br Conclusion br Limitations br Conflict of interest br
Conflict of interest
Financial disclosure The research was supported by National Institute of Mental Health and Neuro Sciences (NIMHANS)Intramural Research Grant ID NIMH/PROJ-RSM/545/2014-15. India.
Introduction Increased central and peripheral inflammation is a consistently replicated finding in bipolar I disorder (BDI) (Modabbernia et al., 2013). In particular, BDI is characterized by an increase in inflammatory cytokines, signalling molecules which are released in response to pathogenic insults and mediate further immune responses (Watkins et al., 1995). Persistent increases in inflammatory cytokines have been linked to downstream effects including neuronal apoptosis, decreased neuroplasticity and changes in monoamine and glutamate signalling, which may contribute to the deterioration in opposite functioning and clinical course seen in many patients (Rosenblat et al., 2014). These changes may have therapeutic implications as well; mood stabilizers such as lithium and valproate may exert their effects by decreasing inflammatory cytokine activity, and anti-inflammatory compounds such as NSAIDS, omega-3 fatty acids and N-acetylcysteine show some promise in the treatment of mood symptoms in BDI (Rosenblat et al., 2016). Elevated inflammatory cytokines may also contribute to cognitive dysfunction in BDI, which is now recognized as a core feature of the disorder that is present from disease onset and is associated with poor functional outcomes (Torres et al., 2011). The most frequently implicated of the cytokines include the pro-inflammatory IL-6, TNFα and IL-1 (Rosenblat et al., 2015). At physiological levels, these cytokines act as neuromodulators and facilitate cognitive processes such as memory and processing speed (McAfoose and Baune, 2009). However, in inflammatory states, these cytokines are involved in a cascade leading to the release of acute phase reactants, reactive oxidative species, and changes in glial function resulting in excitotoxicity and neuronal injury (Muneer, 2016). As mood disorders are characterized by chronic inflammation, these cumulative downstream effects may mediate the persisting cognitive dysfunction seen in BDI (Rosenblat et al., 2015). Furthermore, evidence from animal models suggest that anti-inflammatory agents can improve cognitive functioning, a finding that has been extended to healthy overweight adults as well as older adults with rheumatoid arthritis and at risk for Alzheimer's disease (Chen et al., 2010; Syed et al., 2015; Tobinick et al., 2006; Witte et al., 2014). This raises the possibility that reducing inflammation may have similar pro-cognitive effects in those with bipolar disorder. Recent studies have suggested that in addition to increased pro-inflammatory mediators in BDI are changes in anti-inflammatory cytokines, such as IL-4 and IL-10, which regulate the inflammatory response and moderate the release of pro-inflammatory cytokines (Kim et al., 2007). Anti-inflammatory cytokines also appear to attenuate the deleterious effects of pro-inflammatory cytokines on cognition, as mice deficient in IL-4 and IL-10 demonstrate greater inflammation-induced cognitive impairment compared to controls (Derecki et al., 2010; Richwine et al., 2009). Elevated levels of IL-4 and IL-10 have been reported in BDI, which has been theorized to reflect a compensatory increase in response to pro-inflammatory cytokines, particularly in early phases of the disease (Kauer-Sant'Anna et al., 2009; Modabbernia et al., 2013; Muneer, 2016). Additionally, treatment with mood stabilizers increase anti-inflammatory cytokine levels (Nassar and Azab, 2014). However, whether these cytokines have a significant neuroprotective effect in BDI has not been established. Pro and anti-inflammatory cytokines are therefore candidate therapeutic targets that, if modulated, may arrest cognitive decline and improve brain functioning in BDI. However, as cognitive deficits are present at illness onset, understanding how inflammatory mediators exert their effects early in the disease course would be key to developing neuroprotective treatments (Torres et al., 2010). This is especially pertinent as the balance of pro and anti-inflammatory cytokines alters with disease progression (Kauer-Sant'Anna et al., 2009). TNFα and IL-6 levels, for example, are elevated at illness onset and remain increased. IL-10, conversely, is decreased only in later stage patents, possibly representing failure of anti-inflammatory defenses with disease progression (Kauer-Sant'Anna et al., 2009). These findings suggest that inflammatory mediators play differential roles depending on the disease stage, which presumably would translate into having differential effects on cognition. However, extant studies examining the association between these factors and cognition have examined patients with longer duration of illness, and hence, the nature of this relationship has not been established in earlier stages.