Challenge–dechallenge–rechallenge (CDR) is a medical testing protocol in which a medicine or drug is administered, withdrawn, then re-administered, while being monitored for adverse effects at each stage. The protocol is used when statistical testing is inappropriate due to an idiosyncratic reaction by a specific individual, or a lack of sufficient test subjects and unit of analysis is the individual. During the withdraw phase, the medication is allowed to wash out of the system in order to determine what effect the medication is having on an individual.
Use in drug testing
CDR is one means of establishing the validity and benefits of medication in treating specific conditions as well as any adverse drug reactions. The Food and Drug Administration of the United States lists positive dechallenge reactions (an adverse event which disappears on withdrawal of the medication) as well as negative (an adverse event which continues after withdrawal), as well as positive rechallenge (symptoms re-occurring on re-administration) and negative rechallenge (failure of a symptom to re-occur after re-administration). It is one of the standard means of assessing adverse drug reactions in France.
Fluoxetine and suicide
Peter Breggin asserted that there was an association between fluoxetine (Prozac) use and suicidal ideation. While his research group were investigating the effectiveness and side effects of the medication, Breggin noticed that only certain individuals responded to the medication with increased thoughts of suicide, and used the challenge-dechallenge-rechallenge protocol in an effort to verify the link. Given the low occurrence rate of suicidality, statistical testing was considered inappropriate. Other researchers have similarly suggested that the CDR is useful for researching the adverse effect of suicidality while taking fluoxetine, and Eli Lilly adopted the protocol rather than randomized controlled trials when testing for increased risk of suicide. In addition to suicidality, akathisia is a reaction to medication which is suggested as amendable to a CDR protocol.
Clinical trials using a CDR protocol are also reported for clinicians attempting to assess the effects of a medication on patients. Detection of Dechallenge in spontaneous Reporting System 
CDR has been suggested as a means for patients to perform self-diagnosis, self-treatment and monitoring of their own reactions to medications.
- Spitzer WO (1986). "Importance of valid measurements of benefit and risk". Med Toxicol. 1 Suppl 1: 74–8. PMID 3821430.
- "Guideline for Adverse Experience Reporting for Licensed Biological Products: Definitions". Food and Drug Administration. Archived from the original on 2007-10-07. Retrieved 2008-03-15.
- Begaud B (1984). "Standardized assessment of adverse drug reactions: the method used in France. Special workshop—clinical". Drug Inf J. 18 (3–4): 275–81. PMID 10268556. doi:10.1177/009286158401800314.
- Breggin, Ginger Ross; Breggin, Peter Roger (1995). Talking back to Prozac: what doctors won't tell you about today's most controversial drug. New York: St. Martin's Paperbacks. ISBN 0-312-95606-1.
- Maris, RWM (2002-10-04). "Suicide and Neuropsychiatric Adverse Effects of SSRI Medications: Methodological Issues". Philadelphia, Pennsylvania. Archived from the original on November 20, 2008. Retrieved 2008-03-15.
- Healy D, Whitaker C (2003). "Antidepressants and suicide: risk-benefit conundrums". J Psychiatry Neurosci. 28 (5): 331–7. PMC . PMID 14517576.
- Healy D (2003). "Lines of evidence on the risks of suicide with selective serotonin reuptake inhibitors". Psychother Psychosom. 72 (2): 71–9. PMID 12601224. doi:10.1159/000068691.
- Rothschild AJ, Locke CA (1991). "Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia". J Clin Psychiatry. 52 (12): 491–3. PMID 1752848.
- Banu AB, Alias Balamurugan SA, Thirumalaikolundusubramanian P (2014). "Detection of dechallenge in spontaneous reporting systems: A comparison of Bayes methods". Indian J Pharmacol. 46 (3): 277–80. doi:10.4103/0253-7613.132157.
- Charlton BG (2005). "Self-management of psychiatric symptoms using over-the-counter (OTC) psychopharmacology: the S-DTM therapeutic model—Self-diagnosis, self-treatment, self-monitoring". Med. Hypotheses. 65 (5): 823–8. PMID 16111835. doi:10.1016/j.mehy.2005.07.013.