NIDA-ODS Symposium 12/8/09 Kenneth S. Kendler MD

1. CAFFEINE INTAKE, TOXICITY AND DEPENDENCE AND LIFETIME RISK FOR PSYCHIATRIC AND SUBSTANCE USE DISORDERS:AN EPIDEMIOLOGIC AND CO-TWIN CONTROL ANALYSIS NIDA-ODS Symposium 12/8/09 Kenneth S. Kendler MD Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University

2. Outline of Talk • 1. Review role of genetic factors in the etiology of caffeine use, toxicity and dependence. • 2. Examine role of genes and environment on caffeine intake over development.

3. Outline of Talk • 3. Explore how risk genes for caffeine use disorders relate to risk genes for other forms of psychoactive substance use disorders. • 4. Explore the association between caffeine intake, toxicity and dependent and lifetime risk for common psychiatric and substance use disorders in the general population and within MZ twin pairs.

4. Methods • Studies all done with the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. Sample from Virginia Twin Registry – a population-based register formed from a systematic review of birth certificates in the Commonwealth of Virginia • The caffeine interview section began by asking the respondent to define “a time in your life when you drank caffeine the most.” For that time period, we assessed the frequency of caffeine consumption by first asking, on average, how many days per month they consumed caffeine-containing beverages.

5. Methods • Then, for the typical day when they consumed caffeine, we inquired about the average number of cups of caffeinated coffee, cups of caffeinated tea and servings of caffeinated soda they would consume. • If they reported drinking coffee, we specifically inquired whether the coffee was largely brewed or instant.

6. Methods We converted these reports into daily caffeine consumption using the following estimates of caffeine content: ground coffee 125 mg/cup, instant coffee 90 mg/cup, tea 60 mg/cup and caffeinated soft drinks 40 mg/can. • Caffeine consumption per month was then calculated by multiplying the average consumption per day times the average numbers of days per month in which caffeine was consumed.

7. Methods • We defined heavy use as individuals who, in the last year, reported consuming caffeine at least several days per week and who, when they took caffeine, consumed 625 mg of caffeine per day (equivalent to 5 cups of ground coffee). • Caffeine toxicity was assessed by a single item: During the time when you consumed caffeinated beverages the most, did you ever feel ill or shaky or jittery after drinking caffeinated beverages?

8. Methods • Tolerance was assessed by the response to 2 questions adapted from the Psychoactive Substance Abuse Section of the SCID interview: i) During the time when you were consuming caffeinated beverages the most, did you find that you needed to drink a lot more to get the desired effect than you did when you first drank them? ii)What about finding out that when you drank the same amount, it had much less effect than before?

9. Methods • All individuals who responded positively to the question “... did you every stop or try to cut down on your consumption of caffeinated beverages?”, were asked about the 4 symptoms of caffeine withdrawal listed in criterion B for the Caffeine Withdrawal syndrome in DSM-IV (American Psychiatric Association, 1994): headaches, marked fatigue or drowsiness, marked anxiety or depression and nausea or vomiting. • We defined caffeine dependence as the sum of endorsed items that evaluated caffeine tolerance and caffeine withdrawal.

10. Reliability • Short-term test-retest reliability data (and 95% CIs) was obtained on our caffeine related measures from 334 twins interviewed a mean (SD) of 5.4 (6.4) weeks apart. The intraclass correlation for lifetime maximal caffeine intake was +0.74 (0.68-0.78). The unweighted kappa values for heavy use and toxicity were, respectively, 0.69 (0.57-0.80) and 0.62 (0.53-0.72). The weighted kappa for symptoms of caffeine dependence equaled 0.59 (0.52-0.66).

12. Caffeine Use over Development

15. Relationship between Caffeine Dependence and other Psycho-active Substance Use Disorders • Explore the association between caffeine intake, toxicity and dependent and lifetime risk for other substance use disorders. • 4,865 members of male-male and female-female pairs from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders. • Main Outcome Measure Lifetime symptoms of abuse of and dependence on cannabis, cocaine, alcohol, caffeine, and nicotine

16. .82 Illicit Substance Genetic Factor Licit Substance Genetic Factor .82 .77 .68 .15 .52 Cannabis Dependence Cocaine Dependence Alcohol Dependence Caffeine Dependence Nicotine Dependence .20 .31 .35 .56 .68 A A A A A E1 .27 .48 .37 .14 .18 Cannabis Dependence Cocaine Dependence Alcohol Dependence Caffeine Dependence Nicotine Dependence .47 .28 .53 .80 .48 E E E E E

17. CAFFEINE INTAKE, TOXICITY AND DEPENDENCE AND LIFETIME RISK FOR PSYCHIATRIC AND SUBSTANCE USE DISORDERS: AN EPIDEMIOLOGIC AND CO-TWIN CONTROL ANALYSIS • Sample from Virginia Twin Registry – a population-based register formed from a systematic review of birth certificates in the Commonwealth of Virginia • Data on caffeine use was available on 3,706 subjects (51.8% female). Of these 3,706 subjects, 103 (2.8%) denied a lifetime history of any regular caffeine use.

18. Analyses • Standard analyses using the SAS procedure GENMOD, we corrected for the twin structure of the data by the use of generalized estimating equations. The model contained sex and age as covariates.

19. Levels of significance: # if p < 0.0001, * if p < 0.0010, ‡ if p < 0.0100, † if p < 0.0500 ° per 100 mg/day of caffeine

20. Levels of significance: # if p < 0.0001, * if p < 0.0010, ‡ if p < 0.0100, † if p < 0.0500 °° per symptom of caffeine dependence

21. Analyses • Using the SAS procedure GLIMMIX, we then applied a generalized hierarchical linear model treating the twin pair as a random effect. These analyses can be understood as a quantitative and more statistically efficient version of a conditional logistic regression (i.e., a co-twin control analysis).

24. CAFFEINE INTAKE, TOXICITY AND DEPENDENCE AND LIFETIME RISK FOR PSYCHIATRIC AND SUBSTANCE USE DISORDERS: AN EPIDEMIOLOGIC AND CO-TWIN CONTROL ANALYSIS • Conclusions - In the entire sample, measures of maximal caffeine use, heavy caffeine use, and caffeine-related toxicity and dependence were significantly and positively associated with all 7 psychiatric and substance use disorders. • Within MZ twin pairs, controlling for genetic and family environmental factors, these associations, while positive, were all non-significant.

25. CAFFEINE INTAKE, TOXICITY AND DEPENDENCE AND LIFETIME RISK FOR PSYCHIATRIC AND SUBSTANCE USE DISORDERS: AN EPIDEMIOLOGIC AND CO-TWIN CONTROL ANALYSIS • However, a number of these ORs within MZ twin pairs came close to statistical significance and the overall pattern of results – with 27/28 ORs exceeding unity – is extremely improbable. • We interpret these results as suggesting that within MZ twin pairs, the twin who consumes more caffeine or reports more caffeine associated toxicity or dependence is at some increased risk for psychopathology. However, the magnitude of this increase is modest and too small to be detected at traditional levels of statistical significance in our sample.

26. Overall Conclusions • 1. Caffeine intake, heavy use, toxicity, tolerance and withdrawal are all moderately heritable. • 2. Genetic differences emerge early in development, although shared environment is also important in the first few years of use. • 3. Genetic risk factors for caffeine dependence are only weakly related to shared genetic risk factors for dependence on other licit psychoactive substances and illicit substances.

27. Overall Conclusions • 4. Maximal lifetime caffeine intake and caffeine associated toxicity and dependence are moderately associated with risk for a wide range of psychiatric and substance use disorders. • 5. Analyses of these relationships within MZ twin pairs suggest that most of the observed associations are not causal. Rather, familial factors, which are probably in part genetic, predispose both to caffeine intake, toxicity and dependence and the risk for a broad array of internalizing and externalizing disorders.

28. Key Collaborators – Twin Studies • Mike Neale PhD • Charles Gardner PhD • Steve Aggen PhD • John Myers MA • Carol Prescott PhD • Danielle Dick PhD • Lindon Eaves PhD DPhil

29. Support • NIDA DA-011287 for this specific work. • NIMH, NIDA and NIAAA for support for the VATSPSUD study over the years • Rachel Banks Endowment Funds • Virginia Commonwealth University’s generous support for the Virginia Institute for Psychiatric and Behavioral Genetics • No conflicts of interest