Updated 17 February 2013

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Pathway Analysis of Autism, Bipolar, and Schizophrenia Genes
Could Cannabis Foster Schizophrenia by Weakening Immunity?
Cannabis and Negative Symptoms
Awkward Movements Due to Prenatal Hypoxia?
Why Pregnancy May Relieve Schizophrenia Symptoms
Is Schizophrenia More Common Than Studies Suggest?
Schizophrenia: A Conjectured Daytime Psychobiological Invasion by Rapid Eye Movement (REM) Sleep
Does Birth Order Influence Schizophrenia Risk?
What Is the Relation of Head Trauma to Schizophrenia?
Electrical Stimulation for Schizophrenia?
Estrogen, Development, and Schizophrenia
Schizophrenia and Psychiatric Diagnosis: Back to the Drawing Board!
Prodrome, Hallucinations, and Prediction
Is There a Link Between Schizophrenia and Stroke and Homocysteine?
Link Between Epilepsy/Epilepsy Drugs and Schizophrenia?
The Chimpanzees in the Zoos Do It ... Or Do They?
"Reverse" Translational Research

Pathway Analysis of Autism, Bipolar, and Schizophrenia Genes—5 April 2011
Chris Carter

The several hundred genes implicated in autism, bipolar disorder, or schizophrenia etch out signaling networks that relate to the pathology of each disease: for example, neuroactive ligands, ErbB signaling or LTP in schizophrenia, axon guidance or adhesion in autism, or adhesion, circadian control, neurotrophin and PI signaling in bipolar disorder.

Immune activation is present in all of these diseases, and immune-related genes (chemokines, cytokines, antigen presentation, T cell signaling, etc.) are heavily represented in these pathways.

Pathogens have been implicated as risk factors in all of these, and many other diseases, and pathogen defense pathways (RIG-1, NOD signaling, etc.) are also prevalent. Pathogen entry pathways are heavily represented, with the toxoplasmosis pathway heading the list in schizophrenia.

Susceptibility genes can therefore be related to the pathological processes inherent in each disease, but also to immune activation and to the bacterial and viral risk factors that are likely responsible for such activation. It is worth considering whether a shift towards drugs targeted at pathogen elimination could have a significant effect on the incidence and severity of these diseases.

These and other pathways relating to viral lifecycles (herpes simplex and the AIDS virus, HIV-1) are posted at www.polygenicpathways.co.uk/pwaysportal.htm.

References:
Ashwood P, Krakowiak P, Hertz-Picciotto I, Hansen R, Pessah IN, Van de Water J. Altered T cell responses in children with autism. Brain Behav Immun. 2010 Sep 15. Abstract

Kunz M, Ceresér KM, Goi PD, Fries GR, Teixeira AL, Fernandes BS, Belmonte-de-Abreu PS, Kauer-Sant'anna M, Kapczinski F, Gama CS. Serum levels of IL-6, IL-10 and TNF-α in patients with bipolar disorder and schizophrenia: differences in pro- and anti-inflammatory balance. Rev Bras Psiquiatr. 2011. Abstract

Could Cannabis Foster Schizophrenia by Weakening Immunity?—2 December 2009
“An ordinary guy with schizophrenia”

Frequent use of cannabis is correlated with the risk of developing schizophrenia. Could it be that cannabis lowers the immune functioning of people at risk for schizophrenia, making them more susceptible to viruses, etc., and increasing their likelihood of developing schizophrenia?

Cannabis and Negative Symptoms—2 December 2009
Jonathan Burns

What is the latest thinking on whether cannabis users manifest fewer negative symptoms in schizophrenia? I know there is some support for the idea that cannabis attenuates negative symptoms (e.g., Schofield et al., 2006; but see also D’Souza et al., 2009). If this is so, what is the mechanism by which this happens?

The other (popular) notion is that the negative syndrome in schizophrenia compromises patients' ability to access cannabis (see Compton et al., 2007). I don’t agree with this latter suggestion because in many regions (e.g., here in South Africa), cannabis is cheap and easily available to individuals of all descriptions, so negative symptoms are hardly likely to stop an individual from accessing the stuff.

Also, has anyone come across any work on whether the relative concentrations of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) affect the levels of negative symptoms? In other words, if THC is low and CBD high, is there greater or lesser reduction in negative symptoms?

References:
Compton MT, Whicker NE, Hochman KM. Alcohol and cannabis use in urban, African American, first-episode schizophrenia-spectrum patients: Associations with positive and negative symptoms. J Clin Psychiatry. 2007;68:1939-45. Abstract

D’Souza DC, Sewell RA, Ranganathan M. Cannabis and psychosis/schizophrenia: Human studies. Eur Arch Psychiatry Clin Neurosci. 2009;259:413-31. Abstract

Schofield D, Tennant C, Nash L, Degenhardt L, Cornish A, Hobbs C, Brennan G. Reasons for cannabis use in psychosis. Aust N Z J Psychiatry. 2006;40:570-74. Abstract

Reply by Will Carpenter

The question of negative symptoms and cannabis use is not adequately understood, and several factors may play a role. Brian Kirkpatrick and others have explored the relationship in a subgroup of schizophrenia subjects defined by primary, trait-negative symptoms (i.e., deficit schizophrenia) and found substantially less cannabis use in comparison to non-deficit schizophrenia (Kirkpatrick et al., 1996). Possible reasons include (and these are not mutually exclusive):

1. diminished positive reinforcement;
2. reduced social context that facilitates cannabis use;
3. reduced motivation and purposeful activity; and
4. reduced anxiety (restricted affect) and boredom (low motivational state).

Awkward Movements Due to Prenatal Hypoxia?—17 October 2009
Steve McArdle

Does the high incidence of lack of motor coordination in pre-schizophrenics mean they had prenatal hypoxia?

Reply by Mary Cannon

This is a very interesting question. I looked at this issue in an analysis I carried out on the Dunedin birth cohort (Cannon et al., 2002). In this analysis, three obstetric complications were significantly related to risk of later schizophrenia: low Apgar score, hypoxia at birth, and small size for gestational age.

The individuals who later developed schizophrenia or schizophreniform disorder had significantly poorer motor performance on standardized tests between ages three and 11. However, the significant association between poor motor performance and later schizophrenia/schizophreniform disorder persisted even after adjusting for obstetric complications. This would seem to indicate that the motor deficits in schizophrenia are largely independent of obstetric complications. Still, there could be an interaction effect, which I did not have the power to examine in this cohort. I would be interested to hear if others have carried out similar analyses.

Reference: Cannon M, Caspi A, Moffitt TE, Harrington H, Taylor A, Murray RM, Poulton R. Evidence for early-childhood, pan-developmental impairment specific to schizophreniform disorder: Results from a longitudinal birth cohort. Arch Gen Psychiatry. 2002;59:449-56. Abstract

Why Pregnancy May Relieve Schizophrenia Symptoms—7 January 2009
Marvin Slay

For over 35 years, I have known a woman who has schizophrenia. I noticed that during her pregnancies her symptoms lessened considerably. Has there been any research connecting hormones or other pregnancy-related chemistries with their effects on schizophrenia?

Reply by Jayashri Kulkarni

It is a common observation that women with schizophrenia do improve when pregnant; this supports the theory that estrogen is a protective hormone. Estrogen levels are very high during pregnancy, and we assume that the "antipsychotic" effect of estrogen is maximal at this time. We know that estrogen decreases dopamine and serotonin levels in rat brains (Reicher-Rössler and Häfner, 1993; Kulkarni and Fink, 2000; Hearle and McGrath, 2000), and this is probably the way in which estrogen "protects" against schizophrenia.

Of importance also is the sudden decline in estrogen levels after the baby is born. Within 72 hours of giving birth, there are major fluctuations in the hormone chemistry. As suggested by the term "postpartum psychosis," the postnatal period is a time of great vulnerability for the emergence of first-time psychosis or the relapse of schizophrenia. The increase in the number of women experiencing psychosis after childbirth is probably due to the sudden loss of "protection" by estrogen.

Another important implication of the "estrogen protection" hypothesis is that vulnerable women in their menopause can relapse with schizophrenia or even develop severe mental illness for the first time (Reicher-Rössler and Häfner, 1993; Seeman, 1996). As in the postpartum period, estrogen levels drop during menopause, which can lead to loss of brain "protection."

Our research has focused on estrogen as a treatment for women with schizophrenia. We have had some excellent results, particularly for women whose schizophrenia started in the postnatal period, although we have seen some good clinical outcomes also for women who developed schizophrenia without pregnancy (see SRF related news story). I am very keen to advocate the safe use of estrogen treatment in my older female patients, especially women going through menopause. Clearly, good medical monitoring is important with respect to breast screens, pap smears, etc., when using hormone treatments.

References:
Reicher–Rössler A, Häfner H. Schizophrenia and oestrogens–-Is there an association? Eur Arch Psychiatry Clin Neurosci 1993;242(6):323-328. Abstract

Kulkarni J, Fink G. Hormones and psychosis. In Castle D, McGrath J, Kulkarni J. (Eds.), Women and schizophrenia. Cambridge, UK: United Press, 2000;51-66.

Hearle J, McGrath J. Motherhood and schizophrenia. In Castle D, McGrath J, Kulkarni J. (Eds.), Women and schizophrenia. Cambridge, UK: United Press, 2000;79-94.

Seeman MV. The role of estrogen in schizophrenia. J Psychiatry Neurosci 1996(2);21:123-127. Abstract

Kulkarni J, de Castella A, Fitzgerald PB, Gurvich CT, Bailey M, Bartholomeusz C, Burger H. Estrogen in severe mental illness: A potential new treatment approach. Arch Gen Psychiatry 2008;65(8);955-960. Abstract

Is Schizophrenia More Common Than Studies Suggest?—16 November 2008
Name withheld

I am seeking good empirical data on the percentage of people who have schizophrenia or psychosis, and I question whether self-report instruments, such as the Canadian Community Health Survey, undercount people with schizophrenia. Some of those who have paranoia or who are hospitalized, in prison, or homeless may not report their illness. Here in Canada, we keep quoting the 1 percent figure, but I feel that there are many undiagnosed people with schizophrenia.

Reply by John McGrath

The lifetime prevalence of schizophrenia is around 1 per 100; however, the exact estimates often vary between sites. Some show much lower and others much higher prevalence.

When community-based surveys of psychotic disorders are performed, it is not unusual for extra care to be taken to include people who are not in contact with services (e.g., the homeless). The prevalence of psychosis in the prison population is much higher than in the general community, and often these surveys are done specifically based on this population. Psychiatric hospitals are often included in community-based surveys. Surveys that are based solely on households (sometimes called "door knock" surveys) will miss people who are homeless or institutionalized.

The various types of bias are well understood, and thus prevalence estimates are usually assumed to be underestimates of the true prevalence. Because schizophrenia is associated with increased mortality, prevalence surveys can also underestimate the full impact of this poorly understood group of disorders (since you have to be alive to be counted in prevalence surveys).

More information about the prevalence of schizophrenia and the mortality associated with schizophrenia can be found on the website of the Queensland Centre for Mental Health Research.

Schizophrenia: A Conjectured Daytime Psychobiological Invasion by Rapid Eye Movement (REM) Sleep—12 October 2007
Claude Gottesmann

The cognitive function of the rapid eye movement (REM) dreaming sleep stage is still an open question. (Read more...)

Does Birth Order Influence Schizophrenia Risk?—24 April 2007
Name withheld

Could first-born children be more at risk? This situation appears to exist in both my and my husband's families.

Reply by Carsten Bøcker Pedersen

The potential association between sibship characteristics (e.g., birth order, sibship size, and birth interval to siblings) and the risk of schizophrenia has been investigated previously (Westergaard et al., 1999; Bender et al., 2000; McDonald et al., 2001; Sham et al., 1993; Malama et al., 1988; Smits et al., 2004). Sham et al. found a decreased risk in first-born children, and an increased risk in children with siblings who were 3 to 4 years older. Westergaard et al. could not replicate these findings but found an increased risk associated with no siblings, three or more siblings, and with short birth interval to siblings. Pedersen and Mortensen (Pedersen and Mortensen, 2004) replicated the findings by Westergaard et al., and found that some of the increased risk associated with no siblings, and three or more siblings, was attributable to change of residence and urbanization during upbringing.

If one observes that first-born children have an increased risk of later developing schizophrenia, then this finding may be confounded (i.e., attributable) to age; Table 1 in Pedersen et al. shows that in Denmark the crude incidence for first-born children is 3.39 per 10,000 person years, while the crude incidence for second-born children is 3.30 per 10,000 person-years. However, the same table shows that when adjusting for age (as well as other confounders), first-born children do not have an increased risk of schizophrenia.

What Is the Relation of Head Trauma to Schizophrenia?—15 February 2007
Name withheld

I am a mother of a 21-year-old son with paranoid chronic schizophrenia, and I don't know if the following information may help in any research. My son was a "head banger" when he was a baby/toddler. He would bang his head into things over and over again with no regard to pain. It didn't matter if it was on a soft couch or on hard pavement or while sitting in the front of a grocery cart; he would bang his head repeatedly on the cart's handle. He would bang his head wherever we happened to be on whatever was closest to him. He always had bruises all over his forehead. I have to say it was always a little embarrassing as a mom to always have a bruised up baby. Luckily for me he even did it in front of his pediatrician on her metal table! I don't know if others with schizophrenia were head bangers as babies/toddlers or if this information may help in some way.

Reply by Dolores Malaspina

Head injuries are common and schizophrenia is uncommon. Nonetheless, there is strong evidence that traumatic brain injury may triple the risk for schizophrenia; from about 1 percent of the general population to about 3 percent of those with head injury (Malaspina et al., 2001). Our work shows that the effect may be especially important in those with a family history for schizophrenia. [Ed. Note: See a new review: Corcoran and Malaspina Traumatic Brain Injury as a Risk Factor for Schizophrenia.]

Electrical Stimulation for Schizophrenia?—28 August 2006
By Edwin Cooper

After an article ("Back from the Dead") in the Sept. 2006 Wired Magazine about the use of electrical stimulation for vegetative states in the USA and Japan (see also Cooper et al., 2005), I have received some inquiries from families of patients with reduced levels of consciousness. But recently, for the first time, there was a question about whether right median nerve electrical stimulation (RMNS) would help a person with schizophrenia. RMNS affects both dopaminergic and glutamatergic neurotransmission, but maybe not in ways that would help schizophrenic persons. Has anyone heard of using electrical stimulation—in any of its forms like functional e-stimulation, implanted (muscle, nerve, cord, brain), transcutaneous electrical nerve stimulation (TENS), or median nerve stimulation—for treatment of schizophrenia?

Reply by Ralph Hoffman

Although there have been a number of studies examining effects of median nerve stimulation on evoked potentials in persons with schizophrenia, I am aware of no studies of this perturbation as a potential therapeutic intervention for this group. Similarly, there are no clinical trials or case reports, as far as I know, considering other forms of electrical stimulation such as VNS for persons with schizophrenia.

Estrogen, Development, and Schizophrenia—17 April 2006
By Saundra Barnes

During the mid-1960s, a new method to determine pregnancy by medical doctors was to administer a 7- to 14-day regime of birth control pills to women. I know this was not done for a long period of time, but at age 21, I was one of those women, and the son born to me in 1966, now 40, is schizophrenic. I accidentally came across another woman whose pregnancy was also determined the same way, with a son approximately the same age as mine who is also schizophrenic, and another woman whose son died before he was a year old. I don't recall the name of his disorder, only that his liver grew too large, and his brain did not develop. Through Internet research, I found only one article that stated this method of determining pregnancy was ever used for any length of time. This short article stated that the use of birth control pills (which were very, very strong at that time) was discontinued because experiments with fish resulted in damage to both the blood vessel and nerve formations in their brains and sexual organs. My son also had a hydrocele at age 18, and the doctor repairing this said the blood vessels in his testicles were unusually scrambled, like spaghetti.

I cannot help but wonder if the giving of massive doses of female hormones to a developing fetus has ever been researched, or if studies have shown there was any significant rise in numbers of schizophrenics at that age level.

Reply by Alan Brown

There is a large literature on diethylstilbestrol (DES), a synthetic estrogen that was given to prevent miscarriage, and abnormalities in those who were exposed in utero. The strongest finding is an increased risk of clear cell cancer of the vagina and cervix, and there are some abnormal outcomes in exposed males as well, including genital abnormalities. So this could potentially explain the testicular abnormalities in your son. There are no studies of DES or birth control pills and schizophrenia; I don't believe we are able to examine that in our existing datasets.

The estrogens also play important roles in brain development—there are estrogen receptors in the brain, although most of the literature relates to differences in brain areas directly related to sex differences such as the hypothalamus. I am not familiar, however, with research on excess estrogen and brain development in animal studies.

Thank you for the question.

Schizophrenia and Psychiatric Diagnosis: Back to the Drawing Board!—5 April 2006
By Avi Peled

In recent years our current psychiatric diagnostic system has come under increasing criticism. The DSM-V Prelude Project, sponsored by the American Psychiatric Association and the U.S. National Institute of Mental Health, has drafted a white paper entitled "A Research Agenda for DSM-V," which spells out some of the more serious shortcomings of the DSM system, including:

• "Despite many proposed candidates, not one laboratory marker has been found to be specific in identifying any of the DSM-defined syndromes."

• "Epidemiological and clinical studies have shown extremely high rates of comorbidities among the disorders, undermining the hypothesis that the DSM syndromes represent distinct etiologies."

• "The efficacy of many psychotropic medications cuts across the DSM-defined categories." (This relates to SSRIs being equally effective for "depression" and "anxiety disorders" even though they are different DSM-entities.)

• "Reification of DSM-IV entities, to the point that they are considered equivalent to diseases, is more likely to obscure than to elucidate research findings."

Finally it is stated, "It can be concluded that the field of psychiatry has thus far failed to identify a single neurobiological phenotypic marker or gene that is useful in making a diagnosis of a major psychiatric disorder or for predicting response to psychopharmacologic treatment."

These insights may present a gloomy outlook on the psychiatry of our century. In this regard, Allen Frances, the chairperson of the task force that produced DSM-IV, and Helen Egger commented that, "We are at the epicycle stage of psychiatry where astronomy was before Copernicus and biology before Darwin" (Frances and Egger 1999). However, one must not forget that Darwin's and Copernicus's eras were exciting times for the relevant scientific fields.

Who is our Darwin or Copernicus? The Research Agenda for DSM-V calls for a "paradigm shift" in psychiatric diagnosis, suggesting that a revolution should occur in this field; however, we know that science progresses by evolution not revolution. Thus, we should look for the future of psychiatric diagnosis back in history. In my opinion, our Darwin is Theodore Meynert and his pupil Sigmund Freud (before his psychoanalytic era). As far back as before 1898, Meynert wrote, "After two cells have been simultaneously excited (equivalent to the simultaneous arousal of two ideas), an association fibre opens up between them." A "train of thought" is simply the consequence of excitation flowing through a series of cortical cells that have been associated because of previous simultaneous excitations. Every person, of course, has a unique pattern of experience and so develops a unique pattern of cortical associations that represent his or her memories. These associations are the anatomical substrate of a person's "individuality," and Meynert referred to them collectively as the ego (German Ich).

Freud, in a series of letters later titled "The Project," started to describe the mental functions as emerging from neuronal network functions. In 1948, Donald Hebb formulated what would later become Hebbian algorithms and Hebbian cell ensembles. In their 1986 book titled Parallel Distributed Processing: Exploration in the Microstructure of Cognition, McClelland and Rumelhart continued to show how neuronal network models can simulate brain functions and lay the groundwork to explain mental functions using brain-related formulations. Since then, much has been written about the relevance of these models to explain and even simulate mental disorders, (to mention some pioneers, Jonathan Cohen from Princeton and Ralph Hoffman from Yale University). My book, entitled Brain Dynamics and Mental Disorders: Project for a Scientific Psychiatry, begins to systemically collect formulations from systems science and relate them to mental disorders. The ambitious task of the book is to relate mental disorders to brain disturbances. A brief review of the book can be found in the book review section of the American Journal of Psychiatry. In addition, the website Theoretical Psychiatry is dedicated to introducing dynamic system theories and non-linear complexity science to the definitions and research of mental disorders, and contains an easy introduction to the subject).

Using dynamic system theory, brain activity can be conceptualized geometrically in terms of states and trajectories in a space of possible states. Mental disorders can be reconceptualized as perturbations to the optimal brain dynamic organization. Thus, a new brain-related diagnostic system is proposed for psychiatry. Instead of "schizophrenia," "neural complexity breakdown" or "fast plasticity disturbance" will be diagnosed. Neural complexity breakdown could be of the segregation type, that is, disconnection type when delusions, hallucinations, and loosening of associations prevail, or it can be of the "integrated type," where over-connectivity restricts thought processes and causes perseverations. Hierarchical brain organization may also be disturbed; thus, bottom-up insufficiency may cause negative symptoms and top-down shift may cause systemized delusions.

References
Frances AJ, Egger HI: Whither psychiatric diagnosis Aug NZJ Psychiatry 1999, 33:161-165. Abstract

Hebb DO, The Organization of Behavior. New York: John Wiley & Sons, 1949.

Rumelhart DE, McClelland JL, Parallel Distributed Processing: Exploration in the Microstructure of Cognition, PDP Research group ed., Vol. 1 and 2. Cambridge: MIT Press, 1986. Group TPR, ed.

Prodrome, Hallucinations, and Prediction—21 March 2006
By Sarah Ream

I have schizoaffective disorder. Starting from when I was a preteen, I had visual hallucinations that I thought were normal; I saw roaches running around and then realized that there was nothing there. I also have always seen shadows and movement, that turned out to be nothing, from my peripheral vision. It didn't occur to me until recently that other people don't experience that. (This lack of awareness is equal to my not knowing that I needed glasses until I was given an eye test in the seventh grade.) When I had my psychotic break, the hallucinations that caused the most trouble were the visual ones.

My questions are: Do people who hear commanding voices as teens and/or adults experience auditory hallucinations from an early age and perhaps do not realize that other people do not experience the same thing? And can this be used to predict the future type and severity of schizophrenia that a person might later develop? Is it possible to predict this through brain scans?

Reply by Ralph Hoffman—Posted 10 April 2006

Much of our research pertains to auditory hallucinations or "voices." We have found that about 5-10 percent of people who manifest this symptom during adulthood (as part of the illness of schizophrenia, schizoaffective disorder, or bipolar disorder) previously experienced "voices" during childhood. These individuals tended to start out believing, as you indicate, that these experiences were basically a normal part of life. We also work with many people whose auditory hallucinations emerged in late teenage years or adulthood with a very discrete onset. Often these individuals can remember the exact circumstances of the first "voice," such as when and where the experience occurred, and what the voice actually "said," even many years after this initial event. We are conducting studies using functional magnetic resonance imaging that enable us to map parts of the brain that appear to be responsible for producing auditory hallucinations, and are attempting to use these results to develop alternative treatment approaches. We haven't specifically explored whether childhood versus adult onset of "voices" predicts the type or severity of later schizophrenia, but this is an excellent question which we should address. We are also becoming increasingly interested in the visual phenomena that you mentioned, namely, a sense of movement in peripheral vision that can be very distressing and that can lead to more fully formed visual hallucinations. It is always a great opportunity for us to be able to work with individuals who can provide clear descriptions of these experiences and reflect on their nature.

Is There a Link Between Schizophrenia and Stroke and Homocysteine?—10 January 2006
By Jen Bailey

Are there any statistical data that show a high incidence of strokes in families where there is a history of schizophrenia (i.e., where strokes occur in family members not diagnosed with schizophrenia)? I have seen reports of marked elevations of homocysteine in persons with schizophrenia, particularly in males.

It is my understanding that a direct relationship to elevations of homocysteine and increased incidence of stroke is unproven. B6 and B12 are known to reduce homocysteine levels. I understand as a lay person that such supplementation has no therapeutic use in treatment for schizophrenia. I do wonder if blood levels of B6 or B12 can appear normal in people with schizophrenia while there is some undetectable dysregulation in how the body utilizes the B vitamins.

Reply by Alan Brown—Posted 10 January 2006

[Ed. Note: Please see also the recent review by Brown and Susser.]

I am not aware of any literature that supports an increased incidence of strokes in families where there is a history of schizophrenia, although it is an interesting question. It's worth keeping in mind, however, that the findings of homocysteine elevations in schizophrenia vary among studies, with some positive, some negative, and some in subgroups. In our own study, we showed an association, but only for patients with low folate (Susser et al., 1998).

There is also an association between a polymorphism in the methylenetetrahydrofolate reductase MTHFR gene, which is involved in the metabolism of folate and homocysteine, and schizophrenia, with several replications and a few non-replications; a meta-analysis showed about a 1.5-fold increase in schizophrenia risk for individuals with the polymorphism (Muntjewerff et al., 2005). There is a relationship between homocysteine and risk of stroke (for a review, see Schwammenthal and Tanne, 2004), but it isn't clear if treating it prevents further strokes.

As far as treatment of schizophrenia with the B vitamins, I know of no literature, although there was a randomized clinical trial that showed improvement in psychotic symptoms in schizophrenia patients after treatment with folate (Godfrey et al., 1990). If elevated homocysteine is related to symptoms of schizophrenia, it is at least conceivable that a trial of vitamin B12 or B6 might be worth investigating in future research studies, though I wouldn't recommend it for people with the disorder at this time. But I think we need to first clear up the discrepancies regarding whether and in what subgroups of schizophrenia homocysteine is truly elevated. We have some very recent work showing that mothers with elevated homocysteine in third trimester serum samples have offspring with an increased risk of schizophrenia; we weren't able to look at folate and have yet to examine the B vitamins in these sera.

Link Between Epilepsy/Epilepsy Drugs and Schizophrenia?—8 November 2005

I have noticed that many studies of schizophrenia rule out people who have had seizures or epilepsy. I had a couple of grand mal seizures at the age of three. After that, I took phenobarbital and later dilantin. I did this until I was 9 or 10. I never had another seizure, but when I was 23 I was diagnosed with schizophrenia. No one else in my extended family has the illness or has had seizures.

Reply by Will Carpenter—Posted 1 November 2005

There is no known relationship between schizophrenia and the use of phenobarbital and dilantin, and there is not likely to be one since there has been extensive use of both of these drugs in seizure patients being seen by a neurologist, and no association has been noted. An early study suggested that epilepsy reduced the likelihood of developing schizophrenia, but this is not known and is probably not likely. Could a gestational problem cause vulnerability to schizophrenia and seizures? Gestational problems in general are a risk factor for both, but it is not known if the two are related. It is important to keep in mind that some antipsychotic drugs lower seizure threshold, and the treating doctor should be told of a history of seizures in order to take this into account in prescribing medication.

The Chimpanzees in the Zoos Do It ... Or Do They?—15 October 2005
By Jim Kennedy (SRF advisor)

What if the group of schizophrenia risk genes all can be found in the relatively small group of genes that are different between chimpanzees and humans? This in light of the fact that schizophrenia has major symptomatology in higher cognitive domains and in language.

Reply by Tim Crow—Posted 1 November 2005

When Jim Kennedy sent us this entry, he added the note, "Tim Crow would have several thoughts about this idea." And Tim Crow certainly did. Read Do chimpanzees suffer from schizophrenia?

"Reverse" Translational Research—15 October 2005
By Mark Opler

At the Lieber Center, we are formulating a research framework that we've dubbed "reverse translational research." In brief, usually the term "translational research" is taken to mean going from the bench to the clinic (sometimes called "bench-to-bedside".) Our concept is that while this is an important move, we also need to go from the clinic to the bench, i.e., designing and carrying out studies specifically to inform basic research, design and test new animal model or similar experiments, and then go BACK to the clinic ... A cyclical process of "translation and reverse translation".

What's more, we propose that epidemiology be an integral part of this cycle. Many new, exciting findings are coming out of epidemiology that inform us about potential causes, and also about the possible relationships between etiology and course of illness, symptomatology, etc. Epidemiology can provide us with clues to common causal pathways, in turn helping us design new models that not only test the impact of dysfunction in the CNS, but also reflect the mechanisms through which schizophrenia and related disorders arise in various populations. Protective and causal mechanisms suggested by Epidemiology may lead us to research foci that are outside of current thinking in clinical research or neurobiology.

Thus, both clinical research and epidemiologic approaches are brought to bear on basic science, allowing the best methods to be applied to the most relvant questions. We would love to get feedback on this idea.