The overall outcome of bipolar disorder patients is improved by treatment in a specialized bipolar clinic, but the treatment of bipolar II disorder appears to be suboptimal, the results of a European study indicate.

Due to beliefs over the apparent “soft” nature of bipolar II disorder, despite patients being symptomatic for longer and having more chronicity and comorbidity than those with bipolar I disorder, the condition may be undertreated, with a risk for a more recurrent course.

To investigate the course of bipolar disorder further, Benedikt Amann, from Complex Assistencial en Salut Mental in Barcelona, Spain, and colleagues studied 18 bipolar II disorder and 31 bipolar I disorder patients. The patients were assessed monthly for an average of 26 months using the life-chart methodology “clinician version, the Young Mania Rating Scale, the Inventory of Depressive Symptoms, the Clinical Global Impression ” Bipolar Version, and the Global Assessment of Functioning.

Dividing follow-up into three terms “ first year, third to fifth half year, and sixth to eighth half year ” the team found that the increase in euthymic days in the second versus the third term was significant, but the difference between the second and third terms was not significant. A similar pattern was seen for depressive and manic days.

In each 6-month interval, both bipolar I and II disorder patients had more days marked as (sub)depressive than (hypo)manic, aside from in the last three intervals, during which bipolar II patients had more hypomanic days than bipolar I disorder patients.

While both bipolar I and II patients had reductions in the number of high “moderate to severe depressive days between the first and eighth half years, the number of high “moderate to severe manic days increased slightly by 2.0% in bipolar I disorder patients from the first to the second term and then decreased slightly by 1.9% until the end of follow-up. Similar findings were observed for hypomanic days.

Interestingly, the percentage of days on anticonvulsants increased during follow-up for bipolar I disorder patients but decreased in bipolar II disorder patients, with the opposite pattern seen for antidepressant use. Bipolar I disorder patients were also prescribed significantly more mood stabilizers than bipolar II disorder patients.

The team concludes in the journal Acta Psychiatrica Scandinavica: “Bipolar II disorder seems to be correlated with a worse course as regards to depressive episodes and a more difficult-to-treat course of the illness.

“Our results suggest pronounced differences in terms of an increase of euthymic days between bipolar I and bipolar II favoring bipolar I disorder after therapy.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2009

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None of several polymorphisms of a gene in chromosome 12 previously linked to bipolar disorders are involved in susceptibility to mood disorders, the results of a UK study indicate.

Chromosomal region 12q24 has been implicated in both bipolar disorder and unipolar mood disorder in linkage studies, and the gene P2RX7, which is located within this chromosomal region, has been suggested as a susceptibility gene for bipolar disorder and unipolar depression.

To investigate further, Elaine Green, from the University of Wales College of Medicine in Cardiff, and colleagues studied 687 bipolar I disorder patients, 1036 unipolar recurrent major depression patients, and 1204 healthy controls.

All participants were genotyped for single nucleotide polymorphisms (SNPs) of the P2RX7 gene, including the non-synonymous (missense) SNP rs2230912. This results in amino-acid polymorphism Q460R, which has previously been suggested to be pathologically relevant in mood disorders.

Writing in the American Journal of Medical Genetics Part B Neuropsychiatric Genetics, the team reports that none of the polymorphisms studied had significant allelic or genotypic association with bipolar disorder compared with controls, with unipolar depression compared with controls, or with combined mood disorder compared with controls.

Furthermore, sequencing of two families with chromosome 12-linked bipolar disorder and Darier’s disease did not reveal any rare variants that could explain the previously observed linkage.

The team concludes: “We have found no evidence that the non-synonymous SNP rs2230912 influences susceptibility to mood disorder in our study population…

“Nonetheless it remains possible that variation within parts of the gene that were not well tagged within the current study may influence risk for mood disorder or that the effect in the population we studied was too small to be detected in our sample.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2009

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Bipolar patients with a current mood episode who have subthreshold symptoms of the opposite polarity have worse outcomes than those without such symptoms, Australian study findings suggest.

Mixed clinical states in bipolar disorder are diagnostically complex and have treatment implications. While the current criteria specify that mixed states require the presence of full symptoms for both depressive and manic episodes, the impact of subthreshold symptoms of opposite polarity has not been fully examined.

To investigate further, S Dodd, from the University of Melbourne in Victoria, and colleagues studied 239 patients with either bipolar I disorder or schizoaffective disorder, bipolar type, dividing them into either those having pure, mixed (?3 concurrent hypomanic symptoms), or no depression (63, 33, and 143 patients, respectively) or pure, mixed (?2 concurrent depressive symptoms), or no mania (3, 33, and 203 patients, respectively). Clinical data were collected every 3 months for 24 months.

At 24 months, mixed depression and pure depression groups had significantly worse outcomes on almost all measures than patients with no depression at study entry. Young Mania Rating Scale (YMRS) total scores were significantly higher in the mixed depression than pure depression groups. In addition, both manic and depressive symptomatologies were higher in mixed depression patients than other participants at every visit during follow-up.

Compared with other patients, those with mixed mania had significantly worse scores on the Short Form Health Survey Physical Component Score, 21-item Hamilton Depression Rating Scale total score, YMRS total score, Clinical Global Impressions Scale Mania, Depression, and Bipolar subscales, and Streamlined Longitudinal Interview Clinical Evaluation from the Longitudinal Interval Follow-up Evaluation total score.

Again, depressive and manic symptom scores were higher for mixed mania patients versus other participants at every visit, the team notes in the Journal of Affective Disorders.

“In participants with a current mood episode, the presence of subthreshold symptoms of the opposite polarity predicted an adverse prognosis,” the team says.

“Identification of three or more hypomanic symptoms in currently depressed participants or two or more depressive symptoms in currently manic participants was associated with poorer clinical outcomes over a 24-month period.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2009

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• If Bipolar Disorder Is Over-Diagnosed, What Are The Actual Diagnoses?

Variations in a candidate gene for bipolar disorder and schizophrenia affect cortical functioning linked to perception and monitoring in healthy children as young as 10??”12 years of age, UK researchers have discovered.

Although the roots of adult psychopathology emerge during childhood and adolescence, the majority of genetic studies linked to brain imaging have focused on adult participants and the role of genetic risk in biological vulnerability in childhood has been little explored.

To investigate further, Andrea Mechelli, from King’s College London, and colleagues studied 102 healthy boys aged 10??”12 years, including 18 pairs of monozygotic twins, 24 pairs of dizygotic twins, and 18 singletons.

The participants were genotyped for the single nucleotide polymorphism (SNP) 8NRG243177 (rs6994992) of the neuregulin 1 (NRG1) gene, a candidate gene for both schizophrenia and bipolar disorder. The team also performed magnetic resonance imaging during a perceptual matching task, and administered the Weschler Abbreviated Scales of Intelligence and the Strengths and Difficulties Questionnaire.

In all, 43 individuals carried the CC variant of the SNP 8NRG243177, 52 had the CT variant, and 7 had the TT variant. NRG1 genotype was not associated with demographic characteristics or with response accuracy or reaction times on the task.

While TT homozygotes showed no areas of reduced brain activation during the perceptual task relative to CC homozygotes and CT heterozygotes, they showed significantly greater activation during perceptual matching relative to fixation in a network comprising the precuneus bilaterally, and the left cuneus, middle occipital gyrus, angular gyrus and caudate nucleus.

The team notes in the journal Behavior Genetics that, after correcting for the non-independence of twin data, the association with increased activation in the caudate nucleus was no longer significant.

“We report that the high-risk variant is associated with increased brain activation during a task engaging perceptual and monitoring processes in children as young as 10??”12 years of age, consistent with previous findings with healthy adult participants,” they conclude.

“Our results are consistent with the idea that genetic variation in NRG1 affects cortical function to moderate vulnerability to psychopathology from childhood, before the possible manifestation of any symptoms in late adolescence and adulthood.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2009

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Contrary to US Food and Drug Administration (FDA) reports, anti-epileptic drugs (AEDs) do not increase suicide risk among bipolar disorder patients and may even be protective against suicide, say US researchers.

Although an FDA advisory committee stated in 2008 that AEDs, which are used widely in mood disorder patients, are associated with an increased risk for suicidality , the committee did not vote to place a black box warning on AEDs for this risk.

To investigate the purported association further, Robert Gibbons, from the University of Illinois at Chicago, and colleagues studied data from a medical claims database on 47,918 bipolar disorder patients with a minimum 1-year of follow-up both before and after the index date of their illness.

In all, 13,385 patients received one of the 11 AEDs included in the analysis, while 25,432 did not receive any of the 11 AEDs or lithium, the team reports in the Archives of General Psychiatry.

There was no significant difference in suicide attempts following treatment between patients given an AED and those not treated with an AED or lithium, at 13 per 1000 person-years in both groups.

Interestingly, the rate of suicide attempts was significantly greater before any AED treatment than after, at 72 per 1000 person-years and 13 per 1000 person-years, respectively.

Suicide rates among patients treated with an AED only were also significantly lower than those seen among patients not treated with a central nervous system drug, at 3 per 1000 person-years versus 15 per 1000 person-years, respectively, despite having an almost three-fold increased risk prior to treatment.

The team concludes: “The present analysis provides no evidence that AEDs increase risk for suicide attempts in patients with bipolar disorder.

“Most AEDs and lithium are associated with reduction in suicide attempt rates relative to pretreatment levels in patients who are ultimately prescribed these drugs.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2009

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• Communication Within The Brain Impaired By Genetic Variant With Possible Consequences Schizophrenia Or Manic Depression
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Major depressive disorder (MDD) is a heterogeneous disorder that contains a substantial proportion of patients with clinically significant subthreshold bipolar disorder, study results indicate.

MDD is the most common mood disorder and is highly comorbid with anxiety and substance use disorders, while bipolar disorder is considerably less prevalent. However, concerns have been raised that MDD is overdiagnosed and bipolar disorder consequently underdiagnosed.

To investigate further, Petra Zimmermann, from the Max Planck Institute of Psychiatry in Munich, Germany, and colleagues studied 2210 community individuals aged 14??”24 years, assessing mental disorders, personality traits, sociodemographic characteristics and criminal acts, and parental disorder, and following-up the participants annually for 3 years.

Overall, 23.2% of patients were diagnosed with MDD by the third follow-up, while 3.0% had bipolar I disorder and 1.4% bipolar II disorder. Of those with MDD, 58.6% met the criteria for pure MDD and 41.4% were found to have subthreshold bipolar disorder, at a cumulative incidence of 9.3%.

MDD patients with subthreshold bipolar disorder were more likely to convert to any bipolar disorder than other MDD patients, at 7.2% versus 1.7%, or an odds ratio of 4.57, with DSM-IV criterion D particularly associated with conversion.

Subthreshold bipolar disorder was also associated with a significantly higher rate of panic disorder than pure MDD, at 12.3% versus 4.7%, as well as nicotine dependence and alcohol dependence, at 43.6% versus 32.7% and 17.9% versus 9.9%, respectively. Furthermore, subthreshold bipolar disorder was linked with a tendency toward more criminal acts than pure MDD, at 25.1% versus 18.9%.

The researchers conclude in the Archives of General Psychiatry: “This study might be seen as additional evidence that MDD is a heterogeneous phenotype that is overdiagnosed at the expense of bipolar disorder.

“A broadening of the concept of bipolarity and a more comprehensive screening of bipolarity might be substantial not only for future research but also for providing adequate treatment to patients with a serious mental disorder characterized by a considerably increased risk of a chronic course with a debilitating decrease in functioning.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2009

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Both attention deficit hyperactivity disorder (ADHD) and pediatric bipolar disorder (PBD) patients exhibit prefrontal dysfunction, although it is more extensive in the former group, conclude US researchers.

Both PBD and ADHD patients commonly have deficits of impulsivity, inattention, and poor behavioral inhibition. While the neural basis for these deficits has been examined, it has not been sufficiently contrasted and compared with healthy controls.

To investigate further, Alessandra Passarotti and colleagues from the University of Illinois Medical Center at Chicago studied 15 PBD patients with type I mixed or manic disorder, 11 ADHD patients, and 15 mentally healthy controls, with average ages of 13.20, 13.09, and 14.13, respectively.

The team performed functional magnetic imaging on the participants during a response inhibition task that examined the ability to inhibit execution of a motor response to a target when a stop cue is presented shortly before the target.

There were no significant demographic differences among the three groups. Both the PBD and ADHD groups had significant lower accuracy on the response inhibition task than controls, at 80% and 81% versus 87%, with no significant difference between the patient groups.

Compared with healthy controls, the PBD group had less activation on the right medial frontal gyrus, left inferior/middle frontal gyrus, and in the right pregenual anterior cingulate cortex (ACC), as well as increased activation in the left superior temporal gyrus and inferior parietal lobule and right posterior cingulate cortex.

The ADHD group had, compared with controls, less activation in the right dorsolateral prefrontal cortex (DLPFC), bilateral superior frontal gyrus, bilateral ventrolateral prefrontal cortex (VLPC), and left superior temporal gyrus, along with greater activation in the bilateral caudate and left cerebellum.

Furthermore, ADHD patients had reduced activity in the bilateral inferior frontal gyrus/VLPFC, bilateral middle frontal gyrus/DLPFC, right superior frontal gyrus, right middle temporal cortex, and left posterior cingulate versus PBD patients, and reduced activity in the occipital cortex and left post-central gyrus, the team notes in the journal Psychiatry Research: Neuroimaging.

The team concludes: “While in ADHD response inhibition de?cits may be driven by a more extensive dysfunction of the prefrontal cortex and motor control systems, in PBD they may be driven by more localized dysfunction of regulatory VLPFC and ACC regions.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2009

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Individuals at high risk for bipolar hypomania have increased access to negative specific memories, say UK researchers who suggest that encouraging positive memory recall may benefit bipolar disorder patients.

Previous studies have indicated that bipolar disorder patients recall more overgeneral than specific autobiographical memories, particularly during depressive episodes. It has also been hypothesized that the opposite pattern may occur during mania/hypomania.

To investigate further, Steven Jones, from Lancaster University, and colleagues studied 38 individuals, of whom 21 were categorized as at high risk and 17 as at low risk of hypomania on the Hypomanic Personality Scale (HPS). The participants were also administered the Internal States Scale (ISS) and the Autobiographical Memory Test (AMT).

The team reports in the journal Memory that there were no demographic differences between high-risk and low-risk participants. However, high-risk individuals had significantly higher scores on the ISS subscales of perceived conflict and activation.

On the AMT, there were no significant differences between the overall number of memories recalled between high- and low-risk participants in response to cue words, and no differences in the number of pleasant memories recalled.

Interestingly, high-risk individuals recalled significantly more unpleasant specific, as opposed to general, memories in response to cue words than low-risk individuals, at 4.00 versus 3.21.

The team concludes: “By focusing on modifying the schema that are produced within each phase of bipolar disorder, more functional cognitive processes could be encouraged.

“For example, by promoting the retrieval of specific positive memories and theintegration of negative memories into the autobiographical knowledge base, a more adaptive focus of attention could be endorsed, which may help to prevent and reduce the severity of episodes.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2009

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For people with bipolar I disorder*, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. These are the conclusions of the BALANCE study, published Online First (www.thelancet.com) and in an upcoming Lancet, written by Professor John R Geddes, Clinical Trials Unit for Mental Illness, University of Oxford, UK, and colleagues. However, BALANCE could not confirm or refute an advantage of combined therapy over lithium monotherapy.

Bipolar disorder is a disabling mental illness that is characterised by episodes of both elevated or irritable mood and depression. Although acute episodes can be succeeded by a period of remission, most patients have a recurrent or chronic illness, making bipolar disorder one of the most important causes of disability at ages 15-44 years. Many patients do not respond to monotherapy, and combinations of drugs are often recommended despite little evidence. Lithium plus valproate is often recommended after failure of first-line monotherapy. Should this combination have additive pharmacological effects and prove better than monotherapy, it could be an appropriate first-line therapy.

In the randomised BALANCE trial, 330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were allocated to lithium monotherapy, valproate monotherapy, or both agents in combination after an active run-in** of 4-8 weeks on the combination. Patients were followed for up to 24 months, and the primary outcome was initiation of new intervention for an emergent mood episode.

The researchers found that 54% of people in the combination therapy group, 59% in the lithium group, and 69% in valproate group had a primary outcome event during follow-up. In terms of relative risk, those given combination therapy were 41% less likely to have a primary outcome event versus those given valproate; while those given lithium were 29% less likely to have an event than those given valproate. Both these findings were statistically significant. Patients given combination therapy were also 18% less likely to have an event versus those given lithium monotherapy, but this finding was not statistically significant. A total of 16 participants had serious adverse events after randomisation, that were judged not to be related to the trial treatments: seven receiving valproate monotherapy (three deaths); five lithium monotherapy (two deaths); and four combination therapy (one death).

The authors say: “The results of BALANCE show that for people with bipolar I disorder for whom long-term therapy is clinically indicated, combination therapy with lithium plus valproate is more likely to prevent relapse than is monotherapy with valproate. The 41% relative benefit is irrespective of baseline severity of illness, is maintained for up to 2 years, and is most apparent in prevention of manic relapse.”

They conclude: “The main BALANCE findings have important implications for clinical decisions about long-term therapy for bipolar disorder. First, valproate monotherapy is recommended by clinical practice guidelines as a first-line option for long-term therapy. Our results suggest that patients should be advised that a better outcome would be likely with combination therapy with lithium plus valproate semisodium or lithium alone. Second, guidelines suggest that patients who have frequent relapses during treatment with lithium monotherapy could switch to valproate monotherapy. The results of BALANCE suggest that these patients would fare better if they changed to combination therapy.”

In an accompanying Comment, Dr Rasmus W Licht, Mood Disorders Research Unit, Aarhus University Hospital, Denmark, says that the results of BALANCE, even without a placebo group, confirm the long-term efficacy of lithium, not only for the prevention of mania but also for prevention of depression.

He says: “On the basis of their overall results, the BALANCE group rightly challenges the recommendation by present clinical guidelines that valproate monotherapy is a first-line option for long-term treatment.”

He concludes: “By a diligent balance of external and internal validity, BALANCE surely reflects its acronym. It is remarkable indeed that a clear signal could be detected despite the straightforward study procedures, including the allowance of co-medication, and there is no doubt that the trial sets the stage for future large-scale, simple, investigator-sponsored trials.”

**run-in: The purpose of the run-in was to limit randomisation to patients who could tolerate the medicines in the short-term to allow a proper evaluation of their longer-term effects. When a run-in isn’t used, the post-randomisation drop-out rate is often very high and this can limit a trial’s ability to produce valid and useful results

Source
The Lancet

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Bipolar disorder patients in the manic phase have a unique signature of motor activity compared with schizophrenia patients and healthy individuals, US researchers have discovered using a novel experiment.

Increased motor activity is a central feature of mania in bipolar disorder and appears to reflect dopaminergic dysregulation, yet it has been studied almost solely using self-report and observer-rated scales.

Arpi Minassian and colleagues from the University of California, San Diego, therefore used an ambulatory monitoring device called the LifeShirt to measure motor activity in the human Behavioral Pattern Monitor, in which 28 bipolar disorder patients in the manic phase, 17 schizophrenia patients, and 21 healthy controls were presented with an unfamiliar room containing novel objects.

Dividing the 15-minute session into three 5-minute epochs, the team found that bipolar disorder patients displayed significantly more motor activity than controls during all three epochs, and significantly more motor activity than schizophrenia patients in the first two epochs. There were no significant differences between schizophrenia patients and controls in any of the epochs.

Bipolar disorder patients showed high levels of activity throughout the session, with some attenuation toward the end, while schizophrenia patients had slightly increased bursts of activity toward the end of the session and healthy controls showed consistent activity.

Modest correlations between elevated mood and activity were seen in bipolar disorder patients, while motor activity correlated with symptom ratings of increased motor activity in schizophrenia patients.

Reduced motor activity in schizophrenia was related to higher blunted affect and suspiciousness. There were no significant associations with patient medication.

The team says in the Journal of Affective Disorders: “Manic bipolar disorder patients exhibited significantly greater motor activity compared to both non-patients and schizophrenia patients when exposed to a novel exploratory environment and assessed with quantitative methods.”

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a trading division of Springer Healthcare Limited. © Springer Healthcare Ltd; 2010

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