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Suicide and Altitude….Relevance for Life in the Mountains

Suicide and Altitude….Relevance for Life in the Mountains. Perry F. Renshaw M.D., Ph.D. VISN19 Rocky Mountain MIRECC Investigator. With more than a little help from my friends…. Namkug Kim Ph.D. Kristen Delmastro B.S. Tracy Hellem R.N. Doug Kondo M.D. YH Sung M.D.

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Suicide and Altitude….Relevance for Life in the Mountains

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  1. Suicide and Altitude….Relevance for Life in the Mountains Perry F. Renshaw M.D., Ph.D. VISN19 Rocky Mountain MIRECC Investigator

  2. With more than a little help from my friends….. Namkug Kim Ph.D. Kristen Delmastro B.S. Tracy Hellem R.N. Doug Kondo M.D. YH Sung M.D. Deborah Yurgelun-Todd Ph.D.

  3. Age-adjusted Suicide Rates per 100,000 Population 2000-2006

  4. Established Theory #1 Source: Pat Bagley. The Salt Lake Tribune. Sunday, July 14, 2010.

  5. Established Theory #2 Source: Dyer Realty, Inc.

  6. Off the Deep End Source: www.images.com

  7. Age Adjusted Suicide Rate and Mean Elevation of Each US County r=0.51 Source: Kim et al. (2010) American Journal of Psychiatry. In press.

  8. Table 1 Correlations between elevation and age adjusted suicide rates Per-County Per-State*** r-value p-value r-value p-value Age Adjusted Suicide Rate 0.51* 1.45E-175* 0.79 3.81E-11 Age Adjusted Firearm Suicide Rate 0.41** 3.33E-99** 0.64 1.08E-6 Age Adjusted non-Firearm Suicide Rate 0.32** 1.24E-58** 0.53 1.15E-4 * 2618 Counties (excluding Alaska, Hawaii) **2368 Counties (excluding Alaska, Hawaii) ***48 states + DC (excluding Alaska, Hawaii) Source: Kim et al. (2010) American Journal of Psychiatry. In press.

  9. Correlation Between Suicide Risk Factor and Age-Adjusted Suicide Rate Risk Factor/Suicide Rate Correlation Source: Kim et al. (2010) American Journal of Psychiatry. In press.

  10. Circumstances Associated With Suicide Deaths % of suicide deaths Source: Psychiatry News. June 4, 2010; 45 (11): 1.

  11. Image from Google images

  12. Having at Least One Major DepressiveEpisode in Past Year vs. Altitude Correlation r-value 0.1865(p-value; 0.0004) Source: DelMastro et al. (2010) Submitted.

  13. Top 5 Classes of Drugs by # of Prescriptions in Utah * # of prescriptions in UT by class of drug * This data is for patients with commercial insurance only. Source: May, H. (2010, June 24). Depression and diabetes drive up health care costs. The Salt Lake Tribune, pp. A1, A8.

  14. Image from: cocagrowers.org

  15. Cocaine, Altitude, and Suicide • Longstanding history of coca leaf use by high mountain dwellers. Coca leaf use proportional to altitude in Peru. • Coca said to reduce symptoms of altitude sickness (nausea, dizziness, headache, fatigue). • Cocaine use highly associated with suicide, more than alcohol or other drugs of abuse.

  16. Cocaine Use in Past Year vs. Altitude of Substate Region of Residence t = 6.5725, df = 323, p = 1.985e-10 R = 0.343574 Analysis by Namkug Kim, Ph.D. References: 1) Substance Abuse and Mental Health Services Administration, Office of Applied Statistics, 2008b. Substate substance abuse estimates from the 1991-2001 National Surveys on Drug Use and Health. Rockville, MD. http://oas.samhsa.gov/substate2k5/SecD.htm. 2) National Geospatial-Intelligence Agency and National Aeronautics and Space Administration, 2000. Shutte Radar Topography Mission (STRM) Dataset. United States Geological Survey, Souix Falls, SD.

  17. Can Brain Chemistry Change with Altitude….?

  18. Creatine Kinase Reaction PCr2- + ADP3- + H+ Cr + ATP4- Spatial and temporal buffer of ATP concentration (i.e. energy supply) in muscle & brain

  19. Ratios of PCr/γ-ATP in left ventricle wall in Sherpas in acclimated and deacclimating states compared to lowlanders *Acclimated Sherpas: as soon as possible after arrival from altitude **Deacclimating Sherpas: after 27 days at low altitude ***Lowlanders: subjects acclimatized to altitude of about 300m (Table generated with data from Hochachka et al., PNAS, 1996)

  20. Baseline PCr Levels in: MDD Treatment RespondersMDD Non-RespondersControls “Baseline PCr” as a Predictorof Treatment Response - Sensitivity = 83%- Specificity = 75%Area under the ROC curve = 0.88 (Iosifescu et al., Biological Psychiatry2008;63:12)

  21. Δ PCr Δ β-NTP Lyoo et al. Psychiatry Research: Neuroimaging 123 (2003) 87-100.

  22. Typical in-vivo spectra (a) In-vivo brain 31PMR spectra vs. MT saturation time tsat, while saturating γ-ATP to measure the apparent relation rate R1’, and (b) spectra for thermal equilibrium magnetizations with and without RF bleedover effect. The signal intensity of PCr line is plotted with respect to the saturation time to measure the apparent relaxation rate R1’.

  23. Is any of this clinically significant?

  24. Adults with MDD treated with escitalopram + creatine or placebo Renshaw and Lyoo. Unpublished data.

  25. Changes in CDRS Scores with Creatine * Treatment begins at Week 0 ** Treatment ends at Week 8

  26. SLC VA Open Label Creatine Trial (IND and IRB submitted) Creatine Begin Creatine End MDD subjects Weeks 1, 2, 4, 6 Week 10 Screen Week 0 Week 8 • Male, 18-55yrs • Comorbidities OK (no substance abuse) • MADRS ≥18 • Minimal response to adequate trial of antidepressant med • SCID, CSSRS, MADRS, CGI • Labs, vitals • CSSRS, MADRS, CGI • MRI/MRS • Vitals • CSSRS, MADRS, CGI • AE’s, Vitals • CSSRS, MADRS, CGI • MRI/MRS • Labs, vitals • CSSRS, MADRS, CGI • AE’s, Vitals

  27. Other ways forward…. Changes in brain pH Changes in sunlight intensity

  28. Brain pH before, at end, and after 1 wk at simulated altitude of 4,267m (Goldberg et al., 1992)

  29. Pyrimidines in Humans Cytidine Cytidine Uridine UTP CTP Cytidine

  30. The Effect of TAU on Depression: (MADRS) Score Ratings

  31. MRS and Energy:The Effects of TAU in Raising Brain pH in subjects with Bipolar Disorder Line plot of Brain pH pre and post TAU treatment in Bipolar subjects who responded to TAU treatment

  32. CDRS-R Scores During 6 weeks of Treatment with Uridine *Treatment begins Week 0 **Treatment ends Week 6

  33. Locations of latitude/suicide studies Several study findings suggest there is an increase in suicide rates in April – June in the northern hemisphere and November – December in the southern hemisphere (red dots). One study suggested seasonality did not influence a change in suicide rates (green dot).

  34. Increased Intensity of Sunlight with Altitude The proportion of atmosphere that the light must pass through before striking the Earth relative to its overhead path length, and is equal to Y/X. Therefore, an increase in altitude results in an increase in sunlight intensity. http://pvcdrom.pveducation.org/SUNLIGHT/AIRMASS.HTM

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