A Randomized Trial to Assess the Efficacy and Safety of ABT-126, a Selective α7 Nicotinic Acetylcholine Receptor Agonist, in the Treatment of Cognitive Impairment in Schizophrenia.

OBJECTIVE: The authors sought to evaluate the efficacy and safety of ABT-126, a selective α7 nicotinic receptor partial agonist, in stable patients with schizophrenia. METHOD: A 12-week, double-blind, placebo-controlled, parallel-group phase 2 study was conducted in 22 centers in the United States. Clinically stable patients with schizophrenia were randomly assigned to receive once-daily dosing with 10 mg of ABT-126, 25 mg of ABT-126, or placebo. The primary efficacy measure was change from baseline to week 12 on the MATRICS Consensus Cognitive Battery (MCCB) composite score compared with placebo, tested by a one-sided t test. Secondary measures included MCCB domain scores and UCSD Performance-Based Skills Assessment total score, each tested by two-sided t tests. RESULTS: A total of 207 subjects were randomized, of whom 165 (81%) completed the study. ABT-126 showed an improvement that fell short of significance on the MCCB composite score at week 12 (least squares mean difference from placebo, 1.3 and 1.5 for the 10 mg and 25 mg groups, respectively). A significant treatment-by-smoking status interaction was observed on the mean change from baseline to final MCCB composite score: nonsmokers (N=69) demonstrated a difference from placebo of 2.9 (SE=1.4) in the 10 mg group and 5.2 (SE=1.6) in the 25 mg group, whereas no differences were observed in smokers (N=113). Among the nonsmokers in the ABT-126 25 mg group (N=19), significant improvements compared with placebo occurred at final assessment for verbal learning (least squares mean difference=5.5, SE=1.9), working memory (least squares mean difference=5.4, SE=2.0), and attention/vigilance (least squares mean difference=8.7, SE=2.5). The most frequently reported adverse events for ABT-126 were dizziness, diarrhea, and fatigue (all <8% incidence). CONCLUSIONS: ABT-126 demonstrated a procognitive effect in nonsmoking subjects, particularly in verbal learning, working memory, and attention.

The scopolamine model as a pharmacodynamic marker in early drug development.

RATIONALE: Drug development is a high-risk and high failure enterprise, and studies that provide an early read on the pharmacodynamic activity of novel compounds could save time and money, increasing the efficiency of the drug development process. OBJECTIVE: Preclinical and clinical experiments were designed to examine the utility of the scopolamine-induced cognitive impairment model in predicting pharmacodynamic signals of putatively procognitive compounds, utilizing the acetylcholinesterase inhibitor donepezil for illustration. METHODS/RESULTS: In normal healthy rats, scopolamine (0.3 mg/kg) significantly impaired performance on the two-platform water maze and on the T-maze. The deficits in water maze performance were reversed by donepezil at 0.5 and 1.0 mg/kg. There was a trend towards reversal of scopolamine-induced deficits in performance on the T-maze with 1.0 mg/kg donepezil. In normal healthy humans, scopolamine (0.3 and 0.5 mg) reliably impaired performance on the Cognitive Drug Research test battery composite scores (power of attention, continuity of attention, quality of working memory, quality of episodic secondary memory, and speed of memory) in a dose- and time-dependent manner. Donepezil (10 mg) significantly attenuated the scopolamine-induced impairment in cognition on power of attention, continuity of attention, quality of working memory, and speed of memory. CONCLUSIONS: These findings suggest that reversal of scopolamine-induced cognitive impairment is a viable model for predicting pharmacodynamic signals of procognitive compounds in both animals and humans. The utility of the scopolamine-induced cognitive impairment model is discussed and illustrated at various decision points in drug development, with a focus on Go/No Go decisions.

Linear relationship of valproate serum concentration to response and optimal serum levels for acute mania.

OBJECTIVE: Several studies have shown that achieving adequate serum valproate levels is critical to rapid stabilization of acute mania, but estimates of the target therapeutic level have been imprecise. A post hoc analysis of pooled intent-to-treat data from three randomized, placebo-controlled studies of divalproex treatment for acute mania was performed to test a hypothesized linear relationship between serum concentration and response and to determine optimal blood levels for treatment of acute mania. METHOD: Subjects (N=374) were stratified into seven groups (six valproate serum level ranges and placebo), and effect size was determined for each. Linearity of dose response was tested with both parametric and nonparametric techniques. ANOVA was used to compare the response at each serum level range with that of placebo as well as the lowest valproate level (< =55.0 microg/ml). The mean serum valproate level was then determined for all subjects with an effect size greater than or equal to the maximal effect derived from linear modeling. RESULTS: The fit of blood level and response to a linear model was good. Efficacy was significantly greater than placebo beginning at the 71.4-85.0 microg/ml range and for all higher valproate levels; the 94.1-107.0 and >107.0 microg/ml groups were superior to the lowest valproate serum level group. The effect size associated with highest serum levels (>94 microg/ml) was 1.06 (0.59 after placebo correction). Subjects obtaining this effect or greater (N=84) had a mean serum level of 87.5 microg/ml. Blood levels in the lowest effective range were 60% more effective than placebo and in the higher ranges were 120% more effective. Tolerability appeared similar for all groups. CONCLUSIONS: The results of this study suggest that there is a linear relationship between valproate serum concentration and response and that the target blood level of valproate for best response in acute mania is above 94 microg/ml.

Relationship between serum valproate and lithium levels and efficacy and tolerability in bipolar maintenance therapy.

Background. In spite of widespread recognition of the importance of maintenance treatment for bipolar disorder, there are relatively few available well-designed clinical trials that have provided rigorous evidence for the efficacy of specific agents. One approach used effectively in analyses of lithium studies has been the stratification of efficacy and tolerability results based on serum drug concentrations. Therefore, we conducted a similar analysis of the efficacy of divalproex or lithium, based on serum concentrations in the maintenance treatment of bipolar I disorder in a recent 12-month placebo-controlled trial. Methods. This was a post-hoc analysis of results obtained in a 12-month, double-blind, placebo-controlled trial of divalproex and lithium involving 372 patients (intent-to-treat). The patient set was stratified into four therapeutic drug concentration ranges (Non-therapeutic, Low Therapeutic, Medium Therapeutic, and High Therapeutic) for both divalproex and lithium. Efficacy measures were Kaplan-Meier survival analyses of time to discontinuation for any reason, time to discontinuation for a protocol-defined manic episode, and time to discontinuation for a manic or depressive episode. Results. Significant differences between divalproex at the Medium Therapeutic range (75-99.9 µg/ml) and placebo were demonstrated in Kaplan-Meier survival results for discontinuation for any reason (median survival time: divalproex, 8 months; placebo, 4 months; P<0.05) and for discontinuation for a manic or depressive episode (median survival time: divalproex, 8 months; placebo, 3 months, P=0.003). At 12 months, the proportion of divalproex-treated patients (Medium Therapeutic range) who did not discontinue for a protocol-defined manic episode (85%) was higher than the proportion of lithium (Medium Therapeutic range; 70%) or placebo-treated (83%) patients. Conclusions. Divalproex at the Medium Therapeutic range provided significantly better bipolar maintenance treatment response than placebo in survival analyses, suggesting a possible serum concentration target range for clinicians in providing optimal treatment response. The value of this analytic approach, used for the first time here for divalproex, is discussed, along with a call for further research into optimal therapeutic drug levels.

Divalproex ER prophylaxis in migraineurs with probable chronic migraine and probable medication-overuse headache: a case series.

This case series prospectively evaluated divalproex ER in 15 headache clinic migraine patients fulfilling International Headache Society criteria for probable chronic migraine and probable medication-overuse headache. Divalproex ER was initiated at 500 mg QHS and increased after Week 2 to 1000 mg QHS for a total treatment period of 2 months. Mean headache days per month dropped from 21.6 to 10.4 at month 1 and 8.9 at month 2. All 10 patients who completed the study rated their satisfaction with treatment as changed from unsatisfied at baseline to satisfied at study completion. The results of this study support the prophylactic efficacy of divalproex ER in migraine patients with probable chronic migraine and probable medication-overuse headache.

The safety and early efficacy of oral-loaded divalproex versus standard-titration divalproex, lithium, olanzapine, and placebo in the treatment of acute mania associated with bipolar disorder.

BACKGROUND: Previous studies have examined the safety and tolerability of oral-loaded divalproex sodium in the treatment of acute mania, but not the early efficacy of this dosing strategy. The purpose of this study was to evaluate the early efficacy of oral-loaded divalproex. METHOD: In this pooled analysis, 348 subjects from 3 randomized, double-blind, parallel-group, active- or placebo-controlled studies were used to compare the efficacy, safety, and tolerability of oral-loaded divalproex with standard-titration divalproex, lithium, olanzapine, or placebo. Subjects were inpatients diagnosed with acute mania associated with bipolar I disorder (DSM-III-R or -IV and SADS-Change Version). Patients were administered oral-loaded divalproex (20 or 30 mg/kg/day on days 1 and 2 followed by 20 mg/kg/day, and increased at physician's discretion), standard-titration divalproex initiated at 250 mg t.i.d. and titrated to 40-150 microg/mL, lithium (300 mg t.i.d. initial dose) titrated to 0.4 to 1.5 mEq/L, olanzapine (10 mg q.d. initial dose) up to 20 mg/day, or placebo. RESULTS: The results demonstrate an early efficacy advantage for oral-loaded divalproex compared to standard-titration divalproex at days 5, 7/8, and 10. Efficacy was improved over lithium on day 7/8. There were no efficacy differences between divalproex loading and olanzapine. Divalproex loading showed greater efficacy than placebo at all time points. Divalproex loading was as well tolerated or better tolerated than the other active treatments as measured by adverse events and changes in laboratory parameters. CONCLUSION: These results suggest the oral loading of divalproex leads to a more rapid antimanic effect when compared with standard-titration divalproex, lithium, or placebo and is better tolerated than olanzapine and as well tolerated as lithium or standard-titration divalproex.

Memory for frequency of bizarre and common stimuli: limitations of the automaticity hypothesis.

In 2 experiments, the influence of intention to process frequency on accuracy of memory for frequency of bizarre and common sentences was investigated. The results from multiple regression analyses indicated that intentional processing increased the accuracy of frequency judgments when memory for frequency was tested after a 2-min (Experiment 1) and after a 48-hr (Experiment 2) retention interval. Furthermore, the results of Experiment 2 indicated that unintentional processors tended to overestimate frequencies of bizarre relative to common items after a delay. The implications of the results are discussed with regard to L. Hasher and R. T. Zacks's (1984) automaticity hypothesis, human performance, and the accuracy of judgments of frequency of occurrence of unusual events.