Bipolar Disorder: Current Pathophysiology and the Potential for Alternative/ Complementary Medicine in Future Treatment Options

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Omar Farooq is an international medical graduate currently completing his Canadian licensing exams and working as a volunteer student researcher at Dr. Roger S. McIntyre’s Mood Disorders Psychopharmacology Unit (MDPU) at Toronto Western Hospital, University Health Network. Omar has a particular interest in complementary and alternative medicine, having had previous experience in that field during his studies as a medical student. Here is his submission:

Bipolar Disorder (BD) is one of the leading causes of disability worldwide that manifests during adolescence/ early adulthood, affecting men and women equally [1]. The past decade has witnessed substantial progress in the treatment of BD. However, patients receiving conventional pharmacological treatment often remain treatment refractory and/or exhibit clinically significant residual symptoms, cognitive dysfunction, and psychosocial impairment. Taken together, a priority research and clinical agenda is to identify pathophysiological mechanisms subserving mood disorders to improve therapeutic efficacy [2].

Elevated peripheral levels of pro-inflammatory mediators such as interleukin (IL)-1, IL-6, tumor necrosis factor-alpha (TNF-α) and their receptors (i.e., TNF-R1 and TNF-R2) have consistently been reported among individuals during both depressive and manic episodes [3-6]. This abnormal elevation of inflammatory cytokines has also been reported to persist into euthymia [2]. Progressive impairment of disparate cognitive functions has been consistently described in BD. For example, impairments in attention, executive function and verbal memory have been reported to affect synaptic transmission via inflammatory factors. Inflammation can influence the role of microglia in synaptogenesis (synapse formation) and pruning, a process of removing or pruning weak synapses and connections, resulting ultimately in more efficient synaptic configurations [7]. Moreover, mechanisms that have been purported to contribute to BD pathology include, but are not limited to, direct effects of pro-inflammatory cytokines on monoamine levels, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, pathologic microglial cell activation, impaired neuroplasticity and structural and functional brain changes [2].

The pathophysiology of BD tends to differ in early versus late disease (3,4). The term neuroprogression has been used to explain this phenomenon. The structural and functional changes that occur over the course of disease progression are attributed to changes in inflammatory cytokine levels and neurotrophins, as well as mitochondrial dysfunction, oxidative stress and epigenetic effects (3,4).

In the nervous system, Inflammation can be viewed as an immune response that primarily aims to identify and prevent threats to the neuronal environment. Stimuli triggering inflammation can vary from physical trauma, ischemia/hypoxia, or cellular damage due to multiple initiating stimuli including exposure to neurotoxicants; the foregoing aggravates may result in synaptic degeneration and neuronal loss. There is considerable evidence suggesting that traditional mood stabilizers modulate neuroinflammation (7). For example, pre-clinical studies have demonstrated that lithium and valproate may exert neuroprotective effects via anti-inflammatory properties (7).In keeping with the anti-inflammatory approach, various adjunctive anti-inflammatory agents, such as acetyl-salicylic acid (ASA), celecoxib, anti-TNF-α agents, minocycline, curcumin and omega-3 fatty acids, are being investigated for use in mood disorders [2].

Toona Sinensis (TS) is a well-known Chinese herb widely available in Asia. The leaves of TS are also a popular ingredient in recipes from Taiwan, China, and Malaysia. In traditional Chinese medicine the leaves of TS are used for treating diseases like enteritis, dysentery, diabetes, and bacterial and viral infections (9). Recently research into the aqueous extract of TS leaves has begun to investigate the claims laid by traditional Chinese medicine. More than eight compounds have been identified with potential beneficial effects. Five of the compounds identified belong to Flavanols (quercetrin, kaempferol-3-O-a-L-rhampyranoside, astraglin, quercetin, kaempferol) and three belong to derivatives of gallic acid (methyl gallate, ethyl gallate and 1,2,3,4,6-penta-O-galloyl-b-D-glucopyranose) [8]. Each of these compounds was subsequently subjected to in vitro tests to determine free radical and superoxide anion radical scavenging, metal chelation, and reducing power (8). The results showed that almost all of the individual compounds exhibited significant anti-oxidant properties [8]. Another recent study conducted sought to investigate the effects of aqueous extracts of TS leaves on in vitro models of neuroinflammation. The effect of TS leaf extract on murine microglia stimulated by lipopolysaccharide (LPS) was determined by calculating levels of TNF-α, NO and iNOS as well as observing changes in cell morphology (9). The study demonstrated that the TS leaf extract displays significant suppression of LPS-induced NO production, TNF-α secretion, and inducible NO synthase protein expression in a concentration-dependent manner (9). In addition, the potential therapeutic effects of TS leaf extract on the murine microglia after LPS treatment was also investigated. Results showed a positive anti-inflammatory effect of TS leaf extract in LPS-stimulated BV-2 microglia post-treatment [9]. The leaves of TS have been shown to possess a multitude of ant-inflammatory and anti-oxidative compounds and exhibit favorable results as mediators of neuroinflammation in in vitro studies. Toona Sinensis could serve as a potential therapeutic agent in the treatment of BD. However, further studies both in vitro and in vivo are necessary.
As efforts are underway to understand the pathophysiology of BD, current medical and research findings support the theory of BD as a chronic, progressive, multi-system disorder . Inflammation appears relevant to bipolar disorder across several important domains. Studies conducted on the TS leaf extract have identified a number of compounds that exhibited significant anti-oxidant, anti-inflammatory and neuroprotective effects in vitro. Although further clinical studies are warranted, if the beneficial effects of TS extract can be substantiated it could serve as an adjuvant therapy for long term management of BD.

References

1. WHO, Global Burden of Disease:2004 update
2. The effect of tumor necrosis factor antagonists on mood and mental health-associated quality of life: novel hypothesis-driven treatments for bipolar depression? Soczynska JK, Kennedy SH, Goldstein BI, Lachowski A, Woldeyohannes HO, McIntyre RS. Neurotoxicology. 2009 Jul;30(4):497-521.
3. Cytokine Alterations in Bipolar Disorder: a Meta-Analysis of 30 Studies. Amirhossein Modabbernia, Shervin Taslimi, Elisa Brietzke and Mandana Ashrafi. Biological Psychiatry, 2013,July;74(1):15-25.
4. Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis. Munkholm K, Braüner JV, Kessing LV, Vinberg M. J Psychiatr Res. 2013 Sep;47(9):1119-33.
5. Levels of TNF-α, soluble TNF receptors (sTNFR1, sTNFR2), and cognition in bipolar disorder. Doganavsargil-Baysal O, Cinemre B, Aksoy UM, Akbas H, Metin O, Fettahoglu C, Gokmen Z, Davran F. Hum Psychopharmacol. 2013 Mar;28(2):160-7.
6. A preliminary report of increased plasma levels of IL-33 in bipolar disorder: further evidence of pro-inflammatory status. Barbosa IG, Morato IB, de Miranda AS, Bauer ME, Soares JC, Teixeira AL. J Affect Disord. 2014 Mar;157:41-4.
7. Is bipolar disorder an inflammatory condition? The relevance of microglial activation. Stertz L, Magalhães PV, Kapczinski F. Curr Opin Psychiatry. 2013 Jan;26(1):19-26.
8. Flavonols and derivatives of gallic acid from young leaves of Toona sinensis (A. Juss.) Roemer and evaluation of their anti-oxidant capacity by chemical methods. Yang H, Gu Q, Gao T, Wang X, Chue P, Wu Q, Jia X. Pharmacogn Mag. 2014 Apr;10(38):185-90.
9. The aqueous extract from Toona sinensis leaves inhibits microglia-mediated neuroinflammation. Wang CC, Tsai YJ, Hsieh YC, Lin RJ, Lin CL. Kaohsiung J Med Sci. 2014 Feb;30(2):73-81