Review of British Journal of Psychiatry publication by Siskind et. al. in 2022 entitled 'Rates of Treatment-Resistant Schizophrenia from First-Episode Cohorts: Systematic Review and Meta-Analysis', presented by Dr. Robert Ferris and Dr. Daere Akobo. Note: uploading to SlideShare causes disruption of slide layout, creating text overlap. Original layout visible on download. Sources for all imagery and resources listed in references section. I do not claim ownership of any images or graphics. Slides for educational purposes only, and should not replace clinical judgement. No monetary gain was made for this work.

1. SCHIZOPHRENIA FROM FIRST-
EPISODE
COHORTS: SYSTEMATIC REVIEW
AND
META-ANALYSIS
Dr. Robert Ferris & Dr. Daere Akobo
Journal Review

2. Background
 Lifetime prevalence of schizophrenia is 7 per
1000 people6
 Not all patients respond to 1st line
antipsychotic medication; poor response to
treatment leads to a diagnosis of Treatment-
Resistant Schizophrenia (TRS)
 TRS is associated with high levels of
functional impairment8, healthcare usage,
societal costs9 and physical health
comorbidity10

3. Background
 A consensus definition of TRS has been
developed by the Treatment-Resistant
Schizophrenia: Treatment Response and
Resistance in Psychosis (TRRIP) Working
Group3, which includes the following:
 Current symptoms of at least moderate severity
and moderate or worse functional impairment
 Prior treatment with at least two different
antipsychotics, each for at least 4–6 weeks
minimum duration at total daily dose equivalent of
at least 600mg chlorpromazine

4. Treatment-Resistant Schizophrenia
(TRS)
 There remains a lack of clarity as to the proportion of
patients with TRS
 The most effective medication for TRS is clozapine,
which offers
 Improvement in positive symptoms7
 Improved rates of hospital admissions11
 Decreased overall mortality12
 Clozapine use, due to its potential adverse-effects, is
typically limited to patients who have had ≥2 previous
failed responses to first-line antipsychotics
 Implementation of clozapine therapy is, therefore,
sometimes regarded as an indicator of TRS1
 Regional differences in rates of clozapine prescribing
negatively affects its use as a proxy for TRS rates

5. The Study1

6. The Study1
 Quantifying the rates of patients with TRS may
highlight the need to improve access to clozapine and
increase opportunities of a clozapine trial for patients
with TRS
 Cross-sectional studies examining the proportion of
patients with TRS may overestimate the true rate
because of selection bias
 In contrast, longitudinal first-episode cohort studies
may more accurately quantify the incidence of
patients with TRS
 However, first-episode cohort studies from single sites may
not be generalisable
 Combination of first-episode cohorts from multiple sites
provides more robust data set

7. The Study1
 Literature was systematically reviewed with
this in mind
 Longitudinal cohort studies of people with First-
Episode Psychosis (FEP) and First-Episode
Schizophrenia (FES)
 The proportion that met criteria for TRS at
follow-up were identified, then meta-analysis
was performed in order to quantify rates of
TRS

8. Inclusion Criteria
 Cohort studies of individuals with FEP or FES
who were diagnosed according to DSM-IV,
DSM-5 or ICD-10 classifications
 Presence of clear definition of (TRS)
consistent with the TRRIP Working Group’s
standardised definition3
 Presence of longitudinal information on
pharmacological interventions
 Reports on the proportion of the FEP/FES
population who went on to develop a
treatment-resistant form of the illness
 Follow-up period of at least 8 weeks

9. Exclusion Criteria
 Papers with >75% overlap of included data-sets
with another paper
 Study populations which had already been
exposed to previous antipsychotic treatment
before entry into the cohort
 Where substance-induced psychosis could not be
excluded at time of follow-up
 Study designs that did not specifically capture all
sequential first-episode patients, such as cross-
sectional or randomised controlled trials, were
excluded as it could not be ascertained if the
criteria for participation in these studies
constituted a selection bias

10. Methodology
 Systematic review and meta-analysis
 8,273 citations, ultimately yielding 12 clinical
trials deemed fit for inclusion, including 1
unpublished data set
 These studies covered a total of 11,958
individuals
 Studies from Canada (n = 2), Denmark (n = 1),
England (n = 2), Japan (n = 1), Turkey (n = 1),
India (n = 1), USA (n = 1) and Ireland (n = 1);
two studies had multiple international locations
 Proportion of male study participants was 61.9%
(SD 10.4%)

11. Methodology
 Median duration of follow-up 26 months
(range 2–120 months)
 Nine cohorts comprised participants with
FES and three cohorts comprised
participants with FEP
 Nine studies used prospective data
collection; data for the remaining three was
collected retrospectively
 Two studies provided data on involuntary
treatment status

12. Included Trials

13. Data Extraction and Publication
Bias
 Two authors independently extracted data,
which was validated by two other authors from
the research team
 Publication bias was explored using funnel pot
asymmetry testing for statistical significance
with both Kendall’s τ and Egger’s regression
when meta-analyses included ≥10 studies

14. Results
 Overall rate of TRS was 22.8% (95% CI
19.1–27.0%, P < 0.001, I2 = 91.8%)
 Rates of TRS were significantly lower in FEP
cohorts compared with FES cohorts (17.8%
vs. 24.4%, P = 0.046)

15. Results

16. Discussion
 Rate of TRS was 22.8% in combined FEP
and FES cohorts, rising to 24.4% when only
FES cohorts included
 Rates of TRS were significantly lower in FEP
cohorts compared with FES cohorts (17.8%
vs. 24.4%, P = 0.046)

17. Discussion
 Men 1.5 times as likely as women to develop
TRS (95% CI 1.11–2.21, P = 0.010, I2 = 74%)
 In keeping with previous findings that men are one and
a half times more likely to develop schizophrenia than
women4
 Males generally diagnosed at a younger age5

18. Critical Appraisal
 Measured using the Critical Appraisal Skills
Programme (CASP) Checklist for Systematic
Review13
 10-question tool for appraisal of systematic review

19. Section A: Are the results valid?
1. Did the review address a clearly focused
question?
 YES: the review sought to measure rates of TRS
from FEP and FES presentations
2. Did the authors look for the right type of papers?
 YES: All were cohort studies, appropriate for
assessing single defined outcome from defined
populations
3. Do you think all the important, relevant studies
were included?
 YES: The authors utilised several different
databases; PubMed, PsycINFO, EMBASE, CINAHL
and the Cochrane Database of Systematic Reviews,
including unpublished data

20. Section A: Are the results valid?
4. Did the review’s authors do enough to assess quality
of the included studies?
 YES: Studies were assessed as low risk of bias and high
strength of reporting (three or more points), or high risk of
bias and low strength of reporting (fewer than three points)
using modified Newcastle–Ottawa Scale
 Six of twelve included studies were deemed to be of high
quality
 Only English-language studies were used
5. If the results of the review have been combined, was
it reasonable to do so?
 CAN’T TELL: All were similar study types, examining
common outcomes
 However, there was a mix of prospective and
retrospective used (retrospective more prone to bias)

21. Section B: What are the
results?
6. What are the overall results of the review?
 As previously-described, rates of TRS are provided as
percentage values of measured cohorts, and also
divided based on FEP vs. FES presentations
 Overall rate of TRS was 22.8%
 Rates of TRS in FEP cohorts 17.8% vs. 24.4% in FES
cohorts
7. How precise are the results?
 95% CI 19.1–27.0%, P < 0.001, I2 = 91.8%
 Study examines progression from both FEP and FES
only: rates of TRS in those with pre-existing
diagnoses not captured

22. Section C: Will the results help
locally?
8. Can the results be applied to the local
population?
 YES: authors posit that “Early identification of
people with FES who fail to respond to first or
second antipsychotic trials can assist in timely
provision of evidence-based treatments for TRS
such as clozapine”
 In Ireland, clozapine treatment is widely available,
and its use may be considered a reliable indicator
for TRS
 These results indicate benefits of prompt use
 However, potential contributing factors which may

23. Section C: Will the results help
locally?
9. Were all important outcomes considered?
 CAN’T TELL: Contributors of lost-to-follow-up
cohort? Concomitant diagnoses? Involuntary
admission status?
 Unclear to what extent these would effect
outcomes
10. Are the benefits worth the harms and costs?
 YES: Meta-analysis of TRS rates from first
presentation
 No harms/costs apparent from measurement
alone

24. Reference
s
1. Siskind D., Orr S. et al. (2022), ‘Rates of treatment-resistant schizophrenia
from first-episode cohorts: systematic review and meta-analysis’, BJPsych
220: 115–120. doi: 10.1192/bjp.2021.61
2. Psycom.net, ‘Schizophrenia’, accessed at
https://www.psycom.net/schizophrenia on 12/05/2022
3. Howes O.D., McCutcheon R. et al. (2017), ‘Treatment-Resistant
Schizophrenia: Treatment Response and Resistance in Psychosis
(TRRIP) Working Group consensus guidelines on diagnosis and
terminology’, Am J Psychiatry 174(3): 216–29
4. Aleman A., Kahn R.S., Selten J-P. (2003), ‘Sex differences in the risk of
schizophrenia: evidence from meta-analysis’, Arch Gen Psychiatry 60(6):
565–71
5. Sommer I.E., Tiihonen J et al. (2020), ‘The clinical course of schizophrenia
in women and men—a nation-wide cohort study’, NPJ Schizophr 6: 12
6. Saha S., Chant D. et al. (2005), ‘A systematic review of the prevalence of
schizophrenia’, PLoS Med 2(5): e141
7. Siskind D., McCartney L. et al. (2016), ‘Clozapine v. first-and second
generation antipsychotics in treatment-refractory schizophrenia:
systematic review and meta-analysis’, Br J Psychiatry 209(5): 385–92
Thank
you.

25. References (contd.)
8. Lasevoli F., Giordano S. et al. (2016), ‘Treatment resistant schizophrenia is
associated with the worst community functioning among severely-ill highly-
disabling psychiatric conditions and is the most relevant predictor of poorer
achievements in functional milestones’, Prog Neuropsychopharmacol Biol
Psychiatry 65: 34–48
9. Kennedy J.L., Altar C.A. et al. (2014), ‘The social and economic burden of
treatment-resistant schizophrenia: a systematic literature review’, Int Clin
Psychopharmacol 29(2): 63–76
10. Firth J., Siddiqi N. et al. (2019), ‘The Lancet Psychiatry Commission: a blueprint for
protecting physical health in people with mental illness’, Lancet Psychiatry 6(8):
675–712
11. Land R., Siskind D. et al. (2017), ‘The impact of clozapine on hospital use: a
systematic review and meta-analysis’, Acta Psychiatr. Scand. 135(4): 296–309
12. Vermeulen J.M., van Rooijen G. et al. (2019), ‘Clozapine and long-term mortality
risk in patients with schizophrenia: a systematic review and meta-analysis of
studies lasting 1.1–12.5 years’, Schizophr Bull 45(2): 315–29
13. Critical Appraisal Skills Programme (2018), ‘CASP Systematic Review Checklist’,
accessed at https://casp-uk.b-cdn.net/wp-content/uploads/2018/03/CASP-
Systematic-Review-Checklist-2018_fillable-form.pdf on 23/05/2022
Thank
you.