Plenary

PL01 THE LANCET SERIES ON GLOBAL MENTAL HEALTH: FROM EVIDENCE TO ACTION

Vikram Patel; Martin Prince; K. S. Jacob; Shekhar Saxena, Mario Maj

The Lancet Series on Global Mental Health comprises six articles documenting the current evidence base for global mental health, with a focus on low and middle income countries. The Series culminates with a strident call for action to the global health community to scale up services for mental disorders in these countries. The Series has been developed by an international group of mental health and public health experts, representing academic, policy and civil society perspectives. This landmark series of publications was launched in London on 3 September 2007.

In the first five review articles, the Series provides the information and evidence base for global action on mental health. The reviews demonstrate the high burden of mental disorders, the links and interrelationships between mental disorders and other health conditions and the relevance of mental health for the achievement of Millennium Development Goals. The massive needs are juxtaposed with scarcity of resources for mental health along with their inequitable distribution and inefficient utilization. Evidence for the effectiveness of interventions for treatment and prevention of mental disorders in low and middle income countries is reviewed, demonstrating the encouraging evidence for low-cost treatments for some mental disorders. The current state of mental health systems in countries is presented, showing that in most countries mental health services are woefully inadequate to meet the needs of populations. The Series then systematically examines the barriers to responding to the evidence in policy and practice.

This evidence is utilized, in the final Call to Action article, to make a call to scale up services for mental disorders in all countries, but especially in low and middle income countries. Estimates of likely financial resources necessary for scaling up are provided; just $2 per person per year in low-income countries and $3-4 in lower middle-income countries-modest compared to scaling-up costs for other major contributors to global disease burden. Indicators to monitor progress are suggested and research priorities to assist scaling up are identified. The Series concludes that the evidence and solutions for global mental health burden are at hand. What we need is the political will, concerted action by a range of global health stakeholders, and the resources to implement them. The time to act is now.

This session will provide an overview of all five reviews and the Call for Action paper. The session will be chaired by Professor Mario Maj, a member of the Lancet Global Mental Health Group, and will include lead authors of the six articles (Professor Martin Prince, Institute of Psychiatry, London; Professor Vikram Patel, London School of Hygiene & Tropical Medicine; Professor KS Jacob, Christian Medical College, Vellore, India; and Dr Shekhar Saxena, WHO). Each author will present a brief overview of their paper and the session will end with the chairperson presenting his vision of the WPA's response to the Series.

PL02 ALZHEIMER'S DISEASE: TRANSLATING BASIC RESEARCH INTO CLINICAL EVIDENCE

Colin L. Masters

There is compelling evidence that the Aβ-amyloid peptide is the central biochemical marker of Alzheimer's disease. Aβ itself is the most likely cause of the neurodegeneration which is manifest in synaptic dysfunction and eventual neuronal loss. Pathways up-stream of Aβ production [the proteolytic processing of the amyloid precursor protein (APP) at the α- (δ), β-, and γ- (ε-) sites] provide therapeutic targets amenable to protease inhibition/modulation. Strategies which affect the trafficking of APP into either the α- or β-secretase compartments may also prove of value. Downstream, pathways which promote the degradation of Aβ or modulate its clearance from the brain also offer windows for therapeutic opportunity.

At the center, however, lies the mechanism through which Aβ undergoes a toxic gain-of-function to induce neuronal damage. This provides the most direct route for therapeutic intervention, with the least risk of therapeutic side-effects, since the toxicity of Aβ is unlikely to mimic any normal function. Two principal hypotheses have emerged to explain the toxicity of Aβ: redox chemistry associated with the Cu/Zn metal binding sites on Aβ (His 6, 13/14, Tyr 10, with an influence of Met 35) and lipid interactions associated with the α/β conformation of the hydrophobic C-terminus. Drugs targeting either or both of these mechanisms are now in clinical development with encouraging preliminary results.

Despite two decades of research on APP, the normal function of this integral membrane protein remains elusive. We speculate that in excitatory neurons, the glutamatergic synapse requires strict modulation of extracellular divalent metal ions such as Cu/Zn/Mg, and that APP has evolved as a metallo-protein which functions through its proteolytic release from the membrane and signalling through its cytoplasmic domain. Peturbation of its normal function or processing may lead to excessive β-secretase production of the Aβ fragment, the accumulation of which in turn leads to a toxic gain-of-function. Either as a soluble oligomer or insoluble amyloid fibril, the accumulation of the Aβ peptide provides a pivotal biomarker. This is now being developed as a neuroimaging target and as a blood/CSF biomarker for efficacy of therapeutic intervention, and for gene-linkage discovery.