Review
Pathways underlying neuroprogression in bipolar disorder: Focus on inflammation, oxidative stress and neurotrophic factors

https://doi.org/10.1016/j.neubiorev.2010.10.001Get rights and content

Abstract

There is now strong evidence of progressive neuropathological processes in bipolar disorder (BD). On this basis, the current understanding of the neurobiology of BD has shifted from an initial focus on monoamines, subsequently including evidence of changes in intracellular second messenger systems and more recently to, incorporating changes in inflammatory cytokines, corticosteroids, neurotrophins, mitochondrial energy generation, oxidative stress and neurogenesis into a more comprehensive model capable of explaining some of the clinical features of BD. These features include progressive shortening of the inter-episode interval with each recurrence, occurring in consort with reduced probability of treatment response as the illness progresses. To this end, emerging data shows that these biomarkers may differ between early and late stages of BD in parallel with stage-related structural and neurocognitive alterations. This understanding facilitates identification of rational therapeutic targets, and the development of novel treatment classes. Additionally, these pathways provide a cogent explanation for the efficacy of seemingly diverse therapies used in BD, that appear to share common effects on oxidative, inflammatory and neurotrophic pathways.

Research highlights

Bipolar disorder is associated with an active process of neuroprogression. ▶ Oxidative, inflammatory and neurotrophic factors play a role in the process. ▶ Both available treatments and novel options impact these pathways.

Introduction

Despite Kraepelin (1921) first noting that manic-depressive illness has an accelerating and progressive course, the molecular foundations for this disease progression are only just beginning to be explained. By contrast, there is a wealth of clinical data supporting this pattern of an accelerating and progressive disease course which includes the observation of a progressive reduction in the inter-episode duration with recurrence (Kraepelin, 1921, Zis et al., 1980, Roy-Byrne et al., 1985, Kessing et al., 1998). Increasing episode number is linked to a reduction in the likelihood of response to appropriate treatment, both biological such as lithium (Franchini et al., 1999, Swann et al., 1999), and psychological such as CBT (Scott et al., 2006). People with more recurrent bipolar disorder (BD) tend to have higher rates of comorbidity, especially substance abuse (Brady and Goldberg, 1996), more difficulty with social adjustment (Matza et al., 2005) and increased risk of hospitalisation (Goldberg and Ernst, 2002), suicide (Hawton et al., 2005) and forensic complications (Conus and McGorry, 2002). These clinical observations suggest that BD is at least in part a neuroprogressive disorder where there is the potential for a potentially modifiable pathophysiological process to occur over the longitudinal trajectory of the illness and that part of this neuroprogressive pathophysiology is associated with inadequately compensated metabolic stress. The end point of such neuroprogressive changes would be tissue damage, structural changes and functional sequelae that are the neural substrate of mood regulation, that has the potential to increase the risk of further recurrence and reduce the potential of treatment response (Waddington et al., 1998). It is likely that this process is present or accelerates during acute exacerbations of the illness, and this paper will present data that this may be particularly true of manic relapse.

Section snippets

The structural basis and functional sequelae of neuroprogression in bipolar disorder

The observed clinical progression of BD is reflected by growing evidence of stage-related structural brain changes in affected individuals. Structural abnormalities are not consistently found at illness onset, but more commonly found in chronic and more recurrent forms of the illness. An example being, ventricular enlargement has been reported in individuals with recurrent illness that was not apparent in a cohort with during first-episode of mania (Strakowski et al., 2002). These observations

The biochemical foundation of neuroprogression

While Kraepelin first described the progressive nature of the disorder, Post (1992) laid the foundations of the current understanding of the progressive nature of the pathophysiology of the disorder (Post, 1992). Post based his argument on experiments using kindling in animals as a model for seizures where it was shown that if exogenous agents induced enough seizures, changes in the CNS would occur that induced spontaneous endogenous seizures in the experimental animal. Importantly, kindling

Dopaminergic system

Several lines of pharmacological evidence support the notion that excessive dopamine neurotransmission is involved in the development of manic symptoms (Berk et al., 2007c). Agents that drive dopamine, such as amphetamine, are amongst the best models of mania, whilst dopamine D2 antagonists (Chengappa et al., 2004, Berk and Dodd, 2005, Malhi et al., 2005) are robustly anti-manic (Frey et al., 2006a, Frey et al., 2006b). When considering the potential for dopamine to affect CNS function it is

Neuroprotection

Neuroprotection may be a viable and realistic goal in treating BD. There are two types of pathological processes amenable to intervention. Firstly, normal physiological processes that happen in excess, for example excitotoxicity, pruning or excessive apoptotic activity. Secondly, the failure of trophic processes, such as reduced neurogenesis, senescence of progenitor cell generation and differentiation can also be targeted. Such an approach would involve regulating the processes of growth,

Neuroprotective effects of known bipolar agents

One of the conundrums in BD is that many of the agents that are useful in managing the disorder at first glance appear to share few properties. However, it is now known that established mood stabilizers impact the pathways and mechanisms that are associated with neuroprogression in BD. For instance, lamotrigine, lithium and VPA reduce oxidative stress (Cui et al., 2007, Eren et al., 2007, Kim et al., 2007a, Ng et al., 2008) and atypical antipsychotics also reduce oxidative stress, not only via

N-acetyl cysteine

N-acetyl cysteine (NAC) is not only a precursor to the primary free radical scavenger, glutathione, but in addition has many other biological effects including increasing glutamate in the nucleus accumbens and anti-inflammatory properties (Dodd et al., 2008). NAC additionally enhances neuronal differentiation of mouse embryonic stem cells, and has been shown to enhance the extension of neuritogenesis (Qian and Yang, 2009). Similarly, it increases neuronal survival and the number of regenerating

Implications

In summary, we are now beginning to understand the underlying processes of neuroprogression in BD that include inflammatory cytokines, neurotrophins, mitochondrial dysfunction, oxidative stress and epigenetic effects. These parameters appear to be sensitive to the stage of illness, and indeed are the first biochemical indicators of the staging model in BD (McGorry et al., 2006, Berk et al., 2007d). While the interactions of these systems are beginning to be elucidated it remains difficult to

Conclusions

The pathways explored in his review appear to be common targets of the otherwise diverse and seemingly unrelated treatments (lithium, valproate, atypical antipsychotics) that share efficacy in the treatment of BD. To date, it has been difficult to explain the shared efficacy of these superficially diverse therapies. These emerging data suggest that these common targets may be more central to the biological foundation of the disorder than hitherto appreciated. They additionally open the door to

Acknowledgement

The authors would like to gratefully acknowledge the assistance of Sherilyn Goldstone in the preparation of this manuscript.

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    Disclosures: Michael Berk has received Grant/Research Support from Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Geelong Medical Research Foundation, Australian Rotary Health Research Fund, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Organon, Novartis, Mayne Pharma and Servier, has been a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Pfizer, Sanofi Synthelabo, Servier, Solvay and Wyeth, and served as a consultant to Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck and Servier. Flavio Kapczinski is supported by INCT-TM, CNPq, CAPES, SMRI and NARSAD. Is a consultant for, or receives research grants from Janssen, Lilly, Astra Zeneca, Abbott and Servier. Ana Cristina Andreazza has been supported by the Michael Smith Health Research Foundation and CAPES. Olivia Dean has received Grant/Research Support from Stanley Medical Research Foundation, Marian and E.H. Flack Trust, the Australia Rotary Health Research Fund and NHMRC. Clarissa Severino Gama has received unrestricted research grants from CNPq-Universal (477974/2009-0), CNPq-INCT-TM, CAPES and FIPE-HCPA. She has been a paid speaker for Lundbeck and Astra Zeneca and a consultant for Actelion Pharmaceuticals Ltd. She has received travel awards from Lilly and Janssen. Seetal Dodd has received Grant/Research Support from Stanley Medical Research Foundation, NHMRC, Beyond Blue, Geelong Medical Research Foundation, Australian Rotary Health Research Fund, Bristol Myers Squibb, Eli Lilly, Organon, Novartis, Mayne Pharma and Servier, has been a speaker for Eli Lilly. Brian Dean has received Grant/Research Support from the NHMRC, NIH, Stanley Medical Research Foundation, NARSAD, Eli Lilly and the Rebecca L. Cooper Medical Research Foundation; has been a speaker for Eli Lilly and Janssen Cilag and has acted as a Consultant for Merck and Bristol Myer Squibb. Pedro Magalhães is supported by a scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Brazil. Gin Malhi has served on a number of international and national pharmaceutical advisory boards, received funding for research and has been in receipt of honoraria for talks at sponsored meetings worldwide involving the following companies: Astra Zeneca, Eli Lilly, Janssen-Cilag, Lundbeck, Organon, Pfizer, Ranbaxy, Servier and Wyeth.

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