Pharmacometabolomics Research Projects

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Projects in the Department of Psychiatry and Behavioral Sciences

Under the Molecular Psychiatry program at Duke, we bring the power of metabolomics technologies to interrogate perturbations in networks and pathways in psychiatric disorders such as schizophrenia, depression, Alzheimer’s disease and addiction disorders. Additionally we investigate metabolic effects of drugs used for the treatment of these diseases. We are grateful for the funding we have received for these projects from the Stanley Foundation, NASAD, National Institute of Neurological Disorders and Stroke (NINDS), National Institute of General Medical Sciences (NIGMS) National Institute of Mental Health( NIMH), and the Alzheimer’s Drug discovery Foundation.

Schizophrenia: A major public health problem

Schizophrenia is arguably one of the most disabling of all diseases, being relatively common, with onset typically in adolescence and running a lifelong disabling course. Approximately 5 percent of patients end their lives by suicide and overall patients die prematurely (from cardiometabolic deaths not just suicide) some 25 years earlier than the general population. Schizophrenia, by any estimate a devastating condition, is characterized by highly distressing positive symptoms (e.g. delusions and hallucinations), negative symptoms (e.g. impaired volition, and emotion), impaired cognition and social functioning. Although the exact  etio-pathobiology of schizophrenia remains elusive, fundamental abnormalities in phospholipids (which play a critical role in membrane structure/ function and neurotransmission) as well as key neurotransmitter pathways (dopamine, serotonin, glutamate) are evident in schizophrenia.

In Schizophrenia we have used lipidomics analysis and confirmed that there are major changes in phospholipids early in the disease process (Kaddurah-Daouk et al. 2007). Additionally, we have mapped, in greater detail, perturbations in neurotransmitter and purine pathways (Yao et. al. 2009, 2010, 2011). Metabolic signatures of three antipsychotic drugs are being studied and a first report describing their impact on lipid metabolism has been published (Kaddurah-Daouk et al. 2007).

Alzheimer’s Disease

Alzheimer’s disease (AD) is the leading cause of dementia affecting over 5 million people in the US with more than 10 million aging baby boomers estimated to be at risk over the next decades. Although the cause for AD is still not known, it is clear that there are profound biochemical alterations in multiple pathways in the AD brain. The lack of validated “mega” metabolic platforms has limited the ability to simultaneously study the dozens of different biochemical pathways that may be affected in AD both in relation to each other as well as in relation to other biomarkers and progression. Such studies could also help derive peripheral biomarkers (e.g. plasma or urine) that would offer simplicity and cost effectiveness for use in a wide range of settings. Metabolomics is the systematic study of the “metabolome”, the complete repertoire of small molecules present in cells, tissues or organisms. Metabolomics provides a powerful new approach to evaluate global biochemical changes in AD.

In AD, we have several ongoing studies where we are mapping metabolic signatures early in the disease process and comparing metabolic changes that occur centrally and peripherally. Metabolic data are also being integrated with data from imaging studies and other omics data.

Addictions

In Addiction disorders we have mapped metabolic signatures for exposure to cocaine and opioids (Mannelli et al. 2009 & Patkar et al. 2009).

Projects within the Pharmacometabolomics Research Network