Effects of the KCNQ channel opener ezogabine on functional connectivity of the ventral striatum and clinical symptoms in patients with major depressive disorder.

Major depressive disorder (MDD) is a leading cause of disability worldwide, yet current treatment strategies remain limited in their mechanistic diversity. Recent evidence has highlighted a promising novel pharmaceutical target-the KCNQ-type potassium channel-for the treatment of depressive disorders, which may exert a therapeutic effect via functional changes within the brain reward system, including the ventral striatum. The current study assessed the effects of the KCNQ channel opener ezogabine (also known as retigabine) on reward circuitry and clinical symptoms in patients with MDD. Eighteen medication-free individuals with MDD currently in a major depressive episode were enrolled in an open-label study and received ezogabine up to 900 mg/day orally over the course of 10 weeks. Resting-state functional magnetic resonance imaging data were collected at baseline and posttreatment to examine brain reward circuitry. Reward learning was measured using a computerized probabilistic reward task. After treatment with ezogabine, subjects exhibited a significant reduction of depressive symptoms (Montgomery-Asberg Depression Rating Scale score change: -13.7 ± 9.7, p < 0.001, d = 2.08) and anhedonic symptoms (Snaith-Hamilton Pleasure Scale score change: -6.1 ± 5.3, p < 0.001, d = 1.00), which remained significant even after controlling for overall depression severity. Improvement in depression was associated with decreased functional connectivity between the ventral caudate and clusters within the mid-cingulate cortex and posterior cingulate cortex (n = 14, voxel-wise p < 0.005). In addition, a subgroup of patients tested with a probabilistic reward task (n = 9) showed increased reward learning following treatment. These findings highlight the KCNQ-type potassium channel as a promising target for future drug discovery efforts in mood disorders.

The Safe Use of Electroconvulsive Therapy in a Patient With a Repaired Arteriovenous Malformation: Images Showing Surgical Clips.

We present images showing surgical clips from a remotely repaired cerebral arteriovenous malformation in a patient treated safely with electroconvulsive therapy.

General Anesthesia in a Patient With Urticaria Pigmentosa Referred for Electroconvulsive Therapy.

Urticaria pigmentosa is a rare disorder characterized by an abnormal systemic proliferation of mast cells. In this condition, various triggers can induce either cutaneous histamine release, resulting in rash, or generalized histamine release, resulting in symptomatic hypotension, syncope, or in its severest form, an anaphylactoid reaction resistant to most resuscitative measures. Many anesthetic agents and adjuncts are known potential triggers, and patients who require surgery or procedures under anesthesia must be managed carefully. In this review, we describe the safe use of general anesthesia for electroconvulsive therapy in a patient with urticaria pigmentosa and discuss the association between psychiatric disorders and mastocytoses.

Depression severity in electroconvulsive therapy (ECT) versus pharmacotherapy trials.

OBJECTIVE: We sought to compare the level of severity of depressive symptoms on entry into electroconvulsive therapy (ECT) clinical trials versus pharmacotherapy clinical trials. DATA SOURCES: English-language MEDLINE/PubMed publication databases were searched for ECT literature (search terms: ECT, electroconvulsive therapy, depression, and Hamilton) for clinical trials in which depressed patients had baseline Hamilton Rating Scale for Depression (HRSD) scores. For comparison, we used a convenience sample of 7 large pharmacotherapy trials in major depression (N = 3677). The search included articles from 1960 to 2011. STUDY SELECTION: We included 100 studies that met the following criteria: ECT trial for depression, patients adequately characterized by diagnosis at baseline, and patients rated at baseline by 15-item HRSD (HRSD15), HRSD17, HRSD21, HRSD24, or HRSD28, with mean (SD) and sample size (n) reported. For the comparator pharmacotherapy trials, we chose to use a subset of the studies (excluding one study of minor depression) in the widely publicized meta-analysis of Fournier et al, as well as the STAR*D study and one additional study by Shelton et al. This provided 7 studies of major depression using HRSD17 (total N = 3677). DATA EXTRACTION: Data extracted included number of subjects and baseline and final HRSD scores, with mean (SD) values. RESULTS: Of 100 ECT studies, 56 studies (N = 2243) used the HRSD17 version. The mean baseline HRSD17 score in the ECT trials was 27.6, the mean in the pharmacotherapy trials was 21.94, a statistically, and clinically, significant difference. In a subanalysis of the 16 ECT studies that used the HRSD24 version, the mean baseline score was 32.2. CONCLUSIONS: This selective literature review confirms that patients who entered ECT clinical trials were more severely ill than those who entered the selected comparator pharmacotherapy trials. Such data highlight the critical role of ECT in the treatment of severe and treatment-resistant mood disorders.

Electroconvulsive therapy (ECT) in Parkinson's disease: ECS and dopamine enhancement.

INTRODUCTION: In addition to its effects in major psychiatric illness, electroconvulsive therapy (ECT) is known to have a beneficial effect on the core motor symptoms of Parkinson's disease (PD). This effect is believed to be mediated via dopamine in the striatum. Electroconvulsive shock (ECS), the animal analogue of ECT, is the model in which investigators have sought to elucidate the specific dopaminergic mechanisms by which ECT exerts its therapeutic effect in PD. Electroconvulsive shock has been given to intact animals as well as to animals with neurotoxic lesions that create parkinsonism. METHODS: In this paper, we selectively review the electroconvulsive shock literature on dopamine in the striatum. RESULTS: Electroconvulsive shock, and by extension, ECT, is associated with increased dopamine release and modulation of dopamine receptors. CONCLUSION: Better understanding of how ECT works to enhance dopaminergic systems in the brain could help to make it a more accepted treatment for PD.

Dosing and effectiveness of ketamine anesthesia for electroconvulsive therapy (ECT): a case series.

OBJECTIVE: To provide additional data about the clinical efficacy and dosing range for ketamine used as the induction agent in electroconvulsive therapy (ECT). METHOD: We reviewed the clinical data in our academic hospital ECT service over the last four years for patients who had received ketamine as the sole, or adjunctive, anesthesia induction agent. We extracted clinical data about antidepressant response as well as absolute and weight-based dosing for ketamine. RESULTS: We found nine patients who were treated with ketamine as the anesthetic at some point during the course of their treatment (eight as the sole agent, one as adjunctive). The median induction dose for ketamine was 1.1 mg/kg. For most patients, there was demonstrable clinical benefit. CONCLUSIONS: Ketamine has a role as an alternative induction anesthetic agent in ECT. Our case series adds to the literature on the concomitant use of ECT and ketamine.

Dextromethorphan/quinidine pharmacotherapy in patients with treatment resistant depression: A proof of concept clinical trial.

BACKGROUND: At least one-third of patients with major depressive disorder (MDD) have treatment-resistant depression (TRD), defined as lack of response to two or more adequate antidepressant trials. For these patients, novel antidepressant treatments are urgently needed. METHODS: The current study is a phase IIa open label clinical trial examining the efficacy and tolerability of a combination of dextromethorphan (DM) and the CYP2D6 enzyme inhibitor quinidine (Q) in patients with TRD. Dextromethorphan acts as an antagonist at the glutamate N-methyl-d-aspartate (NMDA) receptor, in addition to other pharmacodynamics properties that include activity at sigma-1 receptors. Twenty patients with unipolar TRD who completed informed consent and met all eligibility criteria we enrolled in an open-label study of DM/Q up to 45/10mg by mouth administered every 12h over the course of a 10-week period, and constitute the intention to treat (ITT) sample. Six patients discontinued prior to study completion. RESULTS: There was no treatment-emergent suicidal ideation, psychotomimetic or dissociative symptoms. Montgomery-Asberg Depression Rating Scale (MADRS) score was reduced from baseline to the 10-week primary outcome (mean change: -13.0±11.5, t19=5.0, p<0.001), as was QIDS-SR score (mean change: -5.9±6.6, t19=4.0, p<0.001). The response and remission rates in the ITT sample were 45% and 35%, respectively. LIMITATIONS: Open-label, proof-of-concept design. CONCLUSIONS: Herein we report acceptable tolerability and preliminary efficacy of DM/Q up to 45/10mg administered every 12h in patients with TRD. Future larger placebo controlled randomized trials in this population are warranted.

Case report: transient left bundle branch block associated with ECT.

We present the first reported case of transient left bundle branch block (LBBB) occurring during electroconvulsive therapy (ECT). LBBB is an important clinical finding, as it is associated with a significant increase in mortality. Physicians providing ECT should be aware of the significance of new-onset LBBB; it may occur during treatment.