2007 Edition, N. 3    MEDWORKS    Vol. 40 – No. 2 – 2007
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THE TRIALS AND TRIBULATIONS OF ARIPIPRAZOLE
The objective of the study was to assess the efficacy and safety of aripiprazole in outpatients with post traumatic stress disorder (PTSD) on a 12-week, open-label trial. Twenty-two subjects with DSM-IV diagnosis of PTSD participated; 16 were combat veterans…- p.2
THE SECRET DESIGN OF A SECRET AGENT
Although the positive symptoms of schizophrenia are more likely than the negative symptoms to result in a patient’s hospitalization, positive symptoms tend to respond more completely to antipsychotic drugs. Current therapies have only a limited effect on negative symptoms. Consequently, broad-spectrum agents that effectively treat both positive and negative symptoms are needed.- p.2
PSYCHIATRISTS’ SURVEY THEIR BRETHEREN
An online survey was conducted to assess psychiatrists’ familiarity with the metabolic syndrome and its components in patients with bipolar disorder, and characterize their perspectives and practices regarding its impact on patient management. See the results for yourselves.- p.3
HEART AND SOUL: DONEPEZIL FOLLOWING HEART SURGERY
In the post-coronary artery bypass graft surgery setting with mild cognitive decline, donepezil did not improve composite cognitive performance, but improved some aspects of memory. Donepezil was well tolerated and had no significant effects on EKG parameters. Other results…- p.3
HOW FAST IS FAST ENOUGH?
These researchers compared the speed of onset of action of the extended release (XR) formulation of alprazolam with that of the compressed tablet (CT) formulation in a sample of outpatients with DSM-IV panic disorder. Diary records of hourly antianxiety benefit from a 9-week open label switch study of 30-patients stabilized on alprazolam-CT for 3 weeks and then switched to an equivalent dose of alprazolam-XR, were used to examine the timing and magnitude of clinical benefit on both formulations.- p.4
ALSO: Simple Options for Improving Signal Detection in Antidepressant Clinical Trials – p.4
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PROSPECTIVE STUDY TO EVALUATE THE EFFICACY OF ARIPIPRAZOLE AS A MONOTHERAPY IN PATIENTS WITH SEVERE CHRONIC POSTTRAUMATIC STRESS DISORDER: AN OPEN TRIAL
The objective of the study was to assess the efficacy and safety of aripiprazole in outpatients with posttraumatic stress disorder (PTSD) on a 12-week, open-label trial. Twenty-two subjects with DSM-IV diagnosis of PTSD participated; 16 were combat veterans. The primary outcome measure was PTSD symptom severity assessed with the Clinician Administered PTSD Scale (CAPS). Secondary outcome measures included the Positive and Negative Symptoms Scale and the Hamilton Depression and Anxiety Scales. All subjects had a CAPS score of 60 at baseline. Lifetime history of psychotic disorders or bipolar illness was exclusionary. The overall analysis across time was Repeated Measures ANOVA, using Bonferroni corrections. Fourteen subjects completed 12 weeks of treatment. Eight subjects dropped-out due to side effects. For patients who discontinued, missing values were estimated using “the last observation carried forward” method. Significant improvements were seen on: CAPS total, all its subscales, positive symptoms, anxiety and depression scores. Fourteen participants were classified as responders, defined by 20% or greater improvement on CAPS total score. Of the 13 subjects who completed final ratings, CAPS total scores improved significantly (P .011). Two subjects attained remission of PTSD (CAPS 20), and three had a final CAPS 26. The mean daily dose of aripiprazole was 12.95 mg. The most common side effects were somnolence (54.5%), restlessness (50%), insomnia (36.4%), and asthenia (31.8%). These results indicate that aripiprazole was effective in about two thirds of subjects that tolerated this medication. The initially high dropout rate may be related to intolerability due to a high starting dose (10 mg), suggesting beginning treatment at lower doses. These preliminary results are encouraging; a double blind study seems warranted.  Gerardo Villarreal, MD, Lawrence A. Calais, RN, CCRC, Jose M. Cañive, MD, S. Laura Lundy, BS, Jacob Pickard, MA, and Gregory Toney, PharmD.
Psychopharmacology Bulletin.2007;40(2):6-18.
ASENAPINE IN THE TREATMENT OF NEGATIVE SYMPTOMS OF SCHIZOPHRENIA: CLINICAL TRIAL DESIGN AND RATIONALE
Although the positive symptoms of schizophrenia are more likely than the negative symptoms to result in a patient’s hospitalization, positive symptoms tend to respond more completely to antipsychotic drugs. When positive symptoms are controlled, residual negative symptoms may remain. If these negative symptoms persist, they can have a considerable impact on a patient’s ability to function in society. Current therapies have only a limited effect on negative symptoms. Consequently, broad-spectrum agents that effectively treat both positive and negative symptoms are needed. One obstacle to the regulatory approval of an agent for treating negative symptoms is the difficulty of designing a trial to demonstrate efficacy for these symptoms. Agreeing on a definition of negative symptoms, establishing patient inclusion criteria, and determining how to account for confounding factors represent only a few of the challenges to study design. How these challenges can be met is illustrated in the design of a series of clinical trials to assess the efficacy of asenapine, a psychopharmacologic agent being developed for the treatment of schizophrenia and, in particular, the treatment of negative symptoms associated with schizophrenia. These trials, the protocols for which are described in this paper, will not only determine the efficacy of asenapine but will add to our knowledge of patients with predominant, persistent negative symptoms, an understudied and inadequately treated patient population.  Larry Alphs, MD, PhD, John Panagides, PhD, and Scott Lancaster, MS.
Psychopharmacology Bulletin. 2007;40(2):41-53.
AWARENESS OF METABOLIC CONCERNS AND PERCEIVED IMPACT OF PHARMACOTHERAPY IN PATIENTS WITH BIPOLAR DISORDER: A SURVEY OF 500 US PSYCHIATRISTS
An online survey was conducted to assess psychiatrists’ familiarity with the metabolic syndrome and its components in patients with bipolar disorder, and characterize their perspectives and practices regarding its impact on patient management. Participants were US psychiatrists from a random sample of those in the AMA database. Qualified respondents practiced 4–30 years, spent 50% of their time in direct patient care, and treated 25 bipolar patients in the last month. Results were collected and tabulated by Harris Interactive® from Nov–Dec 2005. Results: Five hundred psychiatrists qualified and completed the survey, and 50 respondents also participated in follow-up interviews. Most respondents (94%) viewed metabolic syndrome as a significant health risk requiring monitoring and treatment. While 76% have diagnosed it, only 28% correctly identified the five NCEP diagnostic criteria. Medication adverse effects of greatest concern were weight gain, glucose intolerance, and dyslipidemia. During treatment, 78% of respondents reported monitoring weight, 69% glucose, 61% lipids, and 52% blood pressure. Most respondents (92%) reported referring patients to specialists or primary care for metabolic abnormalities. Changes in metabolic profile were reported to prompt many psychiatrists (85%) to stop or switch bipolar medications, especially those who treat a large number of bipolar patients (89%). The follow-up interviews supported a change in practice patterns over the last 5 years. Conclusions: Nearly all respondents have metabolic concerns with medical therapies used to treat bipolar disorder. Many now routinely monitor weight and other metabolic parameters. Most have
referred patients for medical management and adjusted bipolar therapies due to metabolic abnormalities.  Trisha Suppes, MD, PhD, Susan McElroy, MD, and Robert Hirschfeld, MD.
Psychopharmacology Bulletin. 2007;40(2):22-37.
DONEPEZIL FOR COGNITIVE DECLINE FOLLOWING CORONARY ARTERY BYPASS SURGERY: A PILOT RANDOMIZEDCONTROLLED TRIAL
To study the effect of donepezil in treating patients with cognitive decline following coronary artery bypass graft (CABG) surgery. Methods: Forty-four patients, with at least a 0.5 SD decline at 1 year post-CABG on at least one cognitive domain compared to their pre-CABG baseline score, were randomized to treatment with donepezil (titrated to 10 mg daily) or placebo in a 12-week double-blind, single center, randomized study. A composite cognitive change score served as the primary outcome. Secondary outcome measures included tests of memory, attention, psychomotor speed, and executive function. Results: The composite cognitive outcome did not show significant treatment effects. Secondary measures varied in their sensitivity to donepezil effects with the largest effects seen on the Wechsler Visual Memory Scale-Delayed and Immediate recall tests. More than twice (52% vs. 22%) as many donepezil-treated patients showed a significant improvement compared with placebo patients on Delayed recall. Tests with weak effect sizes and minimal trends favoring donepezil were the Boston Naming and Digit Symbol. However, most of the other instruments (e.g., Digit Span, Trails B, and Controlled Word Association) showed no treatment benefits. More donepezil-treated than placebo-treated patients experienced diarrhea, but other adverse effects and safety measures did not differ between groups. Conclusion: In the post-CABG mild cognitive decline setting, donepezil did not improve composite cognitive performance but improved some aspects of memory. Donepezil was well tolerated and had no significant effects on EKG parameters. Because of limitations such as small sample size and multiplicity of tests, these findings are preliminary but add to our knowledge of cholinergic effects in vascular mild cognitive decline.  P. Murali Doraiswamy, MD, Michael A. Babyak, PhD, Therese Hennig, PA-C, Ranak Trivedi, PhD, William D.White, MPH, Joseph P. Mathew, MD, Mark F. Newman, MD, and James A. Blumenthal, PhD
Psychopharmacology Bulletin. 2007;40(2):54-62.
THE SPEED OF ONSET OF ACTION OF ALPRAZOLAM-XR COMPARED TO ALPRAZOLAM-CT IN PANIC DISORDER
This study compares the speed of onset of action of the extended release (XR) formulation of alprazolam with that of the compressed tablet (CT) formulation in a sample of outpatients with DSM-IV panic disorder. Diary records of hourly antianxiety benefit from a 9-week open label switch study of 30-patients stabilized on alprazolam- CT for 3 weeks and then switched to an equivalent dose of alprazolam-XR, were used to examine the timing and magnitude of clinical benefit on both formulations. The magnitude of benefit at the first hour after the first morning dose was similar for both formulations. The peak benefit, over the hours after the first morning dose, was also similar and 90% of peak benefit that was achieved in the first hour on both formulations. Mean time to peak benefit was similar (1.5 h for alprazolam-CT vs. 1.6 h for alprazolam-XR) and the percent of patients achieving peak benefit in the first hour was also similar. Compared to the CT formulation, alprazolam-XR had a much longer duration of therapeutic action (11.3 4.2 h vs. 5.1 1.7 h). The results, which may be related to the biotechnology (and resultant pharmacokinetic profile) of the XR preparation, suggest that alprazolam-XR has value as a “rescue” as well as a prophylactic or maintenance treatment in panic disorder. These results must be viewed in the context of the study limitations including its small size, the lack of independence of groups in a switch study, and the limitations of the diary records used.  David V. Sheehan, MD, MBA, Kathy Harnett Sheehan, PhD, and B.A. Raj, MD.
Psychopharmacology Bulletin. 2007;40(2):63-81.
SIMPLE OPTIONS FOR IMPROVING SIGNAL DETECTION IN ANTIDEPRESSANT TRIALS
Previous experience with antidepressant studies highlight the difficulties in discriminating an effective drug from placebo. In hopes of improving signal detection, three easy-to-implement methodologies were employed during the development of a recently approved antidepressant. Experimental Design: Results from alternative and traditional methods could be compared directly because most studies employed both methods. This database included 11 double-blind, placebo-controlled trials (some with multiple dose arms and/or active comparators) yielding 22 treatment arms of antidepressants at or above the minimally effective dose noted in their U.S. labels. Principal Results agreed with the previous evidence showing that the performance of a likelihoodbased, mixed-effects model repeated measures (MMRM) analysis was superior to that of analysis of covariance with missing values imputed using the last observation carried forward (LOCF) approach; MMRM correctly identified drug as superior to placebo in 14/22 (63.6%) comparisons versus 11/22 (50.0%) for LOCF. In agreement with previous studies, use of subscales of the Hamilton Depression Rating scale (HAMD) improved signal detection compared to the HAMD total score. Using MMRM with HAMD subscales correctly identified drug as superior to placebo in up to 17/22 (77.3%) comparisons. Excluding double-blind, placebo lead-in responders did not increase the frequency of correctly identifying drug-versus-placebo differences. Conclusions: The 22 drug-versus-placebo comparisons in this report offer a small amount of evidence and therefore may not be convincing on their own, although results do agree with previous research. Researchers may be able to take advantage of these easy-to-implement methods while we wait for further improvements in other areas.  Craig H. Mallinckrodt, PhD, Adam L. Meyers, MS, Apurva Prakash, BA, Douglas E. Faries, PhD, and Michael J. Detke, MD, PhD.
Psychopharmacology Bulletin. 2007;40(2):101-114.