Lithium Compared With Newer Therapies as Adjunct to Antidepressants

The likelihood of help or harm, also known as the risk/benefit ratio, was found to be more favorable for lithium.

When assessing the efficacy and tolerability of adjunctive agents used to supplement standard treatment for acute major depressive episodes, lithium appears to be somewhat superior to second-generation antipsychotics (SGAs) and intranasal esketamine, according to the findings of a systematic review and meta-analysis recently published in the Journal of Psychopharmacology.

To clarify the efficacy and tolerability of adjunctive treatment options for major depression, the study authors obtained data from randomized, placebo-controlled trials to calculate the odds ratio (OR) vs placebo, the numbers-needed-to-treat (NNT), and the numbers-needed-to-harm (NNH) when adding SGAs, esketamine, and lithium to antidepressant therapy. The analysis included a total of 49 drug-placebo pairs.

“Random-effects meta-analysis of trials of adding SGAs vs placebo to antidepressants yielded highly significant superiority of SGAs overall (OR, 1.59; 95% CI, 1.44-1.75; z = 9.16, P <.0001),” the study authors reported. Findings also showed that the efficacy of lithium was the highest among the agents evaluated (OR, 2.22; 95% CI, 1.44-3.43; P =.0003) and that the efficacy ofesketamine was between SGAs and lithium (OR, 1.94; 95% CI, 1.52-2.46; P <.0001). 

Based on findings assessing NNT, lithium was found to be the most effective adjunctive therapy compared with placebo (NNT, 5; 95% CI, 4-10), followed by esketamine (NNT, 7; 95% CI, 5-10), and SGAs overall (NNT, 11; 95% CI, 9-15). Regarding individual SGAs, aripiprazole, olanzapine plus fluoxetine, risperidone, and ziprasidone were found to be more effective, with NNT values less than 10, compared with quetiapine (NNT, 13), brexpiprazole (NNT, 16), and cariprazine (NNT, 16).

Lithium was observed to be the most tolerable adjunctive therapy (NNH, 9; 95% CI, 5-106), followed by intranasal esketamine (NNH, 5; 95% CI, 4-6) and all SGAs pooled (NNH, 5; 95% CI, 4-6). When the SGAs were assessed individually, quetiapine was found to have the highest NNH (3) and brexpiprazole had the lowest (19). The likelihood of help or harm (LLH), also known as the risk/benefit ratio (NNH/NNT), was also found to be more favorable for lithium (LHH, 1.80; 95% CI, 1.25-10.60) compared with esketamine (LHH, 0.71; 95% CI, 0.60-0.80) and all SGAs pooled (LHH, 0.45; 95% CI, 0.17-0.77).

The authors did note that most of the trials involving lithium as an adjunct therapy involved older antidepressants.  

“Based on meta-analyses to determine the OR and NNT, several modern drugs developed as antipsychotics as well as intranasal esketamine were effective as adjuncts to antidepressants for acute major depressive episodes, but lithium was somewhat more effective and better tolerated,” they concluded. “The findings encourage clinical consideration of lithium as a particularly attractive adjunct in the treatment of major depression.”


Vázquez GH, Bahji A, Undurraga J, Tondo L, Baldessarini RJ. Efficacy and tolerability of combination treatments for major depression: Antidepressants plus second-generation antipsychotics vs. esketamine vs. lithium. Journal of Psychopharmacology. Published online July 9, 2021. doi: 10.1177/02698811211013579.

This article originally appeared on MPR