Treatment Strategy to Prevent Mood Disorders Following Traumatic Brain Injury

Traumatic Brain Injury Clinical Trial

Official title:

Treatment Strategy to Prevent Mood Disorders Following Traumatic Brain Injury

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00704379
• Other study ID #: R01NS055827
• Secondary ID: 1R01NS055827-01A
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: June 20, 2008
• Last updated: August 10, 2015
• Start date: June 2008
• Est. completion date: April 2014

Study information

• Verified date: August 2015
• Source: Baylor College of Medicine
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to examine the efficacy of sertraline to prevent the onset of mood and anxiety disorders during the first six months after traumatic brain injury.

Description:

Traumatic brain injury (TBI) is a leading cause of death and disability among young adults. Mood disorders are the most frequent psychiatric complication of TBI, and have a large impact on family functioning, interpersonal relationships, and ability to return to work or school. Furthermore, a significant proportion of these disorders will progress to more chronic and treatment refractory forms. In spite of their clinical relevance, mood and anxiety disorders remain largely unrecognized and not adequately treated, contributing to greater disability and decreased participation in the aftermath of TBI.

The goals of this study are to learn more about how people recover from brain injury and to evaluate the effect of sertraline (also known as Zoloft) compared to placebo (an inactive substance) in preventing the occurrence of emotional and behavioral problems—such as depression, lack of motivation, anxiety, irritability or aggressive outbursts—following TBI.

In the study, a group of 104 participants with TBI—recruited immediately after resolution of posttraumatic amnesia—will be randomly assigned to receive six months of double-blind treatment with sertraline or placebo.

This study will determine how these emotional and behavioral problems influence thinking, physical recovery, and return to a productive life six months after brain injury. Researchers will also determine if certain brain changes can predict the occurrence of behavioral problems and if treatment with sertraline can prevent them. Additionally, the researchers will examine the effect of sertraline on frequent post-TBI behavioral disorders such as aggression, impulsivity, poor decision making and apathetic symptoms.

Magnetic resonance imaging (MRI)-based volumetry and diffusion tensor imaging will be used to examine the structural correlates of mood and anxiety disorders and to evaluate them as biological predictors of treatment response and community reintegration. The researchers hypothesize that early preventive treatment with sertraline will reduce mood and behavioral symptoms, prevent the occurrence of structural and functional brain changes associated with the onset of mood disorders, increase access to and participation in rehabilitation programs for TBI, and, consequently, improve psychosocial outcome.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 94
• Est. completion date: April 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

• Age 18 years or over.

• Meeting the Center for Disease Control (CDC) criteria for TBI.

• Mild, Moderate, or Severe TBI as categorized by initial Glasgow Coma Scale (GCS) scores 13 to 15, 9 to 12, or 3 to 8, respectively.

• Complete recovery from Post Traumatic Amnesia (PTA) within 4 weeks of the traumatic episode.

Exclusion Criteria:

• Penetrating head injuries.

• Clinical or neuro-radiological evidence of associate spinal cord injury.

• Patients with severe comprehension deficits (i.e., those who are not able to complete part II of the Token Test) that precludes a thorough neuropsychiatric evaluation.

• Presence of Diagnostic and Statistical Manual IV defined mood, anxiety or psychotic disorder at the time of enrollment to the study. However, patients with a history of alcohol abuse or alcohol dependence during the year preceding TBI will be included in the study.

• Patients who were taking antidepressants at the time of TBI or during a six month period prior to the traumatic event.

• Patients who have failed an adequate previous trial with sertraline or had side effects that prompted the discontinuation of this medication.

• Pregnant women or women that plan to become pregnant during the period of the study.

• Severe complicating illness such as neoplastic disease or uncompensated heart, renal or liver failure.

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Brain Injuries
• Mood Disorders
• Traumatic Brain Injury

Intervention

Drug:
• Placebo
an inactive substance
• Sertraline
Sertraline and placebo will be given in a double blind fashion via an equal number of identical tablets administered once daily. Once stabilized in the targeted dosage (100 mg per day), sertraline serum levels will be monitored twice during the course of the intervention. Blood samples will be obtained randomly, one during the first and one during the second trimesters of the protocol.

Locations

Country	Name	City	State
United States	Baylor College of Medicine	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
Baylor College of Medicine	National Institute of Neurological Disorders and Stroke (NINDS)

Country where clinical trial is conducted

United States, 

References & Publications (29)

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Arciniegas DB, Topkoff J, Silver JM. Neuropsychiatric Aspects of Traumatic Brain Injury. Curr Treat Options Neurol. 2000 Mar;2(2):169-186. — View Citation

Bechara A, Damasio H, Tranel D, Damasio AR. The Iowa Gambling Task and the somatic marker hypothesis: some questions and answers. Trends Cogn Sci. 2005 Apr;9(4):159-62; discussion 162-4. Review. — View Citation

Büki A, Povlishock JT. All roads lead to disconnection?--Traumatic axonal injury revisited. Acta Neurochir (Wien). 2006 Feb;148(2):181-93; discussion 193-4. Epub 2005 Dec 20. Review. — View Citation

Duman RS, Monteggia LM. A neurotrophic model for stress-related mood disorders. Biol Psychiatry. 2006 Jun 15;59(12):1116-27. Epub 2006 Apr 21. Review. — View Citation

Fann JR, Burington B, Leonetti A, Jaffe K, Katon WJ, Thompson RS. Psychiatric illness following traumatic brain injury in an adult health maintenance organization population. Arch Gen Psychiatry. 2004 Jan;61(1):53-61. — View Citation

Fann JR, Uomoto JM, Katon WJ. Sertraline in the treatment of major depression following mild traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2000 Spring;12(2):226-32. — View Citation

Graham DI, McIntosh TK, Maxwell WL, Nicoll JA. Recent advances in neurotrauma. J Neuropathol Exp Neurol. 2000 Aug;59(8):641-51. Review. — View Citation

Huisman TA, Schwamm LH, Schaefer PW, Koroshetz WJ, Shetty-Alva N, Ozsunar Y, Wu O, Sorensen AG. Diffusion tensor imaging as potential biomarker of white matter injury in diffuse axonal injury. AJNR Am J Neuroradiol. 2004 Mar;25(3):370-6. — View Citation

Jorge R, Robinson RG. Mood disorders following traumatic brain injury. Int Rev Psychiatry. 2003 Nov;15(4):317-27. Review. — View Citation

Jorge R, Robinson RG. Mood disorders following traumatic brain injury. NeuroRehabilitation. 2002;17(4):311-24. Review. — View Citation

Jorge RE, Robinson RG, Arndt S. Are there symptoms that are specific for depressed mood in patients with traumatic brain injury? J Nerv Ment Dis. 1993 Feb;181(2):91-9. — View Citation

Jorge RE, Robinson RG, Arndt SV, Forrester AW, Geisler F, Starkstein SE. Comparison between acute- and delayed-onset depression following traumatic brain injury. J Neuropsychiatry Clin Neurosci. 1993 Winter;5(1):43-9. — View Citation

Jorge RE, Robinson RG, Arndt SV, Starkstein SE, Forrester AW, Geisler F. Depression following traumatic brain injury: a 1 year longitudinal study. J Affect Disord. 1993 Apr;27(4):233-43. — View Citation

Jorge RE, Robinson RG, Moser D, Tateno A, Crespo-Facorro B, Arndt S. Major depression following traumatic brain injury. Arch Gen Psychiatry. 2004 Jan;61(1):42-50. — View Citation

Jorge RE, Robinson RG, Starkstein SE, Arndt SV, Forrester AW, Geisler FH. Secondary mania following traumatic brain injury. Am J Psychiatry. 1993 Jun;150(6):916-21. — View Citation

Jorge RE, Robinson RG, Starkstein SE, Arndt SV. Depression and anxiety following traumatic brain injury. J Neuropsychiatry Clin Neurosci. 1993 Fall;5(4):369-74. — View Citation

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Jorge RE, Starkstein SE. Pathophysiologic aspects of major depression following traumatic brain injury. J Head Trauma Rehabil. 2005 Nov-Dec;20(6):475-87. Review. — View Citation

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Salmond CH, Menon DK, Chatfield DA, Williams GB, Pena A, Sahakian BJ, Pickard JD. Diffusion tensor imaging in chronic head injury survivors: correlations with learning and memory indices. Neuroimage. 2006 Jan 1;29(1):117-24. Epub 2005 Aug 9. — View Citation

Santarelli L, Saxe M, Gross C, Surget A, Battaglia F, Dulawa S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C, Hen R. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003 Aug 8;301(5634):805-9. — View Citation

Sheline YI, Barch DM, Donnelly JM, Ollinger JM, Snyder AZ, Mintun MA. Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biol Psychiatry. 2001 Nov 1;50(9):651-8. — View Citation

Silver JM, Hales RE, Yudofsky SC. Psychopharmacology of depression in neurologic disorders. J Clin Psychiatry. 1990 Jan;51 Suppl:33-9. Review. — View Citation

Tateno A, Jorge RE, Robinson RG. Pathological laughing and crying following traumatic brain injury. J Neuropsychiatry Clin Neurosci. 2004 Fall;16(4):426-34. — View Citation

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* Note: There are 29 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to Onset of Diagnostic and Statistical Manual (DSM) IV Defined Mood and Anxiety Disorders Associated With Traumatic Brain Injury (TBI)	Following the DSM-IV (now updated by the DSM-5), depressive disorders associated with TBI are categorized as Mood Disorder Due to Another Medical Condition with subtypes: 1) With major depressive-like episode (if the full criteria for a major depressive episode [MDE] are met) or 2) With depressive features (prominent depressed mood but full criteria for a MDE are not met); and 3) with mixed features (e.g. significant irritability, pressured speech and formal thought disorder).; On the other hand, bipolar and related disorders due to TBI are subdivided in: 1) with manic or hypomanic like episode; 2) with manic features; and 3) with mixed features.; A similar conceptual framework has been used to define Anxiety Disorder due to another Medical Condition, in this case, TBI. According to DSM-IV/DSM-5, such diagnosis can be made when, besides an evident pathophysiological relationship with TBI, panic attacks or generalized anxiety are the prominent features of the clinical presentation.	6 months after TBI	No
Secondary	Total Community Integration Questionnaire Scores	The Community Integration Questionnaire (CIQ) is intended as a brief, reliable measure of an individual's level of integration into the home and community following traumatic brain injury. Total CIQ scores were used as the outcome measure. Range: 0 to 25. Higher scores indicate higher levels of integration into the home and community following TBI.	6 months after TBI	No
Secondary	Iowa Gambling Task Score	The Iowa Gambling Task (IGT) evaluates decision making ability. During IGT subjects have to choose between decks of cards which yield high immediate gain but larger future loss (i.e., long term loss), and decks which yield lower immediate gain but a smaller future loss (i.e., a long term gain). The task consists of four decks of cards: A, B, C, and D. The goal in the task is to maximize profit. Subjects are required to make a series of card selections. The decks A and B are long term loss decks and the decks C and D are long term gain decks. The IGT Score reported is the combination of the raw score for each deck combined in the following way: (C+D) - (A+B). The range for this score is: -100 to 100. Higher values of this score indicate better decision making ability.	6 months after TBI	No
Secondary	Memory Function Composite	This outcome measures memory function and is a composite of five standardized scores: Brief Visuospatial Memory Test - Revised, Delayed Recall and California Verbal Learning Test, Short Delay Free Recall Number Correct and Discriminability, and Long Delay Free Recall Number Correct and Discriminability. Standardized scores (i.e., z-scores) for each test of this composite were obtained by subtracting the mean raw score of all participants to the raw score of each participant and dividing the result by the standard deviation of the raw scores of all participants. The composite score was obtained by averaging the z-scores of the four memory tests mentioned previously. Range: -3 to 3. Higher scores represent better memory function.	6 months following traumatic brain injury	No
Secondary	Social Functioning Examination Total Score	The Social Functioning Examination (SFE) is a semi-structured interview that measures social functioning in areas such as interpersonal relationships, work adjustment, use of community resources and satisfaction with living environment. Range: 0 to 1. Higher scores denote lower levels of social functioning.	6 months after TBI	No
Secondary	Neuroimaging Variables (i.e., Fractional Anisotropy [FA] of Frontal White Matter Such as the Cingulate Gyrus)	FA is a measured obtained from Diffusion Tensor Imaging, an image modality of Magnetic Resonance Imaging (MRI). FA is a unitless index. Range: 0 to 1. FA describes the degree of anisotropy of a diffusion process. A value of zero means that diffusion is unrestricted or equally restricted in all directions. A value of one means that diffusion occurs only along one axis and is fully restricted along all other directions. In the context of this study, FA measures the integrity of the cingulate gyrus white matter. Higher FA values reflect higher integrity of the cingulate gyrus white matter tract. Average FA values for the right and left cingulate gyri were summed.; One aim of this project was to identify predictors of the occurrence of mood disturbances during the first 6 months following TBI. The hypothesis for this aim was that patients who develop a mood or anxiety disorder six months after TBI present at baseline with lower FA of the cingulate gyrus than those who do not.	Baseline	No