James Kimball

Insomnia Severity is an Indicator of Suicidal Ideation During a Depression Clinical Trial

OBJECTIVE Insomnia has been linked to suicidal ideas and suicide death in cross-sectional and longitudinal population-based studies. A link between insomnia and suicide has not been previously examined in the setting of a clinical trial. Herein we describe the relationship between insomnia and suicidal thinking during the course of a clinical trial for depression with insomnia. METHODS Sixty patients aged 41.5±12.5 years (2/3 women) with major depressive episode and symptoms of insomnia received open-label fluoxetine for 9 weeks and also received blinded, randomized eszopiclone 3mg or placebo at bedtime after the first week of fluoxetine. Insomnia symptoms were assessed with the Insomnia Severity Index (ISI), and suicidal ideation was assessed with The Scale for Suicide Ideation (SSI). Depression symptoms were assessed with the depressed mood item and the anhedonia item from the Hamilton Rating Scale for Depression-24 (HRSD24), as well as a sum score for all non-sleep and non-suicide items from the HRSD (HRSD20). Measurements were taken at baseline and weeks 1, 2, 4, 6, and 8. SSI was examined by generalized linear mixed models for repeated measures as the outcome of interest for all 60 participants with ISI and various mood symptoms as independent variables, with adjustment for age, gender, treatment assignment, and baseline SSI. RESULTS Higher levels of insomnia corresponded to significantly greater intensity of suicidal thinking (p<0.01). The depressed mood item of the HRSD, and the sum of the HRSD20, both corresponded to greater suicidal thinking (p<0.001). The anhedonia item did not correspond with suicidal thinking. When both ISI and the depressed mood item, or ISI and the anhedonia item, were included together in the same model, the ISI remained an independent predictor of suicidal thinking. CONCLUSIONS The results support the concept that insomnia may be a useful indicator for suicidal ideation and now extend this idea into clinical trials. Insomnia remains an independent indicator of suicidal ideation, even taking into account the core symptoms of depression such as depressed mood and anhedonia. The complaint of insomnia during a depression clinical trial might indicate that more direct questioning about suicide is warranted.

Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the treatment of pharmacoresistant major depression: assessment of relapse during a 6-month, multisite, open-label study

BACKGROUND Although transcranial magnetic stimulation (TMS) can be an effective acute antidepressant treatment, few studies systematically examine persistence of benefit. OBJECTIVE We assessed the durability of antidepressant effect after acute response to TMS in patients with major depressive disorder (MDD) using protocol-specified maintenance antidepressant monotherapy. METHODS Three hundred one patients were randomly assigned to active or sham TMS in a 6-week, controlled trial. Nonresponders could enroll in a second, 6-week, open-label study. Patients who met criteria for partial response (i.e., >25% decrease from the baseline HAMD 17) during either the sham-controlled or open-label study (n = 142) were tapered off TMS over 3 weeks, while simultaneously starting maintenance antidepressant monotherapy. Patients were then followed for 24 weeks in a naturalistic follow-up study examining the long-term durability of TMS. During this durability study, TMS was readministered if patients met prespecified criteria for symptom worsening (i.e., a change of at least one point on the CGI-S scale for 2 consecutive weeks). Relapse was the primary outcome measure. RESULTS Ten of 99 (10%; Kaplan-Meier survival estimate = 12.9%) patients relapsed. Thirty-eight (38.4%) patients met criteria for symptom worsening and 32/38 (84.2%) reachieved symptomatic benefit with adjunctive TMS. Safety and tolerability were similar to acute TMS monotherapy. CONCLUSIONS These initial data suggest that the therapeutic effects of TMS are durable and that TMS may be successfully used as an intermittent rescue strategy to preclude impending relapse.

Seizure length and clinical outcome in electroconvulsive therapy using methohexital or thiopental.

Seizure duration is an extensively studied and controversial indicator of treatment quality in electroconvulsive therapy. Previous research comparing the effect of the barbiturate anesthetics methohexital and thiopental on seizure duration has yielded conflicting results. A recent period of unavailability of methohexital in the United States allowed for retrospective comparison of seizure length as well as clinical improvement in treatment using each agent. Retrospective review was made of 837 treatments administered to 97 patients between January 2, 2002, and May 31, 2003, examining anesthetic, seizure duration, and Global Assessment of Functioning (GAF) scores of inpatients at hospital admission and discharge. Analysis of variance of treatments 2-5 showed no significant effect for anesthetic on seizure duration. Analysis on a treatment-by-treatment basis revealed a marginally significant trend toward shorter EEG seizures in the thiopental group at the second treatment (50.5 ± 23.6 s vs. 61.1 ± 27.9 s; P = 0.07) and fifth treatment (41.7 ± 16.9 s vs. 51.8 ± 24.0 s; P = 0.07). A difference approaching statistical significance revealed shorter convulsion length in the thiopental group at treatment 5 (29.0 ± 12.3 s vs. 34.8 ± 12.3 s; P = 0.07). Comparison of GAF score improvement at hospital discharge revealed no significant difference (GAF increase 26.4 ± 9.4 for methohexital-treated patients vs. 24.8 ± 12.0 for thiopental-treated patients; t = 1.00, df = 82, P > 0.1). Trends approaching significance in treatments 2 and 5 revealed shorter seizures in the thiopental group. However, data on clinical recovery reveals no greater improvement in the methohexital group. Thus, this study calls further into question the premise that choice of barbiturate anesthetic may affect clinical efficacy.

Prediction of antidepressant response in both 2.25 × threshold RUL and fixed high dose RUL ECT

UNLABELLED Some forms of electroconvulsive therapy (ECT) can result in generalized seizures that lack efficacy, therefore physiological markers of treatment adequacy would be helpful. EEG measures of seizure quality, such as EEG regularity and post-ictal suppression, have largely supplanted seizure duration as a marker for seizure adequacy, yet no predictive algorithm has gained wide clinical acceptance. Electrographic seizure durations of less than 25 s still prompt re-stimulation in many settings. We re-examined the utility of EEG seizure duration and other measures of EEG seizure as predictors of antidepressant response to right unilateral (RUL) ECT. METHODS Seventy-two adult patients with major depression were randomized to either titrated RUL ECT at 2.25 times initial seizure threshold or RUL ECT at a fixed dose of 403 mC. Intent-to-treat responder status (defined by 60% reduction in HRSD scores and final score of 12 or less after the last RUL ECT session) was identified as the dependent variable in a nominal logistic regression model including EEG seizure quality candidate variables, controlled for age and gender. RESULTS A model including EEG seizure duration, EEG regularity, post-ictal suppression, age and gender and randomization status was significantly predictive of intent-to-treat responder status at treatment 2 (R2=.21 p<.003; N=66) and treatment 4 (R2=.27 p<.0004; N=67). The model remained significant at these time points even when randomization status (titrated moderately suprathreshold vs. high fixed dosage) was removed (Treatment 2: R2=.18 p<.007; Treatment 4: R2=.23 p<.0007). CONCLUSION EEG markers of seizure adequacy, including EEG seizure duration, are modestly predictive of antidepressant response for both titrated moderately suprathreshold and high fixed dosage RUL ECT.

Health-related quality of life in a clinical trial of ECT followed by continuation pharmacotherapy: effects immediately after ECT and at 24 weeks.

Objective: To examine the determinants of health-related quality of life (HRQOL) immediately after a clinical trial of electroconvulsive therapy (ECT) for major depression and then again after 24 weeks of a continuation pharmacotherapy in a clinical trial comparing nortriptyline (NT) plus lithium (Li) versus venlafaxine (VEN) plus Li. Method: During acute ECT, 184 patients randomized to treatment with moderate-dosage bilateral (BL) ECT or high-dosage right unilateral (RUL) ECT completed the Medical Outcomes Study Short Form-36 (SF-36) as a measure of HRQOL before and immediately after ECT. They were also randomized to concurrent treatment with placebo, NT, or VEN. Seventy-four of these met remission criteria and agreed to be further randomized to 24 more weeks of VEN + Li versus NT + Li for relapse prevention and completed a final SF-36. Cognitive testing was also completed. Results: Scores from SF-36 were low before ECT, and the SF-36 subscales reflecting mental health were particularly low. Right unilateral electrode placement was associated with better SF-36 scores immediately after ECT, even after controlling for improvement in depression. Medication assignment during ECT (VEN, NT, or placebo) was not related to immediate HRQOL outcome, and cognitive performance was not related to immediate HRQOL. Remission immediately after ECT was associated with robust improvement in SF-36 scores compared with those who did not remit. Remission status remained a strong predictor of HRQOL 24 weeks after ECT, and sustained remitters showed additional gains in HRQOL 24 weeks after ECT. Electrode placement and medication assignment were not predictors at 24 weeks. Conclusions: Using state-of-the-art delivery of acute ECT and continuation antidepressant medication, HRQOL improves remarkably after ECT, and this improvement shows further gains with those persons who sustain remission. Health-related QOL is superior with RUL versus BL ECT in the immediate post-ECT period, but at 24-weeks HRQOL has absent or inconsistent relationship with mode of ECT delivery or type of continuation antidepressant pharmacotherapy.

Improvement in quality of life with left prefrontal transcranial magnetic stimulation in patients with pharmacoresistant major depression: Acute and six month outcomes

BACKGROUND Transcranial magnetic stimulation (TMS) is a safe and effective treatment for major depression. We describe quality of life (QOL) outcomes from acute treatment with TMS, and describe the durability of benefit across 24-weeks. METHODS Three hundred and one medication-free patients with pharmacoresistant major depression were randomized to active or sham TMS in a 6-week controlled trial. Nonresponders to the 6-week blinded phase of the study were enrolled in a 6-week open-label study without unblinding the prior treatment assignment. Responders and partial responders to both the blinded (active or sham treatment) or open acute treatment phases were tapered off TMS over three weeks, while initiating maintenance antidepressant medication monotherapy. These subjects entered the 24-week study to examine the durability of response to TMS. The Medical Outcomes Study-36 Item Short Form (SF-36) and the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) were used to measure overall function and QOL. During the 24-week durability of effect study, QOL assessments were done at study entry and at the end of 24-weeks. RESULTS Statistically significant improvement in both functional status and QOL outcomes was observed in patients treated with active TMS compared with sham TMS during the acute phase of the randomized, sham-controlled trial. Similar benefits were observed in patients who entered the open-label extension study. These improvements were sustained across the 24-week follow up study. CONCLUSIONS Acute treatment with TMS improved functional status and QOL outcomes in patients with major depression. This clinical effect was durable in long-term follow up.

Dexmedetomidine and the Successful Management of Electroconvulsive Therapy Postictal Agitation: A Case Report

Postictal agitation after electroconvulsive therapy is a common and serious condition and when severe, requires prompt intervention to safeguard the patient and medical staff from the potential for mayhem and physical harm. We present a case report on the successful use of dexmedetomidine, an alpha2 agonist, in the postictal management of severe agitation in a 34-year-old morbidly obese woman, after prior modes of intervention had failed to deliver ideal conditions.

Electroconvulsive therapy- and succinylcholine-related asystole.

To the Editor: Asystole following succinylcholine administration has two primary etiologies. One source stems from the potential for extreme hyperkalemia in certain patient groups (burn victims, neurologic injury/pathology patients, trauma victims, or those at long term bed rest) to name a few of the most common etiologies. The second mechanism for asystole following succinylcholine has to do with the molecular structure of succinylcholine, and its resemblance to acetylcholine. This second mechanism was first described during ECT treatment by McCall. In this report, a similar case of asystole following succinylcholine administration is presented. The patient is a 62 year old white female with a history of major depressive disorder who was in the process of undergoing a series of ECT treatments. Past medical history includes hypertension, hypothyroidism, and renal insufficiency due to lithium toxicity. Medications at the time of treatment were levothyroxine, venlafaxine HCl, paricalcitrol, and simvastatin. Serum potassium on the morning of treatment was 4.04 MEQ/L, ECG-normal sinus rhythm. While undergoing her 13th treatment, the patient received prophylactic glycopyrrolate 0.1 mg IV within 30 minutes preceding treatment as per our institutional protocol. Anesthesia was induced using brevital 50 mg, and succinylcholine 60 mg. Immediately following the dosing of succinycholine, asystole ensued lasting approximately 3Y4 seconds. A radial pulse was not detected. Atropine 0.4 mg IV was administered and as preparations to perform cardiac compressions ensued, narrow QRS complexes returned to the ECG screen, and a radial pulse was easily palpable. Her BP was stable, and respirations were controlled via bag-mask ventilation. A bite block was placed and the ECT stimulus was delivered without incident. The patient tolerated the remainder of her treatment well and post anesthesia care unit stay was uneventful. A 12 lead ECG was unremarkable. On a molecular level, succinylcholine and acetylcholine resemble each other. Succinylcholine is essentially two acetylcholine molecules together. The entire parasympathetic nervous system depends on acetylcholine as a neurotransmitter. As a result of this resemblance, when succinylcholine is administered, muscarinic receptors in the sinoatrial node of the heart can be stimulated and this can lead to extreme vagal events, such as asystole. In this case, the fact that the patient_s potassium was well within normal limits before treatment with succinylcholine, and that she had no predisposing conditions that would precipitate a hyperkalemic event (such as burn injury, paraplegia, etc.) and that after atropine a narrow QRS pattern ensued, these points all contributed to quickly suspecting succinylcholine as the culprit for asystole. This contrasts markedly with succinylcholine associated asystole from hyperkalemia where the ECG will show a widening of the QRS, peaked T-waves, and increase in PR interval while in the course of deterioration. Hyperkalemic asystole can be much more ominous, refractory to atropine treatment, and requires alternate therapy to quickly address the elevated potassium. This patient has successfully returned for continued ECT therapy, and IV atropine 0.4 mg has been given prophylactically for each treatment without incident. Though it is impossible to predict if asystole would present again if pretreatment with atropine were to be eliminated; the risk vs. benefit of omitting atropine, in this particular case, weighs heavily towards the benefit of administering it prophylactically. Certainly, an anesthesia provider could opt to avoid succinylcholine altogether by choosing a low dose non-depolarizing agent, such as rocuronium. However, this agent too has its risks and benefits, and would require pharmacologic reversal at the conclusion of the treatment.

Health-related quality of life and the practice of electroconvulsive therapy.

In the past several decades, health-related quality of life (HRQL) measures have become increasingly important as a type of patient-reported outcome documenting the subjective psychosocial burden associated with chronic illness. This article provides an introduction to HRQL, summarizes the measurement of HRQL in major depression and bipolar disorder, and reviews electroconvulsive therapy (ECT) studies that have measured HRQL. Health-related quality-of-life definitions and instruments vary widely but have nonetheless proven useful for evaluating the effects of disease and its treatment. Psychiatric disorders profoundly affect HRQL and, in many cases, exceed or contribute to the disease burden imposed by serious physical illness. An emerging literature demonstrates the importance of ECT in restoring function and HRQL in depressed patients. To keep pace as medicine is transformed along the dimensions outlined by the Institute of Medicines Quality Chasm framework, ECT research must provide evidence supporting its safety and effectiveness and also that the treatment is patient-centered. A research agenda to demonstrate the subjective benefits of ECT must be mirrored by a practice of ECT that is increasingly customized to patient needs and values.

Cardiac rhythm disturbance in a depressed patient after implantation with a vagus nerve stimulator.

A 52-year-old woman with a long-standing history of treatment-resistant depression failed multiple courses of electroconvulsive therapy and various trials of antidepressant medications. As a result, the patient was deemed a good candidate for vagus nerve stimulation (VNS) therapy and underwent VNS insertion in May 2006. However, in December 2007, she began to experience recurrent falls and was referred to a cardiologist for a syncope evaluation. During a portable 30-day cardiac event recording, she was noted to have intermittent second- and third-degree heart block with ventricular standstill, which was felt by her cardiologist to be associated with VNS stimulation. We believe this to be the first reported case of heart block related to VNS in a depressed patient.