Response to letters by Baethge et al. and Martino et al.
Marwaha and Thompson Int J Bipolar Disord
Response to letters by Baethge et al. and Martino et al.
Steven Marwaha 0 2
Andrew Thompson 0 1
0 Unit of Mental Health and Wellbeing, Division of Health Sciences, Warwick Medical School, University of Warwick , Coventry CV4 7AL , UK
1 North Warwickshire Early Interven- tion in Psychosis Service, Coventry and Warwickshire NHS Partnership Trust , Nuneaton , UK
2 Affective Disorders Service (IPU 3-8) , Coventry , UK
We thank Baethge et al. (2017) and Martino et al. (2017) for their interest and comments on our comprehensive literature review (Joyce et al. 2016). We focussed on answering the question of whether treatment given earlier in illness course is more effective than later. As we suggest in our review, this is a central tenet of the scientific basis of espousing early intervention in mental disorders including in bipolar disorders (Marwaha et al. 2016). The challenge is to identify methodologically robust evidence. Whilst we are cautious about the quality of current evidence, our review suggests that available treatments are more effective earlier in illness course. Our conclusions are based on ten studies included in the review. Eight studies, made up of two systematic reviews, and six incorporating primary evidence supported this conclusion. In 2 out of 10 of the included studies, this effect was rendered non-significant after adjusting for confounding. Baethge et al. state that our results do not align with their own work (Baethge et al. 2003a, b;Bratti et al. 2003). They suggest that this discrepancy may be due to omissions in search terms that we used and secondly that our strategy of only including studies in which there was a direct comparison between people earlier and later in illness course is flawed because the latter group will include people who have poor prognosis or treatment resistance and the former with multiple prognoses. Martino et al. also focus on this latter point. Both letters suggest that the staging model of bipolar disorder is a hypothesis and not proven. We agree with Baethge et al. and Martino et al. that the evidence base to investigate our question is limited in several ways, and we were of course at pains to point
this out in the extensive limitations section of the paper.
Indeed in assessing quality, we highlighted the risk of
multiple biases that exist in most of the studies examined
(see figure 2 in paper).
In terms of Baethge et al.’s first point, the main reason
for this discrepancy may be that our review and their
work, in essence, answer distinct though not necessarily
wholly mutually exclusive questions. Our review was not
concerned with latency or delay before first treatment
but with effectiveness of treatment after the first (or first
few) episode(s), and assessing the literature in relation to
episode number and treatment (not necessarily
prophylaxis) and effectiveness. In our strategy, we specifically
avoided the issue of conflating latency or delay with
episode number, in part because delay to first treatment can
be lengthy but is highly variable (Dagani et al. 2016), and
may encompass a range of previous affective symptoms
and episodes (Berk et al. 2007; Howes et al. 2011). In
addition, latency/delay may be just as much a function of
the response of services as illness course. We also noted
that in many studies first admission was aligned to first
episode something which is unlikely to be the case and
confounds analyses in this area. Whilst of course there
may be an association between latency/delay and episode
number, the nature of this is unlikely to be linear. Indeed
in their own work, Baethge et al. (2003a) found that these
two parameters are distinct, in that they report “A greater
therapeutic effect was demonstrated with increased
severity of the illness prior to prophylaxis”, (where
illness severity was defined as hospitalisation rate before
prophylaxis), whilst latency did not show a relationship.
We agree that had we included the terms “delay” we
could have extracted more overlapping papers included
in their review (Baethge et al. 2003b) but it is likely that
our protocol (developed before the work began) would
have excluded these papers as they would not have met
our inclusion criteria.
We agree that the work within Bratti et al. (2003) does
concern our central question more so, though again the
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focus of that review appears to be pre-treatment episode
number and its link to response to lithium treatment
specifically. That paper concludes that there was not a
clear and consistent signal. Our review covered both
pharmacological (not only Lithium) and psychological
treatments and found overall evidence in favour of the
hypothesis that early treatment was more effective. Some
discrepancy may be explained by the specificity of
previous work focussing solely on Lithium and also its use as
an acute treatment or in prophylaxis. Another reason for
discrepancy may be that the evidence base that we
interpreted contained five papers which were published after
their review of 2003.
A major point raised by Baethge et al. as well as
Martino et al., which we would partly agree with, is that those
with multiple episodes have a worse prognosis than
those with a first episode who would be made up of a
group with varying prognoses (though unknown at the
time of sampling). However, given the highly recurrent
nature of bipolar disorder (Angst et al. 2003), it is likely
that the vast majority of the first episode groups would
be likely to go on to develop further episodes; for
example, 50% relapse in as little as a year (Tohen et al. 2003).
This reduces the validity of claims that the conclusions of
our review are entirely dependent on comparing good vs
poor prognosis groups. Some people in the multiple
episode groups are likely to have been treatment resistant
although how many would fulfil strict criteria of having
failed two treatment attempts (Gitlin 2006) in the current
episode is unclear. We also agree that the heterogeneity
in the literature makes comparisons difficult and indeed
it is for this reason we did not attempt a meta-analysis.
We agree with the suggestion of Martino et al. that a
longitudinal study examining effectiveness of treatment
between many consecutive episodes experienced by the
same patient would enable further understanding of this
issue, though wonder how practicable this study design
Both Baethge et al. and Martino et al. raise the question
of whether neuroprogression occurs within bipolar
disorder and whether clinical staging is useful. We suggest in
our paper that our results could be explained by this type
of model, but agree that the evidence is not clear. In
principle, we would take the view suggested by Scott et al.
(2013) that clinical staging of bipolar disorder is a model
with testable assumptions that require further study.
Finally, our esteemed colleagues all suggest that despite
their doubts about the evidence, clinicians should
continue to aim for early diagnosis and early treatment on
ethical and clinical grounds. Whilst of course we agree,
we cannot get away from the fact that especially in
publically funded mental healthcare systems, clinical need
and ethics are not the only actors on the stage. Policy
decisions related to mental health service development
require evidence that an approach is more clinically and
cost-effective than the current framework. It is only by
demonstrating this, whilst explaining the flaws in the
literature, that a rationale for early intervention in
bipolar disorder may be advanced. We hope that our review
forms part of this developing evidence base, though
clearly more work is needed.
In conclusion, whilst we agree with many of the
comments on the methodological quality of the literature,
our review conclusions are based on the available
contemporaneous evidence. We suspect our differing results,
and perhaps differing perspectives are likely to be due to
incorporating this newer evidence and interpreting
findings alongside current hypotheses within the clinical
staging model of mental disorders.
SM led the writing of the response with substantial contributions from AT.
Both authors read and approved the final manuscript.
Availability of data and materials
The data are available in the original review paper.
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