Download Efficacy of atypical v. typical antipsychotics in the treatment of early

The British Journal of Psychiatry (2010)
196, 434–439. doi: 10.1192/bjp.bp.109.066217
Review article
Efficacy of atypical v. typical antipsychotics in the
treatment of early psychosis: meta-analysis
Nicolas A. Crossley, Miguel Constante, Philip McGuire and Paddy Power
Background
There is an ongoing debate about the use of atypical
antipsychotics as a first-line treatment for first-episode
psychosis.
Aims
To examine the evidence base for this recommendation.
Method
Meta-analyses of randomised controlled trials in the early
phase of psychosis, looking at long-term discontinuation
rates, short-term symptom changes, weight gain and
extrapyramidal side-effects. Trials were identified using a
combination of electronic (Cochrane Central, EMBASE,
MEDLINE and PsycINFO) and manual searches.
Results
Fifteen randomised controlled trials with a total of 2522
Over the past decade, atypical (or second-generation) antipsychotics have been increasingly used in the treatment of schizophrenia in preference to ‘conventional’ typical (first-generation)
drugs. However, meta-analyses of clinical trials in participants
with chronic schizophrenia have suggested a limited advantage
of the newer agents in terms of efficacy1–4 and two recent large
trials failed to find a difference between these two classes of
antipsychotics.5,6 Furthermore, economic analyses have raised
doubts about the cost-effectiveness of the newer drugs.7,8 Cost is
an important factor for low- and middle- income countries,
particularly if, as suggested by a previous meta-analysis,9 the cost
of treatment could partly explain the inverse association between
longer duration of untreated psychosis and per capita income. In
this context, it has been suggested that typical antipsychotics are as
useful as atypicals in the treatment of schizophrenia.10
Individuals presenting with a first episode of schizophrenia
differ from those in whom the disorder is well established in that
a higher proportion show a good symptomatic response.11 Moreover, the dose of antipsychotics required to achieve symptomatic
remission is usually lower than in individuals with chronic schizoprhenia,12 and those with a first episode are more susceptible
to extrapyramidal side-effects.13 Their younger age also puts them
at risk of longer exposure to the potential metabolic complications
of newer antipsychotics.14 Avoiding adverse effects when
individuals first start treatment is particularly important as it
may colour their attitude to medication and psychiatric treatment
more generally thereafter. Antipsychotics with a benign side-effect
profile thus offer an advantage in this phase of schizophrenia.
This is particularly important considering the high rates of nonadherence to medication in this population, reported to be as high
as 50%.15 Regarding the question whether atypical or typical
antipsychotics are better for this population a Cochrane metaanalysis from 2003 found that there was not enough evidence at
that time to make recommendations.16
In the UK, a recent update to the National Institute for Health
and Clinical Excellence (NICE) guideline has moved away from
434
participants were included. No significant differences
between atypical and typical drugs were found for
discontinuation rates (odds ratio (OR) = 0.7, 95% CI 0.4 to 1.2)
or effect on symptoms (standardised mean difference
(SMD) = –0.1, 95% CI –0.2 to 0.02). Participants on atypical
antipsychotics gained 2.1 kg (95% CI 0.1 to 4.1) more weight
than those on typicals, whereas those on typicals
experienced more extrapyramidal side-effects (SMD = –0.4,
95% CI –0.5 to –0.2).
Conclusions
There was no evidence for differences in efficacy between
atypical and typical antipsychotics, but there was a clear
difference in the side-effect profile.
Declaration of interest
None.
the previous recommendation of atypical antipsychotics as a
first-line treatment in people presenting with a first episode of
psychosis.17 We performed a meta-analysis to look at the efficacy
and side-effects of atypical versus typical antipsychotics in the
treatment of the early phase of psychosis.
Method
We included randomised controlled trials comparing atypical and
typical antipsychotics in individuals in the early phase of
psychosis. To be included in the meta-analysis, studies had to
use a validated diagnostic system and explicitly define whether
their participants were antipsychotic naive, experiencing a first
episode of psychosis or were in the early phase of psychosis. We
expected to find varying definitions of first episode and early
psychosis, and therefore we accepted any definitions used and
modelled the effects of the different duration of illness in the
analyses. We excluded studies that recruited only participants with
an affective psychosis, or individuals younger than 13 or older
than 65 years of age. Studies needed to report at least one of the
following outcomes: adherence with antipsychotic medication,
symptom scales, weight or any validated measure of extrapyramidal
side-effects.
In line with a recent long-term study,5 we selected ‘discontinuation for any cause’ at 12 months of the assigned antipsychotic
(or when this was not reported, between 6–24 months), which
includes drug efficacy and tolerance, as our primary measure of
effectiveness. We also selected a measure of medication efficacy
consisting of symptom scores at 12 weeks (or when this was not
reported, between 6–18 weeks), as this is the time point at which
a previous study showed that 90% of individuals with a first
episode who responded to medication achieved symptomatic
remission.18 When more than one symptom scale was reported,
we chose to use the Positive and Negative Syndrome Scale
(PANSS) first, then the Brief Psychiatric Rating Scale (BPRS)
Atypical v. typical antipsychotics in the treatment of early psychosis
and then any other validated scale. Two major groups of sideeffects were assessed: weight gain and extrapyramidal side-effects,
using the last reported observation of each study. When studies
reported more than one arm of atypical or typical antipsychotics,
effect sizes and variances of the different drugs were pooled
together per group using number of participants as a weight
factor.
Pertinent randomised controlled trials were identified using an
electronic and a hand-based search. A computer-based search was
performed using the following databases: MEDLINE (1966 to 20th
January 2009), EMBASE (1980 to January Week 3 2009), PsycINFO
(1806 to January Week 2 2009) and Cochrane CENTRAL (The
Cochrane Library 2008, Issue 4). No language constraints were
applied. Subject headings including Psychosis, Schizophrenia,
and Atypical Antipsychotic Agent were used as well as text words
such as ‘first episode’, ‘never medicated’, ‘naı̈ve’ and names of
atypical antipsychotics. Details of the search strategy can be found
in the online supplement. Two of the authors (N.A.C. and M.C.)
independently reviewed all the identified abstracts from the
electronic search, selected the studies included and extracted the
data. Any conflicts were discussed with a third reviewer (P.P.).
References of the identified studies and published reviews on
pharmacological management of first-episode psychosis were also
searched.16,19 One of the authors (N.A.C.) undertook to handsearch data of published abstracts of the 3rd to 5th Conference
on Early Psychosis and 8th to 14th Biennial Winter Workshop
on Schizophrenia to complement the electronic search. Authors
were contacted if data were missing.
As we anticipated different definitions of early psychosis or
first-episode psychosis we expected to find significant clinical
heterogeneity among the studies and therefore decided that using
a random-effects analysis would be appropriate.20 When looking
at adherence rates for antipsychotic medication, we preferred to
use odds ratios instead of risk ratios in spite of their more difficult
interpretation. This allowed us to avoid giving too much weight to
trials with high event rates.21 For continuous variables, weighted
means or standardised mean differences using Hedges’ g were
used. The latter was used when more than one scale was reported
in the outcomes. Heterogeneity was explored using w2. I2 is
another measure of heterogeneity that refers to the proportion
of the variance explained by the between-trial variance. Due to
the easiness in the interpretation, it is also reported in this study.
We used meta-regression to look at potential confounders in our
summary measure. Knowing that we would find a limited amount
of trials to include in each comparison, we only performed the
regression if the variable being controlled for was reported in all
the included studies. We used meta-regressions to look at the
effects of the dose of typical antipsychotic used and the
proportion of antipsychotic-naive participants included. The
European First-Episode Schizophrenia Trial (EUFEST) suggested
that masking status might cause a bias in discontinuation rates
(e.g. unmasked clinicians might discontinue typical drugs sooner
than atypicals if complications arose).22 Masking status was
therefore also included in the model for discontinuation rates.
For the side-effects analysis, we included the assessment point in
time. Given the known difference in side-effect profiles for some
atypicals, we also included in the regression the proportion of
participants taking olanzapine or clozapine when looking at
weight gain, and amisulpride or risperidone when looking at
extrapyramidal symptoms. In order to avoid spurious results
by overfitting the data (e.g. when more than one factor was
reported in all the studies), we opted for a repeated univariate
meta-regression rather than a multiple regression approach.
Results of these meta-regressions should be considered
exploratory because of the multiple comparisons performed.
Publication bias was explored using Egger’s test.23 All analyses
were done using STATA 10.0 running in Windows XP.
Results
Combined searches of the four databases yielded 1053 references.
In total 105 articles were retrieved for further assessment from
which 14 different randomised controlled trials were identified.
Two further trials were identified in the manual search, one of
which could not be included because of a lack of data (the trial
looked at ziprasidone versus haloperidol and was published as a
conference abstract). As a result, we included 15 randomised
controlled trials that recruited a total of 2522 patients. Figure 1
summarises the study selection and exclusion process.
Risperidone was used in nine studies as the atypical antipsychotic,24–32 olanzapine was used in seven trials,13,22,27,28,32–34
and two studies used quetiapine22,35 and clozapine.27,36 Amisulpride
and ziprasidone were used in one study.22 Twelve of the fifteen
studies used haloperidol as the first-generation antipsychotic.
The other three studies used chlorpromazine,36 oral zuclopenthixol25
and sulpiride.27 All but one study32 reported using low doses of
typical antipsychotic, below the usually described cut-off point
of 12 mg of haloperidol or equivalent.1,4 Eight studies reported
using doses lower than haloperidol 5 mg,22,25–27,29,30,33,34, accounting
for more than two-thirds of the total sample of participants
treated with typical antipsychotics included in this review.
Characteristics of the included trials and selected references are
shown in online Table DS1.
Seven studies reported long-term data of discontinuation rates
suitable for pooling, with a total of 1823 participants. Studies used
different definitions of discontinuation, but most reported that
participants were considered as discontinuing the drug due to
1053 references identified
in electronic search
and screened for retrieval
6
105 articles
retrieved
7
6
76 articles excluded:
18: study design not suitable
(non-random, cross-over,
meta-analysis)
9: different population studied
(children, not early psychosis)
5: different intervention studied
25: studied outcome not reported
19: abstract published as full article
29 references
included
8
6
1 article sent by one of the authors
14 RCTs identified
(30 references)
2 RCTs identified from
manual search of
conference abstracts
8
6
7
15 RCTs included
in the meta-analysis
1 RCT not included
due to lack of data
Fig. 1 Flowchart of study selection. RCT, randomised
controlled study.
435
Crossley et al
side-effects or lack of response among other reasons. Only one
study considered discontinuation rates as their primary outcome
and explicitly defined how they measured it.22 There was a nonsignificant greater proportion of individuals prescribed atypical
antipsychotics who were adherent around 1 year (Fig. 2, odds ratio
(OR) = 0.73, P = 0.22). On visual inspection, results appeared to
differ between the different studies and not surprisingly, heterogeneity was significant as assessed with w2 (P50.001). There is
an outlier finding from a small study that used quetiapine,35
and excluding this study did not change the overall result
(OR = 0.64, P = 0.09) and had little effect on the heterogeneity
observed. Masking status was reported in all seven studies. A
meta-regression including masking status as the independent
variable and the odds ratio of each study as the dependent variable
was non-significant. In other words, masking status was not a
significant moderator of the effect sizes of the studies included.
For the short-term symptomatic outcome, 12 trials were
pooled with a total of 1949 participants. Most studies reported
PANSS scores, although a few reported BPRS scores. Therefore
standardised effect sizes were pooled. A small non-significant
trend favouring atypical antipsychotics was found (s.d. = 70.1,
P = 0.12) as shown in Fig. 3. Heterogeneity was not statistically
significant in the comparison according to w2 (P = 0.17). Since
there was no significant heterogeneity found, we repeated the
analysis with a fixed-effect approach as some authors have
suggested, but the difference remained non-significant (s.d. =
70.08, 95% CI 70.17 to 0.02). We performed a meta-regression
using the dose of atypical as a covariate of the effect size. There
was a non-significant trend for comparisons that used higher
doses of typical antipsychotics to report larger effect sizes that
favoured atypicals (1 mg of haloperidol equivalent accounting
for standardised mean difference (SMD) = 0.02 favouring
atypicals, P = 0.09).
For weight gain, a total of seven studies were pooled including
1444 participants. Pooling of the seven studies showed that
individuals on atypical antipsychotics gained an extra 2.1 kg
compared with those on typical antipsychotics (P = 0.04, Fig. 4).
Heterogeneity was present according to w2 (P50.001). One of
the trials27,37 reported body max index (BMI) instead of weight.
In order to include this outcome with the rest of the studies,
participants’ BMIs were transformed to kilograms assuming that
Study
Lieberman36
HGDH38
EPGN26
46
Perez-Iglesias
GRNS30
22
EUFEST
Bustillo35
Overall
...
...
...
...
...
...
...
...
...
...
...
...
...
.
everyone’s height was 1.70 m (an assumption that probably
decreased its variance). Excluding this study from the analysis
had little effect on the results and only marginally decreased
heterogeneity (I 2 decreased from 80 to 74%). Meta-regressions
were performed using the following covariates: amount of time
exposed, typical doses, and percentage of participants receiving
olanzapine or clozapine. None of these factors reached statistical
significance.
For an analysis of extrapyramidal side-effects, nine studies
with 1341 participants were pooled. As described previously, most
of the studies utilised the high-potency antipsychotic haloperidol
and only two used zuclopenthixol and chlorpromazine. Rating
scales reported varied, with five studies using the Simpson–Angus
Scale (SAS),13,28,30,36,38 three studies the Extrapyramidal Symptom
Rating Scale (ESRS),24,26,39 and one the St Hans Rating Scale for
Extrapyramidal Syndrome (SHRS).22 There are differences
between the rating scales, but all of them include an objective
evaluation of parkinsonism. The SHRS and ESRS both
rate dystonia and akathisia, and the latter also includes a
Standardised mean difference
(95% CI)
% Weight
Study
Emsley24
Sanger13
Fagerlund47
Lieberman36
de Haan33
HGDH34
EPGN26
Crespo-Facorro28
Brewer29
GRNS48
Lee31
EUFEST22
Overall
Fig. 3 Comparisons of symptoms scales at short term
(around 3 months) between the two groups.
Effect sizes were standardised using Hedges’ g and pooled using a random-effects
model. Non-significant difference favouring atypicals shown (P = 0.12). Heterogeneity
w2 = 15.3 (d.f. = 11) P = 0.17, I 2 = 28%. EPGN, Early Psychosis Global Network; GRNS,
German Research Network on Schizophrenia; EUFEST, European First-Episode
Schizophrenia Trial.
%
Weight
0.61 (0.27 to 1.36)
13.2
0.44 (0.23 to 0l86)
14.9
Study
1.27 (0.90 to 1.78)
18.1
Lieberman36
0.49 (0.25 to 0.96)
14.8
HGDH38
1.06 (0.53 to 2.10)
14.6
EPGN26
0.36 (0.23 to 0.57)
17.2
Wu37
3.71 (0.82 to 16.84)
7.2
Mean difference
(95% CI)
% Weight
Perez-Iglesias46
Saddichha32
EUFEST22
0.1
1
2.5
Odds ratio
Favours atypicals Favours typicals
Fig. 2 Comparison of discontinuation rates among participants
receiving first- v. second-generation antipsychotics.
P = 0.22. Heterogeneity w2 = 28.55 (d.f. = 6) P50.001, I 2 = 79.0%. EPGN, Early Psychosis
Global Network; GRNS, German Research Network on Schizophrenia; EUFEST,
European First-Episode Schizophrenia Trial.
For clarity purposes, the first author of the first published paper is used in Table DS1
in cases where more than one article reporting outcomes of the study has been included.
436
(0.39 to 0.19) 11.3
(–1.14 to –0.17) 5.2
(–0.30 to 1.33) 2.1
(–0.53 to 0.09) 10.4
(–0.95 to 0.81) 1.8
(–0.46 to 0.04) 13.8
(–0.08 to 0.29) 18.5
(–0.49 to 0.15) 10.0
(–0.71 to 2.66) 0.5
(–0.27 to 0.19) 15.0
(–1.20 to 0.56) 1.8
(–0.27 to 0.19) 9.8
(–0.22 to 0.02) 100.0
–1.5
0
1
Standardised mean difference
Favours atypicals Favours typicals
Odds ratio
(95% CI)
0.73 (0.44 to 1.21) 100.0
–0.10
–0.65
0.51
–0.22
–0.07
–0.21
0.11
–0.17
0.98
–0.04
–0.32
–0.04
–0.10
...
...
...
...
...
...
...
...
...
...
...
...
...
...
...
...
Overall
...
...
...
...
....
...
...
...
...
...
...
...
...
...
.
3.40 (–3.00 to 9.80)
6.7
6.20 (4.14 to 8.26)
17.5
1.00 (–0.75 to 2.75) 18.5
0.30 (–0.53 to 1.13) 20.7
–0.30 (–3.05 to 2.45) 15.3
2.20 (–2.61 to 7.01)
9.6
3.10 (–0.84 to 7.04) 11.7
2.09 (0.09 to 4.09) 100.0
–7.5
0
7.5
Mean difference
Increase weight in typicals Increase weight in atypicals
Fig. 4
Comparison of weight gain between the two groups.
Data expressed in kilograms, and pooled using random-effects model. Significant
weight gain found in atypical group (P = 0.04). Heterogeneity w2 = 29.79 (d.f. = 6)
P50.001, I 2 = 79.9%. EPGN, Early Psychosis Global Network; GRNS, German Research
Network on Schizophrenia; EUFEST, European First-Episode Schizophrenia Trial.
Atypical v. typical antipsychotics in the treatment of early psychosis
Standardised mean difference
(95% CI)
% Weight
Study
...
...
...
...
...
...
...
...
...
...
...
...
...
...
...
.
Emsley24
Sanger13
Glenthøj39
Lieberman36
HGDH38
EPGN26
Crespo-Facorro28
GRNS30
EUFEST22
Overall
–2.5
–0.25
–0.97
–1.06
–0.13
–0.41
–0.37
–0.53
–0.21
–0.37
–0.38
(–0.54
(–1.47
(–2.05
(–0.44
(–0.65
(–0.74
(–0.85
(–0.53
(–0.82
(–0.53
to
to
to
to
to
to
to
to
to
to
0.04) 14.6
–0.47) 7.0
–0.08) 2.1
0.18) 13.6
–0.17) 17.6
0.00) 10.7
–0.20) 12.9
0.11) 13.1
0.07)
8.4
–0.24) 100.0
0
0.5
Standardised mean difference
Favours atypicals
Favours typicals
Fig. 5 Extrapyramidal side-effects in both groups using
standardised mean differences.
A highly significant difference favouring atypicals was found (P50.001). Note that all
individual trials favour atypicals. Heterogeneity w2 =12.3 (d.f. = 8) P = 0.14, I 2 = 35%.
EPGN, Early Psychosis Global Network; GRNS, German Research Network on
Schizophrenia; EUFEST, European First-Episode Schizophrenia Trial.
questionnaire to assess the subjective experience of extrapyramidal
signs. In order to make these different scales comparable, only
parkinsonism scores were extracted from these two scales when
possible, and effect sizes were standardised. This was not possible
in one study which reported global ESRS39 and in another one in
which we used total ESRS at end-point (24 months) of observed
cases provided by one of the authors.26 We repeated this analysis
excluding them. It should be noted that the results of this analysis
apply to parkinsonism and not necessarily to other extrapyramidal
symptoms such as akathisia. We found a significant advantage of
atypicals over typicals as shown in Fig. 5 (s.d. = 70.38 favouring
atypicals, P50.001). Heterogeneity using chi-squared was not
statistically significant (P = 0.14), and a fixed-effects analysis left
the results substantially unchanged (s.d. = 70.37, 95% CI 70.48
to 70.25). Meta-regression analyses looking at dose of typical
antipsychotics, amount of time exposed, and proportion of
individuals receiving risperidone or amisulpride did not produce
any statistically significant results. Exclusion of the two studies
from which global ESRS scores were used did not substantially
change the results.
Discussion
Main findings
We did not find a significant difference between atypical and
typical antipsychotics in discontinuation rates. Discontinuation
seems an appealing concept reflecting both efficacy of a drug
and side-effects, but unfortunately there does not appear to be a
consensus defining what exactly discontinuing a drug is:
definitions of discontinuation ranged from irregularities in the
adherence to a medication regime (e.g., taking lower doses of
the assigned antipsychotic than prescribed for a period of 2 weeks
as in Kahn et al)22 to total discontinuation of the study drug (as in
Schooler et al)26 in the studies included in this meta-analysis. It is
possible that a number of factors underpin these variations in
what is defined as ‘discontinuation’ and this could be one of the
causes of the significant statistical heterogeneity present in that
comparison. Since only one study explicitly defined discontinuation in the context of being the primary outcome,22 we were
not able to analyse whether variation in the definition of discontinuation had an effect on the pooled outcome.
We found no significant difference between atypical and
typical antipsychotics in acute symptomatic effect. Individuals
with first-episode psychosis usually show a good symptomatic
response to antipsychotic treatment,11 and this may have
introduced a ceiling effect that complicated comparisons.
However, even if additional studies had been included such that
the power of the analysis was increased, the estimated effect size
of s.d. = 0.1 (equivalent to two points on the PANSS scale using
the variance found in the biggest study included)26 suggests that
even if a significant difference could be identified it may not be
clinically meaningful. A previously published study found that a
one-step change in the Clinical Global Improvement scale
(allegedly a more ‘clinically meaningful’ scale) required a 15-point
change on the PANSS.40 A meta-analysis of treatment in chronic
schizophrenia found an advantage for atypicals only when
compared with high doses of typicals.1 In the present study,
although the doses of typical antipsychotics prescribed in the
studies we analysed were low, there was a similar trend for
atypicals to be superior when the comparison involved higher
doses of typicals. Although this observation was not significant,
it supports the notion that when using typical antipsychotics in
individuals with a first episode, lower doses of medication are
indicated compared with individuals with chronic schizophrenia.
Although there were no significant differences between
atypicals and typicals in discontinuation rates or symptom
control, we did find differences in their side-effect profile. In line
with previous studies41,42 our meta-analysis found that, on
average, participants prescribed an atypical antipsychotic would
gain 2 kg more than those on typicals, whereas those prescribed
a typical antipsychotic would rate 0.4 standard deviations higher
in the extrapyramidal scales (e.g. approximately one extra point
in the SAS if using the data from one of the studies included).28
We did not find a correlation between these findings and the
use of specific atypical drugs that have been particularly
associated with weight gain or extrapyramidal side-effects. This
does not mean we can exclude any differences between the
atypicals in their side-effect profiles in first-episode participants
as this meta-analysis was not designed to look at within-class
differences, and our meta-regression analysis was probably
underpowered. As most of the studies we analysed included
haloperidol, there is a possibility that the difference in extrapyramidal side-effects between atypicals and low-potency typical
antipsychotics is less marked, as is the case in people with chronic
schizophrenia.2
Future research
This meta-analysis leaves many questions unanswered. First, it
would have been interesting to look at differences in relapse rates
between atypicals and typicals. We decided not to pool this
outcome as there were too few studies reporting it. From the
long-term studies included in this meta-analysis, three reported
relapse rates in participants who achieved remission26,30,38 and
one reported readmissions to hospital in participants recruited
from an in-patient unit.36 Of these four, three reported no
significant differences.30,36,38 The other trial,26 which was the
largest and longest, reported significantly lower relapse rates with
risperidone compared with haloperidol (42.1% v. 54.7%
respectively), even though no differences were found in remission
and medication adherence. As relapse is an important determinant
of long-term outcome, this should be a serious consideration in
the choice of antipsychotic. Further large long-term studies would
be needed to verify this study’s findings. Second, some of the most
important risks with antipsychotics such as diabetes (seen with
some atypicals) or tardive dyskinesia (commonly seen with
437
Crossley et al
typicals) usually appear after years of exposure to these
medications. This makes it exceedingly unlikely that this will ever
be studied using randomised controlled trials. However, these
serious long-term outcomes should also be considered when
deciding upon maintenance medication. Changes in glucose and
lipid blood levels with antipsychotic medication could be seen
as an intermediate outcome in metabolic complications, but the
small proportion of studies reporting this outcome from the
included studies discouraged us to perform a meta-analysis.
Recent criticisms have been raised about the validity of
atypical antipsychotics as a group.43,44 This is backed mostly by
two recent meta-analyses by Leucht et al, who reported differences
within the atypical antipsychotics45 and also when compared with
typical antipsychotics.4 As already mentioned, our meta-analysis
was not designed to look at differences within the atypical antipsychotics. Nevertheless, it should be noted that almost all the
drugs included in this meta-analysis were those that were reported
as more effective than their comparisons for chronic
schizophrenia in the above mentioned studies (namely olanzapine,
risperidone, clozapine and amisulpride).
4 Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation
versus first-generation antipsychotic drugs for schizophrenia: a metaanalysis. Lancet 2009; 373: 31–41.
5 Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO,
et al; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE)
Investigators. Effectiveness of antipsychotic drugs in patients with chronic
schizophrenia. N Engl J Med 2005; 353: 1209–23.
6 Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, et al.
Randomized controlled trial of the effect on Quality of Life of second- vs firstgeneration antipsychotic drugs in schizophrenia: Cost Utility of the Latest
Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry
2006; 63: 1079–87.
7 Rosenheck RA, Leslie DL, Sindelar J, Miller EA, Lin H, Stroup TS, et al; CATIE
Study Investigators. Cost-effectiveness of second-generation antipsychotics
and perphenazine in a randomized trial of treatment for chronic
schizophrenia. Am J Psychiatry 2006; 163: 2080–9.
8 Davies LM, Lewis S, Jones PB, Barnes TRE, Gaughran F, Hayhurst K, et al;
CUtLASS team. Cost-effectiveness of first- v. second-generation antipsychotic
drugs: results from a randomised controlled trial in schizophrenia responding
poorly to previous therapy. Br J Psychiatry 2007; 191: 14–22.
9 Large M, Farooq S, Nielssen O, Slade T. Relationship between gross domestic
product and duration of untreated psychosis in low- and middle-income
countries. Br J Psychiatry 2008; 193: 272–8.
10 Lewis S, Lieberman J. CATIE and CUtLASS: can we handle the truth?
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Implications
This meta-analysis revealed no significant differences between
typical and atypical antipsychotics in discontinuation rates or in
short-term symptomatic response in individuals with first-episode
psychosis. However, treatment with atypical antipsychotics was
associated with relatively more weight gain, whereas treatment
with typicals was associated with a greater incidence of extrapyramidal side-effects. Choice of antipsychotic drug in the
treatment of first-episode psychosis may thus be more influenced
by side-effect profile than efficacy.
Nicolas A. Crossley, MRCPsych, MSc, Miguel Constante, MRCPsych, Division of
Psychological Medicine, Institute of Psychiatry, London; Philip McGuire, FRCPsych,
PhD, Division of Psychological Medicine, Institute of Psychiatry, and Outreach and
Support in South London (OASIS), South London and Maudsley NHS Foundation Trust,
London; Paddy Power, MRCPsych, FRANZCP, MD, Division of Psychological
Medicine, Institute of Psychiatry, and Lambeth Early Onset Services (LEO), South
London and Maudsley NHS Foundation Trust, London, UK
Correspondence: Nicolas A. Crossley, Division of Psychological Medicine,
Institute of Psychiatry PO 67, De Crespigny Park, London SE5 8AF. Email:
[email protected]
First received 17 Mar 2009, final revision 2 Dec 2009, accepted 17 Feb 2010
11 Robinson DG, Woerner MG, Alvir JM, Geisler S, Koreen A, Sheitman B, et al.
Predictors of treatment response from a first episode of schizophrenia or
schizoaffective disorder. Am J Psychiatry 1999; 156: 544–9.
12 Oosthuizen P, Emsley R, Jadri Turner H, Keyter N. A randomized,
controlled comparison of the efficacy and tolerability of low and high
doses of haloperidol in the treatment of first-episode psychosis.
Int J Neuropsychopharmacol 2004; 7: 125–31.
13 Sanger TM, Lieberman JA, Tohen M, Grundy S, Beasley Jr C, Tollefson GD.
Olanzapine versus haloperidol treatment in first-episode psychosis.
Am J Psychiatry 1999; 156: 79–87.
14 Smith M, Hopkins D, Peveler RC, Holt RIG, Woodward M, Ismail K. First- v.
second-generation antipsychotics and risk for diabetes in schizophrenia:
systematic review and meta-analysis. Br J Psychiatry 2008; 192: 406–11.
15 Cotton SM, Lambert M, Schimmelmann BG, Foley DL, Morley KI, McGorry PD,
Conus P. Gender differences in premorbid, entry, treatment, and outcome
characteristics in a treated epidemiological sample of 661 patients with first
episode psychosis. Schizophr Res 2009; 114: 17–24.
16 Rummel C, Hamann J, Kissling W, Leucht S. New generation antipsychotics
for first episode schizophrenia. Cochrane Database Syst Rev 2003; 4:
CD004410.
17 National Institute for Health and Clinical Excellence. Schizophrenia. NICE
Clinical Guideline 82. NICE, 2009 (http://www.nice.org.uk/nicemedia/pdf/
CG82NICEGuideline.pdf).
18 Emsley R, Rabinowitz J, Medori R. Time course for antipsychotic treatment
response in first-episode schizophrenia. Am J Psychiatry 2006; 163: 743–5.
Funding
N.A.C. is in receipt of an Academic Training Fellowship from the National Institute of Health
Research, UK.
19 Robinson DG, Woerner MG, Delman HM, Kane JM. Pharmacological
treatments for first-episode schizophrenia. Schizophr Bull 2005; 31:
705–22.
20 DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials
1986; 7: 177–88.
Acknowledgements
21 Egger M, Davey Smith G. Systematic Reviews in Health Care: Meta-analysis
in Context (2nd edn). BMJ Publishing Group, 2001.
We are grateful to Dr Han Boter, Dr Warrick Brewer, Dr Juan Bustillo, Professor Robin
Emsley, Professor Wolfgang Gaebel, Dr Ragy Girgis, Dr Birte Glenthøj, Professor Rene Kahn,
Mr Keith Karcher, Professor Jeffrey Lieberman, Professor Jonathan Rabinowitz and Dr
Mathias Riesbeck who provided unpublished data to the authors and clarified all the doubts
we had. We would also like to thank Dr Daniel Stahl for statistical advice.
22 Kahn RS, Fleischhacker WW, Boter H, Davidson M, Vergouwe Y, Keet IP, et al;
EUFEST study group. Effectiveness of antipsychotic drugs in first-episode
schizophrenia and schizophreniform disorder: an open randomised clinical
trial. Lancet 2008; 371: 1085–97.
23 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis
detected by a simple, graphical test. BMJ 1997; 315: 629–34.
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On therapy
Ramy Daoud
I worked in medicine for many years before I was drawn to psychiatry. My encounters with patients with physical ailments prefigured
those encounters I would have as a psychiatrist. The cognition of pain. The search for meaning. The elicitation of a story. The laying of
hands on where it hurts. The re-cognition of pain. Sometimes I would cut it out. Sometimes I would cover it up. Sometimes I could do
neither. In these instances, I am reminded of Mural by the Palestinian poet of exile, Darwish. I find it quite a haunting piece, lingering in
the back of my mind before, during, between sessions with patients. A patient knocks at the door of therapy. Therapy: ‘the dialogue of
dreamers’ where the patient ‘shuns body and self . . . to finish that first journey towards meaning, which burnt me, and disappeared.’
Disappeared into absence and no space, where ‘nothing hurts at the door of doom’. In no space, and no time, that insistent voice
says ‘one day I shall become . . .’. And they come, knocking at the door of therapy. Therapy is a space-time, an en-closure
where dis-closure unfolds through language/thoughts (‘one day I shall become a thought’), that threatens to ‘split [the patient’s nascent sense of being like] a burgeoning blade of grass’. A battle-field, between ‘neither being nor nothingness’. Therapy, language, the
act of re-telling one’s story seems to me like a sword ‘wresting being from non-being’, that promises an ‘epiphany’. That epiphany
that comes on the wings of the words: ‘This is your name’. Darwish’s ‘epiphany’ reminds me of Heidegger’s Da-sein and the ecstasy
of temporality. Being which temporalises itself yet unites past, present and future ‘selves’. I believe Darwish wishes to leave this activity of being open: ‘I know this epiphany, and know I’m on my way towards what I don’t know’.
Ramy Daoud is specialty registrar in general adult psychiatry, East Cornwall Community Mental Health Team.
The British Journal of Psychiatry (2010)
196, 439. doi: 10.1192/bjp.196.6.439
439
DSM–IV schizophrenia or schizophreniform All antipsychotic naive
(up to 14 days of antipsychotics
disorder aged 16–40 years and current
psychotic symptoms of moderate severity or allowed)
greater measured by one of the five psychotic
items in BPRS; history of psychosis less than 60
months, no prior treatment with antipsychotic
medication or a total lifetime usage of 514
days
DSM–IV schizophrenia aged 17–28 years
admitted to adolescent clinic specialising
in recent-onset schizophrenia
74% receiving antipsychotic for
DSM–IV schizophrenia, schizophreniform
mean time of 5.9 weeks
disorder, or schizoaffective disorder aged
Rest antipsychotic naive
16–40 years (onset before 35 years),
experienced psychotic symptoms for at least
1 month, scored 54 on at least two PANSS
items or scored 55 on one psychosis item,
had a CGI severity score 54 (moderately ill)
and required treatment with antipsychotic
drugs on a clinical basis; history of psychosis
560 months
31% antipsychotic naive
DSM–IV schizophrenia, schizophreniform
disorder, or schizoaffective disorder aged
16–45 years requiring antipsychotic treatment
upon enrolment; history of psychosis for
51 year, less than 12 weeks of cumulative
exposure to antipsychotics and no more than
two psychiatric hospitalisations for psychosis
DSM–IV schizophrenia aged 18–45 years;
first episode of psychosis, no previous
antipsychotic exposure
Lieberman (2003)36
De Haan (2003)33
HGDH Study Group
(2003)34,38,50–52
Early Psychosis Global
Network (EPGN) (2006)26
Wu (2006)27,37
All antipsychotic naive
Duration of illness of 16.5 months
(mean), but unclear duration of
treatment
All antipsychotic naive
ICD–10 schizophrenia; antipsychotic-naive
patients on their first admission to hospital
Mackeprang
(2002–2007)25,39,47
15/10
59/4
99/84
Recruited
atypical/
typical, n
278/277
131/132
12/12
Clozapine 275.6 mg, olanzapine
83/29
13.7 mg, risperidone 4.2 mg/sulpiride
733 mg
Risperidone 3.3 mg/haloperidol
2.9 mg
Olanzapine 9.1 mg in acute phase,
10.2 mg in continuation phase/
haloperidol 4.4 mg in acute phase,
4.8 mg in continuation phase
Olanzapine 7.5 mg/haloperidol
2.5 mg (fixed doses)
Clozapine plus placebo 400 mg at
80/80
12 weeks, then 300mg/chlorpromazine
plus benztropine 600 mg at 12 weeks,
then 400 mg (median)
Risperidone 3.6 mg/zuclopenthixol
9.6 mg
Olanzapine 11.6 mg/haloperidol
10.8 mg
Duration of treatment for psychosis
DSM–III–R schizophrenia, schizophreniform
of 13 months (mean)
disorder, or schizoaffective disorder, with
BPRS 418 or intolerance of current antipsychotic therapy and aged 418 years; first
episode of psychosis with a duration of less
than 5 years and before 45 years of age
Interventions and doses received
(means reported if otherwise not
stated)
Sanger (1999)13
Duration of psychosis in treatment
or % antipsychotic naive
DSM–III schizophrenia or schizophreniform
No previous antipsychotic treatment Risperidone 6.1 mg/haloperidol
aged 15–45 years; no previous antipsychotic (up to 3 days of emergency
5.6 mg
treatment
treatment allowed)
Inclusion criteria (diagnosis; definition
of early psychosis)
Studies included in analysis
Risperidone Working
Group (1999)24
Studya
Table DS1
Described as ‘double-blind’, and authors
confirmed that allocation, masking and
treatment was concealed
LTF of 6% reported at 24 months
Unclear if allocation was concealed,
described as ‘double-blind’
17% dropped out
Described as ‘double-blind’, and authors
confirmed that allocation, masking and
treatment was concealed
12% of the participants reported to have
dropped out
Unclear if allocation was concealed, ‘open
labelled’
LTF 19%
Subsample analysis of randomised
controlled trial
Unclear if allocation was concealed,
described as ‘double-blind’
Original study reported 1.3% of sample
was lost to follow-up49
Unclear if allocation was concealed,
described as ‘double-blind’
25% reported as non-completers
Quality (concealment of sequence
of allocation, masking, loss to follow-up
or number dropped out reported)
8 weeks
(continued)
Adequate concealment of allocation,
unmasked
7% dropped out
Unclear if allocation was concealed,
Follow-up
described as ‘double-blind’
continued until
LTF of 7% reported
last participant
enrolled had
completed 2 years
of treatment
24 months
6 weeks
52 weeks
13 weeks
6 weeks
6 weeks
Length
of study
The British Journal of Psychiatry (2010)
196, 434–439. doi: 10.1192/bjp.bp.109.066217
Data supplement
1
2
33% antipsychotic naive
Antipsychotic naive
17/15
Olanzapine 12.6 mg, ziprasidone
395/103
107.2 mg, quetiapine 498.6 mg,
amisulpride 450.8 mg/haloperidol 3 mg
Quetiapine 100–600 mg/haloperidol
2–12 mg (range allowed)
68/31
10/10
12 months
2 years
6 weeks
8 weeks
146/143 in 2 years
acute phase,
83/75 in
continuation
phase
8 weeks
12 months
116/56
3/4
Length
of study
Recruited
atypical/
typical, n
LTF, lost to follow-up; BPRS, Brief Psychiatric Rating Scale; PANSS, Positive and Negative Syndrome Scale; CGI, Clinical Global Impression; SAPS, Scale for the Assessment of Positive Symptoms.
a. All references from each selected trial are shown (additional references are cited below).49–59
DSM–IV schizophrenia, schizophreniform
disorder, or schizoaffective disorder aged
18–40 years; <2 years of onset of positive
symptoms and lifetime exposure of
antipsychotics of less than 2 weeks in the
last year or 6 weeks at any time
DSM–IV schizophrenia, schizoaffective or
47% antipsychotic naive
schizophreniform disorder; less than 3 weeks
lifetime exposure to antipsychotics.
Bustillo (2008)35,59
European First-Episode
Schizophrenia Trial
(EUFEST) (2008)22
DSM–IV schizophrenia; antipsychotic naive
Saddichha (2008)32,55–58
Risperidone 4.4 mg and olanzapine
16.5 mg/haloperidol 13.4 mg
Risperidone 4.1 mg/haloperidol
7.6 mg
DSM–IV schizophrenia, antipsychotic naive
Lee (2007)31,54
Antipsychotic naive
Risperidone 3.8 and 4.2 mg/
haloperidol 3.7 mg and 4.1 mg
(both in the acute and continuation
phase respectively)
German Research Network ICD–10 schizophrenia aged 18–60 years;
57% of the participants had an onset
on Schizophrenia (GRNS) participants in their first in-patient treatment of psychosis less than 6 months
(2007)30,48
of psychotic symptoms
before study entry, but unclear
duration of treatment
Risperidone 2 mg/haloperidol 2 mg
(fixed doses)
First episode of psychosis defined as onset All antipsychotic naive
between 16 and 30 years of at least one of the
following: (a) delusions; (b) hallucinations;
(c) disorder of thinking/speech, other than
simple acceleration or retardation; and
(d) disorganised, bizarre, or markedly
inappropriate behaviour, without previous
antipsychotic treatment.
Diagnosis of schizophrenia DSM–IV was
confirmed at 6 months
Interventions and doses received
(means reported if otherwise not
stated)
Brewer 200729
Duration of psychosis in treatment
or % antipsychotic naive
All antipsychotic naive or with a total Risperidone 4 mg, olanzapine
DSM–IV schizophreniform, schizophrenia,
lifetime exposure of <6 weeks
15.3 mg and haloperidol 5.4 mg
schizoaffective, brief reactive psychosis,
in acute phase
schizotypal personality disorder, psychosis
Risperidone 3.6 mg, olanzapine
not otherwise specified aged 15–60 years, with
10.1 mg and haloperidol 2.9 mg at
SAPS psychotic symptoms moderate severity
1 year
or greater; antipsychotic naive or total lifetime
exposure of less than 6 weeks
Inclusion criteria (diagnosis; definition
of early psychosis)
(continued)
Crespo-Facorro
(2006)28,46,53
Studya
Table DS1
Adequate concealment of allocation
sequence, unmasked
LTF 31%
Unclear if allocation was concealed,
reported to be ‘double-blind’
LTF 28%
Unclear if allocation was concealed,
described as ‘double-blind’
Unclear if allocation was concealed,
described as ‘double-blind’
Described as ‘double-blind’, and authors
confirmed that allocation, masking and
treatment was concealed
49% reported to have dropped out in the
acute phase, 68.2% in continuation trial
(including discontinuation of drug)
Unclear if allocation was concealed,
described as ‘double-blind’
LTF 12.5%
Unclear if allocation was concealed,
unmasked
LTF 11%
Quality (concealment of sequence
of allocation, masking, loss to follow-up
or number dropped out reported)
Additional references
49 Tollefson GD, Beasley Jr CM, Tran PV, Street JS, Krueger JA, Tamura RN, et al.
Olanzapine versus haloperidol in the treatment of schizophrenia and
schizoaffective and schizophreniform disorders: results of an international
collaborative trial. Am J Psychiatry 1997; 154: 457–65.
50 Green AI, Tohen MF, Hamer RM, Strakowski SM, Lieberman JA, Glick I, et al.
First episode schizophrenia-related psychosis and substance use disorders:
acute response to olanzapine and haloperidol. Schizophr Res 2004; 66:
125–35.
51 Zipursky RB, Christensen BK, Daskalakis Z, Epstein I, Roy P, Furimsky I, et al.
Treatment response to olanzapine and haloperidol and its association with
dopamine D receptor occupancy in first-episode psychosis. Can J Psychiatry
2005; 50: 462–9.
52 Zipursky RB, Gu H, Green AI, Perkins DO, Tohen MF, McEvoy JP, et al. Course
and predictors of weight gain in people with first-episode psychosis treated
with olanzapine or haloperidol. Br J Psychiatry 2005; 187: 537–43.
53 Perez-Iglesias R, Crespo-Facorro B, Amado JA, Garcia-Unzueta MT,
Ramirez-Bonilla ML, Gonzalez-Blanch C, et al. A 12-week randomized clinical
trial to evaluate metabolic changes in drug-naive, first-episode psychosis
patients treated with haloperidol, olanzapine, or risperidone. J Clin Psychiatry
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54 Lee SM, Chou YH, Li MH, Wan FJ, Yen MH. Effects of haloperidol and
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55 Saddichha S, Ameen S, Akhtar S. Incidence of new onset metabolic
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56 Saddichha S, Manjunatha N, Ameen S, Akhtar S. Effect of olanzapine,
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57 Saddichha S, Ameen S, Akhtar S. Predictors of antipsychotic-induced weight
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OR setous OR majorpin OR clozapine OR clozaril OR leponex)
OR ("Antipsychotic Agents"[Mesh] OR "Antipsychotic Agents
"[Pharmacological Action] OR "Risperidone"[Mesh] OR
"olanzapine "[Substance Name] OR "olanzapine-fluoxetine
combination "[Substance Name] OR "9-hydroxy-risperidone
"[Substance Name] OR "Dopamine Antagonists"[Mesh] OR
"Molindone"[Mesh]) OR "typical antipsychotic*" OR "atypical
antipsychotic*")) AND (("first episode" OR "first onset" OR "early
onset" OR naive OR "never medicated")) AND (((psychosis OR
psychotic OR schizophreni* OR schizoaffective) OR
"Schizophrenia and Disorders with Psychotic Features"[Mesh]))
EMBASE
(exp DEPRESSIVE PSYCHOSIS/ or exp MANIC DEPRESSIVE
PSYCHOSIS/ or exp PARANOID PSYCHOSIS/ or exp
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SCHIZOPHRENIA/ or SCHIZOPHRENIFORM DISORDER/ or
(schizophrenic or schizophrenics).mp. [mp=title, abstract, subject
headings, heading word, drug trade name, original title, device
manufacturer, drug manufacturer name]) AND (("first episode"
or naive or "never medicated" or (never adj3 (antipsychoti$ or
neurolepti$))).mp. [mp=title, abstract, subject headings, heading
word, drug trade name, original title, device manufacturer, drug
manufacturer name]) AND (exp Ziprasidone/ or exp Quetiapine/
or exp Olanzapine/ or exp Risperidone/ or exp ATYPICAL
ANTIPSYCHOTIC AGENT/ or antipsychotics.mp. or exp
Clozapine/ or (risperidon$ or quetiapin$ or clozapin$ or
olanzapin$ or ziprasidon$).mp. [mp=title, abstract, subject
headings, heading word, drug trade name, original title, device
manufacturer, drug manufacturer name]) AND (Randomized
Controlled Trial/ or random$.mp. [mp=title, abstract, subject
headings, heading word, drug trade name, original title, device
manufacturer, drug manufacturer name])
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PubMed
PsycINFO
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OR randomized controlled trials[mh] OR random allocation[mh]
OR double-blind method[mh] OR single-blind method[mh] OR
clinical trial[pt] OR clinical trials[mh] OR ("clinical trial"[tw])
OR ((singl*[tw] OR doubl*[tw] OR trebl*[tw] OR tripl*[tw])
AND (mask*[tw] OR blind*[tw])) OR (placebos[mh] OR placebo*[tw] OR random*[tw] OR research design[mh:noexp] OR follow-up studies[mh] OR prospective studies[mh] OR control*[tw]
OR prospectiv*[tw] OR volunteer*[tw]) NOT (animals[mh] NOT
human[mh]))) AND (((amisulprid* OR amitrex OR deniban* OR
socian* OR solian* OR sulanid* OR sulamid* OR zyprex* OR
olanzapin* OR quetiapine OR seroquel OR ICI-204636 OR (ICI
and 204636) OR ICI204636 OR risperidone OR risperdal OR 9OH-risperidone OR ziprasidone OR cp-88059 OR abilit OR
championyl OR coolspan OR col-sulpir OR digton OR dixibon
OR dobren OR dogmatil OR dolmatil OR drominetas OR eglonyl
OR equilid OR eusulpid OR guastil OR isnamid OR kapiride OR
lavodina OR lebopride OR lusedan OR miradol OR mirbanil OR
misulvan OR neuromyfar OR normum OR omperan OR psicocen
OR quiridil OR sato OR sernevin OR sicofrenol OR sulpiride OR
sulpisedan OR suprium OR sursumid OR tepavil OR tonofit OR
ulpir OR vipral OR zotepine OR lodopin OR nipolept OR zopite
(exp DEPRESSIVE PSYCHOSIS/ or exp MANIC DEPRESSIVE
PSYCHOSIS/ or exp PARANOID PSYCHOSIS/ or exp
SCHIZOAFFECTIVE PSYCHOSIS/ or exp MANIC PSYCHOSIS/
or exp AFFECTIVE PSYCHOSIS/ or exp ENDOGENOUS
PSYCHOSIS/ or exp ACUTE PSYCHOSIS/ or psychosis.mp. or
exp PSYCHOSIS/ or schizophrenia.mp. or exp SIMPLE
SCHIZOPHRENIA/ or exp PARANOID SCHIZOPHRENIA/ or
exp SCHIZOPHRENIA/ or exp CATATONIC SCHIZOPHRENIA/
or exp RESIDUAL SCHIZOPHRENIA/ or exp LATENT
SCHIZOPHRENIA/ or SCHIZOPHRENIFORM DISORDER/ or
(schizophrenic or schizophrenics).mp. [mp=title, abstract,
heading word, table of contents, key concepts]) AND (("first
episode" or naive or "never medicated" or (never adj3
(antipsychoti$ or neurolepti$))).mp. [mp=title, abstract, heading
word, table of contents, key concepts]) AND (exp Ziprasidone/
or exp Quetiapine/ or exp Olanzapine/ or exp Risperidone/ or
exp ATYPICAL ANTIPSYCHOTIC AGENT/ or antipsychotics.mp.
or exp Clozapine/ (risperidon$ or quetiapin$ or clozapin$ or
olanzapin$ or ziprasidon$).mp. [mp=title, abstract, heading word,
table of contents, key concepts]) AND (Randomized Controlled
Trial/ or random$.mp. [mp=title, abstract, heading word, table
of contents, key concepts])
3
COCHRANE
(MeSH descriptor Psychotic Disorders explode all trees OR
(psychosis OR psychotic OR schizophreni* OR schizoaffective))
AND ("first episode" OR "first onset" OR "early onset" OR naive
OR "never medicated") AND (amisulprid* OR amitrex OR
deniban* OR socian* OR solian* OR sulanid* OR sulamid* OR
zyprex* OR olanzapin* OR quetiapine OR seroquel OR ICI204636 OR (ICI and 204636) OR ICI204636 OR risperidone OR
risperdal OR 9-OH-risperidone OR ziprasidone OR cp-88059
OR abilit OR championyl OR coolspan OR col-sulpir OR digton
OR dixibon OR dobren OR dogmatil OR dolmatil OR drominetas
OR eglonyl OR equilid OR eusulpid OR guastil OR isnamid OR
kapiride OR lavodina OR lebopride OR lusedan OR miradol
OR mirbanil OR misulvan OR neuromyfar OR normum OR
omperan OR psicocen OR quiridil OR sato OR sernevin OR sicofrenol OR sulpiride OR sulpisedan OR suprium OR sursumid OR
tepavil OR tonofit OR ulpir OR vipral OR zotepine OR lodopin
OR nipolept OR zopite OR setous OR majorpin OR clozapine
OR clozaril OR leponex OR "Antipsychotic Agents" OR
"Antipsychotic Agents " OR "Risperidone" OR "olanzapine " OR
"olanzapine-fluoxetine combination " OR "9-hydroxy-risperidone
" OR "Dopamine Antagonists" OR "Molindone" OR "typical
antipsychotic*" OR "atypical antipsychotic*")
4
Efficacy of atypical v. typical antipsychotics in the treatment of
early psychosis: meta-analysis
Nicolas A. Crossley, Miguel Constante, Philip McGuire and Paddy Power
BJP 2010, 196:434-439.
Access the most recent version at DOI: 10.1192/bjp.bp.109.066217
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Published by The Royal College of Psychiatrists
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