Relapse Risk After Discontinuation of Antidepressants for Anxiety

Cognitive behavioral therapy and antidepressant medications are first-line treatment strategies for patients with anxiety disorders. It has been estimated that antidepressants are a part of treatment for 57% of those receiving professional care for anxiety.¹ Consensus-based guidelines advise a course of antidepressants ranging from 6 to 24 months for these patients, followed by tapering.

However, recent findings show that long-term use of these drugs is increasing — for example, approximately two-thirds of US patients are continuing their use for at least 2 years.² “Whether clinicians are unnecessarily medicalizing their patients or whether guidelines are too optimistic by advising discontinuation of antidepressants after sustained remission remains unclear,” wrote the authors of a systematic review and meta-analysis published in the September 2017 issue of the British Medical Journal.³

Individuals with anxiety disorders commonly experience relapse following a period of remission. Earlier findings show relapse rates of 26% to 45% among patients with various anxiety disorders who discontinued antidepressants, while continuation of medication was associated with lower relapse rates; protective summary odds ratios varied depending on the type of anxiety disorder, ranging from 0.20 for generalized anxiety disorder to 0.38 for obsessive compulsive disorder.⁴

Whereas these and additional findings on the topic have linked continuation of antidepressants with less frequent relapse, other studies have found conflicting results, and research on the topic is limited overall.^5,6 It is also unknown whether relapse risk in these cases is influenced by antidepressant type, abrupt vs tapered discontinuation, follow-up duration, concurrent psychotherapy, or comorbidity.

To explore these factors, the current authors analyzed 28 randomized double-blind trials with a combined total of 5233 patients who had responded to antidepressants and then were blindly assigned to continuing medication or switching to placebo. The maximum follow-up period was one year. The risk for bias was determined to be low across studies.

The analysis revealed the following observations:

• Increased relapse risk with discontinuation vs continuation of antidepressants (odds ratio [OR], 3.11; 95% CI, 2.48-3.89)
• Shorter time to relapse (n=3002) with discontinuation of antidepressants (hazard ratio, 3.63; 95% CI, 2.58-5.10)
• Relapse prevalence of 36.4% for placebo (95% CI, 30.8%-42.1%; n=28 studies) vs 16.4% (95% CI, 12.6%-20.1%) for antidepressants, although there were considerable differences across studies, likely because of varying durations of follow-up
• There were higher dropout rates in the placebo group (OR, 1.31; 95% CI, 1.06-1.63)
• No significant effects on relapse risk from anxiety type, duration of previous treatment or follow-up, pacing of discontinuation, or concurrent psychotherapy

Psychiatry Advisor interviewed 2 of the paper’s authors, Neeltje Batelaan, MD, PhD, a psychiatrist and senior researcher, and Renske Bosman, MSc, a doctoral student and junior researcher, both of the VU University Medical Center in Amsterdam. They offered the following takeaways for clinicians.

• When antidepressant treatment is started, future discontinuation, including the risk for relapse — as well as discontinuation symptoms — should be discussed, although this was not the focus of their study. Based on the authors experience, this discussion seldom takes place, although it could affect patients’ decisions regarding treatment options (cognitive behavior therapy vs medication).
• The authors state explicitly that they do not advocate never starting antidepressant treatment. Rather they emphasize that it is important that patients be well informed about the pros and cons of different treatment options and can make a decision that fits their individual needs.
• The risks for relapse described in the meta-analysis are relative risks. Thus, continuation of antidepressant treatment is not a guarantee that patients will not have relapse at all, as 16% of those continuing antidepressant therapy still had relapse. The same applies to patients discontinuing antidepressant treatment — whereas 36% had relapse after discontinuation, 64% did not. Whether patients discontinue antidepressants should thus depend on multiple aspects, including relapse risk, but also preferences and side effects of antidepressants.
• The benefit of continuation over discontinuation is restricted to one year of follow-up. After one year, there are no systematic studies available, and as a result it is not known whether a relatively safe timeframe exists during which antidepressants can be discontinued without an increased risk for relapse. This fact is important with regard to how the treatment guidelines for anxiety disorders are interpreted. The lack of information after one year of follow-up should not be interpreted as a recommendation to discontinue antidepressants after one year of follow-up.
• When patients discontinue taking antidepressant medications, they should be monitored for relapse, and treatment should be available in the short term in case of relapse.

Further insights into risk factors and underlying biological mechanisms of relapse are needed, as such knowledge could “contribute to better identification of patients with an increased relapse risk and possibly to the development of treatment strategies with more beneficial long-term outcomes,” according to the paper. 

Research on whether psychological interventions may reduce relapse risk after antidepressant discontinuation would also be helpful. Additionally, there “are indications that for some patients, drug treatment is less effective when reinstated after relapse,” the authors wrote. “This is important because relapse could then turn into chronicity.” Elucidation of these issues could inform decisions about initiating and discontinuing antidepressants in certain patients.

References

1. Bandelow B, Zohar J, Hollander E, Kasper S, Möller H-J; WFSBP Task Force on Treatment Guidelines for Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the pharmacological treatment of anxiety, obsessive-compulsive and post-traumatic stress disorders – first revision. World J Biol Psychiatry. 2008;9:248-312.
2. Mojtabai R, Olfson M. National trends in long-term use of antidepressant medications: results from the U.S. National Health and Nutrition Examination Survey. J Clin Psychiatry. 2014;75:169-177.
3. Batelaan NM, Bosman RC, Muntingh A, Scholten WD, Huijbregts KM, van Balkom AJLM. Risk of relapse after antidepressant discontinuation in anxiety disorders, obsessive-compulsive disorder, and post-traumatic stress disorder: systematic review and meta-analysis of relapse prevention trials. BMJ. 2017;358:j3927.
4. Donovan MR, Glue P, Kolluri S, Emir B. Comparative efficacy of antidepressants in preventing relapse in anxiety disorders – a meta-analysis. J Affect Disord. 2010;123:9-16.
5. Rickels K, Etemad B, Khalid-Khan S, Lohoff FW, Rynn MA, Gallop RJ. Time to relapse after 6 and 12 months’ treatment of generalized anxiety disorder with venlafaxine extended release. Arch Gen Psychiatry. 2010;67:1274-1281.
6. Mavissakalian M, Perel JM. Clinical experiments in maintenance and discontinuation of imipramine therapy in panic disorder with agoraphobia. Arch Gen Psychiatry. 1992;49:318-323.