Patients with major depressive disorder (MDD) commonly experience comorbid anxiety and somatization, which can complicate treatment. Adjunctive therapy with atypical antipsychotics can be an effective treatment option for patients with MDD who had inadequate responses to antidepressant therapy (ADT) alone. Cariprazine is a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist that is approved as an adjunctive treatment for MDD. This post hoc analysis examined the effect of adjunctive cariprazine therapy on anxiety and somatization symptoms in patients with MDD.

A post hoc analysis was conducted using data from a phase 3, double-blind, placebo-controlled, fixed-dose study of patients with MDD who had inadequate responses to ADT alone. Patients were randomized (1:1:1) to receive ADT plus cariprazine 1.5 mg/d, 3 mg/d, or placebo for 6 weeks. The least squares (LS) mean change from baseline to week 6 in Hamilton Rating Scale for Depression (HAM-D) Anxiety/Somatization subscale was measured. The Anxiety/Somatization subscale includes six HAM-D items: anxiety-psychic, anxiety-somatic, gastrointestinal somatic symptoms, general somatic symptoms, hypochondriasis, and insight. The modified intent to treat population included 751 patients (placebo=249; cariprazine 1.5 mg/d=250; cariprazine 3 mg/d=252).

The LS mean change from baseline in HAM-D Anxiety/Somatization subscale at week 6 was significantly greater than placebo + ADT for both cariprazine + ADT dose groups (placebo: -3.22; cariprazine 1.5 mg/d: -4.00, P<.001; 3 mg/d: -3.75, P<.05). LS mean change from baseline in the cariprazine 1.5 mg/d + ADT group was also significantly greater than placebo + ADT on the anxiety-psychic (placebo: -0.88; cariprazine 1.5 mg/d: -1.08, P<.01) and anxiety-somatic (placebo: -0.78; cariprazine 1.5 mg/d: -0.96, P<.05) items. In patients treated with cariprazine 3 mg/d + ADT, LS mean changes from baseline on anxiety-psychic and anxiety-somatic items were numerically larger than placebo + ADT but not statistically significant. Both cariprazine + ADT dose groups had significantly larger LS mean changes compared with placebo + ADT on the gastrointestinal somatic symptoms item (placebo: -0.51; cariprazine 1.5 mg/d: -0.66, P<.01; cariprazine 3 mg/d: -0.68, P<.01). General somatic symptoms, hypochondriasis, and insight items showed no significant difference between placebo + ADT and cariprazine + ADT groups.

Patients treated with adjunctive cariprazine demonstrated greater improvements than patients treated with adjunctive placebo on HAM-D Anxiety/Somatization subscale scores, as shown by reduced scores on anxiety-psychic, anxiety-somatic, and gastrointestinal items. These findings suggest adjunctive cariprazine therapy may be effective in reducing anxiety and somatization symptoms in patients with MDD.

AbbVie

Study Registration Number: NCT03738215

Changes in lifestyle factors are known to affect mood. However, there is insufficient evidence supporting the association between smoking, alcohol consumption, physical activity and depression in middle-aged women who are likely to experience rapid hormonal changes.

We used a nationwide database of medical records in South Korea. 901,721 premenopausal and 943,710 postmenopausal women aged 40 years or older included in this study. Information on smoking, alcohol consumption, physical activity was identified from health examination data and followed up for the occurrence of depression using claims data.

Compared with never-smokers, ex-smokers and current smokers among premenopausal and postmenopausal women showed an increased risk of depression in a dose-dependent manner (aHR 1.13 for ex-smokers; aHR 1.23 for current smokers). Compared with non-drinkers, mild drinkers showed a decreased risk of depression (aHR 0.98 for premenopausal women; aHR 0.95 for postmenopausal women), and heavy drinkers showed an increased risk of depression both among premenopausal (aHR 1.20) and postmenopausal women (aHR 1.05). The risk of depression due to smoking and heavy alcohol consumption was higher in premenopausal women than in postmenopausal women. Compared with those who had not engaged in regular physical activity, those who had engaged showed a decreased risk of depression both among premenopausal (aHR 0.96) and postmenopausal women (aHR 0.95).

Smoking and heavy alcohol consumption increased the risk of depression, and the increased risk was prominent in premenopausal than in postmenopausal women. Regular physical activity decreased the risk of depression both in premenopausal and postmenopausal women.

Vascular abnormalities have been frequently reported in elderly adults as a potential risk factor of late-life depression. However, it is still unclear whether stenosis of cerebral arteries may increase risk of depression in the elderly.

Study participants were 365 patients 65 years or older with depressive disorder who had undergone brain MRI and angiography (MRA) which were assessed by trained radiologists, and the 15-item Geriatric Depression Scale (GDS-15) and the Mini Mental State Examination (MMSE), and blood glucose and lipid profiles.

Of the 365 subjects, 108 had at least one location of cerebral artery stenosis (29.59%). Stenosis was associated with age, marital status, infarction, and atherosclerosis. In multivariable linear regression analysis of different locations of stenosis among the whole sample, only bilateral middle cerebral artery (MCA) stenosis was found to have a significant association with higher GDS-15 score (p= 0.0138), and more than 8 scores in the GDS-15 (p= 0.0045), but no significant associations with ACA (anterior cerebral artery), PCA (posterior cerebral artery) or ICA (internal carotid artery). In multivariable linear logistic analysis of different locations among patients with at least one cerebral artery stenosis, left MCA was found to be significantly related to higher GDS-15 scores but not with right MCA (p = 0.0202).

MCA stenosis is significantly associated with severity of depression in elderly adults with cerebral artery stenosis, especially in those with left MCA stenosis.

• Patients with cerebral artery stenosis found with brain magnetic resonance angiography (MRA) were associated with higher depression severity.

• Stenosis of both left and right middle cerebral artery (MCA) was associated with greater depression severity, with left MCA stenosis having a greater influence on depression severity than right MCA stenosis.

• Higher depression severity in patients with MCA stenosis suggests that depression in elderly patients is mediated at least in part by vascular pathology of MCA supplied regions and careful investigation and management of cerebral artery stenosis and their risk factors may help reduce the severity of depression in elderly patients who visit psychiatrists.

Although people who attempted suicide tend to repeat suicide attempts, there is a lack of evidence on the association between psychiatric service factors and suicide reattempt among them.

We used a nationwide, population-based medical record database of South Korea to investigate the use of psychiatric services before and after the index suicide attempt and the association between psychiatric service factors after the index suicide attempt with the risk of suicide reattempt.

Among 5,874 people who had attempted suicide, the all-cause mortality within 3 months after the suicide attempt was 11.6%. Among all subjects who attempted suicide, 30.6% of them had used psychiatric services within 6 months before the suicide attempt; 43.7% of them had used psychiatric services within 3 months after the suicide attempt. Among individuals who had visited clinics following attempted suicide, the cumulative incidence of suicide reattempt over a mean follow-up period of 5.1 years was 3.4%. About half of suicide reattempts occurred within 1 year after the index suicide attempt. Referral to psychiatric services within 7 days was associated with a decreased risk of suicide reattempt (adjusted hazard ratio, 0.51; 95% confidence intervals, 0.29-0.89).

An early psychiatric referral within 1 week after a suicide attempt was associated with a decreased risk of suicide reattempt.

Patients with major depressive disorder (MDD) often do not respond to antidepressant (ADT) monotherapy; adjunctive treatment is often used to address this unmet need. Cariprazine (CAR), a dopamine D3-preferring D3/D2 and serotonin 5-HT1A receptor partial agonist approved to treat adults with manic, mixed, or depressive episodes of bipolar I disorder, is under investigation as adjunctive therapy for patients with MDD.

This randomized, double-blind, phase 3 placebo (PBO)-controlled study assessed the efficacy, safety, and tolerability of CAR 1.5 and 3 mg/d as an adjunct to ADT in adult patients with MDD (18–65 years) and inadequate response to ADT alone (NCT03738215). The primary endpoint was change from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Hamilton Depression Rating Scale (HAMD-17), Hamilton Anxiety Rating Scale (HAM-A), and Clinical Global Impressions (CGI) were also assessed. Treatment response was defined as at least 50% decrease in MADRS total score at week 6.

Patients (n=751) in the modified intent-to-treat population were randomly assigned to CAR 1.5 mg/d+ADT (n=250), CAR 3 mg/d+ADT (n=252), or PBO+ADT (n=249). Mean age was 44.8 years and 73.4% were female; mean baseline total scores were: MADRS=32.5, HAMD-17=25.9, HAM-A= 21.4. Overall, 89.7% of patients completed the study; rates of discontinuation due to adverse events (AEs) and lack of efficacy were 3.6% and 0.5%, respectively. The difference in MADRS total score change from baseline to week 6 was statistically significant after multiplicity adjustment for CAR 1.5 mg/d vs PBO (-14.1 vs -11.5; adjusted P=.0050), but not for CAR 3 mg/d (-13.1; P=.0727). Differences for CAR 1.5 mg/d vs PBO were observed by week 2 (nominal P=.0453) and maintained at weeks 4 (nominal P<.0001) and 6 (nominal P=.0025). At week 6, more CAR 1.5 mg/d patients (44%) than PBO patients (34.9%) responded to treatment (nominal P=.0446). Greater improvement in the CGI-I scores was observed for CAR 1.5 (nominal P=.0026) and 3 mg/d (nominal P=.0076) vs PBO. At week 6, improvement in HAMD-17 total score reached nominal significance for CAR 1.5 mg/d vs PBO (-13.1 vs -11.1; nominal P=.0017), but not for CAR 3 mg/day (-12.2; P=.0783). HAM-A improvement was greater for CAR 1.5 mg/d vs PBO (nominal P=.0370). There were no deaths; 2 serious AEs occurred in each group (CAR: kidney infection, social stay hospitalization; PBO: depression, multiple sclerosis). The most common CAR AEs (≥5% and twice PBO) were akathisia and nausea.

Cariprazine 1.5 mg/d was effective as adjunctive treatment in adults with MDD and inadequate response to ADT. Cariprazine was generally well tolerated, with a safety profile that was consistent with other indications. Together with results from a prior flex-dose study, these results suggest that adjunctive cariprazine may be an effective option for patients with inadequate response to ADT alone.

AbbVie

Dissociative symptoms may be found in a subset of patients with major depressive disorders (MDD). The Clinician-Administered Dissociative States Scale (CADSS) is a 23-item scale for the measurement of present-state dissociative symptoms with good inter-rater reliability and construct validity that can discriminate patients with dissociative disorders. The total CADSS score is derived by adding the score for each of the 23 items. A score of 4 or more on the CADSS is considered abnormal and clinically meaningful. Uncompetitive N-methyl-d-aspartic acid receptor (NMDAR) channel blockers have been proposed as a treatment for post-traumatic stress disorder (PTSD). REL-1017 is a novel, low potency, NMDAR channel blocker currently in Phase 3 studies for MDD.

This retrospective case series describes a subset of patients from a double-blind, randomized, placebo-controlled, in-patient 7-day, phase 2 trial of oral, once daily, 25 mg (75 mg loading dose on day 1, first dose) and 50 mg REL-1017 (100 mg loading dose on day 1, first dose) as an adjunctive treatment for MDD. This subset of patients was selected based on abnormal CADSS score at baseline, pre-treatment with the study drug. As part of REL-1017 safety evaluation, the CADSS was administered at four timepoints to all study patients: (a) 30 to 60 minutes pre-treatment at baseline on day 1; (b) 2 hours post-treatment on day 1 (after the first dose of study drug); (c) 2 hours post-treatment on day 7 (after the last dose); and (d) prior to discharge on day 9 (2 days after the last dose).

Among the 62 randomized patients, four patients had a CADSS score of at least 4 on day 1 before study drug administration (2 patients in the 25 mg arm [CADSS score 22 and 4]; 1 patient in the 50 mg arm [CADSS score 35]; 1 patient in the placebo arm [CADSS score 6]). Among these 4 patients, starting on day 1, 2 hours post-treatment, the 2 subjects in the 25 mg subgroup (75 mg loading dose) and 1 subject in the 50 mg subgroup (100 mg loading dose) showed a clinically meaningful decrease in their CADSS score, while the single patient in the placebo group showed no change. CADSS scores on Day 1 pre-treatment, day 1 post-treatment, day 7 post last treatment, and on day 9 prior to discharge were 22-2-6-0; 4-0-0-0; 35-14-9-0, and 6-6-n/a-n/a, for the two patients in the 25 mg REL-1017 subgroup, the single patient in the 50 mg REL-1017 subgroup, and the single patient in the placebo group, respectively.

These retrospective case report data potentially signal that REL-1017 may determine rapid and sustained improvement in patients with MDD and concurrent clinically meaningful dissociative symptoms assessed by a CADSS score of 4 or above. Ongoing phase 3 trials with REL-1017 are expected to enroll a total of 1200 outpatients with MDD. These studies will potentially generate additional data that may support the initiation of controlled studies with REL-1017 for the treatment of PTSD.

Relmada Therapeutics

Major depressive disorder (MDD) is the second leading cause of disability and chronic disease burden in the United States. The importance of improving functional outcomes in MDD is increasingly recognized. The Symptoms of Depression Questionnaire (SDQ), a patient-reported measure, was developed to capture the heterogeneity of symptoms of MDD. REL-1017 (esmethadone HCl; d-methadone), is a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker and potential rapid antidepressant currently in Phase 3 development. In a Phase 2a trial, REL-1017 showed robust, rapid, and sustained antidepressant efficacy as adjunctive treatment in patients with MDD. The objective of this study was to assess the effects of REL-1017 on SDQ subscales to better characterize the functional implications of its therapeutic effects.

A double-blind, placebo-controlled, inpatient, two-doses, 25 and 50 mg, three-arm, 1:1:1, randomized, phase 2a trial of REL-1017 was conducted at 10 centers in the United States. Least square (LS) mean scores and Cohen’s effect sizes of the total score of a 44-item of SDQ and its 5 subscales: lassitude, mood, cognitive/social functioning (SDQ-1); anxiety, agitation, anger, and irritability (SDQ-2); desire to be dead (SDQ-3); disruptions in sleep quality (SDQ-4); changes in appetite and weight (SDQ-5) were compared between REL-1017 and placebo.

A total of 62 adult male and female patients (18-65 years of age) diagnosed with MDD participated in the trial. On day 14, the last day of efficacy measurement, the difference from placebo of the LS mean (90% CI) for REL-1017 25 mg and REL-1017 50 mg groups, respectively, showed improvement for both tested doses on SDQ total score (−23.2; P = .0066 [effect size: 0.9]; −26.8 P = .0014 [effect size: 1.1]). Additionally, for SDQ subscales, REL-1017 25 mg and REL-1017 50 mg groups, respectively, showed significant improvement as compared with placebo: SDQ-1 (−13.9; P = .0025 [effect size: 1.0]; −15.0; P = .0009 [effect size: 1.1]), SDQ-2 (−4.6; P = .0398 [effect size: 0.7]; −7.2; P = .0012 [effect size: 1.1]) and SDQ-4 (−2.7; P = .0055 [effect size: 1.0]; −2.8; P = .0029 [effect size: 1.0]). No significant differences were observed between the treated groups and placebo in the SDQ-3 and SDQ-5 subscales.

In patients with MDD, aside from improving the overall CFB compared to placebo in SDQ total score, REL-1017 resulted in clinically meaningful and statistically significant improvements in cognitive/motivational, anxiety/irritability, and sleep-specific domains. The robust, rapid, and sustained efficacy of REL-1017 for MDD is not limited to improving mood, but potentially extends to cognitive, motivational, sleep, and social functions, with potentially meaningful therapeutic and socioeconomic implications. These results may signal disease-modifying effects of esmethadone for MDD that may offer potential advantages over symptomatic treatment with standard antidepressants.

Relmada Therapeutics, Inc.

Body weight variability (BWV) negatively affects the incidence and outcomes of various diseases, but the nature of the association between BWV and depression remains unclear. In this study, we aimed to test the hypothesis that BWV is associated with the risk of new-onset depression.

Data from a nationwide population-based cohort in the Korean National Health Insurance Service database were analyzed for 6 598 570 adults with no history of depression and reports of at least three health examinations. BWV was estimated using variability independent of the mean indices and divided into quartiles (Q1 lowest, Q4 highest BWV). Cox proportional hazard models were applied to assess the risk of depression according to the quartile of BWV.

The incident rate for depression from Q1 to Q4 of BWV was 20.7, 20.3, 20.8, and 22.2 per 1000 person-years, respectively. BWV, especially high BWV, was associated with an increased risk of depression after adjusting for age, sex, smoking, alcohol consumption, physical activity, income, diabetes mellitus, hypertension, and dyslipidemia. The hazard ratio (HR) of new-onset depression was highest in Q4 relative to Q1 in the total population (HR 1.12, p < 0.0001) and was higher in women than in men (HR 1.72 v. 1.16, p < 0.0001). In stratified analyses, regardless of obesity or weight change status at baseline, the risk of depression was increased when bodyweight fluctuated highly during follow-up.

High BWV was associated with an increased risk of depression. Further studies need to evaluate the role of high BWV with respect to the onset of depression.

Treatment for major depressive disorder (MDD) is imprecise and often involves trial-and-error to determine the most effective approach. To facilitate optimal treatment selection and inform timely adjustment, the current study investigated whether neurocognitive variables could predict an antidepressant response in a treatment-specific manner.

In the two-stage Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care (EMBARC) trial, outpatients with non-psychotic recurrent MDD were first randomized to an 8-week course of sertraline selective serotonin reuptake inhibitor or placebo. Behavioral measures of reward responsiveness, cognitive control, verbal fluency, psychomotor, and cognitive processing speeds were collected at baseline and week 1. Treatment responders then continued on another 8-week course of the same medication, whereas non-responders to sertraline or placebo were crossed-over under double-blinded conditions to bupropion noradrenaline/dopamine reuptake inhibitor or sertraline, respectively. Hamilton Rating for Depression scores were also assessed at baseline, weeks 8, and 16.

Greater improvements in psychomotor and cognitive processing speeds within the first week, as well as better pretreatment performance in these domains, were specifically associated with higher likelihood of response to placebo. Moreover, better reward responsiveness, poorer cognitive control and greater verbal fluency were associated with greater likelihood of response to bupropion in patients who previously failed to respond to sertraline.

These exploratory results warrant further scrutiny, but demonstrate that quick and non-invasive behavioral tests may have substantial clinical value in predicting antidepressant treatment response.

SPN-812 (extended-release viloxazine) is a structurally distinct, bicyclic, Serotonin Norepinephrine Modulating Agent (SNMA) under investigation as a treatment for attention-deficit/hyperactivity disorder (ADHD). One concern for any new drug is prolongation of the QT interval, which is associated with increased risk for potentially very harmful ventricular cardiac arrhythmias such as torsades de pointes (TdP). The objective of this study was to assess the effects of SPN-812 at a supratherapeutic dose (1800 mg once daily [QD]) on cardiac repolarization (QTc) in healthy adults.

This study was a Phase 1, double-blind (except for the positive control moxifloxacin), randomized, 3-period, 6-sequence crossover design in healthy adult male and female subjects evaluating the electrocardiographic effects of SPN-812. Subjects were randomized to receive a sequence of all 3 treatments – placebo, 400 mg moxifloxacin (positive control), and 1800 mg SPN-812 (supratherapeutic dose). Treatment was given for 2 consecutive days (separated by a washout of at least 4 days). The primary endpoint was based on concentration-QTc effect modeling, evaluating the relationship between plasma concentrations of SPN-812 and its metabolite 5-hydroxyviloxazine glucuronide (5-HVLX-gluc) with the placebo-adjusted change from baseline in QTcI, ΔΔQTcI (QT interval corrected for HR based on the individual-specific QT interval correction method). Secondary endpoints included time point change from baseline in QTcI, QTcF, HR, PR, and QRS; evaluation of the relationship between the plasma concentration of viloxazine and 5-HVLX-gluc and the placebo-adjusted change from baseline in HR, PR, QRS, and QTcF; evaluation of the relationship between the plasma concentration of moxifloxacin and ΔΔQTcI to demonstrate assay sensitivity; and changes in ECG morphology. Safety endpoints included assessment of adverse events and other parameters.

The relationship between ΔΔQTcI and viloxazine plasma concentration demonstrated a negative slope (p=0.0012). Predicted mean ΔΔQTcI (2-sided 90% CI) for SPN-812 was -9.7 ms (-11.3, -8.1) at the mean Cmax of 12.4 μg/mL. The relationship of 5-HVLX-gluc and ΔΔQTcI similarly demonstrated a predicted negative slope (p=0.0007) with a predicted mean ΔΔQTcI (2-sided 90% CI) of -9.2 ms (-10.8, -7.8) at the mean Cmax of 10.0 μg/mL. Assay sensitivity was confirmed. Concentration-effect modeling demonstrated no relationship between plasma concentrations of viloxazine and 5-HVLX-gluc and other ECG parameters. The secondary time point analyses demonstrated no effect of SPN-812 on QTcI or other ECG intervals. SPN-812 produced no changes in ECG T wave or U wave morphology.

Data from this Phase 1 thorough QT study demonstrate that a supratherapeutic dose of SPN-812, 1800 mg QD, has no effect on cardiac repolarization or other ECG parameters, and is thus not associated with a risk for cardiac arrhythmias such as TdP.

This research was funded by Supernus Pharmaceuticals, Inc., Rockville, MD.

Sexual dysfunction occurs in 40%-60% of patients with major depressive disorder (MDD), due to either the illness itself and/or the effects of antidepressant treatment. The phase-2 CLARITY trial recently demonstrated the efficacy of adjunctive pimavanserin (PIM) for MDD when added to ongoing selective serotonin or serotonin–norepinephrine reuptake inhibitor (SSRI/SNRI) treatment. No new safety observations were reported in this study. This post-hoc analysis examines the potential impact of PIM treatment on sexual function.

Study methodology has been presented previously (APA 2019). Adult male and female patients with moderate-to-severe MDD were randomized to PIM 34 mg/day (n=51) or placebo (PBO, n=152) added to ongoing SSRI/SNRI treatment. Massachusetts General Hospital–Sexual Functioning Inventory (MGH-SFI) and Hamilton Depression Rating Scale, 17-item version (HAMD-17) item 14 (sexual interest) scores were examined by analysis of covariance.

Adjunctive PIM resulted in significantly greater 5-week reduction (improvement) relative to SSRI/SNRI treatment plus placebo on mean MGH-SFI scores (difference –0.634, SE 0.167; P<0.001; effect size [ES], Cohen’s d 0.614). Similarly, PIM resulted in greater improvement compared with placebo on individual MGH-SFI items that applied to both males and females: Interest in Sex (P=0.006; ES=0.483), Ability to Get Sexually Aroused/Excited (P=0.001; ES=0.560), Ability to Achieve Orgasm (P<0.001; ES=0.609), Overall Sexual Satisfaction (P=0.003; ES=0.524). HAMD-17 item 14 scores were also significantly more reduced (improved) with PIM (P<0.001; ES=0.574).

These results underscore the potential of adjunctive PIM for improving sexual function in patients with MDD and inadequate response to SSRIs/SNRIs. Potential benefits should be confirmed in further studies.

ACADIA Pharmaceuticals Inc.

Depression is the leading cause of disability worldwide, with fewer than 50% of treated patients achieving full remission. This study (“CLARITY,” ACP-103-042: NCT03018340) examined the 5-HT2A inverse agonist pimavanserin (PIM) as a potential adjunctive treatment for major depressive disorder (MDD).

Adult female and male subjects with a DSM-5 primary diagnosis of a major depressive episode as part of MDD, inadequate response to ongoing SSRIs or SNRIs of adequate dose and duration as confirmed by the Massachusetts General Hospital Antidepressant Treatment History Questionnaire, and a MADRS total score >20 were randomized to PIM 34 mg/day or placebo (PBO) added to their SSRI/SNRI treatment. A sequential parallel comparison design was used, consisting of two 5-week stages. PBO nonresponders in Stage-1 who met prespecified criteria were re-randomized to PIM or PBO for the second period (Stage-2). The primary efficacy measure was the weighted average of Stage-1 and Stage-2 total scores of the HAMD-17.

Of the 207 patients enrolled, 52 received PIM, and 155 received PBO in Stage 1. Mean age was 46.2 years, and 72.9% of patients were female. Baseline MADRS total (mean [SD]: 31.5 [0.4]) and HAMD-17 total scores (22.2 [0.3]) indicated a moderate overall severity of illness. PIM met the primary endpoint, reducing the weighted Stage-1/Stage-2 HAMD-17 total score relative to PBO (least-square means [LSM] difference, –1.7; standard error [SE], 0.9; P=0.04). Stage-1 PIM patients demonstrated highly significant 5-week improvement on the HAMD-17 (LSM difference=–4.0, SE=1.1; P<0.001; effect size, Cohen’s d: 0.626), separating from placebo by the end of Week 1 (LSM difference=–1.7, SE=0.8; P=0.04). Stage-2 results showed no significant separation among Stage-1 placebo nonresponders (P=0.69). In Stage 2, a substantively smaller number of subjects (n=58) were rerandomized than planned, likely due to restrictive criteria for re-randomization. Greater overall improvement was seen with PIM relative to PBO on the key secondary endpoint, the Sheehan Disability Scale (LSM difference=–0.8, SE=0.3; P=0.004), and positive results were also seen on 7 of the 11 other secondary endpoints, including responder rate (≥50% reduction in HAMD-17 total; P=0.007), Massachusetts General Hospital Sexual Functioning Index (P<0.001), and Karolinska Sleepiness Scale for daytime sleepiness (P=0.02). Discontinuations due to adverse events were low (PIM 1.2%, PBO 3.2%). One serious adverse event was reported in each treatment group, deemed unrelated to treatment. No deaths were reported. Laboratory assessments, electrocardiography, and changes in vital signs were unremarkable, and no new safety signals were reported.

Study data provide evidence of the efficacy, safety, and tolerability of adjunctive PIM in treating MDD inadequately responsive to SSRI or SNRI therapy. Efforts to confirm these results are ongoing in a Phase 3 program.

ACADIA Pharmaceuticals Inc.

Depression is a disorder that causes disability, with a profound adverse impact on all areas of psychosocial functioning. This is particularly true for those with treatment resistant depression (TRD). However, to date, no systematic assessments of psychosocial functioning for patients with TRD have been conducted.

In the present study, we used the Longitudinal Interval Follow-up Evaluation (LIFE) scale to measure psychosocial functioning in 92 patients with TRD. These patients met formal criteria for TRD and were part of a clinical trial examining the efficacy of lithium augmentation of nortriptyline.

Clinicians rated this sample of patients as experiencing mild to moderate impairment in work-related activities, good to fair interpersonal relations, poor level of involvement in recreational activities, and mild impairment of ability to enjoy sexual activity. Patients and clinicians rated global social adjustment as poor.

Patients with formally defined TRD experience significant impairment in psychosocial functioning. In this sample a tendency existed for both clinicians and patients to assign more severely impaired global ratings when compared with ratings for specific functional areas.

This report tests the association of self-reported symptoms of irritability with overt behavior of anger attacks (uncharacteristic sudden bouts of anger that are disproportionate to situation and associated with autonomic activation).

Participants of the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care study who completed Massachusetts General Hospital Anger Attacks questionnaire were included (n = 293). At each visit, the 17-item Hamilton Depression Rating Scale and the 16-item Concise Associated Symptom Tracking scale were used to measure depression, anxiety, and irritability. In those with anger attacks present v. those without anger attacks, separate t tests and mixed model analyses compared afore-mentioned symptoms at baseline and changes with treatment respectively. As anger attacks may occur without aggressive behaviors, analyses were repeated based only on the presence of aggressive behaviors.

At baseline, those with anger attacks (n = 109) v. those without anger attacks (n = 184) had similar levels of depression but higher levels of irritability [effect size (d) = 0.80] and anxiety (d = 0.32). With acute-phase treatment, participants with anger attacks experienced a greater reduction in irritability (p < 0.001) but not in depression (p = 0.813) or anxiety (p = 0.771) as compared to those without anger attacks. Yet, irritability levels at week-8 were higher in those with anger attacks (d = 0.32) than those without anger attacks. Similar results were found in participants with aggressive behaviors.

The presence of anger attacks in outpatients with major depressive disorder may identify a sub-group of patients with persistently elevated irritability.

Buprenorphine/samidorphan (BUP/SAM), a combination of BUP (a µ-opioid receptor partial agonist and κ-antagonist) and SAM (a sublingually bioavailable µ-opioid antagonist), is an investigational opioid system modulator for depression. BUP/SAM has shown efficacy versus placebo as an adjunctive treatment for major depressive disorder (MDD) and a consistent safety profile in previously reported, placebo-controlled clinical studies.1,2

1. To characterize the safety profile following long-term treatment with BUP/SAM

2. To explore depression symptoms and remission rates in patients with MDD following long-term treatment with BUP/SAM

FORWARD-2 (Clinicaltrials.gov ID: NCT02141399) enrolled patients who had participated in 1 of 4 controlled studies as well as de novo patients. All patients had a confirmed diagnosis of MDD, had a history of inadequate response to standard antidepressant therapies (ADTs), and had been treated with an adequate dose of an established ADT for ≥8weeks before BUP/SAM initiation. ADT dosage could be titrated, but the ADT could not be changed. During the study, patients received open-label, sublingual BUP/SAM 2mg/2mg as adjunctive treatment for up to 52weeks. Safety (primary objective) was assessed via adverse events (AEs), vital signs, laboratory analytes, and electrocardiography. Suicidal ideation or behavior (SIB) was evaluated by the Columbia Suicide Severity Rating Scale. Abuse potential, dependence, and withdrawal were assessed by AEs and the Clinical Opiate Withdrawal Scale. Exploratory efficacy endpoints included mean Montgomery–Åsberg Depression Rating Scale (MADRS) scores and remission rate (MADRS ≤10).

Of 1454 total patients, 49% completed the 52-week study, 11% discontinued due to an AE, and 40% discontinued because of other reasons as of the interim data cutoff date (April 30, 2017). Most AEs were of mild/moderate severity. Serious AEs were reported in 3.2% of patients. AEs occurring in ≥10% of patients were nausea, headache, constipation, dizziness, and somnolence. There was no evidence of increased risk of SIB with BUP/SAM. Incidence of euphoria-related events was low (1.2%). After abrupt discontinuation of BUP/SAM, there was little evidence of withdrawal. BUP/SAM was not associated with meaningful changes in laboratory or metabolic parameters or in bodyweight. The mean MADRS score decreased from 22.9 (±9.7) at baseline to 9.8 (±8.8) after 52weeks. The remission rate at 52weeks was 52.5%.

Long-term treatment with BUP/SAM did not reveal any new safety findings and confirmed that the risk of abuse and dependence with BUP/SAM was low. BUP/SAM maintained an antidepressant effect for up to 52weeks of treatment in patients with MDD.

Funding Acknowledgements: Alkermes, Inc.

Subclinical delusional ideas, including persecutory beliefs, in otherwise healthy individuals are heritable symptoms associated with increased risk for psychotic illness, possibly representing an expression of one end of a continuum of psychosis severity. The identification of variation in brain function associated with these symptoms may provide insights about the neurobiology of delusions in clinical psychosis.

A resting-state functional magnetic resonance imaging scan was collected from 131 young adults with a wide range of severity of subclinical delusional beliefs, including persecutory ideas. Because of evidence for a key role of the amygdala in fear and paranoia, resting-state functional connectivity of the amygdala was measured.

Connectivity between the amygdala and early visual cortical areas, including striate cortex (V1), was found to be significantly greater in participants with high (n = 43) v. low (n = 44) numbers of delusional beliefs, particularly in those who showed persistence of those beliefs. Similarly, across the full sample, the number of and distress associated with delusional beliefs were positively correlated with the strength of amygdala-visual cortex connectivity. Moreover, further analyses revealed that these effects were driven by those who endorsed persecutory beliefs.

These findings are consistent with the hypothesis that aberrant assignments of threat to sensory stimuli may lead to the downstream development of delusional ideas. Taken together with prior findings of disrupted sensory-limbic coupling in psychosis, these results suggest that altered amygdala-visual cortex connectivity could represent a marker of psychosis-related pathophysiology across a continuum of symptom severity.

Major depressive disorder (MDD) is a highly heterogeneous condition in terms of symptom presentation and, likely, underlying pathophysiology. Accordingly, it is possible that only certain individuals with MDD are well-suited to antidepressants. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes of depression, such as neuroticism, anhedonia, and cognitive control deficits.

Within an 8-week multisite trial of sertraline v. placebo for depressed adults (n = 216), we examined whether the combination of machine learning with a Personalized Advantage Index (PAI) can generate individualized treatment recommendations on the basis of endophenotype profiles coupled with clinical and demographic characteristics.

Five pre-treatment variables moderated treatment response. Higher depression severity and neuroticism, older age, less impairment in cognitive control, and being employed were each associated with better outcomes to sertraline than placebo. Across 1000 iterations of a 10-fold cross-validation, the PAI model predicted that 31% of the sample would exhibit a clinically meaningful advantage [post-treatment Hamilton Rating Scale for Depression (HRSD) difference ⩾3] with sertraline relative to placebo. Although there were no overall outcome differences between treatment groups (d = 0.15), those identified as optimally suited to sertraline at pre-treatment had better week 8 HRSD scores if randomized to sertraline (10.7) than placebo (14.7) (d = 0.58).

A subset of MDD patients optimally suited to sertraline can be identified on the basis of pre-treatment characteristics. This model must be tested prospectively before it can be used to inform treatment selection. However, findings demonstrate the potential to improve individual outcomes through algorithm-guided treatment recommendations.

The aim of this post-hoc analysis was to evaluate the efficacy of lurasidone in treating major depressive disorder (MDD) with mixed features including irritability.

The data in this analysis were derived from a study of patients meeting DSM–IV–TR criteria for unipolar MDD, with a Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≥26, presenting with two or three protocol-defined manic symptoms, and who were randomized to 6 weeks of double-blind treatment with either lurasidone 20–60 mg/d (n=109) or placebo (n=100). We defined “irritability” as a score ≥2 on both the Young Mania Rating Scale (YMRS) irritability item (#5) and the disruptive-aggressive item (#9). Endpoint change in the MADRS and YMRS items 5 and 9 were analyzed using a mixed model for repeated measures for patients with and without irritability.

Some 20.7% of patients met the criteria for irritability. Treatment with lurasidone was associated with a significant week 6 change vs. placebo in MADRS score in both patients with (–22.6 vs. –9.5, p<0.0001, effect size [ES]=1.4) and without (–19.9 vs. –13.8, p<0.0001, ES=0.7) irritability. In patients with irritable features, treatment with lurasidone was associated with significant week 6 changes vs. placebo in both the YMRS irritability item (–1.4 vs. –0.3, p=0.0012, ES=1.0) and the YMRS disruptive-aggressive item (–1.0 vs. –0.3, p=0.0002, ES=1.2).

In our post-hoc analysis of a randomized, placebo-controlled, 6-week trial, treatment with lurasidone significantly improved depressive symptoms in MDD patients with mixed features including irritability. In addition, irritability symptoms significantly improved in patients treated with lurasidone.