INCREASED CORTICAL THICKNESS IN LATE-LIFE DEPRESSION AFTER ANTI-DEPRESSANT TREATMENT WITH LEVOMILNACIPRAN

Abstract

Introduction Late-life depression (LLD) is associated with significant medical comorbidity, cognitive impairment, and suboptimal treatment response compared to depression in younger adults. More efficacious treatment to improve mood, cognition and quality of life in LLD are urgently needed. Levomilnacipran (LVM) is a novel anti-depressant whose effects on neuroplasticity have not yet been studied. We investigated the effect of LVM on brain cortical thickness in a randomized placebo-controlled trial. Methods Twenty-nine older adults (>60 years) with major depression (48.3% female; mean age=71.5[SD=5.8] years; mean education=16.0[SD=1.7] years) were randomized to either LVM or placebo for 12 weeks. T1-weighted images were acquired at baseline and 12-weeks using a Siemens 3T Prisma system. Freesurfer version 6.0 was used for cortical reconstruction and a whole-brain longitudinal voxel-wise two-stage model was used to investigate between-group differences in symmetrized percent change in cortical thickness from baseline to post-treatment. Age and total intracranial volume were used as covariates. Results Fifteen participants (6 LVM and 9 placebo) completed the study. Both groups improved on the Montgomery-Åsberg Depression Rating Scale (MADRS; main effect of time F(8,111)=5.4, p<.0001; mean ΔMADRS improvement: LVM, -6.37 (SD=2.13), t(111)=2.99, p=.003; placebo, -7.10 (SD=1.91), t=3.71, p=.0003). Dropout and remission rates did not differ between the groups (Fisher exact>=0.07). The LVM group had significantly more side effects compared to placebo (p=0.03). No serious side effects were reported. In addition, the LVM group showed larger increases in cortical thickness in the right postcentral gyrus (primary somatosensory) X=44, Y=-26.9, Y=53.8; cluster size=966mm2), the precentral gyrus (primary motor) (X=17.3, Y=-22.1, Z=15.7; 948.9mm2), and the lateral occipital cortex (visual cortex) (X=19.6, Y=-94.9, Z=15.7; 930mm2) compared to the placebo group. Conclusions Both LVM and placebo groups showed a clinically significant improvement in depression severity over 12 weeks without significant group differences. Side effects were significantly higher with LVM treatment compared to placebo. However, the LVM group demonstrated a gain or preservation of cortical thickness in primary sensorimotor and visual regions compared to the placebo group. Larger and longer follow up studies are required to explore the effect of LVM on neuroplasticity in relationship to clinical outcomes and side effects. This research was funded by Forest research Institute LVM-IT-02 (Allergan Fetzima Study IIT-10018); NCT02466958 Late-life depression (LLD) is associated with significant medical comorbidity, cognitive impairment, and suboptimal treatment response compared to depression in younger adults. More efficacious treatment to improve mood, cognition and quality of life in LLD are urgently needed. Levomilnacipran (LVM) is a novel anti-depressant whose effects on neuroplasticity have not yet been studied. We investigated the effect of LVM on brain cortical thickness in a randomized placebo-controlled trial. Twenty-nine older adults (>60 years) with major depression (48.3% female; mean age=71.5[SD=5.8] years; mean education=16.0[SD=1.7] years) were randomized to either LVM or placebo for 12 weeks. T1-weighted images were acquired at baseline and 12-weeks using a Siemens 3T Prisma system. Freesurfer version 6.0 was used for cortical reconstruction and a whole-brain longitudinal voxel-wise two-stage model was used to investigate between-group differences in symmetrized percent change in cortical thickness from baseline to post-treatment. Age and total intracranial volume were used as covariates. Fifteen participants (6 LVM and 9 placebo) completed the study. Both groups improved on the Montgomery-Åsberg Depression Rating Scale (MADRS; main effect of time F(8,111)=5.4, p<.0001; mean ΔMADRS improvement: LVM, -6.37 (SD=2.13), t(111)=2.99, p=.003; placebo, -7.10 (SD=1.91), t=3.71, p=.0003). Dropout and remission rates did not differ between the groups (Fisher exact>=0.07). The LVM group had significantly more side effects compared to placebo (p=0.03). No serious side effects were reported. In addition, the LVM group showed larger increases in cortical thickness in the right postcentral gyrus (primary somatosensory) X=44, Y=-26.9, Y=53.8; cluster size=966mm2), the precentral gyrus (primary motor) (X=17.3, Y=-22.1, Z=15.7; 948.9mm2), and the lateral occipital cortex (visual cortex) (X=19.6, Y=-94.9, Z=15.7; 930mm2) compared to the placebo group. Both LVM and placebo groups showed a clinically significant improvement in depression severity over 12 weeks without significant group differences. Side effects were significantly higher with LVM treatment compared to placebo. However, the LVM group demonstrated a gain or preservation of cortical thickness in primary sensorimotor and visual regions compared to the placebo group. Larger and longer follow up studies are required to explore the effect of LVM on neuroplasticity in relationship to clinical outcomes and side effects.