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

Papers by Harold Sackeim

Neuropsychopharmacology, Aug 23, 2006

Despite ongoing controversy, there has never been a large-scale, prospective study of the cogniti... more Despite ongoing controversy, there has never been a large-scale, prospective study of the cognitive effects of electroconvulsive therapy (ECT). We conducted a prospective, naturalistic, longitudinal study of clinical and cognitive outcomes in patients with major depression treated at seven facilities in the New York City metropolitan area. Of 751 patients referred for ECT with a provisional diagnosis of a depressive disorder, 347 patients were eligible and participated in at least one post-ECT outcome evaluation. The primary outcome measures, Modified Mini-Mental State exam scores, delayed recall scores from the Buschke Selective Reminding Test, and retrograde amnesia scores from the Columbia University Autobiographical Memory Interview-SF (AMI-SF), were evaluated shortly following the ECT course and 6 months later. A substantial number of secondary cognitive measures were also administered. The seven sites differed significantly in cognitive outcomes both immediately and 6 months following ECT, even when controlling for patient characteristics. Electrical waveform and electrode placement had marked cognitive effects. Sine wave stimulation resulted in pronounced slowing of reaction time, both immediately and 6 months following ECT. Bilateral (BL) ECT resulted in more severe and persisting retrograde amnesia than right unilateral ECT. Advancing age, lower premorbid intellectual function, and female gender were associated with greater cognitive deficits. Thus, adverse cognitive effects were detected 6 months following the acute treatment course. Cognitive outcomes varied across treatment facilities and differences in ECT technique largely accounted for these differences. Sine wave stimulation and BL electrode placement resulted in more severe and persistent deficits.

International Journal of Geriatric Psychiatry, Dec 28, 2010

Objective-In patients with Alzheimer's disease (AD) with psychosis or agitation that respond to h... more Objective-In patients with Alzheimer's disease (AD) with psychosis or agitation that respond to haloperidol treatment, to evaluate the risk of relapse following discontinuation. Methods-In outpatients with AD with symptoms of psychosis or agitation, responders to 20 weeks of haloperidol (0.5 to 5 mg daily) were randomized to a 24-week, double-blind pilot trial of discontinuation on placebo versus continuation haloperidol. Phase A response criteria were minimum 50% reduction in 3 target symptoms, and improvement on the Clinical Global Impression-Change (CGI-C) score for psychosis/agitation. Phase B relapse criteria required 50% worsening in target symptoms and on the CGI-C. Alpha=0.1 was the significance criterion in this pilot study. Results-Of 44 patients, 22 patients responded in Phase A. The sum score of target symptoms, and Brief Psychiatric Rating Scale psychosis and hostile suspiciousness factor scores, decreased in Phase A (p's < .001). Extrapyramidal signs increased in Phase A (p < .01). Of 22 responders, 21 patients entered Phase B, and 20 had at least one follow-up visit. Four of 10 patients (40%) on continuation haloperidol relapsed compared to 8 of 10 patients on placebo (80%, χ 2 =3.3, p=0.07). In survival analyses, time to relapse was shorter on placebo than haloperidol (χ 2 =4.1, p=0.04). Conclusions-Haloperidol open treatment was efficacious, and relapse was greater on placebo than with haloperidol continuation. In patients with AD who have psychosis or agitation and respond to antipsychotic medication, the increased risk of relapse after discontinuation needs to be weighed against the side effects associated with continuing the medication.

Schizophrenia Bulletin, 1988

In neuroimaging studies of human cognitive abilities, brain activation patterns that include regi... more In neuroimaging studies of human cognitive abilities, brain activation patterns that include regions that are strongly interactive in response to experimental task demands are of particular interest. Among the existing network analyses, partial least squares (PLS; McIntosh, 1999; McIntosh, Bookstein, Haxby, & Grady, 1996) has been highly successful, particu-larly in identifying group differences in regional functional connectivity, including differences as diverse as those associated with states of aware-

Behavioral Syndromes in Alzheimer's Disease

International Psychogeriatrics, 1992

The Behavioral Syndromes Scale for Dementia (BSSD) is a new instrument that showed strong interna... more The Behavioral Syndromes Scale for Dementia (BSSD) is a new instrument that showed strong internal consistency and interrater reliability in an outpatient sample of 106 patients with probable Alzheimer's disease. Factor analysis provided support for a priori symptom groupings, particularly the syndromes of disinhibition and apathy-indifference. Dependency (87%), denial of illness (63%), and motor agitation (55%) were common, while sexual disinhibition (2.9%) and self-destructive behaviors (2.9%) were rare. Virtually all symptoms were predominantly minimal to mild in severity. Patients with longer illness duration were more apathetic. Disinhibited behaviors and apathy-indifference increased with greater severity of dementia. Catastrophic reactions, aggression, and agitation were associated with greater functional impairment. There was great heterogeneity in symptom presentation. In Alzheimer's disease, several behavioral changes might be direct manifestations of underlying br...

Cerebral perfusion as a diagnostic marker of early Alzheimer's disease

Neurology, 1988

Clinical diagnosis of Alzheimer's disease (AD) is not fully satisfactory, and laboratory ... more Clinical diagnosis of Alzheimer's disease (AD) is not fully satisfactory, and laboratory markers of this disease are not yet established. We report substantial regional Cerebral Blood Flow (rCBF) abnormalities in patients with documented early stages of the disease, when differential diagnosis is most critical. Thirty-six patients with carefully documented clinical diagnosis of early AD (mean disease duration, 3.25 +/- 1.80 years) and 12 elderly healthy controls participated in rCBF studies using the 133Xe inhalation method. Whole-brain perfusion was significantly (p less than 0.001) lower in the AD group, and a characteristic perfusion deficit was consistently found in temporoparietal cortex of the AD patients. Discriminant analyses demonstrated over 90% correct classification of the two groups. Two subgroups of patients with mildest disease manifestations were equally well discriminated. The similarity of these findings to those in late stages, which have been validated neuropathologically, offers indirect confirmation of validity and specificity. These results suggest that rCBF procedures may provide an accurate and sensitive laboratory marker for early AD.

Neurology, 2000

To determine whether the pathologic mechanisms of AD alter the brain networks subserving performa... more To determine whether the pathologic mechanisms of AD alter the brain networks subserving performance of a verbal recognition task. Background: Functional imaging studies comparing task-related activation in AD patients and controls generally have not used network analysis and have not controlled for task difficulty. Methods: H 2 15 O PET was used to measure regional cerebral blood flow in 14 patients and 11 healthy elders during the performance of a serial verbal recognition task under two conditions: low demand, with study list size (SLS) equal to one; and titrated demand, with SLS adjusted so that each subject recognized words at 75% accuracy. The Scaled Subprofile Model was used to identify networks of regionally covarying activity across these task conditions. Results: In the elders, higher SLS was associated with the recruitment of a network of brain areas involving left anterior cingulate and anterior insula (R 2 ϭ 0.94; p Ͻ 0.0001). Three patients also expressed this network. In the remaining patients, higher SLS was associated with the recruitment of an alternate network consisting of left posterior temporal cortex, calcarine cortex, posterior cingulate, and the vermis (R 2 ϭ 0.81, p Ͻ 0.001). Expression of this network was unrelated to SLS in the elders and more intact AD patients. Conclusions: The patients' use of the alternate network may indicate compensation for processing deficits. The transition from the normal to the alternate network may indicate a point where brain disease has irreversibly altered brain function and thus may have important implications for therapeutic intervention.

Prolactin response to TRH and ECT: A common mechanism?

Biological Psychiatry, 1989

The International Journal of Neuropsychopharmacology, Feb 9, 2007

Staging and Combining Brain Stimulation Interventions

The Journal of ECT, 2021

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...

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

Repetitive transcranial magnetic stimulation: what are the next steps?

Biol Psychiat, 2000

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.

Electroconvulsive Therapy

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

The Effects of Electroconvulsive Therapy on Quantitative Electroencephalograms

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.