Suggestive Evidence for an Antidepressant Effect of Metreleptin Treatment in Patients with Lipodystrophy

Lipodystrophy (LD) syndromes are rare heterogeneous disorders characterized by reduction or absence of subcutaneous fat, low or nondetectable leptin concentrations in blood and impaired hunger/satiety regulation. Metreleptin treatment reverses metabolic complications and improves eating behavior in LD. Because depression in anorexia nervosa (AN), which is also characterized by hypoleptinemia, improves substantially upon treatment with metreleptin, we hypothesized that metreleptin substitution may be associated with an antidepressant effect in patients with LD, too.

In this ancillary study, 10 adult patients with LD were treated with metreleptin. To assess depressive symptoms, the self-rating questionnaire Beck's Depression Inventory (BDI) was filled in at preestablished time points prior (T1) and after initiation of metreleptin (T2: 1 week; T3: 4 weeks; T4: 12 weeks) dosing. The differences between time points were tested with nonparametric Friedman's analysis of variance. Sensitivity analyses were performed upon exclusion of the BDI items addressing appetite and weight changes.

According to their BDI scores, 4 patients had mild depression and 2 had moderate depression at baseline. Friedman's test revealed significant differences in BDI scores between the four time points. Post hoc analyses revealed that the difference between T1 and T3 was significant upon Bonferroni correction (p = 0.034, effect size r = 0.88). The sensitivity analyses upon exclusion of the appetite and weight change items again revealed a significant Friedman's test and significant Bonferroni corrected differences in the revised BDI scores between T1 versus T2 (p = 0.002, r = 0.99) and T1 versus T3 (p = 0.007, r = 0.79).

Our study for the first time revealed suggestive evidence for an antidepressant effect of metreleptin in patients with LD. Metreleptin caused a rapid drop in depression scores within 1 week of treatment. A reduction of the depression score was also observed in 2 of the 3 LD patients whose BDI scores were in the normal range before start of the treatment. The reduction in total scores of BDI was still apparent after 3 months (T4) of dosing. This observation matches findings obtained in clinical case studies of AN patients, in whom depression scores also dropped during the first week of metreleptin treatment. It needs to be noted that by the nature of this observational study without a placebo group, nonspecific treatment expectation affecting mood cannot fully be ruled out.