[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.

rTMS as a Next Step in Antidepressant Nonresponders: A Randomized Comparison With Current Antidepressant Treatment Approaches.

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

Cognitive changes in patients with unipolar TRD treated with IV ketamine: A systematic review.

BACKGROUND: Unipolar treatment-resistant depression (MDD-TRD) is associated with neurocognitive impairment. Ketamine, an emerging treatment for MDD-TRD, may have neurocognitive benefits, but evidence remains limited. METHODS: We conducted a systematic search on EMBASE, Google Scholar, PsycINFO, and PubMed and included studies exploring the cognitive effects of intravenous (IV) ketamine treatment in the management of MDD-TRD following the PRISMA guidelines. We analyzed cognitive scale score changes pre- and post-IV ketamine treatment and the quality of the evidence using the Cochrane risk of bias tool and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). RESULTS: Out of 1171 identified studies, fourteen studies were included in this study. Most studies reported positive cognitive outcomes post-ketamine treatment, including improvements in processing speed, working memory, verbal and visual memory, executive function, attention, emotional processing, and auditory verbal episodic memory. Variability existed, with one study reporting negative effects on verbal memory. Overall, studies exhibited a low risk of bias. LIMITATIONS: Several limitations impacted the results observed, including confining our scope to articles in English, heterogeneity of the included studies, small sample sizes, and the predominance of a female, Western, and Caucasian population, constraining the generalizability of the findings. CONCLUSIONS: IV ketamine treatment shows promise in improving neurocognitive function in MDD-TRD patients. However, further research is warranted to elucidate long-term effects, control for confounders such as concomitant medications, and explore neurocognitive subgroups within the TRD population. These findings underscore the need for comprehensive assessment and management of cognitive symptoms in TRD, informing future clinical practice.

Depression: Managing Resistance and Partial Response to Treatment.

Treatment-resistant depression is defined as absence of remission despite trials of two or more antidepressant medications and can occur in up to 31% of patients with major depressive disorder. Partial response to treatment is defined as less than 50% reduction in depression-rating scores. Before diagnosing treatment-resistant depression or partial response to treatment, adherence to adequate doses and duration of medications should be confirmed. Management strategies include adding psychotherapy, switching antidepressant medication class, or augmenting with additional medications. Current guidelines recommend augmentation with a second-generation antidepressant, an atypical antipsychotic, tricyclic antidepressants, lithium, or a triiodothyronine medication as pharmacologic options. Ketamine and esketamine can also be used as augmentation for treatment-resistant depression and may help reduce suicidal ideation. Electroconvulsive therapy and repetitive transcranial magnetic stimulation may be effective. Pharmacogenetic testing has limited evidence and is not recommended. Nonpharmacologic therapies include psychotherapy, exercise, and focused dietary changes.

[Clinical management of treatment-resistant depression]. / Klinisches Management der therapieresistenten Depression.

Treatment-resistant depression (TRD) is a complex disorder. Although no standardized definition has been established to date, there are promising and well-established treatment options for the condition. Looking at the current pharmacological and neuromodulatory strategies, there is an urgent need for fast-acting and well-tolerated treatment options. The search for new mechanisms of action goes beyond the monoamine hypothesis. For example, esketamine is already an established treatment method that is fast-acting and well tolerated, while psychedelics or esmethadone are currently still undergoing clinical trials. Compounds that can be used off-label, such as dextromethorphan or anti-inflammatory strategies are also presented. Pharmacological approaches that focus on the modulation of the glutamatergic system or belong to the class of psychedelics, appear to be of particular importance for current research and development. These particularly include substances that rapidly exert clinical effects and have a favorable side-effect profile.

IV low dose ketamine infusions for treatment resistant depression: Results from a five-year study at a free public clinic in an academic hospital.

Individuals with major depressive disorder and treatment resistant depression (MDD-TRD) have limited and sometimes poorly tolerated therapeutic options. Low dose ketamine has presented promising and potent antidepressant effects in this population. To support the existent literature, we conducted a longitudinal study examining five years of real-world clinical data on the use of IV low-dose ketamine alongside standard care for MDD-TRD outpatients. For this study we collected demographic information, clinical scale scores, side effects and dropout data. The data was analyzed using descriptive statistics, effect size using Cohen's D analysis, and multivariate ANOVA (MANOVA) to determine the impact of sociodemographic variables. 71 outpatients (50.28 years old, SD: 14.26; female 74.65%) were included in the analysis. The results showed a significant reduction in depressive symptoms and suicide ideation (SI) by treatment endpoint. 54.93% of patients responded to the treatment, 78.26% experienced transient and mild side effects, and 11.27% of dropped out of the treatment. Multivariate analysis showed that the demographic variables did not impact treatment effect or tolerability. The results of this study suggest that IV low dose ketamine treatment is effective, fast-acting, and well tolerated for the management of depressive symptoms and SI in patients with MDD-TRD in naturalistic clinical practice.

Predicting non-response to ketamine for depression: An exploratory symptom-level analysis of real-world data among military veterans.

Ketamine helps some patients with treatment resistant depression (TRD), but reliable methods for predicting which patients will, or will not, respond to treatment are lacking. Herein, we aim to inform prediction models of non-response to ketamine/esketamine in adults with TRD. This is a retrospective analysis of PHQ-9 item response data from 120 patients with TRD who received repeated doses of intravenous racemic ketamine or intranasal eskatamine in a real-world clinic. Regression models were fit to patients' symptom trajectories, showing that all symptoms improved on average, but depressed mood improved relatively faster than low energy. Principal component analysis revealed a first principal component (PC) representing overall treatment response, and a second PC that reflects variance across affective versus somatic symptom subdomains. We then trained logistic regression classifiers to predict overall response (improvement on PC1) better than chance using patients' baseline symptoms alone. Finally, by parametrically adjusting the classifier decision thresholds, we identified optimal models for predicting non-response with a negative predictive value of over 96 %, while retaining a specificity of 22 %. Thus, we could identify 22 % of patients who would not respond based purely on their baseline symptoms. This approach could inform rational treatment recommendations to avoid additional treatment failures.

How different definition criteria may predict clinical outcome in treatment resistant depression: Results from a prospective real-world study.

Management of treatment-resistant depression (TRD) remains a major public health challenge, also due to the lack of a consensus around TRD definition. We investigated the impact of different definitions of TRD on identifying patients with distinct features in terms of baseline characteristics, treatment strategies, and clinical outcome. We conducted a prospective naturalistic study on 538 depressed inpatients. Patients were screened for treatment resistance by two TRD definitions: looser criteria (lTRD) and stricter criteria (sTRD). We compared baseline characteristics, treatment and clinical outcome between the TRD groups and their non-TRD counterparts. 52.97 % of patients were identified as lTRD, only 28.81 % met the criteria for sTRD. sTRD patients showed lower rates of remission and slower symptom reduction compared to non-TRD patients and received more challenging treatments. Surprisingly, patients identified as sTRD also exhibited lower rates of psychiatric comorbidities, including personality disorders, substance abuse, or alcohol misuse. Stricter TRD criteria identify patients with worse clinical outcomes. Looser criteria may lead to overdiagnosis and over treatment. Clinical features known to be possible risk factors for TRD, as psychiatric comorbidities, showed to be more suggestive of a "difficult to manage" depression rather than a proper TRD.

Treatment-Resistant Depression in Real-World Clinical Practice: A Systematic Literature Review of Data from 2012 to 2022.

OBJECTIVE: Real-world evidence in treatment-resistant depression (TRD; commonly defined as non-response to ≥ 2 consecutive treatments at adequate dosage and duration) is lacking. A systematic literature review was conducted to understand disease burden and treatment outcomes for patients with TRD, studied in a real-world setting over the last decade. DATA SOURCES: A literature search was conducted in May 2022 in MEDLINE, Embase, The Cochrane Libraries and PsycINFO, comprising studies published from 2012 to 2022. Bibliographies of all relevant identified systematic reviews and relevant conference proceedings from 2020 to 2022 were manually hand-searched. STUDY SELECTION: Real-world studies, including cohort, cross-sectional, case-control, chart review and registry studies, published in English and reporting outcomes in adults with TRD, were included. DATA EXTRACTION: Extracted data included study and baseline disease characteristics, treatment type, treatment response, clinical outcomes and health-related quality of life. RESULTS: Twenty studies were included. Criteria for TRD varied, but patients typically experienced long-lasting depression (range 1.4 to 16.5 years). Across studies, mean disease severity scores demonstrated moderate to severe depression, reflecting a high burden of disease at baseline. Remission rates were typically low but generally increased with longer follow-up durations. However, the heterogeneity of interventions, follow-up durations (range 2 weeks to 9.4 years) and assessment tools precluded their quantitative synthesis. Studies were frequently limited by low sample size (range 14 to 411 patients) and health-related quality of life was infrequently assessed. CONCLUSIONS: There is a lack of clinical consensus regarding the definition, assessment and monitoring of TRD in real-world practice. Nevertheless, TRD carries a high burden of illness and there is an unmet need for faster and more effective treatments. To better understand the personal burden of affected patients, future studies would benefit from standardisation of severity assessment and measures of treatment effectiveness, as well as greater consideration of health-related quality of life.

Many people continue to experience depression even after trying two or more medications. This is called treatment-resistant depression (TRD). Most of the information we have on TRD comes from clinical trials, which take place under tightly-controlled conditions. It is important to understand the effects of TRD and TRD treatments on people in their day-to-day lives. Researchers studying people's day-to-day lives call this researching in a "real-world setting". We searched for studies carried out in real-world settings in the last 10 years. We found 20 relevant studies. As these studies were in real-world settings, there were many differences between them, including differences in how TRD was diagnosed, the treatments used, how long people were monitored and how results were measured. This made it difficult to compare how successful different treatments were. Most studies included a small number of people and monitored them for a relatively short time. We found people with TRD had usually lived with it for many years and their symptoms were moderate or severe. Only two studies asked people how TRD affected their lives. These two studies found health-related quality of life and work productivity was low. Most studies found lots of people still had symptoms of depression after treatment. However, symptoms typically improved more when studies monitored people for a longer time. To improve our knowledge of TRD, future studies should monitor more people for longer and use the same ways of measuring results. They should also ask how TRD affects people's daily lives.

Differential effectiveness between Ketamine and Esketamine: the predictive role of dissociative features. A treatment-resistant depression case.

More than 10 years ago, the discovery of the antidepressant effects of Ketamine opened the opportunity to develop a novel class of antidepressants. Ketamine induces dissociative symptoms as a major side effect. This rapid-acting antidepressant is available as an endovenous racemic compound and as an intranasal S-enantiomer: Esketamine; which is four-fold more potent for the NMDA receptor. Here we present the critical case of a patient who took both molecules experiencing remission just with endovenous Ketamine, whose impact in terms of dissociative symptoms was greater. In this short report, we discuss the differences between the two drugs and the possibility of dissociative features to predict their efficacy.

Clinical outcomes in the biomarkers of ketamine (Bio-K) study of open-label IV ketamine for refractory depression.

OBJECTIVE: We conducted an open-label clinical trial ("Bio-K") using IV ketamine for treatment-resistant depression to identify biomarkers linked to remission. Here, we report the clinical efficacy and side effect outcomes of Bio-K. METHODS: Across 4 US sites, 75 patients ages 18-65 with treatment-refractory unipolar or bipolar depression received 3 IV ketamine infusions over an 11-day period. Key exclusion criteria were psychotic symptoms, significant substance abuse, unstable medical conditions, and any use of cannabis. Pre-existing antidepressant medication was maintained. Primary outcome was remission as measured by Montgomery-Asberg Depression Rating Scale (MADRS), with secondary outcome of 50 % reduction in Beck Suicide Scale score. Safety monitoring and varying durations of infusions were also key parameters. RESULTS: Using remission as MADRS score <10, after 3 infusions 52 % achieved remission, with 67 % achieving response. Of those achieving response after a single infusion, 66 % (22 of 33) reached remission after 3 infusions, while 40 % (16 of 40) non-responders after the first infusion went on to achieve remission after 3 infusions. Only 20 % of non-responders after 2 infusions achieved remission. Most (81 %) participants had significant suicidal ideation at baseline; of these, two-thirds (67 %) experienced at least a 50 % reduction in suicidality. Side effects were minimal. Uniquely, we had three different types of infusion categories, with individuals receiving: (1) slow (100-min) infusions only or (2) regular (40-min) infusions only or (3) a mix of infusion durations. These three infusion groups showed comparable safety and efficacy. Exploration of clinical factors revealed no link between BMI, age, or gender to remission. CONCLUSIONS: The consistency of outcomes across 4 clinical sites and across multiple instruments, suggests high acute efficacy and safety of IV ketamine for serious depressive episodes. Duration of infusion did not alter outcomes. Meaningfully, 40 % of non-responders after a single infusion did reach remission subsequently, while only 20 % of non-responders after 2 infusions achieved remission, suggesting early response is suggestive for eventual remission. Our data on varying ketamine infusion duration adds novel insights into the clinical administration of this new treatment for refractory and severe patients. Our limitations included a lack of a control group, necessitating caution about conclusions of efficacy, balanced by the utility of reporting "real-world" outcomes across multiple clinical sites. We could also not separately analyze results for bipolar disorder due to small numbers. Together, the Bio-K clinical results are promising and provide significant sample sizes for forthcoming biological markers analyses.

Predictors and Risk Factors of Treatment-Resistant Depression: A Systematic Review.

Objective: To systematically review the literature to identify and categorize the predictors and risk factors for treatment-resistant depression (TRD).Data Sources: Online databases (PubMed, MEDLINE, Embase, and APA PsycNet) and relevant conference sources were searched from inception up to January 24, 2022. The following keywords were used: treatment-resistant depression, depressive disorder, predictors, risk, and biomarkers.Study Selection: All studies that included a definition of TRD were included. A total of 1,686 abstracts were screened, and 57 studies were included in the final data synthesis.Data Extraction: Data were extracted using a data extraction form developed for this study.Results: The most frequently reported mental predictors/risk factors were greater symptom severity (9 studies), suicidality (8 studies), and recurrent depression (6 studies). Cardiovascular disease (4 studies), pain (3 studies), and thyroid dysfunction (3 studies) were the most common physical predictors/risk factors, while younger age (7 studies) and female gender (6 studies) were the most common demographic predictors/risk factors. Higher levels of neuroticism appeared twice in the literature. Several articles reported on genetic, biological, and imaging variables, but results were too heterogenous to identify common predictors/risk factors.Conclusions: TRD is a complex disorder with many contributing factors that need to be identified and addressed earlier in the disease course to prevent its development or facilitate better treatment outcomes. Future work should focus on replicating the key predictors/risk factors identified in this review.

Predicting outcome with Intranasal Esketamine treatment: A machine-learning, three-month study in Treatment-Resistant Depression (ESK-LEARNING).

Treatment-resistant depression (TRD) represents a severe clinical condition with high social and economic costs. Esketamine Nasal Spray (ESK-NS) has recently been approved for TRD by EMA and FDA, but data about predictors of response are still lacking. Thus, a tool that can predict the individual patients' probability of response to ESK-NS is needed. This study investigates sociodemographic and clinical features predicting responses to ESK-NS in TRD patients using machine learning techniques. In a retrospective, multicentric, real-world study involving 149 TRD subjects, psychometric data (Montgomery-Asberg-Depression-Rating-Scale/MADRS, Brief-Psychiatric-Rating-Scale/BPRS, Hamilton-Anxiety-Rating-Scale/HAM-A, Hamilton-Depression-Rating-Scale/HAMD-17) were collected at baseline and at one month/T1 and three months/T2 post-treatment initiation. We trained three different random forest classifiers, able to predict responses to ESK-NS with accuracies of 68.53% at T1 and 66.26% at T2 and remission at T2 with 68.60% of accuracy. Features like severe anhedonia, anxious distress, mixed symptoms as well as bipolarity were found to positively predict response and remission. At the same time, benzodiazepine usage and depression severity were linked to delayed responses. Despite some limitations (i.e., retrospective study, lack of biomarkers, lack of a correct interrater-reliability across the different centers), these findings suggest the potential of machine learning in personalized intervention for TRD.

Overview of treatment-resistant depression.

Patients with major depressive disorder (MDD) often exhibit an inadequate treatment response or failure to achieve remission following treatment with antidepressant drugs. Treatment-resistant depression (TRD) is proposed to identify this clinical scenario. Compared to those without TRD, patients with TRD have significantly lower health-related quality of life in mental and physical dimensions, more functional impairment and productivity loss, and higher healthcare costs. TRD imposes a massive burden on the individual, family, and society. However, a lack of consensus on the TRD definition limits the comparison and interpretation of TRD treatment efficacy across trials. Furthermore, because of the various TRD definitions, there is scarce treatment guideline specifically for TRD, in contrast to the rich treatment guidelines for MDD. In this chapter, common issues related to TRD, such as proper definitions of an adequate antidepressant trial and TRD, were carefully reviewed. Prevalence of and clinical outcomes related to TRD were summarized. We also summarized the staging models ever proposed for the diagnosis of TRD. Furthermore, we highlighted variations in the definition regarding the lack of or an inadequate response in treatment guidelines for depression. Up-to-date treatment options for TRD, including pharmacological strategies, psychotherapeutic interventions, neurostimulation techniques, glutamatergic compounds, and even experimental agents were reviewed.

Psychological aspects and psychotherapy for TRD.

Treatment-resistant depression (TRD) refers to depression that persists even after the patient has undergone adequate trials of two or more antidepressants at appropriate doses and duration. While there may be controversy around this definition, it reflects the real-world clinical situation where drug therapy is often the primary treatment strategy for major depressive disorder. It's important to note that when a patient is diagnosed with TRD, a comprehensive evaluation of their psychosocial aspects should be carried out. Appropriate psychosocial interventions should also be provided to address the patient's needs. Various psychotherapy models have been proven effective in treating TRD, but not all of them have undergone empirical testing. As a result, some psychotherapy models may be underestimated in treating TRD. Clinicians should consult reference materials and assess the patient's psychosocial aspects to select the most appropriate psychotherapy model for TRD patients. Collaboration with psychologists, social workers, and occupational therapists can also provide valuable input in the decision-making process. This ensures that TRD patients receive comprehensive and effective care.

Improving Identification and Treatment Outcomes of Treatment-Resistant Depression Through Measurement-Based Care.

Measurement-based care (MBC) is the systematic screening and ongoing assessment of symptoms, side effects, and adherence to adjust treatments as needed based on these factors. Studies show MBC leads to improved outcomes for depression and treatment-resistant depression (TRD). In fact, MBC may reduce the chances of developing TRD, as it leads to optimized treatment strategies based on symptom changes and compliance. There are many rating scales available for monitoring depressive symptoms, side effects, and adherence. These rating scales can be used in a variety of clinical settings to help guide treatment decisions, including depression treatment decisions.

Approach to Diagnosis and Management of Treatment-Resistant Depression.

Major depressive disorder is a chronic and recurrent illness that affects 20% of adults during their lifetime and is one of the leading causes of suicide in the United States. A systematic measurement-based care approach is the essential first step in the diagnosis and management of treatment-resistant depression (TRD) by promptly identifying individuals with depression and avoiding delays in treatment initiation. As comorbidities may be associated with poorer outcomes to commonly used antidepressants and increase risk of drug-drug interactions, their recognition and treatment is an essential component of management of TRD.

Special Populations: Treatment-Resistant Depression in Children and Adolescents.

Major depressive disorder is a substantial public health challenge impacting at least 3 million adolescents annually in the United States. Depressive symptoms do not improve in approximately 30% of adolescents who receive evidence-based treatments. Treatment-resistant depression in adolescents is broadly defined as a depressive disorder that does not respond to a 2-month course of an antidepressant medication at a dose equivalent of 40 mg of fluoxetine daily or 8 to 16 sessions of a cognitive behavioral or interpersonal therapy. This article reviews historical work, recent literature on classification, current evidence-based approaches, and emerging interventional research.

Treatment-Resistant Late-Life Depression: A Review of Clinical Features, Neuropsychology, Neurobiology, and Treatment.

Major depression is common in older adults (≥ 60 years of age), termed late-life depression (LLD). Up to 30% of these patients will have treatment-resistant late-life depression (TRLLD), defined as depression that persists despite two adequate antidepressant trials. TRLLD is challenging for clinicians, given several etiological factors (eg, neurocognitive conditions, medical comorbidities, anxiety, and sleep disruption). Proper assessment and management is critical, as individuals with TRLLD often present in medical settings and suffer from cognitive decline and other marks of accelerated aging. This article serves as an evidence-based guide for medical practitioners who encounter TRLLD in their practice.