Alternative approaches to refractory depression in bipolar illness

Robert M. Post, Gabriele S. Leverich, Kirk D. Denicoff, Mark A. Frye, Tim A. Kimbrell, Robert Dunn

Research output: Contribution to journalArticlepeer-review

43 Scopus citations


Thus, there appears to be a large variety of approaches to refractory bipolar depression. In contrast to several decades ago, wherein augmentation of lithium with antidepressants and neuroleptics was essentially the only treatment mode available, a panoply of treatment options now exist. However, their relative efficacy in different illness subtypes and stages remains to be better delineated, as do their optimal sequencing and use in combination in individual patients. It is the opinion of these authors and many of our colleagues in the field that initial use of several mood stabilizer drugs in combination may have a preferable long-term outcome in some rapid cycling patients, compared with the immediate use of a unimodal antidepressant with an inadequate single mood stabilizer, although this remains to be systematically studied. The use of thyroid augmentation strategies would appear to have merit in relationship to not only the potential treatment of lithium-related hypothyroidism, but also in augmenting antimanic and antidepressant effects. As one moves toward some of the complex combination treatment strategies discussed in this chapter, one has to be particularly careful about drug interactions and their potential for toxicity as well as therapeutic effects. Perhaps a prevailing guideline would be to use these agents more carefully in combination therapy than in monotherapy, with slow upward titration of dose to individual patients' side effects thresholds, even in preference to targeting of conventional blood level windows. In this way, side effects can be avoided during the assessment of complex combination regimens. In addition, one should be aware of potential pharmacokinetic interactions. For example, with the addition of valproate to carbamazepine, one should reduce the dose of carbamazepine, as valproate will not only increase the free fraction of carbamazepine based on displacement of protein binding, but will lead to increased accumulation of carbamazepine- 10,11- epoxide. This epoxide is not measured in conventional assays but could contribute to the side effects profile (Ketter and Post, 1994). Similarly, valproate will markedly increase blood levels of lamotrigine; the starting dose of this agent should be substantially lower than conventional dosage when these two drugs are used in combination. We suggest the utility of detailed mapping with a formal system-such as the Life Chart Methodology (LCM) (Leverich and Post, 1996)-of mood fluctuation vs. medications in order to optimize and rationalize complex combination therapy. In this way, not only can the nuances of partial response be better defined, but also basic decisions about the therapeutic index and relative likelihood of response can be more readily assessed. We have discussed the other merits of the life chart method as an important clinical treatment tool as well as a research tool in other venues, but reemphasize its potential great importance in the treatment of refractory cyclic bipolar patients, in whom an initial period of remission of depression may, in many instances, be as likely attributable to the natural course of illness as the current intervention being offered. As such, it behooves the clinician to have a systematic database for the more subtle issues of dose titration and sequential addition of medications in complex combination regimens. In the face of inefficiency to one combination strategy, how one moves to the next strategy remains a highly individualized, clinically-based algorithm. We suggest the potential utility of moving towards a new set of mood stabilizers and then repeating some of the unimodal antidepressant additions and augmentation trials in an attempt to overcome refractory depression. Refractory depression in bipolar patients should be viewed as a medical emergency in light of the high potential for suicide in the illness in general (Chen and Dilsaver, 1996) and in patients who have either sustained or episodic refractory depressive breakthroughs. In this regard, it should be noted that refractory depressed patients with highly cyclic presentations of their illness often do not feel that their brief 'well' or hypomanic intervals are of benefit in enhancing a more optimistic view towards therapeutics. In fact, many patients report that cycling is more disruptive to their lives and, in some instances, they would prefer continuous depression to the episodic and unpredictable chaotic mood fluctuations that often accompany refractory bipolar illness. Thus, one should be particularly alert toward the potential for suicide in these patients and maintain a balance of hopeful optimism with careful suicide assessment in the pursuit of more optimal, even if complex, treatment algorithms. As in other late phase medical syndromes and medical emergencies, complex combination treatment is often required. While it may at first consideration seem inappropriate to consider a regimen with four or five drugs for the treatment of refractory bipolar illness, this has been elevated to standard and routine practice in many other areas of medicine, such as the treatment of malignancies, tuberculosis, or congestive heart failure. In these instances, multiple therapeutic modalities with different mechanisms of action are often combined for optimal therapeutics. With the availability of a variety of agents for bipolar illness, it now befits the field to engage in a series of novel and systematic clinical trials in order to better delineate the optimal design strategies for achieving the most rapid response rates in the highest numbers of patients, so that even the most refractory bipolar patients have an excellent chance at achieving substantial clinical remission.

Original languageEnglish (US)
Pages (from-to)175-189
Number of pages15
JournalDepression and Anxiety
Issue number4
StatePublished - 1997


  • Antidepressants
  • Bipolar illness
  • Refractory depression

ASJC Scopus subject areas

  • Clinical Psychology
  • Psychiatry and Mental health


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