Lithium for Severe Depression

“We were actually surprised to find that SSRIs and other antidepressants aren’t really very effective at keeping depressed patients out of hospital. It seems like lithium is a lot more effective than any antidepressant,” said the principal investigator in a recent Finnish population study.¹

This was not a randomized trial. But it did have a strength: sheer size. Dr. Tiihoneh and colleagues studied . . . their entire population!² Of all 123,712 patients hospitalized in Finland for severe unipolar depression during 1987-2012, 40% were re-hospitalized. In 8 years of follow-up after the first hospitalization, those who were taking lithium were just under half as likely to be rehospitalized, compared with the group not taking lithium.

Granted, this is a rather crude measure of treatment effectiveness. Long-term assessment of mood or quality of life would be nice, as attempted in a similar Cochrane review of lithium for unipolar depression by Andrea Cipriani and colleagues.³ But such detailed follow-up is difficult, compared to population-based measures like rehospitalization; data quality was insufficient to report on anything but rehospitalization.

This Cochrane review did not find superiority of lithium over antidepressants for prevention of rehospitalization in unipolar depression. But their net sample size was only 475 patients (assembled from multiple studies in a meta-analysis). So while the Finnish result is stunning, it emerges only because they were looking at a vast number of patients. Remember, statistical significance is a function of sample size as well as treatment efficacy.

Statistical blip or clinical guide?
So is the Finnish finding just an interesting statistic, or should it change your practice? To put this in more direct terms: if your patient is hospitalized for depression after a suicide attempt, should she leave there on lithium? Does the benefit depend on “how bipolar is she?” Several recent studies help address these questions.

In a recent study from Sweden, Jie Song and colleagues studied 51,535 patients who were started on lithium or valproate for bipolar disorder.⁴ The incidence of suicide attempts decreased 14% during lithium treatment but not during valproate treatment. But again, this was a population-based study that found a significant result in part because of the huge sample size. Better would be a randomized trial of lithium looking specifically at the prevention of suicide attempts.

Remarkably, a team from New York completed such a study in 2011. Maria Oquendo (yes, our recent APA president) and colleagues studied patients with bipolar disorder who had a previous suicide attempt.⁵ They randomized patients to lithium or valproate (plus whatever else they needed) and followed them for-get this-nearly 3 years. Fortunately, in that time there were only 18 suicide attempts among their 98 subjects. But as a result, statistical power was low, only enough to detect a 5-fold advantage of one agent over another. Darn-okay, forget that approach.

What if you put together all the patients who were randomized to lithium for a mood disorder (of any kind) versus other medications, and looked at suicide rate? Another Cochrane study by Dr. Cipriani used this approach.⁶ Of 3458 patients, the 40% who received lithium were less likely to die by suicide (2 versus 11 suicides; odds ratio = 0.26-one quarter the rate). Comparison treatments ranged from placebo to amitriptyline to carbamazepine and lamotrigine.

Conclusion
Lithium has already shown value as an augmentation agent in Major Depression: in recent meta-analyses, augmentation with lithium was nearly 3 times more likely to produce a response than placebo.^7,8 Forty percent showed response versus 14.4% in the placebo group, for a number needed to treat (NNT) of 5: you’d need to treat 5 patients with lithium to see an effect of statistical magnitude; a less pronounced effect could be seen in even fewer patients.⁷ True, the antidepressants in these studies were mostly tricyclics, though 3 of 9 studies used SRIs⁸; do we have to wait for yet more studies with newer antidepressants? I think the Finnish population data, while they do not specify an NNT, are compelling-especially given the size of the effect seen (50% lower rehospitalization rate). As advocated in the most recent review,⁹ if my patient was hospitalized with severe depression, and there were no contraindications, she’d likely leave on lithium-regardless of how bipolar she is.

References:

1. Lähteenvuo M, interviewed in Jancin B. Rethinking lithium: it keeps patients with unipolar depression out of the hospital. Clinical Psychiatry News. October 29, 2017.

2. Tiihonen J, Tanskanen A, Hoti F, et al. Pharmacological treatments and risk of readmission to hospital for unipolar depression in Finland: a nationwide cohort study. Lancet Psychiatry. 2017;4:547-553.

3. Cipriani A, Smith K, Burgess S, et al. Lithium versus antidepressants in the long-term treatment of unipolar affective disorder. Cochrane Database Syst Rev. 2006;4:CD003492.

4. Song J, Sjölander A, Joas E, et al. Suicidal behavior during lithium and valproate treatment: a within-individual 8-year prospective study of 50,000 patients with bipolar disorder. Am J Psychiatry. 2017;174:795-802.

5. Oquendo MA, Galfalvy HC, Currier D, et al. Treatment of suicide attempters with bipolar disorder: a randomized clinical trial comparing lithium and valproate in the prevention of suicidal behavior. Am J Psychiatry. 2011;168:1050-1056.

6. Cipriani A, Pretty H, Hawton K, Geddes JR. Lithium in the prevention of suicidal behavior and all-cause mortality in patients with mood disorders: a systematic review of randomized trials. Am J Psychiatry. 2005;162:1805-1819.

7. Bauer M, Adli M, Ricken R, et al. Role of lithium augmentation in the management of major depressive disorder. CNS Drugs. 2014;28:331-342.

8. Nelson JC, Baumann P, Delucchi K, et al. A systematic review and meta-analysis of lithium augmentation of tricyclic and second generation antidepressants in major depression. J Affect Disord. 2014;168:269-275.

9. Smith KA, Cipriani A. Lithium and suicide in mood disorders: updated meta-review of the scientific literature. Bipolar Disord. 2017;19:575-586.