Treatment Resistant Depression (TRD)

The goal of this clinical trial is to learn which treatment works better to help people with treatment-resistant depression stay well after they improve with repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation treatment. It will also learn about the safety of maintenance rTMS and maintenance quetiapine. The main questions it aims to answer are: Does maintenance rTMS help prevent depression from returning better than maintenance quetiapine? Do participants receiving maintenance rTMS have greater improvement in depression symptoms over time than those receiving maintenance quetiapine? What side effects or medical problems occur with each treatment? Researchers will compare maintenance rTMS with maintenance quetiapine after all participants have completed the initial course of rTMS. Participants will: Receive an initial course of rTMS. Be randomly assigned to receive either maintenance rTMS or maintenance quetiapine. Attend regular follow ups to assess depression symptoms with MADRS , assess overall improvement by CGI , and any side effects. Provide blood samples at selected visits to measure brain-derived neurotrophic factor (BDNF), a protein that may be be linked to recovery from depression. Be followed for several months to monitor whether their depression returns and how well they continue to improve.

The goal of this clinical trial is to learn whether two forms of one-day accelerated transcranial magnetic stimulation (TMS) can reduce depressive symptoms in adults with treatment-resistant depression. Treatment-resistant depression is depression that has not improved enough after at least two adequate antidepressant medication treatments. TMS is a non-invasive treatment that uses magnetic pulses to stimulate specific areas of the brain. The main questions this study aims to answer are: * Does continuous theta-burst stimulation (cTBS) targeting the precuneus reduce depressive symptoms 4 weeks after treatment compared with sham stimulation? * Does intermittent theta-burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex reduce depressive symptoms 4 weeks after treatment compared with sham stimulation? Researchers will compare precuneus cTBS, left dorsolateral prefrontal cortex iTBS, and sham stimulation to determine whether either active treatment reduces depressive symptoms more than sham stimulation. Participants will be randomly assigned to one of the three groups and will not be told which treatment they initially receive. Participants will: * Complete screening procedures and baseline assessments of depression, rumination, and cognitive function * Receive 20 sessions of active or sham TMS during one in-person study day * Complete follow-up assessments 1, 2, 3, and 4 weeks after the intervention * Report any side effects or medical problems experienced during the study Participants initially assigned to sham stimulation may choose to receive active TMS after completing the 4-week follow-up period. Those who choose this option will receive either precuneus cTBS or left dorsolateral prefrontal cortex iTBS and will complete additional follow-up assessments.

The goal of this clinical trial is to learn if combining a ketogenic diet with a personalized, accelerated brain stimulation treatment (iTBS) works better than iTBS with a standard healthy diet to reduce depression symptoms in adults with treatment-resistant depression. The main questions it aims to answer are: * Does iTBS combined with a ketogenic diet improve depression symptoms more than iTBS combined with a standard healthy diet? * Does the ketogenic diet change ketone levels over time? * Is it safe, tolerable, and feasible to follow a ketogenic diet during accelerated iTBS treatment? We will compare a ketogenic diet to a Canadian Food Guide-aligned diet, both combined with iTBS, measuring depression severity using standard clinician-rated and self-report scales. Participants will: * Follow either a ketogenic diet or a standard healthy diet for 12 weeks, starting with a 3-week lead-in period before iTBS begins * Undergo a course of personalized, imaging-guided accelerated iTBS while continuing their assigned diet * Complete clinical and cognitive assessments, blood tests, and brain MRI scans before and after treatment * Have their ketone levels checked regularly throughout the 12-week period

The purpose of this research study is to examine how well a medication called lumateperone (Caplyta) works to relieve depression in older adults with treatment-resistant depression. Lumateperone (Caplyta) is approved by the U.S. Food and Drug Administration to treat Major Depressive Disorder in adults who are also taking another antidepressant medication. This study will compare lumateperone (Caplyta) to placebo (a sugar pill without medication).

The disruption of immune system is a key candidate in the pathogenesis of psychiatric disorders, especially those resistant to traditional treatments. Involving complex processes within the brain and peripheral immune system, inflammation may lead to imbalance of neurotransmitter systems and synaptic plasticity and directly contribute to the psychiatric symptoms observed in conditions such as depression, bipolar disorder (BD) and schizophrenia (SCZ). Studies show that treatment-resistant depression (TRD) is associated with elevated levels of inflammatory markers in the blood, which are linked to a lower response to conventional antidepressants. Interventions that modulate this inflammatory response, such as immunomodulatory treatments or therapies targeting pro-inflammatory cytokines, have demonstrated beneficial effects by reducing symptoms and improving patients' quality of life. A thorough understanding of the links between inflammation and treatment resistance therefore paves the way for innovative therapeutic strategies. These approaches could transform current practices by offering more personalized and effective solutions for patients suffering from chronic and resistant psychiatric disorders.

This study is being conducted at Massachusetts General Hospital (MGH) to explore whether adding psychedelic coaching can enhance the effects of ketamine or esketamine maintenance treatment in individuals with treatment-resistant depression (TRD). The investigators are currently enrolling participants who are receiving ongoing maintenance intravenous (IV) ketamine or intranasal esketamine (Spravato) treatment at the MGH Ketamine Clinic. Participation in the study will involve adding coaching sessions to your existing ketamine maintenance treatment.

Major depressive disorder is one of the leading causes of disability worldwide, and a substantial proportion of patients do not achieve adequate improvement with conventional antidepressant treatments. Cannabidiol (CBD), a non-intoxicating cannabinoid derived from Cannabis sativa, has shown potential anxiolytic, anti-inflammatory, and neurobiological effects that may be relevant for depressive disorders. The ANANDA trial is a multicenter, randomized, double-blind, placebo-controlled clinical trial designed to evaluate the efficacy, safety, and tolerability of full-spectrum cannabidiol oil as an adjunctive treatment in adults with treatment-resistant major depressive disorder. A total of 120 participants will be randomly assigned to receive either full-spectrum cannabidiol oil or placebo for 12 weeks while maintaining stable antidepressant treatment. Clinical assessments of depressive symptoms, anxiety, sleep quality, perceived stress, and adverse effects will be performed at baseline, Week 4, and Week 12. Blood samples will be collected at baseline and after 12 weeks to investigate inflammatory and neuroendocrine biomarkers. The primary objective is to evaluate changes in depressive symptoms after 12 weeks of treatment. Secondary objectives include the assessment of anxiety, sleep quality, perceived stress, biological markers, safety, and tolerability. The findings of this study may contribute to the development of new therapeutic approaches for treatment-resistant depression and provide additional evidence regarding the clinical use of cannabidiol in psychiatric disorders.

Depression is one of the leading causes of disability worldwide. Common treatments like antidepressant medications and talk therapy work well for some people, but many others do not improve, even after trying multiple treatments. This study will investigate two alternative treatment options for people whose depression has not responded to standard treatments: repetitive transcranial magnetic stimulation (rTMS), a non-invasive form of brain stimulation, and ketamine, a fast-acting medication. It can be difficult to decide between these interventions in clinical practice, and selecting between them often comes down to patient preference and trial and error. This study is working to optimize the selection approach: using biological and behavioral markers to match each person to identify biomarkers that may predict response to rTMS or ketamine. Investigators believe that differences in how individuals respond to rTMS versus ketamine are partly explained by differences in how their brains are organized, and that these differences can be measured and used to guide intervention decisions. This is an early-stage pilot study designed to test whether this biomarker-based approach is practical and acceptable to patients. Investigators will evaluate how well a combination of brain imaging and clinical data can predict, at the individual level, who is likely to respond to rTMS versus ketamine. The ultimate goal is to develop a reliable, scalable tool that helps clinicians make faster and more informed intervention decisions, reducing the time people with treatment-resistant depression spend searching for an antidepressant that works.

Treatment-resistant depression (TRD) is a major clinical challenge affecting a substantial proportion of patients with major depressive disorder who do not adequately respond to conventional antidepressant treatments. Intermittent theta burst stimulation (iTBS), a non-invasive neuromodulation technique targeting the left dorsolateral prefrontal cortex, has emerged as an effective treatment option for these patients. However, the biological mechanisms underlying treatment response remain poorly understood. This single-center, prospective, investigator-initiated clinical study aims to investigate the effects of iTBS on clinical symptoms, executive functions, and peripheral inflammatory and neuroprotective biomarkers in patients with treatment-resistant depression. Fifty patients with treatment-resistant depression and fifty healthy control participants will be enrolled. Patients will receive active iTBS treatment for four weeks (20 sessions), while healthy controls will undergo baseline clinical, cognitive, and biological assessments without receiving any intervention. Clinical outcomes will be evaluated using the 17-item Hamilton Depression Rating Scale (HAM-D-17), Patient Health Questionnaire-9 (PHQ-9), Clinical Global Impression (CGI), and Insomnia Severity Index (ISI). Executive functions will be assessed using the Wisconsin Card Sorting Test, Trail Making Test A and B, and verbal fluency tests. Peripheral blood samples will be collected before and after treatment to measure inflammatory, neuroplasticity, and neuroprotective biomarkers, including IL-1β, IL-6, IL-10, TNF-α, high-sensitivity C-reactive protein (hs-CRP), brain-derived neurotrophic factor (BDNF), apolipoprotein D (APOD), serum amyloid A1 (SAA1), and serum amyloid A2 (SAA2). Gene expression analyses will also be performed using quantitative polymerase chain reaction (qPCR). The study aims to identify biological mechanisms associated with iTBS treatment response and to explore potential biomarkers that may predict clinical improvement in patients with treatment-resistant depression. The findings may contribute to the development of personalized neuromodulation strategies and biomarker-guided treatment approaches for depression.

Major depressive disorder (MDD) is a significant public health problem and leading cause of worldwide disability. Treatment resistance is common in MDD, however, for these individuals, targeted noninvasive brain stimulation is an alternative. Repetitive transcranial magnetic stimulation (rTMS) and more recently, theta-burst stimulation (TBS), are the noninvasive brain stimulation modalities with the largest evidence base in MDD. Although efficacious, an unacceptable proportion of patients do not significantly improve, and several aspects of the TMS parameter space are under investigation to enhance clinical outcomes. DCS has been shown in a randomized trial of more than double the percent response and remission from traditional TMS. When a one day (ONE-D) TMS protocol was combined with DCS, the measured response rate was 87% at one week. This trial will compare response and remission at six weeks following neuronavigated robotic-enabled Transcranial Magnetic Stimulation + NRX-101 (D-cycloserine/lurasidone) vs. TMS+placebo.

Depression is a common illness, affecting 17% of the population over the course of a lifetime. A third of depressions relapses and progresses to recurrence and resistance to treatments. Despite the optimization of antidepressant medical strategies, 20 to 40% of depressions do not respond to treatment. This is particularly worrying as 6% of non-responder patients will die by committing suicide. Depression has a major impact on quality of life, socio-professional functioning and healthcare consumption. Sometimes, TRD is part of a bipolar illness. In this case, the challenge is even bigger because antidepressants are no well tolerated, further reducing the therapeutic options in case of resistance, the severity and duration of the depressive episodes are the main factors explaining the deterioration of the quality of life and the increasing cost of cares for these patients. The standard treatment for TRD is electroconvulsive therapy (ECT), which results in a response in 60 to 70% of cases after a few weeks of treatment. However, the improvement is often transient and 40% of patients relapse within 6 months of the initial ECT session. Moreover, ECT is often not well tolerated. This therapeutic impasse therefore makes TRD a priority public health target to which it is urgent to provide a realistic medico-economical response. The literature suggests that Vagus Nerve Stimulation (VNS) has unique kinetics of efficacy in depression, particularly in preventing long-term recurrences, and therefore responding to the lack of effective maintenance treatment in TRD. In fact, the benefits of VNS gradually accumulate over 12-24 months, which makes it complementary to more incisive treatments like ECT. Finally, its efficacy-tolerance profile appears to be similar in uni and bipolar TRD, giving VNS a potentially unique place in the therapeutic arsenal in psychiatry. The DepVNS hypothesis is that VNS is a medico-economically efficient therapeutic option to overcome the therapeutic impasse in which patients suffering from uni and bipolar DR currently find themselves due to the frequency of relapses under treatment. The primary objective is to estimate, from a collective point of view, the incremental cost-utility ratio of VNS to treat patients suffering from RD.

Major depressive disorder (MDD) is a common and disabling psychiatric condition, and many patients do not achieve adequate response to standard antidepressant treatments. Accelerated intermittent theta burst stimulation (iTBS) is a promising neuromodulation approach that may provide rapid antidepressant effects. This prospective interventional study aims to evaluate the clinical effectiveness of accelerated bilateral dorsomedial prefrontal cortex iTBS in patients with MDD and to investigate treatment-related changes in neurobiological biomarkers, including cortisol, ACTH, BDNF, IL-1β, IL-6, TNF-α, and CRP. Associations between biomarker changes and treatment response will also be examined.

The primary objective of this study is to evaluate the clinical efficacy of moderate-dose transcranial photobiomodulation (t-PBM) at different frequencies (10 Hz and 40 Hz) in patients with treatment-resistant depression (TRD). It further aims to explore the differential efficacy across various symptom subtypes, with a particular focus on the somatic symptom-dominant subtype. Additionally, this study will collect paired-pulse neurophysiological parameters (e.g., the ratio of cortical inhibition to excitation) to preliminarily explore the neural mechanisms underlying the modulation of cortical excitability by t-PBM intervention, and to analyze their correlation with the magnitude of clinical symptom improvement. The specific aims of this study are as follows: To evaluate the differential efficacy of t-PBM at varying frequencies (10 Hz vs. 40 Hz) in improving clinical depressive symptoms (as measured by scales such as HAM-D and MADRS). To investigate the therapeutic response to t-PBM in patients with the somatic symptom-dominant depression subtype, analyzing its potential suitability for targeting specific symptoms. To explore the changes in paired-pulse TMS parameters (e.g., SICI, ICF, and LICI) before and after t-PBM treatment, gaining preliminary insights into the potential association between its cortical modulatory effects and clinical outcomes.

The trial utilizes a pragmatic, randomized, open label design with two parallel arms. Participants aged 18-65 with a diagnosis of unipolar depressive disorder and without stable remission in the past 12 months are randomized 1:1 to receive either algorithm guided treatment (AGT) or treatment as usual (TAU). The AGT approach incorporates pre-defined treatment steps, critical decision points, and "if-then" rules based on symptom response. It leverages prior treatment history, current symptomatology, and tolerability profiles to personalize the therapeutic sequence and reduce treatment inertia. In contrast, TAU reflects standard clinical practice, where treatment decisions are left to clinician discretion without algorithmic structure. The primary objective of the study is to determine whether AGT leads to a greater reduction in depressive symptoms over a 12-week treatment period, as measured by the 6-item Hamilton Depression Rating Scale (HAMD-6). Secondary objectives include evaluating cognitive and psychosocial functioning, suicide risk, treatment adherence, tolerability, number of medication changes, and long-term outcomes at a 24-week follow-up, providing insights into the longer-term trajectory of TRD management.

The purpose of this trial is to measure depressive symptoms following treatment with ALTO-207 compared with placebo in participants with TRD.

The goal of this clinical trial is to optimize the target brain areas for deep brain stimulation (DBS) for depression based on personalized brain imaging and stereo-electroencephalography（SEEG), to administer long-term DBS treatment in the target brain areas, to assess the effectiveness and safety of DBS for refractory depression and to validate the method of personalized optimization of DBS targets. The main questions it aims to answer are: 1. Where is the optimal DBS target brain region for each patient? 2. What are the optimal DBS parameters for each patient ? 3. What are the neural biomarkers of depression symptoms for each patient? 4. Are the optimized DBS strategies effective in treating refractory depression?

The goal of this clinical trial is to understand the effect of ketamine on the brain in people with treatment-resistant depression (TRD). TRD occurs in around a third of people with depression and leads to higher suicide rates compared to those with major depressive disorder. A desperate need for a rapid acting antidepressant drug (RAAD) is needed to help improve quality of life for people with TRD. Ketamine has been shown to be a RAAD, and esketamine (a form of ketamine) was approved by the FDA to treat TRD. Ketamine has been known to cause dissociative experiences, that can lead to an increase in the "Openness to Experience" personality trait and psychological flexibility that occurs at "peak experience". This has been shown to improve mental health conditions and lower suicide risk. This study aims to further understand if there is a connection between this new change of mind and changes in brain activity. Ketamine has been shown to improve brain plasticity as well, specifically in the frontolimbic region of the brain, an area associated with depression. The investigators are analyzing the brain using functional magnetic resonance imaging (fMRI), a method used to measure brain activity. The frontolimbic region is also associated with cognitive flexibility and emotional processing, an important hurdle in treating TRD. Due to this, the investigators are pairing the ketamine treatment with psychotherapy sessions, to guide the processing experience, which can lead to higher emotional flexibility. The main questions this study aims to answer are: * Are frontolimibic plasticity circuitry changes associated with openness to experience and peak experience? * Is it feasible to recruit and retain people through a two-month KAP study? * Is the structure of the study effective for treating TRD? Participants will: * Visit the facilities 6-8 times * Complete 2 MRI brain scans * Complete 3-4 psychotherapy sessions * Receive 1-2 doses of ketamine * Complete online surveys between 3-4 visits

This observational study investigates the use of Esketamine Intranasal Spray in patients with Treatment-Resistant Depression in Real-World Settings. The study aims to evaluate the clinical outcomes, including efficacy and safety, of esketamine treatment. It also explores predictors of treatment response, focusing on biological pathways such as genetics, neuroimaging, and psychophysical measures. Additionally, the study examines how esketamine impacts patients' life functioning, including social and occupational aspects. The goal is to better understand who benefits most from esketamine and how it affects daily life, to improve personalized care for patients with difficult-to-treat depression.

This study will explore the effects of esketamine (Spravato®), an FDA-approved nasal spray, on adults diagnosed with treatment-resistant depression (TRD). All participants will receive esketamine as prescribed by a healthcare professional in a clinical setting. The purpose of this research is to understand whether adding therapeutic support in the form of preparation and integration sessions - before and after the esketamine doses - can enhance the treatment experience and lead to longer-lasting improvements in mood and functioning. Participants will be randomly assigned to one of two groups: Esketamine with therapeutic support sessions (integration group) Esketamine without additional support (standard care group) Both groups will receive standard monitoring and psychiatric evaluation during the study. The support sessions offered in the integration group are designed to help participants prepare for their treatment sessions and make sense of their experiences afterward, using a structured, evidence-based approach. The study will last approximately 8 weeks per participant, with follow-up assessments. The goal is to learn whether integration therapy can improve treatment outcomes, safety, and satisfaction for individuals with depression that hasn't responded to other treatments.

The purpose of this study is to confirm the efficacy of two recently introduced repetitive transcranial magnetic stimulation (rTMS) interventions - accelerated intermittent theta-burst stimulation (aiTBS) and individualized neuronavigation - in treatment-resistant depression (TRD). Using a three-arm design (neuronavigated aiTBS, non-neuronavigated aiTBS, and sham), this randomized controlled trial (RCT) is the first to specifically investigate the incremental benefit of neuronavigation within an accelerated stimulation protocol, as well as the first confirmatory RCT comparing the efficacy of each of these active treatments vs. sham, overcoming previous generalizability issues and being conducted in an independent, multicenter US TRD sample.

The investigators propose a single-arm, open-label study to evaluate the effectiveness, safety, tolerability and feasibility of at-home transcranial direct current stimulation (tDCS) as a treatment for depression, particularly in cases where patients have not responded well to traditional therapies. Treatment will be delivered over a 2-week period with daily weekday treatments i.e., five tDCS sessions, each lasting 20 minutes, spaced by approximately 20-minute inter-session intervals, for a total of three hours a day. Participants will self-administer treatment at home under direct remote supervision. Pre- and post- treatment neurophysiological biomarkers sessions will also be carried out. The study aims to examine changes in mood, brain activity, and related clinical outcomes before, during, and after treatment, with the goal to provide more information that can be used for future studies. PLEASE NOTE: THERE WILL BE 4 APPOINTMENTS THAT MUST OCCUR IN PERSON IN SAN DIEGO, CA.

The RTMSECT2 study was design to compare the application of electroconvulsive therapy augmented by transcranial magnetic stimulation. Subject will be compared both within groups and in group using psychometric scales and different deliver energy

Study comparing standard repetitive transcranial magnetic stimulation (rTMS) for Depression to a novel targeting approach using brain surface parcellation to locate a specific brain target.

We will be developing an EEG-based biomarker for the effects of ketamine infusion in patients with Depression. We will be analyzing the effects of ketamine infusion on Depression symptoms and EEG signals.

The goal of this study is to collect feasibility data on combining structured exercise aimed to improve physical fitness, and intermittent TBS (iTBS) in treating individuals diagnosed with difficult-to-treat depression who are physically inactive. By conducting this trial, we will compare the therapeutic benefits of the combined approach against the standard treatment of iTBS alone (without exercise). These findings will be used to inform future large-scale projects in which we will investigate, in a larger sample size, whether structured exercise aimed to improve fitness as recommended by most public exercise guidelines (i.e., ≥3x/week, moderate-to-vigorous intensity) serves as an active ingredient that amplifies the effectiveness of iTBS. Ultimately, the insights gained from this study will be valuable for clinicians seeking to alleviate depressive symptoms in MDD through neuromodulation techniques such as iTBS.