Medical Student Research Fellowship for Summer 2011
Mentor: E. Sherwood Brown, M.D., Ph.D.
Department: Psychiatry
Room number: FL8.832 (Paul M. Bass Administrative and Clinical Center)
Mail Code: 8849
Phone number: 214-645-6950
E-mail: sherwood.brown@utsouthwestern.edu
Project title: Antidepressant Treatment at an Inner City Asthma Clinic
Human subjects IRB approved project number (where applicable): 072010-235
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: Asthma is a common, severe, and debilitating medical condition. The prevalence of asthma and asthma-related morbidity and mortality has increased in recent years. Data suggests that depressive symptoms and disorders are common in asthma patients and may be a risk factor for asthma-related morbidity. However, minimal data are available on the treatment of persons with depression and asthma. We initiated a research program on the interactions between asthma and depression. Pilot data were collected looking at the efficacy of citalopram versus placebo in outpatients with major depressive disorder and asthma. The goal was to establish feasibility and safety, determine appropriate outcome measures, and identify patient groups most responsive to the antidepressant therapy. The group receiving citalopram showed greater sustained remission of depressive symptoms and required significantly less oral corticosteroids for asthma symptom control than the group receiving placebo. Change in depressive symptom severity was associated with positive change in asthma-related outcomes. Remitters from depression had greater improvement in scores on measures of asthma symptom control and asthma-related quality of life, and required less as-needed bronchodilator use. Thus, improvement in depression was associated with improvement in asthma. A subsample with more severe depression and frequent oral corticosteroid use showed positive changes in depressive and asthma symptoms and less oral corticosteroid use all favoring the antidepressant group.
We are now conducting a definitive antidepressant trial in outpatients with asthma and major depression based on pilot study information gained regarding effect sizes, predictors of response, and sensitivity of outcome measures. A 12-week randomized, double-blind, placebo-controlled, acute phase trial of escitalopram is ongoing in 80 outpatients with asthma and major depression with a baseline Hamilton Rating Scale for Depression score of ≥ 20 and who frequently require oral corticosteroids and in a group of 142 depressed asthma patients with less severe depression and/or less frequent corticosteroid use. A 12-week continuation phase for depression responders is included. Changes in Asthma Control Questionnaire scores (primary outcome measure), oral corticosteroid use, depressive symptoms, quality of life, and asthma medication adherence are assessed as well as the relationship between changes in depressive and asthma symptom severity. The findings will have implications for asthma treatment.
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
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: 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.
Project title: Reversing Corticosteroid-induced Memory Impairment
Human subjects IRB approved project number (where applicable): 082010-100
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 is associated with changes in memory and hippocampal structure. A consistent finding during corticosteroid exposure is a decline in performance on declarative memory tasks. The human literature is quite limited. However, impairment in declarative memory and hippocampal atrophy, have been reported in patients with corticosteroid excess due to Cushing’s disease, and, more recently by our group, in medically ill patients receiving prescription corticosteroid therapy. These have important implications to patients with mood disorders, as a subset of people with major depressive disorder and bipolar disorder have elevated cortisol levels. 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, or an N-methyl-D-aspartate (NMDA) receptor antagonist.
Our group has developed a research program using patients in medical settings receiving prescription corticosteroid (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 deficits in declarative memory, changes in N-acetyl aspartate (NAA, a marker of neuronal viability), and reduction in hippocampal volume during chronic exposure to prednisone. Lamotrigine is an antiseizure and bipolar disorder medication that decreases glutamate release through interactions with sodium and calcium channels. We conducted both open-label and placebo-controlled trials of lamotrigine in corticosteroid-treated patients finding statistically and clinically significant improvement in declarative memory. A larger and longer definitive trial is now proposed.
We are conducting a randomized, double-blind, placebo-controlled pilot study of lamotrigine in 50 outpatients with asthma receiving chronic oral corticosteroid therapy. We hypothesize that the group receiving lamotrigine will show improvement in declarative memory relative to the placebo group. We also assess NAA and glutamate using spectroscopy and hippocampal and amygdala volume using structural magnetic resonance imaging. The findings will have implications for patients with major depressive disorder and the millions treated each year with prescription corticosteroids.
Project title: Citicoline for Bipolar Disorder and Cocaine Dependence
Human subjects IRB approved project number (where applicable): 122007-039
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: Drug abuse or dependence is extremely in common in patients with bipolar disorder and is associated with increased rates of hospitalization, poor outcome during hospitalization, violence towards self and others, and non-adherence to bipolar disorder treatment. The abuse of cocaine and other stimulants is particularly common in patients with bipolar disorder. However, minimal data are available on the treatment of these patients. No randomized, controlled trials published, to date, have specifically examined the treatment of persons with bipolar disorder and cocaine dependence. Our group has developed a research program that evaluates medications for persons with bipolar disorder and substance dependence. A particularly promising medication that we have investigated is citicoline, an agent that modulates cholinergic systems and membrane phospholipid metabolism. Our randomized, placebo-controlled pilot data from 44 participants suggested that citicoline is very well tolerated and was associated with a statistically significant reduction in cocaine use and improvement in measures of cognition in patients with bipolar disorder and cocaine dependence. Based on these promising but preliminary findings a larger, definitive trial is proposed. We are now conducting a 12-week randomized, double-blind, placebo-controlled, add-on trial of citicoline (2000 mg/day) in 130 outpatients with bipolar I disorder and cocaine dependence. Participants are evaluated three times each week for cocaine use with urine drug screens, weekly for assessment of self-reported cocaine use and craving, and weekly for depressive and manic/hypomanic symptom severity. Executive functioning, attention, and working and declarative memory are assessed at baseline and weeks 3, 6, and 12. Medication adherence is monitored by self-report and with metered dosing caps. Manual based cognitive-behavioral therapy specifically designed for people with bipolar disorder and substance abuse is provided to both treatment groups. Concomitant medication changes, when necessary, are managed using a treatment guideline. We hypothesize that citicoline therapy will be associated with decreased cocaine use and improvement in cognition.
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. Journal of Clinical Psychopharmacology, 24:101-102 (2004).