Treatment-resistant Depression Research Articles

Exploring the multifaceted potential of (R)-ketamine beyond antidepressant applications

(R, S)- and (S)-ketamine have made significant progress in the treatment of treatment-resistant depression (TRD) and have become a research focus in recent years. However, they both have risks of psychomimetic effects, dissociative effects, and abuse liability, which limit their clinical use. Recent preclinical and clinical studies have shown that (R)-ketamine has a more efficient and lasting antidepressant effect with fewer side effects compared to (R, S)- and (S)-ketamine. However, a recent small-sample randomized controlled trial found that although (R)-ketamine has a lower incidence of adverse reactions in adult TRD treatment, its antidepressant efficacy is not superior to the placebo group, indicating its antidepressant advantage still needs further verification and clarification. Moreover, an increasing body of research suggests that (R)-ketamine might also have significant applications in the prevention and treatment of medical fields or diseases such as cognitive disorders, perioperative anesthesia, ischemic stroke, Parkinson’s disease, multiple sclerosis, osteoporosis, substance use disorders, inflammatory diseases, COVID-19, and organophosphate poisoning. This article briefly reviews the mechanism of action and research on antidepressants related to (R)-ketamine, fully revealing its application potential and development prospects, and providing some references and assistance for subsequent expanded research.

Treatment of Refractory Bipolar Depression With Stereotactic Radiosurgery Targeting the Subgenual Cingulate Cortex

Treatment of Refractory Bipolar Depression With Stereotactic Radiosurgery Targeting the Subgenual Cingulate Cortex

Susceptibility to Treatment-Resistant Depression Within Families

Antidepressant responses and the phenotype of treatment-resistant depression (TRD) are believed to have a genetic basis. Genetic susceptibility between the TRD phenotype and other psychiatric disorders has also been established in previous genetic studies, but population-based cohort studies have not yet provided evidence to support these outcomes. To estimate the TRD susceptibility and the susceptibility between TRD and other psychiatric disorders within families in a nationwide insurance cohort with extremely high coverage and comprehensive health care data. This cohort study assessed data from the Taiwan national health insurance database across entire population (N = 26 554 001) between January 2003 and December 2017. Data analysis was performed from August 2021 to April 2023. TRD was defined as having experienced at least 3 distinct antidepressant treatments in the current episode, each with adequate dose and duration, based on the prescribing records. Then, we identified the first-degree relatives of individuals with TRD (n = 34 467). A 1:4 comparison group (n = 137 868) of first-degree relatives of individuals without TRD was arranged for the comparison group, matched by birth year, sex, and kinship. Modified Poisson regression analyses were performed and adjusted relative risks (aRRs) and 95% CIs were calculated for the risk of TRD, the risk of other major psychiatric disorders, and different causes of mortality. This study included 172 335 participants (88 330 male and 84 005 female; mean [SD] age at beginning of follow-up, 22.9 [18.1] years). First-degree relatives of individuals with TRD had lower incomes, more physical comorbidities, higher suicide mortality, and increased risk of developing TRD (aRR, 9.16; 95% CI, 7.21-11.63) and higher risk of other psychiatric disorders than matched control individuals, including schizophrenia (aRR, 2.36; 95% CI, 2.10-2.65), bipolar disorder (aRR, 3.74; 95% CI, 3.39-4.13), major depressive disorder (aRR, 3.65; 95% CI, 3.44-3.87), attention-deficit/hyperactivity disorders (aRR, 2.38; 95% CI, 2.20-2.58), autism spectrum disorder (aRR, 2.26; 95% CI, 1.86-2.74), anxiety disorder (aRR, 2.71; 95% CI, 2.59-2.84), and obsessive-compulsive disorder (aRR, 3.14; 95% CI, 2.70-3.66). Sensitivity and subgroup analyses validated the robustness of the findings. To our knowledge, this study is the largest and perhaps first nationwide cohort study to demonstrate TRD phenotype transmission across families and coaggregation with other major psychiatric disorders. Patients with a family history of TRD had an increased risk of suicide mortality and tendency toward antidepressant resistance; therefore, more intensive treatments for depressive symptoms might be considered earlier, rather than antidepressant monotherapy.

[Clinical management of treatment-resistant depression].

Treatment-resistant depression (TRD) is acomplex 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 afavorable side-effect profile.

Evaluating the efficacy and mechanisms of a ketogenic diet as adjunctive treatment for people with treatment-resistant depression: A protocol for a randomised controlled trial

BackgroundOne-third of people with depression do not respond to antidepressants, and, after two adequate courses of antidepressants, are classified as having treatment-resistant depression (TRD). Some case reports suggest that ketogenic diets (KDs) may improve some mental illnesses, and preclinical data indicate that KDs can influence brain reward signalling, anhedonia, cortisol, and gut microbiome which are associated with depression. To date, no trials have examined the clinical effect of a KD on TRD. Methodsand analysis DIME is a proof-of-concept randomised controlled trial to investigate the efficacy of a six-week programme of weekly dietitian counselling plus provision of KD meals, compared with an intervention involving similar dietetic contact time and promoting a healthy diet with increased vegetable consumption and reduction in saturated fat, plus food vouchers to purchase healthier items. At 12 weeks we will assess whether participants have continued to follow the assigned diet. The primary outcome is the difference between groups in the change in Patient Health Questionnaire-9 (PHQ-9) score from baseline to 6 weeks. PHQ-9 will be measured at weeks 2, 4, 6 and 12. The secondary outcomes are the differences between groups in the change in remission of depression, change in anxiety score, functioning ability, quality of life, cognitive performance, reward sensitivity, and anhedonia from baseline to 6 and 12 weeks. DIME will also assess whether changes in reward sensitivity, anhedonia, cortisol awakening response and gut microbiome may explain any changes in depression severity. DiscussionThis study will test whether a ketogenic diet is an effective intervention to reduce the severity of depression, anxiety and improve quality of life and functioning ability for people with treatment-resistant depression.

Efficacy of Esketamine among patients with treatment resistant depression in a ‘real world' health-care setting in Israel

One in five people will likely suffer from major depressive disorder (MDD) during their life. Thirty percent of those with MDD will experience Treatment Resistant Depression (TRD), which is characterized by a failure to respond to two adequately administered trials of antidepressants. Esketamine is a rapidly acting intranasal antidepressant. Present-day Esketamine research has limited data in real-world populations. This study aimed to assess Esketamine treatment in a real-world community-based population.This naturalistic retrospective study included 94 individuals age 18 and above diagnosed with TRD, treated with Esketamine in an outpatient setting. The treatment was given in a single clinic, from January 2021 to January 2023, following approval of the Institutional Internal Review Board. The treatment included an acute phase (biweekly treatment, continuing 4–8 weeks), followed by a maintenance phase (once a week to once a month, for 6–12 months). Dosing ranged from 28 mg to 84 mg. Demographic and clinical data were retrospectively gathered. Depressive symptoms were assessed using the Quick Inventory of Depressive Symptomatology, at baseline and during each treatment phase.All patients completed the acute phase. About 60% completed the maintenance phase. Linear improvement of depressive symptoms was revealed in both phases. A sub-analysis of patients with comorbid personality disorder revealed a similar improvement pattern in the acute phase with milder improvement during the maintenance phase, compared to the other patients.This study supports the use of Esketamine for TRD, including patients with comorbid personality disorder and previous electroconvulsive therapy.

Drug dependence and prescribing ketamine for treatment-resistant depression in Australia and New Zealand.

Ketamine is a restricted and regulated medication in Australia and New Zealand, which has implications when considering treatment for patients with treatment-resistant depression and a history of illicit drug use, abuse or dependence. Regulations governing prescription of ketamine for treatment-resistant depression vary between jurisdictions in Australia and New Zealand, though most restrict use in those with drug dependence. There is substantial variation in definitions of drug dependence used in each jurisdiction, and between the legal and clinical definitions, with the latter specified in the current International Classification of Diseases, Eleventh Revision and Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. This paper reviews the literature assessing the risk of ketamine misuse and dependence in patients with a history of illicit drug use, abuse or dependence and presents recommendations for psychiatrists who prescribe ketamine in such patients with treatment-resistant depression.

Effects of esketamine nasal spray on depressive symptom severity in adults with treatment-resistant depression and associations between the Montgomery-Åsberg Depression Rating Scale and the 9-item Patient Health Questionnaire.

To examine the effect of esketamine nasal spray (ESK) plus newly initiated oral antidepressant (OAD) versus OAD plus placebo nasal spray (PBO) on the association between Montgomery-Åsberg Depression Rating Scale (MADRS) and 9-item Patient Health Questionnaire (PHQ-9) scores in adults with treatment-resistant depression (TRD). Data from TRANSFORM-1 and TRANSFORM-2 (two similarly designed, randomized, active-controlled TRD studies) and SUSTAIN-1 (relapse prevention study) were analyzed. Group differences for mean changes in PHQ-9 total score from baseline were compared using analysis of covariance. Associations between MADRS and PHQ-9 total scores from TRANSFORM-1/TRANSFORM-2 were assessed using simple parametric, nonparametric, and multiple regression models. In TRANSFORM-1/TRANSFORM-2 (ESK+OAD, n=343; OAD+PBO, n=222), baseline PHQ-9 mean scores were 20.4 for ESK+OAD and 20.6 for OAD+PBO (severe depression). At day 28, significant group differences were observed in least squares mean change (SE) in PHQ-9 scores from baseline (-12.8 [0.46] vs -10.3 [0.53], P<.001) and in clinically substantial change in PHQ-9 scores (≥6 points; 77.1% vs 64%, P<.001) in ESK+OAD and OAD+PBO groups, respectively. A nonlinear relationship between MADRS and PHQ-9 was observed; total scores demonstrated increased correlation over time. In SUSTAIN-1, 57.3% of patients receiving ESK+OAD (n=89) versus 44.2% receiving OAD+PBO (n=86) retained remission status (PHQ-9 score ≤4) at maintenance treatment end point (P=.044). In adults with TRD, ESK+OAD significantly improved severity of depressive symptoms, and more patients achieved clinically meaningful changes in depressive symptoms based on PHQ-9, versus OAD+PBO. PHQ-9 outcomes were consistent with those of clinician-rated MADRS. ClinicalTrials.gov: NCT02417064, NCT02418585, NCT02493868.

The Role of Hormone Replacement Therapy and A Plant Based Diet in Treatment Resistant Depression in Menopausal Women: A Case Report

The Role of Hormone Replacement Therapy and A Plant Based Diet in Treatment Resistant Depression in Menopausal Women: A Case Report

Experiences of Awe Mediate Ketamine’s Antidepressant Effects: Findings From a Randomized Controlled Trial in Treatment-Resistant Depression

BackgroundKetamine, an NMDA receptor antagonist, provides rapid antidepressant effects. Although much research has focused on neural and molecular mechanisms of action, it is critical to also consider psychological mechanisms that may contribute to its therapeutic efficacy. The construct of an awe-inducing experience, which is a well-validated psychological phenomenon tied to emotional well-being, had not been applied previously in ketamine research. MethodsOne hundred sixteen participants with depression, 77 of whom received a ketamine infusion (0.5 mg/kg over 40 minutes) and 39 patients who received saline placebo, completed a validated measure of awe (the Awe Experience Scale [AWE-S]) at 40 minutes postinfusion. AWE scores were examined as potential mediators of depression outcomes (% improvement in Montgomery–Åsberg Depression Rating Scale score ) at 5 postinfusion time points (24 hours and 5, 12, 21, and 30 days). Dissociative effects, measured by Clinician-Administered Disassociative States Scale scores, were tested in parallel mediation models for comparison. ResultsWe found that the psychological experience of awe was strongly reported by participants during ketamine infusion, but not saline infusion, and there were significant associations between total AWE scores and Montgomery–Åsberg Depression Rating Scale score improvement (% change) in the ketamine arm at all 5 time points. Furthermore, at all 5 time points, total AWE scores statistically mediated the relationship between ketamine and Montgomery–Åsberg Depression Rating Scale scores. By contrast, Clinician-Administered Disassociative States Scale scores did not mediate outcomes at any time point. ConclusionsKetamine infusion strongly induced heightened feelings of awe, and these experiences consistently mediated depression outcomes over a 1- to 30-day period, unlike general dissociative side effects. The specific awe-inspiring properties of ketamine may contribute to its antidepressant effects.

Lithium Treatment for Affective Disorders: Exploring the Potential of Salivary Therapeutic Monitoring

Lithium is one of the most effective medications for treatment-resistant depression and bipolar disorder. However, lithium has a narrow therapeutic window: overdosing can lead to life-threatening lithium intoxication while underdosing results in a lack of desired therapeutic effects. Therefore, lithium treatment requires close monitoring with regular laboratory assessments of blood serum concentrations. An alternative method for monitoring lithium at home would increase the safety and empowerment of patients. In our project, we are investigating the potential of saliva as a readily accessible medium. We are exploring a) the best method for collecting and processing saliva, b) methods to measure salivary lithium levels, and c) the correlation between blood serum and saliva concentrations of lithium, and influencing factors; with the aim to develop a Point-of-care home testing device.

Role of electrophysiological activity and interactions of lateral habenula in the development of depression-like behavior in a chronic restraint stress model

Closed-loop deep brain stimulation (DBS) system offers a promising approach for treatment-resistant depression, but identifying universally accepted electrophysiological biomarkers for closed-loop DBS systems targeting depression is challenging. There is growing evidence suggesting a strong association between the lateral habenula (LHb) and depression. Here, we took LHb as a key target, utilizing multi-site local field potentials (LFPs) to study the acute and chronic changes in electrophysiology, functional connectivity, and brain network characteristics during the formation of a chronic restraint stress (CRS) model. Furthermore, our model combining the electrophysiological changes of LHb and interactions between LHb and other potential targets of depression can effectively distinguish depressive states, offering a new way for developing effective closed-loop DBS strategies.

Psychomotor retardation: What about the partial responders to magnetic transcranial stimulation in treatment resistant depression ?

ObjectivePsychomotor retardation is a core clinical component of Major Depressive Disorder responsible for disability and is known as a treatment response marker of biological treatments for depression. Our objective was to describe cognitive and motoric measures changes during a treatment by repetitive Transcranial Magnetic Stimulation (rTMS) within the THETAD-DEP trial for treatment-resistant depression (TRD), and compare those performances at the end of treatment and one month after between responders (>50% improvement on MADRS score), partial responders (25–50%) and non-reponders (no clinically relevant improvement). Our secondary aim was to investigate baseline psychomotor performances associated with non-response and response even partial. MethodsFifty-four patients with treatment-resistant unipolar depression and treated by either high frequency 10 Hz rTMS or iTBS for 4 weeks (20 sessions) underwent assessment including French Retardation Rating Scale for Depression (ERD), Verbal Fluency test, and Trail Making Test A. before, just after treatment and one month later. Results20 patients were responders (R, 21 partial responders (PR) and 13 non-responders (NR). rTMS treatment improved psychomotor performances in the R and PR groups unlike NR patients whose psychomotor performance was not enhanced by treatment. At baseline, participants, later identified as partial responders, showed significantly higher performances than non-responders. ConclusionHigher cognitivo-motor performances at baseline may be associated with clinical improvement after rTMS treatment. This work highlights the value of objective psychomotor testing for the identification of rTMS responders and partial responders, and thus may be useful for patient selection and protocol individualization such as treatment continuation for early partial responders.

Patient and provider perspectives on the phenomenon and effective treatment of treatment-resistant depression: A grounded theory

BackgroundTreatment-Resistant Depression (TRD) is a poorly understood but prevalent clinical phenomenon that lacks a widely accepted definition, explanatory model, or set of practice recommendations. It involves a chronic form of unipolar Major Depressive Disorder (MDD) that fails to respond to at least two first-line clinical treatments. TRD affects as many as 70 % of patients who fail to respond to their first trial of antidepressant medication and 60 % of patients who fail to respond to their first phase of psychotherapy. PurposeThis qualitative study aims to develop a model for understanding the phenomenon of unipolar TRD and the practices involved in its effective treatment. MethodsThis study involved a grounded theory analysis of interviews with four adult-American patients with unipolar TRD and five American providers who routinely treat such patients. ResultsA model of unipolar TRD was developed, explaining common etiological and maintaining factors of unipolar TRD and offering recommendations for guiding effective treatment. LimitationsThis study had a small sample size (N = 9) with limited sociodemographic diversity (all Americans; only two females; one racial/ethnic minority; no sexual minorities), which may limit its generalizability. ConclusionsNevertheless, its emergent theory underscores the importance of TRD patients cultivating positive views of medication and psychotherapy while collaborating with their providers to obtain psychoeducation, build mindfulness/coping skills, enhance social support, and re-engage with pleasurable activities. It recommends that mental health providers focus on processing TRD patients’ subjective experiences, validating patients’ frustrations, and monitoring and calibrating patients’ expectations.

A revisionist model for treatment-resistant and difficult-to-treat depression.

The aim of this study is to consider limitations to the heuristics 'treatment-resistant depression' (TRD) and 'difficult-to-treat' depression (DTD) and to offer a revisionist model. A number of limitations to the two constructs are noted, particularly the risk of each positioning clinical depression as an entity and then applying a linear sequencing management model. Arguing that clinical depression is heterogenous in nature (with categorical and 'fuzzy set conditions), in cause and in response to treatment, allows an alternate model for addressing depressive conditions that are not readily responsive to treatment. A skeletal model for proceeding is offered for consideration and development. If such a model is accepted, then differing criteria for defining treatment resistance and treatment failure might be generated for differing depressive conditions, and condition-specific sequencing algorithms (embracing drug and non-drug strategies) developed for their management.

Structural Brain Connectivity and Treatment Improvement in Mood Disorder.

The treatment of depressive episodes is well established, with clearly demonstrated effectiveness of antidepressants and psychotherapies. However, more than one-third of depressed patients do not respond to treatment. Identifying the brain structural basis of treatment-resistant depression could prevent useless pharmacological prescriptions, adverse events, and lost therapeutic opportunities. Using diffusion magnetic resonance imaging, we performed structural connectivity analyses on a cohort of 154 patients with mood disorder (MD) - and 77 sex- and age-matched healthy control (HC) participants. To assess illness improvement, the MD patients went through two clinical interviews at baseline and at 6-month follow-up and were classified based on the Clinical Global Impression-Improvement score into improved or not-improved. First, the threshold-free network-based statistics was conducted to measure the differences in regional network architecture. Second, nonparametric permutations tests were performed on topological metrics based on graph theory to examine differences in connectome organization. The threshold-free network-based statistics revealed impaired connections involving regions of the basal ganglia in MD patients compared to HC. Significant increase of local efficiency and clustering coefficient was found in the lingual gyrus, insula and amygdala in the MD group. Compared with the not-improved, the improved displayed significantly reduced network integration and segregation, predominately in the default-mode regions, including the precuneus, middle temporal lobe and rostral anterior cingulate. This study highlights the involvement of regions belonging to the basal ganglia, the fronto-limbic network and the default mode network, leading to a better understanding of MD disease and its unfavorable outcome.

Extremely Low Frequency, Extremely Low Magnetic Environment for depression: An open-label trial

Mitochondrial dysfunction has been suggested to play a role in depression pathogenesis. This clinical trial (jRCTs042220011) was conducted to evaluate whether depression symptoms could be alleviated by an Extremely Low Frequency, Extremely Low Magnetic Environment (ELF-ELME), which has been found in basic research studies to enhance mitochondrial membrane potential. Participants were exposed to the ELF-ELME via a head-mounted magnetic field device (10 μTesla, 4 ms, 1–8 Hz/8 s) worn for 2 h per day for 8 consecutive weeks. Four male patients with treatment-resistant depression were enrolled. Significant reductions from baseline in the average total Montgomery–Åsberg Depression Rating Scale (MADRS) score were observed at 4, 6, and 8 weeks. ELF-ELME appears to ameliorate depressive symptoms in patients with major depressive disorder safely and effectively, suggesting that it could be used as an alternative treatment for depressive patients who do not prefer to take antidepressants and in combination with antidepressant therapy for patients who only partially respond to pharmacotherapy.

Psychedelics: reconnecting the brain to heal the mind

Natural psychedelics such as magic mushrooms have a long history of human use of at least 7000 years. Their use underwent a resurgence in the 1950/1960s following the synthesis of LSD as a psychedelic and its use as a medicine with powerful therapeutic benefits. But because non-medical use led to massive cultural changes especially in young people, all psychedelics were banned globally in the early 1970s. Over the past 20 years, there has been a resurrection of psychedelic research. This has revealed their common modes of action as agonists (stimulators) of the serotonin 5-HT2A receptor in the brain and that this activity leads to profound alterations in neuro-circuitry, producing a more integrated and flexible pattern of activity. These brain changes found in healthy volunteers predicted utility in mental illnesses such as depression and addiction and subsequent trials revealed this to be true. A single psychedelic trip can lead to very long-lasting improvements in a range of mental illnesses. From these remarkable and consistent positive outcomes, it seems likely that psychedelic therapy will soon become widely approved in western medicine, as it has already been in Australia for treatment-resistant depression.

Oral esketamine in patients with treatment-resistant depression: a double-blind, randomized, placebo-controlled trial with open-label extension.

About one-third of patients with depression do not achieve adequate response to current treatment options. Although intravenous and intranasal administrations of (es)ketamine have shown antidepressant properties, their accessibility and scalability are limited. We investigated the efficacy, safety, and tolerability of generic oral esketamine in patients with treatment-resistant depression (TRD) in a randomized placebo-controlled trial with open-label extension. This study consisted of 1) a six-week fixed low-dose treatment phase during which 111 participants received oral esketamine 30 mg or placebo three times a day; 2) a four-week wash-out phase; and 3) an optional six-week open-label individually titrated treatment phase during which participants received 0.5 to 3.0 mg/kg oral esketamine two times a week. The primary outcome measure was change in depressive symptom severity, assessed with the Hamilton Depression Rating Scale (HDRS17), from baseline to 6 weeks. Fixed low-dose oral esketamine when compared to placebo had no benefit on the HDRS17 total score (p = 0.626). Except for dizziness and sleep hallucinations scores, which were higher in the esketamine arm, we found no significant difference in safety and tolerability aspects. During the open-label individually titrated treatment phase, the mean HDRS17 score decreased from 21.0 (SD 5.09) to 15.1 (SD 7.27) (mean difference -6.0, 95% CI -7.71 to -4.29, p < 0.001). Our results suggest that fixed low-dose esketamine is not effective in TRD. In contrast, individually titrated higher doses of oral esketamine might have antidepressant properties.

The effect of older age on outcomes of rTMS treatment for treatment-resistant depression.

Clinical outcomes of repetitive transcranial magnetic stimulation (rTMS) for treatment of treatment-resistant depression (TRD) vary widely and there is no mood rating scale that is standard for assessing rTMS outcome. It remains unclear whether TMS is as efficacious in older adults with late-life depression (LLD) compared to younger adults with major depressive disorder (MDD). This study examined the effect of age on outcomes of rTMS treatment of adults with TRD. Self-report and observer mood ratings were measured weekly in 687 subjects ages 16-100 years undergoing rTMS treatment using the Inventory of Depressive Symptomatology 30-item Self-Report (IDS-SR), Patient Health Questionnaire 9-item (PHQ), Profile of Mood States 30-item, and Hamilton Depression Rating Scale 17-item (HDRS). All rating scales detected significant improvement with treatment; response and remission rates varied by scale but not by age (response/remission ≥ 60: 38%-57%/25%-33%; <60: 32%-49%/18%-25%). Proportional hazards models showed early improvement predicted later improvement across ages, though early improvements in PHQ and HDRS were more predictive of remission in those < 60 years (relative to those ≥ 60) and greater baseline IDS burden was more predictive of non-remission in those ≥ 60 years (relative to those < 60). These results indicate there is no significant effect of age on treatment outcomes in rTMS for TRD, though rating instruments may differ in assessment of symptom burden between younger and older adults during treatment.