The effect of zolpidem-CR on the suicide item of the Hamilton Rating Scale for Depression in outpatients with depression, insomnia and suicidal ideation: Lessons learned.

The REST-IT study found the addition of zolpidem-controlled release (CR) provided a significant reduction in observer-rated measurement of suicidal ideation (the Columbia Suicide Severity Rating Scale) in 103 depressed outpatients with insomnia and suicidal ideation, but without significant change in a self-report measure of suicidal ideation (the Scale for Suicide Ideation). This secondary analysis of the REST-IT data examined the suicide item of another observer-rated scale, the Hamilton Rating Scale for Depression (HRSD), further clarifying the impact of insomnia-focused treatment on suicidal ideation. This analysis established a significant advantage for zolpidem-CR compared with placebo on the HRSD suicide item.

A review of clinical studies of electrodermal activity and transcranial magnetic stimulation.

There is a growing body of evidence indicative of changes in autonomic nervous system (ANS) activity in patients with disorders of the central nervous system (CNS). Non-invasive measures of the ANS, including heart rate variability (HRV), electrodermal activity (EDA), and pupillary light reflex (PLR) may have value as markers of symptom severity, subtype, risk profile, and/or treatment response. In this paper we provide an introduction into the anatomy and physiology of EDA and review the literature published after 2007 in which EDA was an outcome measure of cortical stimulation with transcranial magnetic stimulation (TMS). Eleven studies were included and considered regarding the potential of EDA as an outcome measure reflecting ANS activity in TMS research and treatment. These studies are summarized according to study population, experimental methodology, cortical region targeted, and correlation with other measures of ANS activity. Results indicate that EDA changes vary with the frequency and target of TMS. Inhibitory TMS to the dorsolateral prefrontal cortex (dlPFC) was the most common paradigm in these studies, consistently resulting in decreased EDA.

The Role of the Autonomic Nervous System in the Mediation of the Resolution of Suicidal Ideation With Electroconvulsive Therapy: A Hypothesis and Review of Heart Rate Variability Over a Course of Electroconvulsive Therapy.

ABSTRACT: Longitudinal observational studies have shown a meaningful decrease in suicidal thinking and suicidal behavior after receipt of electroconvulsive therapy (ECT). The antisuicide effect of ECT may be related to success in the global relief of the presenting syndrome such as depressive or psychotic illness. However, it is possible that the antisuicide effect is specific to ECT per se, over and above the relief of the clinical syndrome. Electroconvulsive therapy is associated with many observable neurochemical and physiologic effects, and some of these may plausibly be specifically linked to an antisuicide effect. The phenomenon of physiologic hyperarousal has been named as a candidate mechanism driving the risk for suicide. Hyperarousal is associated with decreased neuropsychological executive function responsible for response inhibition and can lead to impulsive action. The level of arousal within the autonomic nervous system (ANS) can be assayed with the pupillary light reflex, electrodermal activity, or with heart rate variability (HRV). This article summarizes the literature on the effects of ECT on HRV 24 to 72 hours after a course of ECT and finds evidence for increases in HRV, which indicates lower levels of arousal in the ANS. This finding suggests that ECT-related reductions in ANS arousal, presumably with corresponding improvements in response inhibition, may be one mechanism whereby ECT reduces risk for suicide.

Daytime autonomic nervous system functions differ among adults with and without insomnia symptoms.

STUDY OBJECTIVES: We gathered data to determine whether daytime assays of the autonomic nervous system would differ between persons with no vs modest insomnia symptoms and would correlate with the severity of insomnia symptoms in patients. METHODS: This report is composed of 2 studies. Study 1 conducted pupillary light reflex (PLR) measurements in community volunteers who were not seeking medical care. Study 2 contrasted PLR and heart rate variability in a different sample of community volunteers and a comparison sample of adults seeking outpatient care for insomnia and psychiatric problems. All measurements were taken between 3 and 5 pm. RESULTS: In Study 1, volunteers with modest insomnia symptom severity had a more rapid PLR average constriction velocity compared with those with no symptoms. In Study 2, lower heart rate variability, indicating higher levels of physiologic arousal, generally were in agreement with faster PLR average constriction velocity, both of which indicate higher levels of arousal. Insomnia symptom severity was highly correlated with faster average constriction velocity in the patient sample. CONCLUSIONS: These studies suggest that (1) daytime measurements of the autonomic nervous system differ between persons with modest vs no insomnia symptoms and (2) insomnia symptom severity is highly correlated with PLR. Daytime measurement of autonomic nervous system activity might allow for daytime point-of-care measurement to characterize the level of physiologic arousal to define a hyperarousal subtype of insomnia disorder. CITATION: McCall WV, Looney SW, Zulfiqar M, et al. Daytime autonomic nervous system functions differ among adults with and without insomnia symptoms. J Clin Sleep Med. 2023;19(11):1885-1893.

Reproducibility of the pupillary light reflex over short intervals in psychiatric patients and community volunteers.

The pupillary light reflex (PLR) is a method for measuring dynamic responses within the autonomic nervous system, and would have potential value as a point-of-care test in a psychiatry clinic if reproducible results could be obtained in a short period of time. We collected PLR from adult community volunteers and depressed outpatients with the purpose of demonstrating (1) that valid data could be obtained >90% of the time from both the community volunteers and the patients, and (2) that reproducible results could be obtained with repeated measurement over short periods of time. Valid data were captured for 90.3% of 76 participants, allowing for two attempts of the PLR per participant. Success rates were similar for depressed patients and community volunteers. Eighteen of these 76 participants provided repeated paired measurements after 5 and 10 min of dark adaptation, producing high correlations for maximum constriction velocity (MCV) between assay 1 and 2 (Pearson's r = 0.71, p < 0.001), but there was a significant 8% increase in velocity for MCV between assay 1 and 2 (∆ = 0.34 ± 0.59 mm/s, p < 0.05). In contrast, PLR measurements were stable when tested in a separate cohort of 21 additional participants at 10 and 15 min of dark adaptation with an MCV Pearson's correlation of r = 0.84, p < 0.001, with a nonsignificant 1% difference between the two time points. These findings indicate an acceptable rate of collecting valid and reproducible PLR data when contrasting two measurements of PLR after 10 or 15 min of dark adaptation in depressed and suicidal patients.

Role of Electroconvulsive Therapy in Treatment-Resistant Schizophrenia in Forensic Psychiatry.

ABSTRACT: Long-term institutionalization of the forensic psychiatry patient population places a psychological burden on patients and family members as well as a financial burden on the health care system at large. Although electroconvulsive therapy is a well-established tool for patients with treatment-resistant schizophrenia, it is infrequently used in the forensic setting. This review serves to demonstrate an example of electroconvulsive therapy in combination with clozapine as a means of reducing length of hospitalization in a forensic psychiatric patient. Furthermore, this review will discuss factors limiting the prescribing of electroconvulsive therapy to this patient population including ethical considerations and availability.

Development of Autonomic Nervous System Assays as Point-of-Care Tests to Supplement Clinical Judgment in Risk Assessment for Suicidal Behavior: A Review.

PURPOSE OF REVIEW: A biomarker point-of-care (POC) test that supplements the psychiatric interview and improves detection of patients at risk for suicide would be of value, and assays of autonomic nervous system (ANS) activity would satisfy the logistical requirements for a POC test. We performed a selective review of the available literature of ANS assays related to risk for suicide. RECENT FINDINGS: We searched PubMed and Web of Science with the strategy: "suicide OR suicidal" AND "electrodermal OR heart rate variability OR pupillometry OR pupillography." The search produced 119 items, 21 of which provided original data regarding ANS methods and suicide. These 21 studies included 6 for electrodermal activity, 14 for heart rate variability, and 1 for the pupillary light reflex. The 21 papers showed associations between ANS assays and suicide risk in a direction suggesting underlying hyperarousal in patients at risk for suicide. ANS assays show promise for future development as POC tests to supplement clinical decision making in estimating risk for suicide.

Longitudinal Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Pharmacotherapy in Major Depressive Disorder in Older Adults: Phase 2 of the PRIDE Study.

OBJECTIVE: There is limited information regarding neurocognitive outcomes of right unilateral ultrabrief pulse width electroconvulsive therapy (RUL-UB ECT) combined with pharmacotherapy in older adults with major depressive disorder. We report longitudinal neurocognitive outcomes from Phase 2 of the Prolonging Remission in Depressed Elderly (PRIDE) study. METHOD: After achieving remission with RUL-UB ECT and venlafaxine, older adults (≥60 years old) were randomized to receive symptom-titrated, algorithm-based longitudinal ECT (STABLE) plus pharmacotherapy (venlafaxine and lithium) or pharmacotherapy-only. A comprehensive neuropsychological battery was administered at baseline and throughout the 6-month treatment period. Statistical significance was defined as a p-value of less than 0.05 (two-sided test). RESULTS: With the exception of processing speed, there was statistically significant improvement across most neurocognitive measures from baseline to 6-month follow-up. There were no significant differences between the two treatment groups at 6 months on measures of psychomotor processing speed, autobiographical memory consistency, short-term and long-term verbal memory, phonemic fluency, inhibition, and complex visual scanning and cognitive flexibility. CONCLUSION: To our knowledge, this is the first report of neurocognitive outcomes over a 6-month period of an acute course of RUL-UB ECT followed by one of 2 strategies to prolong remission in older adults with major depression. Neurocognitive outcome did not differ between STABLE plus pharmacotherapy versus pharmacotherapy alone over the 6-month continuation treatment phase. These findings support the safety of RUL-UB ECT in combination with pharmacotherapy in the prolonging of remission in late-life depression.

Major Depressive Disorder in the Older Adult Associated With Globus Pharyngeus and Weight Loss - An Indication for Electroconvulsive Therapy.

Aspiration pneumonia and extreme weight loss are risks whenever globus pharyngeus (GP) complicates major depressive disorder (MDD) in the older adult. The timely administration of electroconvulsive therapy (ECT) may reverse GP in this context. We review cases of GP in depressed older adults and describe both successful outcomes, as well as a fatal outcome associated with delays in offering ECT. MDD in the older adult complicated by GP and marked weight loss, or repeated aspiration, should be considered an urgent indication for ECT.

The Effects of Focal Electrically Administered Seizure Therapy Compared With Ultrabrief Pulse Right Unilateral Electroconvulsive Therapy on Suicidal Ideation: A 2-Site Clinical Trial.

BACKGROUND: Preliminary data suggest that focal electrically administered seizure therapy (FEAST) has antidepressant effects and less adverse cognitive effects than traditional forms of electroconvulsive therapy (ECT). This study compared the impact of FEAST and ultrabrief pulse, right unilateral (UB-RUL) ECT on suicidal ideation. METHODS: At 2 sites, patients in a major depressive episode were treated openly with FEAST or UB-RUL ECT, depending on their preference. The primary outcome measure was scores on the Beck Scale for Suicide Ideation (SSI). Scores on the suicide item of the Hamilton Rating Scale for Depression (HRSD-SI) provided a secondary outcome measure. RESULTS: Thirty-nine patients were included in the intent-to-treat sample (FEAST, n = 20; UB-RUL ECT, n = 19). Scores on both the SSI and HRSD-SI were equivalently reduced with both interventions. Both responders and nonresponders to the interventions showed substantial reductions in SSI and HRSD-SI scores, although the magnitude of improvement was greater among treatment responders. CONCLUSIONS: Although limited by the open-label, nonrandomized design, FEAST showed comparable effects on suicidal ideation when compared with routine use of UB-RUL ECT. These results are encouraging and support the need for further research and a noninferiority trial.

Safe Administration of ECT in a Suicidal Patient With a Space-Occupying Astrocytoma.

ABSTRACT: Electroconvulsive therapy (ECT) can be lifesaving for patients suffering from treatment-resistant psychiatric conditions, especially acute suicidality or depression. However, space-occupying lesions pose risks associated with ECT use due in part to seizure-induced escalations in blood pressure with corresponding increases in cerebral blood flow and possibly intracranial pressure, subsequently increasing the risk of brain herniation. Here, we present the case of a patient with a left medial temporal lobe astrocytoma, worsening epileptic seizures, and nonepileptic seizures who underwent ECT for major depressive disorder and suicidality. The patient had improvement of depressive symptoms, resolution of suicidality, and brief cessation of nonepileptic seizures. Brief anterograde amnesia contributed to the termination of treatment. This case adds to the growing literature about the feasibility of ECT treatment in cerebral lesions prone to changes in intracranial pressure, such as the usually cystic astrocytomas.

The pupillary light reflex as a point-of-care test for suicide risk: Preliminary results.

The pupillary light reflex (PLR) reflects physiologic arousal, and a potential point-of-care biomarker of suicide risk. We collected data from 9 healthy controls, 6 non-suicidal depressed patients, 7 with prior suicide attempts but not presently suicidal, and 8 depressed patients who were actively suicidal. The pupillary maximum constriction velocity (MCV) was similar between the non-suicidal depressed patients and healthy controls (the "Never suicidal" group). Patients with prior attempt resembled the patients expressing active suicidal ideation (the "Ever suicidal" group). MCV was a significant predictor within a logistic regression model of participants who were "Ever suicidal" versus "Never suicidal".

Double-Blinded Randomized Pilot Clinical Trial Comparing Cognitive Side Effects of Standard Ultra-Brief Right Unilateral ECT to 0.5 A Low Amplitude Seizure Therapy (LAP-ST).

BACKGROUND: Concerns over cognitive side effects (CSE) of electroconvulsive therapy (ECT) still limit its broader usage for treatment-resistant depression (TRD). The objectives of this study were to (1) examine the CSE of Low Amplitude Seizure Therapy (LAP-ST) at 0.5 A compared to Ultra-brief Right Unilateral (UB-RUL) ECT using Time to Reorientation (TRO) as the main acute primary outcome, and (2) to compare effects on depressive symptoms between the two treatment groups. METHODS: Participants were referred for ECT, consented for the study, and were randomized to a course of LAP-ST or standard UB-RUL ECT. TRO and depression were measured by the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS: Eleven patients consented. Of these, eight with a current major depressive episode (MDE) of unipolar or bipolar disorders were randomized. TRO was faster for the LAP-ST (mean = 6.8 min; SE = 4.9) than standard RUL ECT (mean = 15.5 min; SE = 6.5). Depression improved similarly in the two arms of the study from baseline (MADRS: LAP-ST = 41.0; SE = 2.0, RUL = 39.0; SE = 3.8) to endpoint (MADRS score: LAP-ST = 8.0; SE7.2, RUL = 9.5; SE = 3.8). CONCLUSIONS: This pilot, randomized and blinded clinical trial, suggests that the LAP-ST (at 0.5 A) has faster reorientation and possibly lower CSE compared to standard RUL-UB ECT. Caution is advised in interpreting these results due to the small sample size of this pilot study. Thus, future studies with similar design are warranted for replicating these findings.

Treating Posttraumatic Stress Disorder Symptoms With Low Amplitude Seizure Therapy (LAP-ST) Compared With Standard Right Unilateral Electroconvulsive Therapy: A Pilot Double-Blinded Randomized Clinical Trial.

OBJECTIVES: An important barrier to further studying electroconvulsive therapy (ECT) in posttraumatic stress disorder (PTSD) is the cognitive adverse effects. However, recent data suggest that low amplitude seizure therapy (LAP-ST) has no or minimal cognitive adverse effects. The aims of this report were to examine the efficacy of LAP-ST in PTSD and to compare LAP-ST with standard right unilateral (RUL) ECT using a pilot randomized clinical trial. METHODS: Patients were randomized to LAP-ST or RUL ECT. Posttraumatic stress disorder was assessed using clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and symptom severity with PTSD Checklist (PCL). The scores pertaining to PCL were analyzed using descriptive analysis for this pilot study. RESULTS: Eleven patients consented to be enrolled. Seven were randomly allocated to LAP-ST or RUL ECT. Five completed the study and had completed PCL before and after the course. In both groups, PTSD symptoms showed fast improvement. The effect size of improvement seems promising. The mean baseline PCL score for patients in the LAP-ST group was 42.5 (SD = 16.26) and the mean end point PCL score after treatment was 31 (SD = 15.56). The mean baseline PCL score for patients in the standard RUL ECT group was 64.7 (SD = 1.15) and the mean end point was 41 (SD = 15.62). CONCLUSIONS: Both LAP-ST and standard RUL ECT showed reduction in PTSD symptoms with fast improvement. This first PTSD LAP-ST study adds support to the prior LAP-ST proof-of-concept clinical trial that LAP-ST can produce effective therapeutic outcomes. Replication of this trial is warranted in larger clinical trials (ClinicalTrials.gov ID: NCT02583490).

A two-site, open-label, non-randomized trial comparing Focal Electrically-Administered Seizure Therapy (FEAST) and right unilateral ultrabrief pulse electroconvulsive therapy (RUL-UBP ECT).

BACKGROUND: Focal Electrically-Administered Seizure Therapy (FEAST) is a form of electroconvulsive therapy (ECT) that spatially focuses the electrical stimulus to initiate seizure activity in right prefrontal cortex. Two open-label non-comparative studies suggested that FEAST has reduced cognitive side effects when compared to historical data from other forms of ECT. In two different ECT clinics, we compared the efficacy and cognitive side effects of FEAST and Right Unilateral Ultrabrief Pulse (RUL-UBP) ECT. METHODS: Using a non-randomized, open-label design, 39 depressed adults were recruited after referral for ECT. Twenty patients received FEAST (14 women; age 45.2 ± 12.7), and 19 received RUL-UBP ECT (16 women; age 43.2 ± 16.4). Key cognitive outcome measures were the postictal time to reorientation and the Columbia University Autobiographical Memory Interview: Short-Form (CUAMI-SF). Antidepressant effects were assessed using the Hamilton Rating Scale for Depression (HRSD24). RESULTS: In the Intent-to-treat sample, a repeated measures mixed model suggested no between group difference in HRSD24 score over time (F1,35 = 0.82, p = 0.37), while the response rate favored FEAST (FEAST: 65%; RUL-UBP ECT: 57.9%), and the remission rate favored RUL-UBP ECT (FEAST: 35%; RUL-UBP ECT: 47.4%). The FEAST group had numeric superiority in average time to reorientation (FEAST: 6.6 ± 5.0 min; RUL-UBP ECT: 8.8 ± 5.8 min; Cohens d = 0.41), and CUAMI-SF consistency score (FEAST: 69.2 ± 14.2%; RUL-UBP ECT: 63.9 ± 9.9%; Cohens d = 0.43); findings that failed to meet statistical significance. CONCLUSIONS: FEAST exerts similar efficacy relative to an optimal form of conventional ECT and may have milder cognitive side effects. A blinded, randomized, non-inferiority trial is needed.

The benefits and costs of changing treatment technique in electroconvulsive therapy due to insufficient improvement of a major depressive episode.

BACKGROUND: Electroconvulsive therapy (ECT) technique is often changed after insufficient improvement, yet there has been little research on switching strategies. OBJECTIVE: To document clinical outcome in ECT nonresponders who were received a second course using high dose, brief pulse, bifrontotemporal (HD BP BL) ECT, and compare relapse rates and cognitive effects relative to patients who received only one ECT course and as a function of the type of ECT first received. METHODS: Patients were classified as receiving Weak, Strong, or HD BP BL ECT during three randomized trials at Columbia University. Nonresponders received HD BP BL ECT. In a separate multi-site trial, Optimization of ECT, patients were randomized to right unilateral or BL ECT and nonresponders also received further treatment with HD BP BL ECT. RESULTS: Remission rates with a second course of HD BP BL ECT were high in ECT nonresponders, approximately 60% and 40% in the Columbia University and Optimization of ECT studies, respectively. Clinical outcome was independent of the type of ECT first received. A second course with HD BP BL ECT resulted in greater retrograde amnesia immediately, two months, and six months following ECT. CONCLUSIONS: In the largest samples of ECT nonresponders studied to date, a second course of ECT had marked antidepressant effects. Since the therapeutic effects were independent of the technique first administered, it is possible that many patients may benefit simply from longer courses of ECT. Randomized trials are needed to determine whether, when, and how to change treatment technique in ECT.

An exploratory analysis of the association of circadian rhythm dysregulation and insomnia with suicidal ideation over the course of treatment in individuals with depression, insomnia, and suicidal ideation.

STUDY OBJECTIVES: Sleep disturbance is significantly associated with suicidal ideation. However, the majority of past research has examined the relationship between insomnia and suicidality. The current exploratory study examined the relationship of circadian rhythm dysregulation (eveningness, seasonality, and rhythmicity) with suicidality. METHODS: We examined the association of insomnia, eveningness, seasonality, and rhythmicity with suicidal ideation in 103 participants with depression, insomnia, and suicidality within a larger 8-week double-blinded randomized control trial primarily examining whether cautious use of zolpidem extended-release or placebo reduced suicidal ideation. All participants additionally received an open-label selective serotonin reuptake inhibitor. Methodological strengths of the current analyses included consideration of multiple sleep-wake constructs, adjustment for relevant covariates, investigation of relationships over the course of treatment, and use of both self-report measures and objective measurement with actigraphy. RESULTS: Over the course of treatment, self-reported eveningness and greater insomnia severity were independently correlated with greater suicidal ideation, whereas actigraphic delayed sleep timing was related to suicidal ideation at a trend level. At the end of treatment, those with greater suicidal ideation demonstrated lower actigraphic activity levels. There were no significant relationships between self-reported seasonality and actigraphic measures of sleep disturbance and suicidality. CONCLUSIONS: Self-reported delays in sleep timing, objectively lower activity levels, and self-reported insomnia severity correlated independently with greater suicidal ideation in those with depression, insomnia, and suicidality. These exploratory findings highlight the need to consider sleep-wake constructs more broadly in those with suicidality in future research studies in order to improve more definitively both assessment and intervention efforts. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Reducing Suicidal Ideation through Insomnia Treatment; URL: https://clinicaltrials.gov/ct2/show/NCT01689909; Identifier: NCT01689909 Rumble ME, McCall MV, Dickson DA, Krystal AD, Rosenquist PB, Benca RM. An exploratory analysis of the association of circadian rhythm dysregulation and insomnia with suicidal ideation over the course of treatment in individuals with depression, insomnia, and suicidal ideation. J Clin Sleep Med. 2020;16(8):XXX-XXX.