Effects In Treatment-resistant Depression Research Articles

Depression with comorbid borderline personality disorder - could ketamine be a treatment catalyst?

Borderline personality disorder (BPD) is diagnosed in 10-30% of patients with major depressive disorder (MDD), and the frequency of MDD among individuals with BPD reaches over 80%. The comorbidity of MDD and BPD is associated with more severe depressive symptoms and functional impairment, higher risk of treatment resistance and increased suicidality. The effectiveness of ketamine usage in treatment resistant depression (TRD) has been demonstrated in numerous studies. In most of these studies, individuals with BPD were not excluded, thus given the high co-occurrence of these disorders, it is possible that the beneficial effects of ketamine also extend to the subpopulation with comorbid TRD and BPD. However, no protocols were developed that would account for comorbidity. Moreover, psychotherapeutic interventions, which may be crucial for achieving a lasting therapeutic effect in TRD and BPD comorbidity, were not included. In the article, we discuss the results of a small number of existing studies and case reports on the use of ketamine in depressive disorders with comorbid BPD. We elucidate how, at the molecular and brain network levels, ketamine can impact the neurobiology and symptoms of BPD. Furthermore, we explore whether ketamine-induced neuroplasticity, augmented by psychotherapy, could be of use in alleviating core BPD-related symptoms such as emotional dysregulation, self-identity disturbances and self-harming behaviors. We also discuss the potential of ketamine-assisted psychotherapy (KAP) in BPD treatment. As there is no standard approach to the application of ketamine or KAP in individuals with comorbid TRD and BPD, we consider further research in the field as imperative. The priorities should include development of dedicated protocols, distinguishing subpopulations that may benefit most from such treatment and investigating factors that may influence its effectiveness and safety.

Sleep Delta power, age, and sex effects in treatment-resistant depression

Electroencephalographic (EEG) deficits in slow wave activity or Delta power (0.5–4 Hz) indicate disturbed sleep homeostasis and are hallmarks of depression. Sleep homeostasis is linked to restorative sleep and potential antidepressant response via non-rapid eye movement (NREM) slow wave sleep (SWS) during which neurons undergo essential repair and rejuvenation. Decreased Low Delta power (0.5–2 Hz) was previously reported in individuals with depression. This study investigated power levels in the Low Delta (0.5-<2 Hz), High Delta (2–4 Hz), and Total Delta (0.5–4 Hz) bands and their association with age, sex, and disrupted sleep in treatment-resistant depression (TRD). Mann-Whitney U tests were used to compare the nightly progressions of Total Delta, Low Delta, and High Delta in 100 individuals with TRD and 24 healthy volunteers (HVs). Polysomnographic parameters were also examined, including Total Sleep Time (TST), Sleep Efficiency (SE), and Wake after Sleep Onset (WASO). Individuals with TRD had lower Delta power during the first NREM episode (NREM1) than HVs. The deficiency was observed in the Low Delta band versus High Delta. Females with TRD had higher Delta power than males during the first NREM1 episode, with the most noticeable sex difference observed in Low Delta. In individuals with TRD, Low Delta power correlated with WASO and SE, and High Delta correlated with WASO. Low Delta power deficits in NREM1 were observed in older males with TRD, but not females. These results provide compelling evidence for a link between age, sex, Low Delta power, sleep homeostasis, and non-restorative sleep in TRD.

Efficacy of intravenous ketamine and intranasal esketamine with dose escalation for Major depression: A systematic review and meta-analysis

ObjectiveIntravenous (IV) racemic ketamine and intranasal (IN) esketamine have demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). This systematic review aims to evaluate the efficacy and safety of ketamine and esketamine at various dosages for depression. MethodsWe included randomized controlled trials (RCTs) with parallel group dose comparison of ketamine and esketamine for depression/TRD. Ovid Medline, Embase, PsycINFO, Scopus and Cochrane databases were searched. Standardized mean differences were calculated using Hedges'-g to complete random effects meta-analysis. The efficacy outcomes were changes in depression outcomes for IV ketamine and IN esketamine respectively. Safety was assessed by reported adverse effects. ResultsA random effects meta-analysis of studies (n = 12) showed efficacy in reducing depression symptoms with IV ketamine (Hedges'g = 1.52 [0.98–2.22], Z = 4.23, p < 0.001) and IN esketamine (Hedges' g = 0.31 [0.18–0.44], Z = 4.53, P < 0.001) compared to control/placebo. Treatment response was observed at IV ketamine doses ≤0.2 mg/kg, >0.2–0.5 mg/kg and > 0.5 mg/kg. Higher IV ketamine doses (>0.5 mg/kg) did not lead to greater treatment response. Esketamine doses of 56–84 mg were superior to 28 mg dose. LimitationsOverall quality of evidence was low and limited by small number of studies. Publication bias was high. ConclusionsThis meta-analysis suggests that IV ketamine may be efficacious at doses as low as 0.2 mg/kg, with increasing dose response at 0.5 mg/kg, without demonstrable increased benefit at 1 mg/kg, based on a small number of studies. Efficacy for IN esketamine increases with doses above 28 mg with best response being found between 56 and 84 mg for reducing depressive symptoms.

An Update on the Efficacy of Single and Serial Intravenous Ketamine Infusions and Esketamine for Bipolar Depression: A Systematic Review and Meta-Analysis.

Ketamine has shown rapid antidepressant and anti-suicidal effects in treatment-resistant depression (TRD) with single and serial intravenous (IV) infusions, but the effectiveness for depressive episodes of bipolar disorder is less clear. We conducted an updated systematic review and meta-analysis to appraise the current evidence on the efficacy and tolerability of ketamine/esketamine in bipolar depression. A search was conducted to identify randomized controlled trials (RCTs) and non-randomized studies examining single or multiple infusions of ketamine or esketamine treatments. A total of 2657 articles were screened; 11 studies were included in the systematic review of which 7 studies were included in the meta-analysis (five non-randomized, N = 159; two RCTs, N = 33) with a mean age of 42.58 ± 13.1 years and 54.5% females. Pooled analysis from two RCTs showed a significant improvement in depression symptoms measured with MADRS after receiving a single infusion of ketamine (1-day WMD = -11.07; and 2 days WMD = -12.03). Non-randomized studies showed significant response (53%, p < 0.001) and remission rates (38%, p < 0.001) at the study endpoint. The response (54% vs. 55%) and remission (30% vs. 40%) rates for single versus serial ketamine infusion studies were similar. The affective switch rate in the included studies approximated 2.4%. Esketamine data for bipolar depression are limited, based on non-randomized, small sample-sized studies. Further studies with larger sample sizes are required to strengthen the evidence.

Pharmacists’ perspectives on psilocybin in Canada

BackgroundPsilocybin is the main psychoactive component of a naturally occurring psychedelic organism commonly referred to as “magic mushrooms.” Existing literature demonstrates beneficial neurologic effects in treatment-resistant depression, cancer-associated depression and anxiety, and substance use. The evidence base for psilocybin use is on the rise with the U.S. Food and Drug Administration owing to a resurgence in clinical research. As such, pharmacists need to be adequately equipped to navigate questions from consumers and care providers. There is currently no literature describing pharmacists’ perspectives on psilocybin. Evaluating pharmacists’ knowledge, experiences, and opinions about psilocybin may yield beneficial and applicable data to develop educational programs and clinical tools and guide psilocybin policy making. ObjectiveThe objective of this study was to evaluate the interest and opinions of pharmacists on psilocybin as an emerging therapeutic option. MethodsLicensed pharmacists in Canada were invited to participate in an anonymous, online, 44-item survey aimed at evaluating pharmacists’ experiences, knowledge, and attitudes toward psilocybin. Recruitment for the study was done through multiple Canadian pharmacy association newsletters and via LinkedIn. ResultsResults showed that 73% of pharmacists lacked formal education about psilocybin. Forty percent of pharmacists had conversations about psilocybin less than once a month whereas 60% of pharmacists have never received questions about psilocybin. Furthermore, pharmacists are not comfortable with their knowledge with making recommendations (75%), monitoring (57%), or recommending doses of psilocybin (64%) to patients. ConclusionPharmacists are open to embracing a role in psilocybin therapy and dispensing. Creation of clinical practice guidelines and increased accessibility to education materials are necessary to supplement pharmacists’ knowledge on psilocybin and improve their confidence when advising patients.

The Montreal model: an integrative biomedical-psychedelic approach to ketamine for severe treatment-resistant depression.

Subanesthetic ketamine has accumulated meta-analytic evidence for rapid antidepressant effects in treatment-resistant depression (TRD), resulting in both excitement and debate. Many unanswered questions surround ketamine's mechanisms of action and its integration into real-world psychiatric care, resulting in diverse utilizations that variously resemble electroconvulsive therapy, conventional antidepressants, or serotonergic psychedelics. There is thus an unmet need for clinical approaches to ketamine that are tailored to its unique therapeutic properties. This article presents the Montreal model, a comprehensive biopsychosocial approach to ketamine for severe TRD refined over 6 years in public healthcare settings. To contextualize its development, we review the evidence for ketamine as a biomedical and as a psychedelic treatment of depression, emphasizing each perspectives' strengths, weaknesses, and distinct methods of utilization. We then describe the key clinical experiences and research findings that shaped the model's various components, which are presented in detail. The Montreal model, as implemented in a recent randomized clinical trial, aims to synergistically pair ketamine infusions with conventional and psychedelic biopsychosocial care. Ketamine is broadly conceptualized as a brief intervention that can produce windows of opportunity for enhanced psychiatric care, as well as powerful occasions for psychological growth. The model combines structured psychiatric care and concomitant psychotherapy with six ketamine infusions, administered with psychedelic-inspired nonpharmacological adjuncts including rolling preparative and integrative psychological support. Our integrative model aims to bridge the biomedical-psychedelic divide to offer a feasible, flexible, and standardized approach to ketamine for TRD. Our learnings from developing and implementing this psychedelic-inspired model for severe, real-world patients in two academic hospitals may offer valuable insights for the ongoing roll-out of a range of psychedelic therapies. Further research is needed to assess the Montreal model's effectiveness and hypothesized psychological mechanisms.

Changes in white matter microstructure following serial ketamine infusions in treatment resistant depression.

Ketamine produces fast-acting antidepressant effects in treatment resistant depression (TRD). Though prior studies report ketamine-related changes in brain activity in TRD, understanding of ketamine's effect on white matter (WM) microstructure remains limited. We thus sought to examine WM neuroplasticity and associated clinical improvements following serial ketamine infusion (SKI) in TRD. TRD patients (N= 57, 49.12% female, mean age: 39.9) received four intravenous ketamine infusions (0.5mg/kg) 2-3 days apart. Diffusion-weighted scans and clinical assessments (Hamilton Depression Rating Scale [HDRS-17]; Snaith Hamilton Pleasure Scale [SHAPS]) were collected at baseline and 24-h after SKI. WM measures including the neurite density index (NDI) and orientation dispersion index (ODI) from the neurite orientation dispersion and density imaging (NODDI) model, and fractional anisotropy (FA) from the diffusion tensor model were compared voxelwise pre- to post-SKI after using Tract-Based Spatial Statistics workflows to align WM tracts across subjects/time. Correlations between change in WM metrics and clinical measures were subsequently assessed. Following SKI, patients showed significant improvements in HDRS-17 (p-value=1.8 E-17) and SHAPS (p-value=1.97 E-10). NDI significantly decreased in occipitotemporal WM pathways (p< .05, FWER/TFCE corrected). ΔSHAPS significantly correlated with ΔNDI in the left internal capsule and left superior longitudinal fasciculus (r= -0.614, p-value=6.24E-09). No significant changes in ODI or FA were observed. SKI leads to significant changes in the microstructural features of neurites within occipitotemporal tracts, and changes in neurite density within tracts connecting the basal ganglia, thalamus, and cortex relate to improvements in anhedonia. NODDI may be more sensitive for detecting ketamine-induced WM changes than DTI.

Does the intensity of dissociation predict antidepressant effects 24 hours after infusion of racemic ketamine and esketamine in treatment-resistant depression? A secondary analysis from a randomized controlled trial.

Ketamine and esketamine have both shown significant antidepressant effects in treatment-resistant depression (TRD), and conflicting evidence suggests that induced dissociation by these drugs can be a clinical predictor of esketamine/ketamine's efficacy. This study is a secondary analysis from a bi-center, randomized, controlled trial. Participants were randomly assigned 1:1 to receive an IV infusion of esketamine (.25 mg/kg) or racemic ketamine (.50 mg/kg) over 40 minutes. Dissociative symptoms were assessed using the Clinician-Administered Dissociative State Scale (CADSS) 40 minutes following the beginning of the infusion. The variation in depression scores was measured with the Montgomery-Asberg Depression Rating Scale (MADRS), which was administered before the intervention as a baseline measure and 24 hrs, 72 hrs, and 7 days following infusion. Sixty-one patients were included in the analysis. Examining CADSS scores of 15 or below, for every 1-point increment in the CADSS score, there was a mean change of -0.5 (SD = 0.25; p-value 0.04) of predicted MADRS score from baseline to 24 hrs. The results for 72 hrs and 7 days following infusion were not significant. Limitations: This study was not designed to assess the relationship between ketamine or esketamine-induced dissociation and antidepressant effects as the main outcome, therefore confounding variables for this relationship were not controlled. We suggest a positive relationship between dissociation intensity, measured by CADSS, and antidepressant effect 24 hours after ketamine and esketamine infusion for a CADSS score of up to 15 points.

Efficacy and Safety of Esketamine Combined with Antidepressants for Treatment-Resistant Depression: A Meta-Analysis.

To evaluate the efficacy and safety of esketamine + antidepressant in treatment-resistant depression. We searched PubMed, Web of Science, Embase, CNKI, and Wanfang databases to obtain published information on esketamine + antidepressant from inception to July 2022. We searched for randomized controlled studies on the treatment of depression with a double-blind induction phase. Outcome indicators included changes in Montgomery-Asberg Depression Rating Scale (MADRS) scores before and after treatment, effective response rate, remission rate, and changes in self-rating depression scale (SDS). We analyzed data using Review Manager 5.4 and assessed the quality of evidence using Grading of Recommendations Assessment, Development, and Evaluation (GRADE) analysis. A total of seven articles were included, including 701 patients in the esketamine + antidepressant group and 551 in the placebo group. Meta-analysis results showed that esketamine + antidepressant could improve the MADRS score in patients with treatment-resistant depression (MD = -2.68, 95% CI -3.98 to -1.37, P < 0.0001), SDS (MD = -2.9, 95% CI -4.01 to -1.79, P < 0.00001), response rate at the end of the double-blind induction period (RR = 1.28, 95% CI 1.12 to 1.46, P = 0.0002), remission rate at the end of the double-blind induction period (RR = 1.39, 95% CI 1.18 to 1.63, P < 0.0001), Five-Dimensional Health Scale (EQ-5D-5L) (MD = 0.05, 95% CI 0.02 to 0.08, P = 0.00009), Visual Analogue Scale of Health Status (EQ-VAS) (MD = 5.54, 95% CI 2.37 to 8.71, P = 0.0006). Esketamine + antidepressant has an obvious curative effect in treatment-resistant depression and can rapidly improve depression in patients, quality of life and satisfaction, but minor adverse reactions can occur.

Transcutaneous Vagal Nerve Stimulation in Treatment-Resistant Depression: A Feasibility Study

BackgroundMajor depression (MD) contributes significantly to the global burden of disease with up to one-third of patients being treatment resistant. Therefore, the development of new treatment options for treatment-resistant depression (TRD) is needed. Vagus nerve stimulation (VNS) has shown mood improvements in patients with TRD. However, due to high costs related to the implantation and the invasive nature of VNS, an application with transcutaneous VNS (t-VNS) has been developed stimulating a vagal nerve branch in the earlobe (Arnold's nerve). A few studies with t-VNS in MD have shown a possible antidepressant effect, but feasibility is poorly described and patients with TRD have not been investigated. ObjectivesAs the full antidepressant effect of t-VNS takes months we wanted to assess feasibility and side effects of daily treatments. Materials and MethodsSingle-arm feasibility trial assessing compliance, usability, side effects, cognitive speed, and depression in a four-week period with a recommended t-VNS stimulation duration of four hours per day in patients with TRD. The primary outcome was compliance with 80% of the recommended daily treatment time. ResultsCompliance threshold was reached for 80.0% of the 20 included participants. Usability was acceptable. Side effects were few, mild or moderate, mostly as local effects at the contact point in the ear. The device was difficult to use for some participants. A statistically significant reduction in depression severity and an increase in cognitive speed were seen with unchanged suicidal ideation and sleep. ConclusionsWe would recommend larger long-term randomized studies of t-VNS to access any antidepressant effect in TRD. The design of the device might be improved for higher usability.

The role of ketamine in the treatment of treatment-resistant bipolar depression

Treatment-Resistant Depression (TRD) calls for the development of effective interventions for mood elevation and stabilization. Recently, both ketamine and its S-enantiomer (esketamine) have been investigated with successful clinical trials demonstrating effectiveness in TRD. More specifically, in 2019, intranasally administered esketamine, as opposed to the more effective intravenous ketamine, has been approved by the FDA as a treatment option for TRD. Treatment with esketamine, however, potentially comes with major adverse effects, including risk of psychosis, the possibility of abuse and dependence after repeated use, transient but non-negligible change in blood pressure and the heart rate, and potential toxicity on the urothelium and the liver. These risks are minimized when treatment is kept within the recommended dose range and the drug is administered by experienced medical personnel. Nevertheless, these risks appear to be offset by the effectiveness of esketamine in a wide range of depressive symptoms, such as anhedonia, anxiety, cognitive impairment, suicidality, and general dysfunction. This review highlights the need for more phase 4 clinical studies to evaluate esketamine's performance in real life, including long-term effectiveness and risk studies.

Occurrence of Side Effects in Treatment-Resistant Depression: Role of Clinical, Socio-Demographic and Environmental Characteristics.

Introduction: Treatment-resistant depression (TRD) is a disabling psychiatric condition characterized by the failure of two antidepressants (ADs). Since the occurrence of side effects (SEs) appears to be one of the main determinants of early discontinuation of pharmacological treatments contributing to a pseudo-resistance, the purpose of this study was to determine the parameters associated with the occurrence of SEs under ADs in a cohort of patients with TRD.Methods: An observational, cross-sectional, multicentre study was carried out using data from the French network of Expert Centers for TRD. For the 108 patients enrolled in the study, the statistical analyses focused on the overall occurrence and on the profile of the SEs (9 categories, 32 items).Results: SEs were influenced by age and sex and were positively associated with the intensity of anxious, depressive and suicidal symptoms, a history of childhood trauma (sexual abuse, emotional abuse and neglect), and negatively associated with self-esteem, and assessment of overall functioning.Conclusion: Using variables accessible in common practice, these results fall within the dynamic of a more tailored approach to medicine that could allow, through integrated pharmacological management, the continuation of antidepressant treatments, and therefore limit the risk of therapeutic failure.

Copper and Impulsivity in Ketamine Treatment for Treatment-Resistant Mood Disorders.

Treatment-resistant mood disorders, including both major depressive disorder (MDD) and bipolar disorder (BD), are challenging to treat, as limited interventions exist. Ketamine exhibits an antidepressive effect in treatment-resistant depression. Abnormal copper levels might be associated with symptoms of depression. Impulsivity is related to measures of depression, both in MDD and in BD. The aim of this paper is to explore the associations between blood copper levels and impulsivity in patients who are treatment-resistant, in the course of treatment-resistant mood disorders. The paper does not support evidence for the link between copper concentrations and impulsivity outcomes in the course of short-term ketamine treatment.

A Systematic Review on the Efficacy of Intravenous Racemic Ketamine for Bipolar Depression.

Ketamine, a glutamate N-methyl-d-aspartate receptor antagonist, has shown rapid antidepressant effects in treatment-resistant depression. We conducted a systematic review of studies evaluating the efficacy of intravenous ketamine augmentation in treatment-resistant depression patients with bipolar disorder. Major databases were searched for open-label and randomized controlled trials (RCT). Two independent reviewers screened and selected the studies that met the inclusion criteria. Studies were selected following the standard Cochrane methodology, and the findings are reported according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Methodological quality of the included studies was assessed using standardized measures. A total of 1442 articles were screened. Five studies were included in the systematic review (3 RCTs and 2 open-label studies) enrolling 110 subjects (mean age, 45.54 ± 12.65 years; 68.18% female). All the RCTs and open-label studies showed improvement in depressions symptoms after receiving a single infusion of ketamine. Included studies also suggested improvement in suicidal ideation and anhedonia after ketamine infusion. Dissociation and transient increase in blood pressure were the most common reported adverse effects with ketamine. Ketamine infusions did not increase mania symptoms. Limited data show efficacy and feasibility of intravenous racemic ketamine in treatment-resistant bipolar depression. Further studies with larger sample size are required to strengthen the evidence.

Neurocognitive performance of repeated versus single intravenous subanesthetic ketamine in treatment resistant depression

BackgroundKetamine demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). However, evaluation of ketamine's neurocognitive effect in TRD is unclear. We aim to (1) characterize baseline neurocognitive performance as a predictor of the change in severity of depressive symptoms over time, and (2) investigate the association of six versus single intravenous (IV) ketamine and neurocognitive changes from baseline to the end of treatment. MethodsSubjects with TRD were randomized to receive either five IV midazolam followed by a single IV ketamine or six IV ketamine during a 12-day period. Depression symptom assessments occurred prior and 24 h after infusion days using the Montgomery–Åsberg Depression Rating Scale. Neurocognitive tasks were designed to test attention, memory, speed of processing, and set shifting using the CogState battery at baseline and at the end of treatment. ResultsBetter complex working memory at baseline predicted improvement in MADRS scores of ketamine (vs midazolam) after 5 infusions. Most, but not all, neurocognitive functions remained stable or improved after repeated or single ketamine. There was a greater differential effect of treatment on speed of processing, set shifting, and spatial working memory that favors subjects in the six ketamine group. These cognitive improvements from baseline to the end of treatment were robust when controlling for age and changes in depression severity. ConclusionThe study suggests that six IV ketamine compared to single IV ketamine has a mood independent procognitive effect among TRD patients. Large scale studies are needed to confirm whether ketamine enhances cognitive function in TRD.

Ketamine for depression clinical issues.

Major depressive disorder (MDD) is a debilitating illness with significant morbidity and mortality, leading to attempted and completed suicides. It affects interpersonal relationships and also contributes to decreased productivity, causing financial burden to individuals and society. Patients often fail to respond to various antidepressant medication trials resulting in treatment-resistant depression (TRD). Current antidepressant medications work by modulating the monoaminergic systems and takes several weeks to establish a clinical response. Ketamine has been used extensively as an anesthetic agent since the 1970s, and more recent research has shown its rapid and robust effectiveness in TRD the subject of this review. Ketamine is a racemic mixture comprised of two enantiomers (R)-ketamine and (S)-ketamine and acts as an NMDA receptor antagonist. Most research studies have explored its antidepressant and antisuicidal effects by using it as an intravenous infusion or via the intranasal route due to increased bioavailability. Recently an intranasal esketamine spray was approved by the United States Food and Drug Administration (FDA) for TRD as an adjunct to standard antidepressant treatment in a supervised setting. Regarding its safety profile, multiple research studies have established the short-term safety and efficacy of ketamine in TRD. The cardiorespiratory and neuropsychiatric adverse events observed in these studies were mostly transient. However, ketamine is a scheduled agent with abuse potential, making its long-term use challenging and mandating further research.

The metaplastic effects of ketamine on sucrose renewal and contextual memory reconsolidation in rats

Metaplastic effects of the NMDARs blocker ketamine at the neural and behavioural levels have been described as potential mechanisms underlying the beneficial effects in treatment-resistant depression. However, ketamine effects on addictive behaviours are still unexplored. In the present study, we investigated the effects of ketamine given under a “metaplasticity-inducing dose regimen” on sucrose-related renewal and contextual memory reconsolidation in rats.After a molecular analysis of ketamine modulation of GluN2B, GluA1 and mGluR5 receptors levels in nucleus accumbens, hippocampus and amygdala, two behavioural models were used to investigate ketamine effects: i) context-induced renewal of sucrose-seeking, and ii) sucrose memory reconsolidation. Ketamine was administrated 24 h before the renewal test or the retrieval.At the molecular level, ketamine i) decreased GluN2B, GluA1 and mGluR5 receptors in hippocampus, ii) decreased GluA1 and mGluR5 but increased GluN2B in nucleus accumbens and iii) increased GluN2B and mGluR5 in amygdala. At the behavioural level, ketamine given prior to renewal significantly inhibited responding compared to vehicle, while no significant effects were observed on reconsolidation of contextual memory.In conclusion, the molecular analysis of ketamine metaplastic effects in key brain areas suggest a possible involvement of glutamatergic receptors in the inhibition of sucrose renewal but not of contextual memory reconsolidation. The inhibition of renewal could be correlated to hippocampal and accumbal decreased levels of GluA1 and mGluR5, whereas, the lack of effect on contextual memory reconsolidation could be correlated to decreased GluN2B expression in hippocampus, landmark of destabilization-insensitive state.

123. Inhaled Nitrous Oxide as a Rapid Acting Antidepressant

N-methyl-D-aspartate receptor antagonists (e.g., ketamine) have rapid antidepressant effects in treatment-resistant depression (TRD). Ongoing studies demonstrate that nitrous oxide, an inhalational general anesthetic and N-methyl-D-aspartate receptor antagonist, may be a rapidly acting TRD treatment.

Relative effectiveness of tricyclic antidepressant versus monoamine oxidase inhibitor monotherapy for treatment-resistant depression

ObjectivesAntidepressants may be less effective in treatment-resistant depression (TRD). In this exploratory study, we examined the widely held hypothesis that monoamine oxidase inhibitor (MAOI) therapy may be superior to tricyclic antidepressant (TCA) therapy for TRD. We also examined the influence of the number of prior treatment trials on TCA versus MAOI effectiveness in TRD. MethodsData were retrospectively extracted from approximately 2,500 treatment charts of patients with TRD who were attending a university mood disorder clinic between 1983 and 2015. Hierarchical linear modeling was used to examine the efficacy of drug class on outcome as well as the interaction between drug class and the number of prior antidepressant trials. Results147 treatment outcome observations were made from 94 unipolar, depressed patients who either received TCA (N = 47) or MAOI (N = 100) monotherapy for TRD. For patients unresponsive to at least one prior trial, drug class significantly predicted end-of-treatment CGI/S scores, with TCAs showing worse (i.e., higher) end-of-treatment CGI/S scores relative to MAOI therapy (b = 1.04, t = 4.98, p < 0.0001). When examining the interaction between drug class and the number of prior antidepressant trials, the interaction effect was significant (b = −0.50, t = −2.43, p = 0.02); however, the advantage for MAOI versus TCA therapy decreases with more prior, failed, antidepressant trials. ConclusionResults suggest that MAOIs may be more effective than TCAs for early stage TRD. This difference in effectiveness between MAOIs and TCAs diminished as the number of prior treatment trials increased. However, the TCA sample size was limited and the analysis was retrospective with non-randomized conditions.

Nitrous Oxide Induces Prominent Cell Proliferation in Adult Rat Hippocampal Dentate Gyrus.

The identification of distinct and more efficacious antidepressant treatments is highly needed. Nitrous oxide (N2O) is an N-methyl-D-aspartic acid (NMDA) antagonist that has been reported to exhibit antidepressant effects in treatment-resistant depression (TRD) patients. Yet, no studies have investigated the effects of sub-anesthetic dosages of N2O on hippocampal cell proliferation and neurogenesis in adult brain rats. In our study, adult male Sprague-Dawley rats were exposed to single or multiple exposures to mixtures of 70% N2O and 30% oxygen (O2). Sham groups were exposed to 30% O2 and the control groups to atmospheric air. Hippocampal cell proliferation was assessed by bromodeoxyuridine (BrdU) incorporation, and BrdU-positive cells were counted in the dentate gyrus (DG) using confocal microscopy. Results showed that while the rates of hippocampal cell proliferation were comparable between the N2O and sham groups at day 1, levels increased by 1.4 folds at day 7 after one session exposure to N2O. Multiple N2O exposures significantly increased the rate of hippocampal cell proliferation to two folds. Therefore, sub-anesthetic doses of N2O, similar to ketamine, increase hippocampal cell proliferation, suggesting that there will ultimately be an increase in neurogenesis. Future studies should investigate added N2O exposures and their antidepressant behavioral correlates.