Chapter 11. Statistics, Placebo Response, and Clinical Trial Design in Psychopharmacology

Helena C. Kraemer, Ph.D.; Alan F. Schatzberg, M.D.
DOI: 10.1176/appi.books.9781585623860.409248



Drug development is a highly complex process that involves multiple steps of preclinical and clinical pharmacological refinement and testing. Preclinical studies include assessing drug bioavailability, metabolism, and toxicity; effects on known biological targets (e.g., receptor binding); and performance in various animal models of pathology. After sufficient data are obtained in animal studies, drug testing in humans can begin. In the United States, human clinical trials are divided into four phases. Phase I involves testing multiple doses of a drug for bioavailability, pharmacokinetics, and side effects. Phase II studies are dose-finding studies in patients with a given disorder. They can be open-label or double-blind trials. Phase III generally includes pivotal double-blind trials for demonstrating efficacy and safety/tolerability. Phase IV trials, which take place after a drug has received U.S. Food and Drug Administration (FDA) approval and is on the market, are conducted to help clarify potential uses of the drug.

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Acion L, Peterson JJ, Temple S, et al: Probabilistic index: an intuitive non-parametric approach to measuring the size of treatment effects. Stat Med 25:591–602, 2006
Altman DG, Schulz KF, Hoher D, et al: The revised CONSORT statement for reporting randomized trials: explanation and elaboration. CONSORT Group (Consolidated Standards of Reporting Trials). Ann Intern Med 134:663–694, 2001
American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000
Andersen PK, Borch-Johnsen K, Deckert T, et al: A Cox regression model for the relative mortality and its application to diabetes mellitus survival data. Biometrics 41:921–932, 1985
Berger MPF: A comparison of efficiencies of longitudinal, mixed longitudinal, and cross-sectional designs. Journal of Educational Statistics 11:171–181, 1986
Blomqvist N: On the bias caused by regression toward the mean in studying the relation between change and the initial value. J Clin Periodontol 13:34–37, 1986
Borenstein M: The case for confidence intervals in controlled clinical trials. Control Clin Trials 15:411–428, 1994
Borenstein M: Hypothesis testing and effect size estimation in clinical trials. Ann Allergy Asthma Immunol 78:5–16, 1997
Borenstein M: The shift from significance testing to effect size estimation, in Comprehensive Clinical Psychology (Bellak AS, Hersen M, editors-in-chief), Vol 3: Research Methods (Schooler NR, volume editor). Burlington, MA, Elsevier Science, 1998, pp 319–349
Campbell DT, Kenny DA: A Primer on Regression Artifacts. New York, Guilford, 1999
Cohen J: The cost of dichotomization. Applied Psychological Measurement 7:249–253, 1983
Crabbe JC, Wahlsten D, Dudek BC: Genetics of mouse behavior: interactions with laboratory environment. Science 284:1670–1672, 1999
Davis CE: The effect of regression to the mean in epidemiologic and clinical studies. Am J Epidemiol 104:493–498, 1976
deLeeuw J, Kreft I: Random coefficient models for multilevel analysis. Journal of Educational Statistics 11:57–85, 1986
Freedman B: Equipoise and the ethics of clinical research. N Engl J Med 317:141–145, 1987
Grissom RJ: Probability of the superior outcome of one treatment over another. J Appl Psychol 79:314–316, 1994
Grissom RJ, Kim JJ: Effect Sizes for Research: A Broad Practical Approach. Mahwah, NJ, Lawrence Erlbaum, 2005
Hoagwood K, Hibbs E, Brent D, et al: Introduction to the special section: efficacy and effectiveness in studies of child and adolescent psychotherapy. J Consult Clin Psychol 63:683–687, 1995
Hill AB: Medical ethics and controlled trials. BMJ 1(5337):1043–1049, 1963
Humphreys K, Weisner C: Use of exclusion criteria in selecting research patients and its effect on the generalizability of alcohol treatment outcome studies. Am J Psychiatry 157:588–594, 2000
Humphreys K, Weingardt KR, Horst D, et al: Prevalence and predictors of research participant eligibility criteria in alcohol treatment outcome studies, 1970–98. Addiction 100:1249–1257, 2005
Jones LV, Tukey JW: A sensible formulation of the significance test. Psychol Methods 5:411–414, 2000
Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 562–563, 1958
Kemmler G, Hummer M, Widschwendter C, et al: Dropout rates in placebo-controlled and active-control clinical trials of antipsychotic drugs. Arch Gen Psychiatry 62:1305–1312, 2005
Khan A, Warner HA, Brown WA: Symptom reduction and suicide risk in patients treated with placebo in antidepressant clinical trials: an analysis of the Food and Drug Administration database. Arch Gen Psychiatry 57:311–317, 2000
Khan A, Khan SR, Leventhal RM, et al: Symptom reduction and suicide risk among patients treated with placebo in antipsychotic clinical trials: an analysis of the Food and Drug Administration database. Am J Psychiatry 158:1449–1454, 2001
Khan A, Kolts RL, Brodhead AE, et al: Suicide risk analysis among patients assigned to psychotropics and placebo. Psychopharmacol Bull 39:6–14, 2006
Kraemer HC: To increase power in randomized clinical trials without increasing sample size. Psychopharmacol Bull 27:217–224, 1991
Kraemer HC: Toward non-parametric and clinically meaningful moderators and mediators. Stat Med 27:1679–1692, 2008
Kraemer HC, Blasey C: Centring in regression analysis: a strategy to prevent errors in statistical inference. Int J Methods Psychiatr Res 13:141–151, 2004
Kraemer HC, Kupfer DJ: Size of treatment effects and their importance to clinical research and practice. Biol Psychiatry 59:990–996, 2006
Kraemer HC, Robinson TN: Are certain multicenter randomized clinical trial structures misleading clinical and policy decisions? Contemp Clin Trials 26:518–529, 2005
Kraemer HC, Thiemann S: How Many Patients? Statistical Power Analysis in Research. Newbury Park, CA, Sage, 1987
Kraemer HC, Thiemann SA: A strategy to use "soft" data effectively in randomized clinical trials. J Consult Clin Psychol 57:148–154, 1989
Kraemer HC, Frank E, Kupfer DJ: Moderators of treatment outcomes: clinical, research, and policy importance. JAMA 296:1286–1289, 2006
Kraemer HC, Kiernan M, Essex MJ, et al: How and why criteria defining moderators and mediators differ between the Baron and Kenny and MacArthur approaches. Health Psychol 27:S101–S108, 2008
Leber P: The use of placebo control groups in the assessment of psychiatric drugs: an historical context. Biol Psychiatry 47:699–706, 2000
Leber PD, Davis CS: Threats to the validity of clinical trials employing enrichment strategies for sample selection. Control Clin Trials 19:178–187, 1998
MacCallum RC, Zhang S, Preacher KJ, et al: On the practice of dichotomization of quantitative variables. Psychol Methods 7:19–40, 2002
Meehl PE: Theory testing in psychology and physics: a methodological paradox. Philos Sci 34:103–115, 1967
Meinert CL: Clinical Trials: Design, Conduct, and Analysis. New York, Oxford University Press, 1986
MTA Cooperative Group: A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 56:1073–1086, 1999
Rennie D: How to report randomized controlled trials: the CONSORT Statement. JAMA 276:649, 1996
Rothman KJ, Michels KB: The continuing unethical use of placebo controls. N Engl J Med 331:394–398, 1994
Rubin DB: Estimating causal effects of treatments in randomized and nonrandomized studies. J Educ Psychol 66:688–701, 1974
Rubin DB: Teaching statistical inference for causal effects in experiments and observational studies. Journal of Educational and Behavioral Statistics 29:343–367, 2004
Rush AJ Jr, First MB, Blacker D (eds): Handbook of Psychiatric Measures, 2nd Edition. Washington, DC, American Psychiatric Publishing, 2008
Senn S: Regression to the mean. Stat Methods Med Res 6:99–102, 1997
Stigler SM: Regression towards the mean, historically considered. Stat Methods Med Res 6:103–114, 1997
Storosum JG, Wohlfarth T, Gispen-de Wied CC, et al: Suicide risk in placebo-controlled trials of treatment for acute manic episode and prevention of manic-depressive episode. Am J Psychiatry 162:799–802, 2005 (Comment in: Am J Psychiatry 163:329, 2006)
Ware JH: Linear models for the analysis of longitudinal studies. Am Stat 39:95–101, 1985
Wen L, Badgett R, Cornell J: Number needed to treat: a descriptor for weighing therapeutic options. Am J Health Syst Pharm 62:2031–2036, 2005

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In the United States, human clinical trials are divided into four phases. Which phase includes pivotal double-blind trials for demonstrating efficacy and safety/tolerability?
Which of the following statements describe the purpose of a randomized, controlled trial (RCT)?
Effectiveness trials, in contrast to efficacy trials,
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