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

Abstract

Introduction: Lipodystrophy (LD) syndromes are rare heterogeneous disorders characterized by reduction or absence of subcutaneous fat, low or non-detectable 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. Methods: In this ancillary study ten 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 pre-established 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. Results: According to their BDI scores, four patients had mild depression and two 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 vs. T2 (p=0.002, r=0.99) and T1 vs. T3 (p=0.007, r=0.79). Discussion/Conclusion: 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 one week of treatment. A reduction of the depression score was also observed in two of the three LD patients whose BDI scores were in the normal range before start of the treatment. The reduction in total scores of BDI were still apparent after three 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.

Positive effect of leptin substitution on mood and behaviour in patients with congenital leptin deficiency

“…The behavioural effects of metreleptin substitution have recently been evaluated in patients with more common causes of hypoleptinemia, namely lipodystrophy and anorexia nervosa. In a cohort of 10 patients with partial lipodystrophy with low serum leptin concentrations, a significant improvement in a depression score under metreleptin substitution was seen, with changes already visible after 1 week of treatment 43 …”

“…In a cohort of 10 patients with partial lipodystrophy with low serum leptin concentrations, a significant improvement in a depression score under metreleptin substitution was seen, with changes already visible after 1 week of treatment. 43 In five patients with acute anorexia nervosa and hypoleptinemia, metreleptin treatment was also associated with a pronounced improvement of depressed mood. 31,32,44 Interestingly however, anorexia nervosa associated hyperactivity decreased under metreleptin substitution.…”

Case report: Rapid improvements of anorexia nervosa and probable myalgic encephalomyelitis/chronic fatigue syndrome upon metreleptin treatment during two dosing episodes

“…Metreleptin treatment for six to 24 days was associated with a rapid onset and reduction of starvation related symptoms including preoccupation with food, fatigue, depression, inner tension, rigidity, urge to move and hyperactivity. Limited evidence suggests that metreleptin treatment may also have antidepressant effects in other conditions associated with inborn or acquired leptin deficiency (5,7,8).…”