Genome-wide association study identifies genetic variation in neurocan as a susceptibility factor for bipolar disorder.

We conducted a genome-wide association study (GWAS) and a follow-up study of bipolar disorder (BD), a common neuropsychiatric disorder. In the GWAS, we investigated 499,494 autosomal and 12,484 X-chromosomal SNPs in 682 patients with BD and in 1300 controls. In the first follow-up step, we tested the most significant 48 SNPs in 1729 patients with BD and in 2313 controls. Eight SNPs showed nominally significant association with BD and were introduced to a meta-analysis of the GWAS and the first follow-up samples. Genetic variation in the neurocan gene (NCAN) showed genome-wide significant association with BD in 2411 patients and 3613 controls (rs1064395, p = 3.02 × 10(-8); odds ratio = 1.31). In a second follow-up step, we replicated this finding in independent samples of BD, totaling 6030 patients and 31,749 controls (p = 2.74 × 10(-4); odds ratio = 1.12). The combined analysis of all study samples yielded a p value of 2.14 × 10(-9) (odds ratio = 1.17). Our results provide evidence that rs1064395 is a common risk factor for BD. NCAN encodes neurocan, an extracellular matrix glycoprotein, which is thought to be involved in cell adhesion and migration. We found that expression in mice is localized within cortical and hippocampal areas. These areas are involved in cognition and emotion regulation and have previously been implicated in BD by neuropsychological, neuroimaging, and postmortem studies.

Lithium's emerging role in the treatment of refractory major depressive episodes: augmentation of antidepressants.

BACKGROUND: The late onset of therapeutic response and a relatively large proportion of nonresponders to antidepressants remain major concerns in clinical practice. Therefore, there is a critical need for effective medication strategies that augment treatment with antidepressants. METHODS: To review the available evidence on the use of lithium as an augmentation strategy to treat depressive episodes. RESULTS: More than 30 open-label studies and 10 placebo-controlled double-blind trials have demonstrated substantial efficacy of lithium augmentation in the acute treatment of depressive episodes. Most of these studies were performed in unipolar depression and included all major classes of antidepressants, however mostly tricyclics. A meta-analysis including 10 randomized placebo-controlled trials has provided evidence that lithium augmentation has a statistically significant effect on the response rate compared to placebo with an odds ratio of 3.11, which corresponds to a number-needed-to-treat of 5. The meta-analysis revealed a mean response rate of 41.2% in the lithium group and 14.4% in the placebo group. One placebo-controlled trial in the continuation treatment phase showed that responders to acute-phase lithium augmentation should be maintained on the lithium-antidepressant combination for at least 12 months to prevent early relapses. Preliminary studies to assess genetic influences on response probability to lithium augmentation have suggested a predictive role of the -50T/C single nucleotide polymorphism of the GSK3beta gene. CONCLUSION: Augmentation of antidepressants with lithium is currently the best-evidenced augmentation therapy in the treatment of depressed patients who do not respond to antidepressants.

The International Consortium on Lithium Genetics (ConLiGen): an initiative by the NIMH and IGSLI to study the genetic basis of response to lithium treatment.

For more than half a decade, lithium has been successfully used to treat bipolar disorder. Worldwide, it is considered the first-line mood stabilizer. Apart from its proven antimanic and prophylactic effects, considerable evidence also suggests an antisuicidal effect in affective disorders. Lithium is also effectively used to augment antidepressant drugs in the treatment of refractory major depressive episodes and prevent relapses in recurrent unipolar depression. In contrast to many psychiatric drugs, lithium has outlasted various pharmacotherapeutic 'fashions', and remains an indispensable element in contemporary psychopharmacology. Nevertheless, data from pharmacogenetic studies of lithium are comparatively sparse, and these studies are generally characterized by small sample sizes and varying definitions of response. Here, we present an international effort to elucidate the genetic underpinnings of lithium response in bipolar disorder. Following an initiative by the International Group for the Study of Lithium-Treated Patients (www.IGSLI.org) and the Unit on the Genetic Basis of Mood and Anxiety Disorders at the National Institute of Mental Health,lithium researchers from around the world have formed the Consortium on Lithium Genetics (www.ConLiGen.org) to establish the largest sample to date for genome-wide studies of lithium response in bipolar disorder, currently comprising more than 1,200 patients characterized for response to lithium treatment. A stringent phenotype definition of response is one of the hallmarks of this collaboration. ConLiGen invites all lithium researchers to join its efforts.

Frequency of subsyndromal symptoms and employment status in patients with bipolar disorder.

OBJECTIVE: This study investigated the frequency of episodes and subsyndromal symptoms based on employment status in patients with bipolar disorder. METHODS: Patients with bipolar disorder (n = 281) provided daily self-reported mood ratings for 5 months, returning 46,292 days of data. Data were analyzed using three employment status groups: disabled (n = 75), full-time employee or full-time student (n = 135), and other (n = 71). Demographic characteristics were compared by employment status. A univariate general linear model with employment status and other demographic variables as fixed factors and covariates was used to analyze the percent of days in episodes and percent of days with subsyndromal symptoms. RESULTS: While there was no significant difference in the percent of days in episodes among the employment groups, disabled patients suffered subsyndromal symptoms of depression twice as frequently as those in the full-time group. Disabled patients spent 15% more days either in episodes or with subsyndromal symptoms than those in the full-time group, equivalent to about 45 extra sick days a year. CONCLUSION: Frequent subsyndromal symptoms, especially depressive, may preclude full-time responsibilities outside the home and contribute to disability in bipolar disorder. Additional treatments to reduce the frequency of subsyndromal symptoms are needed.

Efficacy of quetiapine monotherapy in rapid-cycling bipolar disorder in comparison with sodium valproate.

BACKGROUND: Rapid-cycling bipolar disorder is often characterized by a lack of response to psychopharmacological treatment, and a standard therapy has not been developed yet. The aim of this study was to examine the long-term efficacy and safety of a monotherapy with quetiapine or sodium valproate (VPA) in patients with rapid-cycling bipolar disorder. METHODS: This open-label, randomized, parallel group monotherapy pilot study was conducted at 3 German centers. A sample of 38 remitted or partly remitted patients with bipolar disorder and rapid cycling (quetiapine n = 22; VPA n = 16) were treated with quetiapine or VPA (flexible dose design) for 12 months. RESULTS: Forty-one percent of the patients with quetiapine and 50% with VPA completed the trial. On the basis of ITT-LOCF, Life Chart Method data showed that patients being treated with quetiapine had significantly less moderate to severe depressive days than patients on VPA (mean +/- SD, 11.7 +/- 16.9 days vs 27.7 +/- 24.9 days; P = 0.04) while they did not differ in the number of days with manic or hypomanic symptoms. Furthermore, according to the Clinical Global Impression Scale, bipolar version, the responder rates tended to be higher for quetiapine than for VPA. There were no differences found evaluating the Hamilton Depression Rating Scale, the Montgomery-Asberg Depression Scale, and the Young Mania Rating Scale. The incidence of adverse events, especially of orthostatic dysregulation, sedation, and weight gain, was significantly higher in the quetiapine group. CONCLUSIONS: In this study, quetiapine was more effective than VPA on the number of depressive days and similar to VPA in the treatment of manic symptoms. Quetiapine was associated with a greater incidence of side effects, particularly orthostatic dysregulation, sedation, and weight gain.

Self-reporting software for bipolar disorder: validation of ChronoRecord by patients with mania.

With the widespread recognition of the value of active patient participation in their care, ChronoRecord software was developed to automate daily self-reporting by patients with bipolar disorder. A prior study demonstrated concurrent validity between self-ratings on ChronoRecord and clinician ratings on the Hamilton Depression Rating Scale (HAMD), but validity with the Young Mania Rating Scale (YMRS) could not be shown due to a lack of data when the outpatients were manic (Bauer et al., Bipolar Disorders 6, 67-74, 2004). This study expanded upon the prior validation study to include inpatients with mania. Self-reported mood ratings on ChronoRecord and clinician ratings on the YMRS were obtained on the same day from 27 inpatients (57 ratings); these data were also combined with the ratings from the 80 outpatients (total 107 patients, 340 ratings). Using Pearson correlation, the self-reported ratings on ChronoRecord were significantly correlated with the YMRS. The accuracy of ChronoRecord to discriminate hypomania and mania was high, as described by the area under the receiver operating characteristic curve. Post-hoc analysis of the level of agreement between ChronoRecord and YMRS ratings was excellent or good in all cases using the kappa statistic. These data demonstrate concurrent validity between ChronoRecord and YMRS.

Self-reported data from patients with bipolar disorder: frequency of brief depression.

OBJECTIVE: Patients with bipolar disorder often report depressive symptoms that do not meet the DSM-IV criteria for an episode. Using daily self-reported mood ratings, we studied how changing the length requirement to that typical of recurrent brief depression (2-4 days) would impact the number of depressed episodes. METHOD: 203 patients (135 bipolar I and 68 bipolar II by DSM-IV criteria) recorded mood daily using ChronoRecord software on a home computer (30,348 total days; mean 150 days). Episodes of depression and days of depression outside of episodes were determined. Symptom intensity (mild versus moderate or severe) was investigated within and outside of depressive episodes. RESULTS: Decreasing the minimum duration criterion for an episode of depression to 2 days increased the number of patients with a depressed episode two and a half times (52 to 131), and quadrupled both the number of depressed episodes per patient (0.62 to 2.88) and the number of depressed episodes for all patients (125 to 584). With a 2-day episode length, 34% of days of depression remained outside an episode. The ratio of days with severe symptoms within episodes remained consistent (about 25%) in spite of decreasing the episode length to 2 days. Considering only days with severe symptoms, about 25% remained outside of episodes even with a 2-day length. None of the results distinguished bipolar I from bipolar II disorder. LIMITATIONS: Self-reported data, computer access required, relatively short study length, no control group. CONCLUSION: Brief depressive episodes and single days of depression outside of episodes occur frequently in both bipolar I and bipolar II disorder. Moderate or severe symptoms occur during brief episodes at a ratio similar to that for episodes that meet the DSM-IV criteria.

Trimipramine pharmacokinetics after intravenous and oral administration in carriers of CYP2D6 genotypes predicting poor, extensive and ultrahigh activity.

OBJECTIVE: The tricyclic antidepressant trimipramine is one of the drugs with the most pronounced differences in pharmacokinetics caused by the CYP2D6 genetic polymorphism. However, the effect of CYP2D6 genotype on steady state kinetics and on bioavailability has not been studied so far. In addition, we were interested in trimipramine pharmacokinetics in genetically defined ultra rapid metabolizers. METHODS: We studied intravenous and multiple dose oral application of 50 mg trimipramine in five, seven, and three healthy volunteers with CYP2D6 genotypes predicting deficient, highly active and ultrarapid metabolism. The latter group included carriers of one wild-type and one duplication allele. Trimipramine and desmethyltrimipramine concentrations were measured by HPLC over a time interval of 72 h after intravenous and after one oral application. RESULTS: Both bioavailability and systemic clearance significantly depended on CYP2D6 genotype with a linear gene dose relationship. Mean bioavailability was 44, 16 and 12% in carriers of zero, two and three active genes of CYP2D6, respectively, and the corresponding data for systemic clearance were 12.0, 24.2, and 30.3 l/h. Consequently, the mean total oral clearances were 27.3, 151, and 253 l/h in poor, extensive and ultrarapid metabolizers. CONCLUSIONS: High bioavailability combined with low systemic clearance of trimipramine in poor metabolizers of CYP2D6 substrates results in a very high exposure to trimipramine with the risk of adverse drug reactions. On the other hand, the extremely high systemic and presystemic elimination may result in sub-therapeutic drug concentrations in carriers of CYP2D6 gene duplications with a high risk of poor therapeutic response.

Bupropion and 4-OH-bupropion pharmacokinetics in relation to genetic polymorphisms in CYP2B6.

Bupropion is applied in depression and smoking cessation. Genetic polymorphisms in cytochrome P450 2B6 (CYP2B6) may cause variability in bupropion pharmacokinetics since hydroxylation is known to be mediated by CYP2B6. Bupropion may be a probe drug for CYP2B6 activity in humans. Bupropion pharmacokinetics were studied after a single oral dose of 150 mg in 121 healthy male volunteers. The amino acid polymorphisms R22C, Q172H, S259R, K262R and R487C were analysed by polymerase chain reaction and restriction fragment length polymorphism and plasma concentrations were measured by high-performance liquid chromatography. Pharmacokinetic analysis was performed by non-parametric methods and by population pharmacokinetic modelling. A unimodal distribution of bupropion and hydroxybupropion kinetic parameters was detected with a mean (range) area under the curve (AUC) of 3.64 (0.89-8.14) micromol.h/l for bupropion and 25.5 (6.72-75.3) micromol.h/l for hydroxybupropion. Population kinetic analysis revealed that bupropion total clearance via CYP2B6 alleles *1, *2, *5 and *6 did not differ, but clearance via allele *4 was 1.66-fold higher compared to wild-type allele *1 (P=0.001). Corresponding to the high clearance of bupropion, carriers of the CYP2B6 genotype *1/*4 had significantly higher Cmax of hydroxybupropion compared to all other genotypes (P=0.03). Only a minor fraction of the variability in bupropion and hydroxybupropion kinetics could be explained by the known CYP2B6 amino acid variants, in particular by the CYP2B6*4 allele. The role of this allele should also be studied in other CYP2B6 substrates, including cyclophosphamide, halothane, mianserin, promethazine and propofol.

Bone mineral density during maintenance treatment with supraphysiological doses of levothyroxine in affective disorders: a longitudinal study.

BACKGROUND: This prospective study was designed to determine whether patients with prophylaxis-resistant affective disorders, receiving adjunctive maintenance therapy with supraphysiological doses of levothyroxine (L-T4), show evidence of accelerated bone loss compared to the reference population database. METHODS: In 21 patients, bone mineral density (BMD) of the spine (lumbar vertebrae L1-L4) and femur (femoral neck, trochanter, and Ward's triangle) was measured by dual energy X-ray absorptiometry (DXA). BMD measurement was performed first after patients had been on thyroid-stimulating hormone (TSH)-suppressive therapy with L-T4 (mean dose=411 mcg/d) for an average of 16.4 months and again after 33.6 months of L-T4 (mean dose=416 mcg/d) therapy. RESULTS: There was no statistically significant difference between the actual percentage decline in bone mineral density and the expected percentage decline in any of the measured bone regions. In a stepwise linear regression analysis, age was identified as a predictor of percentage change in BMD. After controlling for age, the only other variable that showed a consistent trend was the dose of L-T4, with higher doses being positively correlated with the percentage decline of BMD. LIMITATIONS: Relatively small sample size, no bone density assessment prior to treatment with L-T4, no patient control group with mood disorders who did not receive L-T4 treatment, and bone density follow-up intervals were variable. CONCLUSIONS: This study did not demonstrate evidence that long-term treatment of affectively ill patients with supraphysiological doses of L-T4 significantly accelerates loss of bone mineral density compared to the age-matched reference population. However, the decline of BMD in one individual patient underscores that caution is indicated and that regular assessment of BMD during longer-term supraphysiological thyroid hormone treatment is needed.

The Hypomania Checklist-32 and the Mood Disorder Questionnaire as screening tools--going beyond samples of purely mood-disordered patients.

BACKGROUND: Bipolar disorders are often not recognized. Several screening tools have been developed, e.g., the Hypomania Checklist-32 (HCL-32) and the Mood Disorder Questionnaire (MDQ) to improve this situation. Whereas the German HCL-32 has been used in non-clinical samples, neither the HCL-32 nor the MDQ has been validated in German samples of mood-disordered patients. Additionally, hardly any prior study has included patients with non-mood disorders or has considered potential effects of comorbid conditions. Therefore the goal of this study was to test the validity of both scales in a diverse patient sample while also taking into account psychiatric comorbidity. METHOD: A multi-site study was conducted involving seven centers. Patients (n=488) completed the HCL-32 and MDQ and were independently interviewed with the Structured Clinical Interview for DSM (SCID). RESULTS: Sensitivity for bipolar I was similar for HCL-32 and MDQ (.88 and .84) but slightly different for bipolar II (.90 and .83), specificity, however, was higher for MDQ. In general, a comorbid condition led to increased scores in both tools regardless of whether the primary diagnosis was bipolar or not. LIMITATIONS AND DISCUSSION: Although we included not just mood-disordered patients, detailed subgroup analyses for all diagnostic categories were not possible due to sample sizes. In summary, HCL-32 and MDQ seem fairly comparable in detecting bipolar disorders although their effectiveness depends on the goal of the screening, psychiatric comorbidity, and potentially the setting.

Relationship among latitude, climate, season and self-reported mood in bipolar disorder.

OBJECTIVE: Many researchers have analyzed seasonal variation in hospital admissions for bipolar disorder with inconsistent results. We investigated if a seasonal pattern was present in daily self-reported daily mood ratings from patients living in five climate zones in the northern and southern hemispheres. We also investigated the influence of latitude and seasonal climate variables on mood. METHOD: 360 patients who were receiving treatment as usual recorded mood daily (59,422 total days of data). Both the percentage of days depressed and hypomanic/manic, and the episodes of depression and mania were determined. The observations were provided by patients from different geographic locations in North and South America, Europe and Australia. These data were analyzed for seasonality by climate zone using both a sinusoidal regression and the Gini index. Additionally, the influence of latitude and climate variables on mood was estimated using generalized linear models for each season and month. RESULTS: No seasonality was found in any climate zone by either method. In spite of vastly different weather, neither latitude nor climate variables were associated with mood by season or month. CONCLUSION: Daily self-reported mood ratings of most patients with bipolar disorder did not show a seasonal pattern. Neither climate nor latitude has a primary influence on the daily mood changes of most patients receiving medication for bipolar disorder.

Genetic variants in FKBP5 affecting response to antidepressant drug treatment.

INTRODUCTION: Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is a pathogenic mechanism of depression, and genetic polymorphisms in HPA axis genes have been described to influence response to antidepressant drugs. In particular, two polymorphisms in FKBP5, a co-chaperone of the glucocorticoid receptor, were strongly associated with response to therapy. We aimed to analyze whether these findings could be reproduced in a different sample of otherwise comparable inpatients with major depression. METHODS: Genotyping for the two variants within the FKBP5 gene was performed using PCR-restriction fragment length polymorphism and Taqman real-time PCR in a cohort of 179 inpatients who were monitored for the first 3 weeks of antidepressant drug treatment. The early response to antidepressant drugs was assessed as percentage of decline in Hamilton depression score after 3 weeks, responders versus nonresponders were distinguished by a 50% decrease. RESULTS: The FKBP5 variants rs3800373 and rs1360780 were highly linked, and carriers of the FKBP5 variants had a trend towards a higher chance to respond (p = 0.04; odds ratio: 1.8; 95% CI: 0.98-3.3). When analyzing drug-specific subgroups, the effect was seen mainly in the subgroups of patients treated with antidepressant drug combinations or with venlafaxine. CONCLUSION: In this study, an effect of FKBP5 variants on antidepressant drug response was confirmed in an independent cohort of depressed patients; however, with an odds ratio of 1.8 the effect size was smaller than that described earlier.

Lithium augmentation therapy in refractory depression: clinical evidence and neurobiological mechanisms.

OBJECTIVE: This systematic review examines the evidence and discusses the clinical relevance of lithium augmentation as a treatment strategy for refractory major depressive episodes. It also examines hypotheses on the mode of action of lithium augmentation, with a focus on serotonin (5-HT) and neuroendocrine systems, and proposes recommendations for future research. METHOD: We searched the Medline computer database and the Cochrane Library for relevant original studies published in English from January 1966 to February 2003. The key words were as follows: lithium, augmentation strategies, lithium augmentation, major depression, refractory depression, treatment-resistant depression, neuroendocrinology, and serotonin. RESULTS: Of 27 prospective clinical studies published since 1981, 10 were double-blind, placebo-controlled trials, 4 were randomized comparator trials, and 13 were open-label trials. Five of 9 acute-phase placebo-controlled trials demonstrated that lithium augmentation had substantial efficacy. In the acute-treatment trials, the average response rate in the lithium group was 45%, and in the placebo group, 18% (P < 0.001). One placebo-controlled trial showed the efficacy of lithium augmentation in the continuation-phase treatment. Summarizing the open and controlled data, approximately 50% of patients responded to lithium augmentation within 2 to 6 weeks. Animal studies offer robust evidence that lithium augmentation increases 5-HT neurotransmission, possibly by a synergistic action of lithium and the antidepressant on brain 5-HT pathways. CONCLUSIONS: Augmentation of antidepressants with lithium is the best-documented augmentation therapy in the treatment of refractory depression. Emerging data from animal studies suggest that the 5-HTergic system is involved in the augmentatory effect of lithium.