The neurotrophic hypothesis of depression states that the major depressive episode is associated with lower
neurotrophic factors levels, which increase with amelioration of depressive symptoms. However, this hypothesis has not been extended to investigate
neurotrophic factors other than the
brain-derived neurotrophic factor (
BDNF). We therefore explored whether plasma levels of
neurotrophins 3 (NT-3) and 4 (NT-4),
nerve growth factor (
NGF) and
glial cell line derived neurotrophic factor (
GDNF) changed after
antidepressant treatment and correlated with treatment response. Seventy-three patients with moderate-to-severe,
antidepressant-free
unipolar depression were assigned to a pharmacological (
sertraline) and a non-pharmacological (
transcranial direct current stimulation,
tDCS) intervention in a randomized, 2 × 2, placebo-controlled design. The plasma levels of NT-3,
NT-4,
NGF and
GDNF were determined by
enzyme-linked
immunosorbent assay before and after a 6-week treatment course and analyzed according to clinical response and allocation group. We found that
tDCS and
sertraline (separately and combined) produced significant improvement in depressive symptoms. Plasma levels of all
neurotrophic factors were similar across groups at baseline and remained significantly unchanged regardless of the intervention and of clinical response. Also, baseline plasma levels were not associated with clinical response. To conclude, in this 6-week placebo-controlled trial, NT-3,
NT-4,
NGF and
GDNF plasma levels did not significantly change with
sertraline or
tDCS. These data suggest that these
neurotrophic factors are not surrogate
biomarkers of treatment response or involved in the
antidepressant mechanisms of
tDCS.