bridges 2015
TRANSCRIPT
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Longitudinal Study of Pro-inflammatory Cytokines as
Depression Indicators in Relatives of Homicide Victims
Keelan Tobia - Bridges 2015
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Grief vs. Depression
Cytokine
Cytokine Theories & Research
Objectives & HypothesisMaterials & Methods
Study Design
Budget
Works Cited
overview
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Depression
Grief is the normal response to bereavement
Major depression is a common and sometimes fatal mood disorder
Sadness decreases over time Feelings of sadness worsen
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CytokineCytokines communicate with cells to trigger the protective defenses of the immune system.
Pro-inflammatory Cytokines• Small nonstructural proteins that are released during infection, immune
responses, inflammation and trauma
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Reason for studying Cytokines
Can’t we just use anti-depressants?• Although these drugs have greatly improved since their arrival, they
appear to have hit a plateau (30% TRD)• Past decade, inflammation has been revisited as factor of mood
disorders• patients with increased inflammatory cytokines before treatment
have been reported to be less responsive to antidepressant treatment
• Understanding the mechanisms by which inflammation effects brain function to induce mood disorders may lead to new forms of treatment
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Controversy
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Theories on Physiologic Pathways
Potential mechanisms• Inflammatory cytokines are increased during depression and are
produced in the gut, in adipose tissue. • Once produced, the cytokines can access the brain and activate local
central nervous system inflammatory networks to produce alterations in neurotransmitter function, leading to further behavioral alterations.
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Theories on Physiologic Pathways
Pre-clinical evidence suggests that increased cytokines induce mood symptoms by
– decreasing serotonin levels– activating the hypothalamic-pituitary-adrenal (HPA) axis to induce
high levels of glucocorticoid neuron cell death– activating microglial cells to cause pathological synaptic pruning
and induce structural brain changes depression
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Potential Support
In the treatment of hepatitis C, IFN is commonly used to boost the immune system to clear the viral infection• High doses 50% , 90%
Aspirin significantly improved depressive behaviors in fluoxetine treatmentResistant depressiverats
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Objectives• Likelihood of developing MDD after experiencing traumatic event based on
specified factors. • Further investigate the idea of a pertinent subtype of immune-based depression.• Test validity of the findings that claim pro-inflammatory cytokines are related to
depression• Identify threshold that precedes MDD relative to baseline measurements.• If depression and cytokine are linked, determine effectiveness of anti-
inflammatory treatmentAddress • Do people who develop MDD have increased cytokine activity, while those who
share depressive symptoms during bereavement have a reduction in cytokine activity over time?
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Hypothesis
1. Pro-inflammatory cytokines can be used as a valid predictor for the onset of major depression in relatives of homicide victims
2. Aspirin may be an effective additional treatment for those experiencing immune-based depression
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Warrant for the Study
• Potential confounders are relatively unaccounted • Further research, especially longitudinal studies of cytokine
activity as a valid biomarker is needed to produce definitive results
• Research involves studies on animals• Human studies typically compare pre-diagnosed patients with
healthy patients.– Or patients with chronic diseases who are induced with cytokines as
treatment
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Participating Organizations
Collaboration with research-based institutions
• University of Michigan Ann-arbor– Ann Arbor, Michigan
• Johns Hopkins University– Baltimore, Maryland
• UC Berkeley – Berkeley, California
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Materials and MethodsRecruitment
Location • Close proximity to participating institutions• Near and in cities with high homicide rates
Advertising (in-person and online)• Grief share programs• Primary care offices• Hospitals• County assistance offices (financial assistance)• Court houses• Law offices• Police stations • Churches• Mortuary and cemetery offices• Victims advocacy agencies (NOVA & NOPMC)
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Materials and Methods
Homicide: unexpected reckless or intentional taking of another human life by an individual
• 13-55 (Male and Female)• RHVs must meet criteria • Multiple nuclear family members • Recruitment of 1 year• Reimbursement
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Materials and Methods
Screening Process overt inflammation screen (evaluation of medical history)
– To exclude patients who have health disorder known to cause obvious inflammation• cardiovascular disease• Cancer
• Patients with pre-existing depression will also be excluded from the study– The Beck’s Depression Inventory-II (>30)
• Liver disease• Autoimmune disease• Immunodeficiency virus
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Materials and Methods
Baseline Assessments• Blood Analysis for cytokine activity • Depression Severity & Diagnosis
– BDI-II & Psychiatric AssessmentOther Initial Assessments • Health Questionnaire (Potential Confounders)
– BMI (Obesity = BMI> 30)– Medication use– Sleeping habits– Family history of depression– Lifestyle factors (smoking, alcohol consumption, diet, exercise)
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Materials and Methods
Blood Analysis• collect, date, and label blood samples (6 mL collection tubes)• Centrifuge for 15min at 3300 rpm w/ Nanopure water• Place plasma supernatant in 2 mL centrifuge tubes Eppendorf mini
centrifuge 10 min at 2.8 rpm• Plasma cryotubes stored at -150° C • Once samples thaw slowly to room temp undergrad RAs determine
cytokine levels using Instant ELISA kit (eBioscience®)• Follow recommendations for biomarkers• Final reading using SpectraMax Plus plate reader
TNFR1, IL-6, CRP, TNFRa, IFN
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The Beck Depression Inventory (BDI-II)
1-10_______considered normal11-16______Mild mod disturbance17-20______Borderline clinical dep.21-30______Moderate depression31-40______Severe depression>40________Extreme depression
Depression Severity Assessment• Used alongside psychiatric
assessments to determine diagnosis
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SPSS
All statistical analysis using Statistical Package for Social Sciences – Continuous data – Correlational– Categorical data – Cross-sectional analysis– Onset of depression between variables
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Relative of Homicide Victim Questionnaire(as best described)Evaluation of closeness to victim• How were you informed of the homicide?• Age of victim• Biological or non-biological.• Age difference• Ability to understand event• Cause of Death (may or may not be known at time of interview)• Knowledge of Gang affiliation• Known criminal offenses (violent and non-violent crimes)• Instant death or prolonged death
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• Severity of crime – Alcohol related car crash, shot, stabbed, rape-involved murder,
torture, dismemberment, abandoned• Witness• Relationship of the RHV to the murder victim• Last time RHV had contact with victim• Level of regret in relationship between victim• Closure
– Suspect arrested or convicted– If arrested, status of trial
Coping Systems section• Religiosity• Support systems available• primary coping mechanisms
– (asked every six months)
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Materials and Methods
Demographic Questionnaire • Age• Gender• Ethnicity• Education • Current marital status• Professional or Employment
Status• Household income• Best describes occupation
Personality Questionnaire (1-5)(Resilience and SAS)• Am a bad loser• Not easily affected by my
emotions• Can stand criticism• Believe that events in my life are
determined only by me• Can handle opposition• Respond well to change
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Timeline
• Once a participant has given consent for study, initial overt inflammation screening will be given and assessments will begin1st year Every month Health Assessment, ELISA test, BDI (12 times) Psychiatric Evaluation/ Diagnosis (6 times) Relative Homicide Victim Questionnaire Personality assessment Demographic Questionnaire 2nd year Health Assessment, ELISA test, BDI (12 times) Psychiatric Evaluation/ Diagnosis (6 times)
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Timeline
3rd year Health Assessment, ELISA test, BDI (12 times) Psychiatric Evaluation/ Diagnosis (6 times)Next 3 months (Experiment) New baseline Health Assessment, ELISA test, BDI (3 times) Psychiatric Evaluation/ Diagnosis (3 times) Fluoxetine Aspirin
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Design
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Design
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Treatment
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Budget$226,800.00 Instant® ELISA kits by eBioscience
$2,000.00 Advertisements
$30,000.00 My salary
$40,000.00 CO Principal Investigators salaries
$64,800.00 undergraduate researchers salaries
$54,000.00 Participant reimbursement
$108.00 Cotton balls
$1,476 Becton-Dickinson hypodermic single-use needles and syringes
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Budget$385.00 3 HpmTM Reusable Tourniquet Cuffs (128.50 x 3)
$3063.96 3,600 6ml BD Vacutainer Plus Venous Blood Collection Tubes
$340.20 Alcohol wipes
$500.00 Undergraduate computer programmer salary
$14,850.00 3 SpectraMax Plus plate reader (Molecular Devices)
$103.52 8 rolls of 3MTM Medical Cloth Adhesive Tape 12.94 x 4
$1800 Fluoxetine (SRI) dosage based on
$1125 Bayer Aspirin Low Dose 81mg Child/ Adult
$555,000 Psychiatrist salaries for diagnosis & prescriptions
$991,352 Total Cost
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Elisa; 226,800
Advertisements; 2,000
my salary; 25,000
CO PI; 40,000
und research; 64,800
Participants ; 54,000
syringes & needles; 1,476
tourniquets; 385blood collection tubes; 3,064
Alcohol wipes; 340Comp pro; 5003 Used Spec; 14,850 8 rolls med tape;
104
Psychiatrists; 555,000
cotton balls; 108 aspirin; 1,125 fluoxetine; 1,800
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Works cited
Al-Hakeim, H. Al-Rammahi, D., & Al-Dujaili, A. (2015). IL-6, IL-18, sIL-2R, and TNFa proinflammatory markers in depression and schizophrenia patients who are free of overt inflammation. Journal of Affective Disorders, 106-114.
Charles, L. R., Capuron, L., & Andrew, H. M. (2006). Evolutionary imperatives for the depression-inflammation link. Trends in Immunology, 27(1), 24-31
Felger, J., & Lotrich, F. (2013). Inflammatory cytokines in depression: Neurobiological mechanisms and therapeutic implications. Neuroscience, 199-229
Jo, W., Zhang, Y., Emrich, H. ,& Dietrich, D. (2015). Glia in the cytokine-mediated onset of depression: Fine tuining the immune response. Frontiers in Cellulare Neuroscience, 9,
Kelber, O., Okpanyi, S. , Abdel-Aziz, H., & Khayyal, M. (2014). Brain, joint, gut: inflammation as link between depression, rheumatism and irritable bowel syndrome. Planta Medica, 80(16), 1361.
Rosenblat, J., Cha, D., Mansur, R., & Mcintyre, R. (2014). Inflamed moods: A review of interactions between inflammation and mood disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 23-34
Sayers, J. (2001). The world health report 2001; mental health: New understanding, new hope. (books & electronic media). Bulletin of the World Health Organization, 79(11), 1085
Wang, Y., Yang, F., Liu, Y., Gao, F., & Jiang, W. (2011). Acetylsalicylic acid as an augmentation agent in fluoxetine treatment resistant depressive rats. Neuroscience Letters, 74-79