Wednesday, January 14, 2015

Do Mood Stabilizers Work for Depression?

Because modern antidepressants so often fail to give people relief, it's become fashionable in recent years for prescribers to add an adjunctive mood stabilizer (such as Lamictal, Depakote, lithium, valproate, or Tegretol) into a patient's antidepressant mix, yielding a so-called "cocktail" aimed at producing better results. This is a particularly popular approach with bipolar illness (where mood stabilization is critical), although it's also increasingly used in treatment of unipolar depression.

I decided to take a look at the scientific literature to see what evidence there is that such cocktails work. I almost wish I hadn't.

I was stunned to find that the evidence on adjunctive mood stabilizers is both scanty and low-quality, with studies often unblinded as to assessment, open-label (unblinded as to the patient's knowing what he's taking), with small study populations, and producing no clinically significant effect.

One study of lamotrigine (Lamictal, a popular, well tolerated anti-seizure medication with mood-stabilizing side effects) involved just 14 people. Another involved 31 patients. A study with 40 patients found "Adjunctive treatment with lamotrigine did not result in a significant difference in HAM-D total score at the endpoint of the study when compared with paroxetine alone." Another study, with just 20 patients (and no placebo arm), found "there was no significant difference between treatment groups." Another (a lamotrigine monotherapy study) looked at depression-score improvements in 32 epilepsy patients (and 38 controls); this was, at least, a randomized, double-blind, placebo controlled study. And it did find significantly better improvement on Beck Depression Inventory scores, after 12 weeks, for the lamotrigine group (8.9 point drop) versus the placebo group (1.7 point drop), but two things need to be noted about this otherwise-good study. First, the patients (with an average Beck score of 18, at the beginning) were not very depressed. (Moderate depression is 19 to 29 on the Beck scale.) Secondly, when your epileptic seizures go away (which they did tend to, in this study) your mood naturally tends to lighten quite a bit. The investigators claimed to have corrected for this. I don't believe it for a second. You'd have to be crazy to count this study as "proof positive" that lamotrigine works for depression (in non-epileptic patients, particularly).

When I eventually stumbled onto a double-blind, placebo-controlled study involving 350 bipolar patients, published in The New England Journal of Medicine, I thought I'd hit the jackpot. This study, by Sachs et al. (2007), seemed like it would finally shed light on the whole mood-stabilizers-plus-antidepressants issue. But it turns out to be a real mess, one of the shoddiest, muddiest piece-of-crap studies I've ever seen in NEJM, which many consider to be a top-flight journal.

Even if we overlook the conflict of interest issue, namely the fact that most of the paper's 20 authors have received "consulting" and speaking fees from Abbott Labs, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Merck, Pfizer, Sanofi, and Wyeth (indeed, many individual authors received fees from every one of these companies), we're left with a horribly complex study design in which patients received either bupropion (Wellbutrin) or paroxetine (Paxil) as an antidepressant, or a placebo, combined with a mood stabilizer consisting of lithium or valproate or a combination of lithium and valproate or carbamazepine (Tegretol); and then, in 2004, "the protocol was amended to define mood stabilizers operationally as any FDA-approved antimanic agent." When you look to see what the latter means, it means (for 8% of one group and 11% of another group) "atypical antipsychotic drugs" that are never named! Nowhere in the study are we told the identity of the "atypical antipsychotic drugs," no doubt to avoid embarrassment of sponsors.

Even though a third of people left the study (and another 7% had worsening of symptoms; think about that), there is no intent-to-treat analysis, per se. We're merely advised that "Except where noted, analyses are based on the last observation carried forward."

The study ran 26 weeks (which is fairly long) and used a stringent outcome measure: 8 weeks of euthymia (remission, essentially). The measurement tool for this? "A standardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition." Except, after you adapt something, in what sense is it now "standardardized"?

Parsing this study only makes me crazy, so let me cut to the chase and mention the principal finding, which was that 23.5% of patients receiving a mood stabilizer plus antidepressant therapy had a durable recovery, whereas  27.3% of those receiving a mood stabilizer plus a matching placebo met remission standards. (Yes, you read that right: the placebo group outperformed the treatment group. And yes, they considered an antidepressant to be the adjunctive drug, not mood stabilizers.) What they really found, of course, is that neither Wellbutrin nor Paxil is efficacious for bipolar illness when measured against lithium, valproate, lithium plus valproate, Tegretol, or unnamed atypical antipsychotics.

Naturally, the authors try to spin the results as positively as they can, but their Conclusion says it all:
The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder.
Longer-term studies? Longer than 26 weeks? Are you kidding me? Seriously?

Goodwin et al. (2004) did find, in a pooled analysis of two 18-month double-blind studies of lamotrigine monotherapy (versus placebo) that lamotrigine (Lamictal) was superior to placebo in extending the time between interventions for depression, but cites "median survival: placebo, 270 days [95% CI = 138 to not calculable]; lithium, median not calculable; lamotrigine, median not calculable." So I'm not sure what their conclusion is based on, and anyway, who cares about times between intervention? What about obviating the need for an intervention?

I haven't done an exhaustive, systematic review of the literature. However, Ryan J. Van Lieshout and Glenda M. MacQueen (BJPsych, 2010) did do such a review. Because of heterogeneity of study designs, this systematic review deserves to be read in detail. The authors did find that mood stablizers (in the 10 studies that were looked at for clinical response) produced a signifcant effect relative to placebo in monotherapy (no antidpressant used); risk ratio was expressed as 1.3. For adjunctive use-cases (antidepressant plus mood stabilizer), across six studies involving 1,322 participants, combination therapy was not superior to monotherapy (RR= 0.85).

You can find good quality studies that show a beneficial effect of lamotrigine in monotherapy for bipolar depression; but in bipolar, you're looking to stabilize mood (eliminate or reduce mood-switches), and so outcomes are often measured on that basis (rather than on a basis of treating depression, per se). Extrapolating bipolar results to unipolar depression is thus (in my opinion) ill advised. Very few good-quality studies (in fact, none that I could find) specifically address the adjunctive use of mood stabilizers in treatment of unipolar depression. The systematic literature review by Vigo and Baldessarini (2009) on this subject found "suggestive evidence of beneficial effects of carbamazepine, lamotrigine, and valproate that require further study, especially for long-term adjunctive use." I think that probably sums it up. The evidence is suggestive, at best, and the whole matter needs further study.

The science I saw was shoddy, scant, and unconvincing. Much of it should never have been published in the first place.

I'm 100,000 words into a book about mental illness—part science, part memoir—based on my experience with bipolar illness and my wife's experience with schizoaffective disorder. Please add your name to the mailing list to be notified when free sample chapters are ready. And if you know someone who may benefit from this kind of info, please pass the word along. Thanks so much!


  1. Kas, do you know of the Science Based Medicine site? Because this is the kind of article they publish, and I bet they would be happy to repost it.

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