Dependence, withdrawal and rebound of CNS drugs: an update and regulatory considerations for new drugs development

Lerner, Alicja; Klein, Michael

doi:10.1093/braincomms/fcz025

Cited by 62 publications

(95 citation statements)

References 175 publications

(252 reference statements)

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“…In our late-discharged group, the average THC-COOH values did not drop below the cutoff value of 50 ng/ml even after 24 abstinent days. While this is in line with previous findings (42,43), it also supports the existence of a special population among chronic cannabis users with a delayed THC terminalphase elimination from the body (16,(43)(44)(45)(46). While prolonged CWS courses have previously been described and ascribed to psychiatric comorbidities (39,40), our late group showed no such association with psychiatric comorbidity nor with age nor cannabis history data.…”

Section: Protracted Cws and Thc-cooh Eliminationsupporting

confidence: 93%

Is the Urine Cannabinoid Level Measured via a Commercial Point-of-Care Semiquantitative Immunoassay a Cannabis Withdrawal Syndrome Severity Predictor?

et al. 2020

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Background: For cannabis-dependent subjects, the relationship between cannabis withdrawal syndrome (CWS) severity and the urine cannabinoid concentrations are unclear; we investigated this using a commercial point-of-care (POC) enzyme immunoassay detecting 11-nor-9-carboxy-Delta-9-tetrahydrocannabinol (THC-COOH).Methods: Observational study of 78 adult chronic cannabis-dependent subjects assessed over a 24-day inpatient detoxification treatment, with 13 serial measurement days. Repeated Measures Correlation and Multilevel Linear Models were employed.Results: Absolute urinary THC-COOH levels significantly correlated with Marijuana Withdrawal Checklist (MWC) scores across the entire study duration (r = 0.248; p < 0.001). Correlation between serial creatinine-adjusted THC-COOH ratios and serial MWC scores emerged as significant only in the sample with higher MWC scores (>11 points) at admission (n = 21; r = 0.247; p = 0.002). The aforementioned significant relationships have persisted when replacing the absolute THC-COOH-levels with the (relative) day-to-day change in urinary THC-COOH levels. MWC scores were significantly correlated with the Clinical Global Impression-Severity (CGI-S; r = 0.812; p < 0.001). Females showed a significantly slower decline in urine THC-COOH levels and prolonged CWS course characterized by substantial illness severity (per CGI-S), occurring in nearly 30% of cases.Conclusion: Urine cannabinoid levels (THC-COOH) determined by POC assay significantly predicted CWS severity (moderate correlation), guiding detoxification treatment duration. In patients with MWC > 11 points upon admission, creatinine-adjusted THC-COOH ratios also significantly predicted CWS severity—again with moderate effect size. Females showed prolonged urinary THC-COOH elimination and cannabis withdrawal.

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Section: Protracted Cws and Thc-cooh Eliminationsupporting

confidence: 93%

Is the Urine Cannabinoid Level Measured via a Commercial Point-of-Care Semiquantitative Immunoassay a Cannabis Withdrawal Syndrome Severity Predictor?

et al. 2020

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“…Various authors have stressed that prolonged antidepressant use can cause neurochemical adaptations (physical dependence) and corresponding withdrawal reactions upon dose reduction or discontinuation comparable with other central nervous system (CNS) drugs like benzodiazepines, stimulants or opioides. 18,22,47,48 There is now compelling evidence from clinical trials, observational studies and user surveys that stopping antidepressants can cause severe and persistent withdrawal reactions in a substantial portion of users. 49,50 Withdrawal symptoms include, among others, anxiety, panic, irritability, aggression, lethargy, flu-like symptoms, electric-shock sensations (brain zaps), fatigue, dizziness, tremor, dysphoria, bouts of crying, suicidality, insomnia, anorexia and nausea.…”

Section: Withdrawal Confounding In Relapse Prevention Trialsmentioning

confidence: 99%

“…47,57,58 Rebound disorders and persistent post-acute withdrawal disorders have also been described with various other CNS drugs, including opioids, benzodiazepines, stimulants, antipsychotics and lithium. 48,59…”

Section: Withdrawal Confounding In Relapse Prevention Trialsmentioning

confidence: 99%

How effective are antidepressants for depression over the long term? A critical review of relapse prevention trials and the issue of withdrawal confounding

Hengartner

2020

Therapeutic Advances in Psychopharmacology

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The aim of this article is to discuss the validity of relapse prevention trials and the issue of withdrawal confounding in these trials. Recommendations for long-term antidepressant treatment are based almost exclusively on discontinuation trials. In these relapse prevention trials, participants with remitted depression are randomised either to have the antidepressant abruptly discontinued and replaced by inert placebo or to continue active treatment. The drug–placebo difference in relapse rates at the end of the maintenance phase is then interpreted as a prophylactic drug effect. These trials consistently produce remarkable benefits for maintenance treatment. However, the internal validity of this trial protocol is compromised, as research has shown that abruptly stopping antidepressants can cause severe withdrawal reactions that lead to (or manifest as) depression relapses. That is, there is substantial withdrawal confounding in discontinuation trials, which renders their findings uninterpretable. It is not clear to what degree the drug–placebo separation in relapse prevention (discontinuation) trials is due to withdrawal reactions, but various estimations suggest that it is presumably the majority. A review of findings based on other methodologies, including real-world long-term effectiveness trials like STAR*D and various naturalistic cohort studies, do not indicate that antidepressants have considerable prophylactic effects. As absence of evidence does not imply evidence of absence, no definitive conclusions can be drawn from the literature. To enable a thorough risk–benefit evaluation, real-world effectiveness trials should not only focus on relapse prevention, but also assess antidepressants’ long-term effects on social functioning and quality of life. Thus far, reliable long-term data on these outcome domains are lacking.

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“…42 When the drug is removed, the responses overshoot and the homeostasis is disturbed, leading to the psychobiological discomforts called withdrawal symptoms or syndromes. 28,[43][44][45][46] In sum, "withdrawal effects are part of the pharmacology of a drug". 47 However, psychological and social-interpersonal factors, not necessarily reducible to neurobiology, contribute.…”

Section: Psychotropic Drug Discontinuation and Withdrawal Effectsmentioning

confidence: 99%

Withdrawal effects confounding in clinical trials: another sign of a needed paradigm shift in psychopharmacology research

Cohen

Recalt

2020

Therapeutic Advances in Psychopharmacology

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Randomized controlled trials’ ability to produce evidence useful for people to decide whether to take, continue taking, or stop taking psychotropic drugs has been intensely critiqued, along with the trials’ commercial, ideological, and regulatory contexts. This article applies the critique to the topic of withdrawal effects confounding the outcomes of relapse-prevention trials where prescribed psychotropic drugs are discontinued. Until recently, the complexity and reach of withdrawal and post-withdrawal effects were neglected by mainstream psychiatry, but not by lay users of prescribed psychotropics. This article discusses withdrawal effects as part of the pharmacology of psychotropic drugs but shaped by psychosocial factors, and possibly shaping the presentation of psychological distress generally. It outlines biases and misconceptions in assumptions, design, and reporting of general efficacy trials and findings from a recent review of 80 discontinuation trials. In theory, relapse-prevention trials are tautological and exaggerate efficacy. In publications, they pay little attention to the central feature of their design, favor abrupt or rapid discontinuations, do not attend to environmental factors, and provide insufficient data to allow re-analyses. Thus, relapse-prevention RCTs likely confound the detection of their main outcome of interest: “relapse.” Using slower tapers, active placebo controls, and specific covariates in analyses would reduce the risk of withdrawal confounding, and better reporting would reduce the opaqueness of trials. The crisis in psychopharmacology is fueled partly by the disconnect between claims of therapeutic efficacy from so-called best-evidence methods despite unchanging population-level indicators of psychiatric sickness. Only by “stacking the deck” against trial sponsors’ hoped-for outcomes can psychopharmacology trials regain scientific credibility.

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Dependence, withdrawal and rebound of CNS drugs: an update and regulatory considerations for new drugs development

Cited by 62 publications

References 175 publications

Is the Urine Cannabinoid Level Measured via a Commercial Point-of-Care Semiquantitative Immunoassay a Cannabis Withdrawal Syndrome Severity Predictor?

Is the Urine Cannabinoid Level Measured via a Commercial Point-of-Care Semiquantitative Immunoassay a Cannabis Withdrawal Syndrome Severity Predictor?

How effective are antidepressants for depression over the long term? A critical review of relapse prevention trials and the issue of withdrawal confounding

Withdrawal effects confounding in clinical trials: another sign of a needed paradigm shift in psychopharmacology research

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