Posts Tagged ‘mental illness’

Schizophrenia’s cause ?

Thursday, January 28th, 2016

nature13595-f1

Today there is an article in the Washington Post that describes a genetic site that may be the source of schizophrenia.

The researchers, chiefly from the Broad Institute, Harvard Medical School and Boston Children’s Hospital, found that a person’s risk of schizophrenia is dramatically increased if they inherit variants of a gene important to “synaptic pruning” — the healthy reduction during adolescence of brain cell connections that are no longer needed.

In patients with schizophrenia, a variation in a single position in the DNA sequence marks too many synapses for removal and that pruning goes out of control. The result is an abnormal loss of gray matter.

For years that has been a search for the reason why this mental illness appears in adolescence in people who seemed normal until that stage of development. It is known that adolescence is the time for”pruning” of excessive neuron synapses. Now, it seems that this may be the target f the genetic defect.

The fact that the answer might come from genetics has been known for a while.

To date, around 30 schizophrenia-associated loci10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 have been identified through GWAS. Postulating that sample size is one of the most important limiting factors in applying GWAS to schizophrenia, we created the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC). Our primary aim was to combine all available schizophrenia samples with published or unpublished GWAS genotypes into a single, systematic analysis24. Here we report the results of that analysis, including at least 108 independent genomic loci that exceed genome-wide significance. Some of the findings support leading pathophysiological hypotheses of schizophrenia or targets of therapeutic relevance, but most of the findings provide new insights.

The new paper, just out yesterday in epub, has narrowed the search to the C4 gene on chromosome 6.

After conducting studies in both humans and mice, the researchers said this new schizophrenia risk gene, called C4, appears to be involved in eliminating the connections between neurons — a process called “synaptic pruning,” which, in humans, happens naturally in the teen years.

It’s possible that excessive or inappropriate “pruning” of neural connections could lead to the development of schizophrenia, the researchers speculated. This would explain why schizophrenia symptoms often first appear during the teen years, the researchers said.

This is huge news. I have a chapter on my own experiences in treating schizophrenic men in the early 1960s in my book, War Stories: 50 years in medicine.

My teacher, George Harrington, told me he thought schizophrenia had to be organic in origin and he speculated that it could be deficiency of an unknown vitamin. Genetics were very primitive in those days. The discovery of the number of human chromosomes had only recently been announced when I began medical school. The number was only discovered in 1956, six years before I began medical school.

Using postmortem human brain samples, the researchers found that variations in the number of copies of the C4 gene that people had, and the length of their gene, could predict how active the gene was in the brain.

The researchers then turned to a genome database, and pulled information about the C4 gene in 28,800 people with schizophrenia, and 36,000 people without the disease, from 22 countries. From the genome data, they estimated people’s C4 gene activity.

They found that the higher the levels of C4 activity were, the greater a person’s risk of developing schizophrenia was.

The researchers also did experiments in mice, and found that the more C4 activity there was, the more synapses were pruned during brain development.

This is not therapy by any means but it is a huge step toward something that may prevent the disease is susceptibles.

Autism

Thursday, March 19th, 2009

Autism is a childhood developmental condition that has had a suspected increase in incidence in recent years. It causes a major mental developmental arrest at an early age. Some children begin to develop speech and then regress, a factor that has led to unfortunate theories of causation, such as the hysteria about childhood immunization. Now, a cluster of cases among Somali immigrants in Minnesota might offer some new leads to the cause.

Autism and schizophrenia share some similarities in that both conditions result in problems with social interaction and functional behavior. The autistic child fails to develop speech and other social behavior such as emotional attachment to others. Schizophrenia has similar effects on interpersonal behavior. The autistic child often seems to live in a world cut off from others, responding to inner stimulation but unable to relate to parents or other children. Similarly, the schizophrenic is unable to interpret visual cues and social interaction is difficult. The schizophrenic typically has auditory hallucinations, hearing voices. The autistic child may have similar inner stimuli but is unable to express what is happening because of speech failure.

There are theories about schizophrenia as a consequence of brain development, especially the phenomenon of cerebral dominance which gives us speech and handedness. Now, new theories implicate hormone changes that might be common to both conditions. Animal studies have suggested this association.

Understanding the neurobiological substrates regulating normal social behaviours may provide valuable insights in human behaviour, including developmental disorders such as autism that are characterized by pervasive deficits in social behaviour. Here, we review the literature which suggests that the neuropeptides oxytocin and vasopressin play critical roles in modulating social behaviours, with a focus on their role in the regulation of social bonding in monogamous rodents. Oxytocin and vasopressin contribute to a wide variety of social behaviours, including social recognition, communication, parental care, territorial aggression and social bonding. The effects of these two neuropeptides are species-specific and depend on species-specific receptor distributions in the brain. Comparative studies in voles with divergent social structures have revealed some of the neural and genetic mechanisms of social-bonding behaviour. Prairie voles are socially monogamous; males and females form long-term pair bonds, establish a nest site and rear their offspring together. In contrast, montane and meadow voles do not form a bond with a mate and only the females take
part in rearing the young. Species differences in the density of receptors for oxytocin and vasopressin in ventral forebrain reward circuitry differentially reinforce social-bonding behaviour in the two species.

This is from Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 2006 Dec 29;361(1476):2187-98., “Oxytocin, vasopressin and pair bonding: implications for autism.”, by Hammock EA, Young LJ.

This may seem a rather far fetched association with human autism but there is more.

CNS neuroscience & therapeutics. 2008 Fall;14(3):165-70., “Oxytocin levels in social anxiety disorder.”, by Hoge EA, Pollack MH, Kaufman RE, Zak PJ, Simon NM.

Department of Economics, Claremont University, Claremont, CA, USA.
ehoge@partners.org

Oxytocin is a neuropeptide recently associated with social behavior in animals and humans, but the study of its function in populations with social deficits such as autism, schizophrenia, and social anxiety disorder has only recently begun. We measured plasma oxytocin in 24 patients with Generalized Social Anxiety Disorder (GSAD) and 22 healthy controls using an enzyme-linked immunosorbent assay. There were no significant differences in oxytocin level (pg/mL) between patients (M=163.0, SD=109.4) and controls (M=145.0, SD=52.9, z=0.21, P=0.8). Within the GSAD sample, however, higher social anxiety symptom severity adjusted for age and gender was associated with higher oxytocin level (R2=0.21, beta=0.014, SE=0.006, t=2.18, P=0.04). In addition, dissatisfaction with social relationships was associated with higher oxytocin levels (R2=0.18, beta=-0.20, SE=0.10, t=-2.01, P=0.05). Our data provide preliminary support for a link between social anxiety severity and plasma oxytocin. These findings may suggest a possible role for oxytocin as a facilitator of social behavior, an effect which may not be fully utilized in individuals with severe social anxiety.

This is very preliminary but the existence of the Somali cluster of autism cases might allow further work in this association. Oxytocin has been known as the hormone that begins labor and brings the mother’s milk “down” but it is increasingly seen as having other roles in human behavior. It is not unusual to see the hormones, originally thought to have a single function, assume new roles as physiology is investigated. It would be very interesting if these hormones turn out to play a major role in mental illness. Freud is finally gone from the treatment of major mental illness.

“This is one of the first looks into the biological basis for human attachment and bonding,” said Rebecca Turner, PhD, UCSF adjunct assistant professor of psychiatry and lead author of the study. “Our study indicates that oxytocin may be mediating emotional experiences in close relationships.”

The study builds upon previous knowledge of the important role oxytocin plays in the reproductive life of mammals. The hormone facilitates nest building and pup retrieval in rats, acceptance of offspring in sheep, and the formation of adult pair-bonds in prairie voles. In humans, oxytocin stimulates milk ejection during lactation, uterine contraction during birth, and is released during sexual orgasm in both men and women.

Vasopressin is also involved, especially in males. Vasopressin is a hormone secreted by the pituitary gland and associated with water retention by the kidney. It now appears that it has other functions, as well.

Progress in brain research. 2008;170:337-50.

Neuropeptides and social behaviour: effects of oxytocin and vasopressin in
humans.

Heinrichs M, Domes G.

Department of Psychology, Clinical Psychology and Psychobiology, University of
Zurich, Zurich, Switzerland.

The fundamental ability to form attachment is indispensable for human social relationships. Impairments in social behaviour are associated with decreased quality of life and psychopathological states. In non-human mammals, the neuropeptides oxytocin (OXT) and arginine vasopressin (AVP) are key mediators of complex social behaviours, including attachment, social recognition and
aggression. In particular, OXT reduces behavioural and neuroendocrine responses to social stress and seems both to enable animals to overcome their natural avoidance of proximity and to inhibit defensive behaviour, thereby facilitating approach behaviour.

Doesn’t this sound like autism ?

AVP has primarily been implicated in male-typical social behaviours, including aggression and pair-bond formation, and mediates anxiogenic effects. Initial studies in humans suggest behavioural, neural, and endocrine effects of both neuropeptides, similar to those found in animal studies.

Schizophrenia is more common in males and is hereditary. Anxiety is a major factor. There may also be a hereditary association in autism. This is enormously exciting research and might even be the first sign of a cure for these disorders of brain function.

Homelessness

Thursday, July 31st, 2008

I have had strong opinions about the origin of homelessness for a long time. In 1962, I spent a summer working in the VA psych hospital in West Los Angeles. It was one of the more interesting experiences of my life. The professor and chief of the service was George Harrington, one of the most colorful and impressive people I have met in medicine. At that time, psychiatry was dominated by the psychoanalysts and schizophrenia treatment was just starting to use anti-psychotic drugs like Thorazine. Harrington had been trained as an analyst but had a funny story about how he had learned as a medical student that analysis just didn’t work. He was convinced, he told me, that psychosis, particularly schizophrenia which constitutes the vast majority of cases, was an organic disease, possibly even an unknown vitamin deficiency. Time has proved him correct and present-day treatment is with drugs that target specific receptors for neurotransmitters like GABA and serotonin. There are theories of the cause that may be startling to those who have not spent time reading the literature. For example:

Schizophrenia and prehistory: the price we pay for language?
Robert Kaplan
Graduate School of Medicine
Wollongong, Australia
liaison3@bigpond.com
ABSTRACT
The defining characteristic of humans is language: the expression of the capacity to handle abstract symbols. A growing body of evidence shows that the essential hu-man features did not occur in a ‘big bang’ in Europe around 50Ka, but developed over a 100-200Ka period in Africa.

Schizophrenia, the most severe psychiatric illness, is remarkably consistent in all populations – average 2% – regardless of climate, geography and industrial conditions. As the Australian Aboriginals, who have the same incidence of schizophrenia, were separated by rising seas from early humans, it is clear the illness is genetic and arose sometime between 137,000 and 60,000 years ago..
The other unique feature of the schizophrenia is that it occurs during the reproductive age; despite the obvious disadvantage, it remains prevalent. This suggests that there is a balancing factor which overcomes the reduced reproductive capacity of patients.

Crow, a leading schizophrenia researcher, has put forward the provocative hypothesis that schizophrenia is a disturbance of language, resulting from problems in development of brain asymmetry. A gene on the short limb of the X chromosome has been identified as the possible site that leads to brain asymmetry, an essential development for language. As a result, the speech centre is located in the dominant [left] hemisphere, eliminating the delay from sending a signal across the commissure.

In view of the earlier onset in males, Crow has postulated homologous X and Y genes.
The ‘psychosis’ gene may be a consequence of the development of language: is schizophrenia the price we pay for language? Recent discoveries at MSA sites in Southern Africa coastal regions – such as the cross-hatched ochre from Blombos – give rise to hopes that further evidence of first human capacity to utilise symbols will be found in this region.

Anyway, treatment was severely disrupted about 40 years ago when the politics of mental illness trumped medicine and the state mental hospitals were emptied onto the street. Some of the sad story is described here. The “homeless problem” arose from this action and has persisted since then, garnished with Maxist rhetoric and vapid social theories. Now sense may slowly be returning.

The homeless population continues to decline, by an estimated 12% per year between 2005 and 2007, according to a new report released Tuesday.

Why ?

Homelessness is one of the few corners of public policy in which traditional liberal ideas have gone largely unchallenged. But Mangano believes that many professional activists, though well intentioned, have given up on ending homelessness. They have accepted the problem as intractable and fallen back on social work and handouts as a way to make broken lives more bearable. In doing so, he says, they have allowed “a certain amount of institutionalism” to take root. The Bush Administration proposes to solve the problem by beginning with the hardest cases: the 10 percent who are severe addicts or mentally ill, and consume half of all resources devoted to homeless shelters. Mangano believes that by moving these chronic cases into “supportive housing”—a private room or apartment where they would receive support services and psychotropic medications—the government could actually save money, and free up tens of thousands of shelter beds. The Bush Administration, spotting an opportunity to increase the return on its investment, is seeking to end chronic homelessness within ten years.

It seems to be working. What is unknown is what the next president will do with this program. This is a subtle way of returning to the institution care of severely psychotic individuals and that may be too much like sense for Obama’s liberal theology

Another death on the ACLU’s conscience

Saturday, February 16th, 2008

The deinstitutionalizing of the mentally ill in the 1970s followed directly from the ACLU lawsuits against committment of the mentally ill. This followed the movie, “One Flew Over the Cuckoo’s Nest.” That is a damn poor way of making public policy but that is what we have. Now we have one more murder to chalk up to the ACLU. Here is another such example. Mental health professionals worry about the effects. Still, nothing is done.The legal situation is chaotic. But still people, psychotic and their victims, continue to die.