Early antidepressant response of deep brain stimulation for depression treatment: a translational study.

Abstract

Background: Deep Brain Stimulation (DBS) in the subgenual cingulated (Cg25) has revealed as a new and promising innovative technique that may be able to provide sustained remission in resistant major depressive disorder. However and strikingly, the first clinical series have reported an initial large effect followed by a decay in the first month of treatment [1][2]. This unexpected phenomenon, attributed to a possible placebo or to an organic cause, remains to be resolved. Methods: To address this question the current study will focus in the early phase of DBS treatment in a translational study. To this end, we characterized the effect of electrode implantation in the infralimbic cortex (the rodent Cg25 correlate), without or with electrical stimulation (i.e. DBS), in experimental animals that are devoid of any placebo effect by using the forced swimming test (mFST), an animal model of antidepressant activity. Furthermore, the effect of analgesic/antiinflammatory drugs that are usually prescribed postoperatively in patients will be evaluated. Additionally, these results will be compared with the early outcome of a controlled clinical trial of DBS procedure in the Cg25 in patients diagnosed with treatment-resistant depression. Results were analyzed by a one- or two-way ANOVA followed by Bonferroni test. p<0.05 were considered to be significant. Results: The preclinical results demonstrated that animals just with electrode implantation showed a similar antidepressant-like effect than those which in addition received electrical brain stimulation. This effect was of similar magnitude than animals treated with imipramine and was not related with a general increase in locomotor activity. This “electrode effect” was via a main action on 5-HT transmission because the decrease of the immobility was accompanied by an increase of swimming behaviour and the antidepressant-like effect was blocked by the pre-treatment with pCPA, inhibitor of serotonin synthesis. On the other hand, this effect was specific to this area because similar procedure in the subthalamic nucleus did not produce any modification. Furthermore, the “electrode effect” could be caused by a regional neuroinflammation because the antidepressant-like effect was self-limiting over the time and correlated with an increase of GFAP inmunoreactivity. In agreement, this effect was prevented by indomethacin or acetaminophen treatment. Accordingly, we studied restrospectively the patients evolution. Thus, we saw that although all patients received bilateral DBS, there was a different evolution over the first month if the patients were treated with analgesic/anti-inflammatory treatment or not. Indeed, non-treated patients showed a dramatic reduction in HDRS score in the first week after intervention and this state was pretty conserved over the month. In contrast, the group that was under analgesic/antiinflammatory treatment reached the response criterion in the first week after intervention but there was a deterioration of depressive symptomatology over the following weeks. Conclusions: Our study shows that electrode implantation is sufficient to produces an early antidepressant-like effect of similar magnitude to those who are receiving DBS too. Moreover, we propose that the use of antiinflamatory drugs may oppose to the early response in DBS-treated patients.