REVIEW OF: Liang L et al, Transl Psychiatry 2022;12(1):4

STUDY TYPE: Systematic review and meta-analysis of randomized controlled trials

Mitochondrial dysfunction is thought to play a role in bipolar disorder, and several controlled trials have examined whether nutritional supplements that support energy production in the mitochondria can treat bipolar depression. This meta-analysis gathered that evidence together for a big-picture view.

The authors identified 13 randomized, placebo-controlled trials that investigated the antidepressive effects of specific mitochondrial modulators in bipolar depression: N-acetylcysteine (NAC; four trials); omega-3 polyunsaturated fatty acids (three trials); inositol (two trials); and one trial each of coenzyme Q10 (CoQ10), creatine monohydrate, vitamin D, and acetyl-L-carnitine/alpha-lipoic acid combination. The primary outcome was the standard mean difference (SMD, aka effect size) based on changes in the Montgomery-Åsberg Depression Rating Scale or the Hamilton Depression Rating Scale. Using Cochrane guidelines, the authors determined that there was a low risk of publication bias among the studies. The total sample size was 605.

Overall, the mitochondrial modulators significantly reduced depression severity compared to placebo, with a moderate effect size (SMD=0.48; 95% CI=[0.14, 0.83]; p=0.007). However, only NAC and CoQ10 individually demonstrated significant reductions in depression severity. Since CoQ10 was only examined in one study, the pooled effect size was mainly driven by NAC, with a wide confidence interval (CI) around NAC’s effect size (SMD=0.88; 95% CI=[0.27, 1.48]; p=0.005). A wide CI means there is more uncertainty about the actual effect size of NAC. It could be as small as 0.27 or as large as 1.48, but it’s important to note that even the lower end of this range still indicates a positive effect on reducing depression severity. A possible explanation for this variance is that NAC takes a long time to work. The longer-term trials (greater than four months) tend to be positive, while the short-term studies tend to be negative.

NAC is safe and well tolerated, with a recommended dosage of 2,000 mg daily.

CARLAT TAKE 

We’re not convinced that there is a class effect with mitochondrial agents, but NAC is worth trying when other options fail in bipolar depression and the patient prefers a nonmedication approach.