Cited by 246Schizophrenia research and treatmentBipolar Disorder and TreatmentMental Health and Psychiatry

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Clinical Risk Following Abrupt and Gradual Withdrawal of Maintenance Neuroleptic Treatment

Viguera, Adele C.·1997·Archives of General Psychiatry

DOI 10.1001/archpsyc.1997.01830130055011

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Abstract

BACKGROUND: Abrupt discontinuation of long-term psychotropic medication can be followed by a high risk of early relapse. This study aimed to quantify the relapse risk over time in patients with schizophrenia following discontinuation of maintenance neuroleptic treatment. METHODS: Data on the timing of relapses in patients with schizophrenia after withdrawal from neuroleptic therapy were located by a computerized literature search, combined with new data, and evaluated by survival analysis. RESULTS: Data were found for 1210 schizophrenic subjects: 1006 (795 inpatients and 211 outpatients) were withdrawn abruptly from oral neuroleptic therapy, and 204 discontinued treatment gradually (> or = 3 weeks) or stopped treatment with depot neuroleptic drugs. After abrupt discontinuation of oral medication, the risk of relapse reached 50% within 30 weeks, with remarkably little additional risk thereafter to 3.7 years; inpatients relapsed more rapidly than did outpatients (10 vs 18 weeks to a 25% relapse risk). In studies including subjects whose drug therapy was withdrawn abruptly (n = 49) vs gradually (n = 58), relapse was earlier after abrupt discontinuation (25% risk in 6 vs 10 weeks), with a persistent difference for at least 6 months. CONCLUSIONS: The relapse risk was high within 6 months of discontinuing oral neuroleptic therapy, particularly in hospitalized patients. Most patients who remained stable for 6 months continued to do so for long periods without medication, indicating clinical heterogeneity. Drug-withdrawal stressors, related to long-term pharmacodynamic adaptations, are implicated. Since the risk was lower after gradually discontinuing oral neuroleptic therapy or stopping depot injections, early relapse may be spared by a slow removal of drugs.

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“They were also less likely to report experiencing relapse of psychosis or mania during withdrawal, consistent with an earlier meta-analysis that set the threshold for gradual withdrawal at three weeks or more (Viguera et al., 1997), but inconsistent with a more recent meta-analysis using the same three-week definition…”
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Hutton, P., Morrison, A. P., Yung, A. R., Taylor, P. J., French, P., & Dunn, G. (2012) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.2012.01858.x · Cited by 26
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Including Children and Adolescents With Schizophrenia in Medication-Free Research
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“For patients who did not receive any treatment, the relapse rate was based on data from a study conducted by Viguera et al.28, where higher relapse rates were reported in patients without treatment.”
Method
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van Meijel, B., van Meijel, B., Kahn, R. S., & Grypdonck, M. (2002) · Journal of Psychiatric and Mental Health Nursing · doi:10.1046/j.1365-2850.2002.00500.x · Cited by 25
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“…mg/day) or placebo for 12 months; included patients were stably remitted on antipsychotics for 12 months; patients in the maintenance arm relapsed in 41% [95% confidence interval (CI) 29–53] against 79% (95% CI 68– 90) in the discontinuation arm, though relapse criteria were very low threshold.”
Background
Impact of Side-Effects of Atypical Antipsychotics on Non-Compliance, Relapse and Cost
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“The speed at which medication should be reduced is still unknown, although from the review study of Viguera et al. (1997) it seems that patients discontinuing treatment gradually (> 3 weeks) have a lower risk of relapse than those being withdrawn from oral neuroleptic therapy abruptly.”
Background
Gradually tapering off antipsychotics: lessons for practice from case studies and neurobiological principles
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Spielmans, G. I., & Kirsch, I. (2013) · Annual Review of Clinical Psychology · doi:10.1146/annurev-clinpsy-050212-185533 · Cited by 21
“…relapse following medication discontinuation is not unique to antidepressants; similar phenomena have also been observed after removal of popularly used medications in bipolar and psychotic disorders (Franks et al. 2008, Goodwin et al. 2011, Moncrieff 2006, Tsai et al. 2011, Viguera et al. 1997).”
Background
Addressing non‐adherence to antipsychotic medication: a harm‐reduction approach
ALDRIDGE, M. A. (2011) · Journal of Psychiatric and Mental Health Nursing · doi:10.1111/j.1365-2850.2011.01809.x · Cited by 21
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“I am aware that many of the studies showing greater rates of relapse for people on placebo(20) are abrupt withdrawal studies, whereas gradual withdrawal, following sound pharmacological principles, has a much lower rate of relapse.(21) I have found out that antipsychotics cause a discontinuation syndrome that can be c…”
Background
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“Medication nonadherence has been found to result in deterioration of social function, relapse, rehospitalization, poor outcome, and high economic costs (Casper and Regan, 1993; Weiden and Olfson, 1995; Viguera et al, 1997; Bergen et al, 1998).”
Background
The effects of abrupt antipsychotic discontinuation in cognitively impaired older persons: A pilot study
Azermai, M., Petrović, M., Engelborghs, S., Elseviers, M. M., der Mussele, S. V., Debruyne, H., Bortel, L. M. V., & Stichele, R. V. (2012) · Aging & Mental Health · doi:10.1080/13607863.2012.717255 · Cited by 19
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“In this context, Baldessarini and colleagues have introduced the notion of pharmacologic stress factors (Suppes et al., 1997; Viguera et al., 1997) into the debate on neuroleptic and lithium discontinuation syndromes.”
Background
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“There is a known paradox in discontinuation studies: while up to 50% of patients with schizophrenia relapse by 6–10 months following discontinuation, those who remain stable during the first few months post-discontinuation are much less likely to relapse subsequently (Viguera et al., 1997).”
Background
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Background
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Jeste, D. V., Palmer, B. W., & Harris, M. J. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(99)00208-5 · Cited by 17
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“gradual discontinuation), the definition of relapse, and the follow-up duration or treatment in the maintenance group [76].”
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“potential for withdrawal symptoms and rebound effects [5] and carries a greater risk for relapse than more gradual withdrawal [44].”
Background
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Rabin, C. R., & Siegel, S. J. (2012) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-25761-2_11 · Cited by 14
“department visits, rehospitalization, and deterioration in social function (Adams and Howe 1993; Bergen et al. 1998; Casper and Regan 1993; Cramer and Rosenheck 1998; Rittmannsberger et al. 2004; Valenstein et al. 2001; Viguera et al. 1997; Weiden and Olfson 1995).”
Background
Discontinuing psychotropic agents
Baldessarini, R. J., Viguera, A. C., & Tondo, L. (1999) · Journal of Psychopharmacology · doi:10.1177/026988119901300314 · Cited by 14
“We have presented evidence that such responses follow rapid discontinuation of lithium in manic depressive disorders (Baldessarini and Tondo, 1998), neuroleptics in schizophrenia (Viguera et al., 1997), and antidepressants in recurrent major depression (Viguera et al., 1998).”
Background
The Physician/Investigator's Obligation to Patients Participating in Research: The Case of Placebo Controlled Trials
Glass, K. C., & Waring, D. R. (2005) · The Journal of Law Medicine & Ethics · doi:10.1111/j.1748-720x.2005.tb00520.x · Cited by 14
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“Fifty to 75 percent of stable patients who discontinue antipsychotic medications relapse within a year (2,3,4,5), and current practice guidelines recommend long-term maintenance treatment for most patients (6).”
Background
Commentary on strategies for switching antipsychotics
Davis, J. M., & Leucht, S. (2008) · BMC Medicine · doi:10.1186/1741-7015-6-18 · Cited by 13
“It is less clear whether this occurs with other antipsychotic drugs [2].”
Background
Systematic review of involuntary hospitalisation and long-term compliance
Cossu, G., Gyppaz, D., Kalcev, G., Manca, A. R., Angermeyer, M., Zreik, T., & Carta, M. G. (2023) · International Review of Psychiatry · doi:10.1080/09540261.2022.2119074 · Cited by 13
“On the other hands it is likely that people who have undergone involuntary hospitalisation already tended to have poor compliance known as risk factor for involuntary admission (Walker et al., 2019).”
Background
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Bressington, D. T., & White, J. (2015) · Journal of Psychiatric and Mental Health Nursing · doi:10.1111/jpm.12249 · Cited by 14
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Lincoln, T. M., Sommer, D., Quazzola, M., Witzgall, T., & Schlier, B. (2021) · Psychological Medicine · doi:10.1017/s0033291721005146 · Cited by 11
“Some studies have tested whether gradual or abrupt discontinuation is more effective, with most (Baldessarini, Tondo, Ghiani, & Lepri, 2010; Groot & van Os, 2020; Viguera, 1997) but not all (Batelaan et al.”
Background
Guidelines for Discontinuation of Antipsychotics in Patients Who Recover From First-Episode Schizophrenia Spectrum Disorders: Derived From the Aggregated Opinions of Asian Network of Early Psychosis Experts and Literature Review
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“Some 34 but not all 71 publications support this assertion, showing that most relapses occur many months and years after discontinuation rather that shortly after discontinuation.”
Result
Poor Adherence to Antipsychotic Medication in People with Schizophrenia: Diffusion, Consequences and Contributing Factors
Sacchetti, E., & Vita, A. (2013) · Springer eBooks · doi:10.1007/978-88-470-2679-7_1 · Cited by 11
“of treatment with antipsychotics for any reason has been reported to occur in almost 50 % of cases within the first 2 months [25, 204] and the immediate postdischarge period has been associated with heightened risk for non-compliance [84, 85, 205, 206].”
Background
Psychopharmacoteratophobia: Excessive fear of malformation associated with prescribing psychotropic drugs during pregnancy: An Indian perspective
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“Attempt has been made as to how a psychotropic medication may be discontinued,[50,51] in such situation, an appropriate approach may be: • If the patient is asymptomatic for more than 6 months and on single medication ‐ If the medication is a high potency then quarter dose reduction weekly with continuous observation…”
Background
Impact of depression and social support on nonadherence to antipsychotic drugs in persons with schizophrenia in Thailand
Suttajit (2010) · Patient Preference and Adherence · doi:10.2147/ppa.s12412 · Cited by 11
“Nonadherence often leads to negative consequences, including relapse, rehospitalization, poor functional outcomes, and suicide.(3,4) Several factors have been found to be associated with nonadherence, including illness-related factors (eg, severity of symptoms, insight, duration of illness), treatmentrelated factors (…”
Antipsychotic Drugs: When and How to Withdraw Them?
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Nonresponse of Adrenocorticotropic Hormone in First-Ever Lactate-Induced Panic Attacks in Healthy Volunteers
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Sudden discontinuation and reinstitution of olanzapine-associated atypical neuroleptic malignant syndrome in a patient undergoing lung surgery.
Zhao, Z., Zhang, H., Wang, S., & Chen, X. (2015) · PubMed Central · Cited by 10
Switching to Amisulpride
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Pharmacological strategies for relapse prevention in schizophrenia
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Helping people to discontinue antipsychotics: if, when and how
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“In one meta-analysis, 50% of relapses occurred in the ﬁ rst three months following switch to placebo, for example 39 .”
Attitudes of patients and family members towards implantable psychiatric medication
Dankert, M. E., Brensinger, C. M., Metzger, K. L., Li, C., Koleva, S. G., Mesén, A., LaPrade, B., Wiguna, T., Han, C., Farooq, S., et al. (2008) · Schizophrenia Research · doi:10.1016/j.schres.2008.05.008 · Cited by 8
“Poor medication adherence leads to poor function, relapse, and rehospitalization (Adams and Howe, 1993; Casper and Regan, 1993; Weiden and Olfson, 1995; Viguera et al., 1997; Bergen et al., 1998; Cramer and Rosenheck, 1998; Valenstein et al., 2001; Rittmannsberger et al., 2004).”
Background
Reducing Off-Label Antipsychotic Use in Older Community-Dwelling Adults With Dementia: A Narrative Review
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“discontinuation or rapid reduction of an antipsychotic is associated with greater risk of adverse drug withdrawal events than gradual reduction over several weeks.(4,46) Therefore, a gradual dose reduction may not only alleviate adverse drug withdrawal events, but may lead to more favorable outcomes.”
Background
Schizophrenia and Related Psychoses
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Relapse prevention in patients with schizophrenia : A nursing intervention study
van Meijel, B. (2003) · Utrecht University Repository (Utrecht University) · Cited by 7
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“Nonadherence to antipsychotic medication treatment leads to several clinically relevant outcomes, including psychotic relapse, increased clinic and emergency department visits, rehospitalization, and deterioration in social function (Adams and Howe 1993; Bergen et al. 1998; Casper and Regan 1993; Cramer 1998; Rittmann…”
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“A substantial proportion of studies employed abrupt discontinuation of oral antipsychotic medication which increased relapse rate compared to gradual withdrawal, particularly in the first 6 months following discontinuation (Viguera et al., 1997).”
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“Most of the comparison groups used in these studies consist of patients who are switched rather abruptly to placebo following the acute treatment phase, which further increases their relapse risk (Viguera et al., 1997).”
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“Psychological decompensation if the treatment is interrupted are not uncommon and can result in severe maternal and fetal complications like premature delivery, fetal growth retardation [9,10].”
Background

Authors: Viguera, A. C.
Affiliations: Harvard University (US)
Corresponding author: Viguera, Adele C.
ORCID: Viguera, Adele C.
Venue: Archives of General Psychiatry
Publisher: American Medical Association (AMA)
Published: 1997-01-01
Volume: 54
Issue: 1
Pages: 49
ISSN: 0003-990X (ISSN-L)
DOI: 10.1001/archpsyc.1997.01830130055011
OpenAlex: W2153434361
Cited by: 246
References: 49
Citations by year: 2026: 1 · 2025: 3 · 2024: 6 · 2023: 6 · 2022: 5 · 2021: 9 · 2020: 10 · 2019: 10 · 2018: 10 · 2017: 6 · 2016: 6 · 2015: 14 · 2014: 8 · 2013: 13 · 2012: 14
FWCI: 7.81
Type: journal article
Language: en
Open access: closed
Locations: Archives of General Psychiatry (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5k05mh047370-25)
National Institute of Mental Health (P01MH031154, MH-31154, MH47370)
Topics: Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
Social Sciences › Arts and Humanities › Philosophy › Mental Health and Psychiatry
Keywords: schizophrenia, neuroleptic withdrawal, abrupt discontinuation, relapse risk, long-term antipsychotic treatment, depot neuroleptics
MeSH terms: Administration, Oral, Ambulatory Care, Delayed-Action Preparations, Drug Administration Schedule, Female, Follow-Up Studies, Hospitalization, Humans, Injections, Intramuscular, Male, Recurrence, Risk Factors, Schizophrenia, Schizophrenic Psychology, Substance Withdrawal Syndrome, Antipsychotic Agents, Survival Analysis

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Clinical Risk Following Abrupt and Gradual Withdrawal of Maintenance Neuroleptic Treatment

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