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. 2025 May:107:102710.
doi: 10.1016/j.arr.2025.102710. Epub 2025 Feb 28.

Systematic review of clinical effectiveness of interventions for treatment resistant late-life depression

Beatriz Pozuelo Moyano  1 , Denise Gomez Bautista  2 , Karla Jocelyn Porras Ibarra  3 , Christoph Mueller  4 , Armin von Gunten  5 , Pierre Vandel  5 , Setareh Ranjbar  5 , Robert Howard  3 , Allan H Young  6 , Robert Stewart  6 , Suzanne Reeves  3 , Vasiliki Orgeta  3 ; European Task Force for treatment resistant depression in older people
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Free article

Systematic review of clinical effectiveness of interventions for treatment resistant late-life depression

Beatriz Pozuelo Moyano et al. Ageing Res Rev. 2025 May.
Free article

Abstract

Background: Treatment-resistant late-life depression (TRLLD) affects nearly half of older adults with major depression. This systematic review evaluates published evidence of effectiveness of both pharmacological and non-pharmacological treatments for TRLLD.

Methods: A search of MEDLINE, EMBASE, CINAHL, PsycINFO, the Cochrane Library, and online trial registries up to March 2024 was conducted to identify randomized controlled trials (RCTs) evaluating pharmacological and non-pharmacological interventions for TRLLD.

Results: Seven studies assessed the effectiveness of pharmacological interventions (antidepressants, antipsychotics, mood stabilizers, or ketamine) and another seven examined non-pharmacological approaches (psychotherapy, electroconvulsive therapy, repetitive transcranial magnetic stimulation (rTMS), and computerized cognitive remediation). Aripiprazole (2 studies), venlafaxine (1 study), ketamine (1 study), and lithium (1 study) were associated with a reduction in depressive symptoms post-treatment compared to the comparator treatment group. rTMS (2 studies), sequential bilateral theta burst stimulation (1 study) and cognitive remediation (1 study) also showed significant improvements in depressive symptoms post-treatment compared to a comparator treatment group. Quality of evidence varied from very low to medium among the included studies. Most studies reported data on small sample sizes.

Conclusions and implications: We identified a small number of RCTs evaluating treatments for TRLLD. Aripiprazole augmentation appears to be an effective treatment based on two studies, with an acceptable side effect profile. Other treatments may be effective, but the evidence is based on very low-quality evidence. Future large-scale RCTs are urgently needed to draw firm conclusions.

Keywords: Late life depression; Older people; Randomized controlled trials; Resistant depression; Treatment.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Stewart, R. declares research support in the last 3 years from GSK and Takeda. Young, A.H. declares the following competing interests: i) Employed by King’s College London; ii) Honorary Consultant South London and Maudsley NHS Foundation Trust (NHS UK); iii) Editor of Journal of Psychopharmacology and Deputy Editor, BJPsych Open; iv) Paid lectures and advisory boards for the following companies with drugs used in affective and related disorders: Flow Neuroscience, Novartis, Roche, Janssen, Takeda, Noema pharma, Compass, Astrazenaca, Boehringer Ingelheim, Eli Lilly, LivaNova, Lundbeck, Sunovion, Servier, Allegan, Bionomics, Sumitomo Dainippon Pharma, Sage, Neurocentrx, Otsuka; v) Principal Investigator in the Restore-Life VNS registry study funded by LivaNova.Principal Investigator on ESKETINTRD3004: “An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression.”; vi) Principal Investigator on “The Effects of Psilocybin on Cognitive Function in Healthy Participants”; vii) Principal Investigator on “The Safety and Efficacy of Psilocybin in Participants with Treatment-Resistant Depression (P-TRD); viii) ”Principal Investigator on “A Double-Blind, Randomized, Parallel-Group Study with Quetiapine Extended Release as Comparator to Evaluate the Efficacy and Safety of Seltorexant 20 mg as Adjunctive Therapy to Antidepressants in Adult and Elderly Patients with Major Depressive Disorder with Insomnia Symptoms Who Have Responded Inadequately to Antidepressant Therapy.’’ (Janssen); ix) Principal Investigator on “An Open-label, Long-term, Safety and Efficacy Study of Aticaprant as Adjunctive Therapy in Adult and Elderly Participants with Major Depressive Disorder (MDD).’’ (Janssen); x) Principal Investigator on “A Randomized, Double-blind, Multicentre, Parallel-group, Placebo-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Aticaprant 10 mg as Adjunctive Therapy in Adult Participants with Major Depressive Disorder (MDD) with Moderate-to-severe Anhedonia and Inadequate Response to Current Antidepressant Therapy.’’ xi) Principal Investigator on “A Study of Disease Characteristics and Real-life Standard of Care Effectiveness in Patients with Major Depressive Disorder (MDD) With Anhedonia and Inadequate Response to Current Antidepressant Therapy Including an SSRI or SNR.’’ (Janssen); xii) UK Chief Investigator for Compass; COMP006 & COMP007 studies; xiii) UK Chief Investigator for Novartis MDD study MIJ821A12201. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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