Objective:Altered glutamatergic neurotransmission is implicated in the pathogenesis of major depressive disorder. AXS-05 (dextromethorphan-bupropion) is an oral NMDA receptor antagonist and sigma-1 ...receptor agonist, which utilizes inhibition of CYP2D6 to increase its bioavailability. This phase 2 trial assessed the efficacy and safety of dextromethorphan-bupropion in the treatment of major depressive disorder.Methods:This randomized, double-blind, multicenter, parallel-group trial evaluated dextromethorphan-bupropion versus the active comparator sustained-release bupropion in patients 18–65 years old with a diagnosis of major depressive disorder of moderate or greater severity. Patients were randomly assigned to receive either dextromethorphan-bupropion (45 mg/105 mg tablet) or bupropion (105 mg tablet), once daily for the first 3 days and twice daily thereafter, for a total of 6 weeks. The primary endpoint was overall treatment effect on Montgomery-Åsberg Depression Rating Scale (MADRS) score (average of the change from baseline for weeks 1–6), assessed in all randomized patients whose diagnosis and severity were confirmed by an independent assessor and who received at least one dose of study medication and had at least one postbaseline assessment.Results:Of 97 patients randomized, 17 did not have a confirmed diagnosis and severity based on the independent assessment, resulting in 80 patients in the efficacy population (dextromethorphan-bupropion, N=43; bupropion, N=37). The mean change from baseline in MADRS score over weeks 1–6 (overall treatment effect) was significantly greater with dextromethorphan-bupropion than with bupropion (−13.7 points vs. −8.8 points; least-squares mean difference=−4.9; 95% CI=−3.1, −6.8). MADRS score change with dextromethorphan-bupropion was significantly greater than with bupropion at week 2 and every time point thereafter (week 6: −17.3 vs. −12.1 points; least-squares mean difference=−5.2, 95% CI=−1.1, −9.3). Remission rates were significantly greater with dextromethorphan-bupropion at week 2 and every time point thereafter (week 6: 46.5% vs. 16.2%; least-squares mean difference=30.3%, 95% CI=11.2, 49.4). Response rates (≥50% decrease in MADRS score from baseline) at week 6 were 60.5% with dextromethorphan-bupropion and 40.5% with bupropion (least-squares mean difference=19.9%, 95% CI=−1.6, 41). Most secondary outcomes favored dextromethorphan-bupropion. The most common adverse events with dextromethorphan-bupropion were dizziness, nausea, dry mouth, decreased appetite, and anxiety. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, or sexual dysfunction.Conclusions:In patients with major depression, dextromethorphan-bupropion (AXS-05) significantly improved depressive symptoms compared with bupropion and was generally well tolerated.
Previous studies have suggested that neuropeptide Y (NPY) levels may be altered in patients with major depressive disorder (MDD), post‐traumatic stress disorder (PTSD) and chronic stress. We ...investigated, through systematic review and meta‐analysis, whether the mean levels of NPY are significantly different in patients with MDD, PTSD or chronic stress, compared to controls. The main outcome was the pooled standardized mean difference (SMD) with 95% confidence intervals between cases and controls, using the random‐effects model. Heterogeneity and publication bias were evaluated. Thirty‐five studies met eligibility criteria. Meta‐regression determined that medication and sex could explain 27% of the between‐study variance. Females and participants currently prescribed psychotropic medications had significantly higher levels of NPY. NPY levels were significantly lower in plasma and cerebrospinal fluid (CSF) in PTSD patients versus controls. Patients with MDD had significantly lower levels of NPY in plasma compared to controls, but not in the CSF. The magnitudes of the decrease in plasma NPY levels were not significantly different between PTSD and MDD. However, chronic stress patients had significantly higher plasma NPY levels compared to controls, PTSD or MDD. Our findings may imply a shared role of NPY in trauma and depression: nevertheless, it is not clear that the association is specific to these disorders. Psychotropic medications may help restore NPY levels. Further controlled studies are needed to better delineate the contribution of confounding variables such as type of depression, body mass index, appetite or sleep architecture.
We did a rigorous meta‐analysis to clarify discrepancies in the literature concerning the plasma and cerebrospinal fluid levels of neuropeptide Y (NPY) in subjects with major depressive disorder (MDD), post‐traumatic stress disorder (PTSD), and chronic stress. The overall effect size of the 35 pooled studies indicates that NPY levels are lower in patients with PTSD and MDD, compared to healthy controls (but not in chronic stress). Moreover, we found strong evidence of that the use of psychotropic medications and female gender are associated with higher levels of NPY.
Objective
Adiponectin, which is secreted from adipose tissue, is a protein hormone. Although a large body of studies have found that circulating adiponectin levels increase in anorexia nervosa (AN) ...and caloric restriction, the effect of subtypes of AN and modifiers of adiponectin in AN are not yet known.
Methods
A systematic search of electronic databases was performed using the search terms “adiponectin,” “anorexia nervosa,” and “eating disorder” up to January 2021. All studies published in peer‐reviewed journals, which included cases and control groups, were selected. The main outcome was the pooled standardized mean difference (SMD) in adiponectin levels between cases and controls, using the random‐effects model. Modifiers of SMD were tested via meta‐regression. Heterogeneity and publication bias were evaluated.
Results
Thirty‐four studies met all eligibility criteria. The total sample of AN participants (Hedges' g = .765, p < .0001), and specifically the binge‐eating/purging (Hedges' g = 1.211, p < .00001) and restrictive subtypes (Hedges' g = .913, p < .00001) of AN have increased adiponectin plasma levels compared with healthy controls. Meta‐regression determined that insulin, IGF‐1, BMI, triglyceride, resistin, glucose, IL‐6 levels are significant modifiers of adiponectin levels.
Discussion
Compared with controls, adiponectin levels are higher in AN overall, and specifically in the binge‐eating/purging and the restrictive AN subtypes. Many of metabolic parameters of glucose metabolism and pro‐inflammatory molecules modify the relationship between AN and adiponectin levels. Adipose tissue is important to maintain metabolic stability.
Public Significance
Anorexia nervosa is a psychiatric disorder associated with a severe decrease in body weight and multiple metabolic abnormalities, including an increase in the hormone adiponectin. In this paper, we used meta‐analysis, a powerful statistical method, to aggregate data from 34 rigorously selected research reports. This enabled us to understand the value of adiponectin to differentiate clinical subtypes of anorexia nervosa and the relations between adiponectin and other important metabolic parameters.
Resumen
Objetivo
La adiponectina, que es secretada del tejido adiposo, es una hormona proteica. Aunque una gran cantidad de estudios han encontrado que los niveles circulantes de adiponectina aumentan en la anorexia nerviosa (AN) y la restricción calórica, el efecto de los subtipos de AN y los modificadores de la adiponectina en la AN aún no se conocen.
Métodos
Se realizó una búsqueda sistemática en bases de datos electrónicas utilizando los términos de búsqueda "adiponectina", "anorexia nerviosa" y "trastorno de la conducta alimentaria" hasta enero de 2021. Se seleccionaron todos los estudios publicados en revistas revisadas por pares, que incluían casos y grupos de control. El resultado principal fue la diferencia de medias estandarizada (DME) agrupada en los niveles de adiponectina entre los casos y los controles, mediante el modelo de efectos aleatorios. Los modificadores de DME se probaron mediante metarregresión. Se evaluaron la heterogeneidad y el sesgo de publicación.
Resultados
Treinta y cuatro estudios cumplieron todos los criterios de elegibilidad. La muestra total de sujetos con AN (g de Hedges = 0.765, p < 0.0001), y específicamente los subtipos de atracones/purgaciones (g = 1,211 de Hedges, p < 0.00001) y restrictivos (g = 0.913, p < 0.00001) de AN tienen incrementados los niveles plasmáticos de adiponectina en comparación con los controles sanos. La metarregresión determinó que los niveles de insulina, IGF‐1, IMC, triglicéridos, resistina, glucosa, IL‐6 son modificadores significativos de los niveles de adiponectina.
Discusión
En comparación con los controles, los niveles de adiponectina son más altos en la AN en general, y específicamente en los subtipos de atracones/purgaciones y AN restrictiva. Muchos de los parámetros metabólicos del metabolismo de la glucosa y las moléculas proinflamatorias modifican la relación entre los niveles de AN y adiponectina. El tejido adiposo es importante para mantener la estabilidad metabólica.
Repetitive transcranial magnetic stimulation (rTMS) is a non‐invasive brain stimulation method increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that ...rTMS may help to treat addictions, but evaluation in multicenter randomized controlled trials (RCTs) is needed. We conducted a multicenter double‐blind RCT in 262 chronic smokers meeting DSM‐5 criteria for tobacco use disorder, who had made at least one prior failed attempt to quit, with 68% having made at least three failed attempts. They received three weeks of daily bilateral active or sham rTMS to the lateral prefrontal and insular cortices, followed by once weekly rTMS for three weeks. Each rTMS session was administered following a cue‐induced craving procedure, and participants were monitored for a total of six weeks. Those in abstinence were monitored for additional 12 weeks. The primary outcome measure was the four‐week continuous quit rate (CQR) until Week 18 in the intent‐to‐treat efficacy set, as determined by daily smoking diaries and verified by urine cotinine measures. The trial was registered at ClinicalTrials.gov (NCT02126124). In the intent‐to‐treat analysis set (N=234), the CQR until Week 18 was 19.4% following active and 8.7% following sham rTMS (X2=5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X2=7.219, p=0.007). The reduction in cigarette consumption and craving was significantly greater in the active than the sham group as early as two weeks into treatment. This study establishes a safe treatment protocol that promotes smoking cessation by stimulating relevant brain circuits. It represents the first large multicenter RCT of brain stimulation in addiction medicine, and has led to the first clearance by the US Food and Drug Administration for rTMS as an aid in smoking cessation for adults.
Intravenous ketamine demonstrated rapid antidepressant effects in an optimized study design, improving depression severity in 64% of treatment-resistant patients 24 hours after a single dose. The ...double-blind trial provides evidence for the role of the N-methyl-d-aspartate glutamate receptor in depression, a receptor not currently activated by existing antidepressant drugs.
ObjectiveKetamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, has shown rapid antidepressant effects, but small study groups and inadequate control conditions in prior studies have precluded a definitive conclusion. The authors evaluated the rapid antidepressant efficacy of ketamine in a large group of patients with treatment-resistant major depression.MethodThis was a two-site, parallel-arm, randomized controlled trial of a single infusion of ketamine compared to an active placebo control condition, the anesthetic midazolam. Patients with treatment-resistant major depression experiencing a major depressive episode were randomly assigned under double-blind conditions to receive a single intravenous infusion of ketamine or midazolam in a 2:1 ratio (N=73). The primary outcome was change in depression severity 24 hours after drug administration, as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS).ResultsThe ketamine group had greater improvement in the MADRS score than the midazolam group 24 hours after treatment. After adjustment for baseline scores and site, the MADRS score was lower in the ketamine group than in the midazolam group by 7.95 points (95% confidence interval CI, 3.20 to 12.71). The likelihood of response at 24 hours was greater with ketamine than with midazolam (odds ratio, 2.18; 95% CI, 1.21 to 4.14), with response rates of 64% and 28%, respectively.ConclusionsKetamine demonstrated rapid antidepressant effects in an optimized study design, further supporting NMDA receptor modulation as a novel mechanism for accelerated improvement in severe and chronic forms of depression. More information on response durability and safety is required before implementation in clinical practice.
False suffocation alarm hypothesis has been widely used to explain carbon dioxide hypersensitivity in panic disorder (PD). However, hypersensitivity to carbon dioxide has been observed in other ...psychiatric disorders. We explored the specificity of carbon dioxide inhalation as a panic provocation test among psychiatric disorders via network meta-analysis.
A systematic literature search on PubMed, EMBASE, and PsycNET was performed to acquire the studies using the carbon dioxide provocation test in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and checklists. Odds ratios (OR) for a panic attack (PA) induced by the carbon dioxide inhalation tests were extracted from each of the original studies and were pooled using the random-effects model.
Network meta-analysis on a pool of 2181 participants from 41 studies was used to compare the efficacy of carbon dioxide provocation tests among psychiatric disorders. The network meta-analysis showed that the odds for PA in response to carbon dioxide inhalation are higher in patients with PD, premenstrual dysphoric syndrome (PMDD), and social anxiety disorder (SAD) than healthy controls (HC). The odds for PA were not significantly different among patients with generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), major depressive disorder (MDD), and healthy controls (HC).
The vulnerability to the carbon dioxide provocation test is not limited to PD. The specificity of the test for PD is questionable, as individuals suffering from PMDD and SAD are also significantly more responsive to carbon dioxide inhalation compared to HC, OCD, MDD, and GAD. There may be shared underpinning biological mechanisms between PD, PMDD, and SAD.
Background Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report ...including 10 participants with treatment-resistant major depression (TRD) found that six ketamine infusions resulted in a sustained antidepressant effect. In the current report, we examined the pattern and durability of antidepressant effects of repeated ketamine infusions in a larger sample, inclusive of the original. Methods Participants with TRD ( n = 24) underwent a washout of antidepressant medication followed by a series of up to six IV infusions of ketamine (.5 mg/kg) administered open-label three times weekly over a 12-day period. Participants meeting response criteria were monitored for relapse for up to 83 days from the last infusion. Results The overall response rate at study end was 70.8%. There was a large mean decrease in Montgomery–Åsberg Depression Rating Scale score at 2 hours after the first ketamine infusion (18.9 ± 6.6, p < .001), and this decrease was largely sustained for the duration of the infusion period. Response at study end was strongly predicted by response at 4 hours (94% sensitive, 71% specific). Among responders, median time to relapse after the last ketamine infusion was 18 days. Conclusions Ketamine was associated with a rapid antidepressant effect in TRD that was predictive of a sustained effect. Future controlled studies will be required to identify strategies to maintain an antidepressant response among patients who benefit from a course of ketamine.
Background The N -methyl-D-aspartate glutamate receptor antagonist ketamine, delivered via an intravenous route, has shown rapid antidepressant effects in patients with treatment-resistant ...depression. The current study was designed to test the safety, tolerability, and efficacy of intranasal ketamine in patients with depression who had failed at least one prior antidepressant trial. Methods In a randomized, double-blind, crossover study, 20 patients with major depression were randomly assigned, and 18 completed 2 treatment days with intranasal ketamine hydrochloride (50 mg) or saline solution. The primary efficacy outcome measure was change in depression severity 24 hours after ketamine or placebo, measured using the Montgomery-Åsberg Depression Rating Scale. Secondary outcomes included persistence of benefit, changes in self-reports of depression, changes in anxiety, and proportion of responders. Potential psychotomimetic, dissociative, hemodynamic, and general adverse effects associated with ketamine were also measured. Results Patients showed significant improvement in depressive symptoms at 24 hours after ketamine compared to placebo ( t = 4.39, p < .001; estimated mean Montgomery-Åsberg Depression Rating Scale score difference of 7.6 ± 3.7; 95% confidence interval, 3.9–11.3). Response criteria were met by 8 of 18 patients (44%) 24 hours after ketamine administration compared with 1 of 18 (6%) after placebo ( p = .033). Intranasal ketamine was well tolerated with minimal psychotomimetic or dissociative effects and was not associated with clinically significant changes in hemodynamic parameters. Conclusions This study provides the first controlled evidence for the rapid antidepressant effects of intranasal ketamine. Treatment was associated with minimal adverse effects. If replicated, these findings may lead to novel approaches to the pharmacologic treatment of patients with major depression.
Replicated international studies have underscored the human and societal costs associated with major depressive disorder. Despite the proven efficacy of monoamine-based antidepressants in major ...depression, the majority of treated individuals fail to achieve full syndromal and functional recovery with the index and subsequent pharmacological treatments. Ketamine and esketamine represent pharmacologically novel treatment avenues for adults with treatment-resistant depression. In addition to providing hope to affected persons, these agents represent the first non-monoaminergic agents with proven rapid-onset efficacy in major depressive disorder. Nevertheless, concerns remain about the safety and tolerability of ketamine and esketamine in mood disorders. Moreover, there is uncertainty about the appropriate position of these agents in treatment algorithms, their comparative effectiveness, and the appropriate setting, infrastructure, and personnel required for their competent and safe implementation. In this article, an international group of mood disorder experts provides a synthesis of the literature with respect to the efficacy, safety, and tolerability of ketamine and esketamine in adults with treatment-resistant depression. The authors also provide guidance for the implementation of these agents in clinical practice, with particular attention to practice parameters at point of care. Areas of consensus and future research vistas are discussed.
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