Ketil J. Oedegaard

Differential responses to lithium in hyperexcitable neurons from patients with bipolar disorder

Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca2+ imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

Impairment across executive functions in recurrent major depression.

Depression is associated with impairment of cognitive functions, and especially executive functions (EFs). Despite the fact that most depressed patients experience recurrence of episodes, the pattern and the severity of executive impairment have not been well characterized in this group of depressed patients. We asked if and to what extent these patients were impaired on a range of neuropsychological tests measuring EFs, and also when confounding factors were adjusted for. Forty-five patients (aged 19–51 years) with moderate to severe (Hamilton score >18) recurrent major depressive disorder (DSM-IV) were compared to 50 healthy controls matched on age, education, gender and intellectual abilities. The subjects were administered a set of neuropsychological tests that assesses sub-components of EFs. The depressed patients were impaired compared to the control group on all selected tests, with a severity of impairment within −1 standard deviation from the control group mean. The group difference was statistically significant for eight of the 10 EFs that were assessed. These were measures of verbal fluency, inhibition, working memory, set-maintenance and set-shifting. The group difference was still significant for all sub-components except for set-shifting (Wisconsin Card Sorting Test) and planning (Tower of London), when additional medication and retarded psychomotor speed was adjusted for. In conclusion, the depressed subjects were mildly impaired across a wide range of EFs. This may have a negative impact on everyday functioning for this group of patients.

Migraine with and without aura: association with depression and anxiety disorder in a population-based study. The HUNT Study

Some data indicate that migraine with aura (MA) is more strongly associated with anxiety disorder and depression than migraine without aura (MoA), but the evidence is not conclusive. In the Nord-Trøndelag Health study 1995-1997, a total of 49 205 (75% of the participants) subjects gave valid answers to both HADS (Hospital Anxiety and Depression Scale) and a validated headache questionnaire. Associations between anxiety disorder/depression and MA/MoA were evaluated by multiple logistic regression analysis. Depression (DEP) [odds ratio (OR) 1.7; 95% confidence interval (CI) 1.2, 2.6] and depression with comorbid anxiety disorder (COM) (OR 1.6; 95% CI 1.2, 2.1) were more likely in women having MA than in those with MoA. No stronger association was found for pure anxiety disorder (ANX) in MA vs. MoA (OR 0.9; 95% CI 0.7, 1.5). Among men, we found no difference in prevalence of depression and anxiety disorders between MA and MoA. This is a new finding that might have relevance for both research and clinical treatment.

Actigraphic registration of motor activity reveals a more structured behavioural pattern in schizophrenia than in major depression.

BackgroundDisturbances in motor activity pattern are seen in both schizophrenia and depression. However, this activity has rarely been studied objectively. The purpose of the present study has been to study the complexity of motor activity patterns in these patients by using actigraphy.FindingsMotor activity was recorded using wrist-worn actigraphs for periods of 2 weeks in patients with schizophrenia and major depression and compare them to healthy controls. Average motor activity was recorded and three non-parametric variables, interdaily stability (IS), intradaily variability (IV), and relative amplitude (RA) were calculated on the basis of these data. The motor activity was significantly lower both in patients with schizophrenia (153 ± 61, mean ± SD, p < 0.001) and depression (187 ± 84, p < 0.001), compared to controls (286 ± 80). The schizophrenic patients had higher IS and lower IV than the controls reflecting a more structured behavioural pattern. This pattern was particularly obvious in schizophrenic patients treated with clozapine and was not found in depressed patients.ConclusionsMotor activity was significantly reduced in both schizophrenic and depressed patients. However, schizophrenic patients differed from both depressed patients and controls, demonstrating motor activity patterns marked by less complexity and more structured behaviour. These findings may indicate that disturbances in motor activity reflect different pathophysiological mechanisms in schizophrenia compared to major depression.

Clinical characteristics of patients with major affective disorders and comorbid migraine.

The present study was undertaken to examine the clinical characteristics of patients with major affective disorders and comorbid migraine. Patients (n = 102) with an index episode of either major depression or mania were interviewed with a semi-structured interview based partly on DSM-IV criteria and partly on Akiskals criteria for affective temperaments. Compared to the patients without migraine (n = 49), the patients with comorbid migraine (n - 53) had a higher frequency of bipolar II disorder (43% vs. 10%), a lower frequency of bipolar I disorder (11% vs. 33%), an approximately equal frequency of unipolar depressive disorder (45% vs. 57%) and a higher frequency of affective temperaments (45% vs. 22%). The migraine patients also had a greater number of anxiety disorders (3.0 vs. 1.9) and a higher frequency of panic disorder and agoraphobia. Gender distribution, age, age at onset of first affective episode, number of previous episodes and symptoms during depressive episodes were similar in both groups. Based on these findings it is suggested that the presence of migraine may be used to delineate a distinct subgroup of the major affective disorders.

Nonlinear Analysis of Motor Activity Shows Differences between Schizophrenia and Depression: A Study Using Fourier Analysis and Sample Entropy

The purpose of this study has been to describe motor activity data obtained by using wrist-worn actigraphs in patients with schizophrenia and major depression by the use of linear and non-linear methods of analysis. Different time frames were investigated, i.e., activity counts measured every minute for up to five hours and activity counts made hourly for up to two weeks. The results show that motor activity was lower in the schizophrenic patients and in patients with major depression, compared to controls. Using one minute intervals the depressed patients had a higher standard deviation (SD) compared to both the schizophrenic patients and the controls. The ratio between the root mean square successive differences (RMSSD) and SD was higher in the schizophrenic patients compared to controls. The Fourier analysis of the activity counts measured every minute showed that the relation between variance in the low and the high frequency range was lower in the schizophrenic patients compared to the controls. The sample entropy was higher in the schizophrenic patients compared to controls in the time series from the activity counts made every minute. The main conclusions of the study are that schizophrenic and depressive patients have distinctly different profiles of motor activity and that the results differ according to period length analysed.

Enduring cognitive dysfunction in unipolar major depression: a test-retest study using the Stroop paradigm.

The aim of the study was to investigate automatic and effortful information processing with the Stroop paradigm in a long term perspective in patients with major depressive disorder (MDD). Patients were tested at two test occasions: at inclusion with a Hamilton Depression Rating Scale (HDRS) score >18, and after 6 months, when most patients had experienced symptom reduction. The Stroop paradigm is considered to measure aspects of attention and executive functioning and consists of three conditions/cards: naming the color of the patches (Color), reading of the color-words (Word) and naming the ink color of color-words (Color-Word). The Color-Word condition is proved to be the most cognitive demanding task and requires the proband to actively suppress interference and is therefore considered to require more effortful information processing, whereas naming the color of the patches and reading the color-words are expected to be more automatic and less cognitive demanding. A homogenous group of 19 patients with unipolar recurrent MDD according to DSM-IV and a HDRS score of >18 were included in the study. A control group was individually matched for age, gender and level of education. Depressed patients performed equal to the control group on the Color and Word cards at both test occasions. However, the patients were impaired compared with the control group on the Color-Word card task at both test occasions. Thus, the depressed patients showed no improvement of effortful attention/executive performance as a function of symptom reduction. The results indicate that the depressed patients showed impaired cognitive performance on cognitive demanding tasks when symptomatic and that this impairment prevailed after 6 months, despite significant improvement in their depressive symptoms.

The relationship of bulimia and anorexia nervosa with bipolar disorder and its temperamental foundations

BACKGROUND Earlier studies have suggested a relationship between bipolar disorder (BP) and eating disorders (ED), more specifically, bulimia nervosa (BN) and bipolar II disorder (BP-II). In the present report we extend this relationship to broader definitions of bipolarity. METHODS Semi-structured interview of 201 patients with DSM-IV criteria for major affective disorders combined with Akiskal and Mallya criteria for Affective temperaments. To diagnose lifetime comorbid eating disorders DSM-IV criteria for eating disorders (Bulimia Nervosa, BN, Anorexia, AN) were used. RESULTS 33 patients had an eating disorder. When compared to patients without ED the patients with ED had a higher prevalence of bipolar disorders. Using strict DSM-IV criteria, this association was only significant for BN (OR) 4.5 (95% CI 1.1-17.6). When using a broader index of bipolarity including patients having affective temperaments, a significant relation was found for BN (OR) 9.1 (95% CI 1.1-73.6), and for patients with a lifetime history of both BN and AN (OR) 8.6 (95% CI 1.1-70.2).We also found patients with ED to have a significantly higher prevalence of affective temperaments, an earlier onset of major affective disorder and to have more depressive episodes. LIMITATIONS Non-blind evaluation of diagnosis for mood, eating disorders and affective temperaments. CONCLUSION In line with previous reports we describe an association between bulimia nervosa and bipolar disorder. Furthermore we report a relationship between lifetime bulimia and anorexia and cyclothymic and related affective temperaments.

A study of age at onset and affective temperaments in a Norwegian sample of patients with mood disorders.

BACKGROUND Early age at onset of bipolar disorder is clinically important since it predicts a more severe course of illness and a poorer prognosis. Recently the age at onset (AAO) of bipolar disorder (BPD) has been reported different in samples from the USA and Europe (Bipolar Collaborative Network). We have examined the AAO of first major affective episode in major depressive disorder (MDD) and bipolar disorder in a sample of patients consecutively admitted to an affective ward in Norway. We also examined the relation between AAO and affective temperaments. METHODS Semi-structured interview of 119 patients consecutively admitted to an affective ward. Patients were diagnosed according to DSM-IV criteria for major affective disorders and affective temperaments were assessed using Akiskal Mallya criteria. RESULTS Childhood-onset of BPD (before age 13) was found in 13.5% of patients, and early onset BPD (before age 20) in 61.6%. The AAO of first major affective disorder was significantly higher in MDD (n=67) compared to BPD (n=52); (28 Years Median (Min 10-Max 57) vs. 18 Years Median (Min 8-Max 41), p<0.001, Mann-Whitney U). Comparing patients with and without affective temperaments, showed that patients with such temperaments had an earlier AAO in both MDD and BPD (MDD: 20 Years Median (Min 10-Max 56), vs. 30 Years Median (Min 12-Max 57) p=0.006, Mann-Whitney U); BPD: 16 Years Median (Min 8-Max 30) vs. 20 Years Median (Min 12-Max 41, p=0.011, Mann-Whitney U). CONCLUSION Our Norwegian data are more in line with the US than the European data regarding age at onset of bipolar disorders. The presence of an affective temperament presents an additional affirmation of the early occurrence of mood symptoms in early onset forms of both MDD and BPD.

A genome-wide association study of bipolar disorder and comorbid migraine.

Both migraine and bipolar affective disorder (BPAD) are complex phenotypes with significant genetic and nongenetic components. Epidemiological and clinical studies have showed a high degree of comorbidity between migraine and BPAD, and overlapping regions of linkage have been shown in numerous genome‐wide linkage studies. To identify susceptibility factors for the BPAD/migraine phenotype, we conducted a genome‐wide association study (GWAS) in 1001 cases with bipolar disorder collected through the NIMH Genetics Initiative for Bipolar Disorder and genotyped at 1 m single‐nucleotide polymorphisms (SNPs) as part of the Genetic Association Information Network (GAIN). We compared BPAD patients without any headache (n = 699) with BPAD patients with doctor diagnosed migraine (n = 56). The strongest evidence for association was found for several SNPs in a 317‐kb region encompassing the uncharacterized geneKIAA0564 {e.g. rs9566845 [OR = 4.98 (95% CI: 2.6–9.48), P = 7.7 × 10−8] and rs9566867 (P = 8.2 × 10−8)}. Although the level of signficance was significantly reduced when using the Fishers exact test (as a result of the low count of cases with migraine), rs9566845 P = 1.4 × 10−5 and rs9566867 P = 1.5 × 10−5, this region remained the most prominent finding. Furthermore, marker rs9566845 was genotyped and found associated with migraine in an independent Norwegian sample of adult attention deficit hyperactivity disorder (ADHD) patients with and without comorbid migraine (n = 131 and n = 324, respectively), OR = 2.42 (1.18–4.97), P = 0.013. This is the first GWAS examining patients with bipolar disorder and comorbid migraine. These data suggest that genetic variants in the KIAA0564 gene region may predispose to migraine headaches in subgroups of patients with both BPAD and ADHD.