Harold Sackeim - Academia.edu (original) (raw)

Papers by Harold Sackeim

This double-column opus is the work of two experts in the field who assigned 41 other scientists ... more This double-column opus is the work of two experts in the field who assigned 41 other scientists and clinicians to participate in what the editors describe as the first textbook devoted to a comprehensive overview of depression in the elderly. The senior author of each multiauthored chapter had to agree to write the chapter himself or herself, a requirement that boggles my mind. What were the roles of junior authors such as Harold Sackeim and Alexander Glassman? To underscore the importance of this endeavor, the editors tell us that the elderly are rapidly increasing in number. It is estimated that by the year 2030 more than 70 million Americans will be older than 65. We are also told that people older than 85 are the fastest growing group of individuals in the population and that their numbers will double in the decade. The editors state that this book is intended essentially for all clinicians and researchers interested in depression in this population. In answer to a question not...

The American Journal of Psychology, 1982

Brain Stimulation, 2019

Acute variations in physical activity (PA) has been shown to alter the plasticity of the motor co... more Acute variations in physical activity (PA) has been shown to alter the plasticity of the motor cortex, as measured by changes in corticospinal excitability (CSE) in young, physically active adults. However, the longlasting effect of PA patterns on CSE is not well described. Any lingering relation between CSE and preceding days PA pattern may obscure effects from acute interventions. We sought to study the effect on CSE from interand intra-individual variations in PA pattern one day before measurement using data from a randomized cross-over study. Thirteen inactive middle-aged individuals participated in the study. Each participant participated three times and received a standardized instruction to not do any exercise on the day preceding the experiment. Transcranial magnetic stimulation over the M1 was applied to induce recruitment curves in the EMG of the dominant abductor pollicis brevis (APB). CSE was measured as area under the recruitment curve (AURC). We investigated PA pattern during the previous day using hip-worn Actigraph GT3X-BT. Time spent sedentary and in light and moderate-to-vigorous PA was recorded and adjusted for wear time. Multiple linear regressions, controlling for repeated measures were used to study relations between CSE and PA pattern. Analysis of the preliminary results revealed a significant positive relation between time spent sedentary and CSE on the following day (Beta¼0.595, p¼0.004) and a negative relation between time spent in light PA (Beta¼-0.486, p¼0.009) and CSE on the following day. Time spent in moderate-to-vigorous PA tended to be negatively related to CSE on the following day (Beta¼-0.360, p¼0.066). The preliminary results of this study in progress suggest that variations in PA pattern may influence CSE on the following day. Repeated measures comparisons of CSE should therefore control for day-today variations in PA patterns.

Psychological Medicine

Background In difficult-to-treat depression (DTD) the outcome metrics historically used to evalua... more Background In difficult-to-treat depression (DTD) the outcome metrics historically used to evaluate treatment effectiveness may be suboptimal. Metrics based on remission status and on single end-point (SEP) assessment may be problematic given infrequent symptom remission, temporal instability, and poor durability of benefit in DTD. Methods Self-report and clinician assessment of depression symptom severity were regularly obtained over a 2-year period in a chronic and highly treatment-resistant registry sample (N = 406) receiving treatment as usual, with or without vagus nerve stimulation. Twenty alternative metrics for characterizing symptomatic improvement were evaluated, contrasting SEP metrics with integrative (INT) metrics that aggregated information over time. Metrics were compared in effect size and discriminating power when contrasting groups that did (N = 153) and did not (N = 253) achieve a threshold level of improvement in end-point quality-of-life (QoL) scores, and in the...

Contact me when this article is cited. This article has been cited 191 times. Topic collections C... more Contact me when this article is cited. This article has been cited 191 times. Topic collections Contact me when new articles are published in these topic areas. Randomized Controlled Trial the same issue Related Articles published in

JAMA Psychiatry, 2017

Since the 1940s, electroconvulsive therapy (ECT) has been considered the most effective intervent... more Since the 1940s, electroconvulsive therapy (ECT) has been considered the most effective intervention for severe mood disorders. 1 To my knowledge, no treatment, pharmacological or otherwise, has matched ECT in speed or likelihood of remission of major depressive episodes. Electroconvulsive therapy is equally effective in unipolar and bipolar depression and has profound antimanic properties. 2 Several long-term follow-up studies have suggested that patients who receive ECT have reduced mortality of all causes relative to non-ECT control patients. 3 There was a dramatic decrease in ECT use once antidepressant medications were introduced. While this decrease may have slowed in recent years, only a small fraction of potentially appropriate patients receive ECT in the United States. In this issue of JAMA Psychiatry, Slade et al 4 found across 9 states that only 1.5% of general hospital inpatients with severe mood disorder received ECT during their index admission. Historically, the 2 major clinical considerations thought to limit ECT use were its adverse cognitive effects and propensity for relapse. In recent years, both limitations have been substantially addressed. Marked progress has been made in refining the ECT electrical stimulus. In the era of sine-wave stimulation (1940-1980s), the time to recover full orientation following seizure induction averaged several hours, with many patients developing continuous disorientation. 5 The introduction of titration of the ECT electrical dose to the individual seizure threshold and brief pulse stimulation reduced the time to orientation recovery to about 45 minutes for bilateral and 30 minutes for right unilateral ECT. 6 The introduction of ultrabrief stimulation further reduced recovery time to approximately 15 minutes for bilateral and 10 minutes for right unilateral ECT. 7 The most severe and persistent adverse cognitive effect of ECT pertains to memory for past events (retrograde amnesia), and orientation recovery time predicts the magnitude of this longterm amnesia. 8 With the advances in ECT technique that reduced recovery time, there was a parallel decrease in the severity of long-term retrograde amnesia. Recent work has failed to detect any adverse effect of high-dose, ultrabrief pulse right unilateral ECT in memory or other cognitive assessments conducted within days of ECT course termination. 7 In a 2016 large multisite study in geriatric depression, this form of ECT resulted in a 62% remission rate. 9 At the time of the introduction of antidepressant medications, it was estimated that 50% of patients with depression would relapse within 6 months if given placebo following re

Clinical Neurophysiology, Feb 1, 2001

Objectives: To evaluate the therapeutic potential of repetitive transcranial magnetic stimulation... more Objectives: To evaluate the therapeutic potential of repetitive transcranial magnetic stimulation (rTMS) for Parkinson's disease (PD) by delivering stimulation at higher intensity and frequency over longer time than in previous research. Promising bene®cial effects on movement during or after rTMS have been reported. Methods: Ten patients with idiopathic PD were enrolled in a randomized crossover study comparing active versus sham rTMS to the supplementary motor area (SMA). Assessments included reaction and movement times (RT/MT), quantitative spiral analysis, timed motor performance tests, United Parkinson's Disease Rating Scale (UPDRS), patient self-report and guess as to stimulation condition. Results: Two of 10 patients could not tolerate the protocol. Thirty to 45 min following stimulation, active rTMS as compared with sham stimulation worsened spiral drawing (P 0:001) and prolonged RT in the most affected limb (P 0:030). No other signi®cant differences were detected. Conclusions: We sought clinically promising improvement in PD but found subclinical worsening of complex and preparatory movement following rTMS to SMA. These results raise safety concerns regarding the persistence of dysfunction induced by rTMS while supporting the value of rTMS as a research tool. Studies aimed at understanding basic mechanisms and timing of rTMS effects are needed.

American Journal of Geriatric Psychiatry, 2005

Objective: The authors compared the efficacy and side effects of fluoxetine and placebo in elderl... more Objective: The authors compared the efficacy and side effects of fluoxetine and placebo in elderly outpatients with dysthymic disorder. Methods: Patients were randomly assigned to fluoxetine (20 mg-60 mg/day) or placebo for 12 weeks in a double-blind trial. Results: Of 90 randomized patients, 71 completed the trial. In the intent-to-treat sample, random regression analyses of the Hamilton Rating Scale for Depression (Ham-D; 24-item) and Cornell Dysthymia Rating Scale (CDRS) scores at each visit produced significant time ‫ן‬ treatment group interactions favoring the fluoxetine group. Analysis of percentage change in Ham-D scores yielded no effect for treatment group, but a similar analysis of percentage change in CDRS scores yielded a main effect for treatment group, favoring fluoxetine over placebo. In the intent-to-treat sample, response rates were 27.3% for fluoxetine and 19.6% for placebo. In the completer sample, response rates were 37.5% for fluoxetine and 23.1% for placebo. Conclusion: Fluoxetine had limited efficacy in elderly dysthymic patients. The clinical features of elderly dysthymic patients are typically distinct from those of dysthymic disorder in young adults, and the findings suggest that treatments effective for young adult dysthymic patients may not be as useful in elderly dysthymic patients. Further research is needed to identify efficacious treatments for elderly patients with dysthymic disorder, and investigative tools such as electronic/computerized brain scans and neuropsychological testing may help identify the factors that moderate antidepressant treatment response and resistance.

Contemporary Psychiatry, 2001

PLoS ONE, 2011

Background: Rodent studies show that neurogenesis is necessary for mediating the salutary effects... more Background: Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. Materials/Methodology: Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving salineplacebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels. Results: Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation. Conclusion: We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants.

Controlled Clinical Trials, 2004

STAR * D is a multisite, prospective, randomized, multistep clinical trial of outpatients with no... more STAR * D is a multisite, prospective, randomized, multistep clinical trial of outpatients with nonpsychotic major depressive disorder. The study compares various treatment options for those who do not attain a satisfactory response with citalopram, a selective serotonin reuptake inhibitor antidepressant. The study enrolls 4000 adults (ages 18-75) from both primary and specialty care practices who have not had either a prior inadequate response or clear-cut intolerance to a robust trial of protocol treatments during the current major depressive episode. After receiving citalopram (level 1), participants without sufficient symptomatic benefit are

Archives of General Psychiatry, 1996

The efficacy of electroconvulsive therapy (ECT) is determined by stimulus electrical intensity an... more The efficacy of electroconvulsive therapy (ECT) is determined by stimulus electrical intensity and electrode placement. Three theories offer different accounts for why increasing the stimulus dosage of right unilateral ECT enhances antidepressant effects. This study examined the effects of ECT on interictal quantitative electroencephalograms (EEGs), contrasting these theories in their predictions regarding global, lateralized, and topographic changes in ECT-induced slow-wave activity. The time course of EEG changes and associations with efficacy were also determined. Sixty-two inpatients with major depressive disorder were randomized to ECT conditions that differed in stimulus intensity (low vs high dosage) and electrode placement (right unilateral vs bilateral). Resting, eyes closed, 19-lead EEG recordings were obtained at pretreatment, following a single treatment, following an average of 7 treatments, during the week following the ECT course, and after a 2-month follow-up period. Electroconvulsive therapy produced a marked short-term increase in delta and theta power. At a 2-month follow-up, there were no significant alterations in any frequency band. The ECT treatment conditions differed markedly in efficacy. Global and lateralized EEG effects did not distinguish effective and ineffective forms of treatment. Effective forms of ECT resulted in increased delta power in prefrontal regions, and this change was associated with the magnitude of symptomatic improvement. The induction of slow-wave activity in prefrontal cortex is linked to the efficacy of ECT.

Archives of General Psychiatry, 1999

In the 1990s, it is difficult to open a newspaper or watch television and not find someone claimi... more In the 1990s, it is difficult to open a newspaper or watch television and not find someone claiming that magnets promote healing. Rarely do these claims stem from double-blind, peer-reviewed studies, making it difficult to separate the wheat from the chaff. The current fads resemble those at the end of the last century, when many were falsely touting the benefits of direct electrical and weak magnetic stimulation. Yet in the midst of this popular interest in magnetic therapy, a new neuroscience field has developed that uses powerful magnetic fields to alter brain activity-transcranial magnetic stimulation. This review examines the basic principles underlying transcranial magnetic stimulation, and describes how it differs from electrical stimulation or other uses of magnets. Initial studies in this field are critically summarized, particularly as they pertain to the pathophysiology and treatment of neuropsychiatric disorders. Transcranial magnetic stimulation is a promising new research and, perhaps, therapeutic tool, but more work remains before it can be fully integrated in psychiatry's diagnostic and therapeutic armamentarium.

Archives of General Psychiatry, 2007

Background: Antidepressant treatments that achieve a higher remission rate than those currently a... more Background: Antidepressant treatments that achieve a higher remission rate than those currently available are urgently needed. The thyroid hormone triiodothyronine may potentiate antidepressant effects. Objective: To determine the antidepressant efficacy and safety of liothyronine sodium (triiodothyronine) when administered concurrently with the selective serotonin reuptake inhibitor sertraline hydrochloride to patients with major depressive disorder.

Proceedings of the …, 2004

For a coherent and meaningful life, conscious self-representation is mandatory. Such explicit ???... more For a coherent and meaningful life, conscious self-representation is mandatory. Such explicit ???autonoetic consciousness??? is thought to emerge by retrieval of memory of personally experienced events (???episodic memory???). During episodic retrieval, functional ...

Brain Stimulation

OBJECTIVES Electroconvulsive therapy (ECT) is a mainstay in both acute and long-term management o... more OBJECTIVES Electroconvulsive therapy (ECT) is a mainstay in both acute and long-term management of difficult-to-treat depression. However, frequent acute courses of ECT or prolonged maintenance ECT treatment may increase adverse-effect burden and/or reduce patient acceptability. Therefore, we investigated the effectiveness of adjunctive vagus nerve stimulation (VNS) therapy as an alternative strategy for long-term maintenance treatment in ECT-responsive patients. METHODS This retrospective chart review identified maintenance ECT patients with unipolar (n = 5) and bipolar depression (n = 5) from 2 large hospital systems who had a history of ECT response, but the patients had significant residual incapacitating symptoms or increasing concerns regarding the burden associated with ECT and opted to receive adjunctive VNS therapy. The patients were followed for 2 years after VNS implantation. Response and remission were defined as Clinical Global Impression-Severity scale scores of ≤2 and 1, respectively, obtained at 1- and 2-year postimplantation compared with just before VNS implantation. RESULTS One-year postimplantation, 6 of 10 had responded of which 5 met remission criteria. All 10 patients benefited from adjunctive VNS therapy with either fewer hospitalizations and/or ECT sessions. Seven of 10 stopped maintenance ECT by the end of year 1; an additional patient stopped maintenance ECT by year 2. No patients required an acute course of ECT during the 2-year follow-up. There was a statistically significant reduction (P < 0.0001) in mean (SD) Clinical Global Impression-Severity scale scores between baseline (5.4 [0.51]) and the 1-year postimplantation (2.1 [1.37]) time points, and between baseline and the 2-year postimplantation (2.3 [1.16]) time points, whereas no difference existed between the 1- and 2-year postimplantation time points. CONCLUSIONS Vagus nerve stimulation therapy may be a useful maintenance strategy in patients with difficult-to-treat depression receiving maintenance ECT.

Archives of general …, 1987

The Journal of clinical psychiatry, 2001

Most patients treated for an episode of unipolar or bipolar major depression are treatment resist... more Most patients treated for an episode of unipolar or bipolar major depression are treatment resistant in the sense that the majority do not achieve full remission with the first somatic or psychosocial treatment they receive. Little attention has been given to formalizing criteria for evaluating the nature and extent of treatment resistance, even though determining the adequacy and outcome of prior treatment trials is key in clinical decision making about subsequent treatment. Furthermore, determining the adequacy of prior treatment is essential since substantial evidence indicates that large numbers of depressed patients are undertreated, resulting in prolonged episodes and the appearance of "pseudoresistance." Adequacy of antidepressant treatment trials should be defined in terms of thresholds for the dosage and duration of medication, adherence, and clinical outcome. The Antidepressant Treatment History Form is presented as one method to formalize the evaluation of treat...