Optimisation of adherence and discontinuation practices for maintenance antidepressant therapy

Putatively, the maintenance phase of treating major depressive disorder is fundamental to preventing relapse and diminishing the risk/likelihood of recurrence. Therefore, immediately following an acute episode of depression, adherence to antidepressant treatment is important for maintaining wellness and ensuring long-term recovery. It is therefore all the more remarkable that relatively limited research has been conducted into identifying the optimal duration of long-term pharmacotherapy.

The College guidelines for mood disorders (Malhi et al., 2015) proffer tentatively that following the resolution of an initial depressive episode (i.e. once remission has been attained), the effective antidepressant treatment should continue to be prescribed for an additional year, or an additional 3 years where the pattern has been that of recurrent episodes. Recent research examining this process more carefully suggests that the rates of relapse and recurrence are lowered by maintaining therapy for longer (Bauer et al., 2015). However, extending treatment has to be balanced against the risk that when antidepressant treatment is eventually discontinued, the likelihood of experiencing withdrawal symptoms is increased the longer the duration of treatment. The cluster of withdrawal symptoms precipitated by discontinuing medication (e.g. dizziness, nausea, headaches, lethargy, anxiety and irritability) is termed the antidepressant discontinuation syndrome (ADS). Again, puzzlingly limited research has investigated this phenomenon systematically and most contemporary recommendations concerning ADS are essentially derived from expert consensus (Wilson and Lader, 2015).

During the maintenance phase of pharmacotherapy treatment, adherence is a primary concern. This is because patients are usually reluctant to continue medication after the resolution of depressive symptoms, even though the risk of relapse is greatest immediately following remission and then only gradually diminishes over time (Malhi et al., 2015). Following remission, the cost–benefit balance of antidepressant treatment progressively shifts as tolerability and long-term side effects become increasingly important considerations that adversely impact adherence during the maintenance phase. Particularly troublesome side effects include weight gain, sexual dysfunction and fatigue, along with more subtle effects such as dampening of positive affect. Consequently, patients continually evaluate the burden of maintenance therapy against their likely risk of relapse over the course of treatment, crucially threatening treatment adherence.

Uncertainty regarding the optimal duration of maintenance pharmacotherapy coupled with limited knowledge of effective strategies for discontinuation of antidepressants increases the likelihood of non-compliance and ADS. Specifically, Haddad and Anderson (2007) highlight several factors that are likely to be involved in developing ADS. First, abrupt cessation of antidepressant medication is more likely to lead to ADS. Second, duration and dosage of treatment are also important factors in determining the risk and severity of ADS. Both the College guidelines (Malhi et al., 2015) and the World Federation of Societies of Biological Psychiatry Guidelines (Bauer et al., 2015) suggest that gradual tapering of the antidepressant treatment over approximately 4 weeks is prudent and may curb the emergence of withdrawal symptoms. However, the precise timeframe and step-wise reduction of dosage is not stipulated. Clinically there is general consensus that gradual tapering over a period of time, during which the patient can be regularly monitored, is probably the safest approach. This strategic uncertainty reflects a lack of rigorous research into how best to withdraw antidepressant treatment. The few clinical studies that have examined tapering of antidepressants have had limited sample size and have relied on self-report measures with poor validity (Wilson and Lader, 2015). It is important to recognise that trialling different antidepressants is the most common approach to managing depression. As such, in clinical practice, the discontinuation of antidepressant medication is common. Furthermore, antidepressants are seldom maintained long-term or used for prophylaxis per se, and therefore discontinuation inevitably occurs at some point in the course of management.

Three distinguishable phenomena may occur after antidepressant discontinuation: recurrence (return of depressive symptoms after recovery), relapse (emergence of depressive symptoms before recovery is attained) and withdrawal (symptoms related to antidepressant cessation). A randomised controlled trial exploring effective tapering of antidepressants revealed that antidepressant discontinuation increased depressive symptoms and suicidality regardless of the length of the taper (Tint et al., 2008). Although this study had a small sample size, it highlights the effect of discontinuation on risk of relapse and the need for future research to focus on these outcomes rather than exclusively on discontinuation symptoms. Figure 1(B) depicts the need for further research regarding effective discontinuation of antidepressant treatment by highlighting the conceivable outcomes of different tapering strategies.

Figure 1.

(A) Typical step-wise strategy for discontinuing antidepressant medication. The blue line shows the decrement in antidepressant dosage as it is tapered in successive steps. The black line depicts likelihood of relapse, which gradually increases subsequent to the commencement of the tapering process and returns to the pre-morbid, un-medicated level. The red line represents severity of ADS symptoms and emerges somewhat later as antidepressant plasma levels diminish. (B) Comparative efficacy of discontinuation strategies. The solid lines depict a short-term, 2-week tapering strategy (red line) and a gradual 6-week tapering (green line) of antidepressant dosage. The dotted lines represent the probable risk of relapse as antidepressant medication is discontinued over 2 weeks (red dotted line) and over 6 weeks (green dotted line). The dashed lines represent the estimated emergence of ADS withdrawal symptoms as antidepressant dosage is reduced over 2 weeks (red dashed line) and 6 weeks (green dashed line).

This commentary calls for high-quality, empirical research to provide appropriate information to treating physicians and patients on how best to minimise the risk of relapse and onset of ADS during the maintenance and discontinuation phases of antidepressant treatment.