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BACKGROUND AND OBJECTIVES: Treatment-resistant depression is a leading cause of disability. Our center's trial for neurosurgical intervention for treatment-resistant depression involves a staged workup for implantation of a personalized, closed-loop neuromodulation device for refractory depression. The first stage ("stage 1") of workup involves implantation of 10 stereoelectroencephalography (SEEG) electrodes bilaterally into 5 anatomically defined brain regions and involves a specialized preoperative imaging and planning workup and a frame-based operating protocol. METHODS: We rely on diffusion tractography when planning stereotactic targets for 3 of 5 anatomic areas. We outline the rationale and fiber tracts that we focus on for targeting amygdala, ventral striatum and ventral capsule, and subgenual cingulate. We also outline frame-based stereotactic considerations for implantation of SEEG electrodes. EXPECTED OUTCOMES: Our method has allowed us to safely target all 5 brain areas in 3 of 3 trial participants in this ongoing study, with adequate fiber bundle contact in each of the 3 areas targeted using tractography. Furthermore, we ultimately used tractography data from our stage 1 workup to guide targeting near relevant fiber bundles for stage 2 (implantation of a responsive neuromodulation device). On completion of our data set, we will determine the overlap between volume of tissue activated for all electrodes and areas of interest defined by anatomy and tractography. DISCUSSION: Our protocol outlined for SEEG electrode implantation incorporates tractography and frame-based stereotaxy.

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Randomized controlled trials have reported psychoanalytic psychotherapy to improve longer-term post-treatment outcomes in patients with treatment-resistant depression. In this case study, we examine the therapy process of a female trial participant diagnosed with treatment-resistant depression. Structured clinical assessments indicated that the patient's level of depression remained unchanged during and after treatment. Over the course of the therapy, she repeatedly broke away from important others and finally also from the therapy itself, which we linked to the impact of earlier experiences of abandonment on her internal world. In the discussion, we present a variety of reflections that were put forward by the authors during a series of case discussion meetings. Some of these reflections relate to how the inner world of this patient might have triggered a negative therapeutic reaction and a destructive pattern of repetition. The interpretative stance, in which the therapist interpreted this reaction as indicative of a psychic conflict and linked this conflict to the therapeutic relationship, seemed to be experienced by the patient as unhelpful and persecutory. Other elements that were brought up include basic distrust, lack of symbolization and trauma in the patient, as well as the constraints of the research context.

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Electroconvulsive therapy is one of the useful treatment methods for symptom improvement and remission in patients with treatment-resistant depression. Considering the various clinical characteristics of patients experiencing depression, key indicators are extracted from structural brain magnetic resonance imaging, functional brain magnetic resonance imaging, and electroencephalography (EEG) data taken before treatment, and applied as explanatory variables in machine learning and network analysis. Studies that attempt to make reliable predictions about the degree of response to electroconvulsive treatment and the possibility of remission in patients with treatment-resistant depression are continuously being published. In addition, studies are being conducted to identify the correlation with clinical improvement by taking structural-functional brain magnetic resonance imaging after electroconvulsive therapy in depressed patients. By reviewing and integrating the results of the latest studies on the above matters, we aim to present the usefulness of electroconvulsive therapy for improving the personalized prognosis of patients with treatment-resistant depression.

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In this chapter, we explore the historical evolution, current applications, and future directions of Deep Brain Stimulation (DBS) for Treatment-Resistant Depression (TRD). We begin by highlighting the early efforts of neurologists and neurosurgeons who laid the foundations for today's DBS techniques, moving from controversial lobotomies to the precision of stereotactic surgery. We focus on the advent of DBS, emphasizing its emergence as a significant breakthrough for movement disorders and its extension to psychiatric conditions, including TRD. We provide an overview of the neural networks implicated in depression, detailing the rationale for the choice of common DBS targets. We also cover the technical aspects of DBS, from electrode placement to programming and parameter selection. We then critically review the evidence from clinical trials and open-label studies, acknowledging the mixed outcomes and the challenges posed by placebo effects and trial design. Safety and ethical considerations are also discussed. Finally, we explore innovative directions for DBS research, including the potential of closed-loop systems, dual stimulation strategies, and noninvasive alternatives like ultrasound neuromodulation. In the last section, we outline recommendations for future DBS studies, including the use of alternative designs for placebo control, the collection of neural and behavioral recordings, and the application of machine-learning approaches.

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Many clinicians choose psychoanalytic psychotherapy or supportive psychotherapy as the primary method of treating depression with or without antidepressant medications. Despite new antidepressants, 20% or more patients showed inadequate responses to the medications, and remained in chronic courses, known as "treatment-resistant depression (TRD)."In this chapter, we described (1) the reasons for psychotherapy in treating TRD from the perspectives of the hazard of polypharmacy, resistance, and neural mechanisms. (2) Next, we focused on the importance of assessment with two clinical vignettes and the original modality of psychoanalysis, psychoanalytic psychotherapy, and supportive psychotherapy in brief. (3) Finally, we described specific considerations in undertaking psychotherapy for TRD patients in terms of transference, countertransference, and resistance. In addition, the efficacy of psychoanalytic psychotherapy in childhood, adolescent, and late-life depression has been depicted in this paper.

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Introduction: Repetitive transcranial magnetic stimulation (rTMS) is used for treatment-resistant major depressive disorder (MDD) and obsessive-compulsive disorder (OCD), but there are few studies on patient outcomes in Southeast Asia. In this study, we describe the clinical profile and outcome of patients with MDD and OCD treated with rTMS in Singapore. Method: A naturalistic retrospective study of 71 patients (inpatient and outpatient) who received rTMS treatment between June 2018 and April 2023 was conducted. The depressive and obsessive outcome rating scales used were clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS), Yale-Brown Obsessive Compulsive Scale (Y-BOCS), Clinical Global Impressions-Severity (CGI-S) and self-rated Depression Anxiety and Stress Scale-21 (DASS-21). Results: Clinician-rated and self-rated mood and general condition improved significantly. MADRS mean score improved from 28.1 (standard deviation [SD] 7.3) to 20.7 (SD 10.1) (P<0.0001) (20.8% response rate/17% remission rate). CGI-S mean 4.6 (SD 0.8) improved to 3.3 (SD 1.2) (P<0.0001). DASS-21 total mean improved from 67.3 (SD 24.6) to 49.6 (SD 28.0) (P<0.0001). Y-BOCS mean score displayed a trend towards improvement from 30.1 (SD 7.5) to 27.2 (SD 6.9) (P=0.799). However, 44.4% of patients with OCD responded with a minimal 20% reduction in baseline Y-BOCS. Moreover, the subgroup of 35.8% of patients with less than 30 rTMS sessions had contributed disproportionately to nonresponse (85.7%). Patients who received rTMS treatment (>30 sessions) had a trend of larger improvement of MADRS score when compared to patients with (≤30 sessions) (9.4 [SD 9.7] versus 3.8 [SD 12.3] [P=0.078]). Conclusion: Response and remission rates for MDD and OCD suggest patients have a good response to rTMS treatment. Dosing longer rTMS sessions after an acute course helps to maximise effectiveness. Further research to determine predictors of outcome and characterise clinical features of late responders to target treatment more effectively is recommended.

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INTRODUCTION: Depression is a common, serious and often chronic disorder and one of the leading causes of disability worldwide. The annual prevalence of depression is 5-10%, twice as high among women as men and the lifetime prevalence is at least 20%. Up to a third of depressed individuals meet criteria for treatment-resistant depression, where two antidepressants have been tried for at least 6 weeks each at therapeutic doses. As of January 2022 transcranial magnetic stimulation for adults with treatment-resistant depression that has not responded to other forms of treatment has been available by a service that is part of Primary Health Care of the Capital Area in Iceland. METHODS: This is a retrospective cohort study where participants completed a course of magnetic transcranial treatment for depression in the years 2022 and 2023. Two validated self-rating measures were used to assess depression. Information on previous treatment approaches for depression was collected from electronic health records. RESULTS: 104 individuals completed the treatment in these first two years, 60,6% women. Most had unipolar depression (86,5%), but a small subgroup had bipolar depression (13,5%). The proportion of responders varied according to the measures used, 36,1% and 45,7%, respectively, and the same was true for remission where the proportions were 12,4% and 31,5%, respectively, higher for the longer inventory. The drop-out rate was only 12,5% and no serious adverse events were reported during the treatment. CONCLUSION: The results support that magnetic transcranial stimulation, as provided by this service is effective in treating treatment-resistant or longstanding depression in a real life clinical setting and the low drop-out rate supports that the treatment is generally very well tolerated.

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This cohort study investigated whether allostatic load (AL) is associated with treatment response to repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression (TRD). Pre-treatment blood samples measured AL across multiple systems. Pre- and post-treatment mood changes were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Associations between AL and treatment outcomes were explored. Higher pre-treatment AL was significantly associated with poorer post-treatment response status but was not significantly associated with smaller reduction in MADRS score after 4 weeks of treatment. Identifying biomarker profiles informed by the AL model could enhance treatment decisions in TRD, reducing risks associated with prolonged, ineffective rTMS trials and emphasizing the need for reliable predictive biomarkers.

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BACKGROUND: Although there are a few first-line treatment options for bipolar depression, none are rapid-acting. A new rTMS protocol, Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT®), has been shown to have a rapid antidepressant effect in major depressive disorder (MDD). We examined the preliminary safety, tolerability, and efficacy of SAINT for the treatment of depression in a small sample of persons with treatment-resistant bipolar I disorder. METHODS: Participants with treatment-resistant bipolar I disorder currently experiencing moderate to severe depression were treated with open-label SAINT. Resting-state functional MRI (fMRI) was used to generate individualized treatment targets for each participant based on the region of the left dorsolateral prefrontal cortex most anticorrelated with the subgenual anterior cingulate cortex. Participants were treated with 10 iTBS sessions daily, with 50-min intersession intervals, for up to 5 consecutive days. The primary outcome was change in Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to immediate follow-up after treatment. RESULTS: We treated 10 participants and found a mean reduction of 16.9 in MADRS scores, with a 50 % response rate and 40 % remission rate immediately following treatment. 60 % of participants met remission criteria within the 1-month period following treatment. No serious adverse events, manic episodes, or cognitive side effects were observed. LIMITATIONS: Our study has a limited sample size and larger samples are needed to confirm safety and efficacy. CONCLUSIONS: SAINT has shown preliminary feasibility, safety, tolerability, and efficacy in treating treatment-resistant bipolar I depression. Double-blinded sham-controlled trials with larger samples are needed to confirm safety and efficacy.

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OBJECTIVE: Although repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression, little is known about the comparative effectiveness of rTMS and other treatment options, such as antidepressants. In this multicenter randomized controlled trial, rTMS was compared with the next pharmacological treatment step in patients with treatment-resistant depression. METHODS: Patients with unipolar nonpsychotic depression (N=89) with an inadequate response to at least two treatment trials were randomized to treatment with rTMS or to a switch of antidepressants, both in combination with psychotherapy. Treatment duration was 8 weeks and consisted of either 25 high-frequency rTMS sessions to the left dorsolateral prefrontal cortex or a switch of antidepressant medication following the Dutch treatment algorithm. The primary outcome was change in depression severity based on the Hamilton Depression Rating Scale (HAM-D). Secondary outcomes were response and remission rates as well as change in symptom dimensions (anhedonia, anxiety, sleep, rumination, and cognitive reactivity). Finally, expectations regarding treatment were assessed. RESULTS: rTMS resulted in a significantly larger reduction in depressive symptoms than medication, which was also reflected in higher response (37.5% vs. 14.6%) and remission (27.1% vs. 4.9%) rates. A larger decrease in symptoms of anxiety and anhedonia was observed after rTMS compared with a switch in antidepressants, and no difference from the medication group was seen for symptom reductions in rumination, cognitive reactivity, and sleep disorders. Expectations regarding treatment correlated with changes in HAM-D scores. CONCLUSIONS: In a sample of patients with moderately treatment-resistant depression, rTMS was more effective in reducing depressive symptoms than a switch of antidepressant medication. In addition, the findings suggest that the choice of treatment may be guided by specific symptom dimensions.

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Treatment-resistant depression (TRD) is an epidemic with rising social, economic, and political costs. In a patient whose major depressive episode (MDE) persists through an adequate antidepressant trial, insurance companies often cover alternative treatments which may include repetitive transcranial magnetic stimulation (rTMS). RTMS is an FDA-cleared neuromodulation technique for TRD which is safe, efficacious, noninvasive, and well-tolerated. Recent developments in the optimization of rTMS algorithms and targeting have increased the efficacy of rTMS in treating depression, improved the clinical convenience of these treatments, and decreased the cost of a course of rTMS. In this opinion paper, we make a case for why conventional FDA-cleared rTMS should be considered as a first-line treatment for all adult MDEs. RTMS is compared to other first-line treatments including psychotherapy and SSRIs. These observations suggest that rTMS has similar efficacy, fewer side-effects, lower risk of serious adverse events, comparable compliance, the potential for more rapid relief, and cost-effectiveness. This suggestion, however, would be strengthened by further research with an emphasis on treatment-naive subjects in their first depressive episode, and trials directly contrasting rTMS with SSRIs or psychotherapy.

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Importance: Bipolar disorder (BD) is chronic and disabling, with depression accounting for the majority of time with illness. Recent research demonstrated a transformative advance in the clinical efficacy of transcranial magnetic stimulation for treatment-resistant major depressive disorder (MDD) using an accelerated schedule of intermittent theta-burst stimulation (aiTBS), but the effectiveness of this treatment for treatment-refractory BD is unknown. Objective: To evaluate the effectiveness of aiTBS for treatment-refractory BD. Design, Setting, and Participants: This randomized clinical trial, conducted from March 2022 to February 2024, included individuals with treatment-resistant BD with moderate to severe depressive episodes referred from the Penn Bipolar outpatient clinic. Included patients had 2 or more prior failed antidepressant trials by Antidepressant Treatment History Form criteria and no other primary psychiatric diagnosis, were receiving a mood stabilizer for 4 or more weeks, and had a Montgomery-Åsberg Depression Rating Scale (MADRS) score of 20 or higher. Intervention: Prior to treatment, resting-state functional magnetic resonance imaging was used to compute personalized left dorsolateral prefrontal cortex target by connectivity to subgenual anterior cingulate cortex. Patients were randomized 1:1 to 10 sessions per day of imaging-guided active or sham aiTBS for 5 days with 1 session per hour at 90% resting motor threshold for 90 000 pulses total. Main Outcome and Measures: The main outcome was repeated MADRS scores before and after treatment. Results: A total of 24 participants (12 [50%] female; 12 [50%] male; mean [SD] age, 43.3 [16.9] years) were randomized to active (n = 12) or sham (n = 12) aiTBS. All participants completed treatment and 1-month follow-up. MADRS scores were significantly lower in the active group (mean [SD], 30.4 [4.8] at baseline; 10.5 [6.7] after treatment) than in the sham group (28.0 [5.4] at baseline; 25.3 [6.7] after treatment) at treatment end (estimated difference, -14.75; 95% CI, -19.73 to -9.77; P < .001; Cohen d, -2.19). Conclusion and Relevance: In this randomized clinical trial, aiTBS was more effective than sham stimulation for depressive symptom reduction in patients with treatment-resistant BD. Further trials are needed to determine aiTBS durability and to compare with other treatments. Trial Registration: ClinicalTrials.gov Identifier: NCT05228457.

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OBJECTIVE: The objective of the study is to evaluate how electroconvulsive therapy (ECT) affects treatment-resistant depression, bipolar and schizophrenic patient groups, and suicide attempt histories and to evaluate the relationship between treatment variables and patient outcomes. METHOD: In a retrospective cohort study at the inpatient psychiatry clinic of Çam and Sakura City Hospital between January, 2021, and February, 2023, 103 patients receiving ECT were analyzed. They were categorized into two groups according to indications that suicide risk (n = 76) and resistance to pharmacotherapy (n = 27). RESULTS: The analysis revealed no significant age (p = 0.374) or gender (p = 0.304) differences between groups. However, significant differences emerged in diagnostic distribution (p = 0.027), with the suicide risk group receiving more ECT sessions (13.6 ± 11.2, p = 0.025) and experiencing longer total seizure times (427 ± 325 s, p = 0.023) compared to the treatment-resistant group (8.5 ± 4.7 sessions and 279 ± 115 s, respectively). CONCLUSIONS: ECT's therapeutic application does not differ from demographic variables but is influenced by clinical diagnosis, with suicide risk patients receiving more intensive treatment. These findings highlight the necessity of individualized ECT protocols and suggest that diagnostic considerations are critical in optimizing ECT treatment strategies. Despite its retrospective design, the study underscores the importance of personalized ECT regimens and calls for further prospective research to validate these findings.

OBJETIVO: Evaluar cómo la terapia electroconvulsiva afecta a grupos de pacientes con depresión resistente al tratamiento, trastorno bipolar, esquizofrenia y antecedentes de intentos suicidio, y evaluar la relación entre variables de tratamiento y resultados. MÉTODO: En una cohorte retrospectiva en la clínica de psiquiatría para pacientes internados del Çam and Sakura City Hospital, entre el 01/2021 y el 03/2023, se analizaron 103 pacientes que recibieron terapia electroconvulsiva. Estos se clasificaron en dos grupos según los indicios de riesgo de suicidio (n = 76) y de resistencia a la farmacoterapia (n = 27). RESULTADOS: El análisis no mostró diferencias significativas en cuanto a edad (p = 0.374) y sexo (p = 0.304) entre los grupos. Sin embargo, hubo diferencias significativas en la distribución diagnóstica (p = 0.027), con el grupo de riesgo de suicidio recibiendo más sesiones de terapia electroconvulsiva (13.6 ± 11.2; p = 0.025) y experimentando tiempos totales de convulsión más largos (427 ± 325 segundos; p = 0.023) en comparación con el grupo resistente al tratamiento (8.5 ± 4.7 sesiones y 279 ± 115 segundos, respectivamente). CONCLUSIONES: La aplicación terapéutica de la terapia electroconvulsiva no difiere según las variables demográficas, pero sí se ve influenciada por el diagnóstico clínico, recibiendo los pacientes de riesgo de suicidio un tratamiento más intensivo.

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BACKGROUND: Electroconvulsive therapy (ECT) benefits patients with treatment-resistant depression (TRD), but the underlying biological processes are unclear. We conducted an epigenome-wide association study in 32 TRD patients undergoing ECT to depict ECT-associated methylation changes. Illness severity and ECT outcomes were assessed with the Montgomery-Åsberg Depression Rating Scale at baseline (T0) and 1 month after its end (T1). Methylation was profiled at T0 and T1 with the Illumina Infinium Methylation EPIC BeadChip array. RESULTS: Longitudinal T0-T1 analyses showed 3 differentially methylated probes (DMPs) with nominal p values ≤ 10-5, with 2 annotated in the genes CYB5B and PVRL4. Including covariates, we found 4 DMPs for symptoms variation, annotated in FAM20C, EPB41, OTUB1 and ADARB1, and 3 DMPs for response status, with 2 annotated in IQCE and FAM20C. Regional analysis revealed 54 differentially methylated regions (DMRs) with nominal p value area ≤ 0.05, with 9 presenting adjusted p-value area ≤ 0.10, annotated in MCF2L, SLC25A24, RUNX3, MIR637, FOXK2, FAM180B, POU6F1, ALS2CL and CCRL2. Considering covariates, we found 21 DMRs for symptoms variation and 26 DMRs for response (nominal p value area ≤ 0.05), with 4 presenting adjusted p-value area ≤ 0.10 for response, annotated in SNORD34, NLRP6, GALNT2 and SFT2D3. None remained significant after false discovery rate correction. Notably, ADARB1 variants are associated with suicide attempt in patients with psychiatric disorders, and SLC25A24 relates to conduct disorder. Several DMPs and DMRs are annotated in genes associated with inflammatory/immune processes. Longitudinal analyses on females (n = 22) revealed statistically significant DMRs (adjusted p value area ≤ 0.05) and trend-significant DMRs (adjusted p value area ≤ 0.07) for symptoms variation and response status, annotated in genes related to psychiatric disorders (ZFP57, POLD4, TRIM10, GAS7, ADORA2A, TOLLIP), trauma exposure (RIPOR2) and inflammatory/immune responses (LAT, DLX4, POLD4, FAM30A, H19). Pathway analysis on females revealed enrichment for transcriptional activity, growth factors, DNA maintenance, and immune pathways including IRF7 and IRF2. CONCLUSION: Although no significant results were found for the whole cohort, the study provides insights into ECT-associated methylation changes, highlighting DMPs and DMRs related to ECT outcomes. Analyses on females revealed significant DMRs and pathways related to psychiatric disorders and inflammatory/immune processes.

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BACKGROUND: Treatment-Resistant Depression (TRD) challenges psychiatric treatment, with existing guidelines covering only a subset of augmentation strategies. METHODS: A network meta-analysis following PRISMA guidelines examined the efficacy and safety of TRD treatments, analyzing 72 randomized controlled trials from eight databases, assessing response and remission rates, tolerability, and safety through the Cochrane Risk of Bias Tool and CINeMA framework. FINDINGS: Including 12,105 participants, the analysis highlighted ECT, Ketamine, Esketamine, and Psilocybin as superior first-line treatments due to their optimal balance between effectiveness and tolerability. Brexpiprazole and Quetiapine showed no significant efficacy over placebo in response rates, while Esketamine and Psilocybin exhibited lower tolerability. INTERPRETATION: The results advocate for ECT, Ketamine, Esketamine, and Psilocybin as preferred treatments for TRD, guiding clinical practice with evidence-based recommendations for enhancing treatment outcomes. This study underscores the importance of considering both efficacy and safety in selecting augmentation strategies for TRD.

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BACKGROUND: Patient expectations, including both positive (placebo) and negative (nocebo) effects, influence treatment outcomes, yet their impact on acute repetitive transcranial magnetic stimulation (rTMS) for treatment-resistant depression (TRD) is unclear. METHODS: In this single-center retrospective chart review, 208 TRD patients completed the Stanford Expectation of Treatment Scale (SETS) before starting open-label rTMS treatment. Patients were offered two excitatory rTMS protocols (deep TMS or intermittent theta-burst stimulation), which stimulated the left dorsolateral prefrontal cortex. A minimum of 20 once daily treatments were provided, delivered over 4-6 weeks. Primary outcomes were 1) remission, measured by a post-treatment score of <8 on the Hamilton Depression Rating Scale (HAMD-17), and 2) premature discontinuation. The change in HAMD-17 scores over time was used as a secondary outcome. Physicians were blinded to SETS scores. Logistic and linear regression, adjusting for covariates, assessed SETS and HAMD-17 relationships. RESULTS: Of 208 patients, 177 had baseline and covariate data available. The mean positivity bias score (positive expectancy minus negative expectancy subscale averages) was 0.48 ± 2.21, indicating the cohort was neutral regarding the expectations of their treatment on average. Higher positive expectancy scores were significantly associated with greater odds of remission (OR = 1.90, p = 0.003) and greater reduction in HAMD-17 scores (ß = 1.30, p = 0.005) at the end of acute treatment, after adjusting for covariates. Negative expectancy was not associated with decreased odds of remission (p = 0.2) or treatment discontinuation (p = 0.8). CONCLUSIONS: Higher pre-treatment positive expectations were associated with greater remission rates with open-label rTMS in a naturalistic cohort of patients with TRD.

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BACKGROUND: Transcranial magnetic stimulation (TMS) is an evidence-based approach to treatment- resistant Major Depressive Disorder (TRD). Sleep dysfunction is associated with poor outcomes in TRD, however, the impacts of sleep dysfunction on TMS treatment has yet to be defined. This study examined the association between sleep dysfunction and improvement in depression symptoms with TMS treatment for TRD. METHODS: A retrospective observational cohort study was conducted examining all Veterans receiving TMS treatments through the "VA TMS Clinical Pilot Program" over a three-year period. The Patient Health Questionnaire (PHQ-9) sleep item was utilized to assess sleep dysfunction. The association between sleep dysfunction improvements during TMS treatment with depression outcomes was analyzed. RESULTS: 94.3 % (N = 778) of Veterans reported baseline sleep dysfunction. Chi-square analysis demonstrated higher rates of depression remission at the completion of TMS treatment for those with sleep improvement at weeks 1, 3 and 6 (all p < .001). ANOVA comparing sleep improvements and end of treatment PHQ-8 score (modified to remove sleep item) found a statistically significant difference in mean improvements of depression scores at all 3 time points. LIMITATIONS: Limitations include those that are inherent to retrospective studies, as well as limitations in using the PHQ-9 sleep item as the primary means to assess sleep dysfunction. CONCLUSION: This study reports on the largest sample size to date examining the relationship between sleep dysfunction and TMS treatment outcomes for MDD, and found that improvement in sleep dysfunction was associated with greater reductions in end of treatment depression symptoms including higher depression remission rates.

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BACKGROUND: The Patient Health Questionnaire (PHQ-9) and Montgomery-Asberg Depression Rating Scale (MADRS) are commonly used scales to measure depression severity in older adults. METHODS: We utilized data from the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) clinical trial to produce conversion tables relating PHQ-9 and MADRS total scores. We split the sample into training (N = 555) and validation samples (N = 187). Equipercentile linking was performed on the training sample to produce conversion tables for PHQ-9 and MADRS. We compared the original and estimated scores in the validation sample with Bland-Altman analysis. We compared the depression severity level using the original and estimated scores with Chi-square tests. RESULTS: The Bland-Altman analysis confirmed that differences between the original and estimated scores for at least 95 % of the sample fit within 1.96 standard deviations of the mean difference. Chi-square tests showed a significant difference in the proportion of participants at each depression severity category determined using the original and estimated scores. LIMITATIONS: The conversion tables should be used with caution when comparing depression severity at the individual level. CONCLUSIONS: Our conversion tables relating PHQ-9 and MADRS scores can be used to compare treatment outcomes using aggregate data in studies that only used one of these scales.

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Importance: The ELEKT-D: Electroconvulsive Therapy (ECT) vs Ketamine in Patients With Treatment Resistant Depression (TRD) (ELEKT-D) trial demonstrated noninferiority of intravenous ketamine vs ECT for nonpsychotic TRD. Clinical features that can guide selection of ketamine vs ECT may inform shared decision-making for patients with TRD. Objective: To evaluate whether selected clinical features were associated with differential improvement with ketamine vs ECT. Design, Setting, and Participants: This secondary analysis of an open-label noninferiority randomized clinical trial was a multicenter study conducted at 5 US academic medical centers from April 7, 2017, to November 11, 2022. Analyses for this study, which were not prespecified in the trial protocol, were conducted from May 10 to Oct 31, 2023. The study cohort included patients with TRD, aged 21 to 75 years, who were in a current nonpsychotic depressive episode of at least moderate severity and were referred for ECT by their clinicians. Exposures: Eligible participants were randomized 1:1 to receive either 6 infusions of ketamine or 9 treatments with ECT over 3 weeks. Main Outcomes and Measures: Association between baseline factors (including 16-item Quick Inventory of Depressive Symptomatology Self-Report [QIDS-SR16], Montgomery-Asberg Depression Rating Scale [MADRS], premorbid intelligence, cognitive function, history of attempted suicide, and inpatient vs outpatient status) and treatment response were assessed with repeated measures mixed-effects model analyses. Results: Among the 365 participants included in this study (mean [SD] age, 46.0 [14.5] years; 191 [52.3%] female), 195 were randomized to the ketamine group and 170 to the ECT group. In repeated measures mixed-effects models using depression levels over 3 weeks and after false discovery rate adjustment, participants with a baseline QIDS-SR16 score of 20 or less (-7.7 vs -5.6 points) and those starting treatment as outpatients (-8.4 vs -6.2 points) reported greater reduction in the QIDS-SR16 with ketamine vs ECT. Conversely, those with a baseline QIDS-SR16 score of more than 20 (ie, very severe depression) and starting treatment as inpatients reported greater reduction in the QIDS-SR16 earlier in course of treatment (-8.4 vs -6.7 points) with ECT, but scores were similar in both groups at the end-of-treatment visit (-9.0 vs -9.9 points). In the ECT group only, participants with higher scores on measures of premorbid intelligence (-14.0 vs -11.2 points) and with a comorbid posttraumatic stress disorder diagnosis (-16.6 vs -12.0 points) reported greater reduction in the MADRS score. Those with impaired memory recall had greater reduction in MADRS during the second week of treatment (-13.4 vs -9.6 points), but the levels of MADRS were similar to those with unimpaired recall at the end-of-treatment visit (-14.3 vs -12.2 points). Other results were not significant after false discovery rate adjustment. Conclusions and Relevance: In this secondary analysis of the ELEKT-D randomized clinical trial of ECT vs ketamine, greater improvement in depression was observed with intravenous ketamine among outpatients with nonpsychotic TRD who had moderately severe or severe depression, suggesting that these patients may consider ketamine over ECT for TRD.

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