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Role of depot in patients requiring long-term antipsychotic treatment for psychotic disorders

Q5: In individuals with psychotic disorders (including ) who require long term antipsychotic treatment, what is the safety and role of depot antipsychotic medication?

Background

Long-acting depot antipsychotic were developed in the sixties to promote adherence in people with recurrent psychotic disorders, including schizophrenia. Depot 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 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

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

1 Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders

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 (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 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 decanoate and enanthate for schizophrenia. Cochrane Database of Systematic Reviews, (1):CD000307.

Abhijnhan A et al (2007). Depot for schizophrenia. Cochrane Database of Systematic Reviews, (1):CD001718.

Dieterich M et al (1999). Depot decanoate for schizophrenia. Cochrane Database of Systematic Reviews, (1):CD001361.

David A, Quraishi SN, Rathbone J (2005). Depot decanoate and enanthate for schizophrenia. Cochrane Database of Systematic Reviews, (3):CD001717.

Dinesh M, David A, Quraishi SN (2001). Depot 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. 2 Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders

PICO Table

Serial Intervention/Comparison Outcomes Systematic reviews used for Explanation no. GRADE I Depot antipsychotic Symptoms severity Adams et al, 2001 drugs / Oral Antipsychotics drugs Prevention of relapses Adams et al, 2001

Disability and functioning No evidence available

Adverse effects of treatment Adams et al, 2001 (movement disorders, weight gain)

Quality of life No evidence available

Mortality No evidence available

Treatment adherence Adams et al, 2001 Total dropout rates

Users' and families' satisfaction No evidence available with care

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, fluspirilene decanoate 2 2007 David et al, 2005 fluphenazine decanoate and enanthate 6 Mahapatra et al, flupenthixol decanoate 1 1999 Dieterich et al, 2 1999 3 Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders

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 or 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 . Dieterich et al, 1999 included two studies on Haloperidol decanoate versus oral haloperidol (N=22) and versus oral (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.

Summary of findings Quality assessment No of patients Effect Importance Quality No of Other Depot oral Relative Design Limitations Inconsistency Indirectness Imprecision Absolute studies considerations antipsychotics antipsychotics (95% CI)

Symptoms severity (lack of improvement)

4 randomised serious1 no serious serious2 serious3 none  RR 0.68 (0.54 258 fewer per 1000 (from 113 trials inconsistency 35/65 (53.8%) 50/62 (80.6%) VERY CRITICAL to 0.86) fewer to 371 fewer) LOW

Relapses

9 randomised serious1 very serious4 serious2 no serious none  RR 0.96 (0.8 to 14 fewer per 1000 (from 72 trials imprecision 146/420 (34.8%) 154/428 (36%) VERY CRITICAL 1.14) fewer to 50 more) LOW

4 Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders

Disability and functioning

0 no evidence none 0 fewer per 1000 (from 0 fewer 0/0 (0%) available to 0 fewer) 0/0 (0%) RR 0 (0 to 0) CRITICAL 0 fewer per 1000 (from 0 fewer 0% to 0 fewer) Movement disorders (needing anticholinergics)

7 randomised serious1 serious5 serious2 no serious none  RR 1.08 (0.9 to 53 more per 1000 (from 66 trials imprecision 137/197 (69.5%) 134/204 (65.7%) VERY CRITICAL 1.3) fewer to 197 more) LOW

Tardive dyskinesia

3 randomised serious1 no serious serious2 serious6 none  RR 0.66 (0.33 46 fewer per 1000 (from 92 trials inconsistency 12/133 (9%) 19/139 (13.7%) VERY CRITICAL to 1.3) fewer to 41 more) LOW

Quality of life

0 no evidence none 0 fewer per 1000 (from 0 fewer 0/0 (0%) available to 0 fewer) 0/0 (0%) RR 0 (0 to 0) IMPORTANT 0 fewer per 1000 (from 0 fewer 0% to 0 fewer) All-cause mortality

0 no evidence none 0 fewer per 1000 (from 0 fewer 0/0 (0%) available to 0 fewer) 0/0 (0%) RR 0 (0 to 0) IMPORTANT 0 fewer per 1000 (from 0 fewer 0% to 0 fewer) Treatment adherence (total dropouts)

18 randomised serious1 no serious serious2 no serious none RR 1.14 (0.9 to 30 more per 1000 (from 22  106/433 (24.5%) 95/441 (21.5%) IMPORTANT trials inconsistency imprecision 1.45) fewer to 97 more) LOW

Users' and families' satisfaction with care

5 Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders

0 no evidence none 0 fewer per 1000 (from 0 fewer 0/0 (0%) available to 0 fewer) 0/0 (0%) RR 0 (0 to 0) IMPORTANT 0 fewer per 1000 (from 0 fewer 0% 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 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.

6 Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders

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 In terms of proportion of patients showing a global improvement in psychotic symptoms, there base 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).

7 Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders

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 Important issues are the consequences of covert non-adherence (intentional or not) to oral variability and human rights issues 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 In many low and middle income countries, continuous availability of antipsychotic medicines in relevant feasibility issues non specialized health care is a challenge; depot preparations may have the advantage of requiring less quantities per year.

8 Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders

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.

9 Role of depot antipsychotic medication in patients requiring long-term antipsychotic treatment for psychotic disorders

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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