for schizophrenic patients who are refractory to treatment, display violent behaviors, or who are at high risk of suicide. However, it is also the antipsychotic with the worst side effect profile, the highest risk of complications, and the most difficult to prescribe. Experience with clozapine should therefore be included in the education of future physicians.
Collapse
Affiliation(s)
- Eric Fakra
- Pôle Universitaire de Psychiatrie - Solaris, Hôpital Sainte Marguerite, Marseille, France.
| | | |
Collapse
|
|
35
|
Baandrup L, Sørensen J, Lublin H, Nordentoft M, Glenthoj B. Association of antipsychotic polypharmacy with health service cost: a register-based cost analysis. THE EUROPEAN JOURNAL OF HEALTH ECONOMICS : HEPAC : HEALTH ECONOMICS IN PREVENTION AND CARE 2012; 13:355-363. [PMID: 21452062 DOI: 10.1007/s10198-011-0308-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2010] [Accepted: 02/24/2011] [Indexed: 05/30/2023]
Abstract
OBJECTIVE To investigate the association of antipsychotic polypharmacy in schizophrenia with cost of primary and secondary health service use. METHOD Comparative analysis of health service cost for patients prescribed antipsychotic polypharmacy versus antipsychotic monotherapy. Resource utilisation and costs were described using central Danish registers for a 2 year period (2007-2008). We included patients attached to one of two Danish psychiatric referral centres in 1 January 2008 and/or 1 January 2009. Their prescribed treatment with either antipsychotic polypharmacy or monotherapy at the two cross-sectional dates was recorded and used as proxy of polypharmacy exposure during the preceding year. A multivariate generalised linear model was fitted with total costs of primary and secondary health service use as dependent variable, and antipsychotic polypharmacy, diagnosis, age, gender, disease duration, psychiatric inpatient admissions, and treatment site as covariates. RESULTS The sample consisted of 736 outpatients with a diagnosis in the schizophrenia spectrum. Antipsychotic polypharmacy was associated with significantly higher total health service costs compared with monotherapy (2007: 25% higher costs; 2008: 17% higher costs) when adjusting for potential confounders and risk factors. A subgroup analysis suggested that the excessive costs associated with antipsychotic polypharmacy were partly accounted for by the functional level of the patients. CONCLUSION The results demonstrate that antipsychotic co-prescribing is associated with increased use of health care services, even though no causal relations can be inferred from an observational study.
Collapse
Affiliation(s)
- Lone Baandrup
- Centre for Neuropsychiatric Schizophrenia Research, Copenhagen University Hospital, Mental Health Services - Capital Region of Denmark, Glostrup, Nordre Ringvej 29-67, 2600 Glostrup, Denmark.
| | | | | | | | | |
Collapse
|
|
36
|
&NA;. Systematic practice-based interventions may help reduce the widespread use of antipsychotic polypharmacy. DRUGS & THERAPY PERSPECTIVES 2012. [DOI: 10.2165/11606200-000000000-00000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
|
|
37
|
The sustained effects of aripiprazole-augmented clozapine treatment on the psychotic symptoms and metabolic profiles of patients with refractory schizophrenia. J Clin Psychopharmacol 2012; 32:282-4. [PMID: 22388155 DOI: 10.1097/jcp.0b013e3182485871] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
|
|
38
|
Repo-Tiihonen E, Hallikainen T, Kivistö P, Tiihonen J. Antipsychotic Polypharmacy in Clozapine Resistant Schizophrenia: A Randomized Controlled Trial of Tapering Antipsychotic Co-treatment. Ment Illn 2012; 4:e1. [PMID: 25478102 PMCID: PMC4253370 DOI: 10.4081/mi.2012.e1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2011] [Revised: 11/25/2011] [Accepted: 12/06/2011] [Indexed: 11/30/2022] Open
Abstract
There is a considerable disparity between clinical practice and recommendations based on meta-analyses of antipsychotic polypharmacy in clozapine resistant schizophrenia. For this reason, we investigated the clinical response to reducing the use olanzapine that had been previously added on clozapine treatment among seriously ill hospitalized patients. In a randomized controlled trial with crossover design, we studied volunteer patients (N=15) who had olanzapine added on to clozapine in a state mental hospital. Clozapine monotherapy was just as effective as clozapine-olanzapine therapy, according to results from Clinical Global Impression Scale and Global Assessment of Functioning as primary outcome measures. Polypharmacy is widely used in treating schizophrenia, and usually, add-on medications are started because of worsening of the clinical state. A major confounding feature of these add-ons is whether observed improvements are caused by the medication or explained by the natural fluctuating course of the disorder. The present study, in spite of its small size, indicates the necessity of reconsidering the value of polypharmacy in treating schizophrenia.
Collapse
Affiliation(s)
- Eila Repo-Tiihonen
- Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital , Kuopio
| | - Tero Hallikainen
- Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital , Kuopio
| | - Päivi Kivistö
- Department of Forensic Psychiatry, University of Eastern Finland, Niuvanniemi Hospital , Kuopio
| | | |
Collapse
|
|
39
|
Taylor DM, Smith L, Gee SH, Nielsen J. Augmentation of clozapine with a second antipsychotic - a meta-analysis. Acta Psychiatr Scand 2012; 125:15-24. [PMID: 22077319 DOI: 10.1111/j.1600-0447.2011.01792.x] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
OBJECTIVE To examine using meta-analysis the effect of adding a second antipsychotic to established clozapine monotherapy. METHOD A literature search was conducted in April 2011, and randomised placebo-controlled double-blind studies were identified. We performed a meta-analysis of efficacy (as standardised mean difference) and tolerability (withdrawals from trials) and a regression analysis of duration of study versus effect size. We also examined publication bias using funnel-plot analysis. RESULTS Overall, 14 studies were included (734 subjects). Individual study numbers ranged from 10 to 207 (mean 52.6, median 40). Augmentation of clozapine with a second antipsychotic conferred a small benefit over placebo (effect size -0.239 (95% CI: -0.452, -0.026); P = 0.028). Meta-regression of the effect of length of treatment on effect size showed no relationship (P = 0.254). The risk of discontinuing antipsychotic augmentation was no greater than the risk of discontinuing placebo (RR = 1.20, 95% CI 0.80-1.82). There was no evidence of publication bias. CONCLUSION Augmentation with a second antipsychotic is modestly beneficial in patients not responding fully to clozapine. Tolerability seems not to be adversely affected, at least in the short term. Longer studies do not appear to increase the probability of showing positive effects for augmentation.
Collapse
Affiliation(s)
- D M Taylor
- Pharmacy Department, Maudsley Hospital, London, UK.
| | | | | | | |
Collapse
|
|
40
|
Oh SY, Kim YK. Adjunctive treatment of bimodal repetitive transcranial magnetic stimulation (rTMS) in pharmacologically non-responsive patients with schizophrenia: a preliminary study. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:1938-43. [PMID: 21840364 DOI: 10.1016/j.pnpbp.2011.07.015] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2011] [Revised: 07/29/2011] [Accepted: 07/29/2011] [Indexed: 11/26/2022]
Abstract
OBJECTIVES We evaluated the efficacy of bimodal repetitive transcranial magnetic stimulation (rTMS) in treating pharmacologically non-responsive patients with schizophrenia. METHODS Ten patients with DSM-IV schizophrenia, unresponsive to pharmacological treatment, underwent treatment with 15 rTMS sessions, as an adjunctive therapy, for three weeks. Each session comprised 40 trains, beginning every 30s: 20 trains of 10 Hz rTMS to the left dorsolateral prefrontal cortex (DLPFC) with a 3-s duration and 20 trains of 1 Hz rTMS to the left temporoparietal cortex (TPC) with a 30-s duration. We assessed patients via the Positive and Negative Syndrome Scale (PANSS) and Korean Version of the Calgary Depression Scale for Schizophrenia (K-CDSS), at five time points: baseline, Days 8, 15, and 22, and 1 week after final treatment (Day 29). Patients who agreed to take neurocognitive tests underwent neurocognitive function evaluations at baseline and 1 week after final treatment. RESULTS At Day 29, all PANSS subscale scores in had decreased significantly compared to baseline (Z=-2.214, p=0.027, positive; Z=-2.132, p=0.033, negative; Z=-2.023, p=0.043, general pathology; Z=-2.371, p=0.018, total). Effect over time was significant for the PANSS positive and negative subscale scores and total score (χ(2)=13.35, p=0.010; χ(2)=10.27, p=0.036; and χ(2)=16.50, p=0.002, respectively) but not for the general pathology subscale. Among the neurocognitive tests, the fourth and fifth trials and total K-AVLT scores showed significant increases (Z=-2.041, p=0.041; Z=-2.251, p=0.024; and Z=-2.201, p=0.028, respectively), suggesting improvement in short-term auditory verbal memory. CONCLUSIONS Bimodal rTMS stimulation of left DLPFC and left TPC induced clinical improvement in pharmacologically non-responsive schizophrenia patients and may have improved their short-term verbal memories.
Collapse
Affiliation(s)
- So-Young Oh
- Department of psychiatry, Korea University Ansan Hospital, Gojan 1-dong, Danwon-gu, Ansan, Gyeonggi-do 152-703, Republic of Korea
| | | |
Collapse
|
|
41
|
Citrome L. A systematic review of meta-analyses of the efficacy of oral atypical antipsychotics for the treatment of adult patients with schizophrenia. Expert Opin Pharmacother 2011; 13:1545-73. [DOI: 10.1517/14656566.2011.626769] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
|
|
42
|
Correll CU, Shaikh L, Gallego JA, Nachbar J, Olshanskiy V, Kishimoto T, Kane JM. Antipsychotic polypharmacy: a survey study of prescriber attitudes, knowledge and behavior. Schizophr Res 2011; 131:58-62. [PMID: 21419603 PMCID: PMC3159758 DOI: 10.1016/j.schres.2011.02.016] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Revised: 02/08/2011] [Accepted: 02/15/2011] [Indexed: 02/05/2023]
Abstract
OBJECTIVE Although common in psychiatric practice, reasons for antipsychotic polypharmacy (APP) have remained unclear. METHODS Single-site, semi-structured interview study of prescribers at a psychiatric teaching hospital inquiring about APP attitudes and behaviors, including frequency, preferred combinations, rationale and concerns. RESULTS Forty-four prescribers reported using APP in 17.0 ± 10.0% of antipsychotic-treated patients. Although clinicians themselves initiated APP in only 23.3 ± 27.0% of cases, they did not attempt conversion to antipsychotic monotherapy in 40.9 ± 37.7%, despite reported successful conversion in 28.0 ± 30.8% of cases. The following reasons justified most APP (0-10): cross-titration (9.2 ± 1.4), failed clozapine trial (8.2 ± 2.2), randomized controlled evidence (8.0 ± 2.0), and clozapine intolerance (7.7 ± 2.6). Prescribers felt "moderately" (5.0 ± 1.9) concerned about APP (0-10), mostly due to chronic side effects (7.6 ± 2.0), lack of evidence (7.1 ± 2.2), non-adherence risk (6.7 ± 2.3) and mortality risk (6.7 ± 3.2), while increased cost (4.9 ± 2.5) and higher total antipsychotic dose (4.2 ± 2.9) ranked lowest. Comparing high with low APP prescribers (>10% vs. ≤ 10% of patients; mean: 36.1 ± 19.8 vs. 3.4 ± 3.4, p<0.0001), no differences emerged on 25/26 ratings regarding APP justification and 9/9 ratings regarding concerns. In a multivariate analyses, only attending status (OR=10.3, p=0.0043) and endorsing a specific APP preference (OR=21.4, p=0.011) predicted APP use >10% (r(2):0.35, p<0.0001), yet no uniformly preferred APP strategy emerged. CONCLUSIONS High APP prescribers had more clinical experience, less concerns about APP and more likely a preferred APP choice, although no overall preferred strategy emerged. Otherwise, high and low APP prescribers shared attitudes toward APP. Both had inherited most of their APP cases and were reluctant to convert patients to antipsychotic monotherapy.
Collapse
Affiliation(s)
- Christoph U. Correll
- The Zucker Hillside Hospital, Psychiatry Research, North Shore - Long Island Jewish Health System, Glen Oaks, New York, USA, Albert Einstein College of Medicine, Bronx, New York, USA, The Feinstein Institute for Medical Research, Manhasset, New York, USA
| | - Ladan Shaikh
- The Zucker Hillside Hospital, Psychiatry Research, North Shore - Long Island Jewish Health System, Glen Oaks, New York, USA
| | - Juan A. Gallego
- The Zucker Hillside Hospital, Psychiatry Research, North Shore - Long Island Jewish Health System, Glen Oaks, New York, USA
| | - Jeffrey Nachbar
- The Zucker Hillside Hospital, Psychiatry Research, North Shore - Long Island Jewish Health System, Glen Oaks, New York, USA
| | - Vladimir Olshanskiy
- The Zucker Hillside Hospital, Psychiatry Research, North Shore - Long Island Jewish Health System, Glen Oaks, New York, USA
| | - Taishiro Kishimoto
- The Zucker Hillside Hospital, Psychiatry Research, North Shore - Long Island Jewish Health System, Glen Oaks, New York, USA
| | - John M. Kane
- The Zucker Hillside Hospital, Psychiatry Research, North Shore - Long Island Jewish Health System, Glen Oaks, New York, USA, Albert Einstein College of Medicine, Bronx, New York, USA, The Feinstein Institute for Medical Research, Manhasset, New York, USA
| |
Collapse
|
|
43
|
Abstract
OBJECTIVE Clozapine treatment remains the gold standard for treatment-resistant schizophrenia, but treatment with clozapine is associated with several side-effects that complicate the use of the drug. This clinical overview aims to provide psychiatrists with knowledge about how to optimize clozapine treatment. Relevant strategies for reducing side-effects and increasing the likelihood of response are discussed. METHOD Studies of clozapine available in MEDLINE were reviewed. RESULTS A slow up-titration of clozapine is recommended in order to reach the optimal dosage of clozapine and diminish the risk of dose-dependent side-effects. Particularly, in case of partial response or non-response, the use of therapeutic drug monitoring of clozapine is recommended. Plasma levels above the therapeutic threshold of 350-420 ng/ml are necessary to determine non-response to clozapine. To ease the burden of dose-dependent side-effects, dose reduction of clozapine should be tried and combination with another antipsychotic drug may facilitate further dose reduction. For most side-effects, counteracting medication exists. Augmentation with lamotrigine, antipsychotics, or electroconvulsive therapy may be beneficial in case of partial response to clozapine. CONCLUSION Treatment with clozapine should be optimized in order to increase the rate of response and to minimize side-effects, thus diminishing the risk of discontinuation and psychotic relapse.
Collapse
Affiliation(s)
- J Nielsen
- Unit for Psychiatric Research, Aalborg Psychiatric Hospital, Aarhus University Hospital, Denmark.
| | | | | | | |
Collapse
|
|
44
|
De Risio A, Pancheri A, Simonetti G, Giannarelli D, Stefanutto L, Gentile B. Add-on of aripiprazole improves outcome in clozapine-resistant schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2011; 35:1112-6. [PMID: 21447367 DOI: 10.1016/j.pnpbp.2011.03.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2010] [Revised: 03/04/2011] [Accepted: 03/21/2011] [Indexed: 12/16/2022]
Abstract
Although clozapine proved effective in treating 30-50% of the cases of resistant schizophrenia, its clinical use is hampered by significant side effects. To overcome this problem, augmentation with other atypical antipsychotics has been attempted, with conflicting results. A clozapine-aripiprazole combination showed interesting properties, due to the favourable complementary pharmacodynamic receptor profile and to the negligible metabolic interactions. In this retrospective case series, we investigated the change in BPRS scores and metabolic features like BMI, fasting glucose, total and LDL cholesterol, triglycerides, functional outcome HoNOS Rome and PSP scores after aripiprazole augmentation in 16 persons with treatment-resistant schizophrenia who were already treated with clozapine. The results demonstrated a statistically significant improvement in metabolic indices, psychopathology and functional outcome measures from baseline to endpoint (6weeks) after augmentation with aripiprazole. Statistically significant correlations were observed between psychopathological and behavioural measures at baseline and at endpoint. Linear regression analysis defined a tripartite model, in which item HoNOS Rome 11, measuring autonomy in everyday life, explained nearly half of functional outcome PSP score predictive variance, together with BPRS total psychopathology score and HoNOS Rome total social functioning score. Adequately conducted randomised double-blind studies should provide further specific data highlighting the role of a clozapine-aripiprazole combination in improving functional outcome of persons with treatment-resistant schizophrenia.
Collapse
Affiliation(s)
- Alessandro De Risio
- NHS Health Trust n. 10 Veneto Orientale, Unit of Psychiatry of Portogruaro, Via Forlanini 2, 30026 Portogruaro, Venezia, Italy.
| | | | | | | | | | | |
Collapse
|
|
45
|
Abstract
Antipsychotic polypharmacy refers to the co-prescription of more than one antipsychotic drug for an individual patient. Surveys of prescribing in psychiatric services internationally have identified the relatively frequent and consistent use of combined antipsychotics, usually for people with established schizophrenia, with a prevalence of up to 50% in some clinical settings. A common reason for prescribing more than one antipsychotic is to gain a greater or more rapid therapeutic response than has been achieved with antipsychotic monotherapy. However, the evidence on the risks and benefits for such a strategy is equivocal, and not generally considered adequate to warrant a recommendation for its use in routine clinical practice in psychiatry. Combined antipsychotics are a major contributor to high-dose prescribing, associated with an increased adverse effect burden, and of limited value in helping to establish the optimum maintenance regimen for a patient. The relatively widespread use of antipsychotic polypharmacy identified in cross-sectional surveys reflects not only the addition of a second antipsychotic to boost therapeutic response, but also the use of as-required antipsychotic medication (mainly to treat disturbed behaviour), gradual cross-titration while switching from one antipsychotic to another, and augmentation of clozapine with a second antipsychotic where the illness has failed to respond adequately to an optimized trial of clozapine. This review addresses the clinical trial data and other evidence for each of these pharmacological approaches. Also reviewed are examples of systematic, practice-based interventions designed to reduce the prevalence of antipsychotic polypharmacy, most of which have met with only modest success. Guidelines generally agree that if combined antipsychotics are prescribed to treat refractory psychotic illness, this should be after other, evidence-based, pharmacological treatments such as clozapine have been exhausted. Further, their prescription for each patient should be in the context of an individual trial, with monitoring of the clinical response and adverse effects, and appropriate physical health monitoring.
Collapse
Affiliation(s)
- Thomas R E Barnes
- Division of Experimental Medicine,Centre for Mental Health, Imperial College London, Charing Cross Campus, London, UK.
| | | |
Collapse
|
|
46
|
Barnes TRE. Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology. J Psychopharmacol 2011; 25:567-620. [PMID: 21292923 DOI: 10.1177/0269881110391123] [Citation(s) in RCA: 239] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
These guidelines from the British Association for Psychopharmacology address the scope and targets of pharmacological treatment for schizophrenia. A consensus meeting, involving experts in schizophrenia and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from the participants and interested parties, and 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. The practice recommendations presented are based on the available evidence to date, and seek to clarify which interventions are of proven benefit. It is hoped that the recommendations will help to inform clinical decision making for practitioners, and perhaps also serve as a source of information for patients and carers. They are accompanied by a more detailed qualitative review of the available evidence. The strength of supporting evidence for each recommendation is rated.
Collapse
Affiliation(s)
- Thomas R E Barnes
- Centre for Mental Health, Imperial College, Charing Cross Campus, London, UK.
| | | |
Collapse
|
|
47
|
Van Sant SP, Buckley PF. Pharmacotherapy for treatment-refractory schizophrenia. Expert Opin Pharmacother 2011; 12:411-34. [PMID: 21254948 DOI: 10.1517/14656566.2011.528200] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION despite advances in pharmacotherapy of schizophrenia-spectrum disorders, a large percentage of persons with schizophrenia remain at least partially nonresponsive to treatment, leading to increased morbidity/mortality, increased healthcare cost, and poor quality of life for affected individuals. AREAS COVERED this paper comprises a review of recent research in drug therapy for schizophrenia, particularly treatment-refractory schizophrenia, with a focus on research conducted between 2005 and June 2010. Databases that were searched include: Pubmed, CINAHL, Science Direct, Medline and Clinical Trials.gov. Primary search terms were 'treatment-refractory schizophrenia' and 'treatment-resistant schizophrenia', with cross reference to specific agents covered in this article. An objective perspective on current trends in pharmacotherapy for treatment-refractory schizophrenia. We review the available evidence and discuss the strengths and weaknesses of published data in this field. EXPERT OPINION although there have been many advances in pharmacotherapy for schizophrenia, more well-designed trials are required to establish true efficacy and safety of current prescribing trends in clinical practice.
Collapse
Affiliation(s)
- Scott P Van Sant
- Medical College of Georgia, Department of Psychiatry and Health Behavior, Augusta, GA 30912, USA.
| | | |
Collapse
|
|
48
|
Abstract
We describe the pharmacological treatment of schizophrenia and have arranged the manuscript as a simple algorithm which starts from the choice of an antipsychotic drug for an acutely ill patient and concludes with the most important questions about maintenance treatment. In acutely ill patients the choice of drug is mainly based on pragmatic criteria. Among many strategies used for agitated patients, haloperidol plus promethazine is the best examined one. In case of persistent depression or negative symptoms treatment includes antidepressants, and some second-generation antipsychotic drugs (SGAs) have been found somewhat superior to first-generation antipsychotic drugs (FGAs) in these domains. If an antipsychotic is suspected to be ineffective, several factors need to be checked before action is taken. Few trials have addressed strategies such as switching the drug or increasing the dose in case of non-response. Clozapine remains the gold-standard for treatment-refractory patients, while none of the numerous augmentation strategies that have been examined by randomized controlled trials can be generally recommended. Maintenance treatment with antipsychotic drugs effectively reduces relapse rates. Small, not definitive, studies have shown that withdrawing antipsychotics from patients who have been stable for up to 6 yr leads to more relapses than continuing medication. In effect, continuous treatment is more effective than intermittent strategies. The identification of optimum doses for relapse prevention with FGAs has proven difficult, and there is little randomized data on SGAs. Although the randomized evidence on a superiority of depot compared to oral treatment is not ideal, this approach suggests obvious advantages in assuring compliance.
Collapse
|
|
49
|
Zink M, Englisch S, Meyer-Lindenberg A. [Polypharmacy in schizophrenia]. DER NERVENARZT 2010; 82:853-8. [PMID: 21165589 DOI: 10.1007/s00115-010-3196-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND While most guidelines recommend monotherapy with second-generation antipsychotics (SGA) in schizophrenia, the combined application of multiple psychotropic agents is very common, especially in treatment-refractory cases. METHODS This review summarizes the evidence of combined antipsychotic treatment strategies and the augmentation of antipsychotics with mood stabilizers, antidepressants and experimental substances, based on publications accessible in public databases (Medline/Ovid, Google, http://www.clinicaltrials.gov) up to October 2009. RESULTS Polypharmacy aims to address several aspects of treatment resistance and side effects of antipsychotics. Some evidence supports the augmentation of antipsychotics with antidepressants for negative symptoms and comorbid major depressive episodes. The add-on of lithium and mood stabilizers lacks compelling evidence but might be beneficial for specific subgroups. For treatment-resistant cognitive symptoms, cognitive re-mediation seems most promising as no pharmacological add-on strategy has gained convincing evidence so far. Acute dystonic movements should be treated with anticholinergic agents while agitation and anxiety might respond to short-term application of benzodiazepines. Treatment-resistant positive and/or negative symptoms should primarily lead to clozapine monotherapy; the add-on of a second SGA may be considered in single cases. CONCLUSIONS In general, rigorous data on combination therapy in schizophrenia are rare, and further randomized controlled trials (RCT), naturalistic and head-to-head-studies are necessary.
Collapse
Affiliation(s)
- M Zink
- Abteilung fürf Psychiatrie and Psychotherapie, Zentralinstitut für seelische Gesundheit, 68072, Mannheim, Deutschland.
| | | | | |
Collapse
|
|
50
|
Plasma clozapine, norclozapine, and the clozapine:norclozapine ratio in relation to prescribed dose and other factors: data from a therapeutic drug monitoring service, 1993-2007. Ther Drug Monit 2010; 32:438-47. [PMID: 20463634 DOI: 10.1097/ftd.0b013e3181dad1fb] [Citation(s) in RCA: 124] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Therapeutic drug monitoring of plasma clozapine and of its principal plasma metabolite N-desmethylclozapine (norclozapine) (predose or "trough" sample) can help in monitoring adherence, in dose adjustment, and in minimizing the risk of toxicity. To obtain data to assist in the interpretation of analytical results, the results from a clozapine therapeutic drug monitoring service, 1993-2007, have been audited. There were 104,127 samples from 26,796 patients [18,750 (70%) men aged at time of first sample (median, range) 34 (10-89) years, and 7763 (30%) female aged 38 (12-90) years]. Clozapine was not detected (plasma concentration <0.01 mg/L) in 1.5% of samples (prescribed clozapine dose up to 900 mg/d). Plasma clozapine was either below 0.35 mg/L or greater than 0.60 mg/L in 42.5% and 28.4% of samples, respectively; in 0.4% samples plasma clozapine was 2.0 mg/L or more. Although plasma clozapine was broadly related to prescribed dose, there was much variation: 1.2% of samples had plasma clozapine >1.0 mg/L at prescribed clozapine doses up to 150 mg/d (76.2% < 0.35 mg/L), whereas 23.3% of samples had plasma clozapine < 0.35 mg/L at doses of 850 mg/d and over (18.0% > 1.0 mg/L). The highest plasma clozapine and norclozapine concentrations encountered were 4.95 and 2.45 mg/L, respectively. Although the median plasma clozapine:norclozapine ratio was 1.25 at plasma clozapine concentrations < 0.35 mg/L, the median ratio was 2.08 at plasma clozapine concentrations > 1.0 mg/L. Data (median, 10th-90th percentile) for both clozapine and norclozapine by prescribed clozapine dose band are useful in assessing partial adherence. Analysis of the plasma clozapine:norclozapine ratio by clozapine concentration provides clear evidence that clozapine N-demethylation becomes saturated at higher plasma clozapine concentrations and adds urgency to the requirement for dose adjustment should smoking habit change. A clozapine:norclozapine ratio greater then 2 suggests either a nontrough sample, or that clozapine N-demethylation has become saturated.
Collapse
|