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.

Obesity, but not metabolic syndrome, negatively affects outcome in bipolar disorder.

OBJECTIVE: Examine the effects of obesity and metabolic syndrome on outcome in bipolar disorder. METHOD: The Comparative Effectiveness of a Second Generation Antipsychotic Mood Stabilizer and a Classic Mood Stabilizer for Bipolar Disorder (Bipolar CHOICE) study randomized 482 participants with bipolar disorder in a 6-month trial comparing lithium- and quetiapine-based treatment. Baseline variables were compared between groups with and without obesity, with and without abdominal obesity, and with and without metabolic syndrome respectively. The effects of baseline obesity, abdominal obesity, and metabolic syndrome on outcomes were examined using mixed effects linear regression models. RESULTS: At baseline, 44.4% of participants had obesity, 48.0% had abdominal obesity, and 27.3% had metabolic syndrome; neither obesity, nor abdominal obesity, nor metabolic syndrome were associated with increased global severity, mood symptoms, or suicidality, or with poorer functioning or life satisfaction. Treatment groups did not differ on prevalence of obesity, abdominal obesity, or metabolic syndrome. By contrast, among the entire cohort, obesity was associated with less global improvement and less improvement in total mood and depressive symptoms, suicidality, functioning, and life satisfaction after 6 months of treatment. Abdominal obesity was associated with similar findings. Metabolic syndrome had no effect on outcome. CONCLUSION: Obesity and abdominal obesity, but not metabolic syndrome, were associated with less improvement after 6 months of lithium- or quetiapine-based treatment.

Assessment of a multi-assay, serum-based biological diagnostic test for major depressive disorder: a pilot and replication study.

Despite decades of intensive research, the development of a diagnostic test for major depressive disorder (MDD) had proven to be a formidable and elusive task, with all individual marker-based approaches yielding insufficient sensitivity and specificity for clinical use. In the present work, we examined the diagnostic performance of a multi-assay, serum-based test in two independent samples of patients with MDD. Serum levels of nine biomarkers (alpha1 antitrypsin, apolipoprotein CIII, brain-derived neurotrophic factor, cortisol, epidermal growth factor, myeloperoxidase, prolactin, resistin and soluble tumor necrosis factor alpha receptor type II) in peripheral blood were measured in two samples of MDD patients, and one of the non-depressed control subjects. Biomarkers measured were agreed upon a priori, and were selected on the basis of previous exploratory analyses in separate patient/control samples. Individual assay values were combined mathematically to yield an MDDScore. A 'positive' test, (consistent with the presence of MDD) was defined as an MDDScore of 50 or greater. For the Pilot Study, 36 MDD patients were recruited along with 43 non-depressed subjects. In this sample, the test demonstrated a sensitivity and specificity of 91.7% and 81.3%, respectively, in differentiating between the two groups. The Replication Study involved 34 MDD subjects, and yielded nearly identical sensitivity and specificity (91.1% and 81%, respectively). The results of the present study suggest that this test can differentiate MDD subjects from non-depressed controls with adequate sensitivity and specificity. Further research is needed to confirm the performance of the test across various age and ethnic groups, and in different clinical settings.

Lithium tremor revisited: pathophysiology and treatment.

OBJECTIVE: Tremor occurs frequently as a side-effect of lithium, and it is, however, easily overlooked in the clinical setting. In this article, we attempt to review the pathophysiology and the clinical approach of lithium tremor. METHOD: We searched the Pubmed and Cochrane Library for relevant articles up to the year 2012. Sixty-four articles including 10 review papers, 3 clinical trials, and 12 case reports were reviewed. RESULTS: Lithium tremor is classified as a postural tremor and subcategorized as an exaggerated physiologic tremor. Differential diagnosis includes metabolic abnormalities, benign essential tremor, Parkinson's disease, and lithium toxicity. Various methods of evaluating lithium tremor and treatment options are discussed. CONCLUSION: When lithium tremor has developed, thorough history taking, physical examination, and blood examination including serum lithium level are needed. Pharmacotherapy is indicated only in patients with disabling tremor.

Adjunctive zonisamide for treatment refractory anxiety.

The aim of the study was to assess the use of a novel anticonvulsant, zonisamide, in patients with treatment refractory anxiety. Pilot and open study of a cohort of patients with anxiety (n = 10), who were deemed partial or non-responders to anxiolytic therapy, and received adjunctive zonisamide in a naturalistic fashion. The primary outcome measures were the Hamilton Anxiety Scale (HAM-A), the Clinical Global Impression of Severity (CGI-S) and the Clinical Global Impression of Improvement (CGI-I). Patients included were markedly ill with a mean number of previous medication trials of 4.9 +/- 1.9, a baseline HAM-A score of 27.9 +/- 3.8, and a baseline CGI-S score of 5.7 +/- 0.5. Patients improved significantly with an end-point HAM-A score of 12.6 +/- 7.4 (p < 0.001), CGI-S score of 3.6 +/- 1.3 (p < 0.002) and CGI-I score of 2.5 +/- 1.3. Zonisamide at a mean +/- SD dose of 160 +/- 70 mg/day for 9.2 +/- 4.5 weeks was generally well tolerated. Adverse events were generally mild, and no patients discontinued zonisamide because of side effects. Six patients (60%) met responder criteria at end-point (CGI-I