Schizophrenia

[brainwave]

Interesing conclusion to come out of the National Institue of Mental Health. An evolutionary psychologist was pushing this idea for a while two years ago.

I want them to know when this varient of the DARP-32 gene showed up. It would have serious implications if it was around the time of cro-magnon appearance and Neanderthal disappearance. This striatal/ pre-frontal cortex curcit has a huge role in memory, learning, reward, executive planning, etc.


http://www.news(dot) com(dot) au/story/0,23599,21201390-2,00.html

ONE of the most devastating types of mental illness could be a by-product of the evolution of human beings' intelligence, a new genetic study has suggested.
Scientists have discovered that a common version of a particular gene appears both to enhance a key thinking circuit in the brain, and to be linked to a raised risk of schizophrenia.

The findings, from a study by the US National Institute of Mental Health, provide fresh evidence for the theory that schizophrenia is the price some people pay for our species' advanced intellectual abilities.

The research hints that some of the genetic factors that underpin the human brain's cognitive capacities can also go wrong, leaving a sizeable minority prone to mental illness.

In the study, the NIMH team examined a common variant of a gene called DARPP-32. Three-quarters of the subjects studied inherited at least one copy of it.

This common version of the gene appears to make the brain's most sophisticated thinking region more efficient, the researchers found.

It improves the way information is exchanged between the striatum, a brain region that processes reward, and the prefrontal cortex, the brain's executive hub that manages thoughts and actions.

When this circuit works efficiently, the normal outcome is more flexible thinking and better memory.

But the circuit has been linked to brain functions that go wrong in patients with schizophrenia.

An investigation of 257 families with a history of the condition showed the improving version of DARPP-32 was more common among people who had developed the mental illness.

Daniel Weinberger, of NIMH, said it was possible that while a more efficient link between the prefrontal cortex and striatum normally improves cognitive ability, it may have a negative effect when other genetic and environmental factors interfere.

The result could be a predisposition to schizophrenia, known to be caused by a combination of genes and a person's environment.

"Our results raise the question of whether a gene variant favoured by evolution, that would normally confer advantage, may translate into a disadvantage if the prefrontal cortex is impaired, as in schizophrenia," Dr Weinberger said.

"Normally, enhanced cortex connectivity with the striatum would provide increased flexibility, working memory capacity and executive control.

"But if other genes and environmental events conspire to render the cortex incapable of handling such information, it could backfire - resulting in the neural equivalent of a superhighway to a dead end."

Details of the study are published in the Journal of Clinical Investigation.

Previous research, notably by Nobel laureate Paul Greengard, of Rockefeller University, has established that DARPP-32 acts in the striatum to route information to the brain's cortex for processing.

It operates through the neurotransmitter dopamine, thought to be overactive in people with schizophrenia.

The new work, to which Dr Greengard contributed, is the first to show a link between the gene and more efficient brain circuitry, and possibly to schizophrenia.

 

[Laura]

The Insanity Virus

FROM THE JUNE 2010 ISSUE of DISCOVER

Schizophrenia has long been blamed on bad genes or even bad parents. Wrong, says a growing group of psychiatrists. The real culprit, they claim, is a virus that lives entwined in every person's DNA.

By Douglas Fox|Monday, November 08, 2010

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Schizophrenia is usually diagnosed between the ages of 15 and 25, but the person who becomes schizophrenic is sometimes recalled to have been different as a child or a toddler—more forgetful or shy or clumsy. Studies of family videos confirm this. Even more puzzling is the so-called birth-month effect: People born in winter or early spring are more likely than others to become schizophrenic later in life. It is a small increase, just 5 to 8 percent, but it is remarkably consistent, showing up in 250 studies. That same pattern is seen in people with bipolar disorder or multiple sclerosis.

“The birth-month effect is one of the most clearly established facts about schizophrenia,” says Fuller Torrey, director of the Stanley Medical Research Institute in Chevy Chase, Maryland. “It’s difficult to explain by genes, and it’s certainly difficult to explain by bad mothers.”

The facts of schizophrenia are so peculiar, in fact, that they have led Torrey and a growing number of other scientists to abandon the traditional explanations of the disease and embrace a startling alternative. Schizophrenia, they say, does not begin as a psychological disease. Schizophrenia begins with an infection.

The idea has sparked skepticism, but after decades of hunting, Torrey and his colleagues think they have finally found the infectious agent. You might call it an insanity virus. If Torrey is right, the culprit that triggers a lifetime of hallucinations—that tore apart the lives of writer Jack Kerouac, mathematician John Nash, and millions of others—is a virus that all of us carry in our bodies. “Some people laugh about the infection hypothesis,” says Urs Meyer, a neuroimmunologist at the Swiss Federal Institute of Technology in Zurich. “But the impact that it has on researchers is much, much, much more than it was five years ago. And my prediction would be that it will gain even more impact in the future.”

The implications are enormous. Torrey, Meyer, and others hold out hope that they can address the root cause of schizophrenia, perhaps even decades before the delusions begin. The first clinical trials of drug treatments are already under way. The results could lead to meaningful new treatments not only for schizophrenia but also for bipolar disorder and multiple sclerosis. Beyond that, the insanity virus (if such it proves) may challenge our basic views of human evolution, blurring the line between “us” and “them,” between pathogen and host.

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A simple neurological exam showed Torrey that schizophrenics suffered from more than just mental disturbances. They often had trouble doing standard inebriation tests, like walking a straight line heel to toe. If Torrey simultaneously touched their face and hand while their eyes were closed, they often did not register being touched in two places. Schizophrenics also showed signs of inflammation in their infection-fighting white blood cells. “If you look at the blood of people with schizophrenia,” Torrey says, “there are too many odd-looking lymphocytes, the kind that you find in mononucleosis.” And when he performed CAT scans on pairs of identical twins with and without the disease—including Steven and David Elmore—he saw that schizophrenics’ brains had less tissue and larger fluid-filled ventricles.

Subsequent studies confirmed those oddities. Many schizophrenics show chronic inflammation and lose brain tissue over time, and these changes correlate with the severity of their symptoms. These things “convinced me that this is a brain disease,” Torrey says, “not a psychological problem.”

By the 1980s he began working with Robert Yolken, an infectious-diseases specialist at Johns Hopkins University in Baltimore, to search for a pathogen that could account for these symptoms. The two researchers found that schizophrenics often carried antibodies for toxoplasma, a parasite spread by house cats; Epstein-Barr virus, which causes mononucleosis; and cytomegalovirus. These people had clearly been exposed to those infectious agents at some point, but Torrey and Yolken never found the pathogens themselves in the patients’ bodies. The infection always seemed to have happened years before.

Torrey wondered if the moment of infection might in fact have occurred during early childhood. If schizophrenia was sparked by a disease that was more common during winter and early spring, that could explain the birth-month effect. “The psychiatrists thought I was psychotic myself,” Torrey says. “Some of them still do.”

While Torrey and Yolken were chasing their theory, another scientist unwittingly entered the fray. Hervé Perron, then a graduate student at Grenoble University in France, dropped his Ph.D. project in 1987 to pursue something more challenging and controversial: He wanted to learn if new ideas about retroviruses—a type of virus that converts RNA into DNA—could be relevant to multiple sclerosis.

Robert Gallo, the director of the Institute of Human Virology at the University of Maryland School of Medicine and co­discoverer of HIV, had speculated that a virus might trigger the paralytic brain lesions in MS. People had already looked at the herpes virus (HHV-6), cytomegalovirus, Epstein-Barr virus, and the retroviruses HTLV-1 and HTLV-2 as possible causes of the disease. But they always came up empty-handed.

Perron learned from their failures. “I decided that I should not have an a priori idea of what I would find,” he says. Rather than looking for one virus, as others had done, he tried to detect any retrovirus, whether or not it was known to science. He extracted fluids from the spinal columns of MS patients and tested for an enzyme, called reverse transcriptase, that is carried by all retroviruses. Sure enough, Perron saw faint traces of retroviral activity. Soon he obtained fuzzy electron microscope images of the retrovirus itself.

His discovery was intriguing but far from conclusive. After confirming his find was not a fluke, Perron needed to sequence its genes. He moved to the National Center for Scientific Research in Lyon, France, where he labored days, nights, and weekends. He cultured countless cells from people with MS to grow enough of his mystery virus for sequencing. MS is an incurable disease, so Perron had to do his research in a Level 3 biohazard lab. Working in this airtight catacomb, he lived his life in masks, gloves, and disposable scrubs.

After eight years of research, Perron finally completed his retrovirus’s gene sequence. What he found on that day in 1997 no one could have predicted; it instantly explained why so many others had failed before him. We imagine viruses as mariners, sailing from person to person across oceans of saliva, snot, or semen—but Perron’s bug was a homebody. It lives permanently in the human body at the very deepest level: inside our DNA. After years slaving away in a biohazard lab, Perron realized that everyone already carried the virus that causes multiple sclerosis.

Other scientists had previously glimpsed Perron’s retrovirus without fully grasping its significance. In the 1970s biologists studying pregnant baboons were shocked as they looked at electron microscope images of the placenta. They saw spherical retroviruses oozing from the cells of seemingly healthy animals. They soon found the virus in healthy humans, too. So began a strange chapter in evolutionary biology.

Viruses like influenza or measles kill cells when they infect them. But when retroviruses like HIV infect a cell, they often let the cell live and splice their genes into its DNA. When the cell divides, both of its progeny carry the retrovirus’s genetic code in their DNA.

In the past few years, geneticists have pieced together an account of how Perron’s retrovirus entered our DNA. Sixty million years ago, a lemurlike animal—an early ancestor of humans and monkeys—contracted an infection. It may not have made the lemur ill, but the retrovirus spread into the animal’s testes (or perhaps its ovaries), and once there, it struck the jackpot: It slipped inside one of the rare germ line cells that produce sperm and eggs. When the lemur reproduced, that retrovirus rode into the next generation aboard the lucky sperm and then moved on from generation to generation, nestled in the DNA. “It’s a rare, random event,” says Robert Belshaw, an evolutionary biologist at the University of Oxford in England. “Over the last 100 million years, there have been only maybe 50 times when a retrovirus has gotten into our genome and proliferated.”

But such genetic intrusions stick around a very long time, so humans are chockablock full of these embedded, or endogenous, retroviruses. Our DNA carries dozens of copies of Perron’s virus, now called human endogenous retrovirus W, or HERV-W, at specific addresses on chromosomes 6 and 7.

If our DNA were an airplane carry-on bag (and essentially it is), it would be bursting at the seams. We lug around 100,000 retro­virus sequences inside us; all told, genetic parasites related to viruses account for more than 40 percent of all human DNA. Our body works hard to silence its viral stowaways by tying up those stretches of DNA in tight stacks of proteins, but sometimes they slip out. Now and then endogenous retroviruses switch on and start manufacturing proteins. They assemble themselves like Lego blocks into bulbous retroviral particles, which ooze from the cells producing them.

Endogenous retroviruses were long considered genetic fossils, incapable of doing anything interesting. But since Perron’s revelation, at least a dozen studies have found that HERV-W is active in people with MS.

By the time Perron made his discovery, Torrey and Yolken had spent about 15 years looking for a pathogen that causes schizophrenia. They found lots of antibodies but never the bug itself. Then Håkan Karlsson, who was a postdoctoral fellow in Yolken’s lab, became interested in studies showing that retroviruses sometimes triggered psychosis in AIDS patients. The team wondered if other retroviruses might cause these symptoms in separate diseases such as schizophrenia. So they used an experiment, similar to Perron’s, that would detect any retrovirus (by finding sequences encoding reverse transcriptase enzyme)—even if it was one that had never been catalogued before. In 2001 they nabbed a possible culprit. It turned out to be HERV-W.

Several other studies have since found similar active elements of HERV-W in the blood or brain fluids of people with schizophrenia. One, published by Perron in 2008, found HERV-W in the blood of 49 percent of people with schizophrenia, compared with just 4 percent of healthy people. “The more HERV-W they had,” Perron says, “the more inflammation they had.” He now sees HERV-W as key to understanding many cases of both MS and schizophrenia. “I’ve been doubting for so many years,” he says. “I’m convinced now.”

Torrey, Yolken, and Sarven Sabunciyan, an epigeneticist at Johns Hopkins, are working to understand how endogenous retroviruses can wreak their havoc. Much of their research revolves around the contents of a nondescript brick building near Washington, D.C. This building, owned by the Stanley Medical Research Institute, maintains the world’s largest library of schizophrenic and bipolar brains. Inside are hundreds of cadaver brains (donated to science by the deceased), numbered 1 through 653. Each brain is split into right and left hemispheres, one half frozen at about –103 degrees Fahrenheit, the other chilled in formaldehyde. Jacuzzi-size freezers fill the rooms. The roar of their fans cuts through the air as Torrey’s team examines the brains to pinpoint where and when HERV-W awakens into schizophrenia.

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Sabunciyan has found that an unexpectedly large amount of the RNA produced in the brain—about 5 percent—comes from seemingly “junk” DNA, which includes endogenous retroviruses. RNA is a messenger of DNA, a step in the path to making proteins, so its presence could mean that viral proteins are being manufactured in the body more frequently than had been thought.

Through this research, a rough account is emerging of how HERV-W could trigger diseases like schizophrenia, bipolar disorder, and MS. Although the body works hard to keep its ERVs under tight control, infections around the time of birth destabilize this tense standoff. Scribbled onto the marker board in Yolken’s office is a list of infections that are now known to awaken HERV-W—including herpes, toxoplasma, cytomegalovirus, and a dozen others. The HERV-W viruses that pour into the newborn’s blood and brain fluid during these infections contain proteins that may enrage the infant immune system. White blood cells vomit forth inflammatory molecules called cytokines, attracting more immune cells like riot police to a prison break. The scene turns toxic.

In one experiment, Perron isolated HERV-W virus from people with MS and injected it into mice. The mice became clumsy, then paralyzed, then died of brain hemorrhages. But if Perron depleted the mice of immune cells known as T cells, the animals survived their encounter with HERV-W. It was an extreme experiment, but to Perron it made an important point. Whether people develop MS or schizophrenia may depend on how their immune system responds to HERV-W, he says. In MS the immune system directly attacks and kills brain cells, causing paralysis. In schizophrenia it may be that inflammation damages neurons indirectly by overstimulating them. “The neuron is discharging neurotransmitters, being excited by these inflammatory signals,” Perron says. “This is when you develop hallucinations, delusions, paranoia, and hyper-suicidal tendencies.”

The first, pivotal infection by toxoplasmosis or influenza (and subsequent flaring up of HERV-W) might happen shortly before or after birth. That would explain the birth-month effect: Flu infections happen more often in winter. The initial infection could then set off a lifelong pattern in which later infections reawaken HERV-W, causing more inflammation and eventually symptoms. This process explains why schizophrenics gradually lose brain tissue. It explains why the disease waxes and wanes like a chronic infection. And it could explain why some schizophrenics suffer their first psychosis after a mysterious, monolike illness.

The infection theory could also explain what little we know of the genetics of schizophrenia. One might expect that the disease would be associated with genes controlling our synapses or neurotransmitters. Three major studies published last year in the journal Nature tell a different story. They instead implicate immune genes called human leukocyte antigens (HLAs), which are central to our body’s ability to detect invading pathogens. “That makes a lot of sense,” Yolken says. “The response to an infectious agent may be why person A gets schizophrenia and person B doesn’t.”

Gene studies have failed to provide simple explanations for ailments like schizophrenia and MS. Torrey’s theory may explain why. Genes may come into play only in conjunction with certain environmental kicks. Our genome’s thousands of parasites might provide part of that kick.

“The ‘genes’ that can respond to environmental triggers or toxic pathogens are the dark side of the genome,” Perron says. Retroviruses, including HIV, are known to be awakened by inflammation—possibly the result of infection, cigarette smoke, or pollutants in drinking water. (This stress response may be written into these parasites’ basic evolutionary strategy, since stressed hosts may be more likely to spread or contract infections.) The era of writing off endogenous retroviruses and other seemingly inert parts of the genome as genetic fossils is drawing to an end, Perron says. “It’s not completely junk DNA, it’s not dead DNA,” he asserts. “It’s an incredible source of interaction with the environment.” Those interactions may trigger disease in ways that we are only just beginning to imagine.

Torrey and Yolken hope to add a new, more hopeful chapter to this story. Yolken’s wife, Faith Dickerson, is a clinical psychologist at Sheppard Pratt Health System in Baltimore. She is running a clinical trial to examine whether adding an anti-infective agent called artemisinin to the drugs that patients are already taking can lessen the symptoms of schizophrenia. The drug would hit HERV-W indirectly by tamping down the infections that awaken it. “If we can treat the toxoplasmosis,” Torrey says, “presumably we can get a better outcome than by treating [neurotransmitter] abnormalities that have occurred 14 steps down the line, which is what we’re doing now.”

Looking ahead, better prenatal care or vaccinations could prevent the first, early infections that put some people on a path to schizophrenia. For high-risk babies who do get sick, early treatment might prevent psychosis from developing two decades later. Recent work by Urs Meyer, the neuroimmunologist, and his colleague Joram Feldon at the Swiss Federal Institute of Technology drives this point home. When they injected pregnant mice with RNA molecules mimicking viral infections, the pups grew up to resemble schizophrenic adults. The animals’ memory and learning were impaired, they overreacted to startling noises, and their brain atrophied. But this March, Meyer and Feldon reported that treating the baby mice with antipsychotic drugs prevented them from developing some of these abnormalities as adults.

Perron has founded a biotech start-up —GeNeuro, in Geneva, Switzerland—to develop treatments targeting HERV-W. The company has created an antibody that neutralizes a primary viral protein, and it works in lab mice with MS. “We have terrific effects,” Perron says. “In animals that have demyelinating brain lesions induced by these HERV envelope proteins, we see a dramatic stop to this process when we inject this antibody.” He is scheduled to begin a Phase 1 clinical trial in people with MS near the end of this year. A clinical trial with schizophrenics might follow in 2011.

Even after all that, many medical experts still question how much human disease can be traced to viral invasions that took place millions of years ago. If the upcoming human trials work as well as the animal experiments, the questions may be silenced—and so may the voices of schizophrenia.

 

[Laura]

Role of Chronic Bacterial and Viral Infections in Neurodegenerative, Neurobehavioural, Psychiatric, Autoimmune and Fatiguing Illnesses: Part 2

Garth L. Nicolson and Jörg Haier

Schizophrenia

Several microbes have been suspected as pathogenetic factors in schizophrenia, such as Chlamydia species, toxoplasma, and various viruses. For example, a number of studies have reported associations between Toxoplasma gondii infection and the risk of schizophrenia with an overall hazard ratio of 1.24.14 In addition, chlamydial infections have been found in 40% of schizophrenic patients compared to 7% in healthy controls.15 These infections represented the highest risk factor yet found to be associated with schizophrenia that was highly significant (Odds Ratio=9.43, p=1.39 x 10-10), especially with Chlamydophila psittaci (Odds Ratio=24.39, p=2.81 x 10-7). Interestingly, schizophrenic carriers of the HLA-A10 genotype were clearly the most often infected with Chlamydia, especially C. psittaci (Odds Ratio=50.00, p=8.03 x 10-5), pointing to a genetically related susceptibility.15 However, skepticism against the role of bacterial infection in schizophrenia was also fostered by the low impact of anti-infectious treatment on the course of disease progression in schizophrenia.16

Genetic backgrounds and viral infections and/or reactivations as well as cytokine-related pathomechanisms have also been proposed as causative for psychiatric disorders, such as schizophrenia. Specific genetic patterns of MICB polymorphism (MHC class I polypeptide-related sequence B, chromosome 6p21) were identified in patients seropositive for CMV and HSV-1.17 Similar polymorphisms were found for the COMT Val158Met related to serological evidence of HSV-1 infections in individuals with bipolar disorder.18 This serologic evidence of HSV-1 infection appeared to be associated with cognitive impairment in individuals with bipolar disorders19 and was found to be an independent predictor of cognitive dysfunction in individuals with schizophrenia.20 In addition, viral exposure during gestation has been described as a risk factor for schizophrenia. Offspring of mothers with serologic evidence of HSV-2 infection were at significantly increased risk for the development of psychoses (Odds Ratio=1.6; CI 95% 1.1-2.3). These results are consistent with a general model of risk resulting from enhanced maternal immune activation during pregnancy.21 However, this was not confirmed in another study.22 Similar contradictory results were observed in a small group of 8 patients with schizophrenia where reactivation of herpesviruses (HSV-1, CMV, EBV, varicella-zoster virus and human HHV-6) and other viruses (measles, rubella, mumps, influenzaA and B and Japanese encephalitis viruses) during acute onset or exacerbation of schizophrenia was investigated, but none of these viruses were detected in these patients.23 Also, a search for HSV-1 or varicella zoster virus infection in postmortem brain tissue from schizophrenic patients did not reveal evidence of persistent CNS infections with these viruses.24

Schizophrenic patients show a number of cytokine changes that may be important in their condition. For example, differences in interleukin-2, -4 and –6, among other cytokines, have been seen in schizophrenic patients.25-27 Often these changes in cytokines or cytokine receptors have been linked to associated genetic changes found in schizophrenia.28-30 Monji et al.31 recently reviewed the evidence for neuroinflammation, increases in pro-inflammatory cytokines and genetic changes in schizophrenia and concluded that these changes are closely linked to activation of microglia. Although the microglia comprise only about 10% of the total brain cells, they respond rapidly to even minor pathological changes in the brain and may contribute to neurodegeneration through the production of pro-inflammatory cytokines and free radicals. CNS infections could also activate microglia and cause similar events.

 

[Laura]

Antibiotics Found Effective in Schizophrenia
Tetracyclines help treat psychosis as well as tick-borne disorders.
Post published by Richard Horowitz MD on Feb 08, 2014

A controlled clinical trial was just published in the psychiatric literature, showing that minocycline is effective in treating negative symptoms in early phase schizophrenia. A prior pilot study, published in 2010 in the Journal of Clinical Psychiatry, also showed that minocycline was effective in schizophrenia, helping executive functioning such as working memory. The authors postulate that the mechanism of action of minocycline would include affecting glutamate pathways in the central nervous system, blocking nitric oxide-induced neurotoxicity, or inhibiting microglial activation in the brain, causing inflammation. All of these are reasonable potential mechanisms of action. Neither author discusses the obvious fact however that minocycline is a tetracycline antibiotic and that it may be treating an occult infection.

Have infections ever been reported to cause schizophrenia?

Lyme disease causes a wide range of psychiatric manifestations. Published research has shown a higher prevalence of antibodies to Borrelia burgdorferi in psychiatric patients than in healthy subjects. There is also a known geographic correlation of schizophrenia with ticks and tick-borne encephalitis, with peer reviewed literature showing an association of Lyme disease with schizophrenia. Other tick-borne infections, such as Bartonella (cat scratch disease) have also been reported to cause neurological and neurocognitive dysfunction, as well as causing agitation, panic disorder and treatment resistant depression. Minocycline, as well as other tetracycline antibiotics like doxycycline, are well known treatments for neurological manifestations of Lyme disease and associated co-infections like Bartonella. It is therefore plausible that a certain number of cases of severe psychiatric presentations are due to underlying infections, especially since Lyme disease is the number one spreading vector borne infection in the world.

I have seen several patients who came to my medical clinic with a diagnosis of schizophrenia, on anti-psychotic medications like Risperdal. Upon further testing, their Western Blots returned positive for exposure to Borrelia burgdorferi, the agent of Lyme disease. They were given doxycycline (a similar tetracycline antibiotic), and their psychotic symptoms and cognition improved significantly. Working with their psychiatrist, we were able to reduce, and in some cases eliminate, all of their antipsychotic medication. They remained clinically stable as long as they remained on antibiotics. Their psychiatric symptoms returned once they were no longer being treated for Lyme and associated tick-borne disorders, as these organisms have been shown to be able to establish a persistent infection in the body.

When should we suspect Lyme disease as a potential etiological co-factor in psychiatric symptoms? Lyme disease is a multisystemic illness. If a patient presents with a symptom complex that comes and goes with good and bad days, with associated fevers, sweats and chills, fatigue, migratory joint and muscle pain, migratory neuralgias with tingling, numbness and burning sensations, a stiff neck and headache, memory and concentration problems, a sleep disorder and associated psychiatric symptoms (that may or may not be of recent onset), then we should suspect Lyme disease and associated co-infections. Have these patients fill out a Lyme screening questionnaire (link is external) that we developed in my medical office. Among 100 patients who filled out this form, a score above 46 was associated with a high probability of a tick-borne disorder. In that case, blood testing should be performed through a reliable laboratory to look for Lyme and co-infections, including Babesia and Bartonella, which can also significantly increase underlying symptomatology.

Lyme disease is a major cause of psychiatric symptoms. Psychiatric case reports, as reported by psychiatrist Dr Brian Fallon, have linked Lyme disease to paranoia, thought disorders, delusions with psychosis, schizophrenia, with or without visual, auditory or olfactory hallucinations, depression, panic attacks and anxiety, obsessive compulsive disorder, anorexia, mood lability with violent outbursts, mania, personality changes, catatonia and dementia. Other psychiatric disorders in adults due to Lyme disease include atypical bipolar disorder, depersonalization/derealization, conversion disorders, somatization disorders, atypical psychoses, schizoaffective disorder and intermittent explosive disorders. In children and adolescents, Lyme disease can also mimic Specific or Pervasive Developmental Delays, Attention-Deficit Disorder (Inattentive subtype), oppositional defiant disorder and mood disorders, obsessive compulsive disorder (OCD), anorexia, Tourette’s syndrome, and pseudo-psychotic disorders. The take home message: Lyme is the “great imitator”. Don’t exclude Lyme disease and associated infections as a possible underlying cause of psychiatric symptoms, and don’t assume that a positive response to an antibiotic like minocycline is not treating an underlying infection.

Liu, F., Guo, X., Wu, R., et al. (2014). Minocycline supplementation for treatment of negative symptoms in early-phase schizophrenia: A double blind, randomized, controlled trial. Schizophr Res. Published on line: http://www.schres-journal.com/article/S0920-9964%2814%2900014-0/fulltext (link is external)

Levkovita, Y., Mendlovich, S., Riwkes, S., et al. (2010). A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J. Clin Psychiatry 71(2):138-49.

Fallon, B.A., & Nields, J.A. (1994). Lyme disease: A neuropsychiatric illness. Am J Psychiatry 151(11):1571-83.

Fallon, B.A., Kochevar, J.M., Gaito, A., & Nields, J.A. (1998). The underdiagnosis of neuropsychiatric Lyme disease in children and adults. Psychiatric Clinics of North America 21: 693-703.

Hajek, T., Paskova, B., Janovska, D., et al. (2002). Higher prevalence of antibodies to Borrelia burgdorferi in psychiatric patients than in healthy subjects.
Am J Psychiatry 159:297-301.

Hess, A., Buchmann, J., Zettl, U.K., Henschel, S., Schlaefke, D., Grau, G., & Benecke, R. (1999). Borrelia burgdorferi central nervous system infection presenting as an organic schizophrenialike disorder. Biol Psychiatry 45(6):795.

Brown, J.S. Jr. (1994). Geographic correlation of schizophrenia to ticks and tick-borne encephalitis. Schizophr Bull; 20(4):755-75

Breitschwerdt, E.B., Maggi, R.G., Nicholson, W.L., Cherry, N.A., & Woods, C.W. Bartonella sp. bacteremia in patients with neurological and neurocognitive dysfunction. Journal of Clinical Microbiology. 46(9):2856–2861.

Schaller, J.L., Burkland, G.A., & Langhoff, P.J. (2007). Do bartonella infections cause agitation, panic disorder, and treatment-resistant depression? MedGenMed. 9(3):54.

Fallon, B.A., Levin, E.S., Schweitzer, P.J., & Hardesty, D. (2010). Inflammation and central nervous system Lyme disease. Neurobiology of Disease 37: 534-541

Sherr, V.T. (2000). Panic attacks may reveal previously unsuspected chronic disseminated Lyme disease. J. Psychiatric Practice, 6:352-356.

Benke, T., Gasse, T., Hittmair-Delazer, M., & Schmutzhard, E. (1995). Lyme encephalopathy: Long-term neuropsychological deficits years after acute neuroborreliosis. Acta Neurol Scand. 91(5):353-7;

Nicolson G., & Haier, J. (2009). Role of chronic bacterial and viral infections in neurodegenerative, neurobehavioral, psychiatric, autoimmune and fatiguing illnesses: Part I. BJMP 2(4) 20-28. http://www.bjmp.org/content/role-chronic-bacterial-and-viral-infections-neurodegenerative-neurobehavioral-psychiatric-au (link is external)

Krause. P.J. et al. (1996). Concurrent Lyme disease and babesiosis. Evidence for increased severity and duration of illness. JAMA 275(21):1657-1660.

Preac-Mursic, V. et al. (1989). Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis. Infection 17:355-359

 

[MusicMan]

A very interesting treatise, and yet my intellect only absorbs some of the information.

In the case of Multiple Sclerosis, which you mentioned earlier, Dr. Hulda Clark implicates fluke parasites which are enabled to enter the brain and spinal cord by the solvents xylene and toluene, found in paint and thinners, and in some carbonated beverages, and also mercury from dental fillings..

She added that ALL MS cases she had seen harboured the bacterium Shigella in the brain and spinal cord, and that these come from dairy products.

Her protocol for attacking the flukes is zapping at 421KHz to 434KHz, getting rid of family pets and proper cooking of meat products.

ref: "The Cure for All Diseases" Dr Hulda Regehr Clark, pp.204-206. (fair use)

 

[Laura]

I've tried several of the Hulda Clark remedies/devices for a number of things and, as far as I can tell, achieved no objective beneficial results.

 

[Gaby]

Association between Intracellular Infectious Agents and Schizophrenia

_http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3569146/

Clin Psychopharmacol Neurosci. 2012 Aug; 10(2): 117–123. Mi-Hee Park,1 Young-Joon Kwon,1 Hee-Yeun Jeong,1 Hwa-Young Lee,1 Young Hwangbo,2 Hee-Jung Yoon,3 and Se-Hoon Shimcorresponding author1

INTRODUCTION

Several causative factors have been identified in the pathophysiology of schizophrenia. Family and twin studies indicate that there is a strong genetic component, which influences the risk of acquiring schizophrenia. However, epidemiological and neuropathological studies have also indicated that some cases of schizophrenia may be associated with environmental factors, such as birth season or exposure to infectious agents.1,2)

Until now, various microbial agents have been proposed as risk factors for schizophrenia, and they all share similar characteristics; an ability to establish persistent infections within the central nervous system as well as the occurrence of psychiatric symptoms in some individuals infected with these agents. We found several published studies from various research groups with special emphasis on the protozoan organism Toxoplasma (T.) gondii,3) as well as intracellular bacteria Chlamydia.

T. gondii is a neurotropic protozoan parasite that was characterized at the turn of the 20th century and later associated with a series of congenital sensory and neurological conditions.4) Although the definitive hosts are felines such as cats, T. gondii affects almost all warm-blooded animals including humans. In humans, infection is mainly acquired by ingestion of contaminated food or water or through eating undercooked or raw meat that contains tissue cysts.5) This microbe is known to be neurotrophic and infects both neurons and glia.6) Serologically, the first research linking schizophrenia and other psychoses to an increase in antibodies to T. gondii was published in 1953; since then, a number of studies have been carried out.7) A study of newborn and maternal sera of individuals who later developed schizophrenia reported more T. gondii antibodies in their sera compared to normal controls.8) In addition, preliminary analysis of a cohort of individuals in the United States Military indicated that increased levels of Toxoplasma antibodies can be found in individuals prior to the onset of psychotic symptoms, thus obviating the possibility that the finding of increased levels of antibodies is an epiphenomenon associated with exposure occurring after the onset of schizophrenia.9) Phee et al.,10) using indirect fluorescent antibody technique (IFA), found higher positive reaction for T. gondii in chronic schizophrenia patients than in control group.

Chlamydiae were taxonomically categorized into their own order Chlamydiales, with one family, Chlamydiaceae, and a single genus, Chlamydia which included four species: Chlamydia (C.) trachomatis, C. pneumonia, C. psittaci, and C. pecorum.11) Two of the species, C. trachomatis and C. pneumoniae are common human pathogens and can persist in infected monocytes. The primary targets of Chlamydophila infection in the brain are probably microglia cells, which arise from monocyte subpopulations.12) Despite the presence of limited literature, it is evident that Chlamydia may be implicated in the pathogenesis of schizophrenia. Fellerhoff et al.,13) using n-polymerase chain reaction (PCR), found a significant prevalence of C. psittaci, C. pneumoniae, and C. trachomatis in schizophrenic patients, as compared to controls. Fellerhoff and Wank14) also found that prevalence of Chlamydophila DNA in post-mortem brain frontal cortex from patients with schizophrenia was four times greater than in controls. Frykholm15) suggested C. pneumonia as a common etiology of schizophrenia and multiple sclerosis, and reported improvement in several cases of psychotic patients by antibiotic therapy.

Considering all these findings, we conjectured that T. gondii and Chlamydia might play a key role in the etiology of schizophrenia. Although there exists several studies supporting association between schizophrenia and these infectious agents, to the best of our knowledge, almost no research dealing with the subject of present investigation was performed in Korea. In this study, we investigated whether there is a higher prevalence of T. gondii, C. trachomatis and C. pneumonia infection in schizophrenic patients. Likewise, we divided schizophrenic patients into seropositive and seronegative group based on seropositivity of immunoglobulin (Ig) and compared their features to figure out specific trait of infectious agent related to schizophrenic patients. [...]

DISCUSSION

In the present study, we investigated the rate of positive serological reaction to T. gondii, C. pneumoniae, and C. trachomatis in 96 schizophrenic patients and 50 normal controls. Likewise, we divided schizophrenic patients into seropositive and seronegative group based on seropositivity of Ig and compared their features to figure out specific trait of infectious agent-related schizophrenic patients.

We found that the schizophrenic patients had a significantly higher rate of positive IgG antibodies to infectious agents as compared to the normal controls. Especially, antibodies to T. gondii and C. trachomatis were overrepresented in schizophrenic patients. This finding suggests that T. gondii and C. trachomatis infections are associated with schizophrenia.

In accordance to the present study, some of the previous studies reported that Toxoplasma infection represents one risk factor for schizophrenia. Wang et al.3) reported an association between Toxoplasma infection and first episode of schizophrenia, suggesting a 2-5 times increased risk of schizophrenia due to chronic Toxoplasma infection. Niebuhr et al.9) using samples obtained from United States Military members prior to schizophrenia diagnosis, found significant positive association between T. gondii IgG antibody and schizophrenia. Yolken et al.18) found demonstrated that individuals with first episode schizophrenia had significantly increased levels of IgG, IgM and IgA class antibodies to T. gondii. Phee et al.10) found higher positive reaction for T. gondii in chronic schizophrenia patients than control group, especially patients with negative symptoms and our findings are consistent with these studies. However, there are a number of other studies, which did not correspond to the results of present study. Krause et al.19) found no statistical differences measured for T. gondii. Further research is needed to clarify the inconsistency in the study.

For C. trachomatis, our findings were in accordance with previous studies that concluded that C. trachomatis infection is associated with schizophrenia. Krause et al.19) found significantly higher rates of positive antibodies to C. trachomatis when compared to the other infectious agents, suggesting infection as one of the contributing factors for schizophrenia amongst others, like genetic disposition. Fellerhoff et al.13) found significant prevalence of chlamydial infection in schizophrenic group, suggesting chronic infections with chlamydiaceae as the main pathogenic factors in the pathogenesis of schizophrenia, and the requirement of immunotherapy to restore the balance of immune subpopulations. To the best of our knowledge, this is the first report on a positive association of C. trachomatis with schizophrenia in a Korean population.

In the case of C. pneumoniae, despite the presence of several previous studies supporting the contention that C. pneumoniae is a possible risk factor for schizophrenia,13,14) no statistical difference could be measured. Nevertheless, a research corresponded to the result of our study but the reason was uncertain.19) In our study, schizophrenia and control group both showed high IgG seropositivity. High prevalence of C. pneumoniae in Korea and the character of their environment could be the leading causes for high seropositivity in both schizophrenia and control group. Korea is highly endemic with C. pneumoniae infection, with increased prevalence in adults. A research has demonstrated that in healthy subjects over 21 years of age, C. pneumoniae IgG antibody was present in 70% of males and 56% of females.20)

In the present study, it was observed that mainly IgG and not IgM antibodies were elevated in condition of schizophrenia, and this could further indicate that the infections are not acute any more, but have progressed to dormant infections with a persistent immune response. As IgG antibodies are involved in secondary immune response, IgM antibodies appear early in the course of an infection and usually reappear.21) In our study, we just showed the rates of antibody titers, the infectious agents were not investigated directly with PCR. However, there is no evidence from this study that patients with schizophrenia have an increased prevalence of acute infections, but clearly, these patients have had more infections in the past and/or are suffering from a chronic infectious condition.

We also compared the characteristics between schizophrenia patients with detectable IgG antibody (the positive group) and those without detectable IgG antibody (the negative group) to T. gondii and C. trachomatis. For T. gondii, positive group showed less years of education. We cannot assert that infection is the only factor related to years of education, but our findings might be related to previous studies, which demonstrated that schizophrenic patients, who had gestational exposure to infectious agents showed executive dysfunction when compared to unexposed group.22) Impaired executive function might have influenced the ability to keep up their learning, eventually making them to be dropped out of school. In addition, positive group showed higher rate of familial history of mental disorder. This could be a supportive finding for genetic susceptibility of those people, who became schizophrenic due to infection. We conjectured that if high rate of familial history of mental disorder indicates inherited genetic fragility, higher rate of familial history would be present in sero-positive group, which has more probability for infection as etiology of their disorder, when compared to sero-negative group. A number of studies have shown evidence on the interaction of predisposing genes with one or more infectious agents to cause schizophrenia.7,23) C. trachomatis showed no significant difference in character between seropositive and seronegative group.

In addition, we have also compared the PANSS subscale score between schizophrenic patients with seropositive and seronegative group for T. gondii and C. trachomatis infection. For T. gondii, the seropositive group scored significantly higher score in several negative subscales and one general psychopathology scale, 'disturbance of volition'. Fellerhoff et al.,13) treated patients with schizophrenia and other mental disorders with evidence of infection by using adoptive immunotherapy and antibiotics, but no antipsychotics. The improvement in the status of the patients was mainly related with regain of energy and volition, improvement of social withdrawal, which are main components of negative symptom. Based on these findings, we cautiously suggest the relation between negative symptoms and 'disturbance of volition' with infectious agent. In the case of C. trachomatis infection, the seropositive group scored significantly higher score in one general psychopathology subscale, disorientation. Still, evidence to underpin relation between infectious agents and disorientation is insufficient.

Despite numerous studies performed to reveal relation between infectious agents and schizophrenia, it is still controversial whether infectious agents play a causal role in inducing psychotic symptoms. Proving causality is one of the major limitations of studies about the association of schizophrenia and infections. As schizophrenia is constituted of a number of inhomogeneous symptoms, it seems more probable that infections might just be one of the contributing factors among others.13) In the case of schizophrenia, one possible causality could be that infectious agents do not directly cause psychiatric symptoms, but influence the immune balance via the status of a chronic infection. We assume that these different infections have an impact on the immune system and therefore might contribute to psychiatric symptoms. Several studies have identified the important role of immunological parameters in schizophrenia.23) Recently, it has been demonstrated that proinflammatory cytokines that could enhance the activity of the enzyme, indoleamine 2,3-dioxygenase (IDO) plays an important role in the pathophysiology of schizophrenia. The IDO increases tryptophan degradation into kynurenine and decreases tryptophan availability in the brain to synthesize neurotransmitters.24) Reduced type-1 immune response and Increased type-2 immune response in schizophrenic patients promote the production of the endogenous N-Methyl-D-aspratate (NMDA) receptor antagonist, kynurenic acid. A hypofunction of the glutamatergic cortico-striatal pathway is associated with opening of the thalamic filter, which leads to an uncontrolled flow of sensory information to the cortex and promotes psychotic symptoms.25)

There are some limitations in our study: First, the sample size was rather small and therefore the statistical power might be restricted. Although there were 96 patients with schizophrenia in the study, the number of the seropositive patients for T. gondii (n=21), C. pneumoniae (n=64), C. trachomatis (n=27) were small. Therefore, the results of the clinical symptoms of the seropositive and seronegative schizophrenia need to be further verified, especially through prospective studies. Second, it was not possible to evaluate the rate of sexual activity in patients and controls. This aspect seems to be important, as C. trachomatis is a sexually transmitted disease. There are studies showing that schizophrenic patients suffer from sexual dysfunction and possess less social activity and have therefore an impaired sexual life.26) It also remains possible that schizophrenic patients might show riskier sexual behavior.

In conclusion, the present research found that the prevalence of IgG antibody to T. gondii and C. trachomatis in the patients with schizophrenia was higher than that of the control groups. These findings suggest that the elevated rate of infectious agents within the schizophrenic patients could provoke an immunological disturbance that might influence the cerebral neurotransmitter balance. This study lent further weight to the hypothesis that exposure to T. gondii and C. trachomatis may be the risk factors for schizophrenia. Further studies investigating the association between the infection status and immune parameters are needed.

 

[MusicMan]

I've tried several of the Hulda Clark remedies/devices for a number of things and, as far as I can tell, achieved no objective beneficial results.

Hmmm. Even so perhaps we should not throw the baby out with the bath-water.

I noticed Psittacosis mentioned in one of the above extracts. This is commonly associated with birds, particularly domesticated birds.
Domestic pets generally harbour lots of parasites, some of which are readily transmitted to human hosts, in particular the Liver Fluke, which can also come from uncooked meats.
Considering that the fluke has eleven known stages of development, each of which which can manifest at different parts of the body including the brain, it's probably worth figuring out how to get them (and others) out of the body.

I thought Hulda Clark's methods were intriguing, especially her efforts to kill the parasites, to flush them and their associaated toxins out of the kidneys and liver and associated ducts, and to prevent re-infection.

Hopefully we (humanity) can improve on her methods, refine them, maybe even discover new ones.
And also throw out those which don't work.

I'm sure the ptb would do everything in their power to prevent this, and I admire Dr. Clark for making her works available for free on the internet while she was alive.

 

[Laura]

I noticed Psittacosis mentioned in one of the above extracts. This is commonly associated with birds, particularly domesticated birds.
Domestic pets generally harbour lots of parasites, some of which are readily transmitted to human hosts, in particular the Liver Fluke, which can also come from uncooked meats.
Considering that the fluke has eleven known stages of development, each of which which can manifest at different parts of the body including the brain, it's probably worth figuring out how to get them (and others) out of the body.

Albendazole.

 

[MusicMan]

I noticed Psittacosis mentioned in one of the above extracts. This is commonly associated with birds, particularly domesticated birds.
Domestic pets generally harbour lots of parasites, some of which are readily transmitted to human hosts, in particular the Liver Fluke, which can also come from uncooked meats.
Considering that the fluke has eleven known stages of development, each of which which can manifest at different parts of the body including the brain, it's probably worth figuring out how to get them (and others) out of the body.

Albendazole.

Wikipedia has this:
_https://en.wikipedia.org/wiki/Albendazole

I see GlaxoSmithKlein are practically giving it away in developing countries.
If I was a young male interested in producing children I might be wary of it.
Still, if I was suffering from a serious disease, I would be interested.
Did albendazole work for you?

 

[SunEterna]

Hello everyone!
Do we have some infos about schizoid personality disorder and infection?
I guess, as this is a psychic trouble like depression and schizophrenia, it could be related to infection!
I will take some garlic! xD
Peace to you!

 

[SunEterna]

Re: Schizophreniafac

I saw that anhedonia (felt in schizophrenia, depression and by schizoids) can be caused by MDMA and cocaine by damaging the dopaminergic neurotransmetters! So, could it be multifactorial disease? I mean, all kind of poisons in the environnement, stress, parasites... Well, maybe different causes for different peoples doing different things!

 

[Kay Kim]

I was wondering about how and why some people have mental illness like Schizophrenia, so I was searching, and today I found out the answer from Cs transcripts.
It seems like the symptoms develop from a bad diet or genetic or Lizards manipulation.
But, I think there’s also some possibility that the person abuse using some kind of substance that altering mind many years.

Date: August 20th 2011

Q: (Psyche) Does {name redacted} have a brain chemical imbalance due to her food choices? (L) Well, why don't we get to the multiple system breakdown? What systems? Uh... Maybe that's the wrong question. They're trying to tell us to get to some really basic things here. (Psyche) Epigenetics?

A: Yes mainly, but also specific genetic line problems.

Q: (L) Let's try to ask some real simple questions and get through this. What are the primary parts of the systems that are broken down?

A: First, the gene expression has been altered after many years of abuse of the system design.

Q: (L) Is this something like what Gedgaudas writes about that once you’ve been eating carbs and grains and things for so many years, your body gets conditioned to it and it's very very difficult to switch over? Is that part of what it is?

A: Yes and more.

Q: (Ailen) Does your DNA get atrophied or something? (L) I don't know. I think it shuts down certain DNA. (Ailen) Because they're saying that the gene expression has been altered after many years of abuse of the system. (PoB) Is it reversible?

A: It is mostly reversible for {name redacted}, but more difficult for her child who is third generation.

Q: (L) So you're saying that her mother has also put her system through improper use of the natural genetic profile?

A: Yes.

Q: (L) Okay. What's the next question? (Psyche) We were checking some statistics and we realized that full siblings of schizophrenics are nine times more likely than the general population to have schizophrenia, and four times more likely to have bipolar disorder. Is {name redacted} affected by this genetic tendency?

A: Oh indeed! However this requires explanation. First of all, the genetics that are associated with schizophrenia can be either a doorway or a barrier. Second, the manifestation of schizophrenia can take non-ordinary pathways. That is to say that diet can activate the pathway without the concomitant benefits.

Q: (Burma) I think that they're saying that schizophrenia could essentially be a way to be open to seeing other aspects of reality but diet can make it so it basically just makes you crazy without actually seeing anything.

A: Primitive societies that eat according to the normal diet for human beings do not have "schizophrenics", but they do have shamans who can "see".

Q: (Perceval) So a schizophrenic on animal fat is a shaman. (L) Well, wait a minute. There's something real subtle here. What I think you're saying is that when these genetic pathways are activated through wrong diet, it screws up the shamanic capacity?

A: Yes.

Q: (L) So, schizophrenia as we understand it or have witnessed it is a screw-up of something that could or might manifest in a completely different way on a different diet? Is that it?

A: Yes

Q: (L) And that's what you meant by not only a doorway, but also a barrier because the person who is on the wrong diet and has schizophrenia is barred from being able to be a bridge between the worlds. They kind of get lost. They're barred from having a normal life, and they're also barred from coming back from their delusions or whatever they're seeing even if they're not delusions. Maybe they’re seeing, but they're unable to help or do anything.

October 25, 1994

Q: (L) Are Lizards responsible for paranoid schizophrenia?

A: Some.

Q: (L) In a general sense, in the majority of cases, what is the cause of paranoia or schizophrenia?

A: Lizard manipulation of energies.

Q: (L) Why?

A: To feed off the negative results.

Q: (L) So it isn't necessarily attachments?

A: No.

Q: (L) Do Lizards use attachments of dark energies to effect their purposes?

A: Yes.

Q: (L) In a lot of cases of paranoid schizophrenia are attachments used?

A: Yes.

Q: (L) Are they perpetuating schizophrenia through genetics?

A: Can. Or mental and emotional. Environmental life experiences.

Q: (L) Why does it not usually show up until adolescence? Is this because adolescents are being abducted and having implants put in?

A: Not necessarily.

 

[thisplacerocks]

Q: (L) Are they perpetuating schizophrenia through genetics?

A: Can. Or mental and emotional. Environmental life experiences.

I think m k ... u l t r a is a possible cause of schizophrenia. There are various degrees of harshness of it. Basically the handler uses trauma to create "alters", split personalities in the victim's mind. This is the environmental life experiences mentioned by the Cs. The more popular examples are celebrities.

According to Fritz Springmeier, there are bloodline families who undergo ritual abuse in each generation, the side effect is it makes their offsprings more amenable to mind programming. This means schizophrenia can be passed through genetics. Gloria Vanderbilt is one example of someone from a bloodline family.

This ritual also includes inserting demons into the victims. I think demons might have some relationships with lizards?

Some parents sell their kids as lab rats for this abuse, sadly.

Not all victims are aware they are programmed.

 

[Tyomodachi]

This may explain why keto may improve the symptoms of schizophrenia.

Impaired Glucose Homeostasis in First-Episode Schizophrenia
A Systematic Review and Meta-analysis
​

Key Points
Question Do individuals with first-episode schizophrenia already demonstrate evidence of glucose dysregulation?

Findings In this meta-analysis of 14 case-control studies comprising 1345 participants, individuals with first-episode schizophrenia had elevated fasting plasma glucose levels, elevated plasma glucose levels after an oral glucose tolerance test, and elevated fasting plasma insulin levels, as well as greater insulin resistance compared with healthy individuals serving as controls.

Meanings Glucose homeostasis is altered from illness onset in schizophrenia, indicating that patients are at increased risk for type 2 diabetes as a result; this finding has implications for the monitoring and treatment of patients with schizophrenia.


Abstract
Importance Schizophrenia is associated with an increased risk of type 2 diabetes. However, it is not clear whether schizophrenia confers an inherent risk for glucose dysregulation in the absence of the effects of chronic illness and long-term treatment.

Objective To conduct a meta-analysis examining whether individuals with first-episode schizophrenia already exhibit alterations in glucose homeostasis compared with controls.

Data Sources The EMBASE, MEDLINE, and PsycINFO databases were systematically searched for studies examining measures of glucose homeostasis in antipsychotic-naive individuals with first-episode schizophrenia compared with individuals serving as controls.

Study Selection Case-control studies reporting on fasting plasma glucose levels, plasma glucose levels after an oral glucose tolerance test, fasting plasma insulin levels, insulin resistance, and hemoglobin A1c (HbA1c) levels in first-episode antipsychotic-naive individuals with first-episode schizophrenia compared with healthy individuals serving as controls. Two independent investigators selected the studies.

Data Extraction Two independent investigators extracted study-level data for a random-effects meta-analysis. Standardized mean differences in fasting plasma glucose levels, plasma glucose levels after an oral glucose tolerance test, fasting plasma insulin levels, insulin resistance, and HbA1c levels were calculated. Sensitivity analyses examining the effect of body mass index, diet and exercise, race/ethnicity, and minimal (≤2 weeks) antipsychotic exposure were performed.

Data Synthesis Of 3660 citations retrieved, 16 case-control studies comprising 15 samples met inclusion criteria. The overall sample included 731 patients and 614 controls. Fasting plasma glucose levels (Hedges g = 0.20; 95% CI, 0.02 to 0.38; P = .03), plasma glucose levels after an oral glucose tolerance test (Hedges g = 0.61; 95% CI, 0.16 to 1.05; P = .007), fasting plasma insulin levels (Hedges g = 0.41; 95% CI, 0.09 to 0.72; P = .01), and insulin resistance (homeostatic model assessment of insulin resistance) (Hedges g = 0.35; 95% CI, 0.14 to 0.55; P = .001) were all significantly elevated in patients compared with controls. However, HbA1c levels (Hedges g = −0.08; CI, −0.34 to 0.18; P = .55) were not altered in patients compared with controls.

Conclusions and Relevance These findings show that glucose homeostasis is altered from illness onset in schizophrenia, indicating that patients are at increased risk of diabetes as a result. This finding has implications for the monitoring and treatment choice for patients with schizophrenia.



Introduction
Large-scale epidemiologic studies have established that people with schizophrenia die 15 to 30 years earlier than the general population and that 60% or more of this premature mortality is due to causes not related to the central nervous system,1-5 predominantly cardiovascular.6 Rates of type 2 diabetes are estimated to be 2 to 3 times higher in schizophrenia than in the general population, with a prevalence of 10% to 15%.7,8 Although antipsychotic use may contribute to this association, a link between schizophrenia and diabetes was already observed in the 19th century, long before the introduction of antipsychotics and in an era when diets did not have such a propensity to induce metabolic derangements.9,10 For over a decade, there has been a drive to identify whether schizophrenia confers an inherent risk for the development of type 2 diabetes by investigating patients at illness onset before the potentially confounding effects of chronic illness and long-term antipsychotic treatment. Several studies have focused on the presence or absence of type 2 diabetes in patient cohorts compared with controls. The results from meta-analyses of these studies examining the prevalence of type 2 diabetes in individuals with first-episode psychosis and controls have found no significant differences between the 2 groups.11,12 However, there are 2 limitations with restricting analyses to an established diagnosis of type 2 diabetes. The first limitation is that patients may be less likely to seek medical attention, so there is the risk of underreporting. The second is that the development of type 2 diabetes takes time, with peak onset in middle age, and so may not have had time to develop in patients with first-episode schizophrenia. Type 2 diabetes shows a progression through a period of insulin resistance, elevated insulin levels, and impaired glucose tolerance (prediabetes) before the development of symptoms and a patient eventually receiving a diagnosis of type 2 diabetes. If a study’s outcome is whether criteria are met for a diagnosis of type 2 diabetes, significant alterations in glucose homeostasis between patient and control groups may be missed. In view of these limitations, we performed a meta-analysis of studies that focused on measures of glucose control in individuals either at risk for psychosis or in their first episode of psychosis. The aim of our meta-analysis was to test the hypothesis that individuals with first-episode schizophrenia exhibit alterations in glucose homeostasis compared with matched controls.

Methods
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Results
Retrieved Studies
After exclusion of studies reporting on overlapping data sets, 16 case-control studies26-41 comprising 15 samples met inclusion criteria and were analyzed. The search process is demonstrated in Figure 1, and the final studies selected are summarized in the Table. The overall sample included 731 patients and 614 controls.

Fasting Plasma Glucose Concentration
Fasting plasma glucose concentration in patients and controls was analyzed using data from 14 studies comprising 718 patients and 599 controls.26-39 Fasting plasma glucose concentration was significantly elevated in patients compared with controls (Hedges g = 0.20; 95% CI, 0.02 to 0.38; P = .03) (Figure 2). There was significant between-sample heterogeneity, with an I2 value of 58.29% (Cochran Q = 31.17; P = .003). Findings of the Egger test (P = .07) suggested that publication bias was not significant. Restricting the analyses to antipsychotic-naive patients by excluding the 3 studies that included patients with up to 2 weeks of antipsychotic treatment37-39 demonstrated that fasting plasma glucose concentration remained significantly elevated in patients compared with controls (Hedges g = 0.30; 95% CI, 0.11 to 0.48; P = .002). A sensitivity analysis examining studies in which patients and controls were matched for diet and exercise parameters29,31-33,35,36 demonstrated that fasting plasma glucose concentration remained significantly elevated in patients compared with controls (Hedges g = 0.25; 95% CI, 0.07 to 0.43; P = .007) (eFigure 6 in the Supplement). However, after restricting the analyses to BMI-matched studies,26-33,37-39 there was no longer a significant difference in fasting plasma glucose concentration in patients compared with controls (Hedges g = 0.20; 95% CI, −0.03 to 0.44; P = .08). A sensitivity analysis examining studies in which patients and controls were matched for ethnicity26,31,34,36,37,39 demonstrated that fasting plasma glucose concentration remained significantly elevated in patients compared with controls (Hedges g = 0.19; 95% CI, 0.03 to 0.35; P = .02).


Plasma Glucose Concentration After OGTT
Plasma glucose concentration after OGTT was analyzed using data from 4 studies comprising 271 patients and 237 controls.34-37 Plasma glucose concentration was significantly elevated in patients compared with controls (Hedges g = 0.61; 95% CI, 0.16-1.05; P = .007) (Figure 2). Between-sample heterogeneity was significant, with an I2 value of 82.40% (Cochran Q = 17.05; P = .001). A sensitivity analysis examining studies in which patients and controls were matched for ethnicity34,36,37 demonstrated that fasting plasma glucose concentration after OGTT remained significantly elevated in patients compared with controls (Hedges g = 0.78; 95% CI, 0.40-1.17; P < .001). In the context of low study numbers, sensitivity analyses to assess the impact of BMI, antipsychotics, or diet and exercise were not performed.


Fasting Plasma Insulin Concentration
Fasting plasma insulin concentration in patients and controls was analyzed using data from 11 studies26,28,30-34,37-40 comprising 512 patients and 448 controls. Fasting plasma insulin concentration was significantly raised in patients compared with controls (Hedges g = 0.41; 95% CI, 0.09-0.72; P = .01) (Figure 3). Between-sample heterogeneity was significant, with an I2 value of 80.80% (Cochran Q = 52.09; P < .001). Findings of the Egger test (P = .12) suggested that publication bias was not significant. Excluding the 3 studies that included patients with up to 2 weeks of antipsychotic treatment37-39 to restrict the analyses to antipsychotic-naive patients demonstrated that fasting plasma insulin concentration remained significantly elevated in patients compared with controls (Hedges g = 0.47; 95% CI, 0.03-0.91; P = .04). Exclusion of 1 study that examined non–BMI-matched patients and controls34 demonstrated that fasting plasma insulin concentration remained significantly elevated in patients compared with controls (Hedges g = 0.38; 95% CI, 0.04-0.72; P = .03). A sensitivity analysis examining studies in which patients and controls were matched for ethnicity26,31,34,37,46 demonstrated that fasting insulin concentration remained significantly elevated in patients compared with controls (Hedges g = 0.49; 95% CI, 0.30-0.68; P < .001). In the context of low study numbers, a sensitivity analysis to assess the impact of diet and exercise was not performed.



Insulin Resistance
Insulin resistance as measured using the HOMA-IR tool in patients and controls was analyzed using data from 10 studies26,28-32,34,38,39,41 comprising 485 patients and 400 controls. HOMA-IR was significantly raised in patients compared with controls (Hedges g = 0.35; 95% CI, 0.14-0.55; P = .001) (Figure 3). Between-sample heterogeneity was moderate but significant, with an I2 value of 55.40% (Cochran Q = 20.18; P = .02). Findings of the Egger test (P = .10) suggested that publication bias was not significant. Excluding the 2 studies that included patients with up to 2 weeks of antipsychotic treatment38,41 to restrict the analyses to antipsychotic-naive patients demonstrated that HOMA-IR remained significantly elevated in patients compared with controls (Hedges g = 0.44; 95% CI, 0.23-0.65; P < .001). Exclusion of 1 study that examined non–BMI-matched patients and controls34 demonstrated that HOMA-IR remained significantly elevated in patients compared with controls (Hedges g = 0.31; 95% CI, 0.09-0.53; P = .005). A sensitivity analysis examining studies in which patients and controls were matched for ethnicity26,31,34,39 demonstrated that HOMA-IR remained significantly elevated in patients compared with controls (Hedges g = 0.66; 95% CI, 0.43-0.88; P < .001). In the context of low study numbers, a sensitivity analysis to assess the impact of diet and exercise was not performed.


HbA1c Analysis
The HbA1c levels were analyzed using data from 4 studies27,34,38,41 comprising 166 patients and 164 controls. The HbA1c levels were not altered in patients compared with controls (Hedges g = −0.08; 95% CI, −0.34 to 0.18; P = .55) (eFigure 7 in the Supplement). Between-sample heterogeneity was moderate as indicated by an I2 value of 31.50%, but a Cochran Q value of 4.38 (P = .22) suggested nonsignificant heterogeneity. Of these 4 studies, 2 studies examined patients with up to 2 weeks of antipsychotic use,38,41 and 1 study examined non–BMI-matched patients and controls.34 In the context of low study numbers, sensitivity analyses were not performed.


Discussion
Our main findings are that patients with schizophrenia show raised fasting plasma glucose levels, reduced glucose tolerance, raised fasting plasma insulin levels, and increased insulin resistance at illness onset. With the exception of fasting glucose levels, these alterations were also seen when analyses were restricted to antipsychotic-naive and BMI-matched samples. When analysis was restricted to diet and exercise–matched samples, significance was maintained for raised fasting glucose levels in patients. All results remained significant when analyses were restricted to samples matched for race/ethnicity. No significant differences were demonstrated in HbA1c levels, although this result should be interpreted with caution owing to the small sample size used in this analysis. The results of our meta-analysis extend recent studies showing high rates of diabetes in patients with chronic schizophrenia by demonstrating that altered glucose homeostasis is present from illness onset.

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Full article: Impaired Glucose Homeostasis in First-Episode Schizophrenia