One of the major advances over the past 20 years in psychiatry is the capacity not
only to identify people at incipient risk for psychosis and other disabling mental
disorders, but also to improve their levels of distress and functioning and reduce
their risk of progression to sustained psychotic disorder, at least while treatment
is being provided and for at least 1–2 years from baseline. These statements are supported
by level 1 Cochrane evidence and one would expect this progress to be understood and
valued by a field in need of positive findings pointing to better outcomes. It is
therefore puzzling why recent meta-analyses appear to have focused on second order
issues and in doing so have distracted from the key message of this research literature
and fuelled the traditional skepticism and pessimism with which our discipline is
so replete.
The latest example of this phenomenon are the two network meta-analyses by Davies
et al. (1, 2) of preventive interventions in the clinical high risk (CHR, otherwise
termed ultra-high risk) for psychosis population. The primary focus of the first meta-analysis
(1) is transition to psychosis rates in these trials, with a secondary focus on acceptability
of treatments, operationalised as study drop-out due to any cause. The analysis showed
no significant efficacy of any one particular intervention over others at 6 and 12
months on either outcome. The authors conclude from their analysis that there is no
evidence that any specific intervention is more effective than any other trialed intervention
in preventing onset of psychosis and that “individuals meeting CHR-P criteria may
be informed that, at present, there is no evidence for specific treatments being more
effective than any others, and current options should be carefully weighted on a personal
basis depending on an individual's needs” (p.206). The second meta-analysis (2) focused
on attenuated positive psychotic symptoms as an outcome, with similar conclusions.
As a general point, this message of how to present current evidence to patients in
the clinical context seems to be negatively weighted and omits the fact that the trials
indicate in group-level analysis that most CHR patients improve in their symptoms
and functioning over time and transition rates are reduced. While it may well be true
that the field has not yet identified a single specific intervention that is more
effective than others (a substantial challenge given the clinical heterogeneity of
the CHR population, as the authors note), the trials do show that most patients improve
in response to treatment provided in specialist research clinics and transitions are
at least delayed. There is of course an important sub-group who manifest persistent
symptoms and functional difficulties that do not respond to treatment. The question
of whether targeted trial interventions pooled together yield improved outcomes compared
to control groups, as suggested by previous meta-analyses (3–5), is in fact not directly
addressed in these current meta-analyses. While different cognitive behavior therapy
(CBT) protocols were pooled together and compared to needs-based intervention (NBI)
and different antipsychotic treatments were pooled together and compared to NBI in
the first meta-analysis (and only pooled antipsychotic treatments in the second meta-analysis),
the authors do not seem to have pooled together all trial interventions (both psychosocial
and pharmacological) in comparison with NBI. If this had been done, similar findings
to previous meta analyses (3–5) may well have emerged.
Another important methodological observation needs to be made. A curious aspect of
both meta-analyses is that McGorry et al “Neurapro” trial (6) has been categorized
as “omega-3 and NBI or placebo and NBI.” However, the psychosocial intervention provided
in this trial was combined CBT and case management, termed cognitive-behavioral case
management (CBCM), i.e., omega-3+NBI+CBT vs. placebo+NBI+CBT (6– 8). The nature of
this psychosocial intervention was in fact critical to the interpretation of the trial's
negative outcome, discussed in detail elsewhere (6, 9, 10). In brief, the manualised
CBCM received by both treatment groups (as well as the use of antidepressant medications
in both groups) may have been sufficiently effective to have produced a ceiling effect
beyond which there was no scope for omega-3 polyunsaturated fatty acids (PUFA) to
confer additional benefit. This may have interfered with being able to properly test
the efficacy of omega-3 PUFA. This possibility is consistent with the fact that the
placebo group in the original omega-3 PUFA trial, also included in the current meta-analyses,
failed to show the level of symptomatic and functional improvement seen in the Neurapro
trial. The classification of the intervention provided in that trial as NBI rather
than as CBCM, while presumably guided by the aim of increasing the statistical power
for the omega-3 comparison, may have had a substantial impact on the meta-analytical
findings, given that it is the largest trial included in the meta-analyses (n = 304)
and may have inflated the effect of NBI (making it statistically more difficult to
find benefit in favor of any of the specific interventions). Indeed, when this trial
was removed from the second meta-analysis in order to conduct sensitivity analyses,
CBT-F plus NBI emerged as significantly more effective than NBI alone at 12 months
on the primary outcome (reduction of attenuated positive psychotic symptoms). This
is consistent with our speculation that if this trial had been coded as CBT rather
than as NBI, NBI may have had a weaker effect in the analyses and other interventions,
most likely CBT, may well have demonstrated a superior effect.
It also strikes us that it would have been important to include functioning and the
range of clinical outcomes (depression, general psychopathology, etc.) as an outcome
in these meta-analyses, particularly as these are often key targets of the psychosocial
interventions and secondary outcomes of the trials included. Not including these outcomes
seems to ignore critical information and leaves us with the unanswered question of
whether any of the specific interventions had a positive effect on these other clinical
outcomes, even if the interventions were not associated with reduced transition rate,
attenuated psychotic symptoms or increased acceptability of treatment. Clearly, a
positive effect of any of the interventions on these outcomes would have important
clinical implications. We note that Devoe et al.'s (11, 12) meta analysis of the effect
of trial interventions on negative symptoms in UHR studies found a trend-level positive
benefit for N-methyl-D-aspartate-receptor (NMDAR) modulators compared to placebo.
We agree with Davies et al that enrichment strategies need to be pursued to guard
against under-powered trials. However, another strategy is to take the approach of
developing interventions that respond to the evolving clinical profile or treatment
response of patients (“adaptive interventions”), such as sequential multiple assignment
randomized trials (SMART trials) (13). These are interventions in which the type or
dosage of treatment is individualized on the basis of patient characteristics, such
as psychological features, clinical presentation or mechanism-linked biomarkers, and
then is repeatedly adjusted over time in response to patient progress. Interventions
can also be tailored at critical decision points according to response or other patient
characteristics, such as specific biomarker changes or comorbidity, and also patient
preference. This approach has the advantage of providing more intensive treatment
for those with persistent symptoms or functional difficulties, rather than simply
continuing with the same treatment regimen, thereby mimicing what tends to occur in
standard clinical practice (and may therefore yield findings that are more useful
for clinical translation). It also has the effect of enriching the sample for psychosis
risk because those who do not respond to initial treatment steps (i.e., those who
are not “rapid responders”) are likely to constitute a sub-group at increased risk
for fully-fledged psychosis in whom further specific treatments can be trialed.
Finally, it may be of value to not only test interventions that target specific sub-groups
within the UHR population based on putative mechanisms in that sub-group (a form of
precision medicine), but also to conduct trials in young people at transdiagnostic
risk. In other words, the aspiration to “narrow” the treatment target can be complemented
by a broadening of clinical population and intervention strategies; as we have recently
argued (14), these strategies are not mutually exclusive. Trialing interventions in
a broad at-risk group is consistent with the diffuse, overlapping clinical presentations
seen in early stages of disorder [the “problem of comorbidity” (15–17)]. The identification
of biopsychosocial mechanisms driving the onset of disorder and developing effective
interventions in this group need to evolve in parallel and inform each other. While
progress with identifying causal mechanisms can certainly guide treatment targets,
waiting for these mechanisms to be identified before testing preventive treatments
does patients a disservice, particularly if the cost-benefit balance of these treatments
is favorable. In turn, effective treatments can, in the spirit of reverse engineering,
shed light on the pathogenesis of disorder.
Author contributions
All authors listed have made a substantial, direct and intellectual contribution to
the work, and approved it for publication.
Conflict of interest statement
The authors declare that the research was conducted in the absence of any commercial
or financial relationships that could be construed as a potential conflict of interest.