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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT01028508.

Keywords: Electroconvulsive therapy; major depression; neurocognitive adverse effects.

Conflict of interest statement

Disclosures/Conflicts of Interest (listed in alphabetical order)

George Alexopoulos. Dr. Alexopoulos reports having served in the speakers bureau of Otsuka, Lundbeck, Takeda, Allergan, Sunovion, and Astra Zeneca.

Samuel H. Bailine. Dr. Bailine reports no conflicts of interest.

Elisabeth Bernhardt. Ms. Bernhardt reports no conflicts of interest.

Mimi C. Briggs. Dr. Briggs reports no conflicts of interest.

C. Munro Cullum. Dr. Cullum reports no conflicts of interest.

Zhi-De Deng. Dr. Deng reports no conflicts of interest.

Emma T. Geduldig. Ms. Geduldig reports no conflicts of interest.

Robert M. Greenberg. Dr. Greenberg reports no conflicts of interest.

Mustafa M. Husain. Dr. Husain reports research support from the National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, Stanley Medical Research Foundation, Neuronetics, Inc., MagStim (equipment only), Brainsway, Inc., NeoSync and consulting income from Cerebain Inc. Speaker bureau for Acadia Pharmaceutical. Consultant to the Neurological Devices Panel of the Medical Devices Advisory Committee, Center for Devices and Radiological Health, Food and Drug Administration (FDA). Editorial Board Member of the Journal of ECT.

Styliani Kaliora. Dr. Kaliora reports no conflicts of interest.

Charles H. Kellner. Dr. Kellner receives honoraria from UpToDate, Psychiatric Times, and Northwell Health and royalties from Cambridge University Press

Rebecca G. Knapp. Dr. Knapp reports no conflicts of interest.

Vassilios Latoussakis. Dr. Latoussakis reports no conflicts of interest.

Lauren S. Liebman. Ms. Liebman reports no conflicts of interest.

Sarah H. Lisanby. Dr. Lisanby has received grant support from the Brain and Behavior Research Foundation, the Stanley Medical Research Foundation, Neosync, Nexstim, NIH, and Brainsway. This manuscript was prepared while Dr. Sarah H. Lisanby was employed at Duke University. The opinions expressed in this article are the author's own and do not reflect the views of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

William V. McCall. Dr. McCall has served as a scientific adviser for Jazz, Sage, and Janssen pharmaceuticals, and he has received research support from the American Foundation for Suicide Prevention, NIMH, PCORI, MECTA Corp, Merck, Vistagen, and Otsuka. He has received royalties from Wolters Kluwer, and honoraria from Anthem, Inc., CME Outfitters, Global Medical Education, and Merck.

Shawn M. McClintock. Dr. McClintock reports research support from the National Institutes of Health. He is a consultant to Pearson Assessment.

Martina Mueller. Dr. Mueller reports no conflicts of interest.

Georgios Petrides. Dr. Petrides has received research support from Amgen, AstraZeneca, Corcept, Eli Lilly, Proteus, St. Jude Medical, and Sunovion, and he has served on an advisory panel for Corcept.

Joan Prudic. Dr. Prudic reports no conflicts of interest.

Peter B. Rosenquist. Dr. Rosenquist reports no conflicts of interest.

Matthew V. Rudorfer. Dr. Rudorfer reports no conflicts of interest.

Shirlene Sampson. Dr. Sampson reports no conflicts of interest.

Abeba Teklehaimanot. Ms. Teklehaimanot reports no conflicts of interest.

Kristen G. Tobias. Dr. Tobias reports no conflicts of interest.

Richard D. Weiner. Dr. Weiner reports no conflicts of interest.

Robert C. Young. Dr. Young has received research support from NIMH.

Published by Elsevier Inc.

Figures

Figure 1.

Trajectories of Memory Domain Neurocognitive Outcomes over the 6-month Study Period By Treatment Arm Using Model-Derived Adjusted Treatment Means California Verbal Learning Test (CVLT) - anterograde verbal learning and memory: These graphs show adjusted least squares means from quadratic mixed effects models with random intercept using unstructured covariance adjusted for site, psychosis, age, Wechsler Test of Adult Reading and Ham-D (time varying).The within group improvement from baseline was statistically significant at p≤0.05 for all CVLT items in both treatment groups (Item, p-value [DF, t-statistic]: Item12 Stable: <0.0001 [474, 9.67], Pharm: <0.0001 [479, 6.10]; Item16 Stable: <0.0001 [469, 8.55], Pharm: <0.0001 [475, 5.93]; Item20 Stable: <0.0001 [472, 9.31], Pharm: <0.0001 [478, 5.97]; Item44 Stable: <0.0001 [473, 7.01], Pharm: <0.0001 [480, 6.00]). There were no significant differences between the ECT plus Medication and Medication only treatment arms at the post-treatment (24 weeks) time point. For the comparison of trajectories of CVLT mean scores over time (time as continuous), there was a significant interaction for CVLT Trial 1–5 Free Recall Total Correct t-score (p [DF, t-statistic]: 0.02 [480, −2.27]) and CVLT Long delay free recall correct standard score (p [DF, t-statistic]: 0.04 [479, −2.11]) AMI-SF - retrograde amnesia for autobiographical information: This graph shows adjusted least squares means from linear mixed effects model with random intercept using unstructured covariance adjusted for site, psychosis, age, Wechsler Test of Adult Reading and Ham-D (time varying). There was no significant differences between the ECT plus Medication and Medication only treatment arms at the post-treatment (24 weeks) time point. The within group improvement from baseline was not statistically significant in both treatment groups.

Figure 2.

Trajectories of Executive Function Neurocognitive Outcomes over the 6- month Study Period By Treatment Arm Using Model-Derived Adjusted Treatment Means Stroop - selective and divided attention and cognitive flexibility: These graphs show adjusted least squares means from quadratic (STROOP Word T-score & STROOP Color-Word T-score) and linear (STROOP Color T-score) mixed effects models with random intercept using unstructured covariance adjusted for site, psychosis, age, Wechsler Test of Adult Reading and Ham-D (time varying). Except for Color-Word T-Score Medication only treatment group, the within group improvement from baseline was statistically significant at p≤0.05 (Measure, p-value [DF, t-statistic]: Word T-Score Stable: 0.0361 [162, 2.11], Pharm: 0.0010 [165, 3.36]; Color T-Score Stable: 0.0076 [164, 2.70], Pharm: 0.0142 [167, 2.48]; Color-Word T-Score Stable: 0.0004 [151, 3.60]). Trail Making Test Parts A and B: The graph of Trail Making Test Part A score shows adjusted least squares means from linear mixed effects model with random intercept using unstructured covariance adjusted for site, psychosis, age, Wechsler Test of Adult Reading and Ham-D (time varying). The within group improvement from baseline was not statistically significant in the Medication only treatment group. The graph of Trail Making Test Part B score shows adjusted least squares means from quadratic mixed effects model with random intercept using unstructured covariance adjusted for site, psychosis, age, Wechsler Test of Adult Reading and Ham-D (time varying). The within group improvement from baseline was statistically significant at p≤0.05 in both treatment arms (Measure, p-value [DF, t-statisticj: TMT Score A Stable: 0.0209 [142, 2.34]; TMT Score B Stable: 0.0242 (142, 2.28), Pharm: 0.0003 [150, 3.72]). Delis Kaplan Executive Function System (D-KEFS): Letter fluency total correct scaled score: The graph shows adjusted least squares means from quadratic mixed effects model with random intercept using unstructured covariance adjusted for site, psychosis, age, Wechsler Test of Adult Reading and Ham-D (time varying). The within group improvement from baseline was statistically significant at p≤0.05 in both treatment arms (p [DF, t-statistic] Stable: <0.0001 [169, 4.11], Pharm: 0.0026 [174, 3.05]). Dementia Rating Scale - IP (DRS-IP): These graphs show adjusted least squares means from linear mixed effects model with random intercept using unstructured covariance adjusted for site, psychosis, age, Wechsler Test of Adult Reading and Ham-D (time varying). The within group improvement from baseline was statistically significant at p≤0.05 for all DRS items in both treatment groups. There were no significant differences between the ECT plus Medication and Medication only treatment arms at the post-treatment (24 weeks) time point for all instrument items.