Treatment-Resistant Depression: The Role of Electroconvulsive Therapy

Electroconvulsive therapy (ECT) is a well-established treatment for severe psychiatric disorders, and its role in modern-day psychiatry continues to expand with rising rates of complex mental illnesses. ECT has proven to be an effective treatment for conditions such as treatment-resistant depression, catatonia, bipolar disorder, schizophrenia, and other serious mental health disorders. Individuals who are resistant to or have contraindications against conventional pharmacologic therapies can particularly benefit from ECT. The procedure involves inducing a brief and controlled generalized seizure by passing an electrical stimulus through a patient's cerebral cortex. The safety of ECT was historically an area of concern due to injuries from the involuntary convulsions during the induced seizure. The use of general anesthesia and adjunct muscle-relaxing agents has made ECT considerably safer in the modern day. The goal of anesthesia in ECT is to induce a quick sedation with adequate depth, to prevent pain and injury from convulsions, and to provide a targeted amnesia. However, many anesthetic agents also function as anticonvulsants and consequently can affect the seizure threshold. The benefits of ECT are inextricably linked to the quality and duration of the induced seizure, therefore, careful consideration must be given to the choice of anesthetic. Alongside its effects on seizure threshold, anesthesia can also affect hemodynamic stability, cardiovascular response, and even the recovery course following ECT. Furthermore, special populations such as elderly patients, pregnant individuals, or those with significant comorbidities require an individual-based approach to anesthetic management. Ultimately, the choice of anesthetic plays an integral role in the therapeutic benefit of ECT. Therefore, strategic management of the anesthetic component of the procedure is critical in improving patient outcomes. This narrative review intends to analyze the dynamic role of anesthesia in ECT by synthesizing current clinical evidence on physiologic changes, pharmacodynamics, procedure optimization, and management of comorbidities and complications.

Electroconvulsive therapy (ECT) is a technique that has been used since 1938 to treat several psychiatric disorders as a replacement for chemically induced seizures. Despite its history of stigma, controversy and low accessibility, ECT is found to be beneficial and efficient in severe cases of depression where medication fails to bring results. Titration tables developed over time, based on evidenced-based medicine, have made this treatment technique safe and, in some cases, the first choice of treatment. The aim of the review was to summarize the research conducted on the efficacy of ECT on major depressive disorder and variables studied such as technique, comorbidities and medication as well as the effects and outcomes of this procedure. At the same time, the application and correlations with other psychiatric and neurological disorders, including catatonia, agitation and aggression in individuals with dementia, schizophrenia, and epilepsy were assessed. There are no statistically demonstrated effects due to the fact that a small number of moderate-quality studies have been published; however, the combination of ECT technique with standard medication and care, can improve patient outcome. Furthermore, with regard to ECT, widespread and robust volume changes in both cortical and subcortical regions have been shown. Antidepressant response and volumetric increases appear to be limited by the specific neuroplasticity threshold of each patient.

We review recent advances in the treatment of treatment-resistant depression (TRD), a disorder with very limited treatment options until recently. We examine advances in psychotherapeutic, psychopharmacologic, and interventional psychiatry approaches to treatment of TRD. We also highlight various definitions of TRD in recent scientific literature. Recent evidence suggests some forms of psychotherapy can be effective as adjunctive treatments for TRD, but not as monotherapies alone. Little recent evidence supports the use of adjunctive non-antidepressant pharmacotherapies such as buprenorphine and antipsychotics for the treatment of TRD; side effects and increased medication discontinuation rates may outweigh the benefits of these adjunctive pharmacotherapies. Finally, a wealth of recent evidence supports the use of interventional approaches such as electroconvulsive therapy, ketamine/esketamine, and transcranial magnetic stimulation for TRD. Recent advances in our understanding of how to treat TRD have largely expanded our knowledge of best practices in, and efficacy of, interventional psychiatric approaches. Recent research has used a variety of TRD definitions for study inclusion criteria; research on TRD should adhere to inclusion criteria based on internationally defined guidelines for more meaningfully generalizable results.

Long-Term Vagus Nerve Stimulation for Severe Refractory Depression: A Case Study With a Six-Year Follow-Up

IntroductionThe Mood Disorder ward, in San Raffaele Turro Hospital, is one of the reference centers for the cure of Treatment-Resistant Depression (TRD), mainly due to the use of Electroconvulsive Therapy (ECT). During the pandemic period, in particular, in 2020, such a procedure was discontinued because it is considered aerosolizing. For this reason, we enhanced already available treatments for TRD; among those one of the most effective is the use of endovenous (EV) ketamine. It’s been more than 20 years since the first time a double-blind randomized placebo-controlled study demonstrated the rapid antidepressant effects of endovenous (EV) ketamine after a single dose (0.5 mg/kg infused in 40 minutes) in 7 patients. Ketamine, an anesthetic drug, has also analgesic, anti-inflammatory, and antidepressant properties. These effects are mainly due to non-competitive antagonism on the NMDA receptor (N-methyl-D-aspartate). We introduce our clinical experience in 7 cases of treatment-resistant depressed (TRD) inpatients; all of them show a high level of pharmacoresistance, assessed in the third degree of Thase Stages (2 or more SSRI/SNRI + at least 1 TCA); 3 of them were previously treated with a complete cycle of Electroconvulsive Therapy (ECT).ObjectivesAssess the efficacy and tolerability of EV ketamine with particular regard to patients previously treated with ECT.Methods7 TRD patients (4 females; 3 males) were recruited in San Raffaele Turro Hospital in April 2020. All patients (6 unipolar and 1 bipolar) were diagnosed with a Major Depressive Episode according to DSM-5 criteria. We administered, under anesthesiological supervision, EV ketamine, 0.5 mg/kg in 40 minutes, twice a week, for three weeks. Every morning medication was postponed on the days of infusion. Clinical scales (HAM-D, SSI, HAMD-A; MADRS, CADSS) were administered to assess symptoms and side effects before, during, and after every administration. Moreover, clinical efficacy’s been assessed in 2 follow-ups: at 3 and 6 months.Results4 patients were in remission (final HAM-D score <8) at the end of the treatment. 4 patients confirmed clinical response (final HAM-D score < 50 % respect baseline value) at the first follow-up. 4 Out of 7 patients were in complete remission at 6 months, and just one of them was between those remitted at the end of the treatment. 4 Out of 4 patients were in complete remission at six months follow-up; 3 of them underwent a cycle of ECT during the course of their illness.ConclusionsThe use of EV ketamine in our TRD patients showed good effectiveness and tolerability. Data on long-term effectiveness are promising, a previous ECT seems to be a predicting factor of remission at follow-up, but not of the end-treatment response. Given that, future research is needed in order to identify predicting factors on relapse prevention efficacy.Disclosure of InterestNone Declared

BackgroundImmune-related mechanisms are increasingly recognised as important in the pathophysiology of depression, particularly treatment-resistant depression (TRD). Preliminary evidence suggests that people with TRD may benefit from anti-inflammatory interventions; however, the relative anti-inflammatory effects of therapies currently recommended for TRD have not been integrated in a specific evidence synthesis. MethodsA systematic search was performed to identify articles published up to February 8, 2021. Results from databases (Pubmed, Embase) and handsearches were reviewed to include any longitudinal study examining circulating marker(s) of inflammation in humans before and after treatment with electroconvulsive therapy (ECT), ketamine, bupropion, lithium, aripiprazole, or quetiapine. We undertook a narrative synthesis of results and risk of bias assessment to incorporate and interpret the evidence. ResultsOf 57 included studies, 34 assessed the effects of ketamine and 12 of ECT, with other medications examined in ≤5 studies each. Results were highly heterogeneous. Numerically, more frequent increases than decreases in pro-inflammatory markers were reported after ketamine, quetiapine and lithium (although more frequent significant decreases were observed for lithium). Findings for ECT and bupropion were even more inconsistent. Two studies consistently reported inflammatory reductions (significant/non-significant) after aripiprazole. ConclusionsTreatment effects on inflammatory proteins are confounded by several factors: ketamine, in most studies, was co-administered with other surgical procedures, while ketamine and ECT findings are also obscured by variable post-procedure assessment timing. The evidence base for other treatments is scant. Greater examination is warranted to establish whether inflammatory biomarkers could be used to stratify TRD patients to a ‘most appropriate’ intervention.

The efficacy of electroconvulsive therapy in treating depressive symptoms has been established by means of innumerable studies developed along the last decades. Electroconvulsive therapy is the most effective biological treatment for depression currently available. The objective of this study was to demonstrate the role of electroconvulsive therapy in the treatment of depression and highlight present aspects related to its practice. We reviewed in the literature studies on efficacy, symptom remission, predictive response factors as well as current aspects regarding quality of life, the patients' perception, mechanism of action, technique and cognitive impairment. The main results found in the this revision were: 1) electroconvulsive therapy is more effective than any antidepressant medication; 2) the remission of depression with electroconvulsive therapy varies, in general, from 50 to 80%; 3) The effect of electroconvulsive therapy in brain-derived neurotrophic factor levels is still controversial; 4) electroconvulsive therapy has a positive effect in the improvement of quality of life; 5) patients submitted to electroconvulsive therapy have, in general, a positive perception about the treatment. Electroconvulsive therapy remains a highly efficacious treatment in treatment-resistant depression. With the improvement of its technique, electroconvulsive therapy has become an even safer and more useful procedure both for the acute phase and for the prevention of new depressive episodes.

Objective: The treatment of psychiatric disorders in pregnancy poses a challenge. Pharmacological treatment of psychiatric disorders in pregnant women is complicated. Electroconvulsive therapy (ECT) has been demonstrated to be effective and safe in the treatment of various psychiatric disorders. In this study, we investigated the safety and the probable complications of either concurrent with or following to ECT treatment among pregnant patients. Method: The 25 pregnancy cases, where ECT was applied between 2006 and 2012, have been reviewed. These patients have been interviewed and their clinical histories have been documented. Both maternal and fetal complications have been followed up. Results: Two patients have been treated with ECT twice during their pregnancies. For this reason, they are treated as two separate cases. The distribution of the cases is as follows: 8 (32%) psychosis, 11 (44%) bipolar disorder, and 6 (24%) depression. Out of these cases, the prognosis distribution is as follows: 10 (40%) full recovery, 11 (44%) partial recovery, and 4 (16%) discharged from hospital prior to the completion of the treatment at the request of their relatives. Two had complications that were early membrane rupture and stillbirth. Conclusion: In our study, no findings were observed regarding unsafe use of ECT during pregnancy.

A 24-year-old man experiencing comorbid body dysmorphic disorder since age 16 years, complicated in recent months by a major depressive episode with psychotic features, showed resistance to various drug and psychotherapy combinations. We suggested electroconvulsive therapy (ECT) to overcome treatment resistance. After 1 ECT cycle, mood and anxiety symptoms improved significantly, delusional interpretations and ideas of reference subsided, and dysmorphophobic symptoms improved as well. Six months later, the patient was doing well with a mood stabilizer/antipsychotic combination. Electroconvulsive therapy may improve symptoms of comorbid body dysmorphic disorder along with mood improvement in treatment-resistant depressive disorder.

Cost-effectiveness modeling of repetitive transcranial magnetic stimulation compared to electroconvulsive therapy for treatment-resistant depression in Singapore

Despite the availability of many newer antidepressant medications, a significant percentage of patients are partial responders or have treatment-resistant depression (TRD). In such cases, there are very few data to indicate what step (combination, augmentation, or switching) should be taken next. The first step in optimizing treatment is to provide an antidepressant trial of adequate duration at a dosage that ensures therapeutic plasma levels. Some patients, including previous nonresponders, may benefit from higher doses. Although a medication trial of 4–8 weeks is often adequate to see some treatment response, patients with TRD may require a longer trial (e.g., 12–16 weeks) to achieve a full response. A framework of time-driven prompts called “critical decision points” can be helpful in determining the appropriate “next step” in treatment of TRD. At each decision point, the clinician assesses a patient's overall improvement and side effect burden and may choose to continue the prescribed dose, increase or decrease the dose, augment treatment with another agent, switch or combine medications. Switching medications is advantageous when there is a need to keep treatment simple or patient compliance is an issue. When a patient partially responds to a given treatment, the clinician should consider augmentation before switching. Potential advantages of augmentation include attaining full response without starting a new medication trial, using lower doses of both agents to minimize side effects, treatment of comorbid disorders such as subclinical hypothyroidism, and quicker treatment response. Combination therapy allows the clinician to treat depression with antidepressant medications that have differing mechanisms of action, thus affecting different neurotransmitter systems. The chapter provides a thorough description of medication use in each of these treatment strategies, including appropriate dosing, switching guidelines, augmentation strategies, and possible drug interactions. Clinical evidence in the literature (or the lack thereof) that support these therapies are reviewed. Alternative treatments to medication are discussed, including psychotherapy (e.g., cognitive behavioral therapy), electroconvulsive therapy (ECT), vagus nerve stimulation, and repetitive transcranial magnetic stimulation (rTMS).

BackgroundAgitation poses a significant challenge in the treatment of schizophrenia. Electroconvulsive therapy (ECT) is a fast, effective and safe treatment for a variety of psychiatric disorders, but no meta-analysis of ECT treatment for agitation in schizophrenia has yet been reported.AimsTo systematically evaluate the efficacy and safety of ECT alone or ECT-antipsychotics (APs) combination for agitation in schizophrenia.MethodsSystematic literature search of randomized controlled trials (RCTs) was performed. Two independent evaluators selected studies, extracted data about outcomes and safety with available data, conducted quality assessment and data synthesis. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) was used to judge the level of the overall evidence of main outcomes.ResultsSeven RCTs from China, including ECT alone (4 RCTs with 5 treatment arms, n=240) and ECT-APs combination (3 RCTs, n=240), were identified. Participants in the studies were on average 34.3(4.5) years of age and lasted an average of 4.3(3.1) weeks of treatment duration. All 7 RCTs were non-blinded, and were rated as low quality based on Jadad scale. Meta-analysis of the pooled sample found no significant difference in the improvement of the agitation sub-score of the Positive and Negative Syndrome Scale (PANSS) when ECT alone (weighted mean difference=-0.90, (95% confidence interval (CI): -2.91, 1.11), p=0.38) or ECT-APs combination (WMD=-1.34, (95%CI: -4.07, 1.39), p=0.33) compared with APs monotherapy. However, ECT alone was superior to APs monotherapy regarding PANSS total score (WMD=-7.13, I2=0%, p=0.004) and its excitement sub-score (WMD=-1.97, p<0.0001) as well as the PANSS total score at 14 days (WMD=-7.13, I2=0%, p=0.004) and its excitement sub-score at 7 and 14 days (WMD=-1.97 to -1.92, p=0.002 to 0.0001) after ECT. The ECT-APs combination was superior to APs monotherapy with respect to the PANSS total score at treatment endpoint (WMD=-10.40, p=0.03) and 7 days (WMD=-5.01, p=0.02). Headache (number-needed-to-harm (NNH)=3, 95%CI=2-4) was more frequent in the ECT alone group compared to AP monotherapy. According to the GRADE approach, the evidence levels of main outcomes were rated as ‘‘very low’’ (37.5%) and “low” (50%).ConclusionPooling of the data based on 7 RCTs from China found no advantage of ECT alone or ECT-APs combination in the treatment of agitation related outcomes in schizophrenia patients. However, ECT alone or ECT-APs combination were associated with significant reduction in the PANSS total score. High-quality RCTs are needed to confirm the current interpretations.

Introduction A new era of treatment for adults with treatment-resistant depression (TRD), which involves psychedelic substances, is dawning. Emerging evidence indicates that psychedelics can exert antidepressant effects through multiple neurobiological and psychological mechanisms. However, it remains to be seen if these new treatments will revolutionize the treatment of TRD. Areas covered The present review focuses on the efficacy of serotoninergic psychedelics psilocybin, lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), ayahuasca, 5‐methoxy‐N,N‐dimethyltryptamine (5-MeO-DMT) and mescaline (3,4,5-trimethoxyphenethylamine), as well as 3,4-methylenedioxymethamphetamine (MDMA), for TRD. A systematic search was conducted for psilocybin in TRD as emerging trials had not yet been subject to review. A narrative review summarized findings on other psychedelics. Expert opinion Psychedelic therapy has created a paradigm shift in the treatment of TRD, as it can maximize therapeutic benefits and minimize potential risks. Psilocybin holds promise as a potential game-changer in the treatment of TRD, with initial evidence suggesting a rapid antidepressant effect sustained for some responders for at least 3 months. Nevertheless, further adequately powered, double-blind, comparator-controlled trials are required to explore and clarify the mechanisms of action and long-term effects of psychedelics in TRD. Psychedelics also hold promise for other psychiatric conditions, such as bipolar depression and post-traumatic stress disorder.

Thioredoxin is not a marker for treatment-resistance depression but associated with cognitive function: An rTMS study

IntroductionEsketamine (ESK) nasal spray and interventional therapies including electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) are indicated for patients with treatment resistant depression (TRD). Little is known about healthcare resource use and associated costs of Medicaid beneficiaries, a population with a high burden of mental health disorders, initiating ESK, ECT or TMS. This study aimed to bridge this gap in knowledge.MethodsMedicaid-insured adults with evidence of TRD (≥2 unique antidepressants of adequate dose and duration) were selected from Merative™ MarketScan® Multi-State Medicaid Database (01/2016-06/2022). Based on therapy initiated on or after 03/05/2019 (ESK approval date for TRD), patients were classified into three cohorts: ESK, ECT, and TMS. Before treatment initiation (index date), patients had ≥12 months of continuous insurance eligibility (baseline period). Mental health (MH)-related resource use and payer costs (USD 2022) were reported per-patient-per-month (PPPM) during the follow-up period, which spanned the index date until the earliest continuous insurance eligibility or data end.ResultsESK cohort included 151 patients (mean age: 40.6 years; female: 70.2%), ECT cohort included 198 patients (mean age: 43.0 years; female: 60.6%), and TMS cohort included 140 patients (mean age: 39.5 years; female: 65.0%).During the follow-up period, the mean number of MH-related inpatient (IP) days trended lower in ESK cohort (0.09) relative to the ECT (3.72) and TMS (0.31) cohorts. Similarly, the mean number of MH-related emergency department (ED) visits trended lower in ESK cohort (0.07) relative to ECT (0.12) and TMS (0.26) cohorts. The mean number of MH-related outpatient (OP) visits in ESK cohort (4.83) trended higher than in ECT cohort (4.37) but lower than in TMS cohort (6.41). Mean MH-related acute care costs during the follow-up period trended lower in ESK cohort (IP: $76; ED: $29) relative to ECT (IP: $1,547; ED: $45) and TMS cohorts (IP: $238; ED: $123). Outpatient costs in ESK cohort ($1,632) exceeded OP costs in ECT ($1,023) and TMS ($1,051) cohorts.ConclusionIn this descriptive analysis, a trend towards lower use and costs of acute MH-related care was observed after the initiation of ESK relative to the initiation of ECT and TMS. This finding should be interpreted with caution, given potential differences in patient profiles, clinical history and setting of administration.FundingJanssen Scientific Affairs, LLC. Analysis Group is a consulting company that has provided paid consulting services to Janssen Scientific Affairs, LLC, which funded the development and conduct of this study.