Stress and health: from molecules to societies

30 08 2012

Here is a great lecture by the truly amazing Prof. Robert Sapolsky from Stanford U.

Prof. Robert Sapolsky





Schizophrenia and Glutamate

28 08 2012

When I was young and pretty, I had a chance to investigate the role of NMDA on negative symptoms of schizophrenia. The theoretical framework of this research was based on the  glutamate hypothesis of schizophrenia. In short, the idea of a glutamatergic abnormality in schizophrenia was first proposed by Kim and colleagues in 1980 based on their findings of low cerebrospinal fluid (CSF) glutamate levels in patients with schizophrenia.Furthermore, the fact that Phencyclidine (PCP) or ketamine (Glutamate antagonists) produces “schizophrenia-like” [negative and positive] symptoms (e.g., delusion and hallucination, avolition, apathy, and blunted affect, deficits in attention, memory, and abstract reasoning and disruptions in prepulse inhibition of startle)  in healthy individuals and profoundly exacerbates pre-existing symptoms in patients with schizophrenia strengthen the glutamate hypothesis.  Moreover, genetic studies suggest that the majority of the genes that have recently been associated with an increased risk for schizophrenia can influence function linked to glutamate receptors. Finally, postmortem receptors studies show changes in glutamate receptor binding, transcription, and subunit protein expression in the prefrontal cortex, thalamus, and hippocampus of subjects with schizophrenia.

I am writing this post in order to inform you about two interesting new papers about this issue. I wonder whether we will see a new line of medications based on this hypothesis.

Here are the papers and their abstracts:

Moghaddam, B, Krystal, J.H. (In press). Capturing the Angel in “Angel Dust”: Twenty Years of Translational Neuroscience Studies of nmda Receptor Antagonists in Animals and Humans. schizophrenia Bulletin

Here, we describe our collaborative efforts to use N-methyl-d-aspartate (NMDA) receptor antagonists as a translational tool to advance our understanding of the pathophysiology of schizophrenia and identify potential new targets for treatment of schizophrenia. We began these efforts in the late 1980s with a keen sense that, in both human and animal studies, we needed to move beyond the dopamine hypothesis of schizophrenia; if the dopamine hypothesis were correct, the existing dopamine antagonists should have cured the disease but they have not. We used NMDA receptor antagonists, not to produce schizophrenia, but as a tool to provide insights into effects of disturbances in glutamate synaptic function in schizophrenia. Our work has provided insights into potential mechanisms that may contribute to disrupted cortical function in schizophrenia and has helped identify potential treatment targets for the disorder. The translational nature of this study made the clinical testing of the first of these targets feasible. Advances in systems neuroscience approaches in animals and humans make new types of translational research possible; however, our concern is that the current obstacles facing translational research funding and academia-industry collaborations threaten the future progress in this field.

Egerton A, Stone JM. (2012).The glutamate hypothesis of schizophrenia: neuroimaging and drug development. Curr Pharm Biotechnol. 2012 Jun 1;13(8):1500-12.

Over the last 50 years, evidence for central involvement of glutamatergic neurotransmission in the pathophysiology of schizophrenia has accumulated. Recent advances in neuroimaging technology now allow several components of glutamatergic neurotransmission to be assessed in the living human brain. Positron emission tomography (PET) or single photon emission tomography (SPET) in combination with select radiotracers allows visualization of glutamatergic receptors in vivo, and magnetic resonance (MR) – based techniques allow mapping of the effects of glutamatergic agents on regional brain activation, and the measurement of regional glutamate concentrations. These imaging studies have provided evidence for regional glutamatergic abnormalities in psychosis, and are beginning to describe both the evolution of these abnormalities over the course of the illness and their response to therapeutic intervention. In parallel, advances in small animal imaging and the development of animal models have provided a platform to explore the neuropathological consequences of glutamatergic abnormality, and the potential antipsychotic efficacy of novel compounds. The molecular diversity of the glutamatergic system has driven the design of several compounds targeting aspects of glutamatergic transmission, and clinical trials have yielded encouraging results. Here, we review the contribution of imaging studies to date in understanding glutamatergic abnormalities in psychosis, and discuss the potential of new glutamatergic compounds for treatment of the disorder.

 





Summer News by NIMH Director

27 08 2012

The last days of this long, hot summer are a good time to catch up on a few of the season’s scientific breakthroughs, which have been coming fast and furious during what has been a down time for many people outside of science.

What about this week’s story of an increase in spontaneous mutations in children of older dads? We already knew that children with autism and schizophrenia were more likely to have been conceived by fathers over 40. And we knew that people with schizophrenia or autism, especially those without a family history of developmental disorders, had a higher number of spontaneous mutations – mutations not found in their parents. The new story, from Kari Stefánsson and colleagues of deCODE Genetics in Iceland, reports that, as men age, they collect spontaneous mutations in their sperm.1 Sperm, which divide every 15 days, collect mutations at a rate of about two per year, with the number of mutations doubling over a 16-year period. Along with a report last month that demonstrates the very high rate of mutations in individual sperm cells,2 we now have a mechanism to explain why paternal age is a risk factor for neurodevelopmental disorders. But the risk is still small, in the range of 2 percent for a man above 40 years of age, and the vast majority of these mutations have no effect. While there has been over a 30 percent increase in birthrates for men over 40 during the past 30 years, increasing paternal age is still a minor factor as a driver for the increased prevalence of autism, certainly not a reason to forego fatherhood.

The strangest discovery of the summer may be the report of bone marrow transplants resolving the symptoms of autism…in mice. Paul Patterson and his colleagues at California Institute of Technology created an autism-like syndrome in mice by exposing them to immune challenges during mid-gestation.3 Once grown up, these prenatally exposed mice showed immune changes but also increased anxiety, decreased social behavior, and repetitive behaviors. A bone marrow transplant, which replaces the immune system, corrected both the immune response and the behavior. This finding, which was unexpected, is surprisingly similar to another recent paper reporting disappearance of the symptoms of Rett syndrome in mice following a bone marrow transplant.4 Both studies suggest that abnormalities of the immune system may underlie some of the symptoms of these neurodevelopmental disorders.

But for me the most disorienting discovery of the summer came from the score of papers in July and August on the microbiome. In the same way that cognitive psychology has redefined how we think about our minds, the microbiome must now redefine how we think about our bodies. Actually the term “our bodies” is no longer accurate. Only 10 percent of our bodies’ genetic material checks out as human DNA: some 90 percent belongs to the trillions of microbes that live on and inside us. If all the cells in our bodies were to take a vote, human cells lose. The reports from the last month begin to map the biogeography of the human body, revealing that we are really a complex ecosystem with regional variation and completely unexpected individual variation in the microbes that make each of us a super-organism. How does this variation influence brain development? What does this variable ecosystem of our bodies mean for the individual differences in our minds? Will the microbiome help us to understand or treat mental disorders? All questions that we can begin to address in the fall.

Lest the microbiome leaves you feeling less impressed about being human, a paper just out from Dan Geschwind and his colleagues at UCLA shows us that the human brain, at least the human frontal lobe, is quite unique in evolution.5 Comparing patterns of gene expression in the human frontal lobe to corresponding areas from chimpanzee and monkey brains, the human expression patterns are not only markedly different but markedly more complex. Certain gene networks, such as the network linking to FoxP2 (a gene implicated in language), appear unique to the human brain.

Of course, there has been much more. New targets for medication development were reported for psychosis6 7 and depression.8 9 10 New findings confirm the role of epigenetics in memory. These tantalizing findings suggest that age-related declines in memory may not be irreversible and suggest new targets for enhancing cognitive function.11 Kurita et al even identify an epigenetic mechanism through which atypical antipsychotic drugs exert their effect, suggesting ways to improve these drugs.12

While this summer may have felt like the doldrums, for science related to mental disorders, it has been tough to keep up.

References

1Kong A, et al. Rate of de novo mutations and the importance of father’s age to disease risk. Nature. Epub 2012 Aug. 22. doi:10.1038/nature11396.

2Wang J, et al. Genome-wide single-cell analysis of recombination activity and de novo mutation rates in human sperm. Cell 2012 Jul 20;150(2):402-12.

3 Hsiao EY, et al. Modeling an autism risk factor in mice leads to permanent immune dysregulation. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12776-81.

4 Derecki NC, et al. Wild-type microglia arrest pathology in a mouse model of Rett syndrome. Nature 2012 Mar 18;484(7392):105-9.

5 Konopka, G, et al. Human-specific transcriptional networks in the brain. Neuron. 2012 Aug 23;75(4):601-617.

6 Law AJ, et al. Neuregulin 1-ErbB4-PI3K signaling in schizophrenia and phosphoinositide 3-kinase-p110δ inhibition as a potential therapeutic strategy. Proc Natl Acad Sci U S A. 2012 Jul 24;109(30):12165-70.

7 Kurita, M, et al. HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci.2012 Aug 5. doi: 10.1038/nn.3181. [Epub ahead of print]

8 Moon HY, et al. Macrophage migration inhibitory factor mediates the antidepressant actions of voluntary exercise. Proc Natl Acad Sci U S A. 2012 Aug 7;109(32):13094-9.

9 Son H, et al. Neuritin produces antidepressant actions and blocks the neuronal and behavioral deficits caused by chronic stress. Proc Natl Acad Sci U S A. 2012 Jul 10;109(28):11378-83.

10 Lim BK, et al. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature. 2012 Jul 11;487(7406):183-9.

11 Oliveira, AM, et al. Rescue of aging-associated decline in Dnmt3a2 expression restores cognitive abilities. Nat Neurosci. 2012 Jul 1;15(8):1111-3.

12 Kurita, M, et al. HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci.2012 Aug 5. doi: 10.1038/nn.3181. [Epub ahead of print]





Is it time to end the distinction between mental and neurological illnesses?

23 08 2012

Probably YESNeurology-Psychiatry





Business Case of Disabilities

22 08 2012

Here is another good example on how hiring people with disabilities is good for business. Do good and Do Well!

Good Job, Walgreens!

 





The Latest Issue of World Psychiartry

19 08 2012

Here is the latest of World Psychiatry, the official journal of the World Psychiatric Association.  Hereby is the TOC of this issue:

EDITORIAL

The self and schizophrenia: some open issues 65
M. MAJ

PERSPECTIVES
The core Gestalt of schizophrenia 67
J. PARNAS

The placebo response: science versus ethics and the vulnerability of the patient
F. BENEDETTI

SPECIAL ARTICLES
Predicting the severity of everyday functional disability in people with schizophrenia: cognitive deficits, functional capacity, symptoms,
and health status
P.D. HARVEY, M. STRASSNIG

Classification of feeding and eating disorders: review of evidence and proposals for ICD-11
R. UHER, M. RUTTER

FORUM – POSITIVE MENTAL HEALTH: MODELS AND CLINICAL IMPLICATIONS
Positive mental health: is there a cross-cultural  definition?
G.E. VAILLANT

Commentaries
Positive mental health: a research agenda
A. CARR

The self-determination theory perspective on positive mental health across cultures
K.M. SHELDON

The clinical role of psychological well-being
G.A. FAVA

Healthy personality development and well-being
C.R. CLONINGER

What is health and what is positive? The ICF solution
M. LINDEN

Subjective positive well-being
P. BECH

Problems in the definitions of positive mental  health
H. KARLSSON

Positive mental health: a note of caution
D.J. STEIN

RESEARCH REPORTS
Quality of hallucinatory experiences: differences between a clinical and a non-clinical sample
G. STANGHELLINI, Á.I. LANGER, A. AMBROSINI,
A.J. CANGAS

Outcomes and moderators of a preventive school-based mental health intervention for children affected by war in Sri Lanka: a cluster
randomized trial
W.A. TOL, I.H. KOMPROE, M.J.D. JORDANS,
A.VALLIPURAM, H. SIPSMA ET AL

MENTAL HEALTH POLICY PAPERS
Peer support among persons with severe mental illnesses: a review of evidence and experience
L. DAVIDSON, C. BELLAMY, K. GUY, R. MILLER

Lessons learned in developing community mental health care in Australasia and the South Pacific
P. MCGEORGE

LETTERS TO THE EDITOR 

WPA NEWS
WPA contribution to the development of the chapter on mental disorders of the ICD-11





NeuroAnalysis & Clinical Brain Profiling

10 08 2012

Today I wish to present a very interesting and [in my opinion] promising way to conceptualize, diagnose and treat psychiatric disorders. This theoretical framework, entitled NeuroAnalysis, an approach that translates clinical phenomenology of mental disorders into their presumed brain-related manifestations at the level of disturbed neural networks. According to the clinical manifestations such translation generates a patient-specific profile of brain disturbances. This is formulated in a testable-prediction manner directly tailored or validation research. The neuroscientific terminology for the translation is called Clinical Brain Profiling (CBP). For example, according to this approach, and based on the professional literature, Psychosis and schizophrenia may be re-conceptualized as disturbances to connectivity and hierarchical dynamics in the brain; mood disorders can be re-conceptualized as disturbances to optimization dynamics and free energy in the brain, and personality disorders can be re-conceptualized as disordered default-mode networks in the brain. While CBP awaits scientific corroboration, it may be a starting point for a future neuroscientific diagnosis in psychiatry. Any thoughts??