Tuula Kieseppä

Circadian clock-related polymorphisms in seasonal affective disorder and their relevance to diurnal preference.

Disturbed circadian rhythms have been observed in seasonal affective disorder (SAD). The aim of this study was to further investigate this connection, and to test for potential association between polymorphisms in circadian clock-related genes and SAD, seasonality (seasonal variations in mood and behavior), or diurnal preference (morningness–eveningness tendencies). A total of 159 European SAD patients and 159 matched controls were included in the genetic analysis, and subsets were screened for seasonality (n=177) and diurnal preference (n=92). We found that diurnal preference was associated with both SAD and seasonality, supporting the hypothesis of a link between circadian rhythms and seasonal depression. The complete case–control material was genotyped for polymorphisms in the CLOCK, Period2, Period3, and NPAS2 genes. A significant difference between patients and controls was found for NPAS2 471 Leu/Ser (χ2=9.90, Bonferroni corrected P=0.035), indicating a recessive effect of the leucine allele on disease susceptibility (χ2=6.61, Bonferroni corrected P=0.050). Period3 647 Val/Gly was associated with self-reported morningness–eveningness scores (n=92, one-way ANOVA: F=4.99, Bonferroni corrected P=0.044), with higher scores found in individuals with at least one glycine allele (t=3.1, Bonferroni corrected P=0.013). A second, population-based sample of individuals selected for high (n=127) or low (n=98) degrees of seasonality, was also genotyped for NPAS2 471 Leu/Ser. There was no significant difference between these seasonality extreme groups, and none of the polymorphisms studied were associated with seasonality in the SAD case–control material (n=177). In conclusion, our results suggest involvement of circadian clock-related polymorphisms both in susceptibility to SAD and diurnal preference.

Major depressive disorder and white matter abnormalities: A diffusion tensor imaging study with tract-based spatial statistics

BACKGROUND A few diffusion tensor imaging (DTI) studies have shown abnormalities in areas of white matter tracts involved in mood regulation in geriatric depressive patients, using a region-of-interest technique. A voxel-based morphometry DTI study of young depressive patients reported similar results. In this study, we explored the structure of the white matter of the whole brain with DTI in middle-aged major depressive disorder (MDD) patients, using novel tract-based spatial statistics. METHODS Sixteen MDD patients and 20 controls underwent DTI. An automated tract-based spatial method (TBSS) was used to analyze the scans. RESULTS Compared with controls, the MDD patients showed a trend for lower values of fractional anisotropy (FA) in the left sagittal stratum, and suggestive decreased FA in the right cingulate cortex and posterior body of corpus callosum. Regressing out the duration and severity of disorder in the model did not change the finding in the sagittal stratum, but dissipated the decrease of FA in latter regions. LIMITATIONS Possibly by reason of a relatively small study sample for a TBSS, the results are suggestive, and should be replicated in further studies. CONCLUSIONS A novel observer-independent DTI method showed decreased FA in the middle-aged MDD patients in white matter regions that have previously connected to the emotional regulation. Lower FA might imply underlying structural abnormalities that contribute to the dysfunction detected in the limbic-cortical network of depressive patients.

Memory and verbal learning functions in twins with bipolar-I disorder, and the role of information-processing speed

BACKGROUND Euthymic bipolar-I disorder (BP I) patients and their siblings have shown impairments in verbal learning and memory functions compared with controls, suggesting that these impairments may be genetic in origin. Reduced information-processing speed has been associated with impaired memory in the elderly, and recently in schizophrenia. The authors compared verbal learning and memory functioning in twins with BP I and co-twins to control twins, and examined whether the observed deficits are related to information-processing speed. METHOD Finnish Medical and Population Registers and Twin Cohorts were used to identify the BP I and control twins. Neuropsychological tests assessing verbal learning and memory, working memory, facial recognition, visual memory, and information-processing speed were administered to 26 BP I twins, 19 non-bipolar co-twins, and 114 controls. Group differences were analyzed by generalized estimation equation modeling. RESULTS BP I patients, but not co-twins, showed impairments in all memory tests compared with controls. Female co-twins showed impairment in verbal learning and memory. Information-processing speed had a significant effect on encoding and learning efficiency. CONCLUSIONS This study showed for the first time that information-processing speed is related to memory functioning and verbal learning in BP I in a population-based, representative and euthymic sample. Furthermore, the data support the view that defects in verbal memory may be related to the genetic factors predisposing to BP I in females.

Reduced left hemispheric white matter volume in twins with bipolar I disorder

BACKGROUND Although the heritability of bipolar I disorder (BPI) is high, few magnetic resonance imaging (MRI) studies of siblings of bipolar patients exist. We performed MRI brain scans on a nationwide sample of twins with BPI, as well as on their co-twins and a demographically balanced sample of control twin subjects, to detect any structural alterations related to the disorder and to the increased genetic risk. METHODS The National Hospital Discharge Register, National Population Register, and Finnish Twin Cohorts were used to identify bipolar twins. Structured diagnostic interviews and MRI scans were obtained for 24 twins with BPI, 15 healthy co-twins, and 27 control twin subjects. RESULTS Patients and co-twins showed a significant decrease in left hemispheric white matter volume. The disparity in patients was -16.1 cm(3) (95% confidence interval [CI] -26.6, -5.6) and in co-twins -11.3 cm(3) (95% CI -22.1, -0.4) compared with control twin subjects. No gray matter decrease was seen in patients or co-twins. CONCLUSIONS The results of this first large-scale MRI study of twins with BPI, their co-twins, and appropriate control twin subjects, suggest that alterations of the left hemisphere white matter in BPI may reflect genetic factors predisposing to the disorder.

Spatial Working Memory Function in Twins with Schizophrenia and Bipolar Disorder

BACKGROUND Family studies are in conflict as to whether schizophrenia and bipolar disorder have independent genetic etiologies. Given the relatively low prevalence (approximately 1%) of these disorders, the use of quantitative endophenotypic markers of genetic liability might provide a more sensitive strategy for evaluating their genetic overlap. We have previously demonstrated that spatial working memory deficits increase in a dose-dependent fashion with increasing genetic proximity to a proband among the unaffected co-twins of schizophrenic patients. Here, we evaluated whether such deficits might also mark genetic susceptibility to bipolar disorder. METHODS The Wechsler Memory Scale-Revised Visual Memory Span and Digit Span subtests were administered to 46 schizophrenic patients, 32 of their unaffected co-twins, 22 bipolar patients, 16 of their unaffected co-twins, and 100 control twins, representing unselectively nationwide twin samples. RESULTS Schizophrenic patients and their unaffected co-twins performed significantly worse than control subjects on the spatial working memory task, whereas only the schizophrenic patients performed significantly below the control subjects on the verbal working memory task. Neither bipolar patients nor their unaffected co-twins differed from control subjects on these measures. CONCLUSIONS Our findings support the hypothesis that impairment in spatial working memory might effectively reflect an expression of genetic liability to schizophrenia but less clearly to bipolar disorder.

Cognitive functioning in patients with familial bipolar I disorder and their unaffected relatives.

BACKGROUND Impairments in verbal learning and memory, executive functions and attention are manifest in some euthymic patients with bipolar disorder (BPD). However, evidence is sparse on their putative role as aetiologically important genetic vulnerability markers for the disorder. This population-based study examined the cognitive functions of affected and unaffected individuals in families with BPD. The aim was to discover whether any cognitive function would indicate genetic liability to the disorder and could thus be regarded as endophenotypes of BPD. METHOD A diagnostic interview and a neuropsychological test battery were administered to 32 familial bipolar I disorder patients, 40 of their unaffected first-degree relatives and 55 controls, all representing population-based samples. RESULTS Unaffected first-degree relatives showed impairment in psychomotor performance speed and slight impairment in executive function. Bipolar patients were impaired in verbal learning and memory compared with unaffected relatives and controls. They also differed from controls in tasks of executive functions. There were no difference between the groups in simple attention and working memory tasks. CONCLUSIONS Impaired psychomotor performance speed and executive function may represent endophenotypes of BPD, reflecting possible underlying vulnerability to the disorder. Verbal memory impairments appear to be more related to the fully developed disorder.

Seasonal changes, sleep length and circadian preference among twins with bipolar disorder

BackgroundWe aimed at studying the seasonal changes in mood and behaviour, the distribution of hospital admissions by season, and the persistence of the circadian type in twins with bipolar disorder and their healthy co-twins.MethodsAll Finnish like-sex twins born from 1940 to 1969 were screened for a diagnosis of bipolar type I disorder. The diagnosis was assessed with a structured research interview, and the study subjects (n = 67) filled in the Seasonal Pattern Assessment Questionnaire (SPAQ) and the Morningness-Eveningness Questionnaire (MEQ). For studying the persistence of the habitual sleep length and circadian type, we used data derived from the Finnish Twin Cohort Questionnaire (FTCQ). Bipolar twins were compared with their healthy co-twins.ResultsBipolar twins had greater seasonal changes in sleep length (p = 0.01) and mood (p = 0.01), and higher global seasonality scores (p = 0.03) as compared with their co-twins with no mental disorder. Sunny days (p = 0.03) had a greater positive effect on wellbeing in the bipolar than healthy co-twins.ConclusionsOur results support the view that bipolar disorder is sensitive to the environmental influence in general and to the seasonal effect in specific. Exposure to natural light appears to have a substantial effect on wellbeing in twins with bipolar disorder.

Heritability of cognitive functions in families with bipolar disorder

Bipolar disorder is highly heritable. Cognitive dysfunctions often observed in bipolar patients and their unaffected relatives implicate that these impairments may be associated with genetic predisposition to bipolar disorder and thus fulfill the criteria of a valid endophenotype for the disorder. However, the most fundamental criterion, their heritability, has not been directly studied in any bipolar population. This population‐based study estimated the heritability of cognitive functions in bipolar disorder. A comprehensive neuropsychological test battery and the Structured Clinical Interview for DSM‐IV were administered to a population‐based sample of 110 individuals from 52 families with bipolar disorder. Heritability of cognitive functions as assessed with neuropsychological test scores were estimated using the Solar package. Significant additive heritabilities were found in verbal ability, executive functioning, and psychomotor processing speed. Genetic contribution was low to verbal learning functions. High heritability, in executive functioning and psychomotor processing speed suggest that these may be valid endophenotypic traits for genetic studies of bipolar disorder.

Circadian Phenotype in Patients with the Co-Morbid Alcohol Use and Bipolar Disorders

AIMS Alcohol misuse is associated with bipolar disorder. Abnormalities in the circadian clockwork play a role in the pathogenesis of bipolar disorder. Alcohol intake is likely to affect the circadian phenotype. We aimed at analysing the behavioural trait of the preference to morning or evening hours for the daily activities in bipolar disorder patients with or without the co-morbid alcohol use. METHODS Our nationwide sample of families included patients with bipolar disorder born during 1940-1969 having at least one hospitalization due to bipolar disorder during 1969-1991 and their first-degree relatives. All the 148 participants were interviewed using the Structured Clinical Interview for DSM-IV Axis I Disorders and assessed using the Morningness-Eveningness Questionnaire whose factor matrix applying for the maximum likelihood principle was calculated for the first time. RESULTS Patients with the co-morbid alcohol use disorder were more of the morning type as compared with patients with bipolar disorder only. CONCLUSIONS Co-morbid patients preferred more the morning hours for their daily activities, indicative of alcohol consumption having an effect on the circadian clock.

Hippocampal Morphology in Lithium and Non-Lithium-Treated Bipolar I Disorder Patients, Non-Bipolar Co-Twins, and Control Twins

Background: Bipolar I disorder is a highly heritable psychiatric illness with undetermined predisposing genetic and environmental risk factors. We examined familial contributions to hippocampal morphology in bipolar disorder, using a population‐based twin cohort design. Methods: We acquired high‐resolution brain MRI scans from 18 adult patients with bipolar I disorder [BPI; mean age 45.6 ± 8.69 (SD); 10 lithium‐treated], 14 non‐bipolar co‐twins, and 32 demographically matched healthy comparison twins. We used three‐dimensional radial distance mapping techniques to visualize hippocampal shape differences between groups. Results: Lithium‐treated BPI patients had significantly larger global hippocampal volume compared to both healthy controls (9%) and non‐bipolar co‐twins (12%), and trend‐level larger volumes relative to non‐lithium‐treated BPI patients (8%). In contrast, hippocampal volumes in non‐lithium‐treated BPI patients did not differ from those of non‐bipolar co‐twins and control twins. 3D surface maps revealed thicker hippocampi in lithium‐treated BPI probands compared with control twins across the entire anterior‐to‐posterior extent of the cornu ammonis (CA1 and 2) regions, and the anterior part of the subiculum. Unexpectedly, co‐twins also showed significantly thicker hippocampi compared with control twins in regions that partially overlapped those showing effects in the lithium treated BPI probands. Conclusions: These findings suggest that regionally thickened hippocampi in bipolar I disorder may be partly due to familial factors and partly due to lithium‐induced neurotrophy, neurogenesis, or neuroprotection. Unlike schizophrenia, hippocampal alterations in co‐twins of bipolar I disorder probands are likely to manifest as subtle volume excess rather than deficit, perhaps indicating protective rather than risk effects. Hum Brain Mapp, 2012.