Question. In my private practice, I have been seeing a woman for three years who is obsessive-compulsive with totally resistant depression. She also has a 10-year history of mild anxiety and migraine headaches. Her husband’s infidelity led to posttraumatic stress disorder. She has made significant suicidal attempts, and has had at least two hospitalizations. No antidepressant in any combination has ever worked for more than a week or two. A course of ECT did not work, either. What is unique is her need for Cogentin in combination with any antidepressant at a true, high, therapeutic dose. The worst of her mood instability is related to premenstrual dysphoric disorder and is clearly hormonal. She is now on Remeron, Cogentin 2 mg. qid and Xanax and Fiorinal. What can I do? What is the role of Cogentin? Where is the dopamine/acetylcholine connection in this woman?
Answer. Having seen many such patients over the years, I appreciate your vigorous approach to this patient’s care. It is rare, for example, to see a patient who has actually had both ECT and an MAOI trial, much less MAOI plus TCA. My gut feeling about this case is that, indeed, there are strong psychodynamic factors at work, but I’ll come back to that in a bit. Usually, in my experience, refractory depression of this sort turns out to be due to 1 of 4 factors:
1. Covert bipolar spectrum disorder of a very mild type;
2. Covert and subtle psychotic features that have not been addressed with antipsychotic medication;
3. Covert physical illness (such as low B-12, folate, or thyroid function); or
4. covert substance abuse/dependence..
But from what you say, neither 1 nor 2 seems very likely, and physical factors seem to have been considered by several good practitioners. Let’s assume these issues have been covered, and that this patient achieves therapeutic blood levels on her various agents. What is the problem, and what can be tried? In my experience, there is a personality type (sometimes called counter-dependent) who is outwardly quite a strong, coping, caregiver type, but is inwardly a real ball of mush. These people cope very well so long as they have successfully managed things and people, but when something goes desperately wrong, these individuals plummet like lead balloons.
They truly seem to fall apart, and sometimes they never come together again. Some of these individuals fit the hysteroid dysphoric type described by Liebowitz and Klein, but some are obsessive-compulsive types whose OC defenses simply crumble under the stress. For these people antidepressants, in my experience, are rarely successful. Moreover, these individuals (who so value control) usually hate taking meds, and experience all manner of bizarre side effects that don’t make much sense pharmacologically. Psychotherapy and support groups are usually the way to go with such individuals. I have seen some respond to MAOIs, however.
But let’s now consider some other possibilities: could this patient have a subtle, covert, subcortical (e.g., basal ganglia) dementing process of some sort? Could that account for her peculiar EPS in response to so many agents? Perhaps an MRI would be helpful to rule out this possibility. I am not sure if she experienced dystonic reactions, or akathisia primarily. If the latter, this may be more related to noradrenergic mechanisms than to the dopamine/acetylcholine (DA/Ach) ratio; that may be why akathisia responds to beta blockers in some cases, but we really don’t know the pathophysiology of akathisia. Of course, the cholinergic model of depression would predict that anticholinergic agents tend to elevate mood; so part of this patient’s need for Cogentin may relate to its mood-elevating properties. Could the chronic use of Fiorinal partly account for her refractory depression? While the time course doesn’t really seem to fit, it is still true that Fiorinal and barbiturates in general can sometimes exacerbate depression, it certainly can’t be doing this patient much good.
What can be tried, beyond the foregoing suggestions? I am assuming she has had a trial on venlafaxine; if not, I’d certainly consider it. First, I would certainly push the Remeron up to the maximum therapeutic dose she can tolerate, ideally, up to 45 mg/day, perhaps in divided doses, but mainly at h.s. note the possibility of Remeron/Xanax interaction via CYP-3A4. It may be necessary to reduce Xanax doses as the Remeron dose is increased). It may be worth trying to potentiate the Remeron with a small amount (5-10 mg) of methylphenidate, though there has been little experience with this maneuver. Since Remeron works primarily on NE and 5-HT, it could also in theory be potentiated by a dopamine agonist. I have used pergolide (Permax) in combination with SSRIs and MAOIs, and it has been well-tolerated in one very refractory case, a patient now taking Nardil and pergolide. For information on pergolide, see Bouckoms et al, Psychopharmacol Bull 1993;29:207-21). Since the patient has had no trials on anticonvulsants, and since she does have some mood instability, I would not rule out a trial on carbamazepine (CBZ). In rare cases, this may convert a refractory depression into a responder (see de la Fuente and Mendlewicz, Biol Psychiatry 1992;32:369-374). Of course, CBZ can reduce plasma levels of many other agents, and should probably not be used with Remeron, since both can have effects on the bone marrow (1 in 1000 risk of agran. with Remeron).
Other options to consider: combination of L-deprenyl and phenylalanine; MAOI plus pergolide, as above; re-trial of ECT (bilaterally); trial on low-dose risperidone or olanzapine (obviously, these are off-label uses, and carry some risk of tardive dyskinesia, etc., but there are indications that both agents have some antidepressant properties, and in a patient with several suicide attempts, I don’t think any reasonable option should be excluded).