Treatment-resistant Depression In Adults Research Articles

Antidepressants Moving in Pipeline

Antidepressants Moving in Pipeline

Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD)

Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18–70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p = 0.02, p-adj = 0.14, d = −0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.

Psychological therapies for treatment-resistant depression in adults.

Psychological therapies for treatment-resistant depression in adults.

PMH23 - Predictors of All-Cause Healthcare Payments Among Patients With Treatment-Resistant Major Depressive Disorder

Treatment-resistant depression (TRD), defined as episodes of major depressive disorder (MDD) that do not respond to at least 2 lines of adequate depression therapy, is associated with a high economic burden. Limited information exists concerning predictors of healthcare payments following TRD identification. This retrospective cohort study used data from the Truven Health MarketScan Commercial and Medicare Supplemental Databases (10/1/2008-9/30/2016). Patients with TRD were ≥18 years old, newly-diagnosed with MDD (≥1 inpatient admission or ≥2 outpatient visits with a primary or secondary MDD diagnosis), and newly treated with at least 3 courses of depression therapy (initiation of third course served as the TRD index date). Cohort study patients were continuously enrolled from a 12-month baseline period prior to the first course of therapy through a 12-month follow-up period after their TRD index date. Study measures included annual total all-cause healthcare payments (2016 USD) during the follow-up period. Adjusted TRD follow-up payments were estimated using a generalized linear model, controlling for demographics, baseline comorbidities, baseline resource use, and first-line class of therapy. TRD patients (n=1,112) had a mean (SD) age of 38.8 (14.1) and 60.6% were female. Mean (SD) total annual all-cause healthcare payments were $10,161 ($34,275) per patient in the TRD follow-up period, of which 34% ($3,423 [$5,817]) were outpatient payments. In multivariate modeling, younger age (18-24, 25-34, 35-44, 45-54, 55-64 vs. 65+), baseline obesity and pain, higher Charlson comorbidity score (2, 3+ vs. 0), and baseline resource use (ED visit, other visit, outpatient visit) were associated with significant increases in annual all-cause healthcare payments during the follow-up period (all P<.05). Annual all-cause healthcare payments in the 12 months following third-line therapy initiation can be substantial, particularly for younger adult TRD patients with obesity or pain-related diagnoses. Efforts to reduce this economic burden are warranted.

27.3 Ketamine for Adolescent Treatment-Resistant Depression

The anesthetic medication ketamine, an anesthetic agent and N-methyl-d-aspartate glutamate receptor antagonist, has recently been studied using sub-anesthetic doses for its antidepressant effects in adults with treatment-resistant depression (TRD). In adult TRD, a single infusion of ketamine has been shown to significantly reduce depression within hours, and serial infusions may improve response rates. However, no information is yet available about ketamine for adolescent TRD. Our study objective was to investigate the efficacy of intravenous ketamine for TRD in adolescents.

Low-dose ketamine for treatment resistant depression in an academic clinical practice setting

BackgroundRecent studies demonstrating a rapid, robust improvement in treatment resistant depression (TRD) following a single sub-anesthetic infusion of ketamine have generated much excitement. However, these studies are limited in their generalizability to the broader TRD population due to their subject exclusion criteria which typically limit psychiatric comorbidity, concurrent medication, and level of suicide risk. This paper describes the safety and efficacy of sub-anesthetic ketamine infusions in a naturalistic TRD patient sample participating in a real-world TRD treatment program within a major university health system. MethodsThe effects of a sub-anesthetic dose (0.5mg/kg) of ketamine infused IV over forty minutes on TRD patients participating in a treatment program at the University of California, San Diego was investigated by retrospectively analyzing the medical charts of 41 adult TRD patients with a diagnosis of Major Depressive Disorder (MDD) or Bipolar Disorder (BD). ResultsSubjects were aged 48.6, 78% white, 36.6% female, and 82.9% had MDD. Significant psychiatric comorbidity existed in 73%. Average pre-infusion BDI score was 32.6 ± 8.4 (S.D) and dropped to 16.8 ± 3.1 at 24-h post-infusion (p < 0.001). The 24-h response (≥ 50% reduction from pre-infusion) and remission (BDI <13) rates were 53.7% and 41.5%, respectively. Three quarters of responders maintained responder status at 7-days. Ketamine infusions were well tolerated with occasional nausea or anxiety and mild hemodynamic effects during the infusion. LimitationsRetrospective nature of this study, lack of control group and use of self-report depression ratings scales. ConclusionsThis is the first published study of sub-anesthetic ketamine infusions in a real-world TRD population. The results suggest that this treatment is effective and well tolerated in this population

Ketamine for Depression: An Update

A decade has now passed since research into the antidepressant effects of ketamine began in earnest, after the clinical trial reported by Zarate et al. in 2006 ( 1 Zarate Jr, C.A. Singh J.B. Carlson P.J. Brutsche N.E. Ameli R. Luckenbaugh D.A. et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006; 63: 856-864 Crossref PubMed Scopus (2608) Google Scholar ). In that proof-of-concept study, 18 medication-free patients with treatment-resistant major depressive disorder (TRD) showed a large reduction in core depressive symptoms within hours of receiving a single low-dose 0.5 mg/kg intravenous infusion of ketamine as measured by the 21-item Hamilton Depression Rating Scale compared with saline placebo. Perhaps most strikingly, the antidepressant effects persisted without additional dosing of ketamine for days or up to several weeks in some cases. While these unexpected findings have been met with justifiable skepticism, replication from independent research programs is now fostering a degree of consensus in the field that ketamine is in fact associated with a true rapid-onset and persistent antidepressant effect, even in patients with TRD ( 2 Murrough J.W. Iosifescu D.V. Chang L.C. Al Jurdi R.K. Green C.E. Perez A.M. et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: A two-site randomized controlled trial. Am J Psychiatry. 2013; 170: 1134-1142 Crossref PubMed Scopus (808) Google Scholar , 3 Newport D.J. Carpenter L.L. McDonald W.M. Potash J.B. Tohen M. Nemeroff C.B. et al. Ketamine and other NMDA antagonists: Early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015; 172: 950-966 Crossref PubMed Scopus (401) Google Scholar ). If the observed effect is true, what are the implications and what are the critical research questions to now be asked? Sex Differences in Effects of Ketamine on Behavior, Spine Density, and Synaptic Proteins in Socially Isolated RatsBiological PsychiatryVol. 80Issue 6PreviewThe mechanistic underpinnings of sex differences in occurrence of depression and efficacy of antidepressant treatments are poorly understood. We examined the effects of isolation stress (IS) and the fast-acting antidepressant ketamine on anhedonia and depression-like behavior, spine density, and synaptic proteins in male and female rats. Full-Text PDF Bidirectional Homeostatic Regulation of a Depression-Related Brain State by Gamma-Aminobutyric Acidergic Deficits and Ketamine TreatmentBiological PsychiatryVol. 80Issue 6PreviewMajor depressive disorder is increasingly recognized to involve functional deficits in both gamma-aminobutyric acid (GABA)ergic and glutamatergic synaptic transmission. To elucidate the relationship between these phenotypes, we used GABAA receptor γ2 subunit heterozygous (γ2+/−) mice, which we previously characterized as a model animal with construct, face, and predictive validity for major depressive disorder. Full-Text PDF Open AccessIntravenous Esketamine in Adult Treatment-Resistant Depression: A Double-Blind, Double-Randomization, Placebo-Controlled StudyBiological PsychiatryVol. 80Issue 6PreviewThe purpose of this study was to assess the efficacy and safety and to explore the dose response of esketamine intravenous (IV) infusion in patients with treatment-resistant depression (TRD). Full-Text PDF Open Access

Pharmacological interventions for treatment-resistant depression in adults

Pharmacological interventions for treatment-resistant depression in adults

Psychological therapies for treatment-resistant depression in adults

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effectiveness of psychological therapies for TRD in adults.

Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes.

(Reprinted with permission from PLoS Med 2013; 10(3): e1001403).

Adjunctive Atypical Antipsychotic Treatment for Major Depressive Disorder: A Meta-Analysis of Depression, Quality of Life, and Safety Outcomes

Atypical antipsychotic medications are widely prescribed for the adjunctive treatment of depression, yet their total risk-benefit profile is not well understood. We thus conducted a systematic review of the efficacy and safety profiles of atypical antipsychotic medications used for the adjunctive treatment of depression. We included randomized trials comparing adjunctive antipsychotic medication to placebo for treatment-resistant depression in adults. Our literature search (conducted in December 2011 and updated on December 14, 2012) identified 14 short-term trials of aripiprazole, olanzapine/fluoxetine combination (OFC), quetiapine, and risperidone. When possible, we supplemented published literature with data from manufacturers' clinical trial registries and US Food and Drug Administration New Drug Applications. Study duration ranged from 4 to 12 wk. All four drugs had statistically significant effects on remission, as follows: aripiprazole (odds ratio [OR], 2.01; 95% CI, 1.48-2.73), OFC (OR, 1.42; 95% CI, 1.01-2.0), quetiapine (OR, 1.79; 95% CI, 1.33-2.42), and risperidone (OR, 2.37; 95% CI, 1.31-4.30). The number needed to treat (NNT) was 19 for OFC and nine for each other drug. All drugs with the exception of OFC also had statistically significant effects on response rates, as follows: aripiprazole (OR, 2.07; 95% CI, 1.58-2.72; NNT, 7), OFC (OR, 1.30, 95% CI, 0.87-1.93), quetiapine (OR, 1.53, 95% CI, 1.17-2.0; NNT, 10), and risperidone (OR, 1.83, 95% CI, 1.16-2.88; NNT, 8). All four drugs showed statistically significant effects on clinician-rated depression severity measures (Hedges' g ranged from 0.26 to 0.48; mean difference of 2.69 points on the Montgomery-Asberg Depression Rating Scale across drugs). On measures of functioning and quality of life, these medications produced either no benefit or a very small benefit, except for risperidone, which had a small-to-moderate effect on quality of life (g = 0.49). Treatment was linked to several adverse events, including akathisia (aripiprazole), sedation (quetiapine, OFC, and aripiprazole), abnormal metabolic laboratory results (quetiapine and OFC), and weight gain (all four drugs, especially OFC). Shortcomings in study design and data reporting, as well as use of post hoc analyses, may have inflated the apparent benefits of treatment and reduced the apparent incidence of adverse events. Atypical antipsychotic medications for the adjunctive treatment of depression are efficacious in reducing observer-rated depressive symptoms, but clinicians should interpret these findings cautiously in light of (1) the small-to-moderate-sized benefits, (2) the lack of benefit with regards to quality of life or functional impairment, and (3) the abundant evidence of potential treatment-related harm. Please see later in the article for the Editors' Summary.

1H magnetic resonance spectroscopy study of thalamus in treatment resistant depressive patients

Treatment-resistant depression (TRD) is a common clinical problem, and represents a considerable challenge to treatment, however, the pathogenesis of this disease is poorly understood. Thalamus is generally believed to have a role in the pathophysiology of depression. In this study, we adopted 1.5T (1)H magnetic resonance spectroscopy ((1)H MRS) to examine possible alterations of thalamus metabolism in 20 adult TRD patients. Our results suggested there might be damage and loss of neurons, as well as membrane phospholipids associated metabolism abnormality in the TRD thalamus.

Vagus nerve stimulation therapy in depression and epilepsy: therapeutic parameter settings

Vagus nerve stimulation (VNS) therapy is an effective adjunctive treatment for chronic or recurrent treatment-resistant depression in adults, and for pharmacoresistant epilepsy in adults and adolescents. VNS therapy is administered through an implanted pulse generator that delivers programmed electrical pulses through an implanted lead to the left vagus nerve. Programmable pulse parameters include output current, frequency, pulse width, and ON/OFF times. Within a range of typical values, individual patients respond best to different combinations of parameter settings. The physician must identify the optimum settings for each patient while balancing the goals of maximizing efficacy, minimizing side effects, and preserving battery life. Output current is gradually increased from 0.25 mA to the maximum tolerable level (maximum, 3.5 mA); typical therapeutic settings range from 1.0 to 1.5 mA. Greater output current is associated with increased side effects, including voice alteration, cough, a feeling of throat tightening, and dyspnea. Frequency is typically programmed at 20 Hz in depression and 30 Hz in epilepsy. Pulse width is typically 250 or 500 micros. The recommended initial ON time is 30 s, followed by 5 min OFF; OFF time > ON time is recommended. As with pharmacotherapy, VNS therapy must be adjusted in a gradual, systematic fashion to individualize therapy for each patient.