Critical Appraisal 1

Alleem Click to edit Master subtitle style Chris Sakinah Maryam Wednesday, 7th Sept 2011

4/14/12

2nd generation vs 1st generation antipsychotic drugs for schizophrenia: a meta analysis
4/14/12

Introduction
Second-generation antipsychotic drugs have a

low tendencyto cause extra-pyramidal side effects but their cost represents a large proportion of mentalhealth budgets compared to first-generation antipsychotic drugs. meta-analysis of blinded studies comparingdifferences in efficacy among second-generation antipsychotics in the treatment of schizophrenia.
4/14/12

The group conducted a systematic reviewand

Results
Olanzapine proved superior to

aripiprazole,quetiapine, risperidone, and ziprasidone. quetiapine and ziprasidone.

Risperidone was moreefficacious than Clozapine provedsuperior to zotepine and, in

doses >400 mg/day, to risperidone.

4/14/12

Conclusions
The findings suggestthat some second-

generation antipsychotics may be somewhat moreefficacious than others, but the limitations of meta-analysismust be considered. individualpatient, small efficacy superiorities must be weighed againstlarge differences in side effects and cost.
4/14/12

In tailoring drug treatment to the

A) Are the result valid?

Click to edit Master subtitle style

4/14/12

Is the question clearly focused

What is being reviewed: - To compare the effects of the 1st and 2nd

generation antipsychotic drugs.

What is the population:

- 150 double blind, mostly short- term studies with 21533 participants.

4/14/12

What is the exposure / intervention? - The mean overall change in symptoms were

assessed with following order:

a) Positive and Negative Syndrome Scale

( PANSS) total score, if not available

b)

Brief Psychiatric Rating Scale ( BPRS)

) What are the outcomes?

- To compare the 1st and 2nd generation drugs for overall efficacy, positive , negative and depressive symptoms, relapse, quality of life , extrapyramidal side effects , weight gain and sedation
4/14/12

Is the search thorough?

What bibliographic databases were

used?

- Cochrane Handbook
What years were searched?

- From august 2005 to October 2006

What languages were searched?

- The research did not restrict to 1 language

4/14/12

 Was any hand-searching conducted or

references in relevant articles obtained?

- Yes, the researcher compile the Cochrane Schizophrenia Group register , regular methodical searches of ten electronic databases with manual searching of relevant journals and conference proceedings

4/14/12

Are the inclusion criteria appropriate - They are meeting criteria A ( adequate

randomisation), B ( usually stated as randomiased without details )

- As for fixed studies the researches selected

only those with optimum doses of second generation antipsychotic drugs

- No, it is not appropriate as the researches did

not select the studies randomly.

4/14/12

Is the inclusion process discussed?

- No they did not discussed , they only stated that it was done according the Cochrane handbook

4/14/12

Is the validity of included studies adequately assessed?

Reproducible, blind assessment? - Yes, at first they compared the double blind

studies with open label ( single blind) and noted open label favored with 2nd generation antipsychotic drugs. Thus they based all subsequent analyses on double blind studies

Method of random selection?

- Yes , as they randomly select from the register of the Cochrane Schizophrenia 4/14/12 Group, US food and Drugs Administration

 Is the analysis on an intention to treat

basis?

- Yes the values of the scales ( BPRS) at study

endpoint, all based on intention to treat

Is missing information obtained from

investigators? - Yes they will contact the authors and the all second generation antipsychotic drug manufacturers.

4/14/12

Is publication bias an issue?

- No, as they assessed by calculation with funnel plot.

Has methodological quality been

assessed?

- No, as they did not stated .

4/14/12

B) Details of individual studies used in Meta analysis or Systematic review edit Master subtitle style Click to

4/14/12

How many individual studies were included in the systemic review/ meta-analysis?

239 studies were included. Out of the 239

150 were double blind studies.
Initially the study inspected 411 out of 4166

citations. Out of the 411 the study excluded 107 studies for the reasons of:

- Inadequate randomization
- No appropriate intervention/ control group - Inappropriate participants, - No usable data - Very short duration
4/14/12

A further 65 studies were excluded after

the absence of double blind was detected as a bias

4/14/12

What type of studies were included?

The research paper only consists of

Randomized Control Trials to compare the effects of 2nd generation antipsychotic drugs with 1st generation antipsychotic drugs. double blind study method was preferred to prevent bias from occurring.

Out of all the randomized control trial,

4/14/12

What are the sample sizes for each study group?

The over all sample size for the meta

analysis (239 studies) was 21533.

4/14/12

Duration of treatment study

The studies chosen for this meta analysis

were of short duration. The study did not specifically mention the specific duration. done <5 days (very short duration)

Despite that, the study excluded studies 12 weeks 11 years

4/14/12

Was the studies focused on any specific gender?

No. In order to rule out selective bias the

patients were chosen randomly. The group did not decide on a specific amount of participants with different gender.

4/14/12

Results
Click to edit Master subtitle style

4/14/12

Outcome measures and combination of studies

Continuous outcomes were analyzed using

weighted (by N) mean differencesand their 95% confidence interval (CI). are clearly indicated.

The primary and secondary outcome measures The pooled effect sizes of each second-

generation antipsychoticversus every other one are shown in Figure 1a & 1b

4/14/12

For sensitivity analyses, the standardized

effect size Hedges g was used to includea few more studies (13.3%) that used scales other than the PANSS.

For missing standard deviations, we either

derived them fromother statistics or used the average standard deviations ofthe other studies.
Risk ratios were used for the

dichotomousmeasure.

Number needed to treat was calculated as the

inverseof the risk difference where appropriate.

The studies were pooledwith the random4/14/12

effects model of Der-Simonian and Laird.

Sensitivity Analyses
The results of the extensive sensitivity

analyses (pharmaceuticalsponsorship, single-blind studies, lower-quality studies, effectivenessstudies, CATIE phase 2, firstepisode studies, Chinese studies,etc.) did not alter the primary findings.

4/14/12

Figure 1a

4/14/12

Figure 1b

4/14/12

Amisulpride

There were no significant differences between amisulpride andolanzapine (N=701), risperidone (N=291), and ziprasidone (N=122).

Aripiprazole

Aripiprazole was less efficacious than olanzapine in two studiessponsored by aripiprazoles manufacturer (N=794, weightedmean difference=5.0, p=0.002). Two further studies found nosignificant difference compared with risperidone (N=372).

Clozapine

Clozapine was not significantly different from

4/14/12

Quetiapine Quetiapine was significantly less efficacious than olanzapine(N=1,449, weighted mean difference=3.7, p<0.001) and risperidone(N=1,953, weighted mean difference=3.2, p=0.003). There wasno significant difference compared with clozapine (N=232) andziprasidone (N=710).

Risperidone

Risperidone was significantly more efficacious than quetiapine(N=1,953, weighted mean difference=3.2, p=0.003) andziprasidone (N=1,016, weighted mean difference=4.6, p=0.002).It was less efficacious than olanzapine (N=2,404, weighted meandifference=1.9, p=0.006). No difference compared with amisulpride(N=291), aripiprazole (N=372), clozapine (N=466), and sertindole(N=493) emerged.

Sertindole

There was no significant difference between sertindole and risperidonein two studies sponsored by sertindoles manufacturer,one in treatment-resistant patients, which found results withrisperidone to be 7 points better, the other without this criterionfinding sertindole 3.5 points better (N=493), leading to significantheterogeneity.

Ziprasidone

4/14/12 Ziprasidone was less efficacious than olanzapine (N=1,291, weightedmean difference=8.3, p<0.001) and risperidone (N=1,016, weightedmean

D) Interpretation of the results Will they help in making decisions about patients?
Click to edit Master subtitle style

4/14/12

Do conclusions flow from evidence that fromreviewed? is the evidence reviewed, a yes,
conclusion can be made.
Based on the results it has stated the

number needed to treat and they have reviewed several studies stating the efficacy of each first generation and second generation anti-psychotic drugs.

4/14/12

There are four second-generation

antipsychotic drugsie, amisulpride, clozapine, olanzapine, and risperidone drugs in their effects on overall symptoms.more efficacious than firstgeneration drugs for treatment of positive and negative symptoms. drugs (aripiprazole, quetiapine, sertindole, ziprasidone, and zotepine) were not significantly different from first-generation antipsychotic
4/14/12

Five second-generation antipsychotic

Are subgroup analyses interpreted cautiously? analysis were interpreted Yes, the subgroup
cautiously from the studies done excluded several studies due to certain reasons:
reasons of inadequate randomization no appropriate intervention or control group inappropriate participants no usable data presentation of a subgroup only very short duration open or single-blind studies were excluded 4/14/12

after the absence of double blind was

Can the conclusions and data be generalised to other settings? (Is the number needed to treat stated or should it be calculated?)
Yes, it can be generalized.

4/14/12

We searched (without language

restrictions) the register of the Cochrane Schizophrenia Group, US Food and Drugs Administration website, and previous reviews 24 for randomised controlled trials. generation antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperi- done, sertindole, ziprasidone, and zotepine) were compared with first-generation anti 4/14/12 psychotic drugs for the treatment of

In which oral formulations of second-

The NNT for one additional responder was

between 6 (95% CI 410) for amisulpride and 15 (936) for risperidone.

4/14/12

Were all important outcomes considered?

Yes there were several outcomes which were reviewed and considered which were
1. 2. 3. 4. 5. 6. 7. 8.

extrapyramidal effect effect of blinding overall efficacy Specific psychopathology relapse quality of life side effects weight gain sedation
4/14/12

Are the benefits worth the harms and the costs?

Yes, because with 4 of the second

generation anti-psychotic drugs taken into account the NNT was 6 compared to a first generation anti-psychotic drugs which is 15. differ in many properties, including efficacy, side-effects, cost (some are now generic), and pharmacology (amisulpride is not a serotonin receptor blocker), they do not form a homogeneous class and neither do 4/14/12 first- generation antipsychotic drugs.

Second-generation antipsychotic drugs

Click to edit Master subtitle style

4/14/12

THANK YOU
Click to edit Master subtitle style

4/14/12