Session Summary: Mitochondrial Systems as Targets for Development of Novel Pharmacological Interventions in CNS Disorders Are Addressed at ISCTM 2010 Autumn Conference

A half-day session, characterizing the role of mitochondria dysfunction in various CNS disorders and the utility of targeting specific aspects of this dysfunction was chaired by Charles Bowden, MD, Professor and former Chairman of  the Department of Psychiatry at University of Texas Health Science Center and Andrew Nierenberg, Professor of Psychiatry and Director, BipolarResearch Program at Massachusetts General Hospital, Harvard Medical school, was held on October 14, 2010, at the 210 Autumn Conference  Meeting of the International Society for CNS Clinical Trials and Methodology (ISCTM) in Baltimore, Maryland.

The session began with a review of basic physiology of the electron transport chain and the role of mitochondria which has been implicated in the formation and maintenance of various neurodegenerative and psychiatric disorders based on numerous lines of evidence including abnormal calcium metabolism, brain energy metabolism, reactive oxygen species and mitochondrial associated genetic defects.  Dr. Nierenberg noted that “although some disorders arise directly from mitochondrial DNA mutation, some stem from nuclear gene mutation, and for many disorders the etiology remains elusive.  It is important to note that while there are only 37 mitochondrial genes, there are over 1,200 genes that code for proteins in mitochondria making the task of targeting gene systems very daunting.”

With a focus on near term applicability Dr. Bowden utilized Depression and Bipolar Disorders as examples of possible methodologies that could be employed in targeting mitochondrial systems citing the utility of certain medication such as valproate, lithium, and gabapentin in bipolar disorder and their effect on calcium signaling, synaptic functioning, histone deacetylase inhibition, apoptosis, neurogenesis and possibly even neuroprotection. These compound along with several lines of data from animal models and molecular evidence have confirmed the role of mitochondria in bipolar disorder.  Dr. Bowden also noted that many well known neurodegenerative diseases including ALS, Huntington’s, Alzheimer’s and Parkinson’s disease which have long been known to be a result of mmitochondria that are physically or functionally altered are also associated with behavioral and psychiatric symptoms.  Dr. Bowden called for  “the need to work more closely with the our neurologist colleagues in order to discover new targets based on underlying pathophysiology as we simply cannot venture into this novel arena with the same strategies that we have used in the past”.

Evidence was also provided for possible utility of already existing drugs and drug combinations that potentially modify mitochondrial systems such as acetyl- L–carnitine plus alpha lipoic acid, N- acetyl-cysteine (a glutathione precursor), Coenzyme Q10 as well as several methodological paradigms to assess their potential efficacy such as measuring brain activity at rest (aka default mode brain), magnetic resonance spectroscopy (especially the N acetyl aspartate to chorine ratio),  and structural and functional MRI (fMRI).  Additionally, DNA microarray technology to analyze gene-expression profiles in the postmortem brain and novel animal models to assess mitochondrial system deregulation are needed to improve targetability of drugs aimed at correcting mitochondria dysfunction.

This session reviewed the many challenges faced when identifying and testing potential mitochondria targets including the complexity of the electron transport chain system dysfunction which can both drive and mediate disease, the lack of known central biomarkers, poor brain penetrance of possible drugs, and the time period that is likely needed in order to change a dynamic system  – with some evidence that typical studies of chronic psychiatric disorders which usually assess drug effects between 8 and 12 week duration would not be sufficient long to see changes.

At the conclusion of the session it was unanimously agreed that the session chairs and attendees should form the foundations of a Mitochondria Targets Working Group moving forward with future collaboration and reporting of efforts in the form of future ISCTM sessions and a white paper. Presentations and video of the session are currently being posted for viewing by ISCTM Members, accessible through the ISCTM Library.

The ISCTM (isctm.org) was founded in 2004 to gather representatives from academic and clinical specialties, the pharmaceutical industry, and regulatory bodies to exchange ideas about important clinical and public-health challenges, to examine the development of novel treatments for major psychiatric and neuropsychiatric disorders, and to support advances in methods of evaluating such treatments that are scientifically sound, ethical, and feasible.  To achieve this mission, ISCTM conducts two scientific meetings per year.  The 6th Annual Scientific meeting will be held February 21-23, 2010 at the Fairmont Hotel, Washington DC. View Preliminary Agenda (Submitted by H. Riordan).