Q. I am working with a 33-year-old female patient who demonstrates classic symptoms of persistent depression, lacking any manic episodes. I have tried her on several medications over the past 18 months and she is either unresponsive or intolerant of the side-effects. Medications prescribed thus far: Paxil, Zoloft, Prozac, Tegratol, Neurontin, Buspar, and Trileptal. All dosages were modified before discontinuing.

I am truly at my wits end and not sure what to do. I am considering Clorazepate, Pamelor, or Wellbutrin, but feel I am missing a helpful combination that I've yet to tap into to. Do you have any insight or suggestions?

A. Sounds like a complicated case! Of course, without evaluating the patient, I can't provide you with direct recommendations, but I do have some thoughts about how one might approach a case like this.

The most basic and critical issue, as you know, is the diagnosis. In most of the cases of apparently refractory or resistant depression that I have seen, some piece of the diagnostic puzzle was missing. Usually, the patient turned out to have a soft bipolar spectrum disorder, such as bipolar II disorder--and, of course, had never had a manic episode. For more on this, you might be interested in reading over any of Dr. Hagop Akiskal's recent papers, or my own attempt to cover this issue (July 2002, Journal of Psychiatric Practice).

Unsuspected substance abuse and/or Axis II disorders, such as Borderline PD, also need to be ruled out. And, of course, unsuspected medical disorders, such as mild hypothyroidism or B12/folate deficiency, also need to be ruled out, as I am sure you have already done!

I am particularly interested in your choices of Tegretol, Trileptal, and Neurontin--all anticonvulsants, with the first two considered true mood stabilizers (Neurontin has not really panned out in that respect). What sort of symptoms prompted your choice of those agents? Was it irritability or mood lability? Anxiety? Insomnia? Could this patient's intolerance of side effects indicate that she was becoming irritable or hypomanic on antidepressants? Anyway, I would re-examine this issue very closely, looking for subtle manifestations of bipolar spectrum disorder.

Second question: is there a pattern to the side effects she gets? For example, does she seem to be intolerant only of agents metabolized via CYP 2D6, such as Paxil and Prozac? (Perhaps she is a poor metabolizer in that cytochrome system). Does she react poorly to very low doses and develop very unusual symptoms, not commonly recognized with the agent? (In my experience, this often indicates a psychogenic origin of the side effects--how is she doing in her psychotherapy, and is that provided by you?). When the patient shows no response at all to an agent, has she shown adequate plasma levels of the agent in question? (She might be a rapid metabolizer or poor absorber--or not taking her meds).

Let's assume all these questions have already been settled, and that your patient has truly been refractory to adequate doses/plasma levels of antidepressants, for an adequate period of time (at least 6 weeks trials, if not longer). Before going to combination treatments, I would select one of the dual-action antidepressants, such as venlafaxine or mirtazepine, aiming to increase serotonin and norepinephrine. A dopamine agonist, such as amantadine, could be added if one or the other of these agents at adequate doses yields a partial response. (For complete non-responders to any agent, I advise discontinuing the agent).

Adding bupropion (Wellbutrin) to one of the SSRIs is also a reasonable strategy for partial responders to SSRIs. Since the SSRIs are not all the same biochemically, you might consider a trial on, say, citalopram--with augmentation using bupropion if there is a partial response. (Again, I would discontinue the agent if there is absolutely no response). Certainly, for many refractory patients, the gold-standard tricyclic antidepressants are good choices, notwithstanding their potential toxicity, either as monotherapy or as augmenters. (All this assumes, of course, that the patient is NOT bipolar--since TCAs can often provoke a switch into mania).

For the anxious/phobic/histrionic or atypical depression, the MAOIs are greatly under-utilized and often very effective agents. Lithium and lamotrigine are useful not only in bipolar depression, but as augmenting agents in unipolar depression (the literature is stronger for lithium on that point, but anecdotal reports suggest that lamotrigine may be useful in refractory unipolar depression).

Finally, of course, ECT is still the most effective somatic treatment we have for severe, refractory depression. In discussing medications, I don't want to under-rate the importance of re-examining the type of psychotherapy, and how the patient seems to react to that-is it psychodynamically-oriented? Cognitive-behavioral? Has she shown strong negative transference reactions? Etc.

There are many other agents that could be considered in severe refractory depression, but before turning to those, I would suggest obtaining a second opinion from a specialist at a mood disorders clinic. I also highly recommend the book "Treatment-Resistant Mood Disorders", edited by Amsterdam, Hornig, and Nierenberg (Cambridge U. Press). This is an encyclopedic work covering all aspects of this frustrating and complicated area.

I hope these suggestions are of some help-good luck!

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July 2003

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