2008projectindex019Brown

Medical Student Research Fellowship for Summer 2008

Mentor: E. Sherwood Brown, M.D., Ph.D.
Department: Psychiatry
Room number: FL8.832 (Exchange Park)
Mail Code: 8849
Phone number: 214-645-6950
E-mail: sherwood.brown@utsouthwestern.edu

Project title: Development of a Model to Examine Corticosteroid Effects on the Hippocampus

Human subjects IRB approved project number (where applicable): 052006-024

Animal subjects IRB approved project number (where applicable): NA

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) patient-based research

Brief Description of Project:

In animals and humans, stress and corticosteroid excess appear to be associated with changes in hippocampal structure and functioning. These findings may have important implications to patients with mood disorders, as a subset of people with major depressive disorder and bipolar disorder show evidence of HPA axis activation. In animals, hippocampal changes secondary to corticosteroids can be attenuated with agents that modulate excitatory amino acids. Histological changes can be prevented and reversed with phenytoin, a glutamate release inhibitor (e.g. phenytoin), or an N-methyl-D-aspartate (NMDA) receptor antagonist. Our group has developed a research program using patients in medical settings receiving prescription corticosteroids (e.g. prednisone) therapy as a model system to explore the effects of cortisol elevations on the human brain. In prior studies we have documented manic symptomatology during acute exposure to high doses of prednisone, depressive symptomatology during chronic exposure to lower dosages of prednisone, and deficits in declarative memory, changes in N-acetyl aspartate (a marker of neuronal viability), and reduction in hippocampal volume. We have found evidence of improvement in mood but not memory with phenytoin compared to placebo in a group of asthma patients receiving prednisone. In this project we examine whether phenytoin can attenuate the effects of corticosteroids on the human hippocampus using functional magnetic resonance imaging (fMRI) in a group of 16 healthy controls who will receiving hydrocortisone, phenytoin, and both medications together in randomized, double-blind, placebo-controlled pilot study in a within-subject crossover design. We hypothesize that hydrocortisone exposure will decrease task-related hippocampal activation and phenytoin given concurrently with phenytoin will attenuate this reduction. As secondary aims, mood and cognition will also be assessed

Project title: Quetiapine for Bipolar Disorder and Alcohol Dependence

Human subjects IRB approved project number (where applicable): 112006-046

Animal subjects IRB approved project number (where applicable): NA

Brief Description of Project: Bipolar disorder is a severe, persistent and common psychiatric illness that is associated with a staggering 46% lifetime prevalence of alcohol-related disorders. When present in patients with bipolar disorder, alcohol dependence is associated with numerous adverse consequences including increased hospitalization, poor outcome during hospitalization, violence towards self and others, and treatment non-adherence. Thus, effective treatment of patients with bipolar and alcohol dependence is a major public health concern. However, to date, only one placebo-controlled trial has been reported in patients with bipolar disorder and alcohol dependence. Our group over the past 8 years has developed a research program that conducts clinical trials in persons with bipolar disorder and substance-related disorders. One particularly promising medication that we have investigated is the atypical antipsychotic quetiapine. Both open-label and placebo-controlled pilot data from our group suggest that quetiapine add-on therapy is well tolerated and associated with a reduction in alcohol use and improvement in mood in patients with bipolar disorder and alcohol dependence. A 12-week randomized, double-blind, placebo-controlled, study of quetiapine add-on therapy in 86 outpatients with bipolar I or II disorder, depressed phase and alcohol dependence with active alcohol use is being conducted. Each receives a psychosocial platform of manual-driven cognitive behavioral therapy specifically designed for patients with bipolar disorder and substance dependence. Outcome measures include alcohol use assessed with the Time Line Follow Back method, Hamilton Rating Scale for Depression, Inventory of Depressive Symptomatology-Self Report,Young Mania Rating Scale, Penn Alcohol Craving Scale, and liver enzymes. Alcohol use is the primary outcome, with alcohol craving, and mood symptoms as secondary outcomes.

Previous Research Activities or Publications with Medical Students:

Ann Bogan (MSIV, UT-Houston) 1998 (one month elective)
Bogan AM, Shellhorn E, Brown ES, McDanald C, Suppes T: Switching outpatients between atypical antipsychotics Progress in Neuro-Psychopharmacology & Biological Psychiatry 24:354-355 (2000).

Bogan AM, Brown ES, Suppes T: Efficacy of divalproex therapy in schizoaffective disorder. Journal of Clinical Psychopharmacology 20:520-522 (2000).

Jacob Moore (MSII, UTSW) Summer 1999
Zielinski TA, Brown ES, Nejtek VA, Moore JJ, Rush, AJ: Depression in asthma: Prevalence and clinical implications. Primary Care Companion to the Journal of Clinical Psychiatry. 2:153-158 (2000).

Nejtek VA, Brown ES, Khan DA. Moore JJ, Van Wagoner J, Perantie DC: Prevalence of mood disorders and relationship to asthma severity in patients at an inner-city asthma clinic. Annals of Allergy, Asthma & Immunology 87:129-133 (2001).

Wendy Chamberlain (MS II UTSW) Summer 2001, Pooja Peranjpe (MS II Summer 2002)

Brown ES, Chamberlain W, Dhanani N, Paranjpe P, Carmody T, Sargeant M: An open label trial of olanzapine for corticosteroid-induced mood symptoms. Journal of Affective Disorders .83:277-281 (2004)

Jason Longoria (MSII, UTSW) Summer 2002
Longoria J, Brown ES, Perantie DC, Bobadilla L, Nejtek VA: Quetiapine for alcohol use and craving in bipolar disorder. J. Clin. Psychopharmacology, 24:101-102 (2004).

Jennifer Lee (MSII, UTSW) Summer 2002
Lee JW, Brown ES, Perantie DC, Bobadilla L: A comparison of single-item visual analog scales with a multi-item likert-type scale for assessment of cocaine craving in persons with bipolar disorder. Addictive Disorders & Their Treatment 1:140-142 (2002).

Tonia Yee (MS II, UTSW) Summer 2003
Yee T, Perantie D, Dhanani N, Brown ES: Drug dreams in patients with bipolar disorder and cocaine dependence. Journal of Nervous and Mental Disease 192:238-242 (2004).

Yee T, Perantie DC, Dhanani N, Brown ES: Are dreams about drugs, substances, or treatment the royal road to prediction of treatment outcome?: reply to Gerevich and Meggyes. Journal of Nervous & Mental Disease 192: 720 (2004).

Sandra Bolanos (MS I UTSW) Summer 2003
Bolanos SH, Brown ES, Khan DA, Hanczyc M, Bauer MS, Dhanani N: Assessment of mood states in patients receiving chronic corticosteroid therapy and in controls with patient-rated and clinician-rated scales. Annals of Allergy, Asthma, & Immunology 92: 500-505 (2004).

Rattapol Srisinroogruang (MS II UTSW) Summer 2003
Srisinroongruang R, Dhanani N, Bauer MS, Brown ES: Comparison of the internal state scale to clinician-administered assessments in patients with bipolar disorder and alcohol abuse or dependence. Journal of Dual Diagnosis 1:61-69 (2005).

Felicia Akingbala (MS II UTSW) Summer 2003
Akingbala F, Dhanani N, Brown ES: Impulsivity in patients with bipolar disorder and cocaine or amphetamine dependence given lamotrigine. Journal of Dual Diagnosis 2: 73-83 (2006).

O. Lizette Solis (MS II UTSW) Summer 2004
Solis OL, Khan DA, Brown ES: Time of onset of major depression in inner-city adults with asthma. Psychosomatics 47: 330-32 (2006).

Joshua Mitchell (MS I UTSW) Summer 2004
Mitchell JD, Brown ES, Rush AJ: Comorbid disorders in patients with bipolar and concomitant substance dependence. Journal of Affective Disorders 102:281-287 (2007).

Rebecca Oppedal (MS I UTSW) Summer 2004
Oppedal,RJ, Khan DA, Brown ES: Hypothyroidism in Patients with Asthma and Major Depressive Disorder. The Primary Care Companion to the Journal of Clinical Psychiatry . 9: 467-468 (2007).

Giacomo Meeker (MS II UTSW) Summer 2005
Brown CK, Meeker G, Brown ES: Examination of a possible interaction between prednisone and newer antidepressants. Primary Care and Community Psychiatry 10:143-147 (2005).

Elizabeth Tucker (MS I UTSW) Summer 2005
Osuji IJ, Tucker E, Brown ES: Declarative memory in patients with bipolar disorder and stimulant abuse given lamotrigine. Journal of Dual Diagnosis (in press).

Justin Wolfshol (MS II UTSW) Summer 2006
Brown ES, Wolfshohl J, Shad MU, Vazquez M, Osuji J: Attenuation of the effects of corticosteroids on declarative memory with lamotrigine. Neuropsychopharmacology (in press).