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.

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.