Alan Schatzberg’s research while affiliated with Palo Alto University and other places

Introduction Suicide has emerged as a public health emergency, but selective treatments remain scarce and unacceptable to those high in need. Perceived stigma represents a central barrier to treatment and thus prevention, but has yet to be evaluated in association with sleep, anti-suicidal treatment response, and other resiliency outcomes. Methods Comprehensive screening (n=310 participants screened, n=59 completed a full-battery eligibility assessment) for current suicide risk (CSSRS>1), DSM-V-defined MDD, and clinically-significant insomnia (ISI>10, PSQI>5) supported inclusion in an open-label suicide prevention clinical trial (iSleep: Insomnia Treatment for Improved Well-Being). A multi-component, non-pharmacological (5-week) treatment (integrating CBTi, IRT, and SRT interventions) was manualized according to session-by-session powerpoints, handouts, and therapist guide sheets. Measures: The Columbia Suicide Severity Rating Scale (CSSRS), Beck Scale for Suicide (BSS), Quick Inventory of Depressive Symptomatology (QIDS-SR), Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index (PSQI), Disturbing Dream and Nightmare Severity Index (DDNSI), Perceived Stigma Scale (PSS), and Rudd Hope Scale (RHS). Assessments occurred at Baseline, Treatment, and Posttreatment (2 weeks, 1,3 mos). Data and safety monitoring procedures supported risk assessment, triage, and outpatient safety planning. Results Thirty-five participants (aged 20-70; M=41 years) were allocated treatment. Perceived Stigma: Significant mean differences were observed in PSS scores at pretreatment among participants, indicating lower perceived stigma ratings toward sleep treatment (PSS-SLP) relative to mental health treatment (PSS-MH) [M=10.0, SD=4.4; M=13.3, SD=6.35, respectively]: t(34)=3.94, p<.001; CI=1.60-5.02. Hope Measures: Paired t-tests revealed significant improvements in RHS scores from pre- to posttreatment phases [M=13.23, SD=4.03; M=16.03, SD=4.4, respectively]: t(30)=-3.03, p<.01; CI=-4.69—0.91. This paralleled large, posttreatment reductions (87%) in suicidal ideation, alongside depression, insomnia, sleep-quality, and nightmare improvements (p<.001). Conclusion Lower perceived stigma was associated with sleep treatment compared to psychological treatment, further supporting the utility of sleep as a modifiable, non-stigmatizing therapeutic target for suicidal behaviors. In addition, use of a rapid-action insomnia intervention (iSleep Treatment) resulted in significant posttreatment improvements in hope and overall well-being. This is the first known report testing perceived stigma in the context of a suicide prevention clinical trial, while demonstrating therapeutic impact to hope and resiliency measures underlying anti-suicidal response. Support (if any) This work was supported by NIH funding (K23MH093490; Bernert).

Background: Our group demonstrated that opioid receptor antagonism attenuates ketamine's acute antidepressant effects. Others have found that low oral doses of a partial mu receptor agonist have antidepressant and anti-suicidal properties. To reduce the burden and risk of repeated ketamine dosing, we explored whether low dose opioid agonism with buprenorphine could extend the anti-suicidal and antidepressant properties of a single administration of intravenous ketamine. Methods: In an ongoing, double-blinded trial to be completed by the end of 2024, 42 participants to date with treatment resistant depression received IV ketamine (0.5mg/kg), followed by randomization two days later to receive either buprenorphine (0.2-0.8mg QOD) or placebo for 4 weeks. The primary outcome was change in the BSSI. Pre-defined secondary outcomes include changes in MADRS, and HAMD-21. Results: On day 3, 52.1% achieved ≥ 50% reduction of BSSI; response/remission rates were 35/17.5% on HAMD-21, and 37.5/25% on the MADRS respectively. By day 31, BSSI decreased from 15.81 to 7.15 (RM-ANOVA F4, 139=28.40, p < 0.0001), HAMD-21 from 24.88 to 16.94 (F4,128=20.98, p < 0.0001), and MADRS from 33.98 to 22.45 (F3, 117 = 18.56, p < 0.0001). Recruitment is ongoing and blinded to buprenorphine treatment. Conclusions: Single dose IV ketamine substantially reduced depression and suicidality with somewhat greater effect observed for suicidality than depression. The benefits were maintained up to date 45, beyond typically reported. While consistent with our hypothesis that opioid agonism will prolong the benefits of ketamine, we can only speculate until study completion. Unblinded results will be presented at SOBP for the first time.

Cognitive impairments contribute significantly to psychosocial dysfunction in major depressive disorder (MDD), yet mechanistically selective treatments targeted to these impairments are lacking. We evaluated guanfacine immediate release (GIR), an alpha 2A receptor agonist, as a novel treatment for selectively improving cognitive control circuit function and behavioral performance in a subtype of depression, the cognitive biotype. Seventeen MDD participants of this biotype completed 6–8 weeks of GIR treatment (target dose: 2mg/night), meeting our per protocol criteria. GIR significantly increased activation and connectivity within the cognitive control circuit. The clinical response rate was 76.5% (defined by ≥ 50% improvement on the 17-item Hamilton Rating Scale for Depression (HRSD-17), exceeding conventional antidepressant rates, and 64.7% achieved remission (HRSD-17 score of ≤ 7). GIR significantly improved cognitive control performance, quality of life, and global life satisfaction. This study is the first to demonstrate both efficacy and target engagement of GIR as a mechanistically selective treatment specifically for the cognitive biotype of depression.

Introduction Suicide represents a public health emergency among veterans, who die by suicide at alarming rates and show elevated sleep disturbances. Selective interventions for military suicide indication are scarce, and available treatments remains mismatched to the acute nature of a suicidal crisis. We sought to develop and test preliminary efficacy of a fast-acting, behavioral insomnia intervention for antisuicidal response in the context of a sham-controlled, randomized trial among veterans. Methods A multicomponent behavioral sleep intervention was developed, integrating: CBT for Insomnia (CBTi) and Imagery Rehearsal Treatment (IRT) within a rapid (4-session) format (SERVE: Sleep Enhancement for Returning Veterans). This was compared to active control, Arousal-Based Treatment of Insomnia (ABTI). Treatments were manualized and matched for therapist contact, materials (manuals, powerpoints, guidesheets), and passage of time. Raters were blind to treatment assignment. Inclusion criteria: (a) age>18, (b) clinically-significant sleep disturbance (Insomnia Severity Index (ISI>10)), (c) DSM-V-Defined Depression, or (d) current suicidal ideation (Columbia Suicidal Severity Rating Scale (CSSRS>1)). A comprehensive data and safety monitoring plan supported standardized risk assessment, safety planning, and triage. Outcomes were assessed at Baseline and Posttreatment (1,3 mos) according to primary (suicidal ideation), secondary (sleep indices), and exploratory (mood, stress indices) outcomes. Results Recruitment occurred by way of comprehensive military partnerships, clinic referrals, and community flyering. Of n=753 new contacts, n=436 participants were screened for inclusion. Of these, n=112 were interviewed by full-battery eligibility assessment, resulting in n=77 veterans enrolled and randomized to: Active Treatment (n=39) vs. Active Control (n=38). Feasibility analyses supported high rates of acceptance, tolerability, and safety. For the full sample, t-tests revealed large posttreatment reductions in suicidal ideation (CSSRS, p<.001; Depressive Symptom Inventory Suicidality Subscale (DSISS)), p<.001), sleep, mood, and stress outcomes (ISI, p<.01; DDNSI, p<.01; QIDS-SR, p<.01; PCL, p<.001). Effects were significant compared to control (DSISS, p<.01; ISI, p<.01). Conclusion A brief, non-pharmacological insomnia intervention resulted in antisuicidal response and large posttreatment improvements in sleep and well-being. This is the first known report testing non-medication insomnia treatment within a sham-controlled, randomized trial for military suicidal behaviors, where results support feasibility, safety, and therapeutic impact to suicidal risk. Support (if any) Work was supported by NIH (K23MH093490), DOD/MOMRP/MSRC funding (W81XWH-10-2-0178)

Introduction Suicide has emerged as a public health crisis, where interventions remain scarce, unacceptable, and inaccessible to those high in need. By comparison, poor sleep is non-stigmatizing, visible, and highly treatable as a risk factor and transdiagnostic intervention target in suicide prevention. Aim 1: To develop, manualize, and test feasibility of a sleep-oriented treatment for suicidal behaviors within an open label clinical trial. Aim 2: To test antisuicidal response and indications of efficacy posttreatment across primary (suicidal ideation), secondary (sleep indices), and exploratory (mood indices) outcomes. Methods A multicomponent selective treatment was developed integrating: CBT for Insomnia (CBTi), Imagery Rehearsal Treatment (IRT), and Social Rythyms Treatment (SRT) (to address insomnia, nightmares, sleep variability) within an abbreviated (5-session) format (iSleep: Insomnia Treatment for Improved Well-Being). Treatment was manualized across session-by-session materials (powerpoints, homework, therapist guidesheets). Participants were enrolled based on screening and inclusion criteria: (a) age >18, (b) clinically-significant sleep disturbance (Insomnia Severity Index (ISI>10)); Pittsburgh Sleep Quality Index (PSQI>5)), (c) DSM-V-Defined Major Depressive Disorder, (d) current suicidal ideation (Columbia Suicidal Severity Rating Scale (CSSRS>1)). Comprehensive data and safety monitoring procedures were used to support risk assessment, triage, and outpatient safety planning. Outcomes were assessed at Baseline, Treatment, and Posttreatment (1,3 mos) timepoints. Results Of n=590 new contacts, n=310 participants were screened for high suicide risk. Fifty-nine participants were interviewed by full-battery eligibility assessment, resulting in n=35 participants enrolled for treatment allocation. Feasibility analyses demonstrated high rates of acceptance, tolerability, and safety. Paired t-tests revealed large posttreatment reductions in suicidal ideation (CSSRS, p<.001), in addition to secondary outcomes of sleep disturbance (ISI, p<.001; DDNSI, p<.001) and depression (QIDS-SR, p<.001). Effects were large and sustained through study follow up. Conclusion A non-pharmacological insomnia intervention (iSleep Treatment) resulted in antisuicidal symptom response and posttreatment improvements in sleep and overall well-being. Effects were large and observed across primary, secondary, and exploratory outcomes. This is the first known report testing use of a newly-developed, multicomponent insomnia treatment within an open label suicide prevention clinical trial, demonstrating excellent feasibility, safety, and therapeutic impact to suicidal risk. Support (if any) Work was supported by NIH (K23MH093490) and DOD/MOMRP/MSRC funding (W81XWH-10-2-0178)