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 predic
tors 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)