Friday, January 23, 2015

The Rollback Phenomenon

The debate around suicidality in patients taking antidepressants (which reached a peak a few years ago, when FDA came out with its famous black box warnings) has been a contentious one, with many papers in the literature "proving," with this or that meta-analytical summary, that antidepressant use doesn't bring demonstrable increased risk of completed suicide.

What many people in this debate seem to be forgetting is that for many years, before SSRIs came on the market, it was accepted, as fact, that depression patients do normally tend to show more evidence of suicidality in the early phases of recovery. This was already well known in 1960. If we look, for example, at Slater and Roth’s Clinical Psychiatry, by Bailliere, Tindall and Cassell (London, 1960), p. 231, we find the statement:
“With beginning convalescence (following initiation of treatment with tricyclic antidepressants), the risk of suicide once more becomes serious as retardation fades.” 
This was standard medical-textbook knowledge, until recently. It used to be called the "roll-back phenomenon."

Various mechanisms have been proposed for the increase in suicidality early in treatment of depression:
  • Activation: This view holds that antidepressants with prominent energizing effects may actually increase suicidal behavior in severely depressed patients whose psychomotor retardation was (in the absence of therapy) keeping them in an avolitional state. Untreated, their own stupor/lethargy inhibited such patients from acting out their suicidal thoughts.
  • Paradoxical worsening of depression: This is the view that, in some patients, depressed moods may actually worsen as a direct result of antidepressant treatment. We know that this does, in fact, happen in some patients.
  • Akathisia: This idea holds that some antidepressants produce a side effect of akathisia, which is known to be associated with suicide risk. (This is a complicated subject, which I will address very soon in another post.) Note that akathisia is actually a complex syndrome with mood, mentation, and motor components. It's far more than just "restless legs" or "restlessness."
  • Anxiety: This is the view that certain antidepressants may induce anxiety and panic attacks, which can lead to suicidal behavior in certain patients. (There is reason to believe, however, that many clinicians have recorded a patient's reports of "anxiety" directly, without considering whether the anxiety was actually reflective of akathisia.)
  • Stage shifts: This is the view that antidepressants may cause a switch from depression into mixed states or a bipolar-like condition. Bipolar illness is known to be associated with very high rates of suicidality. The use of antidepressants does bring a risk of mood switch, even in unipolar patients.
  • Insomnia: This view says that insomnia associated with certain antidepressants may lead to suicidal behavior in some patients.

The last point on this list doesn't make much sense until you realize that suicide rates (when looked at by time of day) reach their peak at 2:00 to 2:59 a.m.

I believe good evidence exists for all of the mechanisms proposed above. The "activation" explanation is quite old and has been relied on by many clinicians to explain rollback. However, it doesn't explain the appearance of agitation and suicidality in so-called "healthy volunteer" trials (in which illness-free volunteers take a drug to prove its safety), which are a routine part of FDA Phase I trials.

In my next post, I'll address one of the above mechanisms in more detail: akathisia (which, it turns out, is much more than mere "restlessness").

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