Regular Article ao acs Discontinuing Psychotropic Drugs from Participants in Randomized Controlled Trials: A Systematic Review David Cohen* Alexander Recalt® > Psychother Psychosom Ok: 10.1159/000886733 Department of Social Welfare, Luskn School of Public Affals, University of California, Los Angeles, CA, USA: Department of Epidemiology, Flekding School of Public Health, Los Angeles, CA, USA uxivessihy A California, Keywords Discontinuation - Withdrawal Psychotropic drugs Randomized controlled trials - Research participants Confounding Abstract, Background and Objective: Methods and justifications for discontinuing psychotropic drugs in randomized controlled trials (RCTS), and RCTs’ acknowledgement of possible with- drawal symptoms following discontinuation, have notbeen examined systematically, which this review aimstodo. Study Eligibility, Data Extraction, and Synthesis: Publications in ‘MEDLINE, EMBASE, and PsycINFO (2000-2017) randomly as- signing participants diagnosed with mental disorders to discontinue antipsychotic, antidepressant, anticonvulsant, antimanic, mood-stabilzing, benzodiazepine, or stimulant drugs. Authors independently extracted data, devised a ‘typology of trials, and assessed trials’ recognition of with- drawal symptoms. Results: Eighty RCTs (70% with industry participation) discontinued drugs from 5,757 participants to investigate relapse prevention (446), successful dis- continuation (2686), architecture of withdrawal (14%), and practicality of discontinuation (105) RCTs of stimulants, an- tidepressants, and antipsychotics mostly aimed to reach conclusions about relapse prevention by testing abrupt or rapid discontinuations; RCTs of benzodiazepines mostly aimed to reduce drug use by testing longer-lasting, support- Ive discontinuation. n 67% of RCTs, no justification was giv- ‘en for the specific discontinuation strategy, which lasted un- ‘der 2 weeks in 60% of RCTS. Possible withdrawal confound ing of tial outcomes was addressed it elighble RCTS. Limitations: Only the published literature was searched. Conclusions and Implications: RCTS use drug discontinua tion to study several key issues in psychopharmacology but Infrequently justify how they implement it or acknowledge ‘that possible withdrawal symptoms may threaten internal validity. Reappraising the use of drug discontinuation and the recognition of withdrawal symptoms in RCTS is required. (220195. rage AG Saal Introduction This systematic review examines methods employed and justifications put forth to deliberately discontinue prescribed psychotropic drugs from participants in ran- domized controlled trials (RCTs) diagnosed with mental Systematic revew registration No: PROSPERO 2016 CRD#2016046014, KARGER, alana com vances ‘220195 Karger AG aa FE aaa ain noeare disorders. Drug treatment involves initiating and also ceasing drugs. The authors of this review knew that the latter procedure was used intentionally in drug trials for six decades (1, 2] and that it carried a degree of risk but could find no systematic examination ofits use, For what purposes RCTs deliberately incorporate in their design a drug discontinuation procedure, and how RCTs actually implement this procedure, has remained generally un- nove. Ineatlier investigations and psychiatric trials that have discontinued drugs, associated withdrawal syndromes, (clusters of unpleasant physiological and psychological symptoms) have been identified for antipsychotics (APs) [1-3), tricyclic antidepressants (ADs) [4], benzodiaze- pines (BZD) [5],and stimulants [6 In the 1990s, reports of unpleasant reactions to stopping selective serotonin reuptake inhibitors (SSRIs) led researchers to describean SSRI withdrawal syndrome (renamed “discontinuation” in industry-sponsored research [7]) and propose guide- lines to manage it [8,9]. An influential review of conse- ‘quences of discontinuing APs [10] triggered discussion conhow abrupt discontinuation of APs and other psycho- tropic drugs might hasten episodes that these drugs were ‘meant to treat [11, 12]. Ensuing recommendations con- curred on discontinuing drugs gradually although how this is interpreted varies (13). Discontinuation lasting 2 ‘weeks or lesshas been definedas “rapid” for ADs [14] and “abrupt” for APs and lithium [11]. ‘Not only may rebound, withdrawal, and even post- withdrawal syndromes follow discontinuation, so may relapse and recurrence. Definitions and diagnostic crte- ria forall these phenomena, however, confirm that they are difficult to differentiate [15-18], which complicates the evaluation of outcomes in practice and in research ‘Therefore, this review also aimed to examine what aware- ness and efforts at recognition of withdrawal syndromes sreflected in modern psychiatric RCTs that discontinue ‘AP, AD, BZD, stimulant, anticonvulsant, or mood-stabi- lizing drugs from participants diagnosed with mental dis- orders. Methods Data Sources and Study Selection PRISMA guidelines modified forthe study alms were followed. EMBASE we searched from January 1, 2000, o Jane 30,2015 and ‘MEDLINE and PeyeINFO fom January 1, 2000, to june 30,2017 (no language restrictions), using keywords for discontinuation ‘oF withdrawal and fr each ofthe major castes of prescribed psy- chotropie drugs (See online suppl. Table 1; forall online suppl. material, see woew-karger-com/doi/10.1159/000496732). Authors screened for reports describing sel, clinician, or tesearcher-ini- ‘lated discontinuation ot reduction (excluding nicotine, opiates, ‘and anticonvulsants in seiaare disorders) to no drug placebo, of ‘another drug, rom fll texts of any publications meeting inchi- ton criteria, authors identified RCTs any randomized assignment (including crossover of some oral participants disgnosed with a ‘mental dtordee (excluding substance abuse or dependence) to >1 condition involving a deig discontinuation. All disagreements ‘were resclved by consents ata Extraction and Analysis, Risk of Bias Asessment ‘Authors independently extracted data on trials, participant characteristics, motivational and environmental factors, discon ‘inustion terminology and strategies. Justification for employing discontinaation were condenced ino a typology Industry artci- pation was asteseed by direct study funding, author employment, ‘donations of drugs or placebo, and editorial asistance. The het- cerogencity of ls precluded meta-analysis of any trial outcomes, Double-blind RCTs were rated on allocation concealment and blinding, andall RCTs were rated for presence(1 point) arabsence (point) of each of 6 features denoting awareness of withdrawl symptoms (anging from meation that withdravel symptoms may ‘merge, to analysis of possible withdrawal confounding on any. study outcome). Results ‘The search yielded 2,496 records, of which 1,886 were ‘excluded (online suppl. Fig. 1). From the remaining 600 articles describing a discontinuation procedure, 231 case reports, 135 reviewsand commentaries, 108 observation- al/naturalistic studies, 38 guidelines, and 8 others were ‘excluded, leaving 80 RCTs (listed in online suppl. Table 2) Study and Participant Characteristics ‘The 80 RCTs included 11,884 participants, of whom 8,757 (49.1%, mean per RCT: 72.0 + 83.2, range 1-532) ‘were discontinued or assigned to discontinuation from at, least 65 drugs:23 BZDsincluding3 Z-drugsin 21 (26.25%) trials, 19 APs in 26 (325%) trials, 16 ADs including agomelatine in 23 (28.75%) trials, 4 stimulants in 7 (8.75%) trials, and 3 others (amotrigine, lithium, prega- balin) in 3 trials (Table 1). Mean sample size slightly dif- fered between drug classes (ranging from 136 to 143), while the mean number of discontinued participants var- ied from 47 in stimulant trials, 75 in AP and 78 in AD tri- als, to 99 in BZD trials. In all, 45 RCTs (56.2%) reported. double-blinded discontinuations, 11 (13.75%) single- blinded, while 24 (30.0%) had no blind or gave unclear descriptions. 2 DapcotherPpchosom DOK 1011590196733 Cohea/Recalt‘Table 1. Diagnoses of participants by discontinued drug class and by numbers of randomized controlled trials (number of trials, with ‘numberof participants discontinued in parentheses) Diagnosis or conation ru clas dicontinued “oul Sc anthem tinal other eychouis depressans dlaepines Major depressive disorder 2025) 1G) 1022) 16) Maas) Schinphrenia and other paychote disorders 110738) 1 (86) n@) Gener anety dior, Pani order dem 7077 rai) 110713) Tisomnis narcolepsy 10228) 8(621) 90649) Dementia dementia with peychossagation or aggression (268) 1163) 708) S Aentonechyperactiviy disorder sco 600) Bipolar disorder, bipolar depesion 229208) 21107) 6206) ‘Ato inlets bites with tantrums agressionorslinjury 5185) 5085) Otsesive compulsive dsorder compulsive buying and shopring sca 5a author ndusry enplaye, dontion of modltin/placho, ctor amisace om indasty fm, concurrent industry grants sithon, seen in 56.25% of trials. Smaller proportions mentioned ‘possible links between discontinuation and precipitating relapse or interfering with its assessment (e.g, “It is pos- sible that, for some individuals for whom relapse oc- curred early .. this represented a ‘rebound’ due to with- son Cl, Seeman P, Seeman MV. Depression treatment by withdrawal of short-term low ose antipsychotic, « proof of concept ran- domized double-lin study | Alec Dison. a Sep165:139-43, Sunder KR, Wisner KL Hansa BH, Perel). Postpartum dopression recurrence versus i= continuation sfadrome: observations fom 2 Fandomnzed controlled tal} Clin Peychis- £2004 Sepi5(9}1266-8. van Reeku GlrkeD, Conn Dy Herrmann 1 Eyaves G, Cohen Ts etal A randomize, Phcebo controlled tal of the dscontinsa. $n oflong. teem antipeychotes in dementia nt Poychogoratr. 2002 fag 14(2)197-210.. (Coghill DR, BanaschewaT,Lacendeeus M, Johnson M, Zuldas A, Anderson CS, ea. 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