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 counterbalanc
ing 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
Schoo
l of Medicine
Atlanta, GA