Treatment-resistant Depression Research Articles

Noncardiac Chest Pain and Hypertensive Urgency During Long-term Intravenous Racemic Ketamine for Treatment-Resistant Depression

Noncardiac Chest Pain and Hypertensive Urgency During Long-term Intravenous Racemic Ketamine for Treatment-Resistant Depression

Microglial and Macrophage Plasticity and Regional Cerebral Blood Flow in the Prenatal Brain and Gut Under Vagus Nerve Stimulation.

An intricate relationship exists between the vagus nerve and systemic immune cell regulation, specifically during fetal development. Little is known about the connection between the vagus nerve and the brain's regional circulatory control. In this chapter, we present a methodology for studying the impact of vagus nerve signaling on these connections in the developing fetus using the sheep model for human fetal physiology. First, we present the protocol to study the connection between the vagus nerve physiology and the regional cerebral blood flow (rCBF). Next, we detail the protocol for measuring how vagal signaling alters microglial cell plasticity in gut and brain. In previous work, our team showed that vagotomy results in amplified redistribution of rCBF toward subcortical structures in the fetal brain. Conversely, efferent VNS reduces rCBF to cortical structures while afferent VNS diminishes the rise of rCBF to subcortical structures (independent of cortical rCBF) when compared to controls in the fetal brain. Additionally, our team showed that Iba-1 expression, a marker for microglial cellular signaling activation, rises in a dose-dependent relationship with systemic inflammatory activation in the setting of vagotomy. The findings support existing preclinical and clinical evidence in adult human physiology that vagotomy is neuroprotective for neurodegenerative diseases such as Parkinson's likely via a glial cell-mediated mechanism. Vagus nerve stimulation (VNS) has also been shown to alter rCBF patterns in adults with treatment-resistant depression, underscoring the importance of further investigation of the relationship between the vagus nerve and rCBF as early as in utero. Together, the body of evidence emphasizes that the vagal pathway is an important player in the programming of microglial cell phenotypes within the developing brain. Further study is needed to better understand the significance of these relationships for the development and treatment of early susceptibility to neuroinflammatory and neurodegenerative disorders in later life. Therefore, we present a methodology for assessing rCBF and morphometric features of microglial and macrophage cell activation to allow future teams to expand on the existing body of work and further examine these relationships at a cellular and systems' levels.

The effect of once-daily vs. twice-daily intermittent theta burst stimulation on suicidal ideation in treatment-resistant depression.

Intermittent theta burst stimulation (iTBS) has demonstrated potential in reducing suicidal ideation (SI) in patients with depression, however, stimulation protocols vary greatly across studies. For this secondary analysis, data from a three-site double-blind, randomized and sham-controlled clinical trial was analyzed to investigate the efficacy of a once-daily versus twice-daily iTBS protocol in the treatment of SI in patients with treatment resistant depression. Secondarily we aimed to explore the associations among SI, anhedonia and quality of life (QOL) measures. The primary outcome for this analysis was SI, which was assessed by computing an average score from four suicidality items on separate depression scales. 158 participants who experienced some degree of SI at baseline were included in the analysis. After 10 days of treatment, 15 (18.3%) participants from the once-daily group and 19 (25%) from the twice-daily group achieved remission from SI which was defined as a SI score of 0. After 30 days of treatment the remission rates were 27 (32.9%) and 30 (39.5%), respectively. There were no significant differences in remission rates between the groups. Moderate correlations between change in SI and change in depressive symptoms were observed. In addition, correlations between change in SI, anhedonia and QOL were observed that remained significant after controlling for change in depressive symptoms. Achieving remission from SI appears to be at least partially correlated to the anti-depressant effect of iTBS. Further studies investigating optimal treatment protocols for the treatment of suicidality with different iTBS schedules are urgently needed. Trial registration Clinicaltrials.gov ID: NCT02729792 ( https://clinicaltrials.gov/ct2/show/NCT02729792 ).

Aperiodic (1/f) neural activity robustly tracks symptom severity changes in treatment-resistant depression.

A reliable physiological biomarker for Major Depressive Disorder is essential for developing and optimizing neuromodulatory treatment paradigms. This study investigates a passive electrophysiologic biomarker that tracks changes in depressive symptom severity on the order of minutes to hours. We analyze brief recordings from intracranial electrodes implanted deep in the brain during a clinical trial of deep brain stimulation for treatment-resistant depression in 5 human subjects (nfemale= 3, nmale = 2). This surgical setting allows for precise temporal and spatial sensitivity in the ventromedial prefrontal cortex, a challenging area to measure. We focused on the aperiodic slope of the power spectral density, a metric reflecting the balance of activity across all frequency bands and serving as a proxy for excitatory/inhibitory balance in the brain. Our findings demonstrate that shifts in aperiodic slope correlate with depression severity, with flatter (less negative) slopes indicating reduced depression severity. This significant correlation was observed in all N=5 subjects, particularly in the ventromedial prefrontal cortex. This biomarker offers a new way to track patient responses to Major Depressive Disorder treatment, paving the way for individualized therapies in both intracranial and non-invasive monitoring contexts.

Reversal Potentials of Tween 20 in ABC Transporter-Mediated Multidrug-Resistant Cancer and Treatment-Resistant Depression Through Interacting with Both Drug-Binding and ATP-Binding Areas on MDR proteins

Drug efflux transporters, especially those belonging to the ATP-binding cassette (ABC) transporter superfamily, play a crucial role in various drug resistance issues, including multidrug resistance (MDR) in cancer and treatment-resistant depression (TRD) in individuals with major depressive disorder. Key transporters in this context include P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1), and breast cancer resistance protein (BCRP). This study aimed to investigate the modulatory effects of polyoxyethylene (20) sorbitan monolaurate (Tween 20) on these efflux transporters in vitro and to evaluate its potential for overcoming drug resistance in two models: an in vitro cancer MDR model and an in vivo TRD model. The findings indicated that 0.001% Tween 20 significantly inhibited the efflux actions of all three transporters. Additionally, 0.005% Tween 20 effectively reversed resistance to paclitaxel, vincristine, doxorubicin, and mitoxantrone in various cancer MDR cell lines. In the in vivo depression-like behavior model, 0.01% Tween 20 markedly enhanced the antidepressant and anxiolytic effects of fluoxetine. Given its strong inhibitory effects on P-gp, MRP1, and BCRP, along with its capacity to reverse drug resistance both in vitro and in vivo, Tween 20 is a compelling candidate for tackling transporter-mediated drug resistance.

Preliminary findings of a randomized controlled trial investigating the efficacy of transcranial magnetic stimulation in treatment-resistant depression: a post-hoc analysis on the role of co-occurring personality disorders

IntroductionDespite the high hopes for the use of transcranial magnetic stimulation (TMS) in the treatment of depression, between 30% and 60.5% of patients do not respond to stimulation. The factors contributing to non-response, especially those related to personality, remain insufficiently investigated. The main aim of our study was to compare the efficacy of active TMS and sham–placebo protocols in combined therapy of treatment-resistant depression with evaluation of possible personality disorders comorbidity.MethodsThe study was conducted between December 2019 and December 2022, as a randomized, double-blind, active comparator-controlled and sham-controlled parallel trial. Patients (n = 41) were randomized into one of two experimental conditions (active TMS vs. placebo) and screened before and after stimulation as well as at a 3-month follow-up. Personality disorders were assessed with The Structured Clinical Interview for DSM-5 Personality Disorders.ResultsThere were no significant differences between the TMS active and sham groups in terms of general characteristics, coexisting personality disorders, and Montgomery–Åsberg Depression Rating Scale scores before stimulation, at the end of stimulation, and after 3 months of stimulation. However, linear regression analysis revealed significant negative associations between the coexistence of personality disorders and the reduction of depressive symptoms from baseline to the end of stimulation. The post-hoc exploratory analysis on the first phase of the RCT confirmed the presence of personality disorders to be a consistent negative influence on the reduction of depressive symptoms post-stimulation, regardless of protocol and experimental condition and demonstrated a smaller percentage reduction in depressive symptoms after stimulation in patients with personality disorders.DiscussionA central conclusion, based on our study, is that transcranial magnetic stimulation for treatment-resistant depression cannot be considered as a method independent of co-occurring personality disorders.

Transformative Therapies for Depression: Postpartum Depression, Major Depressive Disorder, and Treatment-Resistant Depression.

Depressive disorders present an enormous global public health burden. A notable treatment gap exists between the prevalence of depression and our ability to provide rapid-acting, effective treatment that achieves remission. Brexanolone and zuranolone, the first US Food and Drug Administration-approved drugs for postpartum depression, signify a critical advancement in addressing the unmet needs of a vulnerable patient population. Psilocybin shows promise for treatment-resistant depression and for those who have struggled to find relief with existing treatments. This review discusses transformative therapies that represent significant advancements in postpartum depression, major depressive disorder, and treatment-resistant depression.

Effects of repetitive transcranial magnetic stimulation therapy on weight and lipid metabolism in patients with treatment-resistant depression: A preliminary single-center retrospective cohort study.

This study aimed to elucidate the effects of repetitive transcranial magnetic stimulation (rTMS) on weight, body mass index (BMI), and lipid metabolism in patients with treatment-resistant depression (TRD). This retrospective observational study included patients with TRD who received rTMS treatment at the Jikei University Hospital from September 2018 to August 2021. The patients were diagnosed based on the DSM-5 and ICD-10 criteria and treated using the NeuroStar TMS System. For 3-6 weeks, 10-Hz rTMS was administered to the left dorsolateral prefrontal cortex at 120% motor threshold. The primary outcomes were changes in weight and BMI, whereas the secondary outcomes included changes in total, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) cholesterol levels, thyroid function indicators, as well as HAMD-17, HAMD-24, and Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Statistical analysis was conducted using paired t-tests and repeated measures ANOVA. Among the 34 patients (20 men and 14 women) included, no significant changes were observed in weight or BMI after rTMS treatment (average weight reduction: -0.50 kg, 95% CI: -0.14 to 0.56, p = 0.24; average BMI reduction: -0.21, 95% CI: -0.10 to 0.61, p = 0.15). However, significant reductions in total, HDL, and LDL cholesterol levels and FT4 were observed. Furthermore, the HAMD-17, HAMD-24, and MADRS scores significantly increased post-treatment. rTMS treatment did not affect weight or BMI in patients with TRD but is believed to improve lipid metabolism.

Effect of Esketamine Nasal Spray on Cognition in Patients with Treatment-Resistant Depression: Results from Four Phase-3 Studies.

While esketamine is effective in treatment-resistant depression (TRD), detailed information about the effect of esketamine on cognition is relatively scarce. This analysis assessed the effect of short-term (three double-blind [DB] studies; DB1, DB2, and DB4) or long-term maintenance treatment (DB3) with esketamine nasal spray (ESK) compared to an active-comparator+placebo (PBO), on cognition in patients with TRD. Patients (DB1/DB2/DB3: [18-64years, n=747]; DB4: [≥65years, n=137]) with TRD received ESK (DB1/DB2/DB3:56/84mg; DB4:28/56/84mg) or PBO+newly initiated oral antidepressant (OAD) as per treatment schedules. Cognitive assessments- Cogstate battery and Hopkins Verbal Learning Test-Revised, were administered at baseline, Day-28/early withdrawal, and follow-up visits in DB1/DB2/DB4 and at 12-week intervals in DB3 maintenance phase. Descriptive statistics were used to analyze ESK effects on cognition with effect sizes and 95% confidence intervals (CIs) used to express the nature/magnitude of treatment effects relative to active-comparator+PBO. Correlation between depression severity (MADRS scores) and cognition was assessed at baseline and endpoint(s). At baseline, mild-to-moderate impairment in psychomotor function, attention, and memory (working/episodic) were evident. For each DB1/DB2/DB4, group mean performance in z-scores for ESK+OAD and OAD+PBO groups on all cognitive tests remained similar/slightly improved from, baseline at endpoint (Day-28) and follow-up assessments. Similarly, in DB3(limited to participants ≥65years), both groups generally showed improvement in cognitive performance at endpoint(s). Correlations between MADRS scores and performance on the cognitive test battery were small at baseline and endpoint(s). This analysis did not identify evidence of negative effects on cognition following short-term or long-term maintenance treatment with ESK+OAD in patients with TRD.

Lithium - Fifteen Years Later.

The 75th anniversary of introducing lithium into modern psychiatry is recognized, attested by the 1949 paper of John Cade. About this event, my editorial in the special 2010 issue of Neuropsychobiology was titled "Lithium: Sixty Years Thereafter". Since then, fifteen more years have brought further information about lithium. This paper makes a narrative review of the most important articles published in this period. The selected key literature of 2010-2024 addressed lithium prophylactic efficacy in bipolar disorder (BD), including pediatric, recurrent depression, and lithium augmentation of antidepressants in treatment-resistant depression (TRD). Novel data have been obtained for lithium adverse effects (kidney, thyroid) and beneficial outcomes of long-term lithium administration (anti-suicidal, neuroprotective, antiviral, and others). The results on the mechanisms of lithium action covered genetic investigations of the ConLiGen, and in vitro studies with induced pluripotent stem cells and lymphoblastoid cell lines. The underutilization of lithium nowadays was emphasized, and the ways to overcome it were considered. Lithium remains the choice drug for recurrence prevention in BD, also in adolescents, and a significant option for augmentation of antidepressants in TRD. The adverse side effects should be carefully followed and managed according to current guidelines. There are also beneficial lithium impacts, of which anti-suicidal and anti-dementia seem the most important. Most of the results of neurobiological studies on lithium mechanisms may be related to lithium response and some (e.g. immunomodulatory) to the pathogenesis of BD. Better education about lithium could make more patients the beneficiary of this drug.

Physical activity in the treatment-resistant depression and non-remitted depression: a systematic review of randomized controlled trials

Background The objective of this systematic review was to analyze the effects of physical activity (PA) intervention as an adjuvant strategy to pharmacological treatment in people with treatment-resistant depression (TRD) and non-remitted depression (NRD). Methods A search strategy was realized from five databases: PubMed, Cochrane Central Register of Controlled Trials, Scopus, SPORTDiscus, and Web of Science. The Physiotherapy Evidence Database and Oxford’s Evidence Levels were used to classify the quality appraisal. Results Of the 10777 records, 11 randomized controlled studies attained the inclusion criteria. The more significant outcome for this analysis was the improvement of depression by PA or exercise in TRD and NRD. According to the FITT (Frequency, Intensity, Time, and Type) principle, there was some variability in the PA intervention, and except for one article, they all were classified as excellent in terms of quality description. Conclusions This review highlights the potential of PA intervention as an adjuvant program to improve different traits of TRD and NRD. The remission of depression seems to be higher after PA intervention, showing improvements in quality of life, sleep quality, executive function, and vitality.

Electroconvulsive Therapy in a Left Ventricular Assist Device Recipient With Treatment-Resistant Depression.

Depression and heart failure are highly comorbid, with up to 35% of heart failure patients suffering from comorbid depression. Left ventricular assist devices (LVADs) serve as a major lifeline for patients with heart failure; however, despite the drastic improvement in cardiac function following LVAD implantation, up to 24% of LVAD recipients suffer from depression. Depression management in LVAD recipients is often complicated by the recipient's increased risk for antidepressant side effects, adverse drug reactions, and inability to safely receive certain interventional psychiatry therapies, as the LVAD is either a relative or absolute contraindication. Electroconvulsive therapy (ECT) is highly effective for treatment-resistant depression; although it carries increased cardiovascular risks for the LVAD population (particularly bradycardia/hypotension and tachycardia/hypotension), these can be continuously monitored, along with LVAD function, such that with the close cooperation of a multidisciplinary team, the risks of ECT can be minimized. To our knowledge, there is only one published case report of ECT in an LVAD recipient. We present a case of an LVAD recipient with treatment-resistant depression who was successfully treated with ECT. Our case describes an approach by which ECT can be safely delivered to LVAD recipients with a collaborative multidisciplinary team approach.

Masking Influences: A Systematic Review of Placebo Control and Masking in Psychedelic Studies.

Psychedelic-assisted therapy is becoming increasingly acknowledged as an effective therapeutic intervention for various psychiatric illnesses. However, the evaluation of masking success is rarely reported in trials. The objective of the present systematic review was to evaluate placebo-control and masking in studies exploring psychedelic-assisted therapy. Nine (k = 9) studies dating between January 2010 and March 2023 were retrieved using six databases, following strict inclusion and exclusion criteria. The results show that almost 78% of the studies had, at best, "poor" masking success. At the same time, 60% of active placebo and 75% of inactive placebo studies showed large effect sizes. In other words, masking influences, including benign unmasking, cannot be excluded. We therefore conclude that efficacy of psilocybin, Ayahuasca, or LSD is only one of the possible interpretations of large, positive changes in symptomatology for patients suffering from, for example, alcohol use disorder, anxiety with or without life-threatening disease, anxiety and/or depression with life-threatening cancer, treatment-resistant depression or major depressive disorder. We recommend care be taken to increase successful masking procedures and discuss alternative treatment designs to better control for potential masking influences.

Patient experiences of treatment-resistant depression (TRD): A systematic review and qualitative meta-synthesis

Treatment-resistant depression (TRD) occurs when depressive symptoms persist after a patient has tried at least two antidepressants at an appropriate dose for an adequate length of time, as judged by their clinician. Understanding what it is like to live with and seek care for TRD can inform treatment planning and contribute to health technology assessments for depression-related therapies. Our objective was to systematically review this evidence through an investigation of qualitative literature about the experiences of people who have TRD. We searched MEDLINE, CINAHL, PsycINFO, and the Web of Science Core Collection. Publications eligible for inclusion were English-language primary empirical qualitative studies or the qualitative component of mixed methods studies examining adults’ experiences with TRD or with specific treatment options for TRD. Two reviewers independently screened and extracted data, as well as critically appraised included studies using the Standards for Reporting Qualitative Research (SRQR) instrument. This review was guided by integrative meta-synthesis. Data analysis consisted of a staged coding process similar to grounded theory. The protocol was registered in PROSPERO prior to the search (record ID: CRD42022356813). Sixteen studies were included from screening 18,568 results. Two studies focused on the overall experience of TRD and 14 explored experiences of specific treatments such as ketamine. Patients described the depressive symptoms they experienced, a sense of futility and desperation to find an effective treatment, and their experiences with new, sometimes experimental, therapies including deriving benefits beyond the clinical. Overall, few studies have examined the patient experience of TRD, reflecting the clinical complexity of this patient population. As most literature coalesced around experiences of specific treatments, greater examination of the overall experience of TRD is needed to inform clinical practice, and administrative and funding policy decisions for interventions that may be effective for this patient population. PROSPERO registration number: CRD42022356813.

Health-care utilisation and associated economic burden in Major Depressive Disorder and Treatment-Resistant Depression in a longitudinal population-based cohort study of 110.000 patients

Major depressive disorder (MDD), and particularly treatment-resistant depression (TRD), lead to high levels of health-care use and disease burden. The aim of this study was to evaluate and compare the health-care resource utilisation and associated costs in these patient groups. It was a population-wide, retrospective analysis of NHS health-care electronic records in northwest London using the Discover-NOW platform, one of the largest interlinked datasets in Europe hosted by Imperial College Health Partners, which contains coded emergency and routine, primary and secondary, physical and mental health data, covering a population of more than 2.5 million. Eligible patients were adults with a diagnosis of MDD who had been prescribed at least one antidepressant between 2015 and 2020. A total of 110,406 patients were included, 101,333 [92%] with MDD and 9,073 [8%] with TRD. Mean duration of depression was 52.8 (SD 41.7) months for MDD and 70.8 (SD 37.8) months for TRD (p<0.0001). Patients with TRD had significantly higher risks of both psychiatric and somatic comorbidities such as anxiety, asthma, and alcohol misuse (all p<0.0001). They also demonstrated increased primary care and emergency attendance rates, more frequent and longer hospitalizations, and on average 1.5 times greater total healthcare costs compared to MDD patients. Primary care visits represented the largest proportion overall (TRD mean 162 [SD 96] vs. MDD 108 [90] visits per patient, p<0.0001; cost per patient £17,348 [SD £33,040] vs. £12,011 [£25,588], p<0.0001) during the study period. In secondary care, accident and emergency visits accounted for the highest use (TRD mean 5.5 [10.6] vs. MDD 3.54 [SD 6.0] visits per patient, p<0.0001) while non-elective hospitalisations incurred the highest costs (mean £2,518 [£8,064] vs. £1,909 [SD £6,807], p<0.0001). Demand increased with the duration of depression and the number of lines of treatment. The study highlights the substantial clinical and economic burden associated with MDD and especially TRD across different care settings.

A multisite observational real-world study on the effectiveness of repetitive transcranial magnetic stimulation therapy for patients with treatment-resistant depression in Japan

The objective of this study was to reveal the effectiveness of repetitive transcranial magnetic stimulation (rTMS) for Japanese patients with treatment-resistant depression (TRD) in clinical practice, based on real-world data from a nationwide multicenter observational study in Japan.Clinical data of patients with TRD treated with rTMS (NeuroStar TMS treatment system) under public insurance coverage were retrospectively collected from 21 institutes nationwide between June, 2019 and December, 2023. Depression severity was assessed by the 17-item Hamilton Depression Rating Scale (HAMD-17). Response and remission were defined as ≥50% reduction from baseline and ≤7 points on the HAMD-17, respectively. The primary outcome was the changes in the HAMD-17 score from baseline to the endpoint following rTMS. Data from 497 patients with TRD were candidates for this study. The HAMD-17 scores (mean (SD)) improved significantly from 18.9 (5.3) to 9.7 (6.6), respectively. The response and remission rates at the end of rTMS therapy as assessed by the HAMD-17 were 53.5% and 42.8%, respectively. The dropout rate due to adverse effects was 4.2%, and the treatment was generally well tolerated. No convulsive seizures or manic changes were observed. These results indicate that conventional rTMS is effective and safe in Japanese patients with TRD.

Unilateral and bilateral theta burst stimulation for treatment-resistant depression: Follow up on a naturalistic observation study

ObjectivesTheta burst stimulation (TBS) is a novel and faster modality of transcranial magnetic stimulation, which is showing promise as a treatment-resistant depression (TRD) treatment. Though TBS can be applied unilaterally or bilaterally, few studies have compared the effectiveness of both approaches in a naturalistic clinical sample. In this retrospective chart review, we aimed to: (1) replicate previous bilateral sequential TBS effectiveness in a larger cohort of patients at a single centre, (2) present treatment outcome data between unilateral and bilateral TBS approaches, (3) investigate baseline factors associated with our observed outcomes, and (4) examine the sustainability of response, with follow-up data up to 6 months from patients. MethodsWe included 161 patients who received TBS (unilateral: n = 64 (40%), 45.55 ± 14.25 years old, 55% females; bilateral: n = 97 (60%), 47.67 ± 15.11 years old, 58% females). ResultsFirstly, we observed 47% response and 34% remission in the bilateral group, replicating findings from a smaller naturalistic study from our group; patients receiving unilateral TBS displayed 36% response and 26% remission, with no significant differences found between unilateral and bilateral TBS in remission and response rates. Secondly, bilaterally stimulated patients needed fewer treatments than those stimulated unilaterally (27 vs 29 on average respectively, t [159] = 3.31, p = .001), and had significantly lower anxiety symptoms post treatment (GAD-7) relative to patients receiving unilateral stimulation, F (1,148) = 3.95, p = .049. Thirdly, no baseline factors were found to predict treatment outcomes. Lastly, after six months, 69% of patients who met the response criteria did not require additional treatment or a change in medication. ConclusionsOur findings support the efficacy and tolerability of TBS in TRD and indicate that bilateral TBS may have a superior anxiolytic effect and offer a slightly faster time to response.

A new pharmacological strategy against treatment-resistant depression

Major depressive disorder affects more than 50 million people in the world. However, 50% of patients don't respond to two or more drugs or psychotherapeutic treatments, named treatment-resistant depression (TRD). In this work, we propose a new augmentation treatment against TRD based on combining Fluoxetine (FLX) and the N-terminal fragment Galanin, GAL(1–15). In Wistar Kyoto (WKY) rats, akin to endogenous depression genetically, we evaluate GAL(1–15)’s impact on FLX-induced behaviours on tests measuring despair and anhedonia. We explored GALR2 involvement using the antagonist M871 and an in vivo model with siRNA 5-HT1A knockdown. Also, the 5-HT1AR was analyzed by autoradiography binding in several brain regions. We analyze the corticosterone levels and a dexamethasone-suppressed corticotropin-releasing hormone stimulation to study the HPA axis regulation. Our results shows that only the combination of FLX + GAL(1–15) induced antidepressant effects in the WKY animals in Behavioural tests related to despair. This combination also reduced corticosterone levels in the WKY animals and modulated the functional characteristics of the serotoninergic receptor 5-HT1A in the prefrontal cortex. These novel results suggest combining GAL(1–15) with FLX is a new potentiation strategy in TRD cases. It shows the innovative potential of the interactions between the galaninergic and serotonergic systems to find new strategies and drugs against resistant depression.

Glutamatergic Modulators for Major Depression from Theory to Clinical Use.

Major depressive disorder (MDD) is a chronic, burdensome, highly prevalent disease that is characterized by depressed mood and anhedonia. MDD is especially burdensome as approved monoamine antidepressant treatments have weeks-long delays before clinical benefit and low remission rates. In the past 2decades, a promising target emerged to improve patient outcomes in depression treatment: glutamatergic signaling. This narrative review provides a high-level overview of glutamate signaling in synaptogenesis and neural plasticity and the implications of glutamate dysregulation in depression. Based on this preclinical evidence implicating glutamate in depression and the rapid improvement of depression with ketamine treatment in a proof-of-concept trial, a range of N-methyl-D-aspartate (NMDA)-targeted therapies have been investigated. While an array of treatments has been investigated in registered phase 2 or 3 clinical trials, the development of most of these agents has been discontinued. Multiple glutamate-targeted antidepressants are actively in development, and two are approved. Nasal administration of esketamine (Spravato®) was approved by the US Food and Drug Administration (FDA) in 2019 to treat adults with treatment-resistant depression and in 2020 for adults with MDD with acute suicidal ideation or behavior. Oral combination dextromethorphan-bupropion (AXS-05, Auvelity® extended-release tablet) was FDA approved in 2022 for the treatment of MDD in adults. These approvals bolster the importance of glutamate in depression and represent an exciting breakthrough in contemporary psychiatry, providing new avenues of treatment for patients as first-line therapy or with either poor response or unacceptable side effects to monoaminergic antidepressants.

How Should We Expand Access to Psychedelics While Maintaining an Environment of Peace and Safety?

Psychedelics have long been used by individuals seeking peace and a sense of wellness. This article examines widespread adoption of ketamine as a proxy for psychedelics. For ketamine, there is a need to protect vulnerable persons from exploitation that should be balanced against risks of hypermedicalization. This article suggests strategies for striking such a balance, including by carefully differentiating between persons with psychiatric illnesses, such as treatment-resistant depression, who could benefit from psychedelics, and persons using psychedelics for peace and wellness under careful guidance.