The Role of Inflammation in the Pathophysiology of Schizophrenia

In this occasional feature on Psych Congress Network, members of the Psych Congress Steering Committee answer questions asked by audience members at Psych Congress meetings.

QUESTION: Does inflammation play a role in the pathophysiology of schizophrenia, and if so, is there a benefit from anti-inflammatory treatment?

ANSWER: It is safe to assume that inflammation is not a singular, and most likely not even the main, pathophysiological process underpinning development of schizophrenia. Furthermore, presence of dysregulated inflammatory signaling may not be equally influential in all phases of the illness. Nevertheless, there is an accumulation of clinical and preclinical evidence pointing to a relevant role of inflammation in the etio-pathogenesis of schizophrenia.

Evaluating the Inflammatory Status of Patients

A recent study utilizing a clustering procedure noted that 40% of individuals suffering from schizophrenia displayed higher levels of cytokine mRNA expression, compared to only 21% of healthy controls.¹ Dysregulated peripheral inflammatory signaling may precipitate a change in astrocyte and microglia function in the brain. Increased astrocyte tryptophan-dioxygenase activity may produce elevated kynurenine activity, with subsequent compromised glutamate transmission via NMDA, and cholinergic signaling via nicotinic receptors (kynurenine is a functional antagonist at NMDA-Rs and a7nAch-Rs). These alterations may be in part responsible for negative and cognitive symptoms of schizophrenia. Moreover, inflammation-induced microglial release of quinolinic acid may be responsible for excitotoxicity and neural damage in schizophrenia.²

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Other studies have noted elevated levels of interleukin-1 and kynurenine in cerebrospinal fluid of schizophrenia patients, relative to controls, as well as a relationship between peripheral levels of hs-CRP (an inflammatory indicator) and cognition in patients. Discrete immune components may play a role in particular manifestations of schizophrenia. While microglial infiltration seems to have an important role in paranoid schizophrenia, T- and B-lymphocytes may primarily contribute to the pathophysiology of residual schizophrenia. Additionally, greater inflammatory signaling, indirectly reflected by kynurenine levels, may impede treatment response to antipsychotic agents and correlate with higher depression and psychosis scores in patients suffering from schizophrenia. Furthermore, increased microglia counts were noted in postmortem studies of schizophrenia patients who ended their lives with suicide, but were not present if they died due to other causes. Is an inflammatory “flare-up” associated with increased risk of suicide in schizophrenia? The answer to this question awaits further exploration.

If inflammation and immune disturbances play an important role in the pathophysiology of schizophrenia, do anti-inflammatory strategies have a place in the treatment armamentarium? Meta-analyses have indicated a modest, but statistically significant benefit from aspirin, but not celecoxib, with greater effect size for positive symptoms vs. negative, and more pronounced benefit in inpatient, compared to outpatient studies of individuals with schizophrenia.

Can Anti-Inflammatory Agents Be Used to Treat Bipolar Depression?

Minocycline, a tetracyclic antibiotic capable of preventing microglial transformation into an inflammatory phenotype, has generated some interest as a potential treatment for schizophrenia. Several studies have found adjunctive minocycline, combined with standard antipsychotics, to be effective in decreasing negative and cognitive symptoms of schizophrenia, relative to the control group. Additionally, a 12-month randomized controlled trial demonstrated a neuroprotective benefit related to minocycline, whereby adjuvant minocycline use was associated with diminished gray matter volume loss in frontotemporal brain areas of schizophrenia patients, compared with controls.³

In conclusion, emerging evidence does support a role of inflammatory processes at least in a portion of schizophrenic patients. The role of immune perturbations in specific phases of illness needs further elucidation. Preliminary evidence indicates that anti-inflammatory agents may be a useful adjunct to standard treatments, at least in a segment of patients suffering from schizophrenia.

— Vladimir Maletic, MD, MS, Clinical Professor of Psychiatry and Behavioral Science, University of South Carolina School of Medicine, Greenville

References

1.  Fillman SG, Weickert TW, Lenroot RK, et al. Elevated peripheral cytokines characterize a subgroup of people with schizophrenia displaying poor verbal fluency and reduced Broca's area volume. Molecular Psychiatry. 2016;21:1090-1098.

2.  Meyer U, Schwarz MJ, Muller N. Inflammatory processes in schizophrenia: a promising neuroimmunological target for the treatment of negative/cognitive symptoms and beyond. Pharmacology & Therapeutics. 2011;132:96-110.

3.  Chaves C, Marque CR, Maia-de-Oliveira JP, et al. Effects of minocycline add-on treatment on brain morphometry and cerebral perfusion in recent-onset schizophrenia. Schizophr Res. 2015;161:439-445.