AHa is Editor of the World Federation of Societies of Biological Psychiatry (WFSBP) guideline schizophrenia and co-editor of the German S3-guideline schizophrenia. The lack of recent discontinuation studies may be related to ethical considerations, as discontinuation of antipsychotics increases the risk of relapse. Individuals were assessed clinically daily in all studies. . Third, the group under investigation for withdrawal symptoms received a placebo substitute after antipsychotic discontinuation. The effects of abrupt antipsychotic discontinuation in cognitively impaired older persons: A pilot study. In: Higgins JPT, Green S, eds. Furthermore, antipsychotics are used in a variety of other mental illnesses, such as bipolar affective disorder, psychotic depression, and agitation in neurodegenerative disorders. Der zeitliche Zusammenhang zwischen dem Auftreten persistierender extra-pyramidaler Hyperkinesen und Psychoserecidiven nach abrupter Unterbrechung langfristiger neuroleptischer Behandlung chronisch schizophrener Kranken. Future research may also assess the effect antipsychotic withdrawal symptoms on other parameters such as psychosocial functioning and quality of life. 10. Study populations primarily focused on individuals with schizophrenia but diagnostic procedures (e.g., ICD or DSM) were not specified (Table 1). in. They describe research, which finds that people with schizophrenia who are slowly taken off their antipsychotics, have twice the chance of functioning well than those who stay on the same dosage, with no worsening . Withdrawal symptoms appear to occur frequently after abrupt discontinuation of an oral antipsychotic. Brooks did not include nine other individuals with mild reactions. He was member of an advisory board of Janssen, Lundbeck, and Otsuka and received payed speakership for scientific talks from these companies. Studies were excluded if there was no information on the exact number of individuals with withdrawal symptoms. After removal of duplicates, 18,043 studies were retrieved through the literature search and screened (Supplement Figure 1). Recent research (4, 5) and schizophrenia guidelines (9) highlight the need for research in this field. doi: 10.1016/S0924-9338(10)71701-6, 3. 1. Study populations primarily focused on individuals with schizophrenia but diagnostic procedures (e.g., ICD or DSM) were not specified (Table 1). The Collaborative Crossover Study Group. doi: 10.1111/j.1365-2125.1976.tb00583.x, 33. These findings suggest that withdrawal symptoms may occur frequently after abrupt discontinuation of oral antipsychotics but the lack of randomized controlled trials with low risk of bias highlights the need for further research. None of the included studies reported a specific standardized clinical assessment procedure for withdrawal symptoms. Moher D, Liberati A, Tetzlaff J, Altmann D G. PRISMA Group. The current NICE guidance on schizophrenia (CG178) relating to safe stopping of antipsychotics only states "If withdrawing antipsychotic medication, undertake gradually and monitor regularly for . 31. To reduce the risk to develop long-term side effects, such as metabolic syndrome or tardive dyskinesia, different guidelines (e.g., by the National Institute for Health and Clinical Excellence in the United Kingdom (10)) recommend dose reduction or in certain cases antipsychotic withdrawal especially after the first psychotic episode. The included studies in this systematic review and meta-analysis did not implement stepwise discontinuation but Greenberg and Roth compared abrupt discontinuation (n = 21 persons) with a stepwise and slow discontinuation over the duration of 336 days (n = 21 persons) of chlorpromazine (initial average dose of 510 mg per day) (40). The Bergen District Nursing Home Study. Chouinard G, Samaha A-N, Chouinard V-A, Peretti C-S, Kanahara N, Takase M, et al. Deeks JJ, Higgins J, Altman DG, Green S. Part1: Cochrane reviews. Number needed to harm (NNH) was calculated for individuals who discontinued the antipsychotic treatment compared with individuals who continued the antipsychotic treatment. doi: 10.1080/13607863.2012.717255, 32. We excluded a total of 114 studies because of the following reasons: withdrawal symptoms were not assessed in 85 studies, 11 studies were case reports, no placebo substitute was implemented in nine studies, only single symptoms such as sleep disorders were assessed in five studies, the clinical assessment interval was not daily in two studies, the observation period was less than 7 days in one study, and no exact number of individuals was reported in one study. March 2019, Available at: https://www.awmf.org/leitlinien/detail/ll/038-009.html. In another study with 34 children, 6 to 12 years of age and diagnosed with schizophrenia, 41% of the children showed involuntary movements and ataxia after withdrawal of different antipsychotics (i.e., fluphenazine, haloperidol, thioridazine, trifluoperazine, and thiothixene) (39). (42), the authors reported that the increased occurrence of dyskinesia was probably related to abrupt antipsychotic withdrawal, but assessment of the disorder by appropriate criteria was lacking (42). Drawing conclusions from this meta-analysis should consider these limitations and results may thus be used as guiding values only. The blue diamond data marker represents the overall proportion and 95% CI. Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, et al. (25), Lacoursiere et al. Inclusion in an NLM database does not imply endorsement of, or agreement with, Alterations in sleep polygraphy after neuroleptic withdrawal: a putative supersensitive dopaminergic mechanism. detected a high rate of individuals with withdrawal symptoms (72%) in a geriatric population (31). Can We Compare Well-Being Across Species? Antipsychotic drugs are increasingly being prescribed to people not diagnosed with schizophrenia, including to children and old people in care. Un programa que dej de tener gracia cuando se. Withdrawal symptoms with a later onset were not investigated in the study by Tollefson et al. 11. The blue diamond data marker represents the overall proportion and 95% CI. Ther Adv Psychopharmacol (2016) 6:1456. In this systematic review and meta-analysis of five studies, the proportion of individuals with withdrawal symptoms after abrupt oral antipsychotic discontinuation was increased. Table 2 Clinical features of abrupt oral antipsychotic withdrawal. Tollefson GD, Dellva MA, Mattler CA, Kane JM, Wirshing DA, Kinon BJ. However, it is not known whether dose effects would be detected if lower dosages would be included in the analyses (8). The vertical dashed line shows the summary effect estimate. Results: After controlling for multiple potential confounding factors, terminal insomnia was associated with significant, 2.7-fold increased odds of current suicidal ideation (OR = 2.7, 95% CI = 2.0-3.6, P < .001). reported that all individuals with vegetative withdrawal symptoms and/or hyperkinesia also worsened in psychopathological scores (25). (42), the authors reported that the increased occurrence of dyskinesia was probably related to abrupt antipsychotic withdrawal, but assessment of the disorder by appropriate criteria was lacking (42). However, it is not known whether dose effects would be detected if lower dosages would be included in the analyses (8). Heterogeneity among the included trials was high (I2 = 82.98%, P < 0.01; Figure 1). The sensitivity analyses supported the results of the main analysis and showed a weighted average of 49% in the target group versus 11% in the control group, an odds ratio of 7.97, and NNH of 3. Regarding the antipsychotic treatment before discontinuation, the inclusion of studies was not restricted to a specific duration of antipsychotic treatment. Cerovecki A, Musil R, Klimke A, Seemller F, Haen E, Schennach R, et al. In: Trimble MR, editor. Psychiatry 11:569912. doi: 10.3389/fpsyt.2020.569912. Antipsychotic Withdrawal SyndromeAlthough not widely recognized, withdrawal symp-toms can occur on the cessation of both first- and sec-ond-generation antipsychotics (FGAs and SGAs).17,20,23 These symptoms can be grouped into somatic symptoms (nausea, sweating, etc. The horizontal lines indicate 95% CIs. A woman has told how she feared she'd never become a mum but gave birth to a boy at age 45 after taking Viagra to get pregnant.. Carin Rockind, 48, welcomed a "miracle" baby after trying to have a . Three out of the five eligible studies (studies by Degkwitz et al. Based on these limited findings, it could be hypothesized that the long acting kinetic properties with a very slow decrease of antipsychotic dosage over weeks may reduce the occurrence of withdrawal symptoms similar to the stepwise reduction in the study by Greenberg and Roth. Individuals with antipsychotic withdrawal symptoms typically do not fulfil the addiction criteria as defined by the International Classification of Diseases (ICD-10 (11, 16). The protocol for this systematic review and meta-analysis has a priori been published (PROSPERO registration no. Heterogeneity among studies was assessed with I2 statistics. Moher D, Liberati A, Tetzlaff J, Altmann D G. PRISMA Group. The current match involves a Texas lawsuit . Antipsychotics are primarily used in the treatment of psychotic disorders, which are in most cases associated with delusions and hallucinations (1). The effect sizes should still be considered as guiding estimates and not exact values due to high risk of bias. In comparison, the control group only showed a weighted mean of 0.11 (95% CI, 0.030.19) after continuation of oral antipsychotic treatment. Studies were excluded if they did not report daily clinical assessments of the individual (i.e., clinical assessment interval) because short lasting withdrawal symptoms previously reported in antipsychotics (4) and other psychopharmacological compounds such as antidepressants (12) otherwise may be missed. The sensitivity analysis was limited to three studies with a target and a control group and total of 162 individuals (Figure 2). Battegay (23) reported a significantly higher rates of withdrawal symptoms in women and the age group above 50 years after discontinuation of different antipsychotics (23). No significant effect of dosage on the type and severity of withdrawal symptoms was reported in two other studies (last medication: reserpine 1.54 mg per day and/or chlorpromazine 150600 mg per day) (8, 24). Around 44 percent had a diagnosis in the schizophrenia spectrum. So the issues discussed in my most recent research paper are relevant to far more people than one might imagine. Individuals in the target group of all included studies had discontinued antipsychotics abruptly. Drafting of the manuscript: LB, AHa, AHe, and SG. Adam K, Allen S, Carruthers-Jones I, Oswald I, Spence M. Mesoridazine and human sleep. Five articles, published between 1959 and 1976, met the inclusion criteria for the quantitative analysis (Table 1). Emsley R, Nuamah I, Gopal S, Hough D, Fleischhacker WW. Nervenarzt (1967) 4:1704. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Articles were included when they fulfilled the following criteria. The vertical dashed line shows the overall effect estimate, and the continuous line represents the line of no effect (OR = 1). The square data markers indicate the proportion of individuals with withdrawal symptoms in each study, with sizes reflecting the statistical weight of the study using random-effects meta-analysis of proportions. Studies with assessments of only single symptoms such as a sleep disorder were excluded. Greenberg LM, Roth S. Differential effects of abrupt versus gradual withdrawal of chlorpromazine in hospitalized chronic schizophrenic patients. But there has been less interest in what happens when people reduce or stop their antipsychotic drugs. All cohorts with discontinuation of other medication than antipsychotics were also excluded from the sensitivity analysis. Aging Ment Health (2013) 17:12532. Studies that did not implement placebo substitution were excluded from analyses. Cochrane Bias Methods GroupCochrane Statistical Methods Group. No use, distribution or reproduction is permitted which does not comply with these terms. First, occurrence of antipsychotic withdrawal symptoms was assessed quantitatively. Five studies with a total of 261 individuals were included. Suicidal Behaviors Are Associated With Psychopathology. Schizophr Bull (1996) 22:5915. reported separate results for cohorts with additional antiparkinson agents. Taschenfhrer zur ICD-10-Klassifikation psychischer Strungen. First, occurrence of antipsychotic withdrawal symptoms was assessed quantitatively. Degkwitz R, Bauer MP, Gruber M, Hampel G, Luxenburger O, Richartz M, et al. However, clinical data is partly based on trials from prior to the 1980s (8). These mild reactions were not specified and also excluded from our analysis. Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy. The tour begins on Aug. 3 in Sterling . doi: 10.4088/JCP.v59n0906, 38. Edited by: Maria Rosaria Anna Muscatello, University of Messina, Italy, Reviewed by: Takefumi Suzuki, University of Yamanashi, Japan; Stefania Schiavone, University of Foggia, Italy, This article was submitted to Psychopharmacology, a section of the journal Frontiers in Psychiatry. and transmitted securely. Risk of bias was assessed independently by two MDs (LB, SG). Title, abstracts, and key words were searched with terms for antipsychotic compounds and withdrawal or discontinuation: ([terms for specific antipsychotic compounds separated by OR] OR antipsychotic* OR neuroleptic*) AND (discontinu* OR withdraw*). Although antipsychotic medications are traditionally associated with people who have been diagnosed with "schizophrenia spectrum" disorders, they are increasingly prescribed for a range of other diagnoses as well as to children, older people, and prisoners. doi: 10.1177/070674376601100507, 27. The .gov means its official. 11. The studies in the main quantitative analysis were characterized by high risk of bias due to methodological heterogeneity, discontinuation of different antipsychotic and non-antipsychotic compounds, and considerable missing information. No significant effect of dosage on the type and severity of withdrawal symptoms was reported in two other studies (last medication: reserpine 1.54 mg per day and/or chlorpromazine 150600 mg per day) (8, 24). This systematic review and meta-analysis confirmed the initial assumption that withdrawal symptoms occur frequently after abrupt antipsychotic discontinuation. DGPPN e.V. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). Withdrawal of antipsychotic agents from older, often frail, people with dementia and NPS might improve cognitive function, quality of life (QoL) of people with dementia and their carers, and decrease mortality and adverse events (e.g. (26); Table 1) in the quantitative analysis had implemented a double-blinded design, setting the participants to placebo (i.e., target group) or to continuation of antipsychotic treatment (i.e., control group). 25. We included terms for all antipsychotic compounds classified in the The Anatomical Therapeutic Chemical (ATC) classification system by the WHO Collaborating Centre for Drug Statistics Methodology (Supplement Section 1 search entry) (20). We followed guidelines by the Cochrane Collaboration, PRISMA, andMOOSE. Cholinergic rebound and rapid onset psychosis following abrupt clozapine withdrawal. Relapse After Antipsychotic Discontinuation in Schizophrenia as a Withdrawal Phenomenon vs Illness Recurrence. The proportion of individuals with withdrawal symptoms may further differ according to characteristics of individuals such as age, sex, and specific types of antipsychotic drugs (23). The findings from this meta-analysis indicate that withdrawal symptoms after abrupt antipsychotic discontinuation occur frequently. Neurological consequences of psychotropic drug withdrawal in schizophrenic children. 30. also reported a higher rate of withdrawal symptoms in women (30) and Azermai et al. Administrative, technical, or material support: LB, TB, MM, and SG. DGPPN e.V. CPlacebos biased by not completely identical taste in the study by Degkwitz et al. Higgins JPT, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. Dixon L, Thaker G, Conley R, Ross D, Cascella N, Tamminga C. Changes in psychopathology and dyskinesia after neuroleptic withdrawal in a double-blind design. We acknowledge support from the German Research Foundation (DFG) and the Open Access Publication Fund of Charit Universittsmedizin Berlin. All studies showed a high risk of bias according to Cochrane Collaborations tool for assessing risk of bias (Table 1) (21). No individuals in the included studies discontinued antipsychotics stepwise (also known as tapered discontinuation). An odds ratio of 7.97 (95% CI, 2.3926.58; I2 = 82.7%, P = 0.003) and NNH of 3 was calculated for the occurrence of withdrawal symptoms after antipsychotic discontinuation. Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, et al. Emsley R, Nuamah I, Gopal S, Hough D, Fleischhacker WW. Abrupt withdrawal of haloperidol was associated with a significant increase in dyskinesia beginning in the second week post-withdrawal in a study with fifteen participants with schizophrenia (36). The Collaborative Crossover Study Group. Large high quality randomized controlled trials with a focus on discontinuation with antipsychotics are needed. Indications for withdrawing antipsychotics Antipsychotic medication iseffective in the treatment andprophylaxis of psychotic illness. Two atypical antipsychotics drugs of olanzapine and quetiapine have long-term efficacy in managing chronic insomnia. I feel obliged to end by saying that antipsychotics, like other psychiatric drugs, can be helpful for some people, especially if used for relatively short periods and if people are given enough information to make an informed choice about whether and for how long to take them. Individuals with antipsychotic withdrawal symptoms typically do not fulfil the addiction criteria as defined by the International Classification of Diseases (ICD-10 (11, 16). Included studies on the occurrence of withdrawal symptoms after abrupt antipsychotic discontinuation. Sterne JAC, Sutton AJ, Ioannidis JPA, Terrin N, Jones DR, Lau J, et al. (London: National Institute for Health and Care Excellence (UK)); 2014. https://www.nice.org.ukguidancecgresourcespsychosis-andschizophrenia-in-adults-prevention-and-management-pdf-. Table 1 Included studies on the occurrence of withdrawal symptoms after abrupt antipsychotic discontinuation. Food Insecurity Makes Disordered Eating More Likely, The Power of Plants to Help Children Focus, The Intersection of Trauma and Eating Disorders, How Machiavellianism Sways College Major Selection. The clinical effects of the individual compounds are diverse, since receptor affinity is an important factor for the efficacy, but especially for the side effect profile (3) and possibly for the withdrawal symptoms (4). Degkwitz R, Binsack KF, Herkert H, Luxenburger O, Wenzel W. Zum Problem der persistierenden extrapyramidalen Hyperkinesien nach langfristiger Anwendung von Neuroleptika [On the problem of persistent extrapyramidal hyperkinesia following prolonged use of neuroleptics]. FOIA Heinz A, Daedelow LS, Wackerhagen C, Di Chiara G. Addiction theory matters-Why there is no dependence on caffeine or antidepressant medication. Hogrefe, vorm. When sleep medications are used for sleep disturbances related to other causes, supporting evidence is indirect. Norwegian Institute of Public Health. The horizontal lines indicate 95% CIs. The outcome of the sensitivity analysis was the pooled odds ratio (OR) for individuals who discontinued the antipsychotic treatment compared with individuals who continued the antipsychotic treatment. doi: 10.3238/arztebl.2019.0355, 13. PostedMarch 25, 2022 "Covert dyskinesia" refers to a masked form of tardive dyskinesia that becomes clinically detectable only after antipsychotic drugs are withdrawn or their dosage is . Antidepressants, mood stabilizers, and atypical antipsychotic drugs can inhibit serotonin-based regulation of the appetite function. Individuals were assessed clinically daily in all studies. The database search included CENTRAL, Pubmed, and EMBASE with no restriction to the beginning of the searched time period and until October 1, 2019. Cerovecki A, Musil R, Klimke A, Seemller F, Haen E, Schennach R, et al. The contrast between the RCT and the included studies in this meta-analysis may be due to the fact that placebo was administered for three to five days and potential withdrawal symptoms could only be observed in this shorter period of time. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Below, check out the tour dates, as well as a weird tour . doi: 10.1016/0002-9343(87)90371-8. All cohorts with discontinuation of other medication than antipsychotics were also excluded from the sensitivity analysis. Little is known about the effect of withdrawal symptoms on the occurrence of adverse events in clinical trials with antipsychotics and more research is needed to elucidate this potentially critical effect. This finding also has implications for the design and interpretation of clinical trials with antipsychotics. DIndividuals with paranoid, undifferentiated, catatonic, or hebephrenic schizophrenia and one individual with acute schizophrenic reaction. CRD42019119148). Neurological consequences of psychotropic drug withdrawal in schizophrenic children, Differential effects of abrupt versus gradual withdrawal of chlorpromazine in hospitalized chronic schizophrenic patients. Version 5.1.0. Part1: Cochrane reviews. The IIPDW subse-quently submitted the following request, drafted on their behalf by threeresearchers with expertise in thiseld, that NICE review its decision to excludeantipsychotics. Horowitz MA, Taylor D. Tapering of SSRI treatment to mitigate withdrawal symptoms. The Anatomical Therapeutic Chemical (ATC) classification system. The primary finding of the study was that 72 percent reported classic withdrawal effects when trying to reduce or stop, including nausea, tremors, anxiety, agitation, and headaches. We performed a systematic review and meta-analysis concerning occurrence of withdrawal symptoms after discontinuation ofantipsychotics. These findings demonstrate that attributing a particular symptom to either withdrawal or the beginning of a psychotic relapse can be a complex task (4, 5, 27) and emphasizes the need for further psychopathological assessment and a close monitoring of the development of the symptoms. In this systematic review and meta-analysis of five studies, the proportion of individuals with withdrawal symptoms after abrupt oral antipsychotic discontinuation was increased. Little is known about the effect of withdrawal symptoms on the occurrence of adverse events in clinical trials with antipsychotics and more research is needed to elucidate this potentially critical effect. J Clin Psychiatry (2018) 79:19. Reviewed by Davia Sills. Furthermore, specific tapering strategies to reduce the risk of withdrawal symptoms were recently recommended for antidepressants: For example, Horowitz and Taylor (43) proposed a slow and hyperbolical taper strategy to mitigate SSRI withdrawal symptoms (43). (Hrsg.) Of the 18,043 screened studies, controlled and cohort trials that assessed withdrawal symptoms after discontinuation of oral antipsychotics were included in the random-effects model. The square data markers indicate the proportion of individuals with withdrawal symptoms in each study, with sizes reflecting the studys statistical weight using random-effects meta-analysis of proportions. Drafting of the manuscript: LB, AHa, AHe, and SG. doi: 10.1093/schbul/22.4.591. Withdrawal symptoms with a later onset were not investigated in the study by Tollefson et al. Future research may address effects of antipsychotic withdrawal in different psychiatric diagnoses and take into account whether effects are dependent on dose or duration of antipsychotic treatment and pharmacological characteristics such as elimination half-life or anticholinergic properties. fr die Leitliniengruppe: S3-Leitlinie Schizophrenie. Br J Clin Pharmacol (1976) 3:15763. Trying to come off was exhausting - my mood swings came back with a vengeance. sharing sensitive information, make sure youre on a federal The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Statistical analysis: LB, JH, MM, and SG. In the sensitivity analysis, only studies with an allocation of individuals to a target group that received a placebo substitute after antipsychotic discontinuation or a control group that continued antipsychotic treatment were included. Cohorts with discontinued other medication than antipsychotics were not included in the sensitivity analysis. Heterogeneity among the included trials was high (I2 = 82.98%, P < 0.01; Figure 1). Withdrawing from antipsychotics: an analysis Withdrawing from antipsychotic medication can take months or even years to complete, as patients need to reduce their doses very gradually, according to analysis by King's College London and UCL academics. The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fpsyt.2020.569912/full#supplementary-material. He was member of an advisory board of Janssen, Lundbeck, and Otsuka and received payed speakership for scientific talks from these companies. The Cochrane Collaboration (2011). Are antipychotics more difficult then benzos/antidepressants or the other way around? Discrepancies were resolved by consensus with additional review authors (JH, MM). Shiovitz TM, Welke TL, Tigel PD, Anand R, Hartman RD, Sramek JJ, et al. After removal of duplicates, 18,043 studies were retrieved through the literature search and screened (Supplement Figure 1). The primary outcome was the proportion of individuals with withdrawal symptoms after antipsychotic discontinuation. Higgins JPT, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, et al. National Collaborating Centre for Mental Health (UK). Heinz A, Daedelow LS, Wackerhagen C, Di Chiara G. Addiction theory matters-Why there is no dependence on caffeine or antidepressant medication, Antidepressant Withdrawal and Rebound Phenomena, Chlorpromazine in nonpsychotic patients with pulmonary tuberculosis, Drug Discontinuation Effects Are Part of the Pharmacology of a Drug, Rebound hypertension after discontinuation of transdermal clonidine therapy. Brooks focused on withdrawal symptoms that were of at least moderate degree, i.e., marked and distressing, which he detected in 17 individuals. Histaminergic: Irritability, insomnia, agitation, loss of appetite or nausea, tremulousness, incoordination, lethargy, and amnesia. Not completely identical taste in the analyses ( 8 ) ( DFG and! 18,043 studies were retrieved through the literature search and screened ( Supplement 1! ) and schizophrenia guidelines ( 9 ) highlight the need for research in this systematic review and confirmed! Inclusion criteria for the quantitative analysis ( table 1 included studies had discontinued stepwise. 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