Category: Bipolar Disorder

 It is important to identify the endophenotypes — traits associated with a clinical disorder — that can serve as a roadmap for detecting disease-related genes. That is why Deborah L. Levy, Ph.D., associate professor of psychology in the Department of Psychiatry at Harvard Medical School and director of the Psychology Research Laboratory at McLean Hospital, is studying families to detect relatives who are carriers of the genes for schizophrenia and bipolar disorder, even though these individuals don’t have the diseases themselves.

"One of the key issues in any genetic study is to distinguish individuals who are gene carriers from individuals who are not gene carriers," explained Dr. Levy. In single gene disorders, such as cystic fibrosis and Huntington's disease, 25 percent and 50 percent of family members, respectively, have the same illness. In contrast, only 6.5 percent of family members of people with schizophrenia actually have the illness, which means most relatives don’t have symptoms of the illness but may still be gene carriers.

To find the relatives who are likely carriers of genes for schizophrenia and bipolar disorder, Dr. Levy and her colleagues have zeroed in on four discernable schizophrenia-related traits that occur in well family members at a much higher rate than schizophrenia itself: difficulty following a slow moving target with one’s eyes, syntax errors or idiosyncratic use of language, subtle anomalies involving the midline of the face , and difficulty filtering out noises and other irrelevant stimuli (a condition known as sensory gating).

These traits, according to Dr. Levy, are much more common in families with schizophrenia. For example, idiosyncratic use of language (a trait similar to the thought disorder observed in schizophrenia) occurs in 37 percent of clinically unaffected first-degree relatives of individuals with schizophrenia, a rate that is almost six times higher than schizophrenia in the same families. When the rates for thought disorder and schizophrenia and related clinical conditions are combined, the proportion of potential gene-carrying relatives is close to 50 percent, consistent with a dominant gene, and much higher than the 6.5 percent rate of schizophrenia in the same families.

“With diseases like schizophrenia and bipolar disorder, identifying the genes is just the starting point,” noted Dr. Levy. “The ultimate goal is to discover the biological processes these genes initiate in the brain, ultimately leading to better treatments in the future.”

A new study by Rhode Island Hospital and Brown University researchers reports that fewer than half the patients previously diagnosed with bipolar disorder received a diagnosis of bipolar disorder based on a comprehensive, psychiatric diagnostic interview–the Structured Clinical Interview for DSM-IV (SCID).

The study concludes that while recent reports indicate that there is a problem with underdiagnosis of bipolar disorder, an equal if not greater problem exists with overdiagnosis. The study was published online by the Journal of Clinical Psychiatry. Principle investigator Mark Zimmerman, M.D., will present the findings at the annual meeting of the American Psychiatric Association on Wednesday, May 7.

The study method involved 700 psychiatric outpatients who were interviewed using the SCID and completed a self-administered questionnaire between May 2001 and March 2005. The questionnaire asked patients whether they had been previously diagnosed with bipolar or manic-depressive disorder by a health care professional. Family history of bipolar disorder was used as an index of diagnostic validity.

Of the 700 patients, 145 reported they had been previously diagnosed as having bipolar disorder; however, fewer than half of the 145 patients (43.4 percent) were diagnosed with bipolar disorder based on the SCID. Further, the study showed that patients diagnosed with bipolar disorder based on the SCID had a significantly higher morbid risk of bipolar disorder in first-degree relatives.

Unnecessary side effects are a significant concern of overdiagnosis. Because mood stabilizers are the treatment of choice for bipolar disorder, overdiagnosing can unnecessarily expose patients to serious medication side effects, including possible impact to renal, endocrine, hepatic, immunologic and metabolic functions.

Lead author Mark Zimmerman, M.D., director of outpatient psychiatry at Rhode Island Hospital and associate professor of psychiatry and human behavior at The Warren Alpert Medical School of Brown University, notes, "Clinicians are inclined to diagnose disorders that they feel more comfortable treating. We hypothesize that the increased availability of medications that have been approved for the treatment of bipolar disorder might be influencing clinicians who are unsure whether or not a patient has bipolar disorder or borderline personality disorder to err on the side of diagnosing the disorder that is medication responsive." He continues, "This bias is reinforced by the marketing message of pharmaceutical companies to physicians, which has emphasized the literature on the delayed and underrecognition of bipolar disorder, and may be sensitizing clinicians to avoid missing the diagnosis of bipolar disorder."

Zimmerman concludes, "The results of this study suggest that bipolar disorder is being overdiagnosed and we recommend that clinicians use a standardized, validated method in diagnosing bipolar disorder."

The report is from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) Project, for which Zimmerman is the principal investigator. Zimmerman said, "The MIDAS project is unique in its integration of research quality diagnostic methods into a community-based outpatient practice affiliated with an academic medical center."

Despite intriguing findings that omega-3 fatty acid supplements could alleviate depression symptoms, there is still not enough evidence to say whether omega-3s are useful treatments for people with bipolar disorder, according to a review of recent studies.

Nevertheless, omega-3s deserve further study, since they seem to have no serious side effects and most experts recommend the supplements for people with heart disease and some immune disorders, said authors Paul Montgomery, Ph.D., and Alex Richardson, Ph.D., of the University of Oxford.

Montgomery and Richardson found five studies on the effects of omega-3 supplements for bipolar disorder, but only one study of 75 patients provided enough data on the therapy’s outcomes for the researchers to analyze. Patients in the study had less severe depression symptoms while taking the supplements, but omega-3s did not affect their mania symptoms. Patients with bipolar disorder can cycle between periods of mania — elevated mood and energy — and depression.

The review of studies appears in the latest issue of The Cochrane Library, a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews like this one draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

Montgomery said the review makes it clear that there is not enough evidence yet to determine how omega-3s affect bipolar disorder, “and what evidence is currently available is of such a varied and oftentimes questionable nature that no reliable conclusions may be drawn.”

Bipolar disorder is among the top 30 causes of disability worldwide. Clinicians prescribe a variety of mood-stabilizing drugs to treat the complex psychiatric disorder, but the medications rarely cause symptoms to disappear completely and they can have serious side effects.

Recently, a growing handful of studies have suggested that omega-3s can be beneficial for other mood disturbance disorders such as clinical depression, personality disorders and schizophrenia

Different versions of the fatty acids are in vegetable oils such as flax seed oil and in fish oils. Researchers are still not clear how omega-3s work in the body, but they might “play key roles in brain structure and function,” Montgomery said.

For the moment, the few studies available suggest that patients should use omega-3s along with prescribed mood stabilizers, Montgomery said.

Joseph Hibbeln, M.D., who heads the nutritional neurochemistry division of the National Institute on Alcohol Abuse and Alcoholism, said he and his colleagues “strongly recommend” that patients with psychiatric disorders not take omega-3 supplements “in lieu of established psychiatric treatment options.”

Companies that manufacture the supplements, along with government and charity funding, supported some of the studies considered for the review. Montgomery and Richardson have worked as consultants to several fatty acid supplement companies, the review disclosed.

Reference: Montgomery P, Richardson AJ. Omega-3 fatty acids for bipolar disorder. The Cochrane Database of Systematic Reviews 2008, Issue 2.

A new study by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) presents results on the first onset of substance use disorders (i.e., alcohol and drug abuse and dependence) and major mood and anxiety disorders, based on Wave 2 of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC).

This landmark survey is the first conducted in the U.S. to identify rates of first episodes (i.e., incidence) of these disorders in the U.S. population. In addition, it provides information on sociodemographic and psychopathologic risk factors for those disorders–information critical for developing evidence-based preventive interventions–and estimates risk for subsequent comorbid disorders.

Bridget Grant, Ph.D., Chief of NIAAA's Laboratory of Biometry and Epidemiology, and her colleagues found that 1-year incidence rates were highest for DSM-IV alcohol dependence (1.70%), alcohol abuse (1.02%), major depressive disorder (1.51%) and generalized anxiety disorder (1.12%), followed by panic disorder (0.62%), bipolar I disorder (0.53%) and specific phobia (0.44%). One-year incidence rates of DSM-IV social phobia (0.32%), bipolar II (0.21%) and drug abuse (0.28%) and drug dependence (0.32%) were lower but not insignificant. These rates are comparable to or exceed corresponding incidence rates for other common medical diseases such as lung cancer (0.06%), stroke (0.45%) and cardiovascular disease (1.5%).

The study found that men were at greater risk of first onset alcohol abuse, alcohol dependence and drug dependence, and 1-year incidence rates were greatest among 20- to 29-year-olds and individuals who had been separated/divorced/widowed or never married. By contrast, the risk of most incident DSM-IV anxiety disorders, including panic disorder, specific but not social phobia, and generalized anxiety disorder, was greatest among women, and all anxiety disorder incidence rates were greater in the youngest age groups (20- to 54-year-olds).

Among DSM-IV mood disorders examined in this study, the risk of first onset of major depressive disorder (MDD) was greatest among women, and no sex differences in incidence were found for bipolar I and II disorders. Taken together, these results highlight age as an important general risk factor for first onset DSM-IV substance use, mood and anxiety disorders, whereas the effects of sex and marital status appear to be disorder-specific.

Consistent with earlier studies, baseline dysthymia in this study predicted incident MDD, and baseline MDD predicted incident bipolar II disorder, suggesting that MDD precedes hypomania in the development of bipolar II disorder. Consistent with other prospective studies, alcohol abuse and dependence showed strong reciprocal temporal relationships, whereas drug abuse predicted only incident drug dependence.

"The reciprocal relationship between alcohol abuse and dependence suggests that strong common factors may underlie the relationship and provides support for eliminating the hierarchy between the disorders in future DSM revisions," state the authors. Other intriguing findings include reciprocal temporal relationships between MDD and GAD, and GAD and panic disorder, suggesting that common causes underlie those disorders. In addition, substance use disorders did not predict any incident mood or anxiety disorder, the authors note.

"Information on psychiatric risk factors prospectively identified in this study can begin to inform a new class of preventive interventions aimed at preventing a second disorder or set of disorders," said Grant. "As to clinical implications, this study helps to clarify the risk of future disorders posed by chronologically primary disorders, information that may be used to improve treatment planning and counsel patients at risk of developing secondary disorders."

Journal reference: Bridget F. Grant, Ph.D., Ph.D., Risë B. Goldstein, Ph.D., M.P.H., S. Patricia Chou, Ph.D., Boji Huang, M.D., Ph.D., Frederick S. Stinson, Ph.D., Deborah A. Dawson, Ph.D., Tulshi D. Saha, Ph.D., Sharon M. Smith, Ph.D., Attila J. Pulay, M.D., Roger P. Pickering, M.S., W. June Ruan, M.A., Wilson M. Compton, M.D., M.P.E.Sociodemographic and Psychopathologic Predictors of First Incidence of DSM-IV Substance Use, Mood, and Anxiety Disorders: Results from the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions. Molecular Psychiatry advance online publication. April 22, 2008.

Bipolar Disorder (BPD or manic-depressive illness) is one of the most serious of all mental disorders, affecting millions of individuals worldwide. Affected individuals alternate between states of deep depression and mania. While depression is characterized by persistent and long-term sadness or despair, mania is a mental state characterized by great excitement, flight of ideas, a decreased need for sleep, and, sometimes, uncontrollable behavior, hallucinations, or delusions. BPD likely arises from the complex interaction of multiple genes and environmental factors. Unlike some brain diseases, no single gene has been implicated in BPD.

A major limitation to progress in research and treatment has been the lack of an appropriate animal model for BPD. This work was developed to create such a model based on a genetically engineered defect in the GluR6 gene. The glutamate receptor 6 (GluR6 or GRIK2, one of the kainate receptors) gene resides in a genetic linkage region (6q21) associated with BPD. Kainate receptors respond to the neurotransmitter glutamate, and recent research in mood disorders suggests that the glutamatergic system may play a role in causing mood disorders.

Until now, the role of GluR6 in regulating the mood swings of BPD has been unknown. Furthermore, the gene encoding the GluR6 receptor has recently been linked to treatment emergent suicidal ideation with antidepressants in a pharmacogenetic study. Notably, individuals with bipolar disorder are most susceptible to antidepressant-induced dysphoric states. In this study, mice of several strains were used to investigate this issue. Mice who were missing the GluR6 gene were compared with control mice.

The mice underwent a series of tests designed to approximate the symptoms of mania. The researchers found that mice that were missing the GluR6 gene exhibited many of these symptoms. They were more active in multiple tests and super-responsive to amphetamine, which is used in animal models to approximate hyperactivity. These mice also exhibited less anxious or more risk-taking type behavior and less despair-type behavior. They also tended to be more aggressive.

Notably, BPD is most often treated with a class of medications known as mood stabilizers; lithium is perhaps the best known of these medications. The researchers found that chronic treatment with lithium reduced hyperactivity, aggressive displays, and some risk-taking type behavior in mice missing the GluR6 gene. When biochemical tests were conducted, they also suggested that GluR6 may play a unique role in regulating some of the symptoms of mania. This new animal of mania permits researchers to better understand bipolar disorder and to screen for new treatments that if successful in the animal model can then be translated to the clinic.

Citation source: Molecular Psychiatry advance online publication 11 March 2008

A small, three-week trial of tamoxifen, a drug typically used to treat breast cancer, indicates that it also may decrease symptoms of mania in patients with bipolar disorder, according to a new report.

Tamoxifen interferes with the effects of the hormone estrogen, which accounts for its effects against breast cancer, according to background information in the article. However, tamoxifen also inhibits the actions of a family of enzymes known as protein kinase C. Abnormal levels of activity by these enzymes have been associated with bipolar disorder and related dysfunctions, such as distractibility, impaired judgments and disorganized thoughts.

Animal studies and human pilot trials have suggested that tamoxifen may be effective in treating mania–an abnormally elevated mood that features impulsive behavior, higher energy and activity levels, and disconnected thoughts–in patients with bipolar disorder. Ayegül Yildiz, M.D., of the Dokuz Eylül University Medical School, Izmir, Turkey, and colleagues conducted a clinical trial with 66 patients age 18 to 60, all of whom were diagnosed with bipolar disorder and were currently in a manic state or a mixed state that included mania. Participants were randomly assigned to take tamoxifen (40 milligrams to 80 milligrams per day) or identical placebo tablets twice daily for up to three weeks. Participants in both groups also were given up to 5 milligrams per day of the sedative lorazepam as needed to control their symptoms.

A total of 50 patients–29 assigned to take tamoxifen and 21 assigned to take placebo–completed the 21-day trial. Patients in the tamoxifen group had significantly lower scores on tests used to measure the severity of mania at the end of the three-week period, while those in the placebo group had scores that slightly increased. Almost half (48 percent) of patients taking tamoxifen responded to the drug–defined as a reduction of at least half in mania scores–compared with 5 percent of those taking placebo, and 28 percent vs. zero achieved cutoff scores for mania remission.

Patients taking tamoxifen also used less lorazepam during the study–an average of 25.2 milligrams compared with 41.8 milligrams for patients in the placebo group. "Moreover, all subjects used less lorazepam as the trial progressed, and the rate of decrease was 2.5 times greater with tamoxifen," the authors write. Both tamoxifen and placebo were well tolerated.

"The findings encourage further clarification of the role of protein kinase C in the pathophysiologic mechanism of bipolar 1 disorder and development of novel anti–protein kinase C agents as potential antimanic or mood-stabilizing agents," the authors conclude.

Journal reference: Arch Gen Psychiatry. 2008;65[3]:255-263.

This study was supported by a research grant from the Stanley Medical Research Institute.

Editorial: Targeted Therapies Represent Future of Bipolar Disorder Treatment

"The role of tamoxifen per se in the treatment of bipolar disorder still remains to be determined, but its anti-estrogen effects are likely to present a safety challenge," writes Mauricio Tohen, M.D., Dr.P.H., of Eli Lilly Corporate Center, Indianapolis, in an accompanying editorial.

"The evidence-based selection of the therapeutic targets that led to this study hopefully will lead to similar approaches by industry, government and academia in the development of new and better treatments for bipolar disorder," Dr. Tohen concludes. "Undoubtedly, this will be an important step to conquer this devastating disorder that affects millions of patients around the globe."

Reference for editorial: Arch Gen Psychiatry. 2008;65[3]:252-253.

Disclosure: Dr. Tohen is a full-time employee and a stockholder of Eli Lilly and Company.

People with manic depression have a distinct chemical signature in their brains, according to a new study. The research may also indicate how the mood stabilisers used to treat the disorder counteract the changes in the brain that it appears to cause.

Manic depression, which is also known as bipolar disorder, is a debilitating psychiatric condition characterised by alternating mania and depression, affecting about one in every hundred people worldwide. Although it is known that the condition can be treated relatively effectively using the mood-stabilising drugs lithium and valproic acid, the reasons why these treatments work are poorly understood.

The authors of the new study,* from Imperial College London, the University of Cambridge, and the National Institutes of Mental Health in the US, hope that their research will enable a better understanding of the condition and of how it can be treated.

The researchers compared postmortem brain tissue samples of people with manic depression with those of age and gender matched controls. The samples were taken from the dorsolateral prefrontal cortex, which controls the processes involved in higher cognitive functioning. The researchers analysed these samples using Nuclear Magnetic Resonance spectroscopy and found that people with manic depression had different concentrations of chemicals in this area of the brain than those without.

The researchers also used rat models to see the effects of lithium and valproic acid on the metabolite makeup of non-bipolar brain tissue. They found that these drugs caused the opposite chemical changes to those seen in the bipolar brain tissue samples. Chemicals that were increased in the bipolar brain tissue were decreased in rats given the mood stabilising drugs, and vice versa.

The researchers' findings lead them to believe that an upset in the balance of different neurotransmitters known as excitatory and inhibitory neurotransmitters, which are involved in sending signals in the brain, may be central to the disorder. The study also suggests that lithium and valproic acid work by restoring the balance of these neurotransmitters in the brain.

Levels of glutamate, an amino acid which acts as a neurotransmitter in the central nervous system, were increased in post mortem bipolar brain but glutamate / glutamine ratios were decreased following valproate treatment. Levels of another neurotransmitter, gamma-aminobutyric acid, were increased after lithium treatment and decreased in the bipolar brain. Both creatine and myo-inositol were increased in the post-mortem brain but depleted with the medications.

Dr Tsz Tsang, one of the authors of the study from the Department of Biomolecular Medicine at Imperial College London, said: "By identifying a distinct biochemical profile in patients with bipolar disorder, our new research provides a valuable insight into the origins and causes of the disease. Moreover, the changes we see in people's metabolic signatures may give a target for drug therapy, allowing us to see how effective a drug is at correcting these changes.

"In this instance, we have already shown that the biochemical changes which valproic acid and lithium bring about in mammalian models represent almost a mirror image of the perturbations in bipolar disorder. This may provide a useful insight to the actions of these treatments and a basis for which to improve therapy in the future," added Dr Tsang.

*Journal article: "Metabonomic Analysis Identifies Molecular Changes Associated with the Pathophysiology and Drug Treatment of Bipolar Disorder" Molecular Psychiatry, 5 February 2007. Authors: Lan, M.J.; and McLoughlin, G. A.; Griffin, J. L.; Tsang, T. M; Huang, J. T. J.; Yuan, P.; Manji, H.; Holmes, E. and Bahn S.

 Bright light therapy can ease bipolar depression in some patients, according to a study published in the journal Bipolar Disorders. Researchers from the University of Pittsburgh School of Medicine's Western Psychiatric Institute and Clinic studied nine women with bipolar disorder to examine the effects of light therapy in the morning or at midday on mood symptoms.

"There are limited effective treatments for the depressive phase of bipolar disorder," said Dorothy Sit, M.D., assistant professor of psychiatry and the study's first author. "While there are treatments that are effective for mania, the major problem is the depression, which can linger so long that it never really goes away."

In this study, women with bipolar depression were given light boxes and instructed on how to use them at home. The women used the light boxes daily for two-week stretches of 15, 30 and 45 minutes. Some patients responded extremely well to the light therapy, and their symptoms of depression disappeared. The responders to light therapy stayed on the light therapy for an additional three or four months. Four patients received morning light, and five used their light boxes at midday. Participants also continued to take their prescribed medications throughout the study period.

"Three of the women who received morning light initially developed what we call a mixed state, with symptoms of depression and mania that occur all at once — racing thoughts, irritability, sleeplessness, anxiety and low mood," said Dr. Sit. "But when another group began with midday light therapy, we found a much more stable response."

Of the nine women treated, six achieved some degree of response, with several reaching full recovery from depressive symptoms. While most attained their best recovery with midday light, a few responded more fully to a final adjustment to morning light. "People with bipolar disorder are exquisitely sensitive to morning light, so this profound effect of morning treatment leading to mixed states is very informative and forces us to ask more questions," said Dr. Sit. "Did we introduce light too early and disrupt circadian rhythms and sleep patterns?"

People with bipolar disorder are known to be sensitive to changes in outdoor ambient light and to seasonal changes. Researchers are asking whether the risk of suicide in patients with bipolar disorder could be linked to changes in light exposure.

"In our study, 44 percent of patients were full responders, and 22 percent were partial responders," Dr. Sit and her colleagues write. "Light therapy, therefore, is an attractive and possibly effective augmentation strategy to improve the likelihood of full-treatment response."

Optimal response was observed with midday light therapy for 45 or 60 minutes daily, noted Dr. Sit.

Other study authors are Katherine L. Wisner, M.D., Barbara H. Hanusa, Ph.D., and Stacy D. Stull, M.S., all of the Women's Behavioral HealthCARE program at Western Psychiatric Institute and Clinic; and Michael Terman, Ph.D., Columbia University. Article: doi/full/10.1111/j.1399-5618.2007.00451.x

Researchers report funding from the Stanley Foundation, the University of Pittsburgh School of Medicine, National Institute of Mental Health, U.S. Department of Health and Human Services, Pfizer Inc., GlaxoSmithKline and the National Institute of Neurological Disorders and Stroke.

Bipolar disorder, commonly known as manic-depressive disorder, is highly influenced by the circadian system — the body's internal clock — and a specific kind of psychotherapy may help decrease irregularities in the circadian system that can trigger key symptoms of bipolar disorder, according to a study presented today at the American College of Neuropsychopharmacology (ACNP) annual meeting. The results are important because they show for the first time that psychotherapy which focuses on practical lifestyle changes can ease the symptoms of bipolar disorder. Every year nearly six million American adults suffer from bipolar disorder, a brain disorder which causes severe shifts in mood, energy, and ability to function, according to the National Institute of Mental Health.

Maintaining a consistent sleep schedule and wake time can help balance the circadian system, which in turn can help people avoid nighttime sleeplessness or daytime exhaustion, which can increase the risk of new episodes of mania or depression. "Having already found that disruption in daily routines can make individuals with bipolar disorder vulnerable to new episodes of illness, we have now learned that working with patients to achieve and maintain regular social rhythms — including regular sleep patterns and adequate physical activity — will help to protect them against episodes of mania or depression," says Ellen Frank, Ph.D., clinical psychologist and professor of psychiatry and psychology at the University of Pittsburgh School of Medicine.

People with bipolar disorder tend to have extremely sensitive circadian systems, which makes it much more difficult for them to recover from disruptions in sleep and routine. In contrast, people without bipolar disorder generally recover fairly quickly if their systems are thrown off by a change in routine or loss of sleep and might even be temporarily energized by these alterations.

Frank studied 175 adult patients with bipolar disorder and compared the effects of two approaches when combined with a common medical treatment for bipolar disorder, usually lithium carbonate: the first was interpersonal and social rhythm therapy, in which patients use a self-monitoring instrument to record and monitor the regularity of their daily routines–for example, their sleep patterns, meal times and physical activity. The second approach involved an intensive clinical management paradigm focusing just on patients' mood symptoms and management of medication side effects.

The study found that patients who participated in interpersonal and social rhythm therapy in the earlier phases of the trial were able to go longer without a new episode of mania or depression than those who received clinical management.

Frank notes that many study participants had other medical and psychiatric conditions that also had important effects on their treatment outcomes. She adds that her study was conducted in an academic environment using highly trained therapists, so results from other settings might be different.

In a related study presented at the meeting, researchers studying circadian rhythms in mice found that the genes that regulate these rhythms also control the activity of neurons in the brain that utilize dopamine, a neurotransmitter implicated in motivation and emotion. Mice that are lacking some of the key circadian genes closely resemble bipolar patients in the manic state.

Lead researcher Colleen McClung, Ph.D., assistant professor of psychiatry at the University of Texas Southwest Medical Center, says these mice are the most well characterized animal models of human mania that have been described. Symptoms of mania include increased energy, activity, and restlessness; excessively good, euphoric mood; and poor judgment.

While there has long been an association between circadian rhythms and bipolar disorder, no studies have examined whether these rhythmic disruptions contribute to the symptoms associated with bipolar disorder. McClung says the findings of this study bring researchers one small step closer to discovering why bipolar disorder occurs at all, even though the study was done in mice, not humans, and that many more studies will be needed to discover a cure.

 Puberty may have an impact on areas of the brain that contribute to bipolar disorder or schizophrenia in youth, according to a study presented December 7 at the annual meeting of the American College of Neuropsychopharmacology (ACNP).

Researchers studying the brains of youth with bipolar disorder (also known as manic depressive illness) and schizophrenia found that these children have size differences in some brain areas between these disorders and between genders. These changes exist in key areas of the brain that are involved in reward, motivation, sensory input, emotion and memory, and researchers say examining these areas can help researchers understand developmental processes that occur around the time mental disorders develop.

The brains of children with bipolar disorder are different from the brains of children with schizophrenia, and there are brain differences between boys and girls, and investigators say such findings can help them better understand gender's role in brain processes, and how it affects the development of mental illness. Additionally, they could help lay the foundation for identifying different possible treatment approaches to these illnesses in boys and girls.

"To our knowledge, our study is the first to determine if specific areas of the brain differ according to sex and adolescent development, compared to children without these disorders," says Jean A. Frazier, M.D., Director of the Child and Adolescent Neuropsychiatric Research Program at Cambridge Health Alliance, Harvard Medical School, in Massachusetts and an ACNP member.

Frazier and fellow researchers examined 103 brain scans of children and adolescents with bipolar disorder or schizophrenia and found that the nucleus accumbens (a brain structure that is involved in motivation and pleasure) was larger in bipolar disorder. They also found that the thalamus (the part of the brain through which sensory information passes to the cerebral cortex) was smaller in children with schizophrenia.

Frazier's work suggests that as the brain develops, some brain structures may be more vulnerable to mental illness than others in children with these illnesses, particularly during pubertal development. These developmental brain changes may be biomarkers — specific traits — that make the brain more vulnerable to these mental illnesses.

Finally, when Frazier looked at the entire bipolar group compared to healthy children, the hippocampus (the part of the brain which plays a central role in memory) was smaller in youth with bipolar disorder after puberty, particularly in girls. Younger (pre-pubescent) children did not show this difference. These findings suggest that sex hormones may influence how the brains of these vulnerable children develop and that the onset of puberty may be associated with the abnormal brain development seen in these children.

"Future studies need to look at sex differences over time in order to understand more about these mental disorders and the information gleaned from these studies may help researchers determine how to best help children who suffer from these conditions," Frazier says. "This may allow us to find improved treatment, perhaps in a sex-specific way.

The findings add to the evidence that adolescence is a critical period of vulnerability for the development of schizophrenia and bipolar disorder. The onset initiates a set of sex -specific brain developmental processes that may have an important role in the emergence of these disorders.