Schizophrenia is a mental disorder characterized by a breakdown of thought processes and by poor emotional responsiveness. According to the WHO the disorder affects around 0.3–0.7% of people at some point in their life, or 24 million people worldwide as of 2011. There is no general cure and the pharmacologic treatment of schizophrenia leaves much to be desired.

Now the National Institute for Health Research in the U.K. is funding a large research trial on Minocycline beginning this April.

Scientists believe schizophrenia and other mental illnesses including depression and Alzheimer’s disease may result from inflammatory processes in the brain. Minocycline, which is a broad-spectrum tetracycline antibiotic, has anti-inflammatory and neuroprotective effects, which could account for the recent positive findings.

The new hope comes after case reports from Japan in which the drug was prescribed to a young male patient with schizophrenia.  The young man had no previous psychiatric history but became agitated and suffered auditory hallucinations, anxiety and insomnia. Blood tests and brain scans showed nothing unusual and he was started on the powerful anti-psychotic drug Halperidol. The treatment had no effect and he was still suffering from psychotic symptoms a week later when he developed severe pneumonia and was prescribed the antibiotic Minocycline to treat the infection. This treatment surprisingly led to dramatic improvements in his psychotic symptoms. When the pneumonia cleared and Minocycline treatment was stopped, the schizophrenia symptoms reappeared.

This serendipitous observation prompted researchers to test Minocycline in patients with schizophrenia around the world. Trials have already been held in Israel, Pakistan and Brazil, with schizophrenic patients showing significant improvement.

Minocycline might be a safe and effective solution to bring symptoms of schizophrenia under control. But more work on how antibiotics alter the inflammation status of the brain remains to be done, as well as trying to find a permanent treatment. Using antibiotics in this way presents a problem. Antibiotics are compounds that are literally ´against life,´ aimed against microbial pathogens. The treatment of infectious diseases by antibiotics is compromised by the development of antibiotic resistance of microbial pathogens. There is a direct correlation over time between antibiotic use and the increase in antibiotic-resistant bacteria. Researchers therefore need to address this issue but the signs are good: Minocycline has been on the market for a while, is broadly described, and resistance seems to have been avoided thus far.

Further reading:

Background information, video links and animations about schizophrenia can be found at the DNA Learning Center’s G2C Online webpage.

Van Os J, Kapur S. Schizophrenia. Lancet. 2009;374(9690):635–45. doi:10.1016/S0140-6736(09)60995-8. PMID 19700006

Of course, we also know that environment can play a strong role in determining a disease outcome. For identical twins in their first environment,  the womb, each individual had slight environmental differences the moment the zygote split into two.  As identical twins develop, there will always be some environmental differences, many of which are still not fully understood. Before we explain this mystery of differences between identical (or more accurately “semi-identical”) twins as a matter of nature vs. nurture, there is another component that requires consideration.

There are other ways that DNA can be modified which don’t involve changes in DNA sequence (the order of the DNA’s A, C, T, G chemical “spelling”). These modifications often involve enzymes that can, for example, alter how, or if DNA is transcribed into mRNA. One type these DNA modifying enzymes is methyltransferase, which can add methyl modifications to cytosine (C), often resulting in the suppression of a gene. These types of non-sequence based changes are referred to as epigenetic modifications. Taking the sum of all of the epigenetic modifications gives us the term epigenome, the additional heritable information content of the DNA genome.

In a recent study published in the journal Human Molecular Genetics a paper by E.L. Dempster et.al at the Institute of Psychiatry Kings College in London showed that epigenetic DNA modifications between sets of identical twins can vary by as much as 20%. This study is highly significant in its demonstrating why researches will have to go beyond sequencing the DNA genome of patients and start paying more attention to the epigenome. The Kings College study is the first wide-scale study that brings recent technological advances in epigenetic investigation to understanding psychiatric disorder. The study found epigenetic modifications not only in gene regions already known to be involved in disorders like schizophrenia and bipolar disorder, but has revealed new genes that could be potential targets for drugs. Because epigenetic modification involves chemical modification of DNA, aberrant epigenetic modifications can often be targeted by drugs.  Hopefully further exploration of the epigenome will  yield more clues about these often devastating conditions.

Obviously, the earlier individuals have access to information about their health, the longer they have to make appropriate choices. When it comes to mental-health, a properly responsive school environment may be the first place problems can be identified and, if possible mitigated or corrected. The discovery that there are possible early and characteristic differences in scoring on standardized testing, may give crucial warning signs that would allow proper intervention on behalf of affected students, especially those already at higher risk because of a family history of schizophrenia.

The study conducted by Duke University followed 1000 New Zealanders over the course of 30 years, and administered routine standardized testing at age 3, 5, 7, 9, 11, and 13 years of age. By the time study participants had reached 32 years of age, around 1 percent of participants were being treated for schizophrenia, and another 1.5 were diagnosed but untreated. The testing results from those suffering from schizophrenia had characteristic differences by the age of 7; so at least within the first year of schooling, there are already differences that could raise concern.

Doing poorly on certain standardized tests is certainly not in itself an indication of schizophrenia, but it’s the ways in which the children who later suffered from schizophrenia fell behind their peers that is revealing. According to study author Richard Keefe, these children lag behind their peers initially, and then continue to deteriorate. They tended to have more problems with verbal skills and memory; both obvious impediments to successful learning.

Naturally, the question to ask now is can anything be done to improve our early identification of these at-risk children, and intervene? It is already common to treat early identified autistic children with lots of interactive therapy to help them develop and improved social skills. Can we identify potential schizophrenics and stop whatever process that allows the 3-year old “symptomless” child into the 7-year old “high-risk” individual?

The study can be found at:

http://ajp.psychiatryonline.org/cgi/reprint/appi.ajp.2009.09040574v1

Schizophrenia in childhood from G2C Online:

http://www.g2conline.org/819

What did the group find?
Kleinfeld’s group devised a technique that uses elaborately-named “cell-based neurotransmitter fluorescent engineered reporters” (CNiFERs for short) to examine how neurotransmitter receptors are activated. CNiFERs are cells that have been engineered to change color when acted upon by a specific neurotransmitter. The group created CNiFERs that responded to acetylcholine and implanted these cells into the frontal cortex of adult rats. When stimulated, the CNiFERs fluoresced to indicate the presence of acetylcholine in the frontal cortex.

Next, the group injected the rats with clozapine and olanzapine – neuroleptic drugs (antipsychotics) that are often used to treat schizophrenia. The implanted cells ceased to fluoresce, indicating that the drugs were blocking the transmission of acetylcholine. In other words, the group could see how neuroleptics were affecting the frontal cortex simply by looking at its color!

Why is this important?
This is very exciting and potentially very important. It is theoretically possible to create CNiFERs that respond to any neurotransmitter and to implant cells in any part of the brain. The mechanisms by which many psychiatric drugs work is largely a mystery, with selective serotonin reuptake inhibitors (SSRIs, used to treat depressions) being a case in point. With CNiFERs, researchers have a potentially powerful tool to understand how biochemical signals are relayed through the brain and the sites where they are active. This may lead to more effective treatments for disorders and lay bare many of the secrets of biochemistry that have been hidden for so long.

Now before you start thinking that schizophrenics are the only ones to lose their marbles (or large sections of their genomes), It has been previously shown by work like that of Jonathan Sebat of Cold Spring Harbor Laboratory, that deletions, including those larger than a kilobase are common within all of our genomes.  Obviously, or not so obviously, most humans seem to get along quite fine with these deletions. However, it has recently been appreciated that many psychiatric disorders seem to be influenced by this genomic structural variation.

PSYCH-CNV’s project aims to look at how copy number variation (CNV) contributes to the development of schizophrenia, amongst other illnesses. In a recent paper entitled Large recurrent microdeletions associated with schizophrenia (Stefansson et.al., Nature 2008), it was hypothesized that rare copy number variations might carry the bulk of the risk. The paper went on to describe three regions where deletions were associated with schizophrenia and related psychoses. PSYC-CNV will focus on rare and de novo variations in order to explain how these unique changes in genome arrangement and organization can explain disorders.

Interestingly, a new method developed by the Sebat lab also aims at increasing our ability to detect these copy number changes and explore their meaning for schizophrenia. Instead of relying on microarrays, which often provide insufficent resolution to detect small CNVs, this is a next generation sequence based approach. Next generation sequencers, such as the Illumina platform used in the above refrenced paper, involve sequencing short reads of DNA which are then assembled into a genome. Sebat and his collaborators at Albert Einstein looked at a paramater called depth of read, instead of just analyzing paired end runs, the previous approach to detecting CNVs within a genome.

Titled ‘Screening Madness’, the report highlights lazy and derivational stereotypes that perpetuate the myth that people with mental health problems are either stupid or dangerous.

According to Dr Byrne, “Mental health stereotypes have not changed over a century of cinema. If anything, the comedy is crueller and the deranged psycho killer even more demonic.”

Heath Ledger’s Joker is a case in point. Dr. Byrne points out that the character’s violence and humor is based almost entirely on a misunderstanding of schizophrenia. At one point in the film, “Batman describes the Joker as a schizophrenic clown, and when the film’s second hero Harvey Dent becomes Two-Face and embraces evil, the familiar stereotype of schizophrenia is activated.”

“This is omnipresent in cinema misrepresentations – the psycho killer is immortal and sadistic, motivated by madness – in almost all psychosis films, that character will kill.”

The portrayal of mental illness in the media has been something we have focused on for a long time in G2C Online. In an interview with Dr. David Porteous a couple of years ago, he pointed out that there is a real dearth of knowledge about mental health and genetics among the general public, who have been let down by the failings of traditional media:

“All too often I find that when I’m reading articles in the media, genetic concepts used inappropriately and sometimes quite damagingly.”

While Dr. Porteous was referring primarily to the news media, we should have similar expectations of the movie industry, even when we are dealing with the domain of fiction.

This is underlined by a survey in Dr. Byrne’s report, which found that 44% of people believe that people with a mental illness tend to act violently. He points out that people may be arriving at these misperceptions because of what they see on the silver screen – 49% of those surveyed also reported seeing individuals with a mental illness acting violently in films. While we should not draw too many conclusions from a correlation, it is an interesting statistic to ponder.

We have come to expect a high level of professionalism from actors in major roles. Ledger’s preparations for the role of Joker, for example, are legendary. Had the film’s producers shown a similar commitment to understanding mental illness, then perhaps we could have had a more accurate script. Then again, according to moviemistakes.com, which has identified 60 other errors in the movie, this may be far too much to ask.

What did the study show?

Psychosis is a disordered cognitive state that can include disorganized thoughts, delusions, or hallucinations. It is a common symptom of schizophrenia and has been linked to a number of brain areas, including the the dorsolateral prefrontal cortex (DLPFC) and the hippocampus. Schizophrenia is also strongly associated with a number of genes, and a recent genome-wide association study identified a single nucleotide polymorphism in ZNF804A  as particularly important. Now, for the first time, a German research team has confirmed a link between ZNF804A and these brain structures. The group compared 115 participants who were either risk-allele carriers or non-risk-allele carriers and found differences in how their brains connect. For risk-allele carriers, connections were reduced within the DLPFC and also between left and right DLPFC . Conversely, risk-allele carriers showed increased connectivity between the DLPFC and hippocampal areas.

The study, primarily based at the University of Heidelberg, Germany, focused on a single nucleotide polymorphism (SNP) in ZNF804A (rs1344706)

Schizophrenia is a devastating, highly heritable brain disorder of unknown etiology. Recently, the first common genetic variant associated on a genome-wide level with schizophrenia and possibly bipolar disorder was discovered in ZNF804A (rs1344706). We show, by using an imaging genetics approach, that healthy carriers of rs1344706 risk genotypes exhibit no changes in regional activity but pronounced gene dosage–dependent alterations in functional coupling (correlated activity) of dorsolateral prefrontal cortex (DLPFC) across hemispheres and with hippocampus, mirroring findings in patients, and abnormal coupling of amygdala. , show that rs1344706 or variation in linkage disequilibrium is functional in human brain, and validate the intermediate phenotype strategy in psychiatry.

The study is important for a number of reasons. Firstly, it highlights the importance of connectivity (or dysconnectivity) as a neurobiological marker of schizophrenia. Secondly, it establishes ZNF804A as functional in the human brain. Thirdly, it is an example of how genome-wide association studies can align with anatomical data – to quote the authors, it affirms that “the pathophysiology of overt disease” can “mirror candidate gene effects”.

Functional Genomics and Big Picture Science

This third point is important to how we view science as a whole. Scientific research has traditionally relied upon reductionism as the primary means of discovery. To understand the world, reductionism tells us, we must strip it down to its barest elements. The sequencing of the human genome represents the ultimate triumph of this principle — the dis-assembly of an enormously complex living thing into its three billion molecular constituents. While unraveling the genomic structure ushered in a new era for biology and medicine, it laid bare a new problem—that of genomic function. Now that we have disassembled the machine, we have to figure out how to put it back together again.

Scientists have, in many ways, been forced to abandon reductionism and to look instead at the bigger picture – to see how things fits together. Increasingly we see large multi-disciplinary groups, each of which holds a different piece of the picture. In the current example, we have neuroimaging experts, who look at the gross structure of the brain, collaborating with geneticists, who look at m0lecules, and psychiatrists who look at behavior. These collaborations are exciting, because they integrate a number of different perspectives. Ultimately, this represents a triumph for “big picture” science.

What are CNVs?

Copy number variations are spontaneous mutations in the genome that result in duplications or deletions of the genomic sequence. Duplications can produce extra copies of a gene, deletions can remove it altogether. CNVs are an interesting biological phenomenon because they are not inherited from ones parents. Rather, they are acquired de novo when certain sequences of genetic code fail to copy properly. Acquisition of CNVs is unpredicted, random, and spontaneous. Smaller variants are probably very common—each one of us may have one or two.

A raft of studies over the last five-years has propelled CNVs to the forefront of mental health research. CNVs have been linked with a number of disorders including Alzheimer’s (e.g. Rovelet-Lecrux, 2006), autism (e.g. Sebat et al. 2007), bipolar disorder (e.g. Lachman, 2007), and schizophrenia (e.g. Walsh, 2008). The broad theme of these association studies is that individuals with these disorders have more CNVs than the general population. As such, CNVs may be a major causal factor in cognitive (and other) illness.

What is the evidence?

Currently, there is not a great deal of evidence to support Crespi’s hypothesis. A 2008 Nature review paper by Cook & Schere, highlights two genomic loci particularly associated with both: 15q11 – 15q13 and 22q11. However, these are also associated with other disorders including mental retardation. Similarly, there are many loci associated with schizophrenia and not autism and vice-versa. These findings are not a fatal blow to Crespi’s hypothesis, but do recommend a certain level of skepticism.

Crespi also invokes behavioral (phenotypic) evidence, noting that these disorders have similar symptoms, which manifest in opposite directions. Language, social skills, etc., the hypothesis states, are underdeveloped in autistic-spectrum conditions and overdeveloped on the psychotic spectrum. Again, I am not convinced that there is sufficient evidence to substantiate these claims. Crespi points out that glutamate, the brain’s main neurotransmitter, is deficient in schizophrenia and overactive in autism. However, glutamate is associated with a myriad of disorders. Conversely, many biochemicals are associated with schizophrenia and autism.

Professor Jeffrey Lieberman discusses the glutamate hypothesis of schizophrenia.

To Conclude..

Crespi’s hypothesis is interesting and certainly worthy of further comment. Right now, the evidence is not there to substantiate the hypothesis, but that is not to write it off entirely. As genomic technology becomes more powerful, it is increasingly likely that it will be used to inform how we think about diagnosis and psychiatric disorders. Psychologists are compelled to take note of developments in molecular biology, and the two communities are beginning to merge in places. I suspect we will be seeing many papers of this kind in the next few years.

Read more…

G2C Online, schizophrenia resources:

• http://www.g2conline.org/#Schizophrenia

G2C Online, autism resources:

• http://www.g2conline.org/#Autism

CSHL Harbor Transcript article on CNVs (written by me!):

• http://www.cshl.edu/public/HT/pdfs/07_summer_autism.pdf

A review from Science magazine:

• http://www.sciencemag.org/cgi/content/full/324/5924/162b?rss=1