CLINICAL IMPLICATIONS OF THE PLACEBO RESPONSE
A PRELIMNARY REVIEW
Dr. Sadgun Bhandari Consultant Psychiatrist Queen Elizabeth II Hospital Howlands Welwyn Garden City 1
CLINICAL IMPLICATIONS OF THE PLACEBO RESPONSE
QUESTION ARE THERE ANY FINDINGS FROM THE PLACEBO RESPONSE THAT COULD BE USED IN THE TREATMENT OF OUTPATIENTS WITH DEPRESSION
CLINICAL IMPLICATIONS OF THE PLACEBO RESPONSE •
THE RATE OF PLACEBO RESPONSE IN ANTIDEPRESSANT TRIALS IS FAIRLY CONSISTENT AT ABOUT 30 %
WHICH MEANS THAT ON AN AVERAGE 1 IN 3 PATIENTS DO WELL WITH A PLACEBO
THE RESPONSE IS TRUE FOR SHORT TERM TRIALS OF ANTIDEPRESSANTS WHICH USUALLY LAST ABOUT 6-12 WEEKS
DOES THAT MEAN THAT 1 IN 3 PATIENTS COULD IMPROVE WITHOUT ACTIVE TREATMENT?
PROBLEMS WITH DIAGNOSIS • ARE THERE PROBLEMS WITH DEPRESSION IS DIAGNOSED?
• THERE IS VERY LITTLE IN THE LITERATURE WHICH ADDRESSES THIS • IN 1984 THERE WAS SOME CONCERN IN ONE ARTICLE THAT PERHAPS THE DSM III WAS PRONE TO INCLUDE MILDER CASES AND THE CRITERIA NEEDED TO BE STRICTER
CHARACTERISTICS OF PLACEBO RESPONDERS • Placebo responders were significantly more likely to be nonendogenous and were more likely to meet criteria for another Research Diagnostic Criteria diagnosis. Additionally, placebo responders were characterized by a shorter length of illness and reported a lower level of depressive symptomatology • •
Which depressions respond to placebo? Fairchild CJ, Rush AJ, Vasavada N, Giles DE, Khatami M.
CHARACTERISTICS • STUDY LOOKING AT TRIAL CHARACTERISTICS FOUND THAT SEVERITY
DOSING SCHEDULE, THE NUMBER OF TREATMENT ARMS AND NUMBER OF FEMALE PATIENTS WERE MORE LIKELY TO DIFFERENTIATE ANTIDEPRESSANT FROM PLACEBO • KHAN A; KOLTS RL; THASE ME; KRISHNAN KRR; BROWN W
RESPONSE IN ANTIDEPRESSANT TRIALS ALONE? We confirmed that placebo response in MDD is large regardless of the intervention and is associated with depression refractoriness and treatment combination (add-on rTMS studies). The magnitude of the placebo response seems to be related with study population and study design rather than the intervention itself. Placebo Response of Non-Pharmacological and Pharmacological Trials in Major Depression: A Systematic Review and Meta-Analysis AndrĂŠ Russowsky Brunoni1,2, Mariana Lopes1, Ted J. Kaptchuk3, Felipe Fregni1
PLACEBO RESPONDERS DURING LEAD IN PERIOD • Analysis of baseline and postplacebo measures showed that the 10-day placebo responders in our sample were convincingly depressed at baseline and improved significantly after placebo washout. This group of patients differed from 6-week placebo responders in our randomized trials in being more mildly ill, being more chronic, containing fewer cases of primary depression, and having fewer illness precipitants. They differed from placebo nonresponders largely in manifesting milder illness symptoms across the range of psychopathology. The proportion of placebo washout responders declined in the winter months • •
Baseline characteristics of 10-day placebo washout responders in antidepressant trials. Rabkin JG, Stewart JW, McGrath PJ, Markowitz JS, Harrison W, Quitkin FM. 8
PLACEBO RESPONDERS DURING LEAD IN PERIOD â€˘ Depressed patients who showed significant improvement after a 10-day placebo washout trial were followed for 3 months. Twenty-five relapsed and 20 remained well. Relapsing patients more frequently had a family history of depression, more had prior psychiatric treatment, their illness course was more chronic once ill, mean age of onset was younger, and fewer had obvious precipitants. More relapsers had RDC diagnoses of intermittent depressive disorder. Among those with major depressive disorder, fewer relapsers met subtype criteria for simple, situational, or recurrent. Nonaffective psychiatric disorders were present in 64% of relapsers and no placebo responders who remained well. Rabkin JG, McGrath P, Stewart JW, Harrison W, Markowitz JS, Quitkin F.
DOES THE PLACEBO RESPONSE PERSIST
One study looked at 3063 patients who were continued on placebo after the first 12 weeks . 79% of placebo responders remained well. The persistence of the placebo response in antidepressant clinical trials Khan A; Redding N and Brown WA
ELDERLY Placebo response is high in the elderly as well and one study found lower levels of cognitive and sleep disturbance leading to a better response to placebo.
PAEDIATRIC DEPRESSION RATES ARE VERY HIGH. A META-ANALYSIS FOUND THAT THE SINGLE MOST SIGNIFICANT PREDICTOR WERE THE NUMBER OF SITES.
WHAT CAUSES THE PLACEBO RESPONSE IN DEPRESSION • Change in any placebo group occurs for three main reasons: the encouraging effect of being in treatment, the effect of spontaneous remission while in treatment, and because people with chronic symptoms normally seek help when their symptoms are worst and, through natural fluctuations in severity, are likely to be improved when next assessed. • Andrews (2001) 13
WHAT CAUSES THE PLACEBO RESPONSE IN DEPRESSION â€˘ Good clinical care (Andrews, 1993) consists of a review of what the patient did and did not do, with encouragement to resolve problems and resume positive activity. Structured problemsolving and activity scheduling are systematic approaches to achieve these goals (MynorsWallis et al, 1995; Andrews & Jenkins, 1999) that have been demonstrated in randomised controlled trials to be effective. 14
WHAT CAUSES THE PLACEBO RESPONSE IN DEPRESSION â€˘ McLeod et al (1992) reported from a sample of married persons that the median duration of DSM-III-R (American Psychiatric Association, 1987) episodes of depression was 10 weeks, with 75% having episodes of under 22 weeks. Kendler et al (1997) studied a population sample of women and found a median time to recovery of 6 weeks, with 75% recovering in 12 weeks.
WHAT CAUSES THE PLACEBO RESPONSE IN DEPRESSION â€˘ If the population time to recovery were a median of 8 weeks and 75% recovered within 16 weeks, then people recruited into a trial after being depressed for 8 weeks would have a 50% chance of remitting during the conduct of the usual 8-week trial. These two factors, response to encouragement and a 50% probability of spontaneous remission during the trial, could account for the considerable progress of placebo control groups in depression trials. 16
PERCEIVED PLACEBO EFFECT? • Placebo effect • There is a distinction between a “true placebo effect” versus a “perceived placebo effect.”9 A true placebo effect depends on factors such as the attitudes of the physician and the patient, the suggestibility of the patient, and the type of treatment.9 A perceived placebo effect results from the influence of such factors as the natural course of the disease, the tendency of most measures of biological variation to regress toward the mean, and unidentified parallel interventions (eg, patients receiving extra attention during a clinical trial, becoming more aware of the problem, and taking actions that influence outcome).9 17
CONCLUSIONS CLEARLY THE PLACEBO RESPONSE IS HIGH AND PERSISTENT IN DEPRESSION AND OCCURS ACROSS THE WHOLE AGE RANGE. NOT CLEAR IF THIS IS TO WITH THE WAY DEPRESSION IS DIAGNOSED. SEVERITY SEEMS TO BE A SIGNIFICANT ISSUE
CONCLUSIONS DOES THIS MEAN THAT WHEN WE SEE MILDER CASES OF DEPRESSION WE COULD CONSIDER NOT STARTING AN ANTIDEPRESSANT STRAIGHTAWAY. IT WOULD BE IMPORTANT TO CARRY ON PROVIDING FOLLOW-UP IN THE SHORT TERM TO MAKE SURE THAT THE PSYCHOSOCIAL ASPECTS OF TREATMENT CONTINUE. 19
WAITFUL WATCHING â€˘ Dago and Quitkin4 suggest that, before deciding on whether or not to prescribe an antidepressant, clinicians should monitor the elements of the physician-patient relationship that may affect the patient's expectation or hope of being helped by the medication. These authors also recommend that a clinician follow those patients who demonstrate an early clinical improvement without antidepressant treatment until they have two unimproved weeks, and only then prescribe an antidepressant. 20
Doctor Sadgun Bhandari - A PRELIMNARY REVIEW. Doctor Sadgun Bhandari is a General Psychiatrist Consultant and an expert at the management of...