Anti-Epileptic Drugs Found Safe to Treat Bipolar Disorder

WEDNESDAY, Dec. 9 (HealthDay News) -- The risk of suicidality among bipolar disorder patients treated
with anti-epileptic drugs does not increase relative to those taking lithium or no drugs, according to a
study published in the December issue of the Archives of General Psychiatry.

Robert D. Gibbons, Ph.D., of the University of Illinois in Chicago, and colleagues analyzed data from a
medical claims database on 47,918 bipolar disorder patients to ascertain suicide attempt rates among
those taking any of 11 anti-epileptic drugs that were included in a U.S. Food and Drug Administration
alert on increased risk of suicide, as well as rates for those taking lithium, or neither type of medication.

There were 13 suicide attempts per 1,000 person-years for patients taking an anti-epileptic drug and for
patients not treated with an anti-epileptic drug or lithium, but the rate for those treated with anti-
epileptic medications dropped from 72 per 1,000 person-years prior to treatment, the researchers
found.

"Drawing causal inference from observational data is complicated in general, but even more
complicated for the study of suicide," the authors write. "In summary, the present analysis provides no
evidence that anti-epileptic drugs increase risk of suicide attempts in patients with bipolar disorder.
Most anti-epileptic drugs and lithium are associated with reduction in suicide attempt rates relative to
pretreatment levels in patients who are ultimately prescribed these drugs."

The lead author reported serving as an expert witness for Pfizer Pharmaceuticals, which manufactures
gabapentin, one of the drugs used in the study, but Pfizer was not involved in the research data.

Faulty Body Clock May Make Kids Bipolar

ScienceDaily (Nov. 13, 2009) — Malfunctioning circadian clock genes may be responsible for bipolar
disorder in children. Researchers writing in the open access journal BMC Psychiatry found four versions
of the regulatory gene RORB that were associated with pediatric bipolar disorder.

Alexander Niculescu from Indiana University School of Medicine, Indianapolis, US, worked with a team
of researchers at Harvard, UC San Diego, Massachusetts General Hospital and SUNY Upstate Medical
University to study the RORA and RORB genes of 152 children with the condition and 140 control
children. They found four alterations to the RORB gene that were positively associated with being
bipolar. Niculescu said, "Our findings suggest that clock genes in general and RORB in particular may be
important candidates for further investigation in the search for the molecular basis of bipolar disorder".
RORB is mainly expressed in the eye, pineal gland and brain. Its expression is known to change as a
function of circadian rhythm in some tissues, and mice without the gene exhibit circadian rhythm
abnormalities. According to Niculescu, "Bipolar disorder is often characterized by circadian rhythm
abnormalities, and this is particularly true among pediatric bipolar patients. Decreased sleep has even
been noted as one of the earliest symptoms discriminating children with bipolar disorder from those
with attention deficit hyperactivity disorder (ADHD). It will be necessary to verify our association results
in other independent samples, and to continue to study the relationship between RORB, other clock
genes, and bipolar disorder".
Pediatric bipolar disorder is a controversial diagnosis characterized by alternating bouts of depression
and mania in children, although it does not affect all young people in the same way and the duration
and severity of the disorder can vary enormously.

Immune System Activated in Schizophrenia

ScienceDaily (Nov. 18, 2009) — Researchers at the Swedish medical university Karolinska Institutet have
discovered that patients with recent-onset schizophrenia have higher levels of inflammatory substances
in their brains. Their findings offer hope of being able to treat schizophrenia with drugs that affect the
immune system.

The causes of schizophrenia are largely unknown, and this hinders the development of effective
treatments. One theory is that infections caught early on in life might increase the risk of developing
schizophrenia, but to date any direct evidence of this has not been forthcoming.
Scientists at Karolinska Institutet have now been able to analyse inflammatory substances in the spinal
fluid of patients with schizophrenia, instead of, as in previous studies, in the blood. The results show
that patients with recent-onset schizophrenia have raised levels of a signal substance called interleukin-
1beta, which can be released in the presence of inflammation. In the healthy control patients, this
substance was barely measurable.
"This suggests that the brain's immune defence system is activated in schizophrenia," says Professor
Göran Engberg, who led the study. "It now remains to be seen whether there is an underlying infection
or whether the immune system is triggered by some other means."
According to the dominant hypothesis, schizophrenia is related to an overactive dopamine system.
Previous studies have shown that interleukin-1beta can upset the dopamine system in rats in a similar
way to schizophrenia in humans.
"We would have made terrific progress if we were one day able to treat schizophrenia patients with
immunotherapy, as it might then be possible to interrupt the course of the disease at an early stage of
its development," says Professor Engberg.
The group is now studying if the inflammatory process is only activated in connection with the
development of schizophrenia, or whether chronic patients exhibit the same phenomenon.

Anti-Inflammatory Medications May Become A Treatment For Schizophrenia

ScienceDaily (Oct. 28, 2008) — Many of the structural and neurochemical features of schizophrenia are
present long before the full syndrome of schizophrenia develops. What processes tip the balance
between the ultra-high risk states and the development of schizophrenia? One candidate mechanism is
cerebral inflammation, studied by Dr. Bart van Berckel and colleagues in the November 1st issue of
Biological Psychiatry.

Using positron emission tomography, or PET, imaging, the researchers provide evidence of a brain
inflammatory state that may be associated with the development of schizophrenia. The authors
reported increased binding levels of [11C]PK11195, a radiotracer with high affinity for the peripheral
benzodiazepine receptor (PBR) in patients who had carried the diagnosis of schizophrenia for five years
or less. PBR is a molecular target that is present at higher levels in activated microglia. Microglia are
activated during inflammatory states. Drs. van Berckel and Kahn further explain: “It was found that
microglia activation is present in schizophrenia patients early after disease onset, suggesting brain cells
are damaged in schizophrenia. In addition, since microglia can have either a protective or a toxic role,
activated microglia may be the result, but also the cause of damage to brain cells.”
John H. Krystal, M.D., Editor of Biological Psychiatry and affiliated with both Yale University School of
Medicine and the VA Connecticut Healthcare System, adds, “It will be important to understand whether
this process takes place in a special way in association with the first onset of symptoms or whether
inflammation is more generally a process that contributes to worsening of symptoms.”
Because this data suggests that inflammation may contribute to features of the early course of
schizophrenia, a new potential avenue of treatment for schizophrenia may be to use anti-inflammatory
agents. Although some anti-inflammatory medications have already been studied, with limited success,
in schizophrenia patients, a new generation of these drugs that more specifically target activated
microglia have yet to be explored.

Traffic Jam In Brain Causes Schizophrenia Symptoms; Mouse Develops Disease As Teenager, Just Like
Humans

ScienceDaily (Aug. 11, 2009) — Schizophrenia waits silently until a seemingly normal child becomes a
teenager or young adult. Then it swoops down and derails a young life.

Scientists have not understood what causes the severe mental disorder, which affects up to 1 percent of
the population and results in hallucinations, memory loss and social withdrawal.
But new research from the Northwestern University Feinberg School of Medicine has revealed how
schizophrenia works in the brain and provided a fresh opportunity for treatment. In a new, genetically
engineered mouse model, scientists have discovered the disease symptoms are triggered by a low level
of a brain protein necessary for neurons to talk to one another.
A Traffic Jam in Brain
In human and mouse brains, kalirin is the brain protein needed to build the dense network of highways,
called dendritic spines, which allow information to flow from one neuron to another. Northwestern
scientists have found that without adequate kalirin, the frontal cortex of the brain of a person with
schizophrenia only has a few narrow roads. The information from neurons gets jammed up like rush
hour traffic on an interstate highway squeezed to a single lane.
"Without enough pathways, the information takes much longer to travel between neurons and much of
it will never arrive," said Peter Penzes, assistant professor of physiology at the Feinberg School. He is
senior author of a paper reporting the findings published in a recent issue of the Proceedings of the
National Academy of Science. Michael Cahill, a Feinberg doctoral student in neuroscience, is the lead
author.
Mouse Model Develops Disease as a Teenager
Penzes discovered the kalirin effect after he created the mouse model, which has a low level of kalirin
and develops symptoms of schizophrenia as an adolescent (two months old in mouse time). This mimics
the delayed onset of the disease in humans. In normal development, the brain ramps up the production
of kalirin as it begins to mature in adolescence.
New Direction for Treatment
"This discovery opens a new direction for treating the devastating cognitive symptoms of
schizophrenia," Penzes said. "There is currently no treatment for that. It suggests that if you can
stimulate and amplify the activity of the protein kalirin that remains in the brain, perhaps we can help
the symptoms."
Currently the only drug treatment for schizophrenia is an antipsychotic. "The drugs address the
hallucinations and calm down the patient, but they don't improve their working memory (the ability of
the brain to temporarily store and manage information required for complex mental tasks such as
learning and reasoning) or their ability to think or their social behavior," Penzes said. "So you end up
with patients who still can't integrate into society. Many attempt suicide."

Similarities Between Human and Mouse Brains

A few years ago in postmortem examinations of schizophrenic human brains, other scientists had found
fewer connections between the brain cells in the frontal cortex and lower levels of kalirin. But the
scientists couldn't show whether one condition led to the other.
With the new mouse model, Penzes was able to demonstrate that the low level of kalirin resulted in
fewer dendritic spines in the frontal cortex of the brain, the part of the brain responsible for problem
solving, planning and reasoning. Other areas of the brain had a normal number of the dendritic spines.
Human brains and mouse brains share many similarities in the way they function, Penzes said.
The new schizophrenic mouse model also exhibits more schizophrenic symptoms than other models,
making these mice especially good for drug testing and development, Penzes said. The mice with low
amounts of kalirin had a poor working memory, were antisocial and hyperactive.
Penzes said future studies would aim at enhancing the function of kalirin in the brain in an effort to
correct the cognitive symptoms of schizophrenia.