A Phase 1B, randomized, double blind, placebo controlled, multiple-dose escalation study of NSI-189 phosphate, a neurogenic compound, in depressed patients.

We wanted to examine tolerability and efficacy of NSI-189, a benzylpiperizine-aminiopyridine neurogenic compound for treating major depressive disorder (MDD). This was a Phase 1B, double blind, randomized, placebo controlled, multiple-dose study with three cohorts. The first cohort received 40 mg q.d. (n=6) or placebo (n=2), the second cohort 40 mg b.i.d. (n=6) or placebo (n=2), and the third cohort 40 mg t.i.d. (n=6) or placebo (n=2). Twenty-four patients with MDD were recruited, with the diagnosis and severity confirmed through remote interviews. Eligible patients received NSI-189 or placebo for 28 days in an inpatient setting with assessments for safety, pharmacokinetics (PK) and efficacy. Outpatient follow-up visits were conducted until day 84 (±3). NSI-189 was relatively well tolerated at all doses, with no serious adverse effects. NSI-189 area under the curve increased in a dose-related and nearly proportional manner across the three cohorts, with a half-life of 17.4-20.5 h. The exploratory efficacy measurements, including Symptoms Of Depression Questionnaire (SDQ), Montgomery-Asberg Depression Scale (MADRS), Clinical Global Impressions-Improvement (CGI-I), and The Massachusetts General Hospital (MGH) Cognitive and Physical Functioning Questionnaire (CPFQ) showed a promising reduction in depressive and cognitive symptoms across all measures for NSI-189, with significant improvement in the SDQ and CPFQ, and a medium to large effect size for all measures. These improvements persisted during the follow-up phase. In summary, NSI-189 shows potential as a treatment for MDD in an early phase study. The main limitation of this preliminary study was the small sample size of each cohort.

"Ready, willing, and (not) able" to change: young adults' response to residential treatment.

BACKGROUND: Young adulthood represents a key developmental period for the onset of substance use disorder (SUD). While the number of young adults entering treatment has increased, little is known about the mechanisms of change and early recovery processes in this important clinical population. This study investigated during-treatment change in key therapeutic processes (psychological distress, motivation, self-efficacy, coping skills, and commitment to AA/NA), and tested their relation to outcome at 3 months post-treatment. METHODS: Young adults undergoing residential treatment (N=303; age 18-24; 26% female; 95% Caucasian) were enrolled in a naturalistic prospective study and assessed at intake, mid-treatment, discharge, and 3 months following discharge. Repeated-measures and regression analyses modeled during-treatment change in process variables and impact on outcome. RESULTS: Statistically significant medium to large effect sizes were observed for changes in most processes during treatment, with the exception of motivation, which was high at treatment intake and underwent smaller, but still significant, change. In turn, these during-treatment changes all individually predicted 3-month abstinence to varying degrees, with self-efficacy emerging as the sole predictor in a simultaneous regression. CONCLUSIONS: Findings help to clarify the mechanisms through which treatment confers recovery-related benefit among young adults. At treatment intake, high levels of abstinence motivation but lower coping, self-efficacy, and commitment to AA/NA, suggests many entering treatment may be "ready and willing" to change, but "unable" to do so without help. Treatment appears to work, in part, by helping to maintain motivation while conferring greater ability and confidence to enact such change.