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OBJECTIVES: Bipolar disorder (BD) with early disease onset is associated with an unfavorable clinical outcome and constitutes a clinically and biologically homogenous subgroup within the heterogeneous BD spectrum. Previous studies have found an accumulation of early age at onset (AAO) in BD families and have therefore hypothesized that there is a larger genetic contribution to the early-onset cases than to late onset BD. To investigate the genetic background of this subphenotype, we evaluated whether an increased polygenic burden of BD- and schizophrenia (SCZ)-associated risk variants is associated with an earlier AAO in BD patients. METHODS: A total of 1995 BD type 1 patients from the Consortium of Lithium Genetics (ConLiGen), PsyCourse and Bonn-Mannheim samples were genotyped and their BD and SCZ polygenic risk scores (PRSs) were calculated using the summary statistics of the Psychiatric Genomics Consortium as a training data set. AAO was either separated into onset groups of clinical interest (childhood and adolescence [≤18 years] vs adulthood [>18 years]) or considered as a continuous measure. The associations between BD- and SCZ-PRSs and AAO were evaluated with regression models. RESULTS: BD- and SCZ-PRSs were not significantly associated with age at disease onset. Results remained the same when analyses were stratified by site of recruitment. CONCLUSIONS: The current study is the largest conducted so far to investigate the association between the cumulative BD and SCZ polygenic risk and AAO in BD patients. The reported negative results suggest that such a polygenic influence, if there is any, is not large, and highlight the importance of conducting further, larger scale studies to obtain more information on the genetic architecture of this clinically relevant phenotype. peerReviewed

Objectives In mood disorders, chronic stimulation with stress results in aberrant regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Lithium was shown to influence HPA axis function. The underlying genetic background as well as environmental context may influence the stress response, and therefore lithium efficacy. The aim of the present study was to analyze if genetic variants located in genes involved in HPA axis regulation affect the response to long-term lithium treatment in bipolar patients. Methods We included 93 patients with bipolar disorder (32 males and 61 females), aged 31-80 years. The patients had been treated with lithium carbonate for at least 5 years. The magnitude of the lithium response was assessed using the Alda scale. Genotyping was performed for 28 polymorphisms in the genes encoding the following proteins involved in HPA axis regulation: corticotropin-releasing hormone receptor 1 (CRHR1), arginine vasopressin receptor 1B (AVPR1b), FK506 binding protein (FKBP) 5, FKBP4, BCL2-associated athanogene 1 (BAG1), stress induced phosphoprotein 1 (STIP1), glucocorticoid-induced transcript 1 (GLCC1), dual specificity phosphatase 1 (DUSP1) serine and arginine rich splicing factor (SRSF) 3, SRSF9, SRSF5, and acid phosphatase 1 (ACP1). Linkage disequilibrium and haplotype analysis were then performed, followed by statistical analysis (Statistica v.12; Stasoft, Krakow, Poland). Results We found a correlation between stressful life events at first episode and worse response to lithium (P=.019). In single marker analysis, we observed a significant association between three FKBP5 polymorphisms (rs1360780, rs7748266 and rs9296158), one ACP1 variant (rs300774) and one glucocorticoid-induced transcript 1 gene (GLCC1) variant (rs37972) and the degree of lithium response. Five out of seven FKBP5 polymorphisms showed strong linkage with one haplotype demonstrating an association with lithium efficacy (P=.008). No relationship was found between the other analyzed polymorphisms and lithium response. Conclusion The response to lithium may depend on the variants of genes regulating the HPA axis and stressful life events in bipolar patients.

Objectives The therapeutic action of lithium in bipolar mood disorder may be connected with its effect on biological rhythms. In the present study, an attempt was made to investigate an association between multiple single nucleotide polymorphisms (SNPs) and their haplotypes pertaining to four genes involved in regulation of biological rhythms [circadian locomotor output cycle kaput (CLOCK), aryl hydrocarbon receptor nuclear translocator-like (ARNTL), timeless circadian clock (TIMELESS), period circadian clock 3 (PER 3)], and the efficacy of lithium prophylaxis. Methods The study was performed on 115 patients with bipolar mood disorder (45 males, 70 females) with a mean age of 52 ± 12 years, with lithium prophylaxis for 22 ± 8 years, recruited from the outpatients in the Department of Psychiatry, Poznan University of Medical Sciences. The assessment of the lithium prophylactic response was made retrospectively using the Alda scale. Genotyping was done for nine SNPs of the CLOCK gene, 18 SNPs of the ARNTL gene, six SNPs of the timeless circadian clock (TIM) gene, and nine SNPs of the PER3 gene. Results An association with the degree of lithium prophylaxis was found for six SNPs and three haplotype blocks of the ARNTL gene, and two SNPs and one haplotype block of the TIM gene. No association with SNPs or haplotypes of the CLOCK and PER3 genes was observed. Conclusions The results suggest that the ARNTL and TIM genes may be associated with the lithium prophylactic response in bipolar illness. This association may be related to the role of these genes in the predisposition to bipolar mood disorder. Of special interest may be polymorphisms of these genes involved both in the predisposition to bipolar mood disorder and the lithium response.

Bipolar disorder may emerge during several decades of life. Studies from many countries have reported three peaks in the distribution of the age of onset, occurring at about ages 17, 26, and over 40 (1–5). Differences in the distribution of the age of onset were also reported among countries (6), although only limited data are available from some regions of the world. Patients living in North America generally have a younger age of onset than those living in European countries (6–8). In many studies conducted in the USA, about 60% of patients experience the onset of bipolar disorder before the age of 19 (6, 9–12), as compared to a third or less for many studies in European countries (1, 5, 6, 13–16). Diverse factors may contribute to this variation in the age of onset. There is agreement among researchers that both a patient’s genetic makeup and methodological issues in defining onset contribute to the reported differences, and that the variability in the age of onset reflects the genetic heterogeneity underlying bipolar disorder (1–3, 17). A positive family history is one of the strongest predictors of early onset (18). However, in addition to the genetic component, both the broad variability in the age of onset, and the onset peaks occurring after puberty (19) suggest that non-genetic factors may have considerable influence (20). There is limited understanding of how non-genetic factors, such as socioeconomic status and the physical environment, may impact the expression of bipolar disorder (21). In a recent study, a linear association was detected between the age of onset of schizophrenia and latitude, with a much younger onset occurring in individuals living closer to the equator (22). Latitude is often used as a proxy measure of sunlight, such as in studies of seasonal and geographical variation in affective disorders and suicide (23–28). However, more direct measures of the amount of electromagnetic energy striking the surface of the earth are now available, such as solar insolation (29). Sunlight is the primary synchronizer of circadian rhythmicity in most animals, including humans (30), and disruptions in circadian function may contribute to the pathophysiology of bipolar disorder (31). The purpose of this study was to investigate if the age of onset of bipolar I (BP-I) disorder was associated with sunlight at the location of onset, as measured by solar insolation.

Pfennig A, Schlattmann P, Alda M, Grof P, Glenn T, Muller-Oerlinghausen B, Suwalska A, Rybakowski J, Willich SN, Bauer M, Berghofer A. Influence of atypical features on the quality of prophylactic effectiveness of long-term lithium treatment in bipolar disorders. Bipolar Disord 2010: 12: 390–396. © 2010 The Authors. Journal compilation © 2010 John Wiley & Sons A/S. Objectives: There is still debate about whether the quality of long-term efficacy of lithium in patients with bipolar disorders is influenced by atypical features. Extended Cox regression models allow for the use of all follow-up data on diseases with multiple episodes. The aim of the present analysis was to apply the best suited of these models to analyze the influence of atypical features on the widely used outcome measure of time to recurrence in a large multicenter cohort of lithium responders established by the International Group for the Study of Lithium Treated Patients. Methods: A conditional extended Cox model with a random frailty term was applied to the data of 336 bipolar I and II disorder patients, all of whom were responders to lithium with treatment for up to 30 years. Results: Differences were found in the long-term outcome, even in patients who have demonstrated a relatively good response to lithium treatment. The hazard for recurrence was negatively influenced by the presence of atypical features, mainly mood-incongruent psychotic symptoms, interepisodic residual symptomatology, and rapid cycling. Conclusions: As a result of the findings, physicians should regularly reassess the quality of response in bipolar disorder patients with atypical features and, if necessary, modify treatment. Extended Cox regression models are well suited for evaluating long-term outcome and should be used more extensively to analyze treatment outcome in psychiatric and somatic disorders.

Objectives An important side effect of lithium therapy is an influence on thyroid function. It is unclear whether there is a significant association between thyroid function and duration of lithium administration. The aim of the present cross-sectional study was to measure levels of thyroid hormones and antibodies in patients with bipolar disorder receiving lithium for more than ten years. Methods The study was performed in 66 patients (21 males, 45 females) with bipolar mood disorder, receiving lithium for 10–44 (21 ± 9; mean ± standard deviation) years. Thyroid-stimulating hormone (TSH), free thyroxine (fT3), and free triiodothyronine (fT4) were measured by the microparticle enzyme immunoassay. Thyroid peroxidase (TPO) antibodies, thyroglobulin (TG) antibodies, and TSH receptor (TSH-R) antibodies were measured by the radioimmunoassay. Results Some features of hypothyroidism were found in ten (22%) female patients (seven received levothyroxine and three had increased TSH). No abnormality in thyroid hormones was found in male patients. A significant percentage of patients had abnormally high levels of anti-TPO, and anti-TG antibodies, which correlated with TSH and fT3 concentrations. There were no differences in thyroid function between patients receiving lithium for 10–20 years and those taking the drug for more than 20 years. Conclusions These results confirm the greater susceptibility of female subjects for disturbances of thyroid hormones during lithium therapy, with one-fifth of them showing some features of hypothyroidism. Abnormally high levels of anti-TPO and anti-TG antibodies were shown in a significant proportion of patients. However, in contrast to the effect of lithium on kidney function, our results do not show an association between the duration of lithium therapy and thyroid dysfunction.

Objectives The aim of this study was to compare the neuropsychological performance of patients with bipolar or unipolar mood disorders during acute episodes of depression using intelligence and frontal lobe tests. Methods Fifteen patients with bipolar depression (BP) and 30 with unipolar depression (UP) were studied. For the neuropsychological assessment, the following tests: the Wechsler Adult Intelligence Scale-Revised (WAIS-R), the Trail Making Test (TMT), the Stroop test, the verbal fluency test and the Wisconsin Card Sorting Test (WCST) were used. Results The mean intensity of depression and mean duration of illness were similar in both groups. Patients in the BP group achieved significantly lower levels of performance in the non-verbal part of WAIS-R, in both parts of the Stroop test, in the verbal fluency test and also showed a tendency to achieve poorer results in TMT-B than those in the UP group. Bipolar depressed patients also produced significantly poorer results with the WCST as they made twice as many perseverative errors and only completed half of the correct categories compared with the UP patients. The results of the TMT-A tests, which measure psychomotor slowness, were similar in BP and UP patients. No differences between the results of male and female patients were noted in either group. Deterioration of the results associated with duration of the illness was only observed in the UP patients. Conclusions A higher degree of cognitive dysfunction connected with frontal lobe activity during an acute depressive episode was found in bipolar compared with unipolar depressed patients. These results may corroborate other findings pointing to pathogenic distinctions between bipolar and unipolar affective illness and to some similarities between bipolar illness and schizophrenia.

Objectives: The aim of the study was to assess the prophylactic effect of long-term lithium administration in patients with bipolar mood disorders entering treatment in the 1970s and 1980s at the outpatient clinic of the Department of Psychiatry, University of Medical Sciences, Poznan, Poland. Methods: The clinical characteristics of two groups of patients before and during lithium therapy were compared, namely, the 60 bipolar patients who entered lithium prophylaxis in the 1970s and 49 patients who entered in the 1980s. Both groups received the drug over a 10-year period. Results: The patients who entered lithium in the 1970s had fewer previous episodes of depression and more of mania than the patients who entered the therapy in the 1980s, although the total number of affective episodes was similar in both groups. The overall prophylactic efficacy of lithium over a 10-year period of administration was similar in both groups, except for a trend towards a greater number of depressive episodes in the first year of lithium prophylaxis in the 1980s group. The excellent lithium responders constituted 35% of the 1970s patients and 27% of those in the 1980s group. The 1970s patients were maintained on a higher level of serum lithium compared to the patients in the 1980s group and had more lithium-induced side effects. Conclusions: A decrease in lithium prophylactic efficacy in consecutive decades was not observed. Small differences between the bipolar patients entering lithium therapy in the 2 decades were observed in terms of the previous history of illness and during the course of lithium administration.

Objectives: The aim of the study was to test a possible association between the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene and performance on a neurocognitive test, the Wisconsin Card Sorting Test (WCST), in bipolar patients. Methods: Fifty-four bipolar patients were studied, 18 male and 36 female, aged 18–72 (mean 46 years). The number of perseverative errors (WCST-P), non-perseverative errors (WCST-NP), completed corrected categories (WCST-CC), conceptual level responses (WCST-%CONC) and set to the first category (WCST-1st CAT) were measured in relation to the Val66Met genotypes of BDNF. Results: The percentages of subjects with Val/Val, Val/Met and Met/Met genotypes were respectively 81.5, 16.7 and 1.8%. Subjects with Val/Val and Val/Met genotypes did not differ on clinical factors except for the age of onset of the illness, which was earlier in Val/Val than Val/Met genotype (27 years versus 38 years). The performance in all domains of WCST was significantly better in subjects with Val/Val BDNF genotype compared with Val/Met genotype. Conclusions: The results suggest a role of BDNF in prefrontal cognitive function in bipolar illness. The tests of prefrontal cognition may be considered as endophenotypic markers in bipolar illness.