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05 October 2013
European College of Neuropsychopharmacology (ECNP)
BARCELONA, SPAIN (7 October 2013) – Improved understanding of the roles of inflammation and oxidative stress in psychiatric disorders has generated new leads in the search for novel therapies. One such investigative compound currently in clinical trials is an amino acid, N-Acetyl Cysteine (NAC), which appears to reduce the core symptoms of bipolar disorder, schizophrenia, depression, autism and cravings in addictions including cocaine, cannabis abuse and cigarette smoking.
At the start of the decade of the brain, in the early 1990s, there was great hope that a flurry of new treatment discoveries would eventuate. In contrast, today, most pharmaceutical companies have a drying psychiatry and neurology pipeline and many have exited the field entirely. “One of the factors has been an over reliance on typical monoamine pathways as targets for drug discovery,” said Professor Michael Berk, Chair in Psychiatry at Deakin University, Geelong, Australia.
Professor Berk pointed out that the situation regarding new drug development for psychiatric problems was best summarised by former National Institute for Mental Health Director, Steven Hyman:
“drug discovery is at a near standstill for treating psychiatric disorders such as schizophrenia, bipolar disorder, depression and common forms of autism.”
Beyond the monoamine-based drugs, neuroscience has elucidated an array of other important pathways that are involved in most major psychiatric disorders, for example schizophrenia and both unipolar and bipolar depression.
According to Professor Berk, there is now an incontrovertible evidence base that these disorders share inflammation and oxidative stress as part of their disease physiology. In addition, associated pathways including reduction in proteins that stimulate neuronal growth (neurotrophins), and increased cell death (apoptosis), as well as energy generation in organelles called mitochondria are intimately involved. “This understanding provides an entirely new set of treatment targets.”
The amino acid, NAC, seems to have multiple effects on all these pathways: it
- boosts glutathione, which is the body’s major antioxidant defence;
- has anti-inflammatory properties;
- enhances levels of nerve cell growth proteins and the growth of new neurons; and
- reduces cell death pathways.
- It also appears to reduce dysfunction of mitochondria.
These molecular effects of NAC have been investigated in a series of clinical trials, which show that NAC reduces the core symptoms of schizophrenia including negative symptoms such as improved apathy, social interaction and motivation.
It also appears to reduce depression in people with bipolar disorder and at this meeting, new data on its role in unipolar major depression was presented. Furthermore, there is intriguing evidence that it reduces cravings in a number of addictions including cocaine, cannabis and cigarette smoking. “Apart from nausea, it appears to be relatively free of problematic side effects,” said Professor Berk.
In addition to NAC, a range of other compounds that target similar pathways, particularly inflammation, seem to have therapeutic potential. These include aspirin, cyclooxygenase (COX) inhibitors, statins, omega-3 fatty acids and even some anti-diabetic agents such as pioglitazone. “Capitalising on our understanding of inflammation and oxidative stress in major psychiatric disorders appears to give us an entirely new range of potential treatments for these common, severe and disabling conditions,” said Professor Berk.
Diabetes is strongly associated with socioeconomic status (SES): low income, low education, and low occupational status are all linked to a higher risk for diabetes. Trying to understand the mechanisms underlying the association, Silvia Stringhini from the Institute for Social and Preventive Medicine in Lausanne, Switzerland and colleagues report in this week’s PLOS Medicine that a substantial part of it appears to be attributable to chronic inflammation.
“Taking together the evidence linking socioeconomic adversity to inflammation and inflammation to type 2 diabetes” the authors write, “it seems reasonable to postulate that chronically increased inflammatory activity in individuals exposed to socioeconomic adversity over the entire lifecourse may, at least partially, mediate the association between socioeconomic status over the lifecourse and future type 2 diabetes risk.”
To test their hypothesis, they analyzed data from the Whitehall II study. Following the famous original Whitehall study that pioneered the study of social determinants of health, Whitehall II has followed over 10,000 participants, all British civil servants working in London, since the mid 1980s. The study is ongoing, and participants undergo regular health check-ups and also provide extensive information about their social situation every few years.
For their study, the researchers focused on 6387 participants who had provided information on their education level and current occupation (reflective of early adulthood and present socio-economic status, respectively) as well as their father’s occupation (a proxy for childhood socio-economic status). In addition, it was known which of the participants had developed diabetes and when, and whether and when their blood work had shown signs of chronic inflammation.
They found that cumulative exposure to low SES over the lifecourse and a downward trajectory from high SES in childhood to low SES in adulthood were associated with an increased risk of developing type 2 diabetes over the study period. In addition, inflammatory processes, measured repeatedly through biomarkers in the blood, explained as much as one third of this association.
“Assuming that our findings reflect a causal association”, the authors say, “our results suggest that tackling socioeconomic differences in inflammation, especially among the most disadvantaged groups, might reduce social inequalities in type 2 diabetes.”
They suggest that future studies should test interventions that reduce chronic inflammation, as “(such studies) will be necessary to determine the extent to which social inequalities attributable to chronic inflammation are reversible.”
Funding: SS is supported by a post-doctoral fellowship awarded by the Swiss School of Public Health (SSPH+). MK is supported by the Medical Research Council (K013351), UK, the US National Institutes of Health (R01HL036310; R01AG034454), the EU New OSH ERA Research Programme and an ESRC professorship. MS is supported by the British Heart Foundation. MK is partially supported by MRC, Economic and Social Research Council Grant RES 596-28-0001 and National Heart Lung and Blood Institute Grant HL36310. DB was a Wellcome Trust fellow during the preparation of this manuscript. The Whitehall II study has been supported by grants from the British Medical Research Council (MRC); the British Heart Foundation; the British Health and Safety Executive; the British Department of Health; the National Heart, Lung, and Blood Institute (R01HL036310); the National Institute on Aging, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Citation: Stringhini S, Batty GD, Bovet P, Shipley MJ, Marmot MG, et al. (2013) Association of Lifecourse Socioeconomic Status with Chronic Inflammation and Type 2 Diabetes Risk: The Whitehall II Prospective Cohort Study. PLoS Med 10(7): e1001479. doi:10.1371/journal.pmed.1001479
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