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Editorial
Chittaranjan
Andrade
Department of
Psychopharmacology, National
Institute of Mental Health and
Neurosciences, Bangalore
560 029, India
Tel.: +91 80 26 99 51 09
Fax: +91 80 26 56 48 30
andradec@gmail.com
Data from animal models of schizophrenia as well as patients with the illness
suggest that aberrant inflammatory
mechanisms and inflammatory markers
are present in plasma as well as in the
brain before, during, and after the onset
of psychosis; these have been well
reviewed, recently [14]. Clues about
possible inflammatory origins include
association with history of infection and
presence of antibodies against specific
organisms, presence of possible autoantibodies in serum and cerebrospinal fluid,
changes in the levels of inflammatory
cytokines, glial cell activation in the
brain, and others (14). The inflammatory processes may be genetically
driven [4] or resultant from prenatal or
postnatal exposure to infection [3].
Inflammatory hypotheses converge with
rather than supplant existing neurochemical hypotheses, such as the dopaminergic and glutamatergic hypotheses
informahealthcare.com
10.1586/17512433.2016.1095086
ISSN 1751-2433
Editorial
Andrade
All of the six celecoxib studies dosed the drug at 400 mg/
day; patients receiving the drug are at risk of bleeding [17] and
cardiac adverse events [18] with long-term treatment.
There are no data on the effects of aspirin or celecoxib
on other important treatment targets in schizophrenia, such
as social and neuropsychological deficits; given the absence
of improvement in negative symptoms, improvement in these
domains seems rather unlikely. So, the general conclusion
that one may draw appears to be that anti-inflammatory
drugs such as aspirin and celecoxib do not offer clinically
worthwhile benefits in the augmentation of antipsychotic
drugs in patients with schizophrenia [19]; furthermore the
riskbenefit ratio is unfavorable. A note is made here that it
is not easy for the null hypothesis to be rejected in add-on
studies. So, if anti-inflammatory mechanisms truly mediate
schizophrenia pathology, then anti-inflammatory treatments
may yield statistically and clinically significant effect sizes
when used in monotherapy. However, it is unlikely that
such RCTs will ever be conducted given the pre-eminence
of dopamine receptor antagonists in the treatment of the
disorder.
What we do not know is whether anti-inflammatory agents
are of value in subsets of patients, such as those preselected for
antipsychotic refractoriness. Whereas this might be a worthwhile subject for future research, preliminary data suggest that
patients who do not respond adequately to their ongoing antipsychotic may not benefit from celecoxib augmentation [13].
Another line of enquiry would be to examine the benefits of
aspirin or celecoxib in patients in whom the baseline levels of
markers of inflammation cross thresholds of interest. If benefits
are detected, a further possibility would be to examine whether
the benefits are enduring; that is, whether the course of the
illness is improved.
Interestingly, other drugs with anti-inflammatory activity
have also not shown consistent benefits in schizophrenia. For
example, epigallocatechin gallate did not outperform placebo in
a pilot study in patients with schizophrenia or bipolar disorder [20]. There are also many studies on omega-3 fatty acids,
minocycline, and neurosteroids. They were recently
reviewed [5,21] and are not considered further here.
On a parting note, immunological treatments have been
approved for a variety of autoimmune disorders, ranging from
rheumatoid arthritis to multiple sclerosis. If immunological
mechanisms (which are related to anti-inflammatory mechanisms) are involved in schizophrenia, immunological
approaches may merit study, whether or not conventional antiinflammatory treatments work [3]. In this regard, infliximab, a
TNF-alpha antibody, was found to reduce depression rating
scores at 12 weeks in patients with treatment-resistant depression and elevated baseline TNF-a levels [22]. The finding
encourages proof-of-concept schizophrenia studies. However,
enthusiasm must be tempered by the knowledge that there is
no evidence of active brain inflammation as seen, for example,
in patients with multiple sclerosis who are experiencing an
acute exacerbation of illness.
Expert Rev. Clin. Pharmacol.
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informahealthcare.com
References
Editorial
17.
Castellsague J, Riera-Guardia N,
Calingaert B, et al. Safety of non-steroidal
anti-inflammatory drugs (SOS) project.
individual NSAIDs and upper
gastrointestinal complications: a systematic
review and meta-analysis of observational
studies (the SOS project). Drug Saf
2012;35:1127-46
18.
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doi: 10.1586/17512433.2016.1095086