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 RESULTS: Data were found for 1210 schizophrenic subjects: 1006 (795 inpatients and 211 outpatients) were withdrawn abruptly from oral neuroleptic therapy, and 204 discontinued treatment gradually (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 In studies including subjects whose drug therapy was withdrawn abruptly (n = 49) vs gradually (n = 58), relapse was earlier after abrupt discontinuation (25% risk in 6 vs 10 weeks), with a persistent difference for at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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Randomised controlled trial of gradual antipsychotic reduction and discontinuation in people with schizophrenia and related disorders: the RADAR trial (Research into Antipsychotic Discontinuation and Reduction)
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“11 12 Some evidence suggests gradual discontinuation may reduce risk of relapse compared with abrupt discontinuation, 13 although this difference was not confirmed in the analysis by Leucht et al .”
Result
Tapering antipsychotic treatment
Horowitz, M. A., Murray, R. M., & Taylor, D. (2021) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2020.2166 · Cited by 49
Treatment of schizophrenia in pregnancy and postpartum.
Robinson, G. E. (2012) · PubMed · Cited by 45
One-year symptom trajectories in patients with stable schizophrenia maintained on antipsychotics versus placebo: meta-analysis
Takeuchi, H., Kantor, N., Sanches, M., Fervaha, G., Agid, O., & Remington, G. J. (2017) · The British Journal of Psychiatry · doi:10.1192/bjp.bp.116.186007 · Cited by 44
Schizophrenia: Basic and Clinical
Coyle, J. T. (2017) · Advances in neurobiology · doi:10.1007/978-3-319-57193-5_9 · Cited by 45
An analysis of views about supported reduction or discontinuation of antipsychotic treatment among people with schizophrenia and other psychotic disorders
Crellin, N. E., Priebe, S., Morant, N. J., Lewis, G., Freemantle, N., Johnson, S., Horne, R., Pinfold, V., Kent, L., Smith, R., et al. (2022) · BMC Psychiatry · doi:10.1186/s12888-022-03822-5 · Cited by 44
“If done abruptly, this may increase the risk of relapse and significant withdrawal effects [14, 33].”
Background
Psychosocial and socio-demographic correlates of medication compliance among people with schizophrenia
Tsang, H. W. H., Fung, K. M. T., & Corrigan, P. W. (2008) · Journal of Behavior Therapy and Experimental Psychiatry · doi:10.1016/j.jbtep.2008.02.003 · Cited by 44
Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature
Tsai, A. C., Rosenlicht, N. Z., Jureidini, J. N., Parry, P. I., Spielmans, G. I., & Healy, D. (2011) · PLoS Medicine · doi:10.1371/journal.pmed.1000434 · Cited by 43
“This ‘‘bipolar rebound phenomenon’’ has been most often described for lithium, but it has also been observed in the setting of abruptly withdrawn antiepileptic [78], antipsychotic [3,12,48,56, 78–80], and antidepressant medications [59,75,78,81] administered to persons diagnosed with other mood and psychotic disorders.”
Pharmacotherapy of first-episode psychosis
Lambert, M., Conus, P., Lambert, T. J. R., & McGorry, P. D. (2003) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.4.5.717 · Cited by 43
Tolerance in antidepressant treatment
Baldessarini, R. J., Ghaemi, S. N., & Viguera, A. C. (2002) · Psychotherapy and Psychosomatics · doi:10.1159/000063641 · Cited by 42
Barriers to stopping neuroleptic (antipsychotic) treatment in people with schizophrenia, psychosis or bipolar disorder
Moncrieff, J., Gupta, S., & Horowitz, M. A. (2020) · Therapeutic Advances in Psychopharmacology · doi:10.1177/2045125320937910 · Cited by 43
Recurrence Risk in Bipolar Manic-Depressive Disorders after Discontinuing Lithium Maintenance Treatment: An Overview
Baldessarini, R. J., & Tondo, L. (1998) · Clinical Drug Investigation · doi:10.2165/00044011-199815040-00010 · Cited by 42
Adjunctive Antipsychotic Treatment Is Necessary for Adolescents with Psychotic Mania
Kafantaris, V., Dicker, R., Coletti, D. J., & Kane, J. M. (2001) · Journal of Child and Adolescent Psychopharmacology · doi:10.1089/104454601317261582 · Cited by 42
“Fewer withdrawal and rebound phenomena were observed in adult patients on maintenance treatment for schizophrenia after a gradual dose tapering rather than abrupt discontinuation (Viguera et al. 1997), but it is not known if this also applies to the discontinuation of very brief adjunctive antipsychotic treatment in a…”
Influential
Reducing the dose of antipsychotic medications for those who had been treated with high-dose antipsychotic polypharmacy: an open study of dose reduction for chronic schizophrenia
Suzuki, T., Uchida, H., Tanaka, K. F., Tomita, M., Tsunoda, K., Nomura, K., Takano, H., Tanabe, A., Watanabe, K., Yagi, G., et al. (2003) · International Clinical Psychopharmacology · doi:10.1097/00004850-200311000-00003 · Cited by 41
“Because, in this process, many symptoms can emerge as a result of discontinuation (Weiden et al., 1997), and considering the risk following abrupt withdrawal (Viguera et al., 1997), dose reduction was conducted gradually in a conservative way.”
Background
The dilemmas posed by new and fashionable treatments
Healy, D. (2001) · Advances in Psychiatric Treatment · doi:10.1192/apt.7.5.322 · Cited by 39
Potential Adverse Effects of Discontinuing Psychotropic Drugs: Part 4: Benzodiazepine, Glutamate, Opioid, and Stimulant Drugs
(2010) · Journal of Psychosocial Nursing and Mental Health Services · doi:10.3928/02793695-20100730-04 · Cited by 38
Olanzapine as Alternative Therapy for Patients With Haloperidol-Induced Extrapyramidal Symptoms: Results of a Multicenter, Collaborative Trial in Latin America
Silva, J. A. C. E., Alvarez, N. P., Mazzotti, G., Gattaz, W. F., Ospina, J., Larach, V. W., STARKSTEIN, S. E., Oliva, D., Cousins, L., Tohen, M. F., et al. (2001) · Journal of Clinical Psychopharmacology · doi:10.1097/00004714-200108000-00004 · Cited by 38
Choice of maintenance medication for schizophrenia.
Davis, J. M., & Chen, N. (2003) · PubMed · Cited by 38
The neurobiology of relapse in schizophrenia
Remington, G. J., Foussias, G., Agid, O., Fervaha, G., Takeuchi, H., & Hahn, M. (2013) · Schizophrenia Research · doi:10.1016/j.schres.2013.10.009 · Cited by 38
“A comparatively large study examining abrupt vs. gradual antipsychotic discontinuation did indicate higher relapse rates in those exposed to abrupt, compared to gradual, antipsychotic discontinuation (Viguera et al., 1997).”
Influential
Insights on current and novel antipsychotic mechanisms from the MAM model of schizophrenia
Sonnenschein, S. F., & Grace, A. A. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.05.009 · Cited by 37
“It has long been suggested that neuroadaptations to chronically administered psychiatric drugs can produce discontinuation syndromes and facilitate relapse, with rapid withdrawal inducing greater relapse (Viguera et al., 1997).”
Background
Deprescribing antipsychotics: a guide for clinicians
Gupta, S., Cahill, J. D., & Miller, R. (2018) · BJPsych Advances · doi:10.1192/bja.2018.2 · Cited by 35
“Studies have found rates of relapse between 20 and 60% following the discontinuation of an antipsychotic (Gilbert 1995; Viguera 1997; Leucht 2012).”
Background
Reasoning about the optimal duration of prophylactic antipsychotic medication in schizophrenia: evidence and arguments
Haandel, L. B.-V., Slooff, C. J., & van den Bosch, R. J. (2001) · Acta Psychiatrica Scandinavica · doi:10.1034/j.1600-0447.2001.00089.x · Cited by 35
“(37) have reviewed all known withdrawal studies to quantify the relapse risk following discontinuation.”
Background
Recognition of early warning signs in patients with schizophrenia: A review of the literature
van Meijel, B., van der Gaag, M., Kahn, R. S., & Grypdonck, M. (2004) · International Journal of Mental Health Nursing · doi:10.1111/j.1440-0979.2004.00314.x · Cited by 34
Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia
Qubad, M., & Bittner, R. A. (2023) · Therapeutic Advances in Psychopharmacology · doi:10.1177/20451253231158152 · Cited by 33
A clinical case series of switching from antipsychotic polypharmacy to monotherapy with a second-generation agent on patients with chronic schizophrenia
Suzuki, T., Uchida, H., Watanabe, K., Yagi, G., & Kashima, H. (2003) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2003.11.006 · Cited by 30
“All roads lead to medication?” Qualitative responses from an Australian first-person survey of antipsychotic discontinuation.
Salomon, C., & Hamilton, B. E. (2013) · Psychiatric Rehabilitation Journal · doi:10.1037/prj0000001 · Cited by 31
Neuroleptic drugs in the human brain
Kornhuber, J., Wiltfang, J., Riederer, P. F., & Bleich, S. (2006) · European Archives of Psychiatry and Clinical Neuroscience · doi:10.1007/s00406-006-0661-7 · Cited by 31
“…symptoms or neuroleptic malignant syndrome may persist for several weeks after discontinuation of neuroleptic drugs and psychotic patients may not relapse for weeks or months after withdrawal of neuroleptic treatment (Addonizio et al. 1987; Kornhuber and Weller 1994; Viguera et al. 1997).”
Background
Using Pharmacy Data on Partial Adherence to Inform Clinical Care of Patients With Serious Mental Illness
Woltmann, E. M., Valenstein, M. M., Welsh, D. E., Lee, T. A., Wolschon, P. A., Grabowski, J. G., & Reilly, P. A. (2007) · Psychiatric Services · doi:10.1176/ps.2007.58.6.864 · Cited by 31
Short-Term Inpatient Pharmacotherapy of Schizophrenia
Osser, D. N., & Sigadel, R. (2001) · Harvard Review of Psychiatry · doi:10.1080/10673220127892 · Cited by 30
Pharmacotherapy of schizophrenia: Mechanisms of antipsychotic accumulation, therapeutic action and failure
Chestnykh, D., Amato, D., Kornhuber, J., & Müller, C. P. (2021) · Behavioural Brain Research · doi:10.1016/j.bbr.2021.113144 · Cited by 33
Modifying psychotropic drug prescription patterns:A follow‐up survey
UNGVARI, G. S., Chow, L.-Y., Chiu, H. F. K., Ng, F.-S., & LEUNG, A. T. (1997) · Psychiatry and Clinical Neurosciences · doi:10.1111/j.1440-1819.1997.tb03204.x · Cited by 29
The report of the joint WPA/CINP workgroup on the use and usefulness of antipsychotic medication in the treatment of schizophrenia
Fountoulakis, K. Ν., Moeller, H.-J., Kasper, S. F., Tamminga, C. A., Yamawaki, S., Kahn, R. S., Tandon, R., Correll, C. U., & Javed, A. (2020) · CNS Spectrums · doi:10.1017/s1092852920001546 · Cited by 28
“10).(98) A more recent and more technically advanced meta-analysis also reported no difference between abrupt vs gradual discontinuation of either FGA or SGA medication.”
Result
Adherence styles of schizophrenia patients identified by a latent class analysis of the Medication Adherence Rating Scale (MARS): A six-month follow-up study
Jaeger, S., Pfiffner, C., Weiser, P., Kilian, R., Becker, T. M., Längle, G., Eschweiler, G. W., Croissant, D., Schepp, W., & Steinert, T. (2012) · Psychiatry Research · doi:10.1016/j.psychres.2012.03.033 · Cited by 28
“Various studies have demonstrated an increased risk of relapse in patients who discontinue their medication as compared to those who maintain their treatment (Viguera et al., 1997).”
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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