Sultopride for schizophrenia

Antipsychotic medications are the cornerstone in treating people with schizophrenia. These medications fall into two main categories; typical and atypical. The term ‘typical antipsychotics’ refers to older antipsychotics such as haloperidol or chlorpromazine. Atypical antipsychotics are the relatively newer generation of antipsychotics, which began with the introduction of clozapine in the late 1950s. They have a higher potency and lower risk of movement disorders than the older generation of antipsychotics (Takano 2005).

The classification of sultopride into one of these groups is still debatable (Takano 2005). First introduced into psychiatry in Europe in the 1970s, sultopride showed a powerful and constant efficacy in trials and was found to be more effective and rapidly acting than the phenothiazines (Morel 1983); the prototype of typical antipsychotics. Furthermore, based on D2 receptor occupancy, sultopride is about 50 times more potent than sulpiride (Takano 2005), which has a similar neuropharmacological profile to several of the atypical antipsychotic drugs.

Despite being FDA approved, sultopride was not widely used. A maximum of 2% usage was reported in treating acute psychosis (Scotto 1984, Huf 2002, Hardman 1996). It was also later suspended due to undesirable side effects such as cardiacXXXXX (Titier 2005). However, justification for this suspension is still under debate (Titier 2005). Reliable evidence of both sultopride’s efficacy and side effects are needed to determine whether its suspension is sufficiently justified.

Technical Background:
Sultopride’s International Union of Pure and Applied Chemistry (IUPAC) name is [N-(ethyl-1-pyrrolidinyl- 2-methyl) methoxy-2-ethylsulfonyl-5-benzamide] and its Molecular Weight is 354.465 g/mol (CTD 2006, NCBI 2006). It is an antagonist of the D2-like dopamine receptors, and is a member of a large family of receptors that interact with specific intracellular signalling pathways through coupling with G proteins. It is a substituted benzamide related to Sulpiride and presents a high selectivity for D2 and D3 dopaminergic receptor subtypes (Blomme 1998). Sultopride may be given orally or intramuscular. Its half-life is three to five hours and its plasma half-life is about 11 hours. Ninety percent of its excretion is via the kidneys and 5-10% is via the faecal route (Martindale 1989, Kobari 1985 a, Kobari 1985 b).

Objectives

To evaluate the effects of sultopride compared to placebo and other antipsychotic drugs in the treatment of schizophrenia and other types of schizophrenia-like psychoses.

Criteria for considering studies for this review

Types of studies
We included all relevant randomised controlled trials. Where a trial was described as ‘double-blind’, but it was implied that the study was randomised, we included the trial in a sensitivity analysis. If there was no substantive difference within primary outcomes (see ‘types of outcome measures’) when these ‘implied randomisation’ studies were added, then we included these in the final analysis. If there was a substantive difference, we only analysed clearly randomised trials and described the results of the sensitivity analysis in the text. We excluded quasi-randomised studies, such as those allocating by using alternate days of the week.

Types of participants
We included people with schizophrenia and other types of schizophrenia-like psychoses (schizophreniform and schizoaffective disorders). There is no clear evidence that the schizophrenia-like psychoses are caused by fundamentally different disease processes or require different treatment approaches (Carpenter 1994).

Types of intervention
1. Sultopride: any dose or form of application.
2. Placebo or no treatment.
3. ‘Typical’ antipsychotic drugs such as haloperidol or chlorpromazine, any dose or form of application.
4. ‘Atypical’ antipsychotic drugs such as risperidone, olanzapine, amisulpride, any dose or form of application.
5. ‘Standard care’ as defined by treating physician.

Types of outcome measures
1. Leaving the study early

2. Death - suicide and natural causes

3. Global state
3.1 Relapse
3.2 No clinically important change in global state (as defined by individual studies)
3.3 Average endpoint global state score
3.4 Average change in global state scores

4. Service outcomes
4.1 Hospitalisation
4.2 Time to hospitalisation

5. Mental state (with particular reference to the positive and negative symptoms of schizophrenia)
5.1 No clinically important change in general mental state
5.2 Average endpoint general mental state score
5.3 Average change in general mental state scores
5.4 No clinically important change in specific symptoms (positive symptoms of schizophrenia, negative symptoms of schizophrenia, depression, mania)
5.5 Average endpoint specific symptom score
5.6 Average change in specific symptom scores

6. General functioning.
6.1 No clinically important change in general functioning
6.2 Average endpoint general functioning score
6.3 Average change in general functioning scores
6.4 No clinically important change in specific aspects of functioning, such as social or life skills
6.5 Average endpoint specific aspects of functioning, such as social or life skills
6.6 Average change in specific aspects of functioning, such as social or life skills

7. Behaviour
7.1 No clinically important change in general behaviour
7.2 Average endpoint general behaviour score
7.3 Average change in general behaviour scores
7.4 No clinically important change in specific aspects of behaviour
7.5 Average endpoint specific aspects of behaviour
7.6 Average change in specific aspects of behaviour

8. Adverse effects - general and specific
8.1 Clinically important general adverse effects
8.2 Average endpoint general adverse effect score
8.3 Average change in general adverse effect scores
8.4 Clinically important specific adverse effects (particularly movement disorders, and those known to occur more commonly with sultopride such as QT prolongation, arrhythmogenic effects, fever and side effects on endocrine system).
8.5 Average endpoint specific adverse effects
8.6 Average change in specific adverse effects

9. Engagement with services

10. Satisfaction with treatment
10.1 Leaving the studies early
10.2 Recipient of care not satisfied with treatment
10.3 Recipient of care average satisfaction score
10.4 Recipient of care average change in satisfaction scores
10.5 Carer not satisfied with treatment
10.6 Carer average satisfaction score
10.7 Carer average change in satisfaction scores

11. Quality of life
11.1 No clinically important change in quality of life
11.2 Average endpoint quality of life score
11.3 Average change in quality of life scores
11.4 No clinically important change in specific aspects of quality of life
11.5 Average endpoint specific aspects of quality of life
11.6 Average change in specific aspects of quality of life

12. Economic outcomes
12.1 Direct costs
12.2 Indirect costs

13. Cognitive functioning*
13.1 No clinically important change in cognitive functioning
13.2 Average endpoint cognitive functioning score
13.3 Average change in cognitive functioning scores
13.4 No clinically important change in specific aspects of cognitive functioning
13.5 Average endpoint specific aspects of cognitive functioning
13.6 Average change in specific aspects of cognitive functioning

* We chose cognitive function (as defined in the individual studies) as the primary outcome measure.

We grouped outcomes into the short term (up to 12 weeks), medium term (13 to 26 weeks) and long term (over 26 weeks).

 

 

 

 

G Razzouk, MS Azzouz, K Hawasly, A Koudsi

Cochrane Database of Systematic Reviews 2007 Issue 4
The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DOI: 10.1002/14651858.CD006615   This version first published online: 18 July 2007 in Issue 3, 2007
Date of Most Recent Substantive Amendment: 21 May 2007

This record should be cited as: Razzouk G, Azzouz MS, Hawasly K, Koudsi A. Sultopride for schizophrenia. (Protocol) Cochrane Database of Systematic Reviews 2007, Issue 3. Art. No.: CD006615. DOI: 10.1002/14651858.CD006615.

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