Letters to the Editor
Reply: Hemorrhages During Escitalopram–Venlafaxine–Mirtazapine Combination Treatment of Depression
Dear Editor: I thank Dr Al-Adwani for his comments on the treatment of resistant depression, as the topic is a hot one. There are several guidelines on the treatment of depression, which should be distinguished as bipolar disorder I, bipolar disorder II, and major depressive (unipolar) disorder. Among these disorders, the treatment of bipolar II depression is the most understudied, even if bipolar II depression is at least as common as unipolar depression in nontertiary care outpatients (1,2). The several guidelines on the treatment of bipolar and unipolar depression follow different steps. What matters most is that these guidelines are the result of a consensus among academic experts, based on literature reviews and personal opinions, not on data from usual clinical practice. The result is that these guidelines are detached from real-world clinical practice (described as an “often irrelevant evidence base” for clinical practice; 3). Even if we rely on the evidence we can find in the literature, this is of little help; at most it may guide the choice of a second antidepressant when the first one has failed. I have been in clinical practice for 21 years with the National Health Service as part-time consultant and with my private outpatient practice. In this latter setting (which is also the setting of most of my studies), I have thousands of visits yearly. Patients often come to see me after the failure of 1 or 2 antidepressants. When lithium was more in fashion than today, in the 1980s and early 1990s, I used it to boost antidepressants, but the results were often negative. (This difference between literature evidence on the efficacy of lithium added to antidepressants and clinical practice evidence has been reported; see 3.) When some monotherapy trials of antidepressants fail in unipolar depression, most clinicians combine 2 antidepressants with different actions (for example, fluoxetine and desipramine), but this step may fail. Next, a combination of antidepressants with different mechanisms of action may also be tried. The steps I follow in the highly treatment-resistant unipolar depressions (which are different from the steps to be followed in bipolar II depression and in bipolar I depression) are the following: If I get some improvement with 1 full-dose anti- depressant, I add a second one with different biological actions. If this combination works but depression still impairs functioning, I prefer to keep the advantage reached at this stage and to proceed by adding a third antidepressant. If I changed the first or the second antidepressant when I added the third one, I would run the risk of losing the improvement achieved with the first 2 antidepressants if the third antidepressant did not work. As these depressions continue for months, a deterioration of clinical status is very painful (and risky) for these patients. By carefully titrating dosages, I have rarely seen mild serotonin syndromes and mild cardiovascular side effects. When people have this painful (and suicidal) state of multiple antidepressant-resistant depression, I have to do what seems logical to me in the absence of research evidence available for clinical practice. If I wanted to stay on the safe side (legally), I could use 1 antidepressant after the other, taking years to try all of them! The hopelessness of a person living with a severe depression for many months is great, and the suicide risk is also high. As clinicians (not as researchers), it is our duty to save the lives of these people and to dare to go beyond the reassuring (but not based on clinical practice evidence) guidelines when we have to treat a severe, suicidal depression. ECT would be a useful step, of course, but it is not readily available in Italy.
References
1. Benazzi F. Family history validation of a definition of mixed depression. Compr Psychiatry 2005;46:159–66.
2. Angst J, Gamma A, Benazzi F, Ajdacic V, Eich D, Rossler W. Toward a re-definition of subthreshold bipolarity: epidemiology and proposed criteria for bipolar-II, minor bipolar disorders and hypomania. J Affect Disord 2003;73:133–46.
3. March JS, Silva SG, Compton S, Shapiro M, Califf R, Krishnan R. The case for practical clinical trials in psychiatry. Am J Psychiatry 2005;162:836–46.
Franco Benazzi, MD, PhD
Forlí, Italy
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