Neurocognitive Effects of Combined Electroconvulsive Therapy (ECT) and Venlafaxine in Geriatric Depression: Phase 1 of the PRIDE Study

Published:October 11, 2019DOI:


      • What is the primary question addressed by this study? What are the acute neurocognitive effects of ultrabrief pulse, dose titrated, right unilateral ECT, and venlafaxine in elderly adults with major depressive disorder?
      • What is the main finding of the study? There were statistically significant declines in performance across neurocognitive measures. However, the magnitude of decline was clinically modest, with small differences relative to baseline, and some cognitive performance only fell into the mildly impaired range.
      • What is the meaning of the finding? The combination of RUL-UB ECT with venlafaxine is a relatively cognitively safe treatment in late-life depression.



      There is limited information regarding the tolerability of electroconvulsive therapy (ECT) combined with pharmacotherapy in elderly adults with major depressive disorder (MDD). Addressing this gap, we report acute neurocognitive outcomes from Phase 1 of the Prolonging Remission in Depressed Elderly (PRIDE) study.


      Elderly adults (age ≥60) with MDD received an acute course of 6 times seizure threshold right unilateral ultrabrief pulse (RUL-UB) ECT. Venlafaxine was initiated during the first treatment week and continued throughout the study. A comprehensive neurocognitive battery was administered at baseline and 72 hours following the last ECT session. Statistical significance was defined as a two-sided p-value of less than 0.05.


      A total of 240 elderly adults were enrolled. Neurocognitive performance acutely declined post ECT on measures of psychomotor and verbal processing speed, autobiographical memory consistency, short-term verbal recall and recognition of learned words, phonemic fluency, and complex visual scanning/cognitive flexibility. The magnitude of change from baseline to end for most neurocognitive measures was modest.


      This is the first study to characterize the neurocognitive effects of combined RUL-UB ECT and venlafaxine in elderly adults with MDD and provides new evidence for the tolerability of RUL-UB ECT in an elderly sample. Of the cognitive domains assessed, only phonemic fluency, complex visual scanning, and cognitive flexibility qualitatively declined from low average to mildly impaired. While some acute changes in neurocognitive performance were statistically significant, the majority of the indices as based on the effect sizes remained relatively stable.

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        • Butters MA
        • Young JB
        • Lopez O
        • et al.
        Pathways linking late-life depression to persistent cognitive impairment and dementia.
        Dialogues Clin Neurosci. 2008; 10: 345-357
        • Sachs-Ericsson N
        • Hames JL
        • Joiner TE
        • et al.
        Differences between suicide attempters and nonattempters in depressed older patients: depression severity, white-matter lesions, and cognitive functioning.
        Am J Geriatr Psychiatry. 2014; 22: 75-85
        • Cuijpers P
        • Smit H
        Excess mortality in depression: a meta-analysis of community studies.
        J Affect Disord. 2002; 72: 227-236
        • Reynolds CFI
        • Dew MA
        • Pollock BG
        • et al.
        Maintenance treatment of major depression in old age.
        N Engl J Med. 2006; 354: 1130-1138
        • Huang AX
        • Delucchi K
        • Dunn LB
        • et al.
        A systematic review and meta-analysis of psychotherapy for late-life depression.
        Am J Geriatr Psychiatry. 2015; 23: 261-273
        • Sabesan P
        • Lankappa S
        • Khalifa N
        • et al.
        Transcranial magnetic stimulation for geriatric depression: promises and pitfalls.
        World J Psychiatry. 2015; 5: 170-181
        • Lisanby SH
        Electroconvulsive therapy for depression.
        N Engl J Med. 2007; 357: 1939-1945
        • O'Connor MK
        • Knapp R
        • Husain M
        • et al.
        The influence of age on the response of major depression to electroconvulsive therapy: a C.O.R.E. report.
        Am J Geriatr Psychiatry. 2001; 9: 382-390
        • Semkovska M
        • McLoughlin DM
        Objective cognitive performance associated with electroconvulsive therapy for depression: a systematic review and meta-analysis.
        Biol Psychiatry. 2010; 68: 568-577
        • Kumar S
        • Mulsant BH
        • Liu AY
        • et al.
        Systematic review of cognitive effects of electroconvulsive therapy in late-life depression.
        Am J Geriatr Psychiatry. 2016; 24: 547-565
        • Lisanby SH
        • Maddox JH
        • Prudic J
        • et al.
        The effects of electroconvulsive therapy on memory of autobiographical and public events.
        Arch Gen Psychiatry. 2000; 57: 581-590
        • Antosik-Wojcinska A
        • Swiecicki L
        The efficacy and safety of ECT in population before and after 60 years of age.
        Psychiatr Pol. 2016; 50: 1015-1026
        • McClintock SM
        • Choi J
        • Deng ZD
        • et al.
        Multifactorial determinants of the neurocognitive effects of electroconvulsive therapy.
        J ECT. 2014; 30: 165-176
      1. Deng ZD, McClintock SM, Lisanby SH: Brain network properties in depressed patients receiving seizure therapy: a graph theoretical analysis of peri-treatment resting EEG. 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC) 2015; 2203-2206

        • Lee WH
        • Deng Z-D
        • Kim T-S
        • et al.
        Regional electric field induced by electroconvulsive therapy in a realistic finite element head model: influence of white matter anisotropic conductivity.
        Neuroimage. 2012; 59: 2110-2123
        • Loo CK
        • Katalinic N
        • Smith DJ
        • et al.
        A randomised controlled trial of brief and ultrabrief pulse right unilateral electroconvulsive therapy.
        Int J Neuropsychopharmacol. 2014; 18: 1-8
        • Semkovska M
        • Landau S
        • Dunne R
        • et al.
        Bitemporal versus high-dose unilateral twice-weekly electroconvulsive therapy for depression (EFFECT-Dep): a pragmatic, randomized, non-inferiority trial.
        Am J Psychiatry. 2016; 173: 408-417
        • Kellner CH
        • Husain MM
        • Knapp RG
        • et al.
        Right unilateral ultrabrief pulse ECT in geriatric depression: phase 1 of the PRIDE study.
        Am J Psychiatry. 2016; 173: 1101-1109
      2. McElhiney MC, Moody BJ, Sackeim HA: The Autobiographical Memory Interview Short Form: Manual for Administration and Scoring, New York, Department of Psychiatry, New York State Psychiatric Institute, 2001

        • Delis DC
        • Kramer JH
        • Kaplan E
        • et al.
        California Verbal Learning Test-Second Edition. Adult Version. Manual.
        Psychological Corporation, San Antonio, TX2000
        • Delis DC
        • Kaplan E
        • J K
        Delis Kaplan Executive Function System.
        The Psychological Corporation, San Antonio, TX2001
        • Jurica PJ
        • Leitten CL
        • Mattis S
        DRS-2: Dementia Rating Scale-2 Professional Manual.
        Psychological Assessment Resources, Inc., Lutz, FL2001
        • Golden CJ
        • Freshwater SM
        Stroop Color and Word Test: A Manual for Clinical and Experimental Use.
        Stoelting Co., Wood Dale, IL2002
        • Wechsler D
        The Wechsler Test of Adult Reading (WTAR).
        The Psychological Corporation, San Antonio, TX2001
        • O'Kelly M
        • Ratitch B
        Clinical Trials with Missing Data: A Guide for Practitioners.
        John Wiley and Sons, Chichester, West Sussex2014
        • McMullen DP
        Where to target? The precision medicine approach to brain stimulation.
        Biol Psychiatry. 2018; 84: e1-e2
        • Bikson M
        • Brunoni AR
        • Charvet LE
        • et al.
        Rigor and reproducibility in research with transcranial electrical stimulation: an NIMH-sponsored workshop.
        Brain Stimul. 2018; 11: 465-480
      3. Thielscher A, Antunes A, Saturnino G: Field modeling for transcranial magnetic stimulation: A useful tool to understand the physiological effects of TMS? 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), Milan, 2015, pp. 222–225.

        • Thielscher A
        • Opitz A
        • Windhoff M
        Impact of the gyral geometry on the electric field induced by transcranial magnetic stimulation.
        Neuroimage. 2011; 54: 234-243
        • Güllmar D
        • Haueisen J
        • Reichenbach JR
        Influence of anisotropic electrical conductivity in white matter tissue on the EEG/MEG forward and inverse solution. A high-resolution whole head simulation study.
        Neuroimage. 2010; 51: 145-163
        • Deng Z-D
        • Lisanby SH
        • Peterchev AV
        Electric field strength and focality in electroconvulsive therapy and magnetic seizure therapy: a finite element simulation study.
        J Neural Eng. 2011; 8 (016007)
        • Peterchev AV
        • Goetz SM
        • Westin GG
        • et al.
        Pulse width dependence of motor threshold and input-output curve characterized with controllable pulse parameter transcranial magnetic stimulation.
        Clin Neurophysiol. 2013; 124: 1364-1372
        • Dybedal GS
        • Tanum L
        • Sundet K
        • et al.
        Cognitive side-effects of electroconvulsive therapy in elderly depressed patients.
        Clin Neuropsychol. 2014; 28: 1071-1090
        • Weiner RD
        • Rogers HJ
        • Davidson JRT
        • et al.
        Effects of stimulus parameters on cognitive side effects.
        Ann N Y Acad Sci. 1986; 462: 315-325
        • Martin DM
        • Galvez V
        • Loo CK
        Predicting retrograde autobiographical memory changes following electroconvulsive therapy: relationships between individual, treatment, and early clinical factors.
        Int J Neuropsychopharmacol. 2015; 18: 1-8
        • Semkovska M
        • McLoughlin DM
        Retrograde autobiographical amnesia after electroconvulsive therapy: on the difficulty of finding the baby and clearing murky bathwater.
        J ECT. 2014; 30: 187-188
        • Semkovska M
        • O'Grady T
        Unravelling autobiographical retrograde amnesia following bitemporal electroconvulsive therapy: effect of treatment versus effect of time.
        Psychology. 2017; 8: 611-626
        • Semkovska M
        • Keane D
        • Babalola O
        • et al.
        Unilateral brief-pulse electroconvulsive therapy and cognition: effects of electrode placement, stimulus dosage and time.
        J Psychiatr Res. 2011; 45: 770-780
        • Brooks BL
        • Iverson GL
        Comparing actual to estimated base ratesof “abnormal” scores on neuropsychological test batteries: Implications for interpretation.
        Arch Clin Neuropsychol. 2010; 25: 14-21
        • McClintock SM
        • Cullum CM
        • Husain MM
        • et al.
        Evaluation of the effects of severe depression on global cognitive function and memory.
        CNS Spectrums. 2010; 15: 304-313
        • McCall WV
        • Lisanby SH
        • Rosenquist PB
        • et al.
        Effects of a right unilateral ultrabrief pulse electroconvulsive therapy course on health related quality of life in elderly depressed patients.
        J Affect Disord. 2017; 209: 39-45
        • Wagner GS
        • McClintock SM
        • Rosenquist PB
        • et al.
        Major depressive disorder with psychotic features may lead to misdiagnosis of dementia: a case report and review of the literature.
        J Psychiatr Pract. 2011; 17: 432-438
        • Pier KS
        • Briggs MC
        • Pasculli RM
        • et al.
        Successful electroconvulsive therapy for major depression misdiagnosed as Alzheimer dementia.
        Am J Geriatr Psychiatry. 2012; 20: 909-910
        • Hausner L
        • Damian M
        • Sartorius A
        • et al.
        Efficacy and cognitive side effects of electroconvulsive therapy (ECT) in depressed elderly inpatients with coexisting mild cognitive impairment or dementia.
        J Clin Psychiatry. 2011; 72: 91-97
        • Sackeim HA
        • Prudic J
        • Fuller R
        • et al.
        The cognitive effects of electroconvulsive therapy in community settings.
        Neuropsychopharmacology. 2006; 32: 244-254
        • Raes F
        • Hermans D
        • Williams JMG
        • et al.
        Reduced autobiographical memory specificity and rumination in predicting the course of depression.
        J Abnorm Psychol. 2006; 115: 699-704
        • Sackeim HA
        • Dillingham EM
        • Prudic J
        • et al.
        Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects.
        Arch Gen Psychiatry. 2009; 66: 729-737
        • Keefe RSE
        • McClintock SM
        • Roth RM
        • et al.
        Cognitive effects of pharmacotherapy for major depressive disorder: a systematic review.
        J Clin Psychiatry. 2014; 75: 864-876
        • Shilyansky C
        • Williams LM
        • Gyurak A
        • et al.
        Effect of antidepressant treatment on cognitive impairments associated with depression: a randomised longitudinal study.
        The Lancet Psychiatry. 2016; 3: 425-435
        • Raskin J
        • Wiltse CG
        • Siegal A
        • et al.
        Efficacy of duloxetine on cognition, depression, and pain in elderly patients with major depressive disorder: an 8-week, double-blind, placebo-controlled trial.
        Am J Psychiatry. 2007; 164: 900-909
        • Geretsegger C
        • Nickel M
        • Judendorfer B
        • et al.
        Propofol and methohexital as anesthetic agents for electroconvulsive therapy: a randomized, double-blind comparison of electroconvulsive therapy seizure quality, therapeutic efficacy, and cognitive performance.
        J ECT. 2007; 23: 239-243
        • Ding Z
        • White PF
        Anesthesia for electroconvulsive therapy.
        Anesth Analg. 2002; 94: 1351-1364
        • Bryson EO
        • Aloysi AS
        • Farber KG
        • et al.
        Individualized anesthetic management for patients undergoing electroconvulsive therapy: a review of current practice.
        Anesth Analg. 2017; 124: 1943-1956
        • Vasavada MM
        • Leaver AM
        • Njau S
        • et al.
        Short- and long-term cognitive outcomes in patients with major depression treated with electroconvulsive therapy.
        J ECT. 2017; 33: 278-285
        • Dybedal GS
        • Bjolseth TM
        • Benth JS
        • et al.
        Cognitive effects of bifrontal versus right unilateral electroconvulsive therapy in the treatment of major depression in elderly adults: a randomized, controlled trial.
        J ECT. 2016; 32: 151-158
        • Peterchev AV
        • Krystal AD
        • Rosa MA
        • et al.
        Individualized low-amplitude seizure therapy: minimizing current for electroconvulsive therapy and magnetic seizure therapy.
        Neuropsychopharmacology. 2015; 40: 2076-2084
        • Daskalakis ZJ
        • Dimitrova J
        • McClintock SM
        • et al.
        Magnetic seizure therapy (MST) for major depressive disorder.
        Neuropsychopharmacology. 2019;
        • Rosa MA
        • Abdo GL
        • Lisanby SH
        • et al.
        Seizure induction with low-amplitude-current (0.5 A) electroconvulsive therapy.
        J ECT. 2011; 27: 342
        • Lisanby SH
        • Luber B
        • Schlaepfer TE
        • et al.
        Safety and feasibility of magnetic seizure therapy (MST) in major depression: randomized within-subject comparison with electroconvulsive therapy.
        Neuropsychopharmacology. 2003; 28: 1852-1865
        • Deng ZD
        • Lisanby SH
        • Peterchev AV
        Effect of anatomical variability on electric field characteristics of electroconvulsive therapy and magnetic seizure therapy: a parametric modeling study.
        IEEE Trans Neural Syst Rehabil Eng. 2015; 23: 22-31
        • Farzan F
        • Atluri S
        • Mei Y
        • et al.
        Brain temporal complexity in explaining the therapeutic and cognitive effects of seizure therapy.
        Brain. 2017; 140: 1011-1025
        • Jiang B
        • Abbott CC
        • T J
        • et al.
        SMRI biomarkers predict electroconvulsive therapy outcomes: accuracy with independent data sets.
        Neuropsychopharmacology. 2018; 43: 1078-1087
        • Njau S
        • Joshi SH
        • Espinoza R
        • et al.
        Neurochemical correlates of rapid treatment response to electroconvulsive therapy in patients with major depression.
        J Psychiatry Neurosci. 2017; 42: 6-16