Several single nucleotide polymorphisms (SNPs) are linked to response to lithium for the prevention of recurrence in bipolar disorder, including in a region spanning a gene regulated by lithium, say scientists.

As many as 50% of bipolar disorder patients experience recurrence within a year of resolution of an acute episode. While lithium is a first-line treatment for bipolar disorder, it is not clear by which mechanisms the drug prevents the recurrence of mood episodes.

To determine associations between lithium treatment outcomes and SNPs, Roy Perlis, from Massachusetts General Hospital in Boston, and colleagues genotyped 1177 patients with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorders (STEP-BD). Of these, 458 were being treated with lithium carbonate or citrate.

The team then took the SNPs with the greatest evidence of association with lithium responses and examined them for association with positive lithium response among 359 bipolar I or II disorder patients in a cohort from University College London, all of whom were treated with lithium.

The genome-wide analysis of the STEP-BD cohort included approximately 1.4 million SNPs. No SNPs met the threshold for genome-wide significance. However, the greatest evidence of association was seen for an SNP on chromosome 10p15, with three other regions on 21q21, 12q22, and 6p21 found to have significant associations, while others had evidence suggestive of association.

Analysis of the University College London cohort revealed that nine SNPs were associated with lithium responses, five of which, on regions 8q22, 3p22, 11q14, 4q32, and 15q26, had the same direction of effect as seen in the STEP-BD cohort. Logistic regression analysis indicated that SNPs in the five regions were associated with lithium response at hazard ratios of 1.62, 1.45, 1.37, 1.40, 1.47, respectively, in the STEP-BD cohort and odds ratios of 1.71, 1.63, 1.60, 1.48, and 1.81, respectively, in the University College London cohort.

The team observes in the American Journal of Psychiatry that the region 4q32 spans the gene encoding the subunit of the ligand-gated ionotrophic glutamate receptor GluR2/GLURB, which binds to alpha-amino-3-hydroxy-5-methyl-4-isoxazolpropionate and is downregulated by chronic lithium treatment.

“Taken together, our results do suggest a number of regions meriting further investigation,” the team says. “They further highlight the importance of collecting adequate replication cohorts with detailed longitudinal outcomes if the effect of genetic variation on lithium response is to be understood.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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• Combined Lithium Plus Valproate Or Lithium Monotherapy Better At Preventing Relapse In Bipolar Patients Than Valproate Monotherapy (Balance Study)
• 1A binding reductions in euthymic bipolar disorder patients]]>

Patient reporting and severity of adverse drug reactions (ADRs) during long-term lithium treatment for bipolar disorder are affected by both serum lithium concentration and mood state, say Dutch researchers.

Compared with randomized controlled studies, the effectiveness of lithium treatment for bipolar disorders is lower in naturalistic follow-up, with nonadherence one of the major contributory factors. Previous studies have indicated that ADRs are a major reason for discontinuing treatment.

To determine the impact of mood state and lithium ADRs, Antoine Egberts, from Utrecht University, and colleagues conducted a 26-year follow-up study of 186 patients aged ?18 years treated at an outpatient lithium clinic between 1973 and 2000.

Information on the presence and severity of nine specific ADRs that frequently occur as a result of lithium treatment and can be identified by patients was gathered by a research nurse at each monthly scheduled visit. Serum lithium level and mood state were also assessed at each visit.

In all, 94.6% of patients had at least two ADR questionnaires completed during follow-up, giving a total of 8056 questionnaires. The median duration of patient follow-up was 5.7 years. At least one ADR was reported by all but two patients.

The serum lithium level at each interview was within the therapeutic range for 62.5% of patients, and mood state was rated as euthymic in 73.4% of cases. Adjusting for mood state, serum lithium level was significantly associated with the number of present ADRs, as well as with the average severity of all present ADRs.

Further adjustment for mood state, age at study inclusion, gender, and duration of lithium use confirmed that serum lithium was significantly associated with the number and severity of reported ADRs. Specifically, patients with a serum lithium level of 0.6 mmol/l, 0.9 mmol/l, and 1.2 mmol/l had an average number of ADRs of 3.3, 3.6, and 3.8, respectively.

When adjusting for serum lithium level, there was a significant association between mood state and the average number and severity of ADRs, with depressed mood, euthymic, and manic patients having an average of 2.0, 3.3, and 4.6 ADRs, respectively.

Interestingly, of the ADRs, tiredness and concentration deficits were most strongly linked to mood state, while polyuria and polydipsia were mostly strongly linked to serum lithium level.

The team writes in the journal Bipolar Disorders: “In conclusion, we found that both mood state and lithium serum level are independently associated with the prevalence and the severity of patient-reported ADRs in patients on lithium treatment.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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Reduced hippocampal brain-derived neurotrophic factor precursor ([pro]BDNF) expression is common to both major depressive disorder (MDD) and bipolar disorder, UK investigators have discovered.

Brain-derived neurotrophic factor (BDNF) and (pro)BDNF are expressed in the developing and adult hippocampus, and other brain areas linked to schizophrenia and mood disorders. Several studies have also linked BDNF and BDNF polymorphisms to the pathophysiology of psychiatric illness.

To examine alterations in hippocampal levels of (pro)BDNF and receptor proteins TrkB and p75 and the impact of genetic variations on protein expression, C Toro, from Cranfield University, and colleagues studied anterior hippocampal sections from the Stanley Foundation Neuropathology Consortium.

The sections included samples from 15 patients with schizophrenia, 15 with MDD, 15 with bipolar disorder, and 13 age- and gender-matched controls. Immunoautoradiography was used to determine (pro)BDNF, TrkB, and p75 protein densities, and extracted DNA was genotyped for several single nucleotides (SNPs) in the BDNF, NTRK2, and NGFR genes.

All of the mood disorder groups had reduced (pro)BDNF density compared with controls. However, the overall differences were not significant, as any reductions in hippocampal layers were offset by an absence of change in the dentate gyrus.

Specifically, MDD patients had significantly reduced (pro)BDNF density in all three layers of the right hippocampus, while bipolar disorder patients had reductions in the right striatal oriens and striatal radiatum.

The results also show that bipolar disorder patients had bilateral reductions in p75 values compared with MDD, schizophrenia, and control groups in the hippocampus but not in the dentate gyrus. The differences were particularly marked compared with MDD patients.

The team also notes in the Journal of Psychiatric Research that, of the 31 SNPs studied, five were associated with changes in protein density across all hippocampal subregions that may affect hippocampal development.

Discussing the findings, they write: “It is tempting to speculate that a combined impairment of (pro)BDNF and p75 receptor function in bipolar disorder relates to the chronicity of depression rather than the occurrence of mania, however further larger-scale studies are necessary to test this theory.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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• ">
• UNC Study Pinpoints Gene Controlling Number Of Brain Cells
• MTHFR gene not linked to bipolar disorder]]>
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The seasonal spring peak in suicide rates is particularly high among patients with a history of mood disorders, research shows.

Previous research has consistently shown a spring peak in suicide rates and exacerbations of mood disorders, which is “conducive to a hypothesis that the Spring peak in suicide is driven by a seasonal decompensation of mood disorders in spring,” explain Teodor Postolache (University of Maryland School of Medicine, Baltimore, USA) and team.

“If so, one would expect a greater suicide peak in spring among individuals with a history of hospitalization for mood disorders,” they add.

To investigate, the researchers used the Danish Cause of Death Registry to identify all 37,987 individuals who died by suicide in the country between 1970 and 2001.

They also used the Danish Psychiatric Central Register to assess any history of mood disorders among the suicide victims.

The team found that, overall, 17.1% of the suicide victims had been previously hospitalized for bipolar disorder, unipolar depression, or other mood disorders.

A spring peak in suicide rates was evident in individuals with and without a history of hospitalization for mood disorders, but was more prominent in those with such as history.

Specifically, men and women with a history of hospitalization for mood disorders were 1.18 and 1.20 times, respectively, more likely to commit suicide in spring than at other times of the year, while the respective risks in men and women without such a history were 1.07 and 1.11.

Analysis of a smaller sample of suicide victims from between 1981 and 1997, which allowed for adjustment of socioeconomic factors, indicated that a history of hospitalization for mood disorders was associated with a greater risk for spring suicide in men than women, at relative risks of 1.25 and 1.20, respectively.

Postolache and team conclude in the Journal of Affective Disorders: “The key finding of this study suggests that the history of hospitalization for mood disorder increases the spring peak of suicide.”

They add: “The results support the need to further investigate if exacerbation of mood disorders in spring triggers seasonal peaks of suicide. Identifying triggers for seasonal spring peaks in suicide may lead to uncovering novel risk factors and therapeutic targets for suicide prevention.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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• Antiepileptic Drugs Not Associated With Increased Risk Of Suicide Attempts In Patients With Bipolar Disorder
• Two Brown Faculty To Study Brain Development In Infants And Children With Bipolar Disorder

At the edu/stanley/8thbipconf/” target=”_blank” rel=”nofollow”>8th International Conference on Bipolar Disorder this week in Pittsburgh, four distinguished individuals will be honored for their contributions to bipolar disorder research, education and service. The conference is the only venue in the world devoted exclusively to highlighting new research into bipolar disorder

Joyce and Dusty Sang will receive the Mogens Schou Award for Public Service for founding The Ryan Licht Sang Bipolar Foundation, in memory of their only son, Ryan, who had early-onset bipolar disorder and died at the age of 24 in 2004. The foundation’s mission is to foster awareness, understanding and research for child and adolescent bipolar disorder. One of its major initiatives is a “Quest For The Test™” to find an empirical test for bipolar disorder so that early detection and intervention become a reality.

Lakshmi N. Yatham, M.B.B.S., F.R.C.P.C., M.R.C.Psych. (U.K.), will receive the Mogens Schou Award for Education and Advocacy. Dr. Yatham is a professor of psychiatry and associate head for research and international affairs in the Department of Psychiatry, University of British Columbia, Vancouver, where his research focuses on neurobiology and treatment of bipolar disorder and major depression. Dr. Yatham leads a Canadian consortium on bipolar disorder, which is pursuing testing of new treatments for bipolar disorder. He also is chair of the bipolar group of the Canadian Network for Mood and Anxiety Treatments and is actively involved at a national and international level in continuing medical and public education on diagnosis and treatment of bipolar disorder.

Guy Goodwin, D.Phil., F.Med.Sci., will receive the Mogens Schou Award for Research. Dr. Goodwin is the head of the Department of Psychiatry, Oxford University, where his research focuses on the treatment of severe psychiatric illness and the application of neuroscience in understanding the neurobiology of mood disorders. Dr. Goodwin is researching the neurobiology of vulnerability to mood disorders and the psychopharmacology of emotional processing. He also has helped develop the basis for larger-scale clinical trials in bipolar affective disorder (BALANCE and CEQUEL).

“This year’s Mogens Schou Awards continue the strong tradition of honoring those heroes who are making major advances that bring hope to those suffering from bipolar disorder,” said David J. Kupfer, M.D., the Thomas P. Detre Professor and chairman, Department of Psychiatry, University of Pittsburgh School of Medicine.

The Mogens Schou Awards were named in recognition and appreciation of Mogens Schou, M.D., Dr. Med. Sci., honorary president, International Society of Bipolar Disorders, and emeritus professor, The Psychiatric Hospital, Risskov, Denmark. His groundbreaking research over 50 years ago proved lithium’s significant mood stabilizing effects for the treatment of bipolar disorders. The awards ceremony takes place at 8:30 p.m., Friday, June 26, at The Carnegie Museums of Pittsburgh in Oakland.

The Eighth International Conference on Bipolar Disorder, which is being sponsored by the University of Pittsburgh School of Medicine and Western Psychiatric Institute and Clinic of UPMC, is the only venue in the world devoted exclusively to highlighting new research into bipolar disorder. The disease affects both adults and children, devastates families and work relationships, accounts for nearly half of all suicides in the United States, and costs billions in medical bills, missed work and lower productivity.

For more information on the meeting, visit http://www.8thbipolar.org.

Source
8th International Conference on Bipolar Disorder

• Funding Supports ADA Technologies' Development Of Home Monitor For Bipolar Disorder

A new study from Bradley Hospital and The Warren Alpert Medical School of Brown University, as well as two other institutions, adds to mounting evidence that clinicians consider irritability as a symptom when diagnosing pediatric bipolar disorder.

Reporting in the July issue of the Journal of the American Academy of Child and Adolescent Psychiatry, researchers say a small percentage of children with bipolar disorder experience manic episodes without extreme elation - one of the hallmarks of the disorder - and are diagnosed based on irritable mood alone.

“Diagnosing children with bipolar disorder is challenging. One of the chief controversies is whether irritability should be included among the criteria for this diagnosis because it can also overlap with a number of other psychiatric disorders, such as attention deficit hyperactivity disorder,” says lead author Jeffrey Hunt, MD, a child psychiatrist and training director at Bradley Hospital. “Our findings confirm that while irritable-only mania is uncommon, it does exist - particularly in younger children - and should be considered in a bipolar diagnosis.”

Bipolar disorder is characterized by dramatic mood swings from euphoria, elation and irritability - the manic phase of the disorder - to severe depression. Bipolar disorder often begins in late adolescence or early adulthood, although it can develop as early as the preschool years. Recent studies have shown that the number of children and teens being treated for bipolar disorder has grown dramatically in the last decade. Although it is unclear what has caused this increase, experts believe it may be due in part to more aggressive diagnoses by physicians and a greater awareness of pediatric bipolar disorder in the medical community.

Hunt and colleagues studied 361 children between the ages of 7 and 17 with bipolar disorder participating in the multi-site Course and Outcome of Bipolar Illness in Youth (COBY) study at Bradley Hospital and Alpert Medical School, the University of Pittsburgh and the University of California-Los Angeles. COBY is the largest and most comprehensive study of children and adolescents with bipolar disorder to date.

Researchers quantified the frequency and severity of manic symptoms of each participant, including whether irritability and elation were present. Based on this data, the group was then reclassified into three subgroups: elation-only, irritable-only and both elated and irritable.

Approximately 10 percent of children fell into the irritable-only category, while elated-only constituted about 15 percent. Nearly three-quarters experienced both elation and irritability. The irritable-only participants were significantly younger in age than the other two groups; however, there were no other sociodemographic differences between the groups. There were also no significant differences in terms of bipolar subtype, rate of psychiatric comorbidities, severity and duration of illness, and family history of mania and other psychiatric disorders. However, depression and alcohol abuse in second-degree relatives occurred more frequently in the irritable-only subgroup.

“The fact that the irritable-only and elation-only subgroup had similar clinical characteristics and family histories of bipolar disorder provides support for continuing to consider episodic irritability in the diagnosis of pediatric bipolar disorder,” says Hunt, who is an assistant professor of psychiatry and human behavior at Alpert Medical School. Hunt is also training director of the child and adolescent fellowship and triple board residency programs.

The authors say continual, long-term follow-up of this study sample will help clarify whether the presence or predominance of elation or irritability at baseline will predict future clinical outcomes.

The research was funded by a grant from the National Institute of Mental Health. Study co-authors include Jennifer Dyl and the late Henrietta Leonard from Bradley Hospital and Alpert Medical School; Christianne Esposito-Smythers, Martin Keller, Lance Swenson and Robert Stout from Alpert Medical School; Boris Birmaher, David Axelson, Neal Ryan, Benjamin Goldstein, Tina Goldstein, MaryKay Gill and Mei Yang from the University of Pittsburgh Medical Center; and Michael Strober from the David Geffen School of Medicine, University of California at Los Angeles.

Source:
Jessica Collins Grimes
Lifespan

• ">
• A receptor genes have selective influence on bipolar disorder phenotype]]>

Dopamine release in the prefrontal cortex increases flattening of the glucocorticoid rhythm, which may underpin prefrontal dysfunction in bipolar disorder patients, conclude researchers.

Previous studies have shown that bipolar disorder patients have abnormal glucocorticoid secretion, dopaminergic neurotransmission, and prefrontal cortex function, explain Sarah Gartside, from Newcastle University in the UK, and colleagues.

Believing that flattening of the diurnal glucocorticoid rhythm, which is common in bipolar disorder, modulates dopaminergic transmission in the prefrontal cortex, leading to functional abnormalities, the team administered corticosterone 50 µg/ml or 0.5% ethanol vehicle to the drinking water of male rats for 13??”15 days.

Compared with animals given vehicle, those treated with corticosterone had a flattened diurnal rhythm in blood corticosterone concentrations, with levels significantly lower before the diurnal peak and significantly higher at the nadir of the rhythm, and significant adrenal gland atrophy.

Corticosterone-treated animals had significantly increased basal dopamine levels compared with those given vehicle, the team reports in the journal Neuropsychopharmacology. Analysis revealed that depolarization-evoked release was also enhanced, while local blockade of terminal D2 autoreceptors failed to normalize release to control values.

In the ventral tegmental area, levels of mRNAs coding tyrosine hydroxylase and the vesicular monoamine transporter 2, as measured using in situ hybridization, were significantly increased in rats treated with corticosterone compared with vehicle-treated rats.

“The finding of increased dopamine release in the prefrontal cortex suggests a causal link between the neuroendocrine abnormalities observed in mood disorders, and some of the cognitive symptoms of these conditions: the prefrontal cortex plays a key role in cognitive functions including working memory, selective attention, goal directed behavior, and behavioral inhibition with prefrontal dopaminergic neurotransmission strongly influencing these functions,” the researchers write.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

Free abstract

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For bipolar disorder patients, longer admission to hospital is associated with more severe executive functioning deficits at discharge, the results of a US study indicate.

A more severe disease course in bipolar disorder is associated with greater cognitive impairments, with cognitive deficits in euthymic patients predicted by a greater number and longer duration of mood episodes.

To determine whether length of hospitalization to stabilize from an acute episode of mood disturbance is linked to cognitive functioning, Boaz Levy, from Harvard Medical School in Boston, Massachusetts, and colleagues studied 41 patients with bipolar disorder.

In all, 20 patients had a hospital stay that lasted longer than the median stay of 12 days, while the remaining 21 patients had a shorter stay. The participants were administered a neuropsychological battery at discharge and group differences in clinical data and test performance were analyzed.

There were no significant differences between long- and short-stay patients in terms of age at onset of bipolar disorder, previous number of psychiatric admissions, number of psychiatric medications taken on the day of testing or diagnostic subtype on admission. There were also no differences in depressive or manic symptoms, gender, marital status, age, or years of education.

Patients with longer hospital stays had significantly worse performance than those with a short hospital stay on immediate recall and recognition of the figure’s parts on the Rey Complex Figure Test, as well as marginally significant impairment of delayed recall and significant impairments in overall verbal memory.

In addition, performance on tests of executive functioning was significantly worse for patients with longer hospital stay compared with those with a short stay, specifically on the Stroop, Wisconsin Card Sorting Test, and Controlled Oral Word Association Test. There were no significant differences in attention, working memory, and IQ.

The team concludes in the journal Comprehensive Psychiatry: “The current data indicate that longer duration of hospital stay is correlated with more severe deficits in executive functioning during the phase of early remission.

“These results illuminate the challenges patients with bipolar disorder may face after discharge from a long inpatient admission and underscore the need to develop better care for their outpatient recovery.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

Free abstract

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Elevated mood and decreased sleep can discriminate juvenile-onset bipolar disorder (JO-BP) from attention-deficit hyperactivity disorder (ADHD) in children as young as 3 years of age, study results suggest.

“Considerable controversy surrounds the nature of the earliest symptom expression of childhood-onset bipolar illness and its prodromes,” explain Robert Post (Pennsylvania State University Medical School, Hershey, USA) and team.

They add that childhood-onset BP shows a high degree of comorbidity with ADHD and, although differential characteristics emerge later in the course of illness evolution, it is difficult to distinguish one disorder from the other in early childhood.

To gain a better insight into the symptom evolution of these disorders, the researchers examined the course of individual symptoms over the first 10 years of life in 27 children with bipolar disorder with or without ADHD, who were diagnosed before 9 years of age, and 22 children with ADHD alone.

The children were rated by a parent for the severity of 37 symptoms. These were drawn from literature describing common presentations of childhood psychopathology and were rated on a scale from 0 to 3, with 3 representing the most severe degree of impairment in the child’s usual family, social, or educational roles.

The team found the symptoms of hyperactivity, impulsivity, and decreased attention span were highly prevalent and showed a similar course in both groups.

“This might be expected because not only are these classic symptoms of ADHD, but are common in bipolar illness itself,” note the researchers.

However, extended periods of mood elevation and decreased sleep were significantly more common in the bipolar children than in those with ADHD, and were strong differentiators between the two disorders from as young as 3 years of age. Furthermore, the differences between bipolar children and those with ADHD regarding these symptoms increased in magnitude over the first 10 years of life.

Depressive and somatic symptoms were later differentiators that became significant from around 7 years of age.

Irritability and poor frustration tolerance differentiated the two groups only in their greater incidence and severity in bipolar children, compared with a more moderate incidence and course in those with ADHD.

Writing in the journal Bipolar Disorders, Post and team conclude: “These findings suggest the importance of examining juvenile- and adolescent-onset bipolar cohorts separately, especially when considering the earliest or prodromal manifestations of the full-blown illness.

“Those who receive a formal Schedule for Affective Disorders and Schizophrenia for School Age Children-confirmed bipolar diagnosis by an average age of 5 show the beginning of symptom separation from those with ADHD in the first few years of life, which then progressively increases in magnitude.”

Commenting on the implications of the findings, they add: “One can be hopeful that earlier recognition, diagnosis, and concerted treatment with one or more mood stabilizers or atypical antipsychotics in the context of appropriate psychosocial therapies, in lieu of treatment as usual, might yield a better outcome and, ultimately, a more benign course of illness.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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