q5: in individuals with psychotic disorders (including ... · depot antipsychotics simplify the...

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

motturig

Typewritten Text

updated 2012


2

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.


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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


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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)


fewer to 50 more)

VERY

LOW

CRITICAL


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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)


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)


to 0 fewer)

IMPORTANT


to 0 fewer)

All-cause mortality

0 no evidence

available none

0/0 (0%)

0/0 (0%)

RR 0 (0 to 0)


to 0 fewer)

IMPORTANT


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


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0 no evidence

available none

0/0 (0%)

0/0 (0%)

RR 0 (0 to 0)


to 0 fewer)

IMPORTANT


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.


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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).


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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.


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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.


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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

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