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Newsletter No. 2, 2008        www.psychopharmbulletin.com           Volume 41 • Number 2 • 2008  

Psychopharmacology BULLETIN Newsletter

the advance newsletter of Psychopharmacology BULLETIN
Summary—Index of This Issue On-Press

• ORIGINAL RESEARCH
• EVIDENCE-BASED MEDICINE

Are SNRIs More Effective than SSRIs? A Review of the Current State of the Controversy—p.2
The selective serotonin reuptake inhibitors (SSRI) are widely considered to be the first choice for antidepressant therapy. There is evidence from inpatient studies dating to 1986, however, suggesting that the tricyclic antidepressant clomipramine, which inhibits reuptake of both serotonin and norepinephrine, may have greater efficacy than some SSRIs for severe depression. There is controversy whether the newer, better tolerated, and safer serotonin norepinephrine reuptake inhibitors (SNRIs; venlafaxine, duloxetine, and—in some countries—milnacipran and desvenlafaxine) are more efficacious than SSRIs.
Michael E. Thase, MD

Criteria for Defining Symptomatic and Sustained Remission in Bipolar I Disorder: a Post-Hoc Analysis of a 26-Week Aripiprazole Study—pp.2/3
In aripiprazole-treated patients, symptomatic remission rates were consistent at weeks 8, 16, and 26; sustained remission rates at week 8 were retained at weeks 16 and 26. The authors concluded that when discerning an operational definition of remission in patients with a recent manic or mixed episode, the YMRS 7 criterion and sustaining this criterion for 8 weeks can be a useful clinical or research tool for assessing clinical recovery.
Prakash S.Masand, MD, James Eudicone, MS, Andrei Pikalov, MD, PhD, Robert D.McQuade, PhD, Ronald N.Marcus, MD, Estelle Vester-Blokland, MD, and Berit X. Carlson, PhD

Bipolar I Depression Outpatient Treatment Quality and Costs in Usual Care Practice —p.3
Fifty-six percent of the patients diagnosed with bipolar I depression received both an antimanic agent and psychotherapy during their acute phase depression treatment, whereas 15 percent received an antimanic agent without psychotherapy. Eighteen to 28 percent of spending was accounted for by treatment that did not meet the standards of practice guidelines—and two-thirds to three-quarters of it was treatment that included an antidepressant without anantimanic agent (care that is advised by guidelines).
Alisa B.Busch, MD, MS, Richard G.Frank, PhD, and Gary Sachs, MD

Addressing Methodological Issues in Studying Antidepressant Onset Efficacy Using Prespecified Sensitivity Analyses—p.4
Assessing antidepressant onset efficacy presents substantial methodological challenges. Most assessments of onset efficacy are based on post hoc analyses. This article presents a case study of a prospectively designed trial to compare antidepressant onset efficacy. The authors concluded that prospectively designed studies (as opposed to retrospective comparisons) can be implemented and sensitivity analyses can be used to address concerns regarding assumptions and arbitrary decisions.
Ilya Lipkovich, PhD, Craig H.Mallinckrodt, PhD, Apurva Prakash, BA, and Andrew A.Nierenberg, MD

Are SNRIs More Effective than SSRIs? A Review of the Current State of the Controversy

Within 5 years of the introduction of fluoxetine in late 1987, the selective serotonin reuptake inhibitor (SSRI) class of antidepressants had supplanted the tricyclic antidepressants (TCA) as the first-line pharmacotherapy for major depressive disorder throughout much of the industrialized world. There is no doubt that pharmaceutical marketing played a large role in the rapid ascendance of the SSRI class (i.e., the TCAs were no longer patented drugs and, as such, were not marketed, whereas the SSRIs were vigorously promoted). Nevertheless, the SSRIs had a number of real advantages over the TCAs, including being easier to prescribe, better tolerated, and much safer in overdose.

The controversy about the relative efficacy of different types of antidepressants continues in part because there are numerous problems that limit the sensitivity of randomized controlled trials (RCTs) to detect efficacy differences between active antidepressants. Although there is only a partial solution to the problem of inadequately powered studies, meta-analysis permits quantitative synthesis of results from a group of relevant RCTs comparing various types of antidepressants. Meta-analyses of RCTs comparing the SSRIs with two of the SNRIs—venlafaxine and duloxetine—may have greater efficacy, though there is essentially no evidence that either of these drugs is superior to escitalopram. For venlafaxine, which is so far the most extensively studied SNRI, the magnitude of this advantage versus SSRIs other than escitalopram is modest in unselected patient groups (NNT values range between 10 and 15) and appears to be greater versus fluoxetine than other members of the class. For duloxetine, the advantage versus paroxetine and fluoxetine appears to be limited to more severely depressed patients, and confidence in this finding is limited by the fact that the studies used minimum therapeutic doses of SSRIs. With respect to the other two SNRIs, there are no data yet available to evaluate the relative efficacy of desvenlafaxine. Available data suggest that there is no efficacy advantage for milnacipran. The latter finding, coupled with the failure of both venlafaxine and duloxetine to significantly separate from escitalopram, highlights the limited clinical utility of comparisons across particular classes of medication.
Michael E. Thase, MD. Psychopharmacology Bulletin. 2008;41(2):In Press.


Criteria for Defining Symptomatic and Sustained Remission in Bipolar I Disorder:
a Post-Hoc Analysis of a 26-Week Aripiprazole Study (Study CN138-010)
   
Bipolar I disorder is a lifelong episodic illness that is characterized by manic or depressive episodes followed by symptom-free periods. Remission is a key goal after treating an acute episode of bipolar I disorder; however, there are no established definitions to measure clinical recovery, and recurrence occurs frequently in this patient population. Further understanding is needed for the correlation between attaining remission at a specific time point and maintaining sustained remission during treatment. The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) examined time to recurrence of mania, hypomania, mixed state, or a depressive episode in subjects who were symptomatic at study entry but subsequently achieved recovery and determined that recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery.

In conclusion, the use of more rigorous criteria to define symptomatic or sustained remission for fewer patients with bipolar I disorder and may be more useful in assessing remission in clinical trials compared with the standard criterion. These data confirm that sustaining remission is challenging and there is fluctuation in symptomatic stability in the bipolar population. Sustained remission for 8 weeks appears to be a good predictor for continued remission, as shown by the high retention rate of sustained remission at weeks 16 and 26 in aripiprazole-treated patients with bipolar I disorder using either standard or more rigorous criteria. The more rigorous YMRS criterion of 7 also appears to be a more discriminative indicator for the potential to relapse than the standard criterion (YMRS 12). When discerning an operational definition of remission in patients with a recent manic or mixed episode, the YMRS 7 criterion and sustaining this criterion for 8 weeks can bea useful clinical or research tool for assessing clinical recovery.
Prakash S. Masand, MD, James Eudicone, MS, Andrei Pikalov, MD, PhD, Robert D.McQuade, PhD, Ronald N. Marcus, MD, Estelle Vester-Blokland, MD, and Berit X. Carlson, PhD.
Psychopharmacology Bulletin. 2008;41(2):In Press.


Bipolar I Depression Outpatient Treatment Quality and Costs in Usual Care Practice
   
Bipolar disorder treatment is complicated and evolving. Maximizing lithium therapy has historically been recommended as the first-line treatment. More recently, other agents such as lamotrigine, quetiapine, and a combination of olanzapine and fluoxetine have begun to demonstrate efficacy. The role of antidepressants in the treatment of bipolar depression has been uncertain, including concerns that they may induce mania or mood cycling, thus worsening the course of illness. And while practice guidelines have long recommended psychotherapy in the treatment of bipolar depression, only recently have specific psychotherapies been shown to demonstrate efficacy in randomized controlled trials.
   
This study provides new information regarding the longitudinal quality and costs of care for bipolar depression. A sizable proportion of the treatment dollars spent on persons with new episodes of bipolar I depression went toward care that did not meet the standards of practice guidelines—and much of that represented treatment advised against by guidelines because it could worsen the course of the illness. This observation provides an important clinical and policy opportunity to redirect resources to be consistent with practice guideline standards. This study also provides evidence that when conducting studies using administrative data, hospital admissions alone do not adequately describe affective instability for patients with bipolar disorder, since much switch in polarity occurred in the outpatient setting. This knowledge is useful to researchers and policy makers when using administrative data in conducting quality assessment for systems of care.
Alisa B. Busch, MD, MS, Richard G. Frank, PhD, and Gary Sachs, MD.
Psychopharmacology Bulletin. 2008;41(2):In Press.







Addressing Methodological Issues in Studying Antidepressant Onset Efficacy Using Prespecified Sensitivity Analyses
   
Antidepressant medications typically exhibit a delay of at least 2 weeks following the start of therapy before patients experience clinically relevant improvement. During this latency period, patients remain symptomatic and functionally impaired,  with an associated risk for suicide and morbidity, a prolonged reduction in quality of life, and a continued loss of work productivity. In contrast, antidepressants with a more rapid onset of action may offer potential benefits. Therefore, the development of new pharmacotherapies, with rapid onset of action, is an active area of research.
   
Studying onset of antidepressant action poses formidable methodological challenges.  This article illustrates,  however, that prospectively designed studies (as opposed to retrospective comparisons) can be implemented and that sensitivity analyses can be used to address concerns regarding assumptions and arbitrary decisions. Based on these results, we offer the following recommendations when developing future studies to assess antidepressant onset efficacy: A unidimensional subscale assessing core depressive symptoms (such as the HAMD Maier subscale) may be able to better distinguish differing drug effects when compared with the multidimensional HAMD Total score. A traditional assessment schedule (weekly visits) is adequate for assessing treatment group differences when used in conjunction with a categorical repeated measures analytic approach and does not increase the burden of implementing the study, the study cost, or the risk of increased placebo response (as would be more likely for a study using more frequent study visits). Onset of action can be based on 20–30% initial improvement, and the additional requirement that the improvement be sustained or exceeded throughout acute treatment may better differentiate drug effects from placebo.
Ilya Lipkovich, PhD, Craig H.Mallinckrodt, PhD, Apurva Prakash, BA, and Andrew A. Nierenberg, MD
Psychopharmacology Bulletin. 2008;41(2):In Press.
 

 • 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
National 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.

Copyright © 2008 by MedWorks MediaGlobal, LLC.
All rights reserved. Printed in the United States.


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THE ADVANCE NEWSLETTER OF PSYCHOPHARMACOLOGY BULLETIN
Summary—Index of This Issue On-Press

Newsletter No. 4, 2007 www.psychopharmbulletin.com Volume 40 • Number 3 • 2007

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


ORIGINAL RESEARCH • EVIDENCE-BASED MEDICINE

BOYS AND AFRICAN AMERICANS GET THE MOST ATYPICAL ANTIPSYCHOTICS
Psychotropic medications are increasingly being used by children and adolescents. This is particularly true with respect to
atypical antipsychotics such as risperidone, olanzapine, quetiapine, aripiprazole, clozapine, and ziprasidone. Researchers evaluated whether males were receiving more antipsychotics than females, the diagnosis related to its usage, and the effects of race in the use of antipsychotics.—p.2

BRAVE NEWWORLD: STANDARDS FOR TRIALS IN BIPOLAR DISORDER
In 1988, a task force was convened to define operational criteria for change points in the clinical course of unipolar depressive illness. Some years later, a similar effort was made for schizophrenia. These investigators, who comprise a work group of experts on bipolar disorder, was organized to develop consensus operational definitions for bipolar disorder.—p.2

USE OF EVIDENCE-BASED GUIDELINES FOR CHRONIC MENTAL DISORDERS
These findings suggest that the Systematic Treatment Enhancement Program for Bipolar Disorder is most accurately
viewed as an effectiveness trial of evidence-based treatments for bipolar disorder, rather than “treatment as usual.” Tactics thatprovide physicians with a range of reasonable choices, flexibility, and provided multi-modal training in best practices appear to be effective in optimizing the use of evidence-based treatments in this large national trial.—p.3

HOW LONG DO PSYCHIATRISTSWAIT FOR RESPONSE BEFORE SWITCHING AGENTS?
For how long should an antipsychotic be tried before it is considered ineffective and switched is an important, but as yet,
unanswered question in the treatment of schizophrenia. Switching too early leads to classifying actually effective drugs as ineffective. Waiting too long leads to longer suffering and hospitalization. There is now mounting evidence suggesting that hypothesis of the delay of onset of action of antipsychotic drugs was not correct, but rather that antipsychotic effects can already be seen during the first days of treatment.—p. 3

FEAR, ANXIETY, AND THE NEUROIMAGING OF PTSD
The clinical manifestations of PTSD involve both a fear response and an anxiety response. Fear occurs at the time of exposure to trauma while anxiety develops over time. Both emotions can be present in PTSD. Neuroimaging provides a modality or technique to help define the neural circuitry involved in PTSD. The purpose of this paper is to review the neurobiology of fear and anxiety and to review imaging studies to date and suggest further directions for re s e a rc h . — p. 4

THE USE OF ALTERNATIVE MEDICINE IN BIPOLAR PATIENTS
A substantial number of patients diagnosed with bipolar disorder are using complementary and alternative medicine
(CAM). CAM use may be popular among patients because conventional pharmacotherapy for managing bipolar symptoms
can also disrupt quality of life. Mental health providers should be aware of CAM use among patients with bipolar disorder,
and assess the potential impact of CAM use on treatment course.—p.4

PREDICTING ANTIPSYCHOTIC USE IN CHILDREN

Psyc h o t ropic medications are increasingly being used by children and adolescents. In an earlier re p o rt
the authors noted that boys we re receiving atypical antipsychotics more frequently than we re girls (70%
of the claims). Since diagnosis was not available in the data, they we re unable to ascertain the reasons for
this. In the present analysis, the investigators examined a large clinical mental health database in order to
a s c e rtain the reason for antipsychotic use. They evaluated the extent to which race, gender, age and type
of diagnosis accounted for atypical antipsychotic use in children. The authors used an anonymous clinical
database created at Duke Un i versity Medical Center. The database is based on the clinical document of
care in the De p a rtment of Psychiatry. The data is de-identified per HIPAA guidelines and has an IRB
exemption for use in clinical re s e a rch. Patients analyzed we re seen from 1999 to 2005 and we re below
the age of 18 at the time of clinical care. 3268 patients, with a total of 7701 visits comprise the analysis
sample. Age, gender, race and diagnosis we re extracted as predictors of use of atypical antipsychotics.
Results: African Americans we re slightly more likely to use an atypical than whites. Males and older child
ren we re also more likely to use an atypical. Patients whose diagnoses were classified as either psychotic
or internalizing were also more likely to use an antipsychotic.
Ken Gersing, MD, Bruce Bu rchett, PhD., JD, John March, MD, Truls Os t bye, MD, PhD, and
K. Ranga Rama Krishnan, MD
Psychopharmacology Bulletin. 2007;40(3)

DEFINING THE CLINICAL COURSE OF BIPOLAR DISORDER: RESPONSE, REMISSION,
RELAPSE, RECURRENCE, AND ROUGHENING

This manuscript presents working definitions for key clinical course indicators for bipolar disorder,
including response, remission, relapse, recurrence, and roughening. A work group of experts in bipolar disorder
reviewed prior efforts to define clinical course indicators for unipolar depression and for schizophrenia.
Using these efforts as templates, the work group developed consensus operational definitions.
The rationale for each of the definitions was a point in time when a treatment decision needed to be made.
The group defined response as a 50% reduction in a score from a standard rating scale of symptomatology
from an appropriate baseline, regardless of index episode type (manic, depressed, or mixed). In addition,
the other pole cannot be significantly worsened during response. Remission was defined as absence
or minimal symptoms of both mania and depression for at least 1 week. Sustained remission requires at
least 8 consecutive weeks of remission, and perhaps as many as 12 weeks. A relapse/recurrence was defined
as a return to the full syndrome criteria of an episode of mania, mixed episode, or depression following a
remission of any duration. Roughening was defined as a return of symptoms at a sub-syndromal level, perhaps
representing a prodrome of an impending episode. The work group recommends that all reports of
clinical trials in bipolar disorder include results using these definitions. This will introduce standards for
such re p o rts. Hopefully the definitions will be revised and improved over time.
Robert M.A. Hirschfeld, MD, Joseph Calabrese, MD, Mark A. Frye, MD, Philip W. Lavori, PhD, Gary
Sachs, MD, Michael E. Thase, MD, and Karen Wagner, MD, PhD
Psychopharmacology Bulletin. 2007;40(3)

CONCORDANCE WITH TREATMENT GUIDELINES FOR BIPOLAR DISORDER: DATAFROM THE SYSTEMATIC TREATMENT ENHANCEMENT PROGRAM FOR BIPOLARDISORDER

Concordance with evidence-based guidelines in the treatment of chronic mental disorders is typicallylow. This study assesses the degree of concordance to recommendations of published treatment guidelinesfor bipolar disorder in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).Potential demographic and clinical predictors of adherence were examined. STEP-BD treating psychiatristsparticipated in extensive training in evidence-based pharmacological management focusing on publishedclinical practice guidelines. Recommended medications and dosing for each specific mood episodewere extracted from published treatment guidelines and collapsed into a composite guideline. Prescribedmedication information for patients at the first visit in a prospectively observed new-onset mood episode(depressive, mixed, or hypomanic/manic) was then compared to guideline recommendations. The currentstudy included 964 STEP-BD patients, observed over 2 years, who experienced a prospectively observedepisode (n=716 depressive; n=182 hypomanic/manic; n=66 mixed). Guideline concordant treatmentswere prescribed in 81.8% of mixed episodes, 81.9% of hypomanic/manic episodes, and 83.4% of depressiveepisodes, exceeding rates previously reported in randomized controlled trials of guideline implementation.Younger age of onset and receipt of adequate pharmacotherapy at STEP-BD entry predicted thosemore likely to receive guideline-concordant care. The use of guideline concordant pharmacological treatmentswas substantially higher than reported under naturalistic conditions. The authors speculated thatbasic provider education plus a collaborative approach to medication choice may have contributed to thehigh treatment concordance rates in this large national trial. As in other studies, few patient-specific factorswere associated with the likelihood of receiving guideline-concordant care.

Ellen B. Dennehy, PhD, Mark S. Bauer, MD, Roy H. Perlis, MD, Jane N. Kogan, PD, andGary S. Sachs, MD

Psychopharmacology Bulletin. 2007;40(3)

HOW LONG DO PSYCHIATRISTSWAIT FOR RESPONSE BEFORE THEY SWITCH TOANOTHER ANTIPSYCHOTIC?

For how long should an antipsychotic be tried before it is considered ineffective and switched is animportant, but as yet, unanswered question in the treatment of schizophrenia. Switching too early leads toclassifying actually effective drugs as ineffective. Waiting too long leads to longer suffering and hospitalization.There is now mounting evidence suggesting that hypothesis of the delay of onset of action of antipsychoticdrugs was not correct, but rather that antipsychotic effects can already be seen during the first daysof treatment. Studies which randomize non-responders at different time points to either switching or continuingmedication would be needed to determine the optimum duration of a trial, but such are not available.Therefore the recommendations found in guidelines to wait at least 2, 3, 4 or 6 weeks before makinga major change in treatment are not based on scientific evidence. In this context we examined how longpracticing hospital psychiatrists actually wait before they switch drugs for patients with schizophrenia andwhich factors predict longer medication trials.

Johannes Hamann, MD, Werner Kissling, MD and Stefan Leucht, MD

Psychopharmacology Bulletin. 2007;40(3).

FEAR, ANXIETY, AND THE NEUROIMAGING OF PTSD

The clinical manifestations of PTSD involve both a fear response and an anxiety response. Fear occurs at thetime of exposure to trauma while anxiety develops over time. Both emotions can be present in PTSD. Animalexperiments have been designed to measure cued fear, in which there is a clear threat signal (conditioned stimulus)and contextual fear which is the learned fear response that develops to the experimental setting in which previousexperiments took place. As Grillon suggests contextual conditioning is a model for anxiety. While animalstudies have helped differentiate the neuroanatomic areas involved in the fear and anxiety response, currenthuman neuroimaging studies have not yet made this distinction. The most common form of human studies inPTSD use script-driven imagery. The use of these provocation studies measures a spectrum of different emotionsand therefore is a broad measure of emotional reactivity without providing specific information about fearand anxiety. Neuroimaging provides a modality or technique to help define the neural circuitry involved inPosttraumatic Stress Disorder (PTSD). Modalities include structural MRI, functional MRI, PET imaging andMR spectroscopy. Functional studies in particular, have provided insight into key neuroanatomic areas involvedin the pathology of PTSD. Studies that involve fear conditioning, extinction or specific learning tasks are helpfulin correlating specific emotion or function with changes in neurobiologic function.

Eileen P. Ahearn MD, PhD, Timothy Juergens, MD, Tracey Smith, PhD, Dean Krahn, MD MS,and Ned Kalin MD

Psychopharmacology Bulletin. 2007;40(3)

DETERMINANTS OF COMPLEMENTARY AND ALTERNATIVE MEDICINE USE BYPATIENTS WITH BIPOLAR DISORDER

The authors determined the prevalence and correlates of complementary and alternative medicine(CAM) use among patients with bipolar disorder. Patients with bipolar disorder recruited from a large urbanmental health facility from 2004-2006 completed a baseline questionnaire on CAM use, demographics, treatmentperspectives, and behaviors. Additional data on current medications and clinical features were ascertainedvia chart review. Multivariable logistic regression was used to determine the patient socio-demographic, clinical,and treatment factors associated with use of different CAM practices. Of 435 patients, the mean age was 49years; 77% were white, 13% were black, and 10% other race/ethnicity. Patients reported a wide range of CAMuse, including prayer/spiritual healing (54%), meditation (53%), vitamins or herbs (50%), and weight loss supplements(22%). Multivariable analysis controlling for socio-demographic, clinical, and treatment factorsrevealed that patients of other racial/ethnic groups (other than whites or Blacks), those diagnosed with bipolarspectrum disorders (other than bipolar I disorder), and those prescribed anticonvulsants (e.g., valproic acid, carbamazepine)or atypical antipsychotics were the most likely to use CAM. Results: A substantial number ofpatients diagnosed with bipolar disorder are using CAM. CAM use may be popular among patients with thisillness because conventional pharmacotherapy for managing bipolar symptoms can also disrupt quality of life.Mental health providers should be aware of CAM use among patients with bipolar disorder, and assess thepotential impact of CAM use on treatment course.

Amy M. Kilbourne, PhD, MPH, Laurel A. Copeland, PhD, John E. Zeber, PhD, Mark S. Bauer, MD,Elaine Lasky, RN, and Chester B. Good, MD, MPH

Psychopharmacology Bulletin. 2007;40(3)

THE ADVANCE NEWSLETTER OF PSYCHOPHARMACOLOGY BULLETIN
Summary—Index of This Issue On-Press

Newsletter No. 5, 2007 www.psychopharmbulletin.com Volume 40 • Number 3 • 2007

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

• NEGATIVE AND FAILED CLINICAL TRIAL REPORTS

• DRUG DISPOSITION & PHARMACOKINETICS

An Open Letter: Two New Journal Sections Offer Further Checks and Balances—
Failed and Negative Clinical Trial Reports and Invited Commentary
With this issue of Psychopharmacology Bulletin, the journal unveils a new section, entitled “Negative and Failed Clinical
Trial Reports.” which we hope will throw some light on this notable, yet hidden area of medical literature. As is now widely
known, a large percentage of the randomized clinical trials conducted by the pharmaceutical industry end in results that
either do not distinguish the sponsor’s compound from placebo (i.e., a failed trial) or actually document that the reference
compound—typically an already approved medication used for that indication—is significantly more effective than placebo
and the novel compound is not (i.e., a negative trial). Failed trials not only plague the pharmaceutical industry: they are notuncommon among the studies conducted by academically affiliated investigators.—p.2

An Open-Label Study of Tiagabine in Panic Disorder
Achieving remission has emerged as an important goal in the treatment of psychiatric disorders, and several criteria for
remission of anxiety disorders have been proposed.One of the most commonly used criteria for the remission of panic disorderis the absence of panic attacks. On this basis, approximately two-thirds of patients in this study achieved remission with an SSRI, compared with only about one-third of patients receiving tiagabine in the current study. The results from this small, open-label study suggest that the SGRI tiagabine may be of little benefit in patients with panic disorder.—p.3

Adjunctive Risperidone in the Treatment of Generalized Anxiety Disorder
This trial did not provide evidence to support use of adjunctive risperidone in patients with residual symptoms of
GAD despite anxiolytic and/or antidepressant treatment. The trial does suggest several future research avenues, and has provided data to inform methods (both trial design and enhancements to the patient-based and individual symptom focused PaRTS-A tool) and potential types of patient or symptom domains most likely to benefit from adjunctive treatment with an atypical antipsychotic. Ultimately, the large numbers of patients with GAD and persistent symptoms despite anxiolytic/antidepressant treatment provide a compelling rationale for continuing to seek more effective treatments.—p.3

The Effect of Food on the Absorption of Oral Ziprasidone
Collectively, these data confirm previous studies that show food to enhance the bioavailability of ziprasidone with food
and ensure dose-related increases in exposure. In conclusion, these studies reinforce previous findings that ziprasidone should be taken with food to ensure optimal absorption and linear pharmacokinetics. The fat content of the food does not appear to be a major determinant of ziprasidone bioavailability. Food will also provide more consistent daily systemic exposure to ziprasidone and, thus, better symptom control and tolerability—p.4




AN OPEN LETTER FROM THE EDITOR:
TWO NEW SECTIONS OFFER FURTHER CHECKS AND BALANCES—
NEGATIVE AND FAILED CLINICAL TRIAL REPORTS AND INVITED COMMENTARY
With this issue of Psychopharmacology Bulletin, I am pleased to introduce two new features. First, we
are delighted to unveil a new section, entitled “Negative and Failed Clinical Trial Reports.” As is now
widely known, a large percentage of the randomized clinical trials conducted by the pharmaceutical
industry end in results that either do not distinguish the sponsor’s compound from placebo (i.e., a failed
trial) or actually document that the reference compound—typically an already approved medication
used for that indication—is significantly more effective than placebo and the novel compound is not
(i.e., a negative trial). Failed trials not only plague the pharmaceutical industry: they are not uncommon
among the studies conducted by academically affiliated investigators.
There are many reasons why an efficacious drug may not surpass placebo in a particular trial and most
manufacturers (and NIMH-funded investigators) have at least one such skeleton in the closet.
Historically, most of these results have not found its way into the published literature, hiding our failures
and disappointments is human nature.

However, the findings of failed and negative studies are a part of the distribution of results and not
taking them into account can bias attempts to systematically synthesize a body of evidence with metaanalysis.
This bias can have an important, distorting effect in contentious areas that involve relatively
small effects, such as the efficacy of antidepressants in children and teenagers or the comparative efficacy
of different classes of antidepressants.

In an era of increasing skepticism about the intentions—and trustworthiness—of the pharmaceutical
industry, full disclosure of all relevant research results is imperative. To this end, most pharmaceutical
manufacturers have established web sites reporting the results of all relevant studies. However, the quantity
and quality of the data reported on line varies from site to site and not uncommonly are insufficient
for the purposes of meta-analysis. Thus, there remains the need for a “portal” for the results of failed or
negative RCTs results to enter the published literature, which in short is the primary motivation for
Psychopharmacology Bulletin’s new section. It is required that each article reports study flow according to
CONSORT conventions, clearly specifies the primary dependent variable, and reports the results of
greatest interest (means, standard deviations, and—if pertinent—categorical response and/or remission
rates); reports will also be streamlined with respect to relatively short introductions and discussions. I
am pleased to announce that David Sheehan, MD, MBA, has accepted our invitation to serve as section
editor. I can think of no better individual to oversee this new section. David’s thoroughness and
tough-mindedness will help to ensure the success and independence of this section. Before I move on, I
would like to extend thanks to a number of Pfizer scientists, who were especially instrumental in the
creation of the “Negative and Failed Clinical Trial Reports.” section. This undertaking was first
mentioned to our publisher, Jim La Rossa, by Pfizer’s own Cathryn Clary, MD. With the encouragement
of Pfizer’s Chairman and CEO, Jeffrey B. Kindler, not only Cathryn, but Joseph M. Feczko,
MD, and Steven Romano, MD are culling through data for upcoming issues. Special thanks to Gahan
J. Pandina, PhD and colleagues (Ortho-McNeil Janssen Scientific Affairs), who inaugurated the section
with their impressive trial on Adjunctive Risperidone in the Treatment of GAD.
The second new feature—“Invited Commentary”—written on this occassion by Daniel J. Carlat, MD,
has been implemented to provide some counterbalancing perspective to articles that are introducing new
therapeutic developments.
Michael E. Thase, MD. Psychopharmacology Bulletin. 2007;40(3):5-6.

AN OPEN-LABEL STUDY OF TIAGABINE IN PANIC DISORDER
Treatments currently approved for the treatment of panic disorder and shown to be significantly
superior to placebo in double-blind, randomized clinical trials include the SSRIs paroxetine, controlled
release paroxetine, sertraline, fluoxetine,and the SNRI extended release venlafaxine.In addition,
a study has demonstrated that both paroxetine and sertraline had equivalent efficacy in panic disorder.
Differences in study design and outcome measures prevent direct comparisons between the results of
the studies of the SSRIs and those of tiagabine reported here, although some contrasts can be made.
In the study of controlled-release paroxetine, 63% of patients were panic-free by week 10 compared
with 35% of patients who experienced no panic attacks following 10 weeks of tiagabine. Following
paroxetine, the HAM-A total score decreased from 20.9 at baseline to 9.8 at week 10 (53% reduction
from baseline), whereas tiagabine resulted in a change from 24.9 at baseline to 19.0 at week 10 (24%
reduction from baseline). This suggests that the outcomes for tiagabine may not be as clinically significant
as those obtained with the SSRIs.

Achieving remission has emerged as an important goal in the treatment of psychiatric disorders, and
several criteria for remission of anxiety disorders have been proposed.9, 20 One of the most commonly
used criteria for the remission of panic disorder is the absence of panic attacks. On this basis, approximately
two-thirds of patients in the study of paroxetine achieved remission, compared with only about
one-third of patients receiving tiagabine in the current study.
David V. Sheehan, MD, MBA, Kathy Harnett Sheehan, PhD, B. Ashok Raj, MD,
and Juris Janavs, MD. Psychopharmacology Bulletin. 2007;40(3):32-40.

ADJUNCTIVE RISPERIDONE IN THE TREATMENT OF GENERALIZED ANXIETY
DISORDER: A DOUBLE-BLIND, PROSPECTIVE, PLACEBO-CONTROLLED,
RANDOMIZED TRIAL
The objectives of the current study were to assess the impact of adjunctive risperidone compared
with placebo on persistent GAD symptoms despite current anxiolytic/antidepressant treatment. This study
did not identify a treatment benefit for risperidone augmentation in these patients. There are a number of
factors to consider when interpreting these findings. It is possible that little or no efficacy is associated with
this treatment and/or design limitations and confounding factors contributed to these results. This study
had a very high placebo response rate, a phenomenon common in studies of anxiety and depression. In
fact, up to 50% of depression studies testing proven effective antidepressants are not positive trials.

In conclusion, this trial does not provide evidence to support use of adjunctive risperidone in patients
with residual symptoms of GAD despite anxiolytic and/or antidepressant treatment. The trial does suggest several
future research avenues, and has provided data to inform methods (both trial design and enhancements to
the patient-based and individual symptom focused PaRTS-A tool) and potential types of patient or symptom
domains most likely to benefit from adjunctive treatment with an atypical antipsychotic. Ultimately, the large
numbers of patients with GAD and persistent symptoms despite anxiolytic/antidepressant treatment provide a
compelling rationale for continuing to seek more effective treatments.
Gahan J. Pandina, PhD, Carla M. Canuso, MD, Ibrahim Turkoz, MS, Mary Kujawa, MD, PhD,
and Ramy A. Mahmoud, MD, MPH. Psychopharmacology Bulletin. 2007;40(3):41-57.

THE EFFECT OF FOOD ON THE ABSORPTION OF ORAL ZIPRASIDONE
Food, particularly the fat content of meals, influences the absorption of many orally administered drugs.
For many lipophilic drugs, absorption is enhanced when taken with food.
Ziprasidone (5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2-H-indol-2-one)
is a widely used atypical antipsychotic indicated for the treatment of schizophrenia and bipolar disorder. It is a
highly lipophilic compound, and this property impacts its absorption profile with respect to food. The prescribing
information for ziprasidone specifies that the capsules should be taken with food.
Previous pharmacokinetic studies have shown that under fasting conditions, oral doses of ziprasidone
(0.5–40 mg) resulted in approximately dose-pro p o rtional increases in mean maximum observed serum concentration
(Cmax) and mean area under the serum concentration-time curve from time 0–12 hours (AUC)0–12.
Under these fasting conditions, this dose pro p o rtionality was lost at higher doses, although there was evidence
of some increase in overall exposure. When the dose of ziprasidone was taken after food, dose proportionality
was seen in the dose range between 20 and 60 mg. A further study showed that the administration of a single
20-mg dose of ziprasidone in the fed state produced total AUC (AUC0–`) and Cmax values 69% and 67%
greater, respectively, than values in the fasting state, and that taking ziprasidone 2 hours after a meal reduced
d rug absorption compared with taking it with food.

The aims of the pharmacokinetic studies described here were to extend previous investigations of the effect
of food and, specifically, to quantify the impact of the fat content of food on ziprasidone absorption, and to
evaluate the pharmacokinetic linearity and dynamics of drug absorption in relation to fed and fasting conditions
at drug doses above 40 mg.

Collectively, these data confirm previous studies6 that show food to enhance the bioavailability of ziprasidone
with food and ensure dose-related increases in exposure. In conclusion, these studies reinforce previous
findings that ziprasidone should be taken with food to ensure optimal absorption and linear pharmacokinetics.
The fat content of the food does not appear to be a major determinant of ziprasidone bioavailability. Food
will also provide more consistent daily systemic exposure to ziprasidone and, thus, better symptom control
and tolerability.
Jeffrey J. Miceli, PhD, Paul Glue, MD, PhD, Jeffrey Alderman, PhD, and Keith Wilner, PhD
Psychopharmacology Bulletin. 2007;40(3):58-68.


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 AND FAILED CLINICAL TRIAL REPORTS
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

2007 Edition, N. 3    MEDWORKS    Vol. 40 - No. 2 - 2007
------------------------------------------------------------------------
THE TRIALS AND TRIBULATIONS OF ARIPIPRAZOLE
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...- 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
------------------------------------------------------------------------
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.