Attenuation of ketamine-induced impairment in verbal learning and memory in healthy volunteers by the AMPA receptor potentiator PF-04958242.

There is a need to develop treatments for cognitive impairment associated with schizophrenia (CIAS). The significant role played by N-methyl-d-aspartate receptors (NMDARs) in both the pathophysiology of schizophrenia and in neuronal plasticity suggests that facilitation of NMDAR function might ameliorate CIAS. One strategy to correct NMDAR hypofunction is to stimulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) as AMPAR and NMDAR functioning are coupled and interdependent. In rats and nonhuman primates (NHP), AMPAR potentiators reduce spatial working memory deficits caused by the nonselective NMDAR antagonist ketamine. The current study assessed whether the AMPAR potentiator PF-04958242 would attenuate ketamine-induced deficits in verbal learning and memory in humans. Healthy male subjects (n=29) participated in two randomized treatment periods of daily placebo or PF-04958242 for 5 days separated by a washout period. On day 5 of each treatment period, subjects underwent a ketamine infusion for 75 min during which the effects of PF-04958242/placebo were assessed on ketamine-induced: (1) impairments in verbal learning and recall measured by the Hopkins Verbal Learning Test; (2) impairments in working memory on a CogState battery; and (3) psychotomimetic effects measured by the Positive and Negative Syndrome Scale and Clinician-Administered Dissociative Symptoms Scale. PF-04958242 significantly reduced ketamine-induced impairments in immediate recall and the 2-Back and spatial working memory tasks (CogState Battery), without significantly attenuating ketamine-induced psychotomimetic effects. There were no pharmacokinetic interactions between PF-04958242 and ketamine. Furthermore, PF-04958242 was well tolerated. 'High-impact' AMPAR potentiators like PF-04958242 may have a role in the treatment of the cognitive symptoms, but not the positive or negative symptoms, associated with schizophrenia. The excellent concordance between the preclinical (rat, NHP) and human studies with PF-04958242, and in silico modeling of AMPAR-NMDAR interactions in the hippocampus, highlights the translational value of this study.

Abnormal salivary cortisol levels in social phobic patients in response to acute psychological but not physical stress.

BACKGROUND: Little is known about the hypothalamic-pituitary-adrenal axis response to acute stressful behavioral challenges in patients with social phobia. METHODS: Eighteen patients with social phobia and 17 normal volunteers participated in two behavioral stressors: a speech task and physical exercise. RESULTS: Normal volunteers (n = 14) demonstrated a significant 50% increase in salivary cortisol levels to the speech task. Three nonresponding normal volunteers demonstrated a 17% decrease. In contrast, patients with social phobia demonstrated dichotomous changes. Seven social phobia patients demonstrated a significantly higher 90% increase in salivary cortisol to the speech task, whereas the remaining patients (n = 11) were nonresponders demonstrating a 32% decrease in cortisol. Both patient groups were significantly more anxious than the normal volunteers. In contrast to the response to a speech task, social phobics showed a cortisol response to physical exercise of similar magnitude as normal volunteers. CONCLUSIONS: The results indicated dichotomies in magnitude and in distribution of the cortisol response to a speech task between social phobia patients and normal volunteers. Social phobia patients responded differently than normal volunteers to a stressor associated with social evaluation but not to physical exercise. These results suggest adaptation of distinct biological processes specific to different stressful conditions in social phobia.

The antidepressant effect of sertraline is not enhanced by dose titration: results from an outpatient clinical trial.

A previous report suggested that 5 weeks of continued treatment with 20 mg of fluoxetine was approximately as effective as double-blind titration to a dose of 60 mg in patients who had failed to respond to 3 weeks of initial treatment at 20 mg. The current study was undertaken to evaluate whether 150 mg of sertraline was any more effective than 50 mg in treating depressed patients who were non-responders at 3 weeks. Ninety-one outpatients with DSM-IV major depressive disorder who had a 17-item Hamilton Depression Rating Scale (HAM-D) score > or = 18 were treated with open label sertraline for 3 weeks. Patients who did not achieve remission (defined as 17-item HAM-D total score < or = 8 by week 3) were then randomized to 5 more weeks of double-blind treatment with either 50 mg of sertraline or immediate titration to 150 mg of sertraline. Efficacy was assessed at each visit with the HAM-D, Clinical Global Impressions (CGI)-severity and improvement scale, and the Hopkins Symptom Checklist. There were no significant between-group differences in clinical or demographic features at baseline for the three treatment groups. After 3 weeks of open-label treatment, 16 patients were not randomized, of whom 11 (69%) met responder criteria. The remaining patients were randomized, double-blind, to 50 mg of sertraline (n = 37; HAM-D = 19.2 +/- 5.0) or 150 mg of sertraline (n = 38; HAM-D = 18.4 +/- 5.0). PROC-Mixed analyses found no significant difference in slopes for any outcome measure when comparing 50 mg and 150 mg sertraline treatment groups. At week 8 (LOCF), the overall remission rate (HAM-D < or = 8) for 3-week non-responders was 40%, with no statistically significant between-group difference for the 50 mg versus 150 mg doses of sertraline (P > 0.10). A completer analysis yielded similar results. Adverse events were mostly mild on both doses of sertraline and led to few treatment discontinuations. The results suggest that for most patients continued treatment with 50 mg dose of sertraline yields a rate of antidepressant response that is comparable to what is achieved by dose escalation from 50 mg to 150 mg of sertraline after 3 weeks of treatment. While some patients clearly benefit from higher doses, the results of the current study are consistent with the lack of any evidence for a dose-response curve with sertraline in the treatment of depression.

Imipramine and buspirone in treatment of patients with generalized anxiety disorder who are discontinuing long-term benzodiazepine therapy.

OBJECTIVE: Patients with generalized anxiety disorder (N=107) who had been long-term benzodiazepine users (average duration of use=8.5 years) were enrolled in a benzodiazepine discontinuation program that assessed the effectiveness of concomitant imipramine (180 mg/day) and buspirone (38 mg/day) compared to placebo in facilitating benzodiazepine discontinuation. METHOD: After a benzodiazepine stabilization period taking either diazepam, lorazepam, or alprazolam, patients were treated for 4 weeks with imipramine, buspirone, or placebo under double-blind conditions while benzodiazepine intake was kept stable (treatment phase). Patients then entered a 4-6 week benzodiazepine taper and a 5-week posttaper phase with imipramine, buspirone, and placebo treatment being continued until 3 weeks into the posttaper phase, at which time all patients were switched to placebo for 2 weeks. Benzodiazepine plasma levels were assayed weekly. Benzodiazepine-free status was assessed 3 and 12 months posttaper. RESULTS: Study subjects were long-term benzodiazepine users with an average of three unsuccessful prior taper attempts. The success rate of the taper in this study was significantly higher for patients who received imipramine (82.6%), and nonsignificantly higher for patients who received buspirone (67.9%), than for patients who received placebo (37.5%). The imipramine effect remained highly significant even after the analysis adjusted for three other independent predictors of taper success: benzodiazepine dose, level of anxious symptoms at baseline, and duration of benzodiazepine therapy. CONCLUSIONS: Management of benzodiazepine discontinuation can be facilitated significantly by co-prescribing imipramine before and during the benzodiazepine taper. Daily benzodiazepine dose, severity of baseline symptoms of anxiety and depression, and duration of benzodiazepine use were additional significant predictors of successful taper outcome.

Prior benzodiazepine use and buspirone response in the treatment of generalized anxiety disorder.

BACKGROUND: An earlier preliminary report suggested that prior treatment with benzodiazepines might predict a reduced response to buspirone in patients diagnosed with generalized anxiety disorder (GAD). To confirm or refute this hypothesis, the present data analysis was conducted. METHOD: One large data set (N = 735) of GAD patients (DSM-III) treated with buspirone, a benzodiazepine, and a placebo was analyzed by dividing all patients into 3 prior benzodiazepine (BZ) treatment groups: no prior BZ treatment, recent (< 1 month) BZ treatment, and remote (> or = 1 month) BZ treatment. Using an intent-to-treat last-observation-carried-forward (LOCF) data set, acute 4-week treatment response was assessed in terms of clinical improvement, attrition, and adverse events as a function of these 3 prior benzodiazepine treatment groups. RESULTS: Patient attrition was significantly higher (p < .05) in the recent BZ treatment group than in the remote and no prior BZ treatment groups with lack of efficacy given as the primary reason by patients receiving buspirone but not benzodiazepine or placebo. In the buspirone group, adverse events occurred more frequently in the recent BZ treatment group than in the remote BZ treatment and no prior BZ treatment groups. Finally, clinical improvement with buspirone was similar to benzodiazepine improvement in the no prior BZ treatment and remote BZ treatment groups, but less than benzodiazepine improvement in the recent BZ treatment group, leading to the smallest buspirone/placebo differences in improvement in the recent BZ treatment group. CONCLUSION: These data suggest that the initiation of buspirone therapy in GAD patients who have only recently terminated benzodiazepine treatment should be undertaken cautiously and combined with appropriate patient education.

A double-blind, placebo-controlled trial of abecarnil and diazepam in the treatment of patients with generalized anxiety disorder.

In a multicenter, double-blind trial, 310 patients who had received a diagnosis of generalized anxiety disorder were treated for 6 weeks with either abecarnil, diazepam, or placebo at mean daily doses of 12 mg of abecarnil or 22 mg of diazepam administered three times daily. Patients who were improved at 6 weeks could volunteer to continue double-blind treatment for a total of 24 weeks. The maintenance treatment phase allowed the comparison of taper results for the three treatments at several study periods (0-6 weeks, 7-12 weeks, and more than 12 weeks). Slightly more diazepam (77%) and placebo (75%) patients completed the 6-week study than abecarnil patients (66%). At intake and baseline, after a 1-week placebo washout, the patient was required to have a Hamilton Rating Scale for Anxiety score of > or =20. Major adverse events for both abecarnil and diazepam were drowsiness, dizziness, fatigue, and coordination difficulties. Clinical improvement data showed that both abecarnil and diazepam produced statistically significantly more symptom relief than did placebo after 1 week of treatment. At 6 weeks treatment (using last observation carried forward analysis), however, only diazepam still differed significantly (p < 0.01) from placebo. High placebo response (56% moderate to marked global improvement) at 6 weeks, as well as a slightly lower nonsignificant improvement rate observed with abecarnil, a partial y-aminobutyric acid (GABA) agonist, when compared with diazepam, a full GABA agonist, most likely contributed to our findings. Finally, taper results showed that only diazepam and not abecarnil caused the presence of temporary discontinuation symptoms, but only in patients who had been treated for at least 12 weeks.

Pharmacologic strategies for discontinuing benzodiazepine treatment.

Benzodiazepines have been shown to have broad-spectrum activity, rapid onset of action, and a wide therapeutic window compared with other anxiolytic medications. Yet the use of benzodiazepines has been limited by concern regarding dependence, withdrawal, and abuse. Agents such as antidepressants, serotonergic anxiolytics, anticonvulsants, and beta-blockers have been used with varying degrees of success to help facilitate the tapering of benzodiazepines. Carbamazepine, imipramine, valproate, and trazodone have been beneficial in the management of benzodiazepine discontinuation, but not in decreasing the severity of benzodiazepine withdrawal. A stepwise approach to discontinuing benzodiazepines is offered.

Trazodone and valproate in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal symptoms and taper outcome.

Recent uncontrolled research suggested that trazodone and sodium valproate may be helpful in benzodiazepine (BZ) discontinuation. We therefore undertook a double-blind study to assess whether trazodone and valproate, as compared to placebo, would attenuate withdrawal and facilitate discontinuation in BZ-dependent patients with a minimum of 1 year daily BZ use. Seventy-eight patients, taking a mean dose of 19+/-17 mg/day of diazepam (or its equivalent), were stabilized for several weeks on their BZ (16 diazepam, 25 lorazepam, 37 alprazolam) and then for 1-2 weeks, pretreated with trazodone, sodium valproate or placebo before being tapered at 25% per week. All treatments were continued for 5 weeks post-taper. BZ-free status was assessed after 5 and 12 weeks post-taper. Neither trazodone nor valproate had any significant effect on withdrawal severity. Peak physician withdrawal checklist change from baseline to peak severity was 16.4 for trazodone, 18.04 sodium valproate and 18.24 placebo (F = 0.10; NS). Taper success rates were significantly effected by both active agents at the 5-week, but not 12-week, assessment. At 5 weeks post-taper, 79% of sodium valproate and 67% of trazodone, but only 31% of placebo patients were BZ-free (chi2 = 7.34; df 2; P<0.03). Major adverse events for trazodone were sedation and dry mouth, and for valproate, diarrhea, nausea and headaches.

Nefazodone in major depression: adjunctive benzodiazepine therapy and tolerability.

One hundred sixty-six patients suffering from major depressive disorders were treated for 8 weeks with nefazodone in an open study in dosage ranges from 200 to 600 mg. This report focuses primarily on the first week of therapy and on the concomitant use of several benzodiazepines, one of which is not metabolized by the cytochrome system (temazepam). Triazolam response was further evaluated as a function of two nefazodone dosage regimens provided during the first week of therapy, one group receiving nefazodone 200 mg/day for 7 days, and another group receiving nefazodone 200 mg/day for 3 days, followed by 4 days with 400 mg/day. Finally, a comparison of three different nefazodone dosages, the third being 400 mg from day 1 on, was also carried out. Outcome measures included Hamilton Rating Scale for Depression total and the total of the three Hamilton Rating Scale for Depression insomnia items, as well as global improvement, a daily completed sleep questionnaire, and adverse event assessment. A combination of nefazodone with a benzodiazepine (BZ) caused more sedation than nefazodone alone; triazolam, the BZ with the shortest half-life and the highest dependence on the cytochrome 450 system for its metabolism, caused the least amount of sedation, and alprazolam and diazepam, the two daytime benzodiazepines, caused the most sedation. Triazolam caused significant and identical reduction of insomnia in both nefazodone groups. Compared with nefazodone 200 mg given as monotherapy, insomnia was significantly improved--not only by triazolam, but also alprazolam and diazepam, but not temazepam. The addition of nefazodone raised triazolam plasma levels to almost 500%, the plasma level of desmethyl-diazepam 87%, and that of alprazolam 34%. Temazepam plasma levels remained unchanged. When prescribing nefazodone with a benzodiazepine, one should expect an improved sleep pattern initially, but at the cost of clinically relevant daytime sedation. The prediction that temazepam, the only BZ not dependent on the cytochrome mechanism for metabolism, should be the least sedating, and triazolam, because of its cytochromic metabolism interference with nefazodone should be the most sedating, could not be confirmed. In fact, triazolam 0.25 mg capsules seem to be the safest treatment of choice when one has to combine a benzodiazepine with nefazodone in initial stages of therapy, at least of the four benzodiazepines tested in this study.

Gepirone and diazepam in generalized anxiety disorder: a placebo-controlled trial.

This randomized, double-blind clinical trial involving 198 generalized anxiety disorder (GAD) patients was conducted to more clearly define gepirone's role for the treatment of anxiety in daily dosages of 10 to 45 mg compared with diazepam and placebo. A secondary goal was to test for possible discontinuation symptoms after abrupt discontinuation of therapy. After a 1-week washout period, patients were treated for 8 weeks and then abruptly shifted under single-blind conditions for 2 weeks on placebo. The highest attrition rate occurred with patients on gepirone (58%) and the lowest on diazepam (34%). Medication intake for week 4 was 19.5 +/- 12.5 mg/day diazepam and 19.0 +/- 11.5 mg/day gepirone and was similar at week 8. The major adverse events were light-headedness, nausea, and insomnia for gepirone and drowsiness and fatigue for diazepam. Clinical improvement data showed gepirone's anxiolytic response to be delayed, being significant from placebo beginning at week 6, whereas diazepam caused significantly more relief than placebo from week 1 onward. Taper results showed that only diazepam, but not gepirone, caused a temporary worsening of anxiety symptoms or rebound.

An open-label trial of nefazodone in high comorbidity panic disorder.

BACKGROUND: Nefazodone is a recently marketed compound with demonstrated efficacy in major depression. This study was undertaken to assess the efficacy and safety of nefazodone in a sample of panic disorder patients with a high degree of depressive comorbidity. METHOD: Fourteen patients were screened for entry into an open 8-week trial of nefazodone clinically titrated between 200-600 mg. Patients fulfilled DSM-III-R criteria for panic disorder and were allowed to enter with concurrent diagnoses of major depression, dysthymia, generalized anxiety disorder, and depression NOS. Primary outcome measures included panic attack frequency and severity and the Clinical Global Impression scale. RESULTS: At Week 8 of treatment, 10/14 patients (71%) were judged to be much or very much improved with study treatment. Panic attack frequency decreased from a mean of 5.4 at baseline to 2.1 at Week 8, reaching significance by Week 8 (p < .05) as did decreases in phobic anxiety. Improvement in panic attack severity, phobic avoidance, HAM-D, HAM-A, CGI-Severity, and Sheehan Disability Scale scores was significant by Week 4. Five of the 8 patients with comorbid major depression were responders, as were 3/5 patients with generalized anxiety disorder comorbidity. Five of 6 patients with pure panic or minor depressive symptoms responded to the study treatment. None of the patients withdrew because of side effects of nefazodone. CONCLUSION: This report presents preliminary evidence for the efficacy and tolerability of nefazodone in panic disorder and panic with comorbid depression or depressive symptoms.