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Expert Review of Clinical Pharmacology

ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: http://www.tandfonline.com/loi/ierj20

Anti-inflammatory strategies in the treatment of


schizophrenia
Chittaranjan Andrade
To cite this article: Chittaranjan Andrade (2015): Anti-inflammatory strategies
in the treatment of schizophrenia, Expert Review of Clinical Pharmacology, DOI:
10.1586/17512433.2016.1095086
To link to this article: http://dx.doi.org/10.1586/17512433.2016.1095086

Published online: 01 Oct 2015.

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Date: 28 December 2015, At: 18:41

Editorial

Anti-inflammatory strategies in the


treatment of schizophrenia
Expert Rev. Clin. Pharmacol. Early online, 13 (2015)

Downloaded by [University of Veracruzana] at 18:41 28 December 2015

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

Schizophrenia is a major mental illness with a lifetime prevalence of about 1%.


Antipsychotic drugs, with a primary mechanism of action that involves dopamine
receptor blockade, are the mainstay in the treatment of the disorder. However,
despite optimum antipsychotic treatment, few patients return to pre-morbid
levels; the treatment deficit includes refractory positive symptoms, negative
symptoms, mood impairments, cognitive impairments, social impairments, and/or
a variety of medication-related adverse effects, including extrapyramidal
symptoms, metabolic disturbances, hyperprolactinemia, and others. To address
these, antipsychotic treatment has been augmented with psychosocial
interventions, cognitive rehabilitation, different kinds of electrical and magnetic
brain stimulation, and a large range of drugs from the neuropsychiatric as well as,
surprise, the general medical pharmacopeia. The pleomorphic pathophysiology of
schizophrenia includes abnormalities in immunological and inflammatory
pathways, and so it is not surprising that anti-inflammatory drugs have also been
trialed as augmentation agents in schizophrenia. This article critically examines the
outcomes after augmentation with conventional anti-inflammatory interventions;
results from randomized controlled trials do not encourage the use of either
aspirin (1000 mg/day) or celecoxib (400 mg/day), both of which have been
studied for this indication during the past decade and a half.

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

of schizophrenia [3]. If inflammation


contributes even partly to the
pathophysiology of schizophrenia, then
treatments as ordinary as conventional
anti-inflammatory drugs may strike at
the root of the disease process [3]. What
is the evidence, so far?
Among the conventional antiinflammatory drugs, only two have been
systematically studied as antipsychotic
augmentation agents in double-blind,
randomized controlled trials (RCTs).
These are aspirin (two RCTs; pooled
n = 270) and celecoxib (six RCTs;
pooled n = 504). A recent meta-analysis
[5] that examined these two drugs separately found that aspirin but not celecoxib was associated with significant
attenuation of total psychopathology ratings; the benefit associated with aspirin
was, however, small (Hedges g, 0.30).
Another recent meta-analysis [6] that
pooled the data from the two drugs and

KEYWORDS: anti-inflammatory treatment . antipsychotic augmentation . aspirin . celecoxib . NSAIDs .


schizophrenia

informahealthcare.com

10.1586/17512433.2016.1095086

 2015 Informa UK Ltd

ISSN 1751-2433

Downloaded by [University of Veracruzana] at 18:41 28 December 2015

Editorial

Andrade

examined different domains of benefit found no significant


benefit with anti-inflammatory drug augmentation for attenuation of Positive and Negative Syndrome Scale (PANSS) total
scores or PANNS-negative scores; whereas there was significant
decrease in PANSS-positive scores, the benefit was almost negligibly small (Hedges g, 0.19). Because of high heterogeneity,
secondary analyses of PANSS total scores were conducted; these
found a small advantage for aspirin but not celecoxib; for antiinflammatory augmentation in RCTs of in-patients but not
those that included out-patients; and for anti-inflammatory
augmentation in RCTs that included first-episode patients but
not in RCTs of only chronic patients (significant Hedges g
range, 0.290.44). The findings of these analyses must be
viewed with caution because all were exploratory.
Aspirin resulted in significantly improved outcomes in metaanalyses [5,6]. However, one [7] of the two aspirin RCTs has not
yet been published although the abstract appeared in print in
2012. This large (n = 200), 16-week study [7] did not support
aspirin augmentation. The smaller (n = 70), shorter (12-week),
published RCT [8] obtained only a small effect size for PANSS
total (Cohens d, 0.47) and PANSS-positive (Cohens d, 0.39)
ratings. Absolute differences in scores between aspirin and placebo groups were small and of uncertain clinical significance
only 3.8 and 0.9 for PANSS total and PANSS-positive ratings,
respectively. Both these RCTs dosed aspirin at 1000 mg/day,
which could raise the risk of bleeding events (in the upper gastrointestinal tract and elsewhere) to unacceptably high levels
during chronic therapy [9]. Both studies administered pantoprazole 40 mg/day to reduce the specific risk of gastrointestinal
adverse events; the resultant increase in gastric pH could impair
the absorption of some drugs [10].
What about the six celecoxib RCTs? As already stated, in
meta-analysis, celecoxib did not outperform placebo [5,6]. Two
of these RCTs were completed more than a decade ago; both
failed to find an advantage for celecoxib and were never published in full [11,12]. One of these unpublished RCTs [11] was
the largest (n = 270) and the longest (11 weeks) trial among
the six. The other unpublished RCT [12] found PANSS total
score benefits only in an exploratory analysis of patients with
illness duration of <2 years.
Of the remaining four celecoxib RCTs, which were all published, one [13] found no benefits with celecoxib in continuously symptomatic out-patients receiving antipsychotic
medication. Two more, both from the same team [14,15], found
small benefits on some outcome measures, but the results at
the study end point were statistically significant in only one of
these [15]. In the other [14], acceleration of response was
observed, but no statistically significant separation of groups
was found at the end of the study. The last celecoxib trial [16]
obtained strikingly positive results. This was a small (n = 60),
short (8 weeks) trial that emerged from Iran. It obtained an
enormous effect size (Hedges g, 0.93). This result must be
viewed with caution; there is a large number of psychopharmacology RCTs from this part of the world, almost all of which
have large, positive results.
doi: 10.1586/17512433.2016.1095086

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.

Anti-inflammatory treatment of schizophrenia

Financial & competing interests disclosure

C Andrade was recently a Principal Investigator and Medical Monitor


for a multi-center, investigator-initiated, Indian investigation of the efficacy of Sensoril, a branded formulation of Ashwagandha. The study was
funded by Natreon Inc. (USA). C Andrade has received funding from
the Indian Council for Medical Research, Department of Biotechnology,

Downloaded by [University of Veracruzana] at 18:41 28 December 2015

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informahealthcare.com

and Corcept Therapeutics. The funding has supported the purchase of


laboratory supplies and the salaries of research officers. The author has
no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript apart from
those disclosed.

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doi: 10.1586/17512433.2016.1095086