Dr Sadgun Bhandari - A PRELIMNARY REVIEW. Dr. Sadgun Bhandari is a General Psychiatrist Consultant and an expert at the management of Serious Mental Illness especially Schizophrenia and Bipolar Affective Disorder.

1. CLINICAL IMPLICATIONS OF THE PLACEBO
RESPONSE
A PRELIMNARY REVIEW
Dr. Sadgun Bhandari
Consultant Psychiatrist
Queen Elizabeth II Hospital
Howlands
Welwyn Garden City
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2. 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
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3. 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?
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4. PROBLEMS WITH DIAGNOSIS
• ARE THERE PROBLEMS WITH
DEPRESSION IS DIAGNOSED?
THE
WAY
• 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
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5. 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.
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6. CHARACTERISTICS
• STUDY LOOKING AT TRIAL CHARACTERISTICS FOUND THAT
SEVERITY
OF
SYMPTOMS
BEFORE
RANDOMISATION,
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
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7. 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
André Russowsky Brunoni1,2, Mariana Lopes1, Ted J. Kaptchuk3, Felipe
Fregni1
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8. 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.
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9. PLACEBO RESPONDERS DURING LEAD
IN PERIOD
• 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.
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10. 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
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11. 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.
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12. PAEDIATRIC DEPRESSION
RATES ARE VERY HIGH.
A META-ANALYSIS FOUND THAT THE SINGLE
MOST SIGNIFICANT PREDICTOR WERE THE
NUMBER OF SITES.
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13. 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)
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14. WHAT CAUSES THE PLACEBO
RESPONSE IN DEPRESSION
• 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.
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15. WHAT CAUSES THE PLACEBO
RESPONSE IN DEPRESSION
• 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.
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16. WHAT CAUSES THE PLACEBO
RESPONSE IN DEPRESSION
• 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.
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17. 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
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18. 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
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19. 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.
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20. WAITFUL WATCHING
• 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.
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21. PSYCHIATRIC PERSPECTIVE
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