Antidepressants Over the Medium and Long Term: Little to No Evidence

Patient Expert

Last month, in two posts - Antidepressants: the Evidence and Antidepressants Over the Short Term - we examined the scientific evidence for treating depression with antidepressants. I principally relied on three major clinical treatment guidelines that were published over 2009-2010.

These included the American Psychiatric Association's (APA) Practice Guideline for the Treatment of Patients with Major Depressive Disorder, the National Institute for Health and Clinical Practice's (NICE) Guideline on the Treatment and Management of Depression in Adults, and the Canadian Network for Mood and Anxiety Treatments' (CANMAT) Clinical Guidelines for the Management of Major Depressive Disorder in Adults.

In this post, I add a fourth, the Evidence Based Guidelines for Treating Depressive Disorders with Antidepressants issued in 2006 by the British Association of Psychopharmacologists (BAP).

All four guidelines adopt the principle of "evidence-based" medicine. In this context, the expectation is that each treatment recommendation is backed by a substantial body of clinical drug trials and of meta-analyses of these trials. Since we have no shortage of antidepressant trials lasting over six or eight weeks, all four guidelines predictably dealt almost exclusively with short-term treatment.

These short-term trials support a modest advantage of an antidepressant over a placebo, but this was enough for all four guidelines to unequivocally recommend antidepressants in the short-term. Major concerns (such as flaws in how these trials are conducted) and negative or skeptical interpretations were glossed over or ignored.

Nevertheless, a case can be made that for some individuals antidepressants can be extremely beneficial.

After that, the guidelines veer into vagueness and incoherency. All four guidelines recommend continuing on an antidepressant for at least the medium term. Significantly, there is no unambiguous endorsement of long-term antidepressant treatment.

The APA guidelines recommend continuing antidepressant treatment for a period of at least 16-20 weeks after achieving full remission. NICE recommends six months. Neither CANMAT nor BAP offer a specific recommendation based on weeks or months.

The principal reason the guidelines cite for staying on an antidepressant is to prevent relapse. The BAP Guideline notes that relapse rates are high in the six months after remission and level out after that. The Guideline cites a 2003 meta-analysis of 31 studies (Geddes et al) showing that patients who quit their antidepressants are twice as likely to relapse over six to 12 months than those who remained on their antidepressants - 18 percent of antidepressant patients relapsing vs 41 percent on a placebo.

(The BAP notes that the meta-analysis included studies ranging from six to 36 months, but an actual reading of the meta-analysis supports a conclusion based on six to 12 months.)

The APA sites a 2007 two-year trial of Effexor (Keller et al) that shows similar results - one in four Effexor patients relapsing vs nearly one in two on the placebo over 12 months. These numbers held steady over two years.

Both the meta-analysis and the Effexor trial make a strong case for remaining on an antidepressant over the medium term, but real-world StarD studies underwritten by the NIMH suggest a different conclusion. None of the guidelines made reference to STARD. According to Nassir Ghaemi of Tufts University, commenting in a blog on Psychology Today:

Further, and perhaps most humblingly, even if antidepressants worked in the short term (2 months ...), one-half of patients who stayed on them relapsed into depression within one year. At the one year outcome, only about 25% of patients actually had remained well on and tolerated  an antidepressant, much below the levels most clinicians seem to feel occurs in their clinical experience.

As for staying on antidepressants for longer than two years, we are in No-Man's Land. The best that psychiatry can do is make an educated guess. Thus, according to CANMAT:

Although empirical evidence is lacking, longer maintenance treatment should also be considered for patients with depression vulnerability factors including early onset depression, psychosocial adversity, and chronic medical illnesses.

This is a far cry from the common belief that you need to be on an antidepressant the rest of your life.

Okay - listen very carefully - before jumping to conclusions, please do not interpret inconclusive evidence or a total lack of evidence as a green light for going off your antidepressant. Drug trials measure outcomes for large groups of subjects. They fail to differentiate amongst the individuals in these groups. They fail to account for the fact that no two depressions are alike, much less two individuals.

Yes, our ignorance far outweighs our knowledge, but this applies throughout all realms of science, not just psychiatry. Yes, you have every right to be concerned, particularly since we have little knowledge of the possible dangers of staying on an antidepressants over the long-term (which is the topic for a future post). But, again, there may be valid reasons for you - as a unique individual - to remain on your antidepressant. Please discuss your options with your doctor.

If you do decide the time is right for you to go off your antidepressant, please make the decision in consultation with your doctor. Please note that it is dangerous to simply stop your antidepressant cold turkey. A slow wean over several weeks is standard, under the watchful eye of your doctor.

As always, you are the true experts. Please share your experiences with antidepressants. Comments below ...