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Question
Question
Does the rate of discontinuation of antidepressants affect the risk of illness recurrence?
Population
398 patients (137 men) with DSM-IV diagnosis of recurrent major depressive disorder, panic disorder, bipolar I or II disorder who had been treated with antidepressants for an average 8.5 months. Mean age was 41.9 years at antidepressant discontinuation.
Setting
Mood disorders centre affiliated with the University of Cagliari in Sardinia.
Prognostic factors
Rapid discontinuation (over 1-7 days) or gradual discontinuation (over 2 or more weeks).
Outcomes
Time to first new episode of depression or panic following treatment cessation.
Methods
Design
Cohort study.
Follow-up period
Mean follow-up 2.8 years (censored at 100 months).
Main results
62.6% of patients received tricyclic-like agents and 37.4% received other antidepressants during the index episode of major depression or panic. 188 patients discontinued their treatment rapidly and 210 discontinued gradually. 80.7% of patients decided to discontinue their own treatment, the remainder were advised by their prescribing clinician. Patients who were moderately clinically depressed, anxious or hypomanic at the time of discontinuation were excluded. The patients who discontinued rapidly were, on average, younger at onset and at discontinuation, had 0.15 fewer previous non-manic recurrences per year and were 12% less likely to have a family history of psychiatric illnesses. They also had an index exposure to antidepressants that was on average 2.96 months shorter than the gradual discontinuation patients and were 16 times more likely to have chosen to stop treatment themselves. Rapid discontinuation patients had a shorter crude median time to new episode of depression or panic than those who discontinued gradually (crude median: 3.62 months vs 8.42 months; p<0.0001). When adjusting for covariates in Cox regression (diagnosis, prior recurrence rate, concomitant treatment, duration of depression, duration of first new illness episode, total daily antidepressant dose and duration of index treatment) latency to recurrence was shorter following rapid treatment discontinuation (HR 1.50, 95% CI 1.14 to 2.17; p<0.0001). The risk by time functions remained separated for at least 100 months. The type of drug and the drug elimination half life affected the latency to new episode.
Conclusions
Discontinuing antidepressants gradually over at least 2 weeks improves the likelihood that patients with recurrent major depressive disorder, panic disorder, bipolar I or II disorder will remain illness free for a longer time compared to a rapid discontinuation. It is not clear whether the rate of discontinuation affects the absolute proportion of patients who will relapse.
Abstracted from
Commentary
Baldessarini and colleagues have once again examined the risks of rapid versus gradual discontinuation of psychotropic drugs, this time for antidepressants, after they have done similar studies for lithium1 and antipsychotics.2 The current study, like the previous ones, has found some untoward consequences of abrupt discontinuation in comparison with gradual one.
The results coincide well with clinical wisdom. Moreover, the results shed further light on the effects of rapid and gradual discontinuation. First, for both rapid and gradual discontinuation, the interval to the first new illness episode was one fourth or one fifth of the average interepisode interval in the same patients. Second, the survival curves for remaining without relapse after abrupt verus gradual discontinuation were separated immediately after the discontinuation and at least for 100 months. Third, this acceleration of relapse was significantly greater for drugs with relatively short half life than for those with longer elimination half life.
While I recognise that this may be the highest level of evidence pragmatically available regarding this problem (ie, advantages and disadvantages of abrupt vs gradual discontinuation of antidepressants), it is important to bear the following weaknesses in mind when applying the current results to practice. First, as the original authors correctly point out, this is an observational cohort study and many observable and unobserved confounders may have occurred; post-hoc statistical adjustment may not be able to correct for such confounding. It is notable that 94% of abrupt discontinuation was the patients' decision while 69% of gradual discontinuation was so. Also, the authors presented the overall results for unipolar depression, bipolar disorder and panic disorder; in my opinion, it is biologically implausible that the abrupt versus gradual discontinuation of antidepressants may have similar, and hence combinable, effects for these three disorders.
Footnotes
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Sources of funding National Institute of Health, The Lucio Bini Private Donors Mood disorders Research Fund, The Bruce J. Anderson Foundation and the McLean Private Donors Psychopharmacology Research Fund
Footnotes
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Competing interests TAF has received speaking fees from Astellas, Dai-Nippon Sumitomo, Eli Lilly, GlaxoSmithKline, Janssen, Kyorin, Meiji, Otsuka, Pfizer, Schering-Plough, Shionogi and Yoshitomi. He is on the research advisory board for Sekisui Chemicals and Takeda Science Foundation. He has received royalties from Igaku-Shoin, Seiwa-Shoten and Nihon Bunka Kagaku-sha.