Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine.

AIM: The aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis. METHODS: We conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for ≥ 3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually. Safety was assessed by adverse events and laboratory tests. The primary efficacy endpoint was mean monthly headache days in the subset of women reporting perimenstrual migraine (-2 days to +3 days of menses onset) and ≥ 5 moderate or severe migraines per month prior to entering the trial. RESULTS: Telcagepant was generally well tolerated: 66/2660 (2.5%) on telcagepant and 36/1326 (2.7%) on placebo discontinued because of a clinical adverse event. The percentages of patients with clinical adverse events, laboratory adverse events, or discontinuation because of a laboratory adverse event were also similar between treatments. Alanine aminotransferase elevations ≥ 3x normal occurred in 0.6% of women on telcagepant and 0.4% on placebo. Three women on telcagepant vs none on placebo had alanine aminotransferase elevations ≥ 8× normal. In the efficacy subset there was no significant effect of telcagepant (n = 887) vs placebo (n = 447) in mean monthly headache days (treatment difference -0.5 day (95% CI: -1.1, 0.1)). However, telcagepant was associated with a reduction in on-drug headache days (treatment difference -0.4 day (95% CI: -0.5, -0.2), nominal p < 0.001). CONCLUSIONS: Telcagepant 140 mg taken perimenstrually for seven days was generally well tolerated, but was associated with transaminase elevations. Telcagepant did not reduce monthly headache frequency, but did reduce perimenstrual headaches.

Asenapine for the Acute Treatment of Pediatric Manic or Mixed Episode of Bipolar I Disorder.

OBJECTIVE: To evaluate asenapine versus placebo in 403 patients aged 10 to 17 years with bipolar I disorder currently in manic or mixed episodes. METHOD: In this double-blind, placebo-controlled, international trial, patients were randomized 1:1:1:1 to placebo, asenapine 2.5, 5, or 10 mg b.i.d. (twice daily). Primary efficacy measure was change from baseline in Young-Mania Rating Scale (YMRS) total score at day 21. Analyses of patients with/without attention-deficit/hyperactivity disorder (ADHD) and with/without stimulant use were performed. RESULTS: The mean difference in asenapine versus placebo in YMRS was -3.2 (p = .0008), -5.3 (p < .001), and -6.2 (p < .001) for asenapine 2.5, 5, and 10 mg b.i.d., respectively. Treatment-emergent adverse events with an incidence ≥5% and at least twice placebo were somnolence, sedation, hypoesthesia oral, paresthesia oral, and increased appetite. The asenapine groups had a higher incidence of ≥7% weight gain (range, 8.0%-12.0%) versus placebo (1.1%; p < .05). The mean change from baseline in fasting insulin was larger for patients treated with asenapine than those with placebo (asenapine 2.5 mg b.i.d.: 73.375 pmol/L; asenapine 5 mg b.i.d.: 114.042 pmol/L; asenapine 10 mg b.i.d.: 59.846 pmol/L; placebo: 3.690 pmol/L). The mean changes from baseline for lipid parameters and glucose were also larger in asenapine groups than in the placebo group. No safety differences were observed with respect to ADHD and stimulant use. CONCLUSION: All asenapine doses versus placebo were superior based on change in YMRS at day 21. Asenapine was generally well tolerated in patients aged 10 to 17 years with bipolar I disorder in manic or mixed states. Increases in weight and fasting insulin were associated with asenapine. Clinical trial registration information-Efficacy and Safety of Asenapine Treatment for Pediatric Bipolar Disorder; http://clinicaltrials.gov; NCT01244815.

The effectiveness of telephone-based continuing care in the clinical management of alcohol and cocaine use disorders: 12-month outcomes.

This study of continuing care for substance dependent patients compared a telephone-based monitoring and brief counseling intervention (TEL) with 2 face-to-face interventions, relapse prevention (RP) and standard 12-step group counseling (STND). The participants were graduates of intensive outpatient programs who had current dependence on alcohol and/or cocaine. Self-report, collateral, and biological measures of alcohol and cocaine use were obtained over a 12-month follow-up. The treatment groups did not differ on abstinence-related outcomes in the complete sample (N = 359) or on cocaine use outcomes in participants with cocaine dependence (n = 268). However, in participants with alcohol dependence only (n = 91), TEL produced better alcohol use outcomes than STND on all measures examined and better outcomes than RP on some of the measures.

Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention.

OBJECTIVE: To evaluate whether the calcitonin gene-related peptide (CGRP) receptor antagonist telcagepant might be effective for migraine prevention. METHODS: In this randomized, double-blind, placebo-controlled, multicenter trial (ClinicalTrials.gov NCT00797667), patients experiencing 3-14 migraine days during a 4-week baseline were randomized to telcagepant 140 mg, telcagepant 280 mg, or placebo twice daily for 12 weeks. Efficacy was assessed by mean monthly headache days and migraine/probable migraine days (headache plus ≥ 1 associated symptom). RESULTS: The trial was terminated following a recommendation from the Safety Monitoring Board due to hepatotoxicity concerns. At termination, the planned 660 patients had been randomized, 656 had been treated with ≥ 1 dose of study medication, and 14 had completed the trial. The mean treatment duration was 48-50 days. Thirteen patients, all in the telcagepant groups, had an alanine aminotransferase (ALT) elevation ≥ 3 × the upper limit of normal and 7 of these also had an aspartate aminotransferase elevation ≥ 3 × the upper limit of normal. Two patients had very high symptomatic transaminase elevations that occurred within 2-6 weeks of treatment initiation and resolved after treatment discontinuation. The originally planned efficacy analysis over 12 weeks was not performed due to limited data at later time points, but there was evidence that telcagepant resulted in a larger reduction from baseline than placebo for mean monthly headache days (month 1: 140 mg = -2.9, 280 mg = -3.1, placebo = -1.7; p < 0.05) and migraine/probable migraine days (month 1: 140 mg = -2.7, 280 mg = -3.0, placebo = -1.6; p < 0.05). CONCLUSIONS: These data suggest a potential role for CGRP receptor antagonism in migraine prophylaxis. However, the observed aminotransferase elevations do not support the use of telcagepant for daily administration. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with migraine, telcagepant taken daily reduces headache days by 1.4 days per month compared to placebo and causes 2.5% of patients to have elevations of serum ALT levels.

Factors in sustained recovery from cocaine dependence.

The goal was to identify factors that predicted sustained cocaine abstinence and transitions from cocaine use to abstinence over 24 months. Data from baseline assessments and multiple follow-ups were obtained from three studies of continuing care for patients in intensive outpatient programs (IOPs). In the combined sample, remaining cocaine abstinent and transitioning into abstinence at the next follow-up were predicted by older age, less education, and less cocaine and alcohol use at baseline, and by higher self-efficacy, commitment to abstinence, better social support, lower depression, and lower scores on other problem severity measures assessed during the follow-up. In addition, higher self-help participation, self-help beliefs, readiness to change, and coping assessed during the follow-up predicted transitions from cocaine use to abstinence. These results were stable over 24 months. Commitment to abstinence, self-help behaviors and beliefs, and self-efficacy contributed independently to the prediction of cocaine use transitions. Implications for treatment are discussed.

Posttraumatic stress disorder and other psychopathology in substance abusing patients.

Studies demonstrating greater problem severity in substance abuse patients with posttraumatic stress disorder (PTSD) versus those without have rarely considered other co-occurring psychiatric disorders. This study of 466 male veterans recently admitted to outpatient substance abuse treatment attempts to identify problems associated with PTSD versus those associated with other nonsubstance use Axis I disorders. Problem severity, particularly psychiatric, was examined across four groups of patients with substance use disorders (SUDs). Those with: 1, SUDs only (SU-Only); 2, PTSD, but no other Axis I disorders (SU+PTSD); 3, PTSD and other Axis I disorders (SU+PTSD+Axis I); and 4, no PTSD, but other Axis I disorders (SU+other Axis I). Results suggested a hierarchy of psychiatric, and to a lesser extent, other life problem severities associated with these diagnostic groupings. The most severe group was SU+PTSD+Axis I, followed in decreasing severity by the SU+other Axis I, SU+PTSD, and SU-Only groups. Additional analyses comparing the SU+PTSD+Axis I patients with a subgroup of Axis I patients with more than one Axis I disorder (SU+multiple Axis I) revealed few group differences except for more lifetime suicide attempts and psychiatric hospitalizations in the SU+PTSD+Axis I group. The findings suggest that it is not PTSD per se, but the frequent co-occurrence of PTSD and other psychopathology that largely accounts for previously reported greater problem severity of SUD patients with PTSD.