Faculty Bibliography

BACKGROUND: Deep brain stimulation (DBS) of the subcallosal cingulate white matter has shown promise as an intervention for patients with chronic, unremitting depression. To test the safety and efficacy of DBS for treatment-resistant depression, a prospective, randomised, sham-controlled trial was conducted. METHODS: Participants with treatment-resistant depression were implanted with a DBS system targeting bilateral subcallosal cingulate white matter and randomised to 6 months of active or sham DBS, followed by 6 months of open-label subcallosal cingulate DBS. Randomisation was computer generated with a block size of three at each site before the site started the study. The primary outcome was frequency of response (defined as a 40% or greater reduction in depression severity from baseline) averaged over months 4-6 of the double-blind phase. A futility analysis was performed when approximately half of the proposed sample received DBS implantation and completed the double-blind phase. At the conclusion of the 12-month study, a subset of patients were followed up for up to 24 months. The study is registered at ClinicalTrials.gov, number NCT00617162. FINDINGS: Before the futility analysis, 90 participants were randomly assigned to active (n=60) or sham (n=30) stimulation between April 10, 2008, and Nov 21, 2012. Both groups showed improvement, but there was no statistically significant difference in response during the double-blind, sham-controlled phase (12 [20%] patients in the stimulation group vs five [17%] patients in the control group). 28 patients experienced 40 serious adverse events; eight of these (in seven patients) were deemed to be related to the study device or surgery. INTERPRETATION: This study confirmed the safety and feasibility of subcallosal cingulate DBS as a treatment for treatment-resistant depression but did not show statistically significant antidepressant efficacy in a 6-month double-blind, sham-controlled trial. Future studies are needed to investigate factors such as clinical features or electrode placement that might improve efficacy. FUNDING: Abbott (previously St Jude Medical).

Repetitive transcranial magnetic stimulation is a promising treatment for depression and possibly for other psychiatric disorders. Clinical trials show a small but significant benefit compared with sham treatment. Occasional patients respond dramatically, as witnessed in the 2 cases presented here of patients with depersonalization symptoms. The guest discussant, Dr Joshua Berman, analyzes the challenges of finding individualized treatment parameters that could make repetitive transcranial magnetic stimulation more predictably effective.

Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22-68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p=0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p=0.013; remission: 32.6 vs. 14.6%, p=0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment.

INTRODUCTION/BACKGROUND:Transient bradycardia during the stimulation phase of electroconvulsive therapy (ECT) is a well-known clinical observation. The optimal dose of atropine needed to prevent bradycardia has not been determined. This study was designed to investigate the effect of low doses of atropine on heart rate during ECT. METHODS:Patients who received at least 2 different doses of atropine over their series of right unilateral ECT were included in the analysis. The anesthetic consisted of 0, 0.2, 0.3, or 0.4 mg of atropine, methohexital, and succinylcholine. Heart rate was measured by the RR interval, the time between sequential R waves on the electrocardiogram. Analysis was performed using logistic multivariate regression and repeated-measures multivariate analysis of variance. RESULTS:One hundred eighteen ECT sessions were identified from 19 patients. Patients were grouped into 4 groups by atropine dose (0, 0.2, 0.3, or 0.4 mg) with 9, 33, 13, and 63 ECT sessions identified for each dose, respectively. Patients who received atropine had significantly less bradycardia after electrical stimulus and a faster heart rate through the seizure than patients who did not receive atropine. There was no significant difference in heart rate between patients receiving 0.2, 0.3, and 0.4 mg of atropine at any time point. There was no significant difference in heart rate at time points after the seizure conclusion in any group of patients. CONCLUSION/CONCLUSIONS:Low-dose atropine results in significantly less bradycardia after electrical stimulus. There was no significant difference in heart rate across low doses of atropine.

We present the case of a patient with treatment-refractory mania. The patient had been tried on numerous medications, to which she either did not respond well or on which she developed severe side effects, However, the patient improved rapidly when treated with unilateral electropercussive therapy (ECT) following a court order. We outline the legal barriers that have been raised against the use of ECT in patients with mania, who often refuse treatment, and the irony that ECT can be safer than medications for some patients. ECT is underutilized in mania but deserves more frequent consideration. (Journal of Psychiatric Practice. 2011;17:61-66).

Central cholinergic signaling has long been associated with aspects of memory, motivation, and mood, each affected functions in neuropsychiatric disorders such as schizophrenia. In this chapter, we review evidence related to the core hypothesis that dysregulation of central cholinergic signaling contributes to the pathophysiology of schizophrenia. Although central cholinergic circuits are resistant to simplification-particularly when one tries to parse the contributions of various classes of cholinergic receptors to disease related phenomena--the potential role of ACh signaling in Schizophrenia pathophysiology deserves careful consideration for prospective therapeutics. The established role of cholinergic circuits in attentional tuning is considered along with recent work on how the patterning of cholinergic activity may modulate corticostriatal circuits affected in schizophrenia.

Updated findings on the relationship between nicotine and depression are presented. Clinical and preclinical research on nicotine use and depression suggests that nicotine may have some properties in common with antidepressants. Updated findings involve the comorbidity of smoking and major depressive disorder (MDD), the influence of depression during withdrawal on failure to quit smoking, the course of MDD without nicotine and the neurobiology of smoking and depression.

The melanotrophs of the neurointermediate lobe and peptidergic terminals of the neural lobe are regulated by gamma-aminobutyric acid (GABA) via GABA-A receptors and therefore, may be important sites for the modulatory actions of neurally active steroids. These steroid compounds might be produced peripherally, synthesized de novo in the pituitary, or derivatized from circulating steroids, each pathway having different physiological implications. In the present study, we show that neurointermediate lobe tissue can derivatize progesterone to the neurally active steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one. The neurointermediate lobe was found to be four times as active as anterior pituitary and mediobasal hypothalamus in conversion of progesterone to 3 alpha-hydroxy-5 alpha-pregnan-20-one; mediobasal hypothalamus was relatively more active in the production of the intermediate 5 alpha-pregnan-3,20-dione. The identity of the compounds was confirmed by the method of serial isotopic dilution. We observed rates of synthesis in the neurointermediate lobe consistent with the production of physiologically relevant quantities of 3 alpha-hydroxy-5 alpha-pregnan-20-one from concentrations of progesterone which can occur naturally. In support of these findings, we demonstrate the presence of 3 alpha-hydroxysteroid oxidoreductase in neurointermediate lobe by immunocytochemistry.