Psychopharmacology Bulletin Newsletter 1

• ORIGINAL RESEARCH
• EVIDENCE BASED MEDICINE

ORIGINAL RESEARCH: The Trials and Travails
Placebo-Controlled — PTSD
Double-Blind — ADHD
Pilot-Controlled — GAD
Comparative Analysis — ANTIDEPRESSANT TRIALS

A Placebo-Controlled Trial of Guanfacine for the Treatment of PTSD in Veterans —p.2
Lori Davis, MD, L. Charles Ward, PhD, Ann Rasmusson, MD, Jason M. Newell, LCSW, PIP, Elizabeth Frazier MS,
and Steven M. Southwick, MD
Treatment of Children With ADHD: Results of a Randomized, Multicenter, Double-Blind,
Crossover Study of Extended-Release Dexmethylphenidate and d,l-Methylphenidate and Placebo
in a Laboratory Classroom Setting —p.2
Raul Silva, MD, Rafael Muniz, MD, Kevin McCague, MA, Ann Childress, MD, Matthew Brams, MD, and Alice Mao, MD
Efficacy of Duloxetine for the Treatment of Depression: Relationship to Most Recent Trials —pp.2/3
Timothy Petersen, PhD., Roy H. Perlis, MD, Chris Ticknor, MD, Jim Lohr, MD, H. Brent Solvason, MD, PhD, John P. O’Reardon, MD, Madelaine M. Wohlreich, MD, Charissa Andreotti, ScB, Michael Wilson MS, and Maurizio Fava, MD
A Pilot-Controlled Trial of Bupropion XL vs. Escitalopram in Generalized Anxiety Disorder —p.3
Alexander Bystritsky, MD, Lauren Kerwin, BA, Jamie D. Feusner, MD, and Tanya Vapnik, PhD

EVIDENCE-BASED MEDICINE: THE BOTTOM LINE
Psychopharmacotherapy in Eating Disorders: A Systematic Analysis —pp.3/4
Andrea Riedl, MD, Janine Becker, MD, M. Rauchfuss, MD, and Burghard F. Klapp, MD
Clinical and Pharmacoeconomic Evaluation of Switch to Olanzapine in Veterans with Schizophrenia or Schizoaffective Disorder —p.4
Lori L. Davis, MD, Marshall E. Cates, PharmD, BCPP, FASHP, Joette S. Lowe, PharmD, L. Charles Ward, PhD, Jeffrey D. Johnson, RN, BSN, Raela B. Williford, PharmD, Sandra M. Ambrose, MSN, Brandi L. Thomas, LCSW, and Terrell Michael Kashner, PhD, JD, MPH
Patterns of Pharmacotherapy and Treatment Response in Elderly Adults with Bipolar Disorder —p.4
John L. Beyer, MD, Bruce Burchitt, PhD, Kenneth Gersing, MD,
and K. Ranga R. Krishnan, MD

A Placebo-Controlled Trial of Guanfacine for the Treatment of Posttraumatic Stress Disorder in Veterans
Preclinical and clinical studies demonstrate a hyperactivity of the norepinephrine system in patients with posttraumatic stress disorder (PTSD). Alpha-2 adrenergic agonists have been shown to ameliorate symptoms of posttraumatic stress disorder, likely due to their ability to dampen noradrenergic tone. This study tests the ability of the alpha-2 adrenergic agonist, guanfacine to reduce the symptoms of PTSD.
Patients with chronic PTSD were randomized to an 8-week double-blind, placebo-controlled treatment of guanfacine followed by a 2 month open-label extension phase. Patients were maintained on their stable doses of allowed antidepressants during the trial. There were no significant differences in the drug versus placebo responses for the clinician-administered or patient self-report outcome measures in this small sample of predominantly male combat veterans with PTSD. However, the medication was well tolerated. Similar to previous findings, this small pilot study failed to show differences in the response to guanfacine versus placebo in a small sample of predominantly male combat veterans with PTSD. Lori Davis, MD, L. Charles Ward, PhD, Ann Rasmusson, MD, Jason M. Newell, LCSW, PIP, Elizabeth Frazier MS, and Steven M. Southwick, MD. Psychopharmacology Bulletin. 2008;41(1):In Press.

Treatment of Children With ADHD: Results of a Randomized, Multicenter, Double-Blind, Crossover Study of Extended-Release Dexmethylphenidate and d,l-Methyl-phenidate and Placebo in a Laboratory Classroom Setting
The results from this study replicate in many ways those reported in 2 previous studies demonstrating a rapid onset and 12-hour duration of effect with d-MPH-ER in the treatment of children with ADHD. Specifically, in those double-blind, placebo-controlled, crossover studies in children 6 to 12 years old, d-MPH-ER was statistically superior to placebo for all efficacy outcome measures at all time points tested, from 0.5 hours up to 12 hours postdose. All active treatments were well tolerated. The majority of AEs were mild to moderate in severity with abdominal pain, decreased appetite, and headache the most common AEs. No patients withdrew due to AEs. The tolerability profile was similar to that reported for d,l-MPH and d-MPH. Both d-MPH-ER and d,l-MPH-ER at both doses, administered once daily, were effective in treating ADHD symptoms in children 6 to 12 years old as assessed over a 12-hour laboratory classroom day. d-MPH -ER was observed to have an onset of effect 0.5 hours postdose and a duration of action of at least 12 hours. d,l-MPH-ER 36 mg/day and 54 mg/day had a slower onset of effect than d-MPH-ER but had a stronger effect during the later part of the day. Treatment with d-MPH-ER 20 mg/day and 30 mg/day, and d,l-MPH-ER 36 mg/day and 54 mg/day was well tolerated. Raul Silva, MD, Rafael Muniz, MD, Kevin McCague, MA, Ann Childress, MD, Matthew Brams, MD, and Alice Mao, MD.
Psychopharmacology Bulletin. 2008;41(1):In Press.

Efficacy of Duloxetine for the Treatment of Depression: Relationship to Most Recent Antidepressant Trials
Data collected from a multicenter trial that evaluated the safety and efficacy of duloxetine for the treatment of major depressive disorder were analyzed to determine the relationship between response to
previous antidepressant treatment and degree of response to duloxetine. Eighty-two patients, with documented antidepressant usage history, were included in the analysis. Participants were required, at baseline of the duloxetine treatment protocol, to be 18 years of age and meet criteria for major depressive disorder. Patients, whose data were included in these analyses, were classified as belonging to one of three groups based on the most recent antidepressant treatment received: nonresponders, partial responders, and responders without remission. Time to first response, first remission, sustained response and sustained remission during the first 12 weeks of duloxetine treatment were compared across patient groups.
Response and remission with duloxetine treatment ranged between 57% and 68% and 29% and 57%, respectively, and did not differ significantly across previous response levels. An additional analysis, collapsing the partial responder and responder without remission groups, indicated significantly lower rates of remission in those patients who demonstrated nonresponse to the most recent antidepressant treatment. Findings suggest that patient response to duloxetine, when used as a switch treatment, may not be significantly influenced by degree of response to the most recent antidepressant treatment. Timothy Petersen, PhD., Roy H. Perlis, MD, Chris Ticknor, MD, Jim Lohr, MD, H. Brent Solvason, MD, PhD., John P. O’Reardon, MD, Madelaine M. Wohlreich, MD, Charissa Andreotti, ScB, Michael Wilson MS, and Maurizio Fava, MD.
Psychopharmacology Bulletin. 2008;41(1):In Press.

A Pilot Controlled Trial of Bupropion XL vs. Escitalopram in Generalized Anxiety Disorder
Twenty-four participants with GAD between the ages 18 and 64 years enrolled in a 12-week, double-blind, randomized, trial to compare the efficacy and safety of bupropion XL (150-300mg/day) with the
selective serotonin reuptake inhibitor escitalopram (10-20mg/day) in outpatients diagnosed with generalized anxiety disorder.
Findings from this pilot project
suggest bupropion XL may be useful in treating GAD. These preliminary results warrant further research to explore the use of bupropion XL in the treatment of GAD. These results agree with recent controlled and open trials, case reports, and animal studies which have identified decreases in anxiety levels during treatment with bupropion hydrochloride. To our knowledge, the use of bupropion
XL in the treatment of GAD has not been previously studied. This is surprising, considering most treatments used to reduce symptoms of major depression also reduce symptoms of GAD. Clinicians may be hesitant to use bupropion due to past reports of the lack of efficacy and exacerbation of anxiety during treatment initiation in panic disorder patients. However, most antidepressants, including tricyclics and SRIs, also have activating effects during treatment initiation that eventually dissipate. In addition, the slowly releasing formulation of bupropion XL may be better tolerated in these regards than the faster releasing formulations used in previous studies. Alexander Bystritsky, MD, Lauren Kerwin, BA, Jamie D. Feusner, MD, and Tanya Vapnik, PhD. Psychopharmacology Bulletin. 2008;41(1):In Press.

Psychopharmacotherapy in Eating Disorders: A Systematic Analysis
The most common and serious eating disorders, which are particularly prevalent in young women, are anorexia nervosa, bulimia nervosa, and binge-eating disorders. Further, the prevalence of unspecific hyperphagous eating disorders frequently causing obesity is substantially increasing. All of these eating disorders tend to be chronic and comorbid to psychiatric diagnoses.
Due to the multifactorial aetiology these disorders require a multimodal treatment. Among different treatment options, symptomatic psychopharmacotherapy has been an important component and especially in recent decades, it has been subject to many trials. This article gives an overview of the current literature, summarizing diagnostic criteria, epidemiology, and critically discussing psychopharmacotherapy of those eating disorders. Based on the literature and our clinical experience the psychopharmacological recommendations for patients with anorexia nervosa, bulimia nervosa, binge-eating disorder are suggested. Andrea Riedl, MD, Janine Becker, MD, M. Rauchfuss, MD, and Burghard F. Klapp, MD.
Psychopharmacology Bulletin. 2008;41(1):In Press.

Clinical and Pharmacoeconomic Evaluation of Switch to Olanzapine in Veterans with Schizophrenia or Schizoaffective Disorder
This study examines the cost effectiveness outcome of olanzapine treatment in veterans with schizophrenia or schizoaffective disorder. Health care utilization and costs associated with prospective olanzapine treatment were compared with those of retrospective first generation neuroleptic treatment in a mirror image design.
For VA outpatient and inpatient care, study patients incurred an average cost difference of -$1,289 (NS) and -$6,682 (NS), respectively. Combining inpatient and outpatient VA care, patients incurred an annual difference of -$7,971 per patient. These numerically lower costs were due, in part, to a slower growth rate in outpatient encounters, lower overall cost per outpatient encounter, and a lower overall inpatient encounter rate.
Olanzapine treatment resulted in improvements in positive and general psychiatric symptoms, as well as quality of life. Negative symptoms did not significantly change. Though not statistically significant, the post-baseline health care costs and utilization declined. Lori L. Davis, MD, Marshall E. Cates, PharmD, BCPP, FASHP, Joette S. Lowe, PharmD, L. Charles Ward, PhD, Jeffrey D. Johnson, RN, BSN, Raela B. Williford, PharmD, Sandra M. Ambrose, MSN, Brandi L. Thomas, LCSW, and Terrell Michael Kashner, PHd, JD, MPH. Psychopharmacology Bulletin. 2008;41(1):In Press.

Patterns of Pharmacotherapy and Treatment Response in Elderly Adults with Bipolar Disorder
Several guidelines have been proposed for treatment, but there is limited data on best treatment practices in elderly bipolar patients. This study assessed patterns of psychopharmacological treatment and treatment response in acutely ill bipolar patients over the age of 60.
Naturalistic pharmacologic data was obtained on 138 acutely ill elderly bipolar patients from the Duke University Medical Center electronic psychiatric record. Standard mood stabilizers (lithium, valproate, carbamazepine, and lamotrigine) were the most prescribed medications (68%), followed by antipsychotics (54%), and antidepressants (34%). Combination therapy was more common than monotherapy (57% vs 38%). Remission was achieved in 35% of subjects while 32% showed no significant improvement. There was no difference in antipsychotic prescription between old-old and young-old patients.
In this naturalistic, “real-setting” study of pharmacologic treatment, acutely ill elderly bipolar patients were treated primarily with mood stabilizing agents, followed by antipsychotics and antidepressants. Combination therapy is much more common than monotherapy. Results can be useful in understanding the current clinical standard of care in elderly bipolar patients, and are consistent with current clinical guidelines for mixed-age bipolar patients. John L. Beyer, MD, Bruce Burchitt, PhD, Kenneth Gersing, MD, and K. Ranga R. Krishnan, MD. Psychopharmacology Bulletin. 2008;41(1):In Press.

editor-in-chief
Michael E. Thase, MD
University of Pittsburgh
School of Medicine
Pittsburgh, PA

editor emeritus
Charles B. Nemeroff,
MD, PhD
Emory University
School of Medicine
Atlanta, GA

publisher and
editorial director
MedWorks Media Global, LLC
James M. La Rossa Jr.
(T) 310.829.4290
(F) 310.829.4289
ceo@medworksmedia.com

associate editor,
negative trial outcomes
David V. Sheehan, MD, MBA
University of South Florida
College of Medicine
Tampa, FLA

associate editor, brain imaging
J. Douglas Bremner, MD
Emory University
School of Medicine
Atlanta, GA

associate editor,
evidence-based medicine
K. Ranga Rama Krishnan, MD
Duke University Medical Center
Durham, NC

associate editor,
translational neuroscience
Husseini K. Manji,
MD, FRCPC
National Institute of
Mental Health
Bethesda, MD

associate editor, drug disposition
and pharmacokinetics
C. Lindsay DeVane, PharmD
Medical University of
South Carolina
Charleston, SC

associate editor,
complicated case histories
Boadie Dunlop, MD
Emory University
School of Medicine
Atlanta, GA
Dennis S. Charney, MD
National Institute of
Mental Health
Bethesda, MD

Jack M. Gorman, MD
Columbia University
College of Physicians & Surgeons
New York, NY

Steven Hyman, MD
Harvard University
Cambridge, MA

Herbert D. Kleber, MD
Columbia University
College of Physicians & Surgeons
New York, NY

Alan I. Leshner, PhD
National Institutes of Health
Bethesda, MD

Jeffrey A. Lieberman, MD
University of North Carolina
School of Medicine
Chapel Hill, NC

Peter P. Roy-Byrne, MD
University of Washington
School of Medicine
Seattle, WA

Alan F. Schatzberg, MD
Stanford University School of Medicine
Stanford, CA

Carol Tamminga, MD
University of Texas
Southwestern Medical Center
Dallas, TX

Karen Dineen Wagner,
MD, PhD
University of Texas
Medical School
Galveston, TX

Daniel R. Weinberger, MD
N
ational Institute of
Mental Health
Bethesda, MD

This newsletter is a synopsis of topical issues to be published in Psychopharmacology Bulletin. It is provided as a free service to news organizations on record with an interest in psychiatric matters, and to the medical community.

Psychopharmacology Bulletin is a trademark of MedWorks Media Global, LLC, Los Angeles, CA. Psychopharmacology Bulletin is indexed in Index Medicus, EMBASE/Excerpta Medica, Psychological Abstracts, Current Contents, Science Citation Index, and Biological Abstracts under Psychopharmacol Bull.

Psychopharmacology Bulletin is a peer-reviewed journal available through subscription only. Permission to reproduce articles in whole or part must be obtained in writing from the publisher. Opinions and views expressed by authors are their own and do not necessarily reflect the views of the MedWorks Media founder and
publisher James M. La Rossa Jr., the editor Dr. Michael E. Thase, or the editorial advisory board.

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