Targeting the Arginine Vasopressin V1b Receptor System and Stress Response in Depression and Other Neuropsychiatric Disorders.

A healthy stress response is critical for good mental and overall health and promotes neuronal growth and adaptation, but the intricately balanced biological mechanisms that facilitate a stress response can also result in predisposition to disease when that equilibrium is disrupted. The hypothalamic-pituitary-adrenal (HPA) axis neuroendocrine system plays a critical role in the body's response and adaptation to stress, and vasopressinergic regulation of the HPA axis is critical to maintaining system responsiveness during chronic stress. However, exposure to repeated or excessive physical or emotional stress or trauma can shift the body's stress response equilibrium to a "new normal" underpinned by enduring changes in HPA axis function. Exposure to early life stress due to adverse childhood experiences can also lead to lasting neurobiological changes, including in HPA axis function. HPA axis impairment in patients with depression is considered among the most reliable findings in biological psychiatry, and chronic stress has been shown to play a major role in the pathogenesis and onset of depression and other neuropsychiatric disorders. Modulating HPA axis activity, for example via targeted antagonism of the vasopressin V1b receptor, is a promising approach for patients with depression and other neuropsychiatric disorders associated with HPA axis impairment. Despite favorable preclinical indications in animal models, demonstration of clinical efficacy for the treatment of depressive disorders by targeting HPA axis dysfunction has been challenging, possibly due to the heterogeneity and syndromal nature of depressive disorders. Measures of HPA axis function, such as elevated cortisol levels, may be useful biomarkers for identifying patients who may benefit from treatments that modulate HPA axis activity. Utilizing clinical biomarkers to identify subsets of patients with impaired HPA axis function who may benefit is a promising next step in fine-tuning HPA axis activity via targeted antagonism of the V1b receptor.

Fibromyalgia syndrome.

The fibromyalgia syndrome (FM) workshop at OMERACT 8 continued the work initiated in the first FM workshop at OMERACT 7 in 2004. The principal objectives were to work toward consensus on core domains for assessment in FM studies, evaluate the performance quality of outcome measures used in a review of recent trials in FM, and discuss the research agenda of the FM working group. An initiative to include the patient perspective on identification and prioritization of domains, consisting of focus groups and a patient Delphi exercise, was completed prior to OMERACT 8. Patient-identified domains were, for the most part, similar to those identified by clinician-investigators in terms of symptoms and relative importance. However, patients identified certain domains, such as stiffness, that were not included by physicians, and emphasized the importance of domains such as dyscognition and impaired motivation. Many of the principal domains agreed upon by the clinician-investigators, patients, and OMERACT participants, including pain, fatigue, sleep, mood, and global measures, have been used in clinical trials and performed well when viewed through the OMERACT filter. The research agenda items reviewed and approved for continued study included development of objective "biomarkers" in FM, development of a responder index for FM, and coordination with the WHO's International Classification of Functioning Disability and Health (ICF) Research Branch and the US National Institutes of Health's Patient Reported Outcome Measures Information System network (PROMIS) to develop improved measures of function, quality of life, and participation. The OMERACT process has provided a framework for identification of key domains to be assessed and a path toward validation and standardization of outcome measures for clinical trials in FM.

Analysis of electrocardiographic data following use of paroxetine in pediatric depression and obsessive-compulsive disorder.

OBJECTIVE: This retrospective analysis of electrocardiographic (ECG) data investigated the cardiovascular effects of paroxetine 10-50 mg/day in pediatric patients (7-18 years of age). Data were collected from three 8- to 10-week, randomized, placebo-controlled, double-blind trials of paroxetine in pediatric patients with major depressive disorder or obsessive-compulsive disorder. METHOD: Electrocardiograms (ECGs) were retrospectively retrieved from 63 study sites in the United States and Canada. Only patients with at least one screening and one on-treatment ECG were included. ECGs were analyzed for heart rate, QT interval corrected using Bazett's formula (QTcB) and Fridericia's formula (QTcF), at screening and while being treated. PR, R-R, and QRS intervals and the maximum change in QTcB and QTcF from screening to endpoint were determined. Clinically significant thresholds were defined a priori. RESULTS: A total of 1,451 ECGs from 449 patients receiving placebo (n = 207), paroxetine (n = 200), or imipramine (n = 42) were analyzed. Treatment with paroxetine did not significantly increase QTcB or QTcF or any ECG parameters compared with placebo. Treatment with imipramine significantly increased heart rate and QTcB, R-R, and QRS intervals compared with either paroxetine or placebo. CONCLUSIONS: Data from this retrospective study indicate that paroxetine (10-50 mg/day) is unlikely to be associated with significant ECG changes in medically healthy pediatric patients.

Evaluation of suicidal thoughts and behaviors in children and adolescents taking paroxetine.

OBJECTIVE: The aim of this study was to summarize results of a blinded review of potential suicidal events and analyses comparing incidence rates between paroxetine- and placebo-treated pediatric patients. METHOD: One thousand one hundred ninety-one (1191) children and adolescents received paroxetine (n = 642) or placebo (n = 549) during placebo-controlled portions of all acute double-blind trials of paroxetine (n = 5). An expert panel blindly reviewed and categorized all identified cases detected by electronic and manual search of adverse events (AEs), serious AEs, and selected cases as suicidal or non-suicidal behavior. Incidence rates were calculated for suicide-related events and for rating scale items assessing suicidality. RESULTS: Suicide-related events occurred more often in paroxetine (22 of 642, 3.4%) than placebo groups (5 of 549, 0.9%); odds ratio (OR) 3.86 (95% CI 1.45, 10.26; p = 0.003). All suicide-related events occurred in adolescents of at least 12 years, except for 1 of 156 paroxetine-treated children. All suicide attempts occurred in major depressive disorder (MDD); few suicide-related events occurred in patients with a primary anxiety disorder. Suicide item analyses did not reveal significant differences between paroxetine and placebo. CONCLUSIONS: Adolescents treated with paroxetine showed an increased risk of suicide-related events. Suicidality rating scales did not show this risk difference. The presence of uncontrolled suicide risk factors, the relatively low incidence of these events, and their predominance in adolescents with MDD make it difficult to identify a single cause for suicidality in these pediatric patients.

Paroxetine response and tolerability among ethnic minority patients with mood or anxiety disorders: a pooled analysis.

BACKGROUND: Because of the poor quality of mental health care received by minorities, analyses documenting comparable response to and tolerability of medications for anxiety and depression in large samples of minority and majority populations could increase the willingness of providers and patients to use medications in minority populations. METHOD: A pooled analysis of 14,875 adults who participated in 104 double-blind, placebo-controlled paroxetine clinical trials investigating major depression, panic disorder, generalized anxiety disorder, social anxiety disorder, obsessive-compulsive disorder, posttraumatic stress disorder, or premenstrual dysphoric disorder from March 1984 through March 2002. An intent-to-treat analysis with last observation carried forward used the Clinical Global Impressions (CGI) scale to measure dichotomous outcome, classified as either response (CGI score of 1 or 2) or more complete response (CGI score of 1) ("full response"). Minority group differences were examined using logistic regression for the entire sample and repeated for those with major depression. Adverse events greater than 5% and twice the rate of placebo were descriptively tabulated. Finally, a survival analysis examined group differences in speed of onset of response. RESULTS: Hispanic and Asian subjects had a slightly lower response rate, while Asians had the highest rates and Hispanics had the lowest rates of "full response." The more consistent Hispanic outcome differences appeared to be due to a higher placebo response rate. There was no treatment by minority group interaction for depressed patients. Speed of response and adverse effects were similar across groups. CONCLUSIONS: There were few consistent differences in medication response and tolerability. These findings may serve to counteract the greater rate of negative attitudes toward medication use among minorities and reinforce the value of medications used to treat anxiety and depression in minorities.

Efficacy and tolerability of controlled-release paroxetine in the treatment of panic disorder.

OBJECTIVE: To assess the efficacy and tolerability of controlled-release paroxetine (paroxetine CR) in the treatment of adults with panic disorder. METHOD: Paroxetine CR (25-75 mg/day; N = 444) was compared with placebo (N = 445) in patients with DSM-IV panic disorder with or without agoraphobia in 3 identical, double-blind, placebo-controlled, 10-week clinical trials that were pooled for analysis. RESULTS: Paroxetine CR was statistically superior to placebo in the primary outcome measure, percentage of patients who were free of panic attacks in the 2 weeks prior to endpoint. Of the total population that completed or prematurely terminated treatment, 63% and 53% of paroxetine CR-and placebo-treated patients, respectively, were panic-free during the final 2 weeks (p < .005; odds ratio [OR] = 1.63; 95% CI = 1.21 to 2.19). For week 10 completers (72% of total), 73% and 60% of paroxetine CR- and placebo-treated patients, respectively, were panic-free at week 10 (p < .005; OR = 2.11; 95% CI = 1.45 to 3.07). Paroxetine CR was also statistically superior to placebo on the global improvement and severity items of the Clinical Global Impressions scale and in reducing anxiety symptoms as measured by the Hamilton Rating Scale for Anxiety total score and total fear and avoidance on the Marks-Sheehan Phobia Scale. Adverse events leading to study withdrawal were minimal and occurred in 11% of the paroxetine CR group and 6% of the placebo group. Most of the treatment-emergent adverse events were rated as mild to moderate in severity and occurred early in the study. There were no unexpected adverse events, and serious adverse events were uncommon (10 [2.3%] of the 444 patients treated with paroxetine CR vs. 8 [1.8%] of the 445 patients treated with placebo). CONCLUSION: Paroxetine CR is an effective and well-tolerated treatment for panic disorder. Paroxetine CR is associated with low rates of treatment-emergent anxiety as well as low dropout rates from adverse events.

Effectiveness of low doses of paroxetine controlled release in the treatment of major depressive disorder.

CONTEXT: Paroxetine controlled release (CR) is approved for the treatment of major depressive disorder (MDD) in the dosage range of 25 to 62.5 mg daily. However, lower daily doses (12.5 mg and 25 mg) of this formulation have not been investigated in the treatment of MDD. If the 12.5-mg and 25-mg doses are found to be efficacious, these lower doses may well convey a superior tolerability profile for paroxetine CR in the treatment of MDD. OBJECTIVE: To evaluate the antidepressant efficacy and tolerability profile of daily doses of paroxetine CR 12.5 mg and 25 mg versus placebo in the treatment of MDD. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled clinical trial conducted in 40 clinical investigation centers in the United States. PARTICIPANTS: 447 adult (> or = 18 years of age) outpatients who met DSM-IV criteria for MDD and with a baseline 17-item Hamilton Rating Scale for Depression (HAM-D) score of at least 20 comprised the intent-to-treat study population (mean age = 38.8 years; 58.4% female; 75.6% white). INTERVENTION: Eligible patients completing a 1-week single-blind placebo run-in period were randomly assigned to receive once-a-day study medication (paroxetine CR 12.5 mg [N = 156], paroxetine CR 25 mg [N = 154], or placebo [N = 149]) in an 8-week, double-blind, parallel cell comparison. MAIN OUTCOME MEASURES: The primary efficacy measure was the change from baseline to study endpoint (week 8) as measured by the HAM-D. Secondary efficacy measures included change from baseline to study endpoint as assessed by both the depressed mood item on the HAM-D and the Clinical Global Impressions (CGI) Severity of Illness scale (CGI-S). The proportion of patients considered at study endpoint to be in response (CGI-Improvement score of 1 or 2) or in remission (HAM-D < or = 7) in the 3 treatment groups was also compared. Quality of life was assessed by the change from baseline in total score of the short form of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q). Safety observations were made by assessing the proportion of patients who had adverse experiences, including laboratory and electrocardiographic abnormalities, during the treatment period. RESULTS: The primary efficacy analysis revealed that both the 12.5-mg and the 25-mg paroxetine CR treatment groups were associated with significant therapeutic effects (change in HAM-D score) from baseline to study endpoint (LOCF: p = .038, 95% CI = -3.38 to -0.09 and p = .005, 95% CI = -4.06 to -0.74, respectively). Results from the Wilcoxon rank sum test of the depressed mood item of the HAM-D (p = .011, 95% CI = -0.57 to -0.07) demonstrated significant efficacy in the 25-mg treatment group but not in the 12.5-mg group. However, LOCF analysis of the CGI-S revealed significant therapeutic effects for both the 12.5-mg (p = .018, 95% CI = -0.61 to -0.06) and 25-mg (p < .001, 95% CI = -0.78 to -0.22) treatment groups. Significantly more patients in the 25-mg paroxetine CR-treated group than in the placebo-treated group met criteria for response (CGI-Improvement score of 1 or 2, p = .035, OR = 1.68, 95% CI = 1.04 to 2.73) as well as for remission (HAM-D score

From the Bench to the Trench: A Comparison of Sertraline Treatment of Major Depression in Clinical and Research Patient Samples.

BACKGROUND: New medications that enter the marketplace have been tested almost exclusively in controlled clinical trials conducted in specialty research settings. There is some concern that these carefully selected patient samples may not provide information generalizable to the "real world" clinical population. The purpose of this investigation was to compare results from a large, open-label study of sertraline in the treatment of major depression in the clinical practice setting with pooled results from 2 multicenter, double-blind, placebo-controlled studies conducted in specialty research settings. METHOD: Clinical practice patients (N = 1482), aged 21 to 65 years, from 228 psychiatric clinical practice sites across the United States participated in the open-label treatment study (Clinical Practice sample). Patients who met DSM-III-R criteria for moderate-to-severe unipolar major depression (i.e., had pretreatment Hamilton Rating Scale for Depression [HAM-D] scores >/= 18) were treated for 8 weeks with sertraline in a flexible dosing fashion (50-200 mg daily). Outcomes on the HAM-D and Clinical Global Impressions-Improvement scale (CGI-I) were compared with the pooled results from 2 previously published placebo-controlled, multicenter treatment studies of sertraline in outpatients with major depression (N = 280). The overall response to sertraline in the Clinical Practice sample was compared with the outcome from the research study patient sample (Clinical Research sample). Additionally, comparison of outcomes of patients with common depressive subtypes (double depression, anxious depression, and melancholic ["endogenous"] depression) were examined. RESULTS: The percentage of sertraline-treated patients rated as responders on the CGI-I was significantly higher in the Clinical Practice sample compared with the Clinical Research sample (87% vs. 73%; p <.001). Sertraline was also much better tolerated in the Clinical Practice sample than in the Clinical Research sample as evidenced by significantly lower overall reports of adverse events (9.4% vs. 13.2%; p <.05) and lower patient dropout rates (17.5% vs. 34.3%; p <.01). Among clinical practice patients, sertraline was found to be equally effective in treating endogenous/melancholic and anxious subtypes and only mildly less effective in achieving a response in patients with double depression (chronic low-grade depression with a superimposed major depression). A regression analysis identified older age and double depression as being predictors of a slower time to response. More than 70% of patients who reported nonresponse to previous treatment with fluoxetine or a tricyclic antidepressant responded to sertraline. CONCLUSION: The effectiveness and tolerability of sertraline treatment was found to be significantly better in the Clinical Practice sample, suggesting that the results from controlled studies in research settings may represent an underestimate of the benefits of a drug. More effectiveness research is needed to confirm and extend these findings.