Deep brain stimulation normalizes amygdala responsivity in treatment-resistant depression.

Deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule (vALIC) is a promising intervention for treatment-resistant depression (TRD). However, the working mechanisms of vALIC DBS in TRD remain largely unexplored. As major depressive disorder has been associated with aberrant amygdala functioning, we investigated whether vALIC DBS affects amygdala responsivity and functional connectivity. To investigate the long-term effects of DBS, eleven patients with TRD performed an implicit emotional face-viewing paradigm during functional magnetic resonance imaging (fMRI) before DBS surgery and after DBS parameter optimization. Sixteen matched healthy controls performed the fMRI paradigm at two-time points to control for test-retest effects. To investigate the short-term effects of DBS de-activation after parameter optimization, thirteen patients additionally performed the fMRI paradigm after double-blind periods of active and sham stimulation. Results showed that TRD patients had decreased right amygdala responsivity compared to healthy controls at baseline. Long-term vALIC DBS normalized right amygdala responsivity, which was associated with faster reaction times. This effect was not dependent on emotional valence. Furthermore, active compared to sham DBS increased amygdala connectivity with sensorimotor and cingulate cortices, which was not significantly different between responders and non-responders. These results suggest that vALIC DBS restores amygdala responsivity and behavioral vigilance in TRD, which may contribute to the DBS-induced antidepressant effect.

Deep Brain Stimulation of the Ventral Anterior Limb of the Internal Capsule for Treatment-Resistant Depression: A Randomized Clinical Trial.

IMPORTANCE: Patients with treatment-resistant depression (TRD) do not respond sufficiently to several consecutive treatments for major depressive disorder. Deep brain stimulation (DBS) is a promising treatment for these patients, but presently placebo effects cannot be ruled out. OBJECTIVE: To assess the efficacy of DBS of the ventral anterior limb of the internal capsule (vALIC), controlling for placebo effects with active and sham stimulation phases. DESIGN, SETTING, AND PARTICIPANTS: Twenty-five patients with TRD from 2 hospitals in the Netherlands were enrolled between March 22, 2010, and May 8, 2014. Patients first entered a 52-week open-label trial during which they received bilateral implants of 4 contact electrodes followed by optimization of DBS until a stable response was achieved. A randomized, double-blind, 12-week crossover phase was then conducted with patients receiving active treatment followed by sham or vice versa. Response and nonresponse to treatment were determined using intention-to-treat analyses. INTERVENTIONS: Deep brain stimulation targeted to the vALIC. MAIN OUTCOMES AND MEASURES: The change in the investigator-rated score of the 17-item Hamilton Depression Rating Scale (HAM-D-17) was the main outcome used in analysis of the optimization phase. The primary outcome of the crossover phase was the difference in the HAM-D-17 scores between active and sham DBS. The score range of this tool is 0 to 52, with higher scores representing more severe symptoms. Patients were classified as responders to treatment (≥50% decrease of the HAM-D-17 score compared with baseline) and partial responders (≥25 but <50% decrease of the HAM-D-17 score). RESULTS: Of 25 patients included in the study, 8 (32%) were men; the mean (SD) age at inclusion was 53.2 (8.4) years. Mean HAM-D-17 scores decreased from 22.2 (95% CI, 20.3-24.1) at baseline to 15.9 (95% CI, 12.3-19.5) (P = .001), Montgomery-Åsberg Depression Rating Scale scores from 34.0 (95% CI, 31.8-36.3) to 23.8 (95% CI, 18.4-29.1) (P < .001), and Inventory of Depressive Symptomatology-Self-report scores from from 49.3 (95% CI, 45.4-53.2) to 38.8 (95% CI, 31.6-46.0) (P = .005) in the optimization phase. Following the optimization phase, which lasted 51.6 (22.0) weeks, 10 patients (40%) were classified as responders and 15 individuals (60%) as nonresponders. Sixteen patients entered the randomized crossover phase (9 responders [56%], 7 nonresponders [44%]). During active DBS, patients scored significantly lower on the HAM-D-17 scale (13.6 [95% CI, 9.8-17.4]) than during sham DBS (23.1 [95% CI, 20.6-25.6]) (P < .001). Serious adverse events included severe nausea during surgery (1 patient), suicide attempt (4 patients), and suicidal ideation (2 patients). CONCLUSIONS AND RELEVANCE: Deep brain stimulation of the vALIC resulted in a significant decrease of depressive symptoms in 10 of 25 patients and was tolerated well. The randomized crossover design corroborates that vALIC DBS causes symptom reduction rather than sham. TRIAL REGISTRATION: trialregister.nl Identifier: NTR2118.

Urine osmolality, cyclic AMP and aquaporin-2 in urine of patients under lithium treatment in response to water loading followed by vasopressin administration.

Lithium is the drug that is most frequently associated with acquired nephrogenic diabetes insipidus (NDI). The exact mechanism of lithium-induced NDI in man is unknown. The aim of the present study was to investigate the kidney response to minimal and maximal stimulation of the kidney urine concentrating mechanism by measuring urine osmolality, and urine levels of cAMP and AQP-2 in urine of patients under long-term lithium treatment. Twenty patients under long-term lithium treatment were included. The kidney urinary 3',5'-cyclic adenosine monophosphate (cyclic AMP), aquaporin-2 levels and urine osmolality were determined during a situation of minimal kidney urine concentrating activity (induced by water loading) and during a situation following maximal stimulation of kidney urine concentrating activity (induced by 1-desamino-8-D-arginine-vasopressin). Patients were classified as NDI, partial NDI and non-NDI based on maximal reached urine osmolality. The partial correlation (r) between urinary cyclic AMP levels (mol/l) and urine osmolality was 0.94 (P<0.001). No significant correlation was observed between urinary aquaporin-2 levels (mol/mol creatinine) and osmolality nor between urinary cyclic AMP and aquaporin-2 levels. The rise in urinary cyclic AMP but not aquaporin-2 levels upon 1-desamino-8-D-arginine-vasopressin administration after water loading significantly differed between the three categories, decreasing with increasing NDI category. In conclusion we found that in lithium-induced kidney urine concentrating deficit in man, the cyclic AMP generation in response to 1-desamino-8-D-arginine-vasopressin administration after water loading, is impaired. It remains to be elucidated whether principal cells, G-proteins or adenylate cyclase e.g. are the major targets for the mechanism underlying lithium-induced NDI in man.