Andrew Winokur

Demonstration of the Efficacy and Safety of a Novel Substance P (NK1) Receptor Antagonist in Major Depression

The efficacy and safety of a selective NK1 antagonist, L-759274, was investigated in outpatients with diagnosis of major depressive disorder with melancholic features, following evidence obtained with the novel compound aprepitant that Substance P (NK1) antagonists may provide a unique mechanism of antidepressant activity. A randomized, double-blind placebo-controlled study was carried out. Patients, male or female, aged 18–60, scoring ⩾25 points on total of first 17 items of 21-item Hamilton Depression Scale (HAMD), and scoring ⩾4 (moderately ill) on Clinical Global Impressions-Severity Scale were randomized to oral L-759274 40 mg daily (n=66) or placebo (n=62) for 6 weeks. For patients receiving L-759274, improvement (mean decrease from baseline) in HAMD-17 total score was 10.7 points, compared with a mean 7.8 point improvement in patients receiving placebo (p<0.009). Mean scores for item 1 of HAMD-17 (depressed mood) also improved to a greater extent in the active group compared with the placebo group (0.3 points, p<0.058). Compared with placebo, mean scores on Clinical Global Impressions-Improvement Scale improved significantly by the end of the trial (p=0.009). L-759274 was generally safe and well-tolerated. The incidence of sexual side effects was on par with that observed in patients receiving placebo, and the incidences of gastrointestinal effects were low. Antidepressant actions have now been observed with two different highly selective NK1 antagonists (aprepitant and L-759274). NK1 antagonism is a replicated and generally well-tolerated antidepressant mechanism.

Assessment of adrenal gland volume by computed tomography in depressed patients and healthy volunteers: A pilot study

Excessive adrenocortical activation in depression has been postulated to be the result of overactivity of limbic system-hypothalamic function. In contrast, several studies have suggested the possibility that excessive secretion of cortisol might also result, in part, from a heightened adrenocortical responsiveness to adrenocorticotropic hormone (ACTH), or even a mild adrenal hyperplasia. Because computed tomography (CT) may provide a method for assessing an increase in adrenal size, we performed CT scans of the adrenal glands in depressed patients and healthy volunteers, who also received the dexamethasone suppression test. Eight out of 16 patients (50%) had adrenal volumes in excess of the 95th percentile value of the control distribution for adrenal volume. These observations suggest that there may be demonstrable adrenal hypertrophy during depressive illness.

Effects of Psychiatric Medications on Sleep and Sleep Disorders

Insomnia is a significant public health concern that has prompted substantial efforts to develop treatment and management strategies. A significant proportion of complaints of insomnia are related to psychiatric conditions such as anxiety disorders and depression, and treatments for these disorders are known to exert both direct and indirect benefits on sleep as well as some negative effects on sleep and sleep physiology. Insomnia is also a prominent symptom of a number of other psychiatric disorders, including schizophrenia and bipolar disorder. The observed impact of a variety of psychiatric medications on insomnia has prompted an empirically derived practice of treating non-psychiatric disorder-related insomnia with psychiatric medications by clinicians searching for alternatives to established medication treatments for primary insomnia. This article aims to review the evidence of the impact of psychiatric medications on sleep physiology, sleep disorders in psychiatric conditions, and on primary sleep disorders. The potential for exploiting the relevant pharmacological mechanisms of action in drug development for primary insomnia will be addressed as well.

A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression

OBJECTIVE Ketamine, an N-methyl-d-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression. METHOD In a multicenter, double-blind study, adults (ages 18-64 years) with treatment-resistant depression were randomized to receive either intravenous ketamine (0.5 mg/kg of body weight) or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS). RESULTS In total, 67 (45 women) of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was -18.4 (SD=12.0) for ketamine and -5.7 (SD=10.2) for placebo; in the thrice-weekly groups, it was -17.7 (SD=7.3) for ketamine and -3.1 (SD=5.7) for placebo. Similar observations were noted for ketamine during the open-label phase (twice-weekly, -12.2 [SD=12.8] on day 4; thrice-weekly, -14.0 [SD=12.5] on day 5). Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common (≥20%) treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing. CONCLUSIONS Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days.

Amantadine for weight gain associated with olanzapine treatment

Patients with schizophrenia (Sch), schizoaffective, schizophreniform, or bipolar (BP) I disorders [Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)]; not manic or acutely psychotic [Brief Psychiatric Rating Scale (BPRS) total score < or =45]; treated with olanzapine for 1-24 months; and who had gained > or =5% of their initial body weight were examined to determine whether amantadine could attenuate weight gain or promote weight loss. Olanzapine (Olz; 5-20 mg/day) was co-administered with double-blind treatment of 100-300 mg/day amantadine (Olz+Amt, n=60) or placebo (Olz+Plc, n=65). Visit-wise analysis of weight showed that weight change from baseline [last-observation-carried-forward (LOCF)] in the Olz+Amt group was significantly different from the Olz+Plc group at weeks 8 (P=0.042), 12 (P=0.029), and 16 (primary endpoint, mean+/-S.D.: -0.19+/-4.58 versus 1.28+/-4.26 kg, P=0.045). Mean BPRS total score, positive subscale, and anxiety-depression scores improved comparably in both groups, and Montgomery-Asberg Depression Rating Scale (MADRS) total score improved in the Olz+Amt group. Overall, amantadine was safe, was well tolerated, and attenuated weight gain or promoted weight loss in some patients who had gained weight during olanzapine therapy.

ASSOCIATION BETWEEN SUBJECTIVE SLEEP QUALITY AND DEPRESSION ON IMMUNOCOMPETENCE IN LOW-INCOME WOMEN AT RISK FOR CERVICAL CANCER

OBJECTIVE The purpose of this study was to investigate whether subjective sleep quality is more strongly associated with immunocompetence than depression among women at risk for cervical cancer. METHODS Participants were 91 women referred for colposcopy because of abnormal results on a Pap smear. On the day of the procedure. participants completed the Center for Epidemiological Studies Depression Scale, two indices of subjective sleep quality (ie, satisfaction with sleep obtained and degree of sleep restfulness), and a health behaviors assessment questionnaire. Levels of peripheral blood lymphocyte subpopulations (helper T, cytotoxic/suppressor T, NK, and B cells) were also assessed at this time. Approximately 10 days later, the presence of depressive disorder was assessed using the Structured Clinical Interview for DSM-III-R. RESULTS Hierarchical regression analyses revealed that satisfaction with the amount of sleep obtained was significantly associated with the circulating number and percentage of helper T cells (T(H)/CD4+) and the percentage of cytotoxic/suppressor T cells (T(C)/CD8+), after controlling for confounder variables (ie, age, smoking status, and drug use). Depression was significantly associated only with the percentage of T(C) cells. Sleep satisfaction remained significantly associated with the number and percentage of T(H) cells and percentage of T(C) cells after controlling for the variance explained by depression. CONCLUSIONS Results of this study suggest that subjective sleep quality shares a significant and independent portion of the variance with immunity that is not accounted for by depression. Although the long-term impact of these immune alterations on disease progression needs to be directly explored, it may be important to systematically screen for and manage sleep disturbance in women at high risk for cervical cancer.

A 12-Week, Randomized, Double-Blind, Placebo-Controlled, Sequential Parallel Comparison Trial of Ziprasidone as Monotherapy for Major Depressive Disorder

OBJECTIVE To study ziprasidone monotherapy for major depressive disorder, defined according to the DSM-IV. METHOD One hundred twenty outpatients were enrolled between June 2008 and September 2010 in a 12-week study that was divided into two 6-week periods according to the sequential parallel comparison design. Patients were randomized in a 2:3:3 fashion to receive ziprasidone for 12 weeks, placebo for 6 weeks followed by ziprasidone for 6 weeks, or placebo for 12 weeks. The main outcome measure was the 17-item Hamilton Depression Rating Scale (HDRS-17), with the Quick Inventory of Depressive Symptomatology, Self-Rated (QIDS-SR), and Clinical Global Impressions-Severity of Illness scale (CGI-S) serving as the study secondary measures. RESULTS One hundred twenty patients (53 women [44.1%]) were randomized to treatment. The mean (SD) age of these patients was 43.7 (11.0) years. Mean (SD) baseline HDRS-17, CGI-S, and QIDS-SR scores were 19.9 (5.0), 4.3 (0.6), and 15.6 (3.0), respectively. There was no statistically significant difference in reduction of depressive symptoms, response rates, or remission rates between ziprasidone- or placebo-treated patients. This was true for both the study primary as well as secondary outcome scales. CONCLUSIONS In conclusion, treatment with ziprasidone monotherapy was not associated with any statistically significant advantage in efficacy over placebo. Although studies involving larger sample size would be required to have adequate statistical power to detect treatment differences smaller than 2.5 points on the HDRS-17, such differences would be of questionable clinical relevance. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00555997.

Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression: A Randomized Clinical Trial

Importance Approximately one-third of patients with major depressive disorder (MDD) do not respond to available antidepressants. Objective To assess the efficacy, safety, and dose-response of intranasal esketamine hydrochloride in patients with treatment-resistant depression (TRD). Design, Setting, and Participants This phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study was conducted in multiple outpatient referral centers from January 28, 2014, to September 25, 2015. The study consisted of 4 phases: (1) screening, (2) double-blind treatment (days 1-15), composed of two 1-week periods, (3) optional open-label treatment (days 15-74), and (4) posttreatment follow-up (8 weeks). One hundred twenty-six adults with a DSM-IV-TR diagnosis of MDD and history of inadequate response to 2 or more antidepressants (ie, TRD) were screened, 67 were randomized, and 60 completed both double-blind periods. Intent-to-treat analysis was used in evaluation of the findings. Interventions In period 1, participants were randomized (3:1:1:1) to placebo (n = 33), esketamine 28 mg (n = 11), 56 mg (n = 11), or 84 mg (n = 12) twice weekly. In period 2, 28 placebo-treated participants with moderate-to-severe symptoms were rerandomized (1:1:1:1) to 1 of the 4 treatment arms; those with mild symptoms continued receiving placebo. Participants continued their existing antidepressant treatment during the study. During the open-label phase, dosing frequency was reduced from twice weekly to weekly, and then to every 2 weeks. Main Outcomes and Measures The primary efficacy end point was change from baseline to day 8 (each period) in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Results Sixty-seven participants (38 women, mean [SD] age, 44.7 [10.0] years) were included in the efficacy and safety analyses. Change (least squares mean [SE] difference vs placebo) in MADRS total score (both periods combined) in all 3 esketamine groups was superior to placebo (esketamine 28 mg: −4.2 [2.09], P = .02; 56 mg: −6.3 [2.07], P = .001; 84 mg: −9.0 [2.13], P < .001), with a significant ascending dose-response relationship (P < .001). Improvement in depressive symptoms appeared to be sustained (−7.2 [1.84]) despite reduced dosing frequency in the open-label phase. Three of 56 (5%) esketamine-treated participants during the double-blind phase vs none receiving placebo and 1 of 57 participants (2%) during the open-label phase had adverse events that led to study discontinuation (1 event each of syncope, headache, dissociative syndrome, and ectopic pregnancy). Conclusions and Relevance In this first clinical study to date of intranasal esketamine for TRD, antidepressant effect was rapid in onset and dose related. Response appeared to persist for more than 2 months with a lower dosing frequency. Results support further investigation in larger trials. Trial Registration clinicaltrials.gov identifier: NCT01998958

New approaches for the treatment of sleep disorders.

Epidemiological studies have established that sleep disorders are common and often untreated. Besides having a negative impact on overall health, these conditions can significantly disrupt normal daily functions. While a number of drugs are employed in the treatment of sleep disorders, safety, tolerability, and variable efficacy limit their utility. Clinical developments in the area have been facilitated especially by advances in neurobiology and neuropharmacology. In this regard, a wide array of neuroactive substances has been found to be responsible for regulating sleep and wakefulness. Advances in the understanding of neurotransmitter and hormone receptor mechanisms and classifications have led to new opportunities for developing novel therapeutics for treating sleep disorders. Provided in this report is an overview of some of the more prevalent sleep disorders, including narcolepsy, insomnia, obstructive sleep apnea syndrome, and restless legs syndrome, with a summary and critique of medications used to treat these conditions. For each disorder, information is provided on recent approaches taken to develop novel therapeutics based on laboratory findings relating to the underlying biological abnormalities associated with the condition, in addition to approaches that leverage existing therapeutics to develop new treatment options for patients. Significant advances in the future await a better understanding of the underlying pathophysiology of these conditions and of the neurobiological alterations associated with these disorders. It is hoped that some of the research directions described herein will stimulate additional research in this area and thereby help foster the discovery of novel agents for treating major sleep disorders.

The Relationship Between Sleep Disturbances and Psychiatric Disorders: Introduction and Overview.

Changes in the psychiatric diagnostic guidelines with the transition from Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV to DSM-V include acknowledgment that primary sleep disorders such as insomnia can occur in conjunction with medical and psychiatric disorders. This change in viewpoint regarding the definition of primary sleep disorders opens the way to the recognition that patients with psychiatric disorders demonstrate a high prevalence of sleep disturbances, with complaints of insomnia and excessive daytime sleepiness being especially commonly reported. Recent investigations have pointed to a bidirectional relationship between sleep disturbances and psychiatric disorders.