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Various stress experiences affect gene expression of neurotrophic/growth factors in the hippocampus. Among the neurotrophic factors, brain-derived neurotrophic factor (BDNF) has the most prominent role. With the stress producing effects of early life traumas, the level of BDNF decreases and susceptibility to depression develops. Recurrent and insufficiently treated depressive episodes have further impact on decreased BDNF and increase neuronal atrophy. Decreased level of BDNF in patients with major depressive disorder has been demonstrated in many studies and BDNF levels increase after antidepressant treatment, along with symptom recovery, in comparison to those seen in healthy control subjects. This increase cannot be achieved in patients that do not respond to antidepressant treatment. The neuroprotective effect of antidepressants are mediated by mitogen activated protein kinases/extracellular regulated kinases (MAPK/ERK) and wingless/glycogen synthase kinases (Wnt/GSK). In a meta-analysis, 23 studies were evaluated and data for 1504 patients were subjected to statistical analysis. The effect size was calculated as 0.62 (95% confidence interval: 0.36-0.88). As a result of meta-regression, the change in the level of serum BDNF after antidepressant treatment was independent of the change in depressive symptomatology, duration of treatment, and history of antidepressant use. As clinical improvement obtained with antidepressant treatment persists, the level of serum BDNF remains unchanged.
Beside antidepressants, mood stabilizers, especially lithium have been studied with respect to neuroplasticity. Neuroprotective effects of mood stabilizers are mediated by increasing transcriptional activity of (cAMP response element binding protein) CREB, inhibiting GSK-3B and increasing the expression of BDNF. In studies both with lithium and valproate, increased cerebral grey matter volume was reported. In lithium studies increases in left anterior cingulate volume, right anterior cingulate volume, hippocampal volume and amygdala volume, and in valproate studies an increase in left anterior cingulate volume were found. Both mood stabilizers are associated with increased hippocampal N-acetyl aspartate level.
Antipsychotic drugs do not have a group effect. While haloperidol does not have any effect on phosphorilated ERK (pERK), olanzapine increases it. Haloperidol also decreases the level of BDNF and is suggested to have neurotoxic effects. Among the other antipsychotics, clozapine, quetiapine and risperidone prevent cell death. It has been demonstrated that clozapine and quetiapine increase the level of BDNF. Quetiapine is suggested to increase proliferation of mature neurons, although there is no evidence that clozapine and olanzapine have the same effect.