REDEFINING RECOVERY: EXPLORING ANTIDEPRESSANT EFFECTS AND COGNITIVE IMPAIRMENT IN TREATMENT RESISTANT DEPRESSION WITH REPETITIVE TRANSCRANIAL MAGNETIC STIMULATION
Authors: Dey Ayan K , Healey Clara , Nestor Sean M , Rabin Jennifer S , Hamani Clement , Lipsman Nir , Giacobbe *Peter 
Published: February 2025

Abstract

Background
Cognitive dysfunction is a key pathological feature of treatment resistant major depression (TRD) that is often overlooked (1). Persistent deficits in cognition are common and serve as a mediator of psychosocial and functional outcomes. Such deficits are associated with reduced quality of life and increased likelihood of relapsing (2). Subtle cognitive deficits in depressed patients may also evade detection by traditional screening tools. Unfortunately, despite much advancement in treatment options, a significant proportion of patients who achieve symptomatic improvement in mood symptoms do not return to premorbid functioning. More recently, studies have reported promise of Repetitive Transcranial Magnetic Stimulation (rTMS) related improvements across multiple cognitive domains however whether this translates to improved functional outcomes is unknown (3). It is also unknown whether the presence of cognitive complaints impacts the antidepressant effects of rTMS.

Aims & Objectives
Investigate how subjective cognitive complaints impact the antidepressant response to rTMS and its relation to residual self-perceived disability, functional impairment, and quality of life.

Method
Naturalistic study of 457 adults with treatment resistant depression treated with high-frequency rTMS to the left DLPFC at a tertiary academic centre. rTMS treatment was provided 5 days per week for 4-6 weeks at 120% of motor threshold. Participants completed baseline measures of depression severity, perceived cognitive impairment, perceived disability, and quality of life. Measures were repeated at weeks 2, 4 and 6. Binomial logistic regression, linear regression and paired T-tests were then subsequently used for analysis.

Results
We observed robust antidepressant effects of rTMS with statistically significant improvements in depression severity (p&lt;0.001), reported disability (p&lt;0.001) and quality of life (p&lt;0.001) following 4-6 weeks of treatment. However, there was no significant improvement in degree of subjective memory impairment but there was improvement in self-reported attentional capacity (p&lt;0.001). Compared to those reporting minimum to mild memory impairment at baseline, those reporting moderate to severe memory impairment at baseline are less likely to achieve remission of their depressive symptoms with rTMS (20.3% vs. 42.6%). Subjective memory impairment at baseline was found to be a statistically significant independent predictor of remission following rTMS (p = 0.031, Beta = - 0.95), after controlling for age, biological sex, medical comorbidity burden, and baseline depression severity. Furthermore, residual subjective memory impairment following 4-6 weeks of rTMS was an independent predictor of disability (as measured by the WHODAS) above and beyond residual depressive symptoms (p&lt;0.001, Beta = 0.537).

Discussion & Conclusion
Robust antidepressant effects are observed in response to rTMS in adults with TRD, however we observed no significant improvement in subjective memory impairment. Subjective memory impairment at baseline independently predicts poorer remission outcomes following rTMS, confirmed by logistic regression, and residual subjective memory impairment predicts perceived disability. Further research is needed to characterize the neurobiology of subjective memory impairment in order to inform future treatment protocols to optimize clinical and functional outcomes in this population.

References
1. Zuckerman, H., Pan, Z., Park, C., Brietzke, E., Musial, N., Shariq, A. S., Iacobucci, M., Yim, S. J., Lui, L. M. W., Rong, C. and McIntyre, R. S. (2018) 'Recognition and Treatment of Cognitive Dysfunction in Major Depressive Disorder', Frontiers in Psychiatry, 9.
2. Lam, R. W., Kennedy, S. H., McIntyre, R. S. and Khullar, A. (2014) 'Cognitive dysfunction in major depressive disorder: effects on psychosocial functioning and implications for treatment', Canadian journal of psychiatry, 59(12), pp. 649-654.
3. Hammar, Å., Ronold, E. H. and Rekkedal, G. Å. (2022) 'Cognitive Impairment and Neurocognitive Profiles in Major Depression— A Clinical Perspective', Frontiers in Psychiatry, 13.