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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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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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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