Psychiatry

1. Presenter- Dr. Neha Nilakh(Junior Resident)
Moderator- Dr. Astha Singh(Associate Professor)
RELAPSE RISK AFTER DISCONTINUATION OF
RISPERIDONE IN ALZHEIMER’S DISEASE
New England Journal of Medicine
2012 October 18;367:1497-507

2. Background: Treating Alzheimer’s Disease
Symptoms of psychosis or agitation are common
Associated with signs of distress on the part of the
patient, increased burden on caregivers, more rapid
cognitive decline, increased likelihood of
institutionalization and increased health care costs.
Antipsychotic agents show superiority over placebo but
have only low to moderate efficacy for the treatment of
psychosis and agitation-aggression.

3. Purpose
The risk of recurrence of symptoms after discontinuation
of antipsychotic medications in patients with Alzheimer’s
disease has not been established
Antipsychotic drugs are often discontinued due to
concern about adverse effects & federal regulations
that urge early discontinuation
Previous trials have had many significant limitations
Why Risperidone?
Studies showed high efficacy and absence of severe
side effects at low doses

4. Inclusions/Exclusions
 Inclusions:
 Outpatients or residents of assisted living facilities or nursing
homes
 50 to 95 years of age
 Met the criteria for dementia based on the DSM-IV
 Met the criteria for probable Alzheimer’s disease based on the
National Institute of Neurological and Communicative Disorders
and Stoke-Alzheimer’s Disease and Related Disorders
Association
 Score of 4 or more on the NPI at both screening and baseline on
the delusions or hallucinations subscale (psychosis score) or the
agitation-aggression subscale (agitation score)
 Score of 5 to 26 on the MMSE for the case of outpatient and a
score of 2 to 26 in the case of nursing home residents

5. Exclusions:
History of stroke
History of transient ischemic attack
History of uncontrolled atrial fibrillation

6. Methods
Phase A
Administration of open-label, flexible-dose risperidone
for 16 weeks in patients with Alzheimer’s who has
psychosis or agitation-aggression.
After 16 weeks only patients who had a response to
therapy continued to Phase B
Response: reduction of >30% from baseline on the
NPI core score & a score of 1 or 2 on the CGI-C
scale.

7. Phase B
Patients who responded to risperidone were randomly
assigned, in a double blind fashion, into 3 different
regimens.
Group 1: continuation of risperidone for 32 weeks
Group 2: risperidone for 16 weeks followed by
placebo for 16 weeks
Group 3: placebo for 32 weeks
Relapse: increase of >30% from baseline on the NPI
core score or a 5 point increase from the score at the
end of phase A & a score of 6 or 7 on the CGI-C scale.

9. Results
First 16 weeks of Phase B
 Placebo group (group 3) compared to the groups that
continued to receive risperidone (groups 1 & 2) had an
increased risk of relapse [HR=1.94, 95% CI (1.09-3.45),
P=0.02]
 24 of 40 patients in group 3 (60%) has a relapse
compared to 23 of 70 (33%) of patients in groups 1 & 2.

10. Results
Second 16 weeks of Phase B
 The group that discontinued risperidone at week 16
and switched to placebo (group 2) compared to the
group that continued to receive risperidone (group 1)
had an increased risk of relapse [HR=4.88, 95% CI
(1.08-21.98), P=0.02].
 13 of 27 patients in group 2 (48%) has a relapse
compared to 2 of 13 (15%) of patients in group 1

11. Statistics
 Kaplan-Meier Curves:
A way of dealing with differing survival
time
Time to event
Survival times do not have to be actual
survival with death being the event. The
event may be any event of interest
Curves that have many small steps
usually have a higher number of
subjects, whereas curves with large
steps usually have a limited number of
subjects and are thus not as accurate.

12.  In Alzheimer’s patients who had psychosis or agitation
symptoms decreased while taking risperidone, the time to
relapse was shorter among patients who discontinued use of
risperidone compared with patients who continued to receive
risperidone .
 Patients with psychosis or agitation-aggression who have a
sustained response to antipsychotics for 4 to 8 months have
an increased risk of relapse for at least 4 months after
discontinuation
This should be weighed against the risk of adverse effects with
continuation of treatment
 More clinical trials are needed to inform current regulations
that govern clinical practice.
Conclusion

13. Strengths
Double blinded
Multi-center
Risperidone was the only therapy used
One single pharmacy
Weaknesses:
Inadequate sample size
Adverse events in Phase B
Predictors of relapse after discontinuation
Rating: Ib
Strengths/Weaknesses

14.  Devanand D.P, et al. Relapse Risk after Discontinuation of
Risperidone in Alzheimer’s Disease. New England Journal of
Medicine. 2012 October 18;367:1497-507
 Hyman Bradley T, et al. National Institute on Aging–
Alzheimer's Association guidelines for the neuropathologic
assessment of Alzheimer's disease. Alzheimer's & Dementia.
2012 January;8(1):1-13
 Rich Jason T, et al. A practical guide to understanding
Kaplan-Meier curves. Otolaryngology- Head and Neck
Surgery. 2012 September;143(3):331-336
References

15. THANK YOU !