BACKGROUND:Late-life depression (LLD) is common and associated with reduced quality of life, increased cognitive impairment, elevated mortality risk, and substantial healthcare costs. Despite available pharmacological and psychotherapeutic treatments, a substantial proportion of older patients with depression experience insufficient improvement. Repetitive transcranial magnetic stimulation (rTMS) has demonstrated efficacy in treating LLD, albeit full remission of LLD by rTMS is limited. Preliminary evidence suggest synergistic effects of rTMS with psychotherapy. Combining rTMS and behavioral activation (BA), a structured and effective psychological intervention promoting engagement in rewarding activities, may enhance outcome in the treatment of LLD. However, this has not been specifically investigated in older adults. METHODS:This multicenter, assessor-blind, randomized controlled trial will assess the (cost-) effectiveness of combining low-frequency rTMS targeting the right dorsolateral prefrontal cortex (DLPFC) with BA in individuals 60 years and older with treatment-resistant LLD. 148 participants will be randomized to receive rTMS with either BA or neutral conversations over six weeks, with follow-up assessments at 3, 6, and 12 months. The primary objective is to determine whether rTMS with BA leads to greater symptom reduction and superior cost-effectiveness than rTMS without BA. Secondary outcomes include relapse quality of life, treatment acceptability, behavioral engagement, and levels of anhedonia, apathy, and cognitive functioning. DISCUSSION:We hypothesize that rTMS with BA is more (cost-)effective than rTMS without BA. Findings will show whether BA-assisted rTMS is effective. Next, we provide practical insights for integrating BA into routine rTMS care for older adults. TRIAL REGISTRATION:Dutch Clinical Trial Register, NL-OMON57840.

OBJECTIVE:Electroconvulsive therapy (ECT) is a highly effective treatment for depression, yet relapse rates up to 50% within a year are reported. Studies have examined ECT, pharmacological, and nonpharmacological relapse prevention strategies, and although current guidelines provide general recommendations, no consensus-based or operationalized guidance exists regarding optimal relapse prevention after successful ECT for major depressive disorder. The aims of this study were to identify relapse prevention strategies commonly implemented after ECT, to evaluate their perceived effectiveness among international ECT experts, and to establish consensus-based personalized clinical recommendations. METHODS:A multiround Delphi study was conducted with a global panel of 18 ECT experts. Consensus was defined as ≥80% agreement on Likert-scale responses. RESULTS:Consensus was reached on key clinical factors influencing relapse prevention, including treatment resistance, psychiatric comorbidities, and prior ECT response. An essential relapse prevention strategy, namely, pharmacotherapy with lithium and an antidepressant (a tricyclic antidepressant, venlafaxine, or a prior effective antidepressant), was endorsed for all patients. Continuation ECT by means of tapering, rather than abrupt cessation, was recommended for patients at high risk of relapse and with severe or psychotic depression. Psychotherapy was considered beneficial as an adjunctive rather than a standalone treatment. No consensus was reached on the role of repetitive transcranial magnetic stimulation, esketamine, or optimal treatment duration of relapse prevention beyond 6 months. CONCLUSIONS:This Delphi study provides expert-based guidance on relapse prevention following successful ECT for major depressive disorder. While pharmacotherapy and continuation ECT are core strategies, personalized adjustments based on clinical risk factors remain essential. Further empirical research is needed to refine guidelines and improve long-term outcomes.

Abstract Objective Disruption of the excitation/inhibition balance may contribute to the pathophysiology of bipolar disorder, with post-mortem studies reporting abnormalities in GABA-receptors, interneurons and inhibitory signaling in prefrontal areas. Transcranial magnetic stimulation with electroencephalography (TMS-EEG) enables in vivo assessment of cortical excitability/inhibition. This study examined short-latency intracortical inhibition (SICI) after left- and right-dorsolateral prefrontal cortex (DLPFC) stimulation in bipolar depression (BDep, n=10) and healthy controls (HC, n=22). Methods SICI (paired-pulse TMS) and excitability (single-pulse TMS) were quantified using local- and global-mean-field-power. Associations with lithium use and between-group differences in TMS-evoked potential amplitudes were also explored. Results For left-DLPFC stimulation, BDep showed weaker SICI than HC (local: 3.7%±12.5 vs 9.0%±20.3, p=0.05; global: 1.5%±11.7 vs 8.8%±20.6, p=0.10), driven by larger ppTMS responses (weaker inhibition). For right-DLPFC stimulation, BDep showed stronger SICI than HC (local: 17.3%±16.1 vs 0.75%±27.1, p=0.36; global: 16.2%±14.6 vs −1.0%±21.8, p=0.03), driven by a larger spTMS response (enlarged excitability). Stronger right-hemispheric global-SICI was most pronounced in BDep patients not using lithium (17.9%±7.0) vs lithium users (3.9%±11.9) and HC (pFDR=0.03). Conclusions BDep is characterized by reduced cortical inhibition after left-DLPFC stimulation and enlarged cortical excitability after right-DLPFC stimulation; the latter partly normalized by lithium. Significance To our knowledge, this is the first study to apply TMS-EEG to the bilateral DLPFC in BDep, revealing distinct patterns of hemispheric dysfunction. These findings warrant replication in larger samples, to further elucidate the underlying pathophysiology and inform the mechanisms of action of neuromodulation treatments, such as rTMS.

BACKGROUND:Cognitive impairment is a prevalent and burdensome feature of difficult-to-treat depression, yet the symptom-level interdependencies between affective and cognitive domains remain poorly understood. We examined cross-domain interactions using a symptom network approach. METHODS:We conducted an exploratory cross-sectional symptom network analysis in 120 patients with difficult-to-treat depression. Networks included seven harmonized depression symptoms (Hamilton Depression Rating Scale/Montgomery-Åsberg Depression Rating Scale) and three cognitive measures (processing speed, semantic memory, cognitive flexibility). Network structure was estimated using Mixed Graphical Models with LASSO regularization. Bridge symptoms were identified using bridge expected influence indices. RESULTS:The network revealed selective cross-domain connections. Positive associations were observed between reduced appetite and processing speed and cognitive flexibility, as well as between depressed mood and semantic memory. A negative association was observed between suicidal thoughts and semantic memory. Reduced appetite emerged as the most important bridge symptom linking affective and cognitive domains. Stability analyses indicated acceptable stability of bridge nodes, while bootstrapped confidence intervals suggested substantial uncertainty in individual edge estimates, underscoring the exploratory nature of the findings. CONCLUSIONS:This exploratory analysis provides initial evidence for cross-domain, symptom-level relationships in difficult-to-treat depression. These findings highlight heterogeneity that may remain obscured in total-score approaches. Bridge symptoms may represent candidate adjunctive targets, as modulating such nodes could potentially influence multiple domains simultaneously. However, given the modest sample size and limited network stability, the results are hypothesis-generating and require replication in larger, independent cohorts before clinical interpretations can be drawn.

Introduction Repetitive transcranial magnetic stimulation (rTMS) is an established treatment for depression of which the acute and short-term effects have been studied extensively. However, much less is known about the long-term effectiveness of rTMS. This paper aims to investigate the long-term effects of rTMS and antidepressant medication in patients with moderate treatment-resistant depression (≥2 treatment trials). Methods Naturalistic follow-up data was collected for twelve months as part of a clinical trial comparing rTMS and antidepressant medication. Response and remission based on the Hamilton Depression Rating Scale (HDRS-17) were calculated for both groups at end of treatment, as well as at four-, six-, nine- and twelve-months follow-up. Furthermore, the sustained effects of both treatments on anxiety, anhedonia, and rumination were investigated. Results At the end of treatment, response and remission rates were higher in the rTMS group (40.9% and 29.5%) than in the medication group (18.8% and 6.3%). 69% of the patients in the medication group received treatment with rTMS at some point during the follow-up period. Response and remission remained relatively stable over 12 months in both groups. Sustained response was observed in the majority of rTMS and medication responders for whom data was available for the full follow-up period. Conclusion Our findings provide insights into the naturalistic long-term effects of rTMS and antidepressant medication in patients with moderate treatment-resistant depression.

Recent updates to treatment guidelines for depression increasingly incorporate repetitive transcranial magnetic stimulation (rTMS). While rTMS is an established intervention for depression, evidence regarding its use for maintenance treatment remains limited. The Dutch-Flemish Brain Stimulation Foundation convened an expert panel to review the literature, survey clinical practice, and formulate consensus recommendations on maintenance treatment with rTMS in the Netherlands and Flanders. A systematic PubMed search (up to June 2025) identified 22 studies reporting original data on maintenance treatment with rTMS for depression. Approaches could be divided into three categories: tapering (gradual reduction of sessions after acute treatment), maintenance rTMS (fixed-interval sessions), and retreatment (reinitiating rTMS upon relapse). Evidence from one randomized controlled trial and several open-label studies suggests that tapering may help sustain clinical improvement, particularly when the tapering schedule is symptom-guided. For maintenance rTMS, single-session protocols show mixed results, whereas clustered protocols (typically five sessions per month over several days) demonstrate the most benefits, though controlled data are lacking. Retreatment with rTMS is effective in most patients who previously responded to acute rTMS, often requiring fewer sessions. Survey data from 11 Dutch institutions indicate that tapering and maintenance rTMS are applied on a small scale, while retreatment is more common. Patient representatives emphasized the importance of early discussion, flexible scheduling, and structured monitoring to guide maintenance treatment. Overall, evidence supports individualized application of maintenance treatment with rTMS, with a need for further controlled research to establish optimal protocols and long-term effectiveness.

Background: Electroconvulsive therapy (ECT) is an effective treatment for major depressive disorder, yet real-world outcomes may differ from research studies. We compared ECT effectiveness in research versus real-world cohorts and examined whether in- and exclusion criteria and treatment characteristics explain potential differences. Method: 1892 patients with MDD from the Dutch ECT Consortium (12 research, 10 real-world cohorts) were included. Outcomes were response (≥50% HDRS reduction), remission (HDRS <8), and change in depression severity (Δ-HDRS). Cohorts were compared on effectiveness and demographic, clinical and treatment characteristics. Logistic and linear regression estimated associations between cohort type and outcomes, unadjusted and adjusted for in- and exclusion criteria and additional clinical confounders. Results: Research cohorts demonstrated higher response rates (66.8% vs. 58.9%, OR 1.46, 95% CI [1.09–1.95]) and greater symptom reduction (B 2.88, 95% CI [1.86–3.90]), while remission rates did not differ significantly. Cohorts differed on several clinical and treatment characteristics, partly reflecting in- and exclusion criteria used in research cohorts. After adjusting for these selection criteria, differences in response and Δ-HDRS were no longer significant (OR 1.20, 95% CI [0.86–1.69]; B 0.61, 95% CI [−0.29–1.51]). Adjustment for additional confounders marginally changed these estimates. In sensitivity analyses restricted to mixed-sites, differences were not significant in unadjusted and adjusted models. Conclusion: In the Dutch ECT consortium, ECT demonstrates comparable effectiveness across research and real-world settings once patient selection is accounted for. These findings underscore the importance of considering cohort composition when interpreting treatment outcomes.

INTRODUCTION:Postictal agitation (PIA) is an impactful confusional state occasionally occurring after electroconvulsive therapy (ECT). PIA creates dangerous situations for caregivers and patients, prolongs lead times, and sometimes leads to the premature discontinuation of ECT. Despite the impact PIA can have on patients and caregivers, little is known about its incidence and the factors associated with its occurrence. This study aims to investigate putative prognostic factors for PIA. METHODS:We utilized data from the "Rivastigmine for ECT-induced Cognitive Adverse effects in Late-Life depression" (RECALL) prospective cohort study; a study on older adults (≥ 55 years) with a major depressive episode receiving ECT. We investigated several putative prognostic factors based on previous research, biological plausibility, and availability. PIA was defined by either a Richmond Agitation-Sedation score ≥ 2 or the administration of emergency medication specifically for PIA. Mixed-effects logistic regression was used to analyze univariate and adjusted odds ratios for the prognostic factors. RESULTS:We included 142 patients who received 1838 ECT sessions. The incidence of PIA was 34.5% at the patient-level and 9.2% at the session-level. A small subset of older adults (19.7%) accounted for 87.5% of all PIA occurrences. We found that male sex, flumazenil use, and a longer seizure duration were associated with higher odds of developing PIA. Multi-seizure sessions and a higher level of education were associated with lower occurrence of PIA. CONCLUSION:This study identified sex, flumazenil use, seizure duration, the amount of seizures during a session, and education level as prognostic factors for PIA. The pronounced clustering of PIA events within a small subset of patients suggests meaningful interindividual vulnerability, but should be replicated in future studies. If confirmed, these findings could provide actionable insights for preventive treatment strategies. In particular, the use of flumazenil should be critically reconsidered in persons experiencing PIA. TRIAL REGISTRATION:EudraCT 2014-003385-24.

Background: Depressive symptoms cut across bipolar disorder (BD) and major depressive disorder (MDD), yet the extent to which the neurobiology of depressive severity is shared or diagnosis-specific is not well established. Progress is limited because multisite studies pool data from different depression rating scales, obscuring symptom-brain relationships. We used item response theory (IRT), which places these instruments on a single metric, to harmonise depressive symptom severity across five rating scales, and to identify shared and disorder-specific brain correlates of depression across BD and MDD.Methods: This cross-sectional mega-analysis of individual participant data from 52 international ENIGMA MDD and BD Working Group sites studied 11 999 individuals (6,789 healthy controls, 3,307 with BD, 1,903 with MDD) who had completed a depression measure and undergone T1-weighted MRI. We derived general and five symptom-specific IRT scores harmonised across five instruments (HDRS, MADRS, BDI-II, IDS, CES-D), and related them to cortical thickness, surface area, and subcortical volume, adjusting for age, sex, and global brain measures.Findings: Harmonising symptom scores strengthened brain-symptom associations beyond unharmonised total scores. Higher general depression severity was linked to lower cortical thickness, which strengthened after accounting for BD-MDD item-level differences. The disorders diverged: depressive severity was more tightly linked to subcortical structure, especially the hippocampus and thalamus, in MDD than BD, while BD showed lower cortical thickness across a wider cortical extent and more heterogeneous structural variability. Symptom dimensions diverged too: mood/motivational symptoms tracked cortical thickness in both disorders, while anxiety, cognitive-affective, and suicidal-ideation symptoms showed more disorder-specific subcortical and surface-area patterns.Interpretation: IRT harmonisation identified overlapping and disorder-specific associations between depressive severity and brain structure in BD and MDD, highlighting shared neurobiological features while demonstrating meaningful differences between disorders and supporting global efforts to integrate dimensional symptom measures across large-scale, multiscale studies.Funding: This work was supported by the US National Institute of Mental Health (R0I MH129742), including subaward SCON-00003343 awarded to Colm McDonald and Dara Cannon.

Clinical staging models are used to classify the stages of development of disorders across medicine. In this narrative review we explored whether staging in affective disorders may (i) improve the prediction of clinical outcomes, (ii) provide a more precise allocation of treatments to specific patients (iii) whether staging may serve as a framework to proactively integrate prevention and early intervention in the treatment of patients, and (iv) to direct research to studies of factors determining illness progression. Finally we examined (v) why staging may be especially salient in geriatric psychiatry and whether specific staging models are necessary for older patients. Our scope with regard to affective disorders was broad, including both unipolar and bipolar disorders. Although psychiatry has been late in resuming an interest in clinical staging, empirically tested models are available, which may be reliably used to stage the development of affective disorders. Clinical staging, in combination with data about comorbidity and clinical profilers may serve to improve treatment allocation. Progression from early at-risk stages to first episodes remains understudied, but there is sufficient evidence to conclude that prevention or postponement of early progression and the recurrence of affective disorders is effective. Given the change in risk factors, increase in comorbidity and worse prognosis of depression in later life, staging may be especially helpful in older patients. However, this does not mean that other staging models need to be developed, specifically for later life.

INTRODUCTION:Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depressive disorder (MDD), yet some patients only show partial or no response. Recent efforts to enhance rTMS efficacy have focused on combining rTMS with adjunctive interventions, such as psychotherapy, which may yield synergistic effects rather than merely additive effects. Cognitive control training (CCT) activates similar underlying neural circuits as rTMS and has demonstrated antidepressant potential. Given the time-intensive nature of rTMS, augmenting it with CCT may offer a pragmatic, time-efficient and potentially cost-effective solution to increase the therapeutic response of rTMS. This study aims to investigate whether rTMS augmented with CCT is more (cost-) effective in reducing depressive symptoms as opposed to rTMS alone. METHODS:In this international multicenter clinical trial, 132 adult patients with depression will be randomized to receive rTMS either augmented with CCT or placebo task. The trial consists 30 rTMS sessions over eight weeks, followed by a follow-up period up to one year. The primary outcome is the change in depressive severity, assessed with the 17-item Hamilton Depression Rating Scale (HDRS-17) after eight weeks of treatment. Secondary outcomes include an economic evaluation and response and remission after 8 weeks of treatment as well as during follow-up. DISCUSSION:The present study aims to improve the (cost-)effectiveness of rTMS by concurrently combining rTMS with CCT. Findings may support the development of more cost-effective, personalized interventions for the treatment of depression. TRIAL REGISTRATION:This trial is registered within the Overview of medical research in the Netherlands, OMON (code: NL-OMON57187, date: 18 December 2024).

BACKGROUND:Electroconvulsive therapy (ECT) is effective for depression, but symptom dynamics during treatment remain unclear. Network approaches may clarify symptom relations and identify patterns linked to remission. OBJECTIVE:Examining symptom dynamics during ECT using temporal network modeling and comparing baseline and temporal symptom networks between remitters and non-remitters. METHODS:Using the Dutch ECT Consortium (N = 857, unipolar/bipolar depression), we examined seven harmonized symptoms from the 17-item Hamilton Depression Rating Scale (HDRS-17) and Montgomery-Åsberg Depression Rating Scale (MADRS) over the first five weeks of treatment. We estimated baseline networks using partial correlations and temporal networks using Cross-Lagged Panel Network analysis, which quantified each symptom's in-prediction and out-prediction. Between remitters (N = 413) and non-remitters (N = 379), baseline networks were compared using the Network Comparison Test, while temporal networks were compared via network density, Jaccard overlap, and edge correlations. RESULTS:In the full sample (65.2% female, mean age 61.3 ± 15.5 years), suicidal thoughts exerted the strongest influence on other symptoms (i.e., highest out-prediction). Baseline networks did not differ by outcome, but temporal networks did: remitters showed greater density than non-remitters (χ2 = 8.20, p < 0.01), with low overlap in edges (Jaccard = 0.25), and non-significant edge-weight correlations (r = 0.16; p = 0.46) between groups. Remitters displayed integrated affective-vital symptom connections, while non-remitters showed fragmented subnetworks. CONCLUSIONS:Reductions in suicidal thoughts preceded broader symptom improvements, suggesting this symptom warrants monitoring. Remitters showed coordinated symptom reduction where affective and vital symptoms reinforced each other, while non-remitters showed independent reduction. These findings provide insights into symptom dynamics during ECT.

OBJECTIVE:For decades, a persistent claim has been that autobiographical memory loss after electroconvulsive therapy (ECT) for depression might actually contribute to ECT efficacy by reducing or even eliminating autobiographical memories. To test this claim, the primary aim of this study is to examine the association between autobiographical memory loss and remission of depression. The hypothesis is that remitted patients have more autobiographical memory loss after ECT compared to non-remitted patients. METHODS:In 71 patients with major depressive disorder undergoing ECT, autobiographical memory consistency (Kopelman Autobiographical Memory Interview) and depression severity (Montgomery-Åsberg Depression Rating Scale) were assessed before and within 1 week after treatment. Logistic regression analyses were conducted to examine the association between both autobiographical memory loss (i.e., memory consistency) and remission (MADRS < 10), including age, episode duration, baseline MADRS score, and treatment condition as covariates. RESULTS:All logistic regression models were significant. The overall autobiographical memory consistency-score (OR = 1.072, 95% CI [1.018-1.130], p = 0.009) and the consistency-score for recent memories (OR = 1.043, 95% CI [1.006-1.082], p = 0.021) were significantly associated with the odds of remission but in the opposite direction of the hypothesis. A higher age and shorter episode duration further increased the likelihood of remission. Additionally, post hoc analyses showed that the trajectories of autobiographical memory performance over time differed between remitters and non-remitters, indicating a slight decrease in autobiographical memories for more recent events in non-remitters and no change in remitters. CONCLUSIONS:This study shows that, contrary to the hypothesis, remitted patients have less autobiographical memory loss, particularly for recent memories than non-remitters. This refutes the premise that the loss of autobiographical memories contributes to the therapeutic effectiveness of ECT.

Objectives: Recently, we modified the method of dosing charge in daily practice for patients undergoing bilateral electroconvulsive treatment (BL ECT). The aim of this study is to compare the effectiveness of two charges’ dosing protocols—High-Charge Protocol (HCP; based on the modified age-based method) and Dose Titration Protocol (DTP) in BL ECT for the treatment of patients with a depressive episode. Methods: The retrospective analysis compared the outcomes of BL ECT between patients receiving either HCP or DTP treatments. Patients’ mental status was assessed retrospectively using the Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I) scales. EEG parameters, including seizure duration and EEG ictal activity were analyzed. Results: When compared to DTP, the HCP group was older (55 years ± SD 15 vs. 41 years ± SD 17), had lower initial CGI-S (5 [IQR 5–6] vs. 6 [IQR 5–6]) and longer disease duration (15 years [IQR 7–20] vs. 9 years [IQR 3–18]). The DTP group had a higher percentage of remission (n = 17 [77.3%]) compared to the HCP group (n = 23 [43.4%]), with the same average number of sessions performed. In addition, the DTP group had significantly longer average seizure duration (68.6 s [IQR 52.7–84.7] vs. 38.4 s [IQR 33.8–47.1], adj. p < 0.001). Conclusions: Our results suggest that in BL ECT, administering high-charge protocols may have a detrimental impact on ECT effectiveness. Based on our findings, we propose adjusting the dosing in BL ECT according to the individual seizure threshold and avoiding frequent charge increases during the course of treatment.

Electroconvulsive therapy (ECT) is an effective treatment for depression but is often associated with cognitive side effects. In patients, ECT-induced electric field (E-field) strength across brain regions varies significantly due to anatomical differences, which may explain individual differences in cognitive side effects. We examined the relationship between regional E-field strength and change in verbal fluency score (i.e., category fluency animals score from pre- to 1 week post-ECT; as key proxy of cognitive side effects) across different electrode placements in depressed patients. Secondary, we examined the relationship between regional E-field strength and depression outcome. Using T1 magnetic resonance imaging, we performed E-field modeling in a total of 109 patients. Linear mixed models were executed to analyze the relationship between E-field strength across all 118 brain regions and both cognitive and depression outcomes, while correcting for nuisance variables (e.g., age, total number of ECT sessions, and study cohort). We found that a higher E-field strength was significantly associated with a higher decline in verbal fluency (n = 71, false discovery rate [FDR] corrected p < 0.01) in several brain regions in the left hemisphere (e.g., temporal gyrus and operculum cortex). Moreover, numerous significant associations were found only in the 24 patients treated with right unilateral ECT. No significant relationships were found between regional E-field strength and depression outcome. In conclusion, significant associations between verbal fluency and E-field strength were found in areas crucial for linguistic processing and semantic memory. Our findings underscore the importance of considering individualized dosing strategies to optimize cognitive outcome in ECT, while maintaining its antidepressant efficacy.

BACKGRUND:Psychiatric disorders in older adults are underdiagnosed and undertreated, despite their high prevalence and significant impact on medical care utilisation. Given demographic developments and the limited number of specialised psychiatrists, an age-based mental health care division is not sustainable for the future. Which solutions are future-proof? AIM:To describe solutions for a future-proof psychiatry for older adults. METHOD:Literature review and consideration. RESULTS:Future-proof care requires a strategic positioning of old age psychiatrists, focusing on their specific expertise at the intersection of psychiatry and somatics, neurocognitive disorders, the psychosocial characteristics of the third and fourth stages of life, and end-of-life care. This includes an effective role in early detection and consultation in general practice, guidance during transitions in the psychosocial context of individuals, transitions from vitality to physical frailty in mental health care, and within the somatic care chain involving general hospitals and long-term care facilities. CONCLUSION:For future-proof care, strategic positioning of the old age psychiatrist is desirable, as well as investments in research, education, network-based care, and digital technology to flexibly respond to the evolving care demands.

Novel therapies are crucial for patients with major depressive disorder (MDD) since more than 33% of patients do not respond to first-line treatments. A promising novel treatment strategy is an intensive five-day course of Personalised functional connectivity guided Accelerated intermittent Theta burst stimulation (PAiT), modelled after the Stanford Neuromodulation Therapy (SNT) protocol . This new form of repetitive transcranial magnetic stimulation (rTMS) may lead to higher remission rates in patients with treatment-resistant depression (TRD). However, it remains unclear how this accelerated strategy compares to the standard once daily 10Hz rTMS at inducing remission of depression. To compare (cost-)effectiveness using the PAiT protocol and the standard 10Hz rTMS, in patients with TRD. 108 patients will be enrolled in this multicentre randomized controlled trial. Patients will receive stimulation over the left dorsolateral prefrontal cortex using either the PAiT protocol (5 days of 10 sessions/day, resulting in 50 sessions in total, 90.000 pulses) or the standard 10 Hz rTMS, (once daily during 6 weeks, resulting in 30 sessions in total, 90.000 pulses). Personalised targets will be identified in the aiTBS condition based on negative functional coupling between the subgenual anterior cingulate cortex (sgACC) and the DLPFC. In the rTMS condition, DLPFC target locations are identified using the standard Beam-F3 method . In both conditions, coil placement is performed with neuronavigation, navigating either to the personalised functional connectivity target or the Beam-F3 location. Patients will undergo pre and post-treatment (f)MRI scans including cognitive and emotional tasks, and a behavioral task will be performed outside of the scanner. In addition, during stimulation, heart rate will be measured. There are four follow-up measurements, at 7, 12, 26 and 31 weeks post-baseline. We expect that the PAiT protocol is more (cost-)effective than standard 10 Hz rTMS. The results of our study will provide professionals with an adequately powered trial answering whether the PAiT protocol is superior to standard HF-rTMS. In addition, this trial will provide further insights into the underlying mechanisms related to treatment effect, the effects of rTMS/aiTBS on cognitive domains such as executive functioning and emotion, possible differences in side-effects, long-term effects and (contributing factors to) possible relapse. To our knowledge, the current study is the first clinical trial to compare the (cost-)effectiveness of PAiT to standard 10Hz rTMS as treatment for patients with TRD. This trial is registered at clinicaltrials.gov with code: NCT05900271, on June 12th 2023.

Accumulating evidence supports the efficacy of (es)ketamine in the treatment of major depressive disorder (MDD), particularly treatment-resistant depression (TRD). Yet around 50% of the individuals with TRD do not respond to (es)ketamine. Elucidating predictors of response and remission could improve treatment outcomes at the individual level by defining subpopulations that are most likely to benefit from (es)ketamine. This systematic review outlines the predictive value of demographic and clinical characteristics for treatment outcomes of (es)ketamine in MDD. A systematic literature search was performed to retrieve studies investigating the association between baseline characteristics and the likelihood of achieving response and remission following (es)ketamine treatment in MDD. Forty-four studies investigating the association between response and remission and demographic variables, characteristics of the depressive episode, treatment resistance, psychiatric comorbidities, symptomatology, suicidal risk/attempts, family/personal history, medication use, somatic variables, personality traits, and neurocognitive performance were included. The predictive value of demographic and clinical variables for treatment outcomes of (es)ketamine was limited with either no significant relationship or inconsistent results. Findings provide preliminary support for a positive association of response with anhedonia, sleep disturbances, childhood physical abuse, obesity, openness, better episodic memory, and visual learning, poorer neurocognitive performance, slower processing speed, and lower attention, as well as a negative association with melancholic depression, benzodiazepine use, and metabolic syndrome. However, these characteristics have been investigated in a limited number of studies and warrant replication. These findings suggest that (es)ketamine represents a promising treatment prospect for individuals who present clinical characteristics that are often considered difficult to treat.