Treatment-resistant depression: molecular mechanisms and management.

Due to the heterogeneous nature of depression, the underlying etiological mechanisms greatly differ among individuals, and there are no known subtype-specific biomarkers to serve as precise targets for therapeutic efficacy. The extensive research efforts over the past decades have not yielded much success, and the currently used first-line conventional antidepressants are still ineffective for close to 66% of patients. Most clinicians use trial-and-error treatment approaches, which seem beneficial to only a fraction of patients, with some eventually developing treatment resistance. Here, we review evidence from both preclinical and clinical studies on the pathogenesis of depression and antidepressant treatment response. We also discuss the efficacy of the currently used pharmacological and non-pharmacological approaches, as well as the novel emerging therapies. The review reveals that the underlying mechanisms in the pathogenesis of depression and antidepressant response, are not specific, but rather involve an interplay between various neurotransmitter systems, inflammatory mediators, stress, HPA axis dysregulation, genetics, and other psycho-neurophysiological factors. None of the current depression hypotheses sufficiently accounts for the interactional mechanisms involved in both its etiology and treatment response, which could partly explain the limited success in discovering efficacious antidepressant treatment. Effective management of treatment-resistant depression (TRD) requires targeting several interactional mechanisms, using subtype-specific and/or personalized therapeutic modalities, which could, for example, include multi-target pharmacotherapies in augmentation with psychotherapy and/or other non-pharmacological approaches. Future research guided by interaction mechanisms hypotheses could provide more insights into potential etiologies of TRD, precision biomarker targets, and efficacious therapeutic modalities.

Personalised transcranial magnetic stimulation for treatment-resistant depression, depression with comorbid anxiety and negative symptoms of schizophrenia: a narrative review.

ABSTRACT: Transcranial magnetic stimulation (TMS) is a promising intervention for treatment-resistant psychiatric disorders. However, conventional TMS typically utilises a one-size-fits-all approach when determining stimulation targets. Recent retrospective brain circuit-based analyses using lesion network mapping have suggested that a left dorsal lateral prefrontal cortex target has a higher efficacy for alleviating depression symptoms, a dorsomedial prefrontal cortex target is more effective for anxiety symptoms, and a rostromedial prefrontal cortex target is effective for schizophrenia-associated psychiatric symptoms. Nonetheless, symptom-specific brain circuit targeting has not been tested prospectively. We conducted a narrative review of selected literature to investigate individualised targeting for TMS and discuss potential future directions to elucidate the efficacy of this approach.

Efficacy and Safety of Ketamine/Esketamine in Bipolar Depression in a Clinical Setting.

Background: Bipolar disorder represents a significant source of morbidity and elevated mortality risk. Ketamine has emerged as a powerful antidepressant; however, there have been few trials of ketamine in bipolar depression and no trials with esketamine in bipolar depression, and few data exist from real-world settings. Here, we report outcomes from a cohort of patients with bipolar depression treated with ketamine/ esketamine in a real-world setting.Methods: Patients with treatment refractory bipolar depression were referred to Yale Psychiatric Hospital Interventional Services for treatment from October 2014 to November 2023. Appropriate patients were treated with intravenous (IV) ketamine (0.5 mg/kg over 40 minutes) or intranasal esketamine (56 or 84 mg). Diagnosis of bipolar depression was done by clinical evaluation by an attending psychiatrist, based on DSM criteria. Clinical outcomes were tabulated from medical records.Results: Overall, 45 patients with bipolar depression were treated with IV ketamine or intranasal (IN) esketamine during the time period specified. Depression severity outcomes were available for 38 patients that completed an acute series, defined as treatment twice weekly for up to 4 weeks. Overall, 15/38 (39%) achieved clinical response (≥50% improvement on the Montgomery-Asberg Depression Rating Scale [MADRS]) and 5/38 (13.2%) achieved remission (≤10 on MADRS) following the acute series. Mean MADRS scores decreased from 31.1 to 19.2 (38.3% mean improvement). Safety data (hypomania/manic symptoms) were available for all 45 patients (518 patient-months of follow-up). No patients experienced any mania/hypomania during the acute series phase (when treatments are given twice weekly). However, 13/45 (28.9%) patients experienced symptoms consistent with a hypomanic or manic episode at some point following the acute phase while continuing to receive ketamine or esketamine during a maintenance phase. There were 16 manic/hypomanic events, indicating 1 event for every 2.7 patient-years. Only 1 event was severe and resulted in hospitalization.Conclusion: In a small sample of patients with bipolar depression treated with ketamine/esketamine, no evidence of mania/hypomania was seen during the acute phase of treatment. Further research is needed to evaluate whether ketamine or esketamine confers heightened risk of affective switch during maintenance treatment.

Prolonged transcranial magnetic stimulation in a pregnant patient with treatment-resistant depression: a case report.

INTRODUCTION: Perinatal depression is a serious and highly prevalent medical condition in the USA. Nearly 85% of individuals with perinatal depression go untreated, leading to significant morbidity and mortality. There is an urgent need to develop and advance safe and effective treatments for perinatal depression. Transcranial magnetic stimulation is an established intervention for depression in non-pregnant individuals yet is not well studied in perinatal depression. CASE PRESENTATION: A 33-year-old pregnant Latina female presented with severe, recurrent, treatment-resistant depression and suicidal ideation. The patient had previously trialed psychotherapy, multiple antidepressants, and mood stabilizers and had achieved remission with lithium prior to pregnancy. Due to pregnancy and fetal safety concerns, the patient discontinued lithium and consequently suffered progressive worsening of perinatal depression. At 24 weeks gestation and after additional failed medication trials, a prolonged course of transcranial magnetic stimulation was initiated. Following 46 transcranial magnetic stimulation treatments over 9 weeks using two protocol types (repetitive transcranial magnetic stimulation and intermittent theta burst stimulation), she achieved near-remission of perinatal depression and resolution of suicidal ideation. There were no identified maternal or fetal adverse events at 6 weeks post-delivery. CONCLUSION: To our knowledge, this is the first published case of a pregnant individual with perinatal depression who received and tolerated a prolonged transcranial magnetic stimulation course with two distinct protocols (repetitive transcranial magnetic stimulation and intermittent theta burst stimulation) with clinically significant response. Transcranial magnetic stimulation is a well-tolerated and effective intervention that warrants further investigation for use in treatment-resistant perinatal depression.

The Concept of Treatment-Refractory Addiction: Implications for Addiction Treatment Systems and Research.

ABSTRACT: The concept of treatment-refractory addiction, proposed by Eric Strain in this edition of the Journal, has the potential to invigorate the field of addiction treatment and research by focusing on a phenomenon that is familiar to any clinician treating patients with substance use disorders, namely, the patient who does not experience sufficient improvement from standard treatments. An analogy is drawn to the concept of treatment-resistant depression and the STAR*D study, which demonstrated an algorithmic approach to treatment, where if the first antidepressant medication tried did not result in remission from depression, subsequent trials of medications or cognitive behavioral therapy doubled the proportion of patients achieving remission. Recognizing treatment-refractory addiction challenges our field to develop analogous, stepwise, algorithmic approaches to treatment of substance use disorders, moving away from siloed treatment programs toward integrated treatment systems where alternative treatments are available, offering the kind of personalized, tailored forms of care used in the treatment of most other chronic illnesses. Like in STAR*D, research could focus on samples of patients who have not benefitted from initial trials of standard addiction treatments, addressing the key clinical question of what to do next when previous treatments fail.

Thalamocortical Dysconnectivity in Treatment-Resistant Depression.

Thalamocortical connectivity is associated with cognitive and affective processing. The role of thalamocortical connectivity in the pathomechanism of treatment-resistant depression (TRD) remains unclear. This study included 48 patients with TRD and 48 healthy individuals. We investigated thalamocortical connectivity by performing resting-state functional MRI with the bilateral thalamus as the seed. In addition, patients with TRD were evaluated using the Montgomery-Åsberg Depression Rating Scale (MADRS). Compared with the healthy individuals, the patients with TRD exhibited increased functional connectivity (FC) of the thalamus with the insula and superior temporal cortex and reduced the FC of the thalamus with the anterior paracingulate cortex and cerebellum crus II. Our study may support the crucial role of thalamocortical dysconnectivity in the TRD pathomechanism. However, the small sample size may limit the statistical power. A future study with a large sample size of patients with TRD would be required to validate our findings.

Mindfulness-Based Cognitive Therapy for Treatment-Resistant Depression: A protocol for systematic review and meta-analysis.

BACKGROUND: Major Depressive Disorder (MDD) is a global health issue, and a significant portion of individuals with MDD experience Treatment-Resistant Depression (TRD), characterized by the lack of response to adequately trialed antidepressant medication and therapy. This systematic review aims to investigate the effectiveness of Mindfulness-Based Cognitive Therapy (MBCT) as an intervention for individuals with TRD. MATERIALS AND METHODS: We will conduct a thorough search for publications of randomized clinical trials and quasi-experimental studies in MEDLINE, Embase, PsycINFO, Web of Science databases, and ClinicalTrials.gov. Furthermore, reference lists of included studies will be manually screened for additional relevant articles, with no restrictions on language or publication date. The search will be conducted from the inception of the databases until June 2024. Our PICO-guided research questions are: (1) In adults with Treatment-Resistant Depression, is MBCT more effective than standard care or other active treatments in reducing depressive symptoms? (2) In adults with Treatment-Resistant Depression, does MBCT demonstrate a comparable safety profile to standard care or other active treatments? The quality of the included studies will be assessed independently using the Cochrane Risk of Bias Tool (RoB 2). This study seeks to evaluate the effectiveness and tolerability of Mindfulness-Based Cognitive Therapy as an intervention for Treatment-Resistant Depression, and will employ the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology to appraise the confidence in the evidence. PROSPERO REGISTRATION: Prospero registration ID: CRD42023411978. Registered on April 07, 2023.

Comparative Side-Effects of Neurosurgical Treatment of Treatment-Resistant Depression.

INTRODUCTION: Treatment-resistant depression (TRD) is a condition in which patients suffering from depression no longer respond to common methods of treatment, such as anti-depressant medication. Neurosurgical procedures such as ablative surgery, deep brain stimulation, and vagus nerve stimulation have been used in efforts to overcome TRD. OBJECTIVES: This review aims to provide an overview of the side effects of neurosurgery performed in clinical studies related to depression. METHODS: A literature search was conducted through PubMed, MEDLINE, EMBASE, Ovid, and ClinicalTrials.gov databases. RESULTS: This review selected 10 studies for ablative surgery, 12 for deep brain stimulation, and 10 for vagus nerve stimulation, analyzing their side effect profiles of neurosurgery for TRD. The major side effects of each type of neurosurgery were identified, such as incontinence and confusion for ablative surgery, headaches and increased suicide ideation for deep brain stimulation, and voice hoarseness and dyspnea for vagus nerve stimulation. CONCLUSION: The review discusses the merits and demerits of neurosurgery as a treatment option for TRD. It also suggests new insights into decreasing the burden of these neurosurgical side effects so that they can be a viable, high-efficacy treatment method for TRD.

Ketamine and chronic treatment-resistant depression: real-world practice and after relapse.

BACKGROUND: Chronic treatment-resistant depression (TRD) poses a major challenge for clinicians. Ketamine has shown a rapid but short-lived antidepressant effect in several studies involving TRD patients with different demographic and clinical profiles. Our study aimed to assess the antidepressant effect of serial infusion sessions of ketamine in patients with chronic TRD and evaluate the severity of symptoms after relapse and the general psychiatric health of the responding patients. METHODS: In this single arm open-label study, six infusions of ketamine at 0.5 mg/kg were administered to chronic TRD patients for approximately two weeks. Response and remission rates, side effects, adverse events and after-relapse symptoms were evaluated, and patients were followed for three months. RESULTS: 23 patients underwent at least one infusion session, and 18 patients completed the six sessions. Twelve (66.67%) patients responded to the treatment at some point, and 11 (61.11%) patients maintained response after the end of the treatment protocol. One infusion was not sufficient to achieve a response (P > 0.9999, z = 1.81), and more than half of the responders met the response criteria after the third infusion. Only one patient (5.56%) achieved remission at the end of the infusion phase. All but one ketamine responders relapsed within one month after the end of the treatment. There was no statistical difference between baseline and after-relapse MADRS scores (P = 0.7886, 95% CI=-5.512-4.312, R2 = 0,008411). However, a high incidence of serious adverse events related to suicidality was evident; one of the non-responding patients attempted suicide and several attempts to sedate this patient with benzodiazepines failed. Two responding patients ended up with a suicidal attempt or severe suicidal thoughts. CONCLUSIONS: Introducing rapid-acting antidepressant to manage TRD patients in clinical practice demands further investigation, and the benefit-to-harm ratio should be assessed in the light of the increased risk of suicidality.

Randomised controlled trial comparing different intersession intervals of intermittent theta burst delivered to the dorsal medial prefrontal cortex.

BACKGROUND: Intermittent theta burst stimulation (iTBS) is a form of repetitive transcranial magnetic stimulation (rTMS) that can be administered in a fraction of the time of standard rTMS. Applying multiple daily iTBS sessions (ie, accelerated iTBS) may enable patients to achieve remission more rapidly. However, questions remain regarding the optimal time interval between treatment sessions. OBJECTIVE: The overall aim of this study was to compare the efficacy and tolerability of two accelerated bilateral iTBS protocols (ie, 30-min or 60-min intervals) and a once-daily bilateral iTBS protocol (ie, 0-min interval) while the number of pulses was held constant, in patients with treatment-resistant depression (TRD). METHODS: 182 patients with TRD were randomised to receive two sessions per day of bilateral iTBS of the dorsomedial prefrontal cortex (DMPFC) at 60-min, 30-min or 0-min intervals. Sham treatments were delivered using a shielded 'sham coil' which produced the auditory and tactile sensations of stimulation. The primary outcome measure was a change in depression scores on the 17-item Hamilton Rating Scale for Depression (HRSD-17) after 20 days of treatment. RESULTS: HRSD-17 scores improved across all groups; however, these improvements did not significantly differ between the three groups after 20 days of treatment. Similarly, response and remission rates did not differ between the treatment groups. CONCLUSIONS: These results suggest that contrary to our original hypothesis, implementing a 30-min or 60-min interval between two treatment sessions of DMPFC-iTBS does not lead to a more rapid improvement in symptoms, than once-daily iTBS administration. TRIAL REGISTRATION NUMBER: NCT02778035.

Exploring potential working mechanisms of accelerated HF-rTMS in refractory major depression with a focus on locus coeruleus connectivity.

BACKGROUND: This study investigates the effects of accelerated high-frequency repetitive transcranial magnetic stimulation (aHF-rTMS), applied to the left dorsolateral prefrontal cortex (DLPFC), on locus coeruleus (LC) functional connectivity in the treatment of refractory medication-resistant major depression (MRD). METHODS: We studied 12 antidepressant-free refractory MRD patients, focusing on how aHF-rTMS affects the LC, a central component of the brain's noradrenergic system and key to mood regulation and stress response. RESULTS: A stronger decrease in LC functional connectivity following aHF-rTMS treatment resulted in better clinical improvement. We observed such LC functional connectivity decreases with several brain regions, including the superior frontal gyrus, precentral gyrus, middle occipital gyrus, and cerebellum. Moreover, our exploratory analyses hint at a possible role for E-field modeling in forecasting clinical outcomes. Additional analyses suggest potential genetic and dopaminergic factors influencing changes in LC functional connectivity in relation to clinical response. CONCLUSIONS: The findings of this study underscore the pivotal role of the LC in orchestrating higher cognitive functions through its extensive connections with the prefrontal cortices, facilitating decision-making, influencing attention, and addressing depressive rumination. Additionally, the observed enhancement in LC-(posterior) cerebellar connectivity not only highlights the cerebellum's role in moderating clinical outcomes through noradrenergic system modulation but also suggests its potential as a predictive marker for aHF-rTMS efficacy. These results reveal new insights into the neural mechanisms of refractory depression and suggest therapeutic targets for enhancing noradrenergic activity, thereby addressing both cognitive and psychomotor symptoms associated with the disorder.

Effects of ketamine on metabolic parameters in depressive disorders: A systematic review.

BACKGROUND: Persons with Major Depressive Disorder (MDD), notably treatment-resistant depression (TRD), are differentially affected by type 2 diabetes mellitus and associated morbidity. Ketamine is highly efficacious in the treatment of adults living with MDD, notably TRD. Herein, we sought to determine the effect of ketamine on metabolic parameters in animal stress paradigms and human studies. METHODS: We performed a comprehensive search on PubMed, OVID, and Scopus databases for primary research articles from inception to May 5, 2024. Study screening and data extraction were performed by two reviewers (S.W. and G.H.L.). Both preclinical and clinical studies were included in this review. RESULTS: Results from the preclinical studies indicate that in experimental diabetic conditions, ketamine does not disrupt glucose-insulin homeostasis. Within adults with MDD, ketamine is associated with GLUT3 transporter upregulation and differentially affects metabolomic signatures. In adults with TRD, ketamine induces increased brain glucose uptake in the prefrontal cortex. Available evidence suggests that ketamine does not adversely affect metabolic parameters. LIMITATIONS: There are a paucity of clinical studies evaluating the effects of ketamine on glucose-insulin homeostasis in adults with MDD. CONCLUSIONS: Our results indicate that ketamine is not associated with significant and/or persistent disruptions in metabolic parameters. Available evidence indicates that ketamine does not adversely affect glucose-insulin homeostasis. These results underscore ketamine's efficacy and safety as an antidepressant treatment that is not associated with metabolic disturbances commonly reported with current augmentation therapies.

Interventional approaches to treatment resistant depression (DTR) in children and adolescents: A systematic review and meta-analysis.

BACKGROUND: Major depressive disorder (MDD) is highly prevalent in youth. Conventional treatment paradigms primarily involve selective serotonin reuptake inhibitors (SSRIs) and psychotherapy, yet a significant proportion of this population exhibits treatment-resistant depression (TRD). In adults, interventional therapies like Electroconvulsive Therapy (ECT), repetitive Transcranial Magnetic Stimulation (rTMS), and ketamine have shown promise for TRD, but their comparative efficacy remains underexplored in Adolescent and pediatric population. This systematic review and meta-analysis aims to assess the relative effectiveness of ECT, rTMS, and ketamine in treating TRD among adolescents. METHODS: Following PRISMA guidelines, we systematically searched databases for studies of ECT, rTMS, or ketamine for treatment-resistant depression in youth ages 10-24. Three reviewers independently screened for inclusion based on predefined criteria. Included observational and randomized controlled trials reported depression symptoms with measures like HDRS and MADRS in youth treated with ECT, rTMS, or ketamine. Two reviewers extracted data on interventions, patients, and depression symptom outcomes. Chance-adjusted inter-reviewer agreement was calculated. For meta-analysis, we pooled standardized mean differences (SMDs) in depression scores using random effects models and assessed heterogeneity with I2 statistics. RESULTS: Meta-analysis of 10 observational studies examined SMD in depression scores for treatment resistant depression patients treated with ECT, ketamine, or rTMS. Patients treated with ECT had a significantly lower SMD of 1.99 (95 % CI 0.92-3.05, p < 0.001) compared to baseline. Patients treated with ketamine also had a significantly lower SMD of 1.58 (95 % CI 1.04-2.12, p < 0.001). Patients treated with rTMS had the lowest SMD of 2.79 (95 % CI 0.79-4.80, p = 0.006). There was no significant difference between the three groups overall (p > 0.05). Comparative analysis between ECT and ketamine found no significant difference in SMD (p = 0.387). Comparison of ECT versus rTMS found a significant difference in SMD favoring rTMS (p = 0.004). Comparison of ketamine versus rTMS suggested a potential difference in SMD favoring rTMS (p = 0.058). In summary, rTMS resulted in significantly larger reductions in depression scores than ECT, and potentially larger reductions than ketamine. CONCLUSIONS: This meta-analysis illustrates the ability of rTMS, ECT, and ketamine to improve depression in youth. rTMS resulted in the largest improvements, highlighting its potential as a first-line treatment for pediatric treatment-resistant depression given its favorable side effect profile compared to ECT. Further research directly comparing these modalities is needed.

Exploring vortioxetine combination with intranasal esketamine: A feasible alternative to SSRI/SNRI? - Insights from the REAL-ESK study.

BACKGROUND: Treatment-Resistant Depression (TRD) affects almost 30 % of patients with Major Depressive Disorder (MDD). Esketamine Nasal Spray (ESK-NS) has recently been approved for TRD in combination with a Serotonin Specific Reuptake Inhibitor/SSRI or a Serotonin-Norepinephrine Reuptake Inhibitor/SNRI. There is a lack of studies investigating the effectiveness and safety of ESK-NS in combination with other oral antidepressants. AIM: To assess the efficacy of Vortioxetine plus ESK-NS in mitigating depressive symptoms and emotional blunting, as well as its tolerability in TRD subjects, compared to the standard-of-care of SSRI/SNRI plus ESK-NS. METHODS: We conducted a post-hoc analysis of the REAL-ESK study. The study included twenty TRD patients, ten subjects taking Vortioxetine as the main oral antidepressant with ESK-NS, and ten subjects taking SSRI or SNRI with ESK-NS. Psychometric assessments (Montgomery-Åsberg Depression Rating Scale/MADRS, Brief Psychiatric Rating Scale/BPRS) were conducted at baseline(T0), one month(T1), and three months after the treatment initiation(T2). RESULTS: The combination of Vortioxetine and ESK-NS was as effective as the standard-of-care in reducing depressive symptoms, with a higher effect size in reducing emotional blunting at T2. The safety and tolerability profile of the Vortioxetine+ESK-NS combination appeared to be better, with a lower rate of treatment-emergent adverse events. CONCLUSION: The combination of Vortioxetine and ESK-NS may be a valuable alternative to the standard-of-care SSRI/SNRI plus ESK-NS in TRD patients, particularly regarding the reduction of emotional blunting and potentially a better safety and tolerability profile. Further randomized controlled trials with larger sample sizes and prospective designs are needed to confirm these findings.

Optimizing antidepressant benefits: Effect of theta burst stimulation treatment in physically active people with treatment-resistant depression.

Theta burst stimulation (TBS) is a promising therapy for treatment-resistant major depressive disorder (MDD), but a significant proportion of individuals do not respond adequately, necessitating alternative approaches. This study explores whether individuals meeting minimum recommended physical activity levels demonstrate better responses to TBS compared to physically inactive individuals. Using data from a randomized controlled trial (n = 43), participants were categorized as physically active or inactive based on baseline International Physical Activity Questionnaire (IPAQ) scores. Depression scores (Hamilton Rating Scale for Depression, 17-item; HRSD-17) were assessed at baseline, 4, and 6 weeks of TBS treatment. A significant Time X Group effect adjusted for age and baseline depression was observed. Physically active individuals consistently exhibited lower depression scores across time points. At 4 and 6 weeks, there was a significant increase in between-group differences, indicating that the physically active group derived greater benefits from treatment. At 6 weeks, a significantly higher proportion of responders (≥50 % HRSD-17 reduction) were observed in the physically active compared to inactive group. Physical activity significantly contributed to regression and logistic models predicting treatment response. These findings support the potential role of baseline physical activity in enhancing TBS therapy for MDD.

Is lack of goal-conflict-specific rhythmicity a biomarker for treatment resistance in generalised anxiety but not social anxiety or major depression?

BACKGROUND: Anxiety and depression cause major detriment to the patient, family, and society - particularly in treatment-resistant (TR) cases, which are highly prevalent. TR prevalence may be due to current diagnoses being based not on biological measures but on symptom lists that suffer from clinical subjectivity, variation in symptom presentation, and comorbidity. AIMS: Goal-conflict-specific rhythmicity (GCSR) measured using the Stop-Signal Task (SST) may provide the first neural biomarker for an anxiety process and disorder. This GCSR has been validated with selective drugs for anxiety. So, we proposed that GCSR could differ between TR and non-TR individuals and do so differently between those diagnoses normally sensitive to selective anxiolytics and those not. METHODS: We recorded electroencephalograms (EEG) from 20 TR participants (4 GAD, 5 SAD and 11 MDD) and 24 non-TR participants (4 GAD, 5 SAD and 15 Comorbid GAD/MDD (GMD)) while they performed the SST. RESULTS: There was significant positive GCSR in all groups except the GAD-TR group. GAD-TR lacked GCSR in the low-frequency range. However, TR had little effect in SAD or MDD/GMD populations with apparent increases not decreases. CONCLUSIONS: Overall, these results suggest that GAD may occur in two forms: one resulting from excessive GCSR and so being drug sensitive, and the other resulting from some other mechanism and so being TR. In SAD and MDD groups, heightened GCSR could be a consequence rather than the cause, driven by mechanisms that are normally more sensitive to non-selective panicolytic antidepressants.

[The efficacy of magnetic transcranial stimulation in treating treatment-resistant or prolonged depression in a clinical sample].

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.

Deep Brain Stimulation (DBS) in Treatment-Resistant Depression (TRD): Hope and Concern.

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.

Examination of a case of "treatment failure" in long-term psychoanalytic psychotherapy for treatment-resistant depression.

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.

The Importance of Psychotherapy for Treatment-Resistant Depression.

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.