During more than 25 years of clinical practice as a psychopharmacology consultant, many patients were referred to me with so-called “refractory depression.” Most, in fact, had been misdiagnosed with recurrent unipolar depression that “failed to respond to antidepressants.” With careful assessment and observation over many months, these patients usually proved to have conditions that fell along the spectrum of (for lack of a better term) bipolarity. Most had never experienced a frank manic episode, and, rather than having classic “DSM” hypomanic periods, most had experienced strong dysphoric reactions to antidepressants —a phenomenon I discussed some years ago under the rubric of ARAD (antidepressant-induced agitation and dysphoria). These ARAD patients did not “switch” while taking antidepressants, in the formal sense of meeting DSM-4 criteria for mania or hypomania; rather, they almost always felt “wired”, “antsy” and irritable. They typically slept poorly and got into frequent altercations when taking antidepressants. (I discuss ARAD in a podcast on antidepressants and bipolar disorder.) My experience as a consultant eventuated in the development of a scale for detecting the “softer” end of the bipolar spectrum, the BSDS, which Dr. Ghaemi co-developed with me. I also discovered that many of these patients did very well on lithium, either as monotherapy, or--in some cases--in combination with valproate or a low dose of an antipsychotic agent. Once on lithium, many of these patients no longer required antidepressants to ward off serious depressive periods (though it’s doubtful that the antidepressants actually did this).
The December 2015 PL issue observed that as little as 300 mg/day of lithium could reduce suicidal tendencies. Indeed, PL added that, with respect to its anti-suicidal properties, "...there is no minimum effective dose" of lithium. While the same cannot be said with respect to lithium's mood stabilizing properties in bipolar disorder, my experience (and some recent research) suggests that quite low doses of lithium may be beneficial in a subset of patients with bipolar spectrum disorders. This was critical in my practice, since many of my ARAD patients had difficulty tolerating the (expectable) side effects of lithium at standard doses and blood levels; e.g., 300 mg tid, with serum Li levels somewhere in the range of 0.6-0.9 mEq/L (as maintenance). To my surprise, however, I found that a subset of these bipolar spectrum patients could maintain relative mood stability on doses of lithium as low as 300-450 mg/day, with blood levels in the range of 0.3-0.5 mEq/L. A few required adjunctive valproate to maintain stability. Of course, these were patients in clinical practice, not research subjects randomized to low-dose lithium in a placebo-controlled study. And so, as PL would no doubt remind us, my observations must be taken with a large grain of lithium salts! Still, after seeing 50 or more such cases, I reached a state of “provisional belief” in the benefits of low-dose lithium.
Indeed, there is growing interest in the use of very low doses of lithium, not only in the prevention of suicidal behavior, but also in the management of bipolar disorder—and perhaps even in the treatment of some neurodegenerative disorders. Although recent results are mixed, some older data point to the utility of serum lithium levels as low as 0.46 in bipolar patients, with reduction of affective episodes and overall morbidity. One of the unfortunate aspects of psychiatric training in the last 30 years has been the neglect of lithium—with many recent residency graduates having little experience with this remarkable element. Perhaps it’s time to re-discover a remedy whose therapeutic uses may date back to ancient Rome!