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Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders
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Q5: In individuals with psychotic disorders (including schizophrenia) who require long term antipsychotic treatment, what
is the safety and role of depot antipsychotic medication?
Background Long-acting depot antipsychotic medications were developed in the sixties to promote adherence in people with recurrent psychotic disorders, including schizophrenia. Depot antipsychotics simplify the treatment process, are believed to enhance treatment adherence, and eliminate bioavailability problems as well as the risk of overdose. However, there are concerns over adverse effects of depot antipsychotics, including tardive dyskinesia and injection site reactions, lack of flexibility of administration, and low patient acceptance.
Population/Intervention(s)/Comparator/Outcome(s) (PICO)
Population: adults with psychotic disorders, including schizophrenia
Interventions: depot antipsychotic drugs
Comparisons: oral Antipsychotics drugs
Outcomes: symptoms severity
prevention of relapses
disability and functioning
adverse effects of treatment (movement disorders, weight gain)
quality of life
mortality
treatment adherence
Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders
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users' and families' satisfaction with care
List of the systematic reviews identified by the search process INCLUDED IN GRADE TABLES OR FOOTNOTES Adams CE et al (2001). Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. British Journal of Psychiatry, 179:290-9.
EXCLUDED IN GRADE TABLES OR FOOTNOTES The following systematic reviews were included in the meta-review by Adams et al, (2001). In addition, NICE update on Schizophrenia (NICE 2009) did not identify any new evidence for the efficacy and safety of depot antipsychotics beyond that included in Cochrane reviews analyzed by Adams et al (2001). A new review on risperidone (Hosalli & Davis 2003) indicate that there is no evidence to suggest that long-acting risperidone has either greater efficacy or greater risk of adverse effects when compared to oral risperidone. Adams CE, David A, Quraishi SN (2004). Depot bromperidol decanoate for schizophrenia. Cochrane Database of Systematic Reviews, (3):CD001719.
Mahapatra J et al (1999). Depot flupenthixol decanoate for schizophrenia or other similar psychotic disorders. Cochrane Database of Systematic Reviews,
(2):CD001470.
David A et al (2005). Depot fluphenazine decanoate and enanthate for schizophrenia. Cochrane Database of Systematic Reviews, (1):CD000307.
Abhijnhan A et al (2007). Depot fluspirilene for schizophrenia. Cochrane Database of Systematic Reviews, (1):CD001718.
Dieterich M et al (1999). Depot haloperidol decanoate for schizophrenia. Cochrane Database of Systematic Reviews, (1):CD001361.
David A, Quraishi SN, Rathbone J (2005). Depot perphenazine decanoate and enanthate for schizophrenia. Cochrane Database of Systematic Reviews,
(3):CD001717.
Dinesh M, David A, Quraishi SN (2001). Depot pipotiazine palmitate and undecylenate for schizophrenia. Cochrane Database of Systematic Reviews,
(3):CD001720.
Hosalli P, Davis JM (2003). Depot risperidone for schizophrenia. Cochrane Database of Systematic reviews, (4):CD004161.
Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders
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PICO Table
Serial no.
Intervention/Comparison Outcomes Systematic reviews used for GRADE
Explanation
I Depot antipsychotic drugs / Oral Antipsychotics drugs
Symptoms severity Prevention of relapses Disability and functioning Adverse effects of treatment (movement disorders, weight gain) Quality of life Mortality Treatment adherence Users' and families' satisfaction with care
Adams et al, 2001 Adams et al, 2001 No evidence available Adams et al, 2001 No evidence available No evidence available Adams et al, 2001 No evidence available
Total dropout rates
Narrative description of the studies that went into the analysis
The following systematic reviews are included in the meta-review
Systematic review Depot Antipsychotic compared to oral antipsychotic No of RCTs
Abhijnhan et al, 2007
fluspirilene decanoate 2
David et al, 2005 fluphenazine decanoate and enanthate 6
Mahapatra et al, 1999
flupenthixol decanoate 1
Dieterich et al, 1999
haloperidol decanoate 2
Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders
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Dinesh et al, 2001 pipotiazine palmitate 3
All 14 RCTs included hospitalized patients with schizophrenia or non affective psychotic disorders randomized to a depot antipsychotic or a oral antipsychotic.
Abhijnhan et al, 2007 included two RCTs comparing depot fluspirilene to oral chlorpromazine or trifluoperazine in 64 patients. David et al, 2005 included 6 RCTs
(n=419) comparing fluphenazine decanoate with oral neuroleptics. Mahapatra et al, 1999 included just one small low quality study (N=56) of flupenthixol
decanoate versus oral penfluridol. Dieterich et al, 1999 included two studies on Haloperidol decanoate versus oral haloperidol (N=22) and versus oral
quetiapine (N=35). Dinesh et al, 2001 included 3 studies on depot pipotiazine palmitate versus oral antipsychotics involving 219 patients.
GRADE Tables Table 1
Author(s): Lorenzo Tarsitani and Corrado Barbui Date: 2009-07-10 Question: Should Depot antipsychotics vs oral antipsychotics be used for Psychotic disorders including schizophrenia? Settings: Largely in Hospital Bibliography: Adams CE et al (2001). Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. British Journal of Psychiatry, 179:290-9.
Quality assessment
Summary of findings
Importance No of patients Effect
Quality No of
studies Design Limitations Inconsistency Indirectness Imprecision
Other
considerations
Depot
antipsychotics
oral
antipsychotics
Relative
(95% CI) Absolute
Symptoms severity (lack of improvement)
4 randomised
trials
serious1 no serious
inconsistency
serious2 serious3 none
35/65 (53.8%) 50/62 (80.6%) RR 0.68 (0.54
to 0.86)
258 fewer per 1000 (from 113
fewer to 371 fewer)
VERY
LOW
CRITICAL
Relapses
9 randomised
trials
serious1 very serious4 serious2 no serious
imprecision
none
146/420 (34.8%) 154/428 (36%) RR 0.96 (0.8 to
1.14)
14 fewer per 1000 (from 72
fewer to 50 more)
VERY
LOW
CRITICAL
Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders
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Disability and functioning
0 no evidence
available none
0/0 (0%)
0/0 (0%)
RR 0 (0 to 0)
0 fewer per 1000 (from 0 fewer
to 0 fewer)
CRITICAL
0% 0 fewer per 1000 (from 0 fewer
to 0 fewer)
Movement disorders (needing anticholinergics)
7 randomised
trials
serious1 serious5 serious2 no serious
imprecision
none
137/197 (69.5%) 134/204 (65.7%) RR 1.08 (0.9 to
1.3)
53 more per 1000 (from 66
fewer to 197 more)
VERY
LOW
CRITICAL
Tardive dyskinesia
3 randomised
trials
serious1 no serious
inconsistency
serious2 serious6 none
12/133 (9%) 19/139 (13.7%) RR 0.66 (0.33
to 1.3)
46 fewer per 1000 (from 92
fewer to 41 more)
VERY
LOW
CRITICAL
Quality of life
0 no evidence
available none
0/0 (0%)
0/0 (0%)
RR 0 (0 to 0)
0 fewer per 1000 (from 0 fewer
to 0 fewer)
IMPORTANT
0% 0 fewer per 1000 (from 0 fewer
to 0 fewer)
All-cause mortality
0 no evidence
available none
0/0 (0%)
0/0 (0%)
RR 0 (0 to 0)
0 fewer per 1000 (from 0 fewer
to 0 fewer)
IMPORTANT
0% 0 fewer per 1000 (from 0 fewer
to 0 fewer)
Treatment adherence (total dropouts)
18 randomised
trials
serious1 no serious
inconsistency
serious2 no serious
imprecision
none 106/433 (24.5%) 95/441 (21.5%)
RR 1.14 (0.9 to
1.45)
30 more per 1000 (from 22
fewer to 97 more)
LOW IMPORTANT
Users' and families' satisfaction with care
Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders
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0 no evidence
available none
0/0 (0%)
0/0 (0%)
RR 0 (0 to 0)
0 fewer per 1000 (from 0 fewer
to 0 fewer)
IMPORTANT
0% 0 fewer per 1000 (from 0 fewer
to 0 fewer) 1 Many studies are old and random allocation, blindness and dropouts were not well described. 2 Patients who are reluctant to take oral antipsychotics are not included in trials. 3 Less than 200 patients were included in the analysis. 4 I squared for fluphenazine decanoate (6 studies) is 76%. 5 Graphical inspection of forrest plot suggests some heterogeneity. 6 CI includes no effect and ranges from appreciable benefit to harm.
Additional information that was not GRADEd
National Collaborating Centre for Mental Health (NCCMH) 2007: Depot antipsychotics should not be routinely prescribed to pregnant women because there is
relatively little information on their safety, and their infants may show extrapyramidal symptoms several months after administration of the depot. These are
usually self-limiting.
Reference List
Abhijnhan A et al (2007). Depot fluspirilene for schizophrenia. Cochrane Database of Systematic Reviews, (1):CD001718.
Adams CE, David A, Quraishi SN (2004). Depot bromperidol decanoate for schizophrenia. Cochrane Database of Systematic Reviews, (3):CD001719.
Adams CE et al (2001). Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. British Journal of Psychiatry, 179:290-9.
David A, Quraishi SN, Rathbone J (2005). Depot perphenazine decanoate and enanthate for schizophrenia. Cochrane Database of Systematic Reviews,
(3):CD001717.
David A et al (2005). Depot fluphenazine decanoate and enanthate for schizophrenia. Cochrane Database of Systematic Reviews, (1):CD000307.
Dieterich M et al (1999). Depot haloperidol decanoate for schizophrenia. Cochrane Database of Systematic Reviews, (1):CD001361.
Dinesh M, David A, Quraishi SN (2001). Depot pipotiazine palmitate and undecylenate for schizophrenia. Cochrane Database of Systematic Reviews,
(3):CD001720.
Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders
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Hosalli P, Davis JM (2003). Depot risperidone for schizophrenia. Cochrane Database of Systematic reviews, (4):CD004161.
Mahapatra J et al (1999). Depot flupenthixol decanoate for schizophrenia or other similar psychotic disorders. Cochrane Database of Systematic Reviews,
(2):CD001470.
National Collaborating Centre for Mental Health (NCCMH) (2007). Antenatal and Postnatal Mental Health: The NICE guideline on Clinical Management and Service Guidance. London: British Psychological Society & Royal College of Psychiatrists.
NICE (2009). Schizophrenia: core interventions in the treatment and management of schizophrenia in primary and secondary care (update). NICE Clinical Guideline 82.
From evidence to recommendations
Factor Explanation
Narrative summary of the evidence
base
In terms of proportion of patients showing a global improvement in psychotic symptoms, there
is evidence that depot antipsychotics were significantly more effective than oral antipsychotics
in psychotic disorders including schizophrenia (RR 0.68, 0.54 to 0.86).
In terms of relapse prevention, there is no evidence that depot antipsychotics were significantly
more effective than oral antipsychotics (RR 0.96, 0.8 to 1.14).
In terms of treatment adherence, depot antipsychotics did not reduce dropouts compared to
oral antipsychotics (RR 1.14, 0.9 to 1.45).
In terms of disability, functioning, quality of life and satisfaction with care no evidence was
available.
The evidence is inconclusive and so it is not possible to determine if there is a clinical important
difference between depot and oral antipsychotics in the risk of tardive dyskinesia (RR 0.66, 0.33
to 1.3). Additionally, there is evidence suggesting there is unlikely to be a clinically important
difference in terms of movement disorders (RR 1.08, 0.9 to 1.3).
Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders
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Summary of the quality of evidence The quality of evidence was VERY LOW for global improvement in psychotic symptoms and
relapse prevention. The quality of evidence was LOW for treatment adherence and VERY LOW
for neurological adverse events.
Balance of benefits versus harms In terms of effectiveness, there is limited evidence of an advantage in favor of depot
antipsychotics.
In terms of tolerability, there is evidence suggesting there is unlikely to be a clinically important
difference between depot and oral antipsychotics.
Fluphenazine decanoate or enanthate are included in the WHO Model List of Essential Medicine
as medicines used in psychotic disorders.
Values and preferences including any
variability and human rights issues
Important issues are the consequences of covert non-adherence (intentional or not) to oral
daily treatment, that may lead to psychotic relapses, and the risk of bioavailability problems
with oral antipsychotics. In addition, there is no risk of intentional or non intentional overdose
with depot injected treatments.
However, there are significant concerns about the long term safety and tolerability associated
with depot antipsychotic medications. In the long term, possible adverse effects of depot
antipsychotics include tardive dyskinesia, movement disorders, and injection site reactions.
There are also concerns about lack of flexibility of administration and low patient acceptance of
the depot injection perceived as a discriminating and passive experience. However in some
cultures, medicines by injecting route are assumed to be more 'potent' than oral route.
Depot antipsychotic medicines may have the risk of being administered forcibly against the
consent the patient, causing human rights concerns.
Costs and resource use and any other
relevant feasibility issues
In many low and middle income countries, continuous availability of antipsychotic medicines in
non specialized health care is a challenge; depot preparations may have the advantage of
requiring less quantities per year.
Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders
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In many countries, the per day cost may be reduced with the use of depot preparations.
In many countries, availability of health staff needed to administer an injection may be a
problem.
Use of depot preparations require the patient and families to return to the health care facility
at regular intervals, facilitating psychosocial interventions.
Fluphenazine decanoate or enantate is available in WHO Essential Medicine List as
antipsychotic medicines.
Recommendation(s)
Individuals on long term antipsychotic treatment should be given adequate information and encouraged to make a choice between oral
and depot preparations, especially with the view to improve adherence.
Strength of recommendation: STANDARD
Individuals on antipsychotic medicines (oral and depot preparations) should be monitored regularly for symptom relief, functioning and
any adverse effects.
Strength of recommendation: STRONG
Depot antipsychotics should not be routinely prescribed to women with psychotic disorders (including schizophrenia), who are planning a
pregnancy or pregnant or breastfeeding because there is relatively little information on their safety.
Strength of recommendation: STRONG
Any additional remarks
More evidence is needed on comparative effectiveness of depot antipsychotic medication over oral preparations on disability
and functioning, quality of life and on acceptance by users and carers. More evidence is also needed on the long term safety of
these preparations.
Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders
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Update of the literature search – June 2012
In June 2012 the literature search for this scoping question was updated. The following systematic reviews were found to be relevant without changing the
recommendation:
David A, Adams CE, EisenbruchM, Quraishi SN, Rathbone J.Depot fluphenazine decanoate and enanthate for schizophrenia. Cochrane Database of Systematic
Reviews 2004, Issue 2. Art. No.: CD000307. DOI: 10.1002/14651858.CD000307.
Leucht C, Heres S, Kane JM, Kissling Q, Davis JM, Leucht S. Oral versus depot antipsychotic drugs for schizophrenia—A critical systematic review and meta-
analysis of randomised long-term trials. Schizophrenia Research 127 (2011) 83–92