Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.

BACKGROUND: Psilocybin is being studied for use in treatment-resistant depression. METHODS: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). RESULTS: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. CONCLUSIONS: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).

Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial.

Objective: This study compared the impact of 3 eicosapentaenoic acid (EPA) doses versus placebo on inflammatory biomarkers and depressive symptoms.Methods: Sixty-one unmedicated adults (75% female; 45.5 ± 13.8 years) with DSM-5 major depressive disorder (MDD), body mass index > 25 kg/m2, and plasma high-sensitivity C-reactive protein (hs-CRP) ≥ 3.0 mg/L were randomly assigned to receive EPA 1 g/d, 2 g/d, or 4 g/d or placebo for 12 weeks. Prespecified endpoints were a ≥ 0.40 effect size decrease in plasma interleukin (IL)-6, peripheral blood mononuclear cell (PBMC) cytokines, and lipopolysaccharide-stimulated tumor necrosis factor (TNF) production. Response was defined as a ≥ 50% decrease of Inventory of Depressive Symptomatology, Clinician-Rated version (IDS-C30) scores. We compared outcomes for the 3 EPA doses versus placebo.Results: In 45 completers, only median PBMC TNF decreased at 2 g/d EPA. No EPA dose produced a ≥ 0.35 effect size reduction in plasma IL-6 or mitogen-stimulated TNF. Response rates for EPA 4 g/d were 64%, versus 40% for placebo (odds ratio [OR] = 2.63; Cohen d = 0.53), 38% for EPA 1 g/d, and 36% for EPA 2 g/d (all P > .05). EPA 4 g/d showed a significant correlation between percent decrease in plasma hs-CRP and IDS-C30 symptom reduction at 12 weeks (Spearman ρ = 0.691, P = .019).Conclusions: EPA 4 g/d demonstrated a medium effect size for response rates versus placebo. This dose may alleviate MDD in overweight individuals with elevated inflammatory markers, and change in hs-CRP may be correlated with clinical response.Trial Registration: ClinicalTrials.gov identifier: NCT02553915.

Efficacy of Vortioxetine Monotherapy for Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Trial.

PURPOSE/BACKGROUND: There are few efficacious pharmacological treatments for posttraumatic stress disorder (PTSD) and many patients fail to benefit from existing treatments. Vortioxetine, a recently developed antidepressant, acts as a serotonin modulator through inhibition of the serotonin transporter and actions at multiple types of serotonin receptors. Its unique pharmacodynamic profile suggests it may have efficacy for the treatment of PTSD. METHODS/PROCEDURES: We conducted a 12-week placebo-controlled, randomized clinical trial of vortioxetine (flexibly dosed from 10 to 20 mg/d) versus placebo in adults with PTSD. The primary outcome was change from baseline in the past-month version of the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), analyzed using a mixed-model repeated-measures analysis of variance. FINDINGS/RESULTS: Forty-one patients were randomized, and 32 (78%) completed the 12 weeks of treatment. The mean reduction in CAPS-5 scores at week 12 did not significantly differ between the 2 arms; the effect size for the difference in changes between vortioxetine and placebo on CAPS-5 total scores at week 12 was Cohen d = 0.29. However, at week 8, the drug-placebo difference was d = 0.78, which met the multivariate criteria for statistical significance, P = 0.014. IMPLICATIONS/CONCLUSIONS: In this study of 41 patients, vortioxetine did not demonstrate superiority over placebo for adults with PTSD. Future PTSD trials may benefit from stratifying the randomization based on number of years since the index traumatic event and a history of failure to respond to treatment.

Recall accuracy for the symptoms of a major depressive episode among clinical trial participants.

For patients with major depressive disorder (MDD), approaches to treatment differ for those with a single versus recurrent episodes. Based on studies of community samples, however, accuracy is low for identifying past episodes. Recall accuracy among clinical samples with a well-defined major depressive episode (MDE) has not been examined previously. We evaluated episode recall accuracy in 79 MDD patients in follow-up of the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study at 12- and 24-month time-points after starting treatment. Using the Structured Clinical Interview for DSM-IV, patients were asked to recall whether they had been experiencing the nine criterion symptoms of an MDE at the time of their intake assessment. Accuracy of recall for the index MDE was high, with 95% of patients at month 12 and 85% at month 24 recalling sufficient symptoms to meet the diagnostic criteria. Recall accuracy for specific symptoms varied considerably, from >90% for dysphoria and anhedonia, to 55% for psychomotor and weight/appetite changes. For the thoughts of death/suicide criterion, patients with erroneous recall were significantly more likely to recall having had the symptom at the intake evaluation (though they had denied it at the time) than vice versa (p < .007). Patients who have participated in a clinical trial are likely to recall accurately a past MDE up to two years prior. Optimal vigilance for suicidal ideation for treatment-naïve patients should include a combination of self-report and clinician assessments.

Benefits of Sequentially Adding Cognitive-Behavioral Therapy or Antidepressant Medication for Adults With Nonremitting Depression.

OBJECTIVE: Adults with major depressive disorder frequently do not achieve remission with an initial treatment. Addition of psychotherapy for patients who do not achieve remission with antidepressant medication alone can target residual symptoms and protect against recurrence, but the utility of adding antidepressant medication after nonremission with cognitive-behavioral therapy (CBT) has received little study. The authors aimed to evaluate the acute and long-term outcomes resulting from both sequences of combination treatments. METHODS: Previously untreated adults with major depression who were randomly assigned to receive escitalopram, duloxetine, or CBT monotherapy and completed 12 weeks of treatment without achieving remission entered an additional 12 weeks of combination treatment. For patients who did not achieve remission with CBT, escitalopram was added (CBT plus medication group) to their treatment, and for those who did not achieve remission with an antidepressant, CBT was added (medication plus CBT group) to their treatment. Patients who responded to the combination treatment entered an 18-month follow-up phase to assess risk of recurrence. RESULTS: A total of 112 patients who did not achieve remission with a monotherapy entered combination treatment (41 who responded to monotherapy but did not achieve remission and 71 who did not respond to monotherapy). Overall, remission rates after subsequent combination therapy were significantly higher among patients who responded to monotherapy but did not achieve remission (61%) than among patients who did not respond to monotherapy (41%). Among patients who responded to monotherapy but did not achieve remission, the remission rate in the CBT plus medication group (89%) was higher than in the medication plus CBT group (53%). However, among patients whose depression did not respond to monotherapy, rates of response and remission were similar between the treatment arms. Higher levels of anxiety, both prior to monotherapy and prior to beginning combination treatment, predicted poorer outcomes for both treatment groups. CONCLUSIONS: The order in which CBT and antidepressant medication were sequentially combined did not appear to affect outcomes. Addition of an antidepressant is an effective approach to treating residual symptoms for patients who do not achieve remission with CBT, as is adding CBT after antidepressant monotherapy. Patients who do not respond to one treatment modality warrant consideration for addition of the alternative modality.

Effects of Patient Preferences on Outcomes in the Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) Study.

OBJECTIVE: The Predictors of Remission in Depression to Individual and Combined Treatments [PReDICT] study aimed to identify clinical and biological factors predictive of treatment outcomes in major depressive disorder among treatment-naive adults. The authors evaluated the efficacy of cognitive-behavioral therapy (CBT) and two antidepressant medications (escitalopram and duloxetine) in patients with major depression and examined the moderating effect of patients' treatment preferences on outcomes. METHOD: Adults aged 18-65 with treatment-naive major depression were randomly assigned with equal likelihood to 12 weeks of treatment with escitalopram (10-20 mg/day), duloxetine (30-60 mg/day), or CBT (16 50-minute sessions). Prior to randomization, patients indicated whether they preferred medication or CBT or had no preference. The primary outcome was change in the 17-item Hamilton Depression Rating Scale (HAM-D), administered by raters blinded to treatment. RESULTS: A total of 344 patients were randomly assigned, with a mean baseline HAM-D score of 19.8 (SD=3.8). The mean estimated overall decreases in HAM-D score did not significantly differ between treatments (CBT: 10.2, escitalopram: 11.1, duloxetine: 11.2). Last observation carried forward remission rates did not significantly differ between treatments (CBT: 41.9%, escitalopram: 46.7%, duloxetine: 54.7%). Patients matched to their preferred treatment were more likely to complete the trial but not more likely to achieve remission. CONCLUSIONS: Treatment guidelines that recommend either an evidence-based psychotherapy or antidepressant medication for nonpsychotic major depression can be extended to treatment-naive patients. Treatment preferences among patients without prior treatment exposure do not significantly moderate symptomatic outcomes.