Academic literature on the topic 'Treatment-Resistant Depression (TRD)'

(1) Background: Major depressive disorder (MDD) is one of the most prevalent psychiatric disorders worldwide. Although several antidepressant drugs have been developed, up to 30% of patients fail to achieve remission, and acute remission rates decrease with the number of treatment steps required. The aim of the current project was to estimate and describe the population of treatment-resistant depression (TRD) patients in outpatient clinics in Poland. (2) Methods: The project involved a representative sample of psychiatrists working in outpatient clinics, chosen through a process of quota random sampling. The doctors completed two questionnaires on a consecutive series of patients with MDD, which captured the patients’ demographics, comorbidities, and medical histories. TRD was defined as no improvement seen after a minimum of two different antidepressant drug therapies applied in sufficient doses for a minimum of 4 weeks each. The data were weighted and extrapolated to the population of TRD outpatients in Poland. (3) Results: A total of 76 psychiatrists described 1781 MDD patients, out of which 396 fulfilled the criteria of TRD. The TRD patients constituted 25.2% of all MDD patients, which led to the number of TRD outpatients in Poland being estimated at 34,800. The demographics, comorbidities, medical histories, and histories of treatment of Polish TRD patients were described. In our sample of the TRD population (mean age: 45.6 ± 13.1 years; female: 64%), the patients had experienced 2.1 ± 1.6 depressive episodes (including the current one), and the mean duration of the current episode was 4.8 ± 4.4 months. In terms of treatment strategies, most patients (around 70%) received monotherapy during the first three therapies, while combination antidepressant drugs (ADs) were applied more often from the fourth line of treatment. The use of additional medications and augmentation was reported in only up to one third of the TRD patients. During all of the treatment steps, patients most often received a selective serotonin reuptake inhibitor (SSRI) and a serotonin norepinephrine reuptake inhibitor (SNRI). (4) Conclusions: TRD is a serious problem, affecting approximately one fourth of all depressive patients and nearly 35,000 Poles.

Background: Patients with treatment-resistant depression (TRD) have an increased mortality risk compared with other patients with depression, but it is not known how this translates into absolute numbers of excess deaths. Methods: Swedish national registers were used to identify a cohort of 118,774 antidepressant initiators 18–69 years old with a depression diagnosis. Patients who initiated a third consecutive treatment trial were classified as having TRD. Flexible parametric survival models were used to estimate the mortality risk due to all causes and external causes (suicides and accidents), comparing TRD patients with patients with other depression while adjusting for clinical and sociodemographic covariates and including interactions with TRD, age, and Charlson comorbidity index (CCI) for a number of somatic comorbidities. Standardized survival was estimated, as were numbers of excess deaths among TRD patients within each age and comorbidity category. Results: Compared with the mortality risk of other depressed patients, patients with TRD experienced excess deaths in most age and comorbidity categories in the range of 7–16 deaths per 1000 patients during 5 years. Highest numbers for all-cause excess deaths were found among patients 18–29 years old with CCI 1, where 16 [95% confidence interval 5–28] of the expected 37 [25–48] deaths per 1000 patients were excess deaths. The majority of the excess deaths were due to external causes. Conclusion: Patients with TRD experience significant numbers of excess deaths compared with other patients with depression.

Apparent treatment-resistant depression (TRD) is frequently encountered by and poses particular challenges for the old-age psychiatrist. The prevalence of true nonresponse to treatment is not known with accuracy but reports put it at 18% to 40% for the elderly. This article reviews the concept of TRD in the elderly, discussing the factors involved in apparent resistance and the treatment of this group. We suggest that absolute TRD may be a rarer entity than the estimated 18% to 40% if depressed patients are treated carefully and vigorously.

Background. Treatment resistant depression (TRD) continues to present a formidable challenge to clinicians, accounts for over half of the annual costs associated with treatment for depression and causes great frustration to patients. Although there have been studies attempting to define TRD, little information is available as to the cause of TRD. One suggestion is that patients with TRD have a greater frequency of co-morbid psychiatric disorders, which explains their resistance to standard antidepressant treatments. The objective of this study was to compare the co-morbidity of Axis I disorders between a sample of TRD patients and a sample of non-TRD patients.Methods. TRD and non-TRD patients, recruited from two separate antidepressant treatment studies, were assessed for Axis I co-morbidity using the SCID-P for the DSM-III-R. Patients for the two samples were then matched for baseline HAM-D-17 total score and gender.Results. Results reveal that non-TRD patients had a higher rate of both lifetime and current generalized anxiety disorder co-morbidity than did the TRD patients. No other statistically significant differences in Axis I co-morbidity were found.Conclusions. These findings do not support the idea that current or lifetime Axis I co-morbidity is more common in TRD than non-TRD patients. In fact, the only statistical difference showed non-TRD patients with higher co-morbidity rates.

AbstractBackgroundDepression is a disorder that causes disability, with a profound adverse impact on all areas of psychosocial functioning. This is particularly true for those with treatment resistant depression (TRD). However, to date, no systematic assessments of psychosocial functioning for patients with TRD have been conducted.MethodsIn the present study, we used the Longitudinal Interval Follow-up Evaluation (LIFE) scale to measure psychosocial functioning in 92 patients with TRD. These patients met formal criteria for TRD and were part of a clinical trial examining the efficacy of lithium augmentation of nortriptyline.ResultsClinicians rated this sample of patients as experiencing mild to moderate impairment in work-related activities, good to fair interpersonal relations, poor level of involvement in recreational activities, and mild impairment of ability to enjoy sexual activity. Patients and clinicians rated global social adjustment as poor.ConclusionsPatients with formally defined TRD experience significant impairment in psychosocial functioning. In this sample a tendency existed for both clinicians and patients to assign more severely impaired global ratings when compared with ratings for specific functional areas.

Introduction Treatment-resistant depression (TRD) presents a significant challenge in clinical practice. Besides antidepressant medications, neurostimulation methods (ECT, rTMS) and ketamine are viable treatment options. Objectives To objectively evaluate the real effectiveness of treatments within interventional psychiatry in the maintenance treatment. Methods The extensive literature review of the efficacy of ECT, rTMS, and ketamine treatment in the maintenance treatment of TRD and the author’s clinical and research experience will be included in this presentation. Results Neurostimulation, particularly ECT and ketamine treatment are usually effective treatments for patients with TRD. However, both of these treatment modalities do not have sustained benefits and after discontinuing treatment the majority of patients relapse. Ketamine has rapid therapeutic effects in depression, but these effects are short-lived. Continuation treatment with ketamine in the form of intranasal ketamine is an option, but concerns over cognitive impairment, interstitial cystitis and significant addictive potential related to longer use of ketamine are significant limiting factors. rTMS is a first-line treatment option for patients with TRD according to the Canadian CANMAT guidelines. However, the majority of patients may relapse following the course of rTMS. The maintenance rTMS over an extended period of time is usually not feasible as it may significantly affect the waiting time for newly referred patients. Portable TMS machine for home use would be an alternative option for a limited number of patients. Conclusions Maintenance treatment has been always a big clinical challenge in mood disorder psychiatry. Only well-established multimodal treatment is a realistic option for getting long-term benefits in treating patients with TRD. Disclosure No significant relationships.

IntroductionTreatment-resistant depression (TRD) has been a controversial issue for more than 35 years. Despite a large number of publications, clinicians and researchers still know few about the prevalence of TRD since no staging method has been validated.ObjectivesWe sought to assess similarities and differences between the 4 TRD-staging methods published to date and assess TRD prevalence in a clinical sample. We also wanted to look for clinical factors associated with TRD.MethodsWe conducted a clinical study in a psychiatric unit of a university hospital. We designed a hetero-questionnaire to stage TRD according to the 4 methods. Psychiatric diagnosis, depression severity and cognitive status were assessed using standardized tools. Patients were not included in the study if they suffer from schizophrenia, bipolar disorder, current substance dependence or major cognitive impairment.ResultsWe recruited 37 inpatients. Twenty-four had received an inadequate treatment, four had not responded after one adequate antidepressant trial and 9 after two trials. Only 7 were resistant according to the 4 staging methods, which showed several differences. The Massachussetts General Hospital (MGH) method appeared as the most specific and easy-to-use. Complete TRD seemed much less frequent than pseudo-resistance and relative resistance with untreated comorbidity. Chronic depression and comorbidity were frequent in the TRD subgroup.ConclusionThe concept of “difficult-to-treat” depression might be more appropriate for clinical practice than TRD. The MGH tool seems to fit best to clinical practice. Further research is needed to confirm these descriptive findings in a larger sample.

Introduction Due to its relatively high prevalence and recurrent nature, depression causes a major burden on healthcare systems and societies. Objectives To investigate healthcare resource utilization and costs associated with treatment-resistant depression (TRD) compared with non-TRD depression in Finland. Methods Of all patients aged 16-65 years and diagnosed with depression in Finland during 2004-2016, persons with TRD (N=15 405) were identified from nationwide registers and matched 1:1 with comparison persons with depression but no TRD. TRD was defined as initiation of a third treatment trial after having failed two pharmacological treatment trials. Follow-up period covered five years after TRD or corresponding matching data (until end of 2018). Healthcare resource utilization was studied with negative binomial regression and average excess costs of TRD with generalized estimating equations, by adjusting for baseline costs, comorbidity and baseline severity of depression. Results Persons with TRD (mean age 38.7, SD 13.1, 60.0% women) had more healthcare utilization and work disability (sick leaves and disability pensions), adjusted incidence rate ratio for work disability days was 1.72 (95% CI 1.64-1.80). This resulted in higher total costs for persons with TRD, adjusted mean difference 7572 (95% CI 7215-7929) EUR per patient per year, higher productivity losses (due to sick leaves and disability pensions, mean difference 5296, 95% CI 5042-5550) and direct healthcare costs (2002, 95% CI 1853-2151) compared with non-TRD patients. Mean difference was highest during the first year after TRD (total costs difference 11760, 95% CI 11314-12206). Conclusions Treatment-resistant depression is associated with a significant cost burden. Disclosure This study was funded by Janssen-Cilag Finland and the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. ML was partly funded by personal grants from the Finnish Medical Foundation and Emil Aaltonen fou

One hundred and fourteen patients with a diagnosis of “treatment resistant depression” (TRD) were assessed and treated at a Mood Disorders Clinic. Diagnostically, 52 (45.6%) subjects met criteria for bipolar disorder, 49 (42.9%) for recurrent depression, and 13 (11.4%) patients did not fulfill diagnostic criteria for affective disorder which explained their treatment resistance. With appropriate, individualized treatment, 59 of 98 (60.2%) patients had complete symptom remission based on clinical and psychometric ratings (initial Ham-D 26.7, final Ham-D 5.9). Eighteen of 98 patients had partial remission (final Ham-D 15.9) with vigorous pharmacological interventions, and 8 subjects exhibited “absolute” TRD (final Ham-D 23.4). The results suggest the value of specialized mood disorder services. The partial and absolute TRD's were more likely to be older, received more Axis II diagnoses, and had previous histories of drug or alcohol abuse.

Treatment-Resistant Depression (TRD) is defined as major depression characterized by the unsatisfactory response of two or more antidepressant therapies (adequate for dosage and duration), associated with a high incidence of comorbidities, with more marked impairment of functioning socio-occupational and greater risks of relapse, recurrence and suicidality. The high incidence of TRD has advanced scientific research towards the study of molecules with antidepressant action and with different mechanisms of action than those based on the monoaminergic theory. Ketamine is one of these molecules. A non-competitive antagonist of the glutamate N-methyl-D-aspartate (NMDA) receptor, ketamine is mainly used in clinical practice as an anaesthetic and analgesic agent. It has recently been shown that it exerts an antidepressant activity with few and transient side effects at sub anaesthetic doses. Esketamine is the S-enantiomer of ketamine and has recently been FDA approved in the United States for treating depression that has failed to respond to trials of two or more antidepressants. Although the complete molecular mechanism of ketamine is very complex and still partly unknown, it appears that NMDA blockade induces a modulation of several synaptogenic signalling pathways, such as brain-derived neurotrophic factor (BDNF), improving synaptic plasticity of the prefrontal cortex and hippocampus. The design of the observational and retrospective study object of this thesis is evaluating the clinical response following repeated administration of intravenous ketamine (off-label use) and intranasal esketamine in a sample of 16 patients referring to the Psychiatric Clinic of the Siena University Hospital suffering from TRD. The efficacy assessment was performed by administering the Montgomery-Asberg Depression Rating Scale (MADRS) by an expert clinician before and during each entire treatment cycle of ketamine or esketamine intake. The data appeared to be significant in terms of benefit deriver from intravenous ketamine or intranasal S-ketamine therapy. In particular on the core symptoms of depression, such as sadness, apathy, inability to concentrate and fatigue, as shown by a reduction in the total score MADRS at last dose> 27% of baseline score. The most significant effects were achieved in the first 4 weeks of administration. The study limit is the small number of samples, which are still being implemented. To date, ketamine and S-ketamine are proven to be one of the few innovative drug therapies effective and safe for the treatment of TRD.

BACKGROUND: Volumetric changes in mood-relevant distributed limbic/paralimbic neurocircuitry have been reported in the recent literature on the course of Major Depression (MD). A decrease in hippocampal gray matter volumes is one of the possible mechanisms involved in pathogenesis of depression [Nifosì et al. 2010]. Converging evidences suggest that a reduced neurogenesis may occur in this area in recurrent depression and its positive modulation is fundamental for antidepressive action. Neurogenesis is stimulated both by plasticity-inducing stimuli (such as environmental enrichment, exercise, and electrical stimulation) and by antidepressant treatments. In functional imaging studies, Vagal Nerve Stimulation (VNS), a novel approach for treatment resistant depression (TRD), demonstrated that its antidepressive function may be correlated to changes in cerebral blood flow in limbic and prefontal cortex [Zobel et al 2005]. We are exploring if volumetric changes in specific brain areas involved in depression may be obtained with VNS. METHODS: Comparison of data on changes in brain volumes of specific regions of interest in 6 patients affected by TRD treated with VNS (VNS Therapy System™, Cyberonics, Houston, Texas –USA) and 5 TRD cases “treated as usual” (TAU) was performed. Brain MRI scans were detected before the implantation (t0) and after 12 months (t1). Psychopathology was assessed using patient self reports (BDI) and clinical evaluation (HDRS) every three months during the follow-up. RESULTS : Three out of six VNS treated patient showed a good clinical response (Reduction of depressive scores >50% from baseline) in three months of treatment. A significant increase of 22% and 14% of Left and Right hippocampal volumes was found after one year of Vagus Nerve Stimulation. No correlation were found between clinical outcomes measures and increase in volumes. Non responders showed no increase in hippocampal volumes. Preliminary findings from this case series seem to confirm the fundamental role of hippocampal remodelling as a marker for response in TRD.
PREMESSE: Modifiche nella volumetria delle strutture limbiche-paralimbiche coinvolte nella regolazione del tono dell’umore sono state descritte nella letteratura più recente sui Disturbi Depressivi Maggiori (DDM). Una diminuzione nei volumi della sostanza grigia ippocampale è uno dei possibili meccanismi coinvolti nella patogenesi della depressione [Nifosì et al. 2010]. Evidenze convergenti sembrano confermare che in corso di depressione una ridotta neurogenesi possa verificarsi in questa area e che una modulazione positiva di tale processo sia fondamentale per l’azione antidepressiva. La Neurogenesi è stimolata sia da stimoli che rafforzano la plasticità neuronale (come stimolazioni ambientali esterne, esercizio fisico, stimolazione elettrica) sia dai trattamenti antidepressivi. In studi di neuroimaging funzionale, la Stimolazione del Nervo Vago, (VNS) una metodica di recente introduzione per il trattamento della Depressione farmaco Resistente (TRD), è stata dimostrato che la sua azione antidepressiva può essere correlata con modifiche nel flusso ematico cerebrale nella corteccia limbica e prefrontale [Zobel et al 2005]. Obiettivo di questo studio è valutare se modifiche delle volumetrie in specifiche aree coinvolte nella depressione, possano essere ottenuta mediante la VNS. METODOLOGIA: E’ stato effettuato un confronto dei dati sulle modifiche di volume di specifiche regioni d’interesse in 6 pazienti con depressione farmaco resistente trattati mediante VNS (VNS Therapy System™, Cyberonics, Houston, Texas –USA) con i volumi delle stesse aree in 5 casi di TRD trattati in maniera convenzionale. Le Risonanze Magnetiche Nucleari (MRI) cerebrali sono state realizzate prima dell’impianto (t0 ) e dopo 12 mesi( t1). L’entità della depressione è stata valutata mediante scale autosomministrate (BDI ) o etero somministrate (HDRS) ogni tre mesi durante il del monitoraggio clinico. RISULTATI: Tre dei sei pazienti che hanno ricevuto la VNS hanno manifestato una buona risposta clinica (riduzione dei punteggi alle scale per la depressione > 50% dai punteggi iniziali) a tre mesi dall’inizio del trattamento. Un aumento significativo di circa il 22% e del 14% rispettivamente per ippocampo sinistro e destro è stato messo in luce dopo un anno di trattamento mediante VNS. Nessuna correlazione è stata trovata tra le principali variabili indicative dell’andamento clinico e l’aumento dei volumi cerbrali. I pazienti non responsivi alla VNS non hanno manifestato aumenti nei volumi ippocampali. I dati preliminari riscontrati in questo piccolo gruppo sembrano confermare il ruolo fondamentale del rimodellamento ippocampale come marker per la possibile risposta clinica nella TRD.

Depression är ett syndrom som drabbar mer än 300 miljoner människor i världen. Tillståndet förekommer i individuella variationer men vanliga symtom är nedstämdhet, energiförlust, störningar av sömn och aptit samt känslor av skuld och skam. En svår depression kan innebära lidande och stor funktionsförlust för den drabbade. Idag används både psykologisk och farmakologisk behandling, men det finns en problematik kring att det kan dröja veckor eller månader innan klinisk effekt ses av antidepressiva läkemedel. Därutöver blir en tredjedel av patienterna inte tillräckligt hjälpta av den behandling som finns att tillgå. Detta brukar kallas terapiresistent depression (TRD) och är för närvarande svårbehandat. Ketamin är ett narkotikaklassat läkemedel som används för induktion och underhåll av anestesi men som även förekommer som missbruksdrog. Fynd har visat att engångstillförsel av ketamin eventuellt kan ge en snabb antidepressiv effekt hos patienter med TRD. Ketamin är för närvarande inte godkänt för indikationen depression i Sverige. Syftet med denna litteraturstudie var att utvärdera om ketamin har effekt mot TRD. Fem randomiserade kontrollerade studier som hämtats ur databasen PubMed användes. I tre studier undersöktes intravenös tillförsel av ketamin varav en gav upprepade doser, en studie undersökte intravenöst esketamin i varierande doser och en studie undersökte effekten av intranasalt ketamin. Sammantaget visar resultatet att ketamin har effekt mot terapiresistent depression. Efter 24 timmar kunde statistiskt signifikanta skillnader avseende depressionens svårighetsgrad observeras hos de som fått ketamin jämfört med placebo (p <0,05). Ketamin gav 7–16 poängs större reduktion av depressiva symtom än placebo enligt använd skattningsskala, vilket motsvarade en genomsnittlig förändring från svår/medelsvår depression till mild depression. Resultatet visade även statistiskt signifikanta skillnader avseende behandlingsrespons (minst 50 % reduktion av symtompoäng på använd skattningsskala) efter 24 timmar (p <0,05). Andelen patienter med respons varierade mellan 44–71 % jämfört med 0–6 % för placebo och 28 % för aktiv placebo (midazolam). Även om resultatet från aktuella studier verkar lovande för ketamin som antidepressiv behandling krävs ytterligare studier på långtidseffekter och säkerhet vid upprepad tillförsel i en större studiepopulation.
Depression is a syndrome characterized by depressed mood, loss of interest and energy, feelings of guilt or worthlessness and thoughts of death and suicide. Over 300 million people suffer from depression and it is one of the leading causes of disability in the world. Today’s treatment for depression includes psychological treatment as well as pharmacological treatment. While there are many antidepressant drugs, it can take up to weeks or even months before a clinical effect in the severity of the depression can be noticed. In addition, one third of the patients do not achieve remission. These patients, after treatment with two antidepressant medications given at adequate doses for an adequate duration, are considered to have treatment-resistant depression (TRD). Ketamine is a drug long used for its anesthetic and analgesic effects, but it is also known as a party-drug that can cause out-of-body experience. However, it has also been found that a single-dose ketamine may give people with TRD a rapid antidepressant effect, within 24 hours. In contrast to current antidepressant medications which primarily acts on the monoaminergic system, ketamine instead acts on the glutamatergic system. The aim of this study was to evaluate if ketamine has an effect on people suffering from TRD. This study is a literature review where five randomized controlled trials on the effect of ketamine in patients with TRD have been analyzed. Four studies evaluated the effect of intravenous ketamine where one of them used a varied dose frequency and one of them used esketamine in various doses. The fifth study evaluated the effect of intranasal administration of ketamine. All studies were found in the database PubMed. The overall result shows that ketamine has an effect on TRD. After 24 hours all the studies showed a significant improvement in the severity of the depression with ketamine treatment compared to placebo (p <0.05). Ketamine treatment resulted in a 7-16 points larger reduction in depressive symptoms on the scales used compared to placebo. This represents on average a change from severe/moderately severe depression to mild depression. There was also a significant difference in response (at least 50 % reduction in points from baseline on the scale used) after 24 hours with ketamine treatment compared to placebo (p <0.05). The proportion of ketamine treated patients with response varied between 44-71 % compared to 0-6 % for placebo and 28 % for active placebo (midazolam). Even though ketamine seems to have an effect on patients with TRD there is still limited knowledge of how the antidepressant effect shall be maintained and the safety of long-term use. Further studies are needed to determine if ketamine will be an option in future antidepressant treatment against TRD.

Depression, Third Edition provides a succinct clinical guide for the recognition, diagnosis, management, and modalities of treatment of depressive disorders. This new edition includes the DSM-5 diagnostic criteria, updates the latest neurobiological and psychological findings, and summarizes the Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder. The initial chapters deal with the epidemiology, pathogenesis, clinical features, and diagnosis of depression. Basic principles of clinical management are provided, as well as individual chapters dealing with the spectrum of available treatments for depression, including pharmacological, psychological, somatic, and complementary medicine approaches. A final chapter focuses on treatment-resistant depression (TRD) and other special populations including peripartum, elderly and medically ill, and children and adolescents.

Compared with episodic depression, chronic depression and treatment resistant depression have higher rates of comorbidity, more persistent social and vocational disability, an increased risk of suicide, greater medical morbidity and mortality, and greater health care utilization and costs. A large number of antidepressant medications and other psychotropic drugs, depression-focused psychotherapies, and neuromodulation therapies are available for the treatment of depression. Many drugs or psychotherapies are used for the treatment of other psychiatric disorders or medical conditions, and they should be considered relevant when these comorbidities exist with depression. Selecting treatments for depression must take into account the clinical implications of the presence of any comorbidities. Because comorbidity is associated with depressive chronicity and treatment resistance, various approaches to treating chronic depression or TRD have been investigated. Treating depressed patients with comorbid psychiatric, personality, or medical disorders is a clinical challenge that requires effective multidisciplinary collaboration.

An increasing number of approaches permit psychiatrists to directly stimulate the brain. Such therapies are sometimes referred to as neuromodulation, as psychiatrists can either excite or inhibit neuronal firing in the brain. This chapter reviews two such technologies—transcranial magnetic stimulation (TMS) and deep brain stimulation (DBS). Both techniques have FDA approval and are moving into mainstream therapeutic use. Daily prefrontal TMS for 4–6 weeks is FDA approved for treating depression, with minimal side effects. It is now accepted in most treatment algorithms as an approach for patients who have not responded to medications or talking therapy. DBS has virtually replaced ablative neurosurgery for use in medication-refractory movement disorders such as Parkinson’s Disease (PD), where it has the advantages of being reversible (explantable) and adjustable. DBS is now being studied in severe psychiatric conditions, such as intractable obsessive-compulsive disorder (OCD) and treatment resistant depression (TRD).

The keys to optimal management of treatment-resistant depression (TRD) and depression in special populations include careful assessment, selection of evidence-based treatments tailored to the individual, and ongoing monitoring of response and outcome. For TRD, pharmacological strategies include switching antidepressants or adding an adjunctive agent. Adjunctive agents include second-generation (atypical) antipsychotics, other antidepressants, lithium, thyroid hormone, and psychostimulants. There is still a limited evidence base for pharmacotherapy and psychotherapy in special populations such as elderly patients, those with other medical illnesses, pregnant and breastfeeding women, and children and adolescents. For these patients, use and selection of antidepressants depends on an individual risk-benefit assessment.

Deep brain stimulation (DBS) of the subcallosal cingulate cortex (SCC) has potential as a therapeutic intervention for patients with severe treatment-resistant depression (TRD). This chapter reviews the evolution of the research support for SCC DBS. It begins with a key publication that posited a putative neural circuit hypothesis for depression and TRD; this line of research culminated in identification of the SCC as a key node involved in the antidepressant response to somatic interventions. The clinical testing of SCC DBS is then reviewed, from the first proof-of-concept study up to a large, multi-site, randomized clinical trial. The next steps in SCC DBS research are then highlighted via a focus on two papers that describe the development and early testing of a circuit-based, imaging-guided approach to SCC DBS for TRD.

Magnetic seizure therapy (MST) is currently on trial as an alternative to Electro-convulsive therapy (ECT) to treat patients suffering from treatment resistant depression (TRD). This paper is concerned with developing a deeper understanding of the mechanics behind MST by employing finite element analysis (FEA) of brain. To this end, a model that consists of concentric spherical layers that represent a realistic anatomical head model has been employed. Simulations performed via COMSOL Multi-physics helped identify the dimensions and coil types for the MST device as well as the angular probing orientations. Largest induced current due to the externally imposed magnetic field was found in the cerebrospinal fluid (CSF), which act as a barrier to induce current in the gray matter. Different copper coil configurations were experimented with namely the cap coil, stacked coil and the multi-stacked coil. These studies are envisaged to provide a quantitative approach to virtually simulate the MST procedure and hence enhance the benefits clinical trials that are currently underway.