Prevalence and characteristics of depressive disorders in type 1 diabetes

Background: Persons with diabetes and depression have increased risk of complications and increased mortality. We aimed to investigate the prevalence, clinical characteristics and impact with regard to glycosylated haemoglobin (HbA1c) of depressive disorders in persons with type 1 diabetes at an outpatient specialist diabetes clinic. Findings: A total of 51 persons with type 1 diabetes were diagnosed according to Mini International Neuropsychiatric Interview (M.I.N.I) with regard to dysthymia and previous or ongoing depressive episodes during spring 2005. HbA1c was measured at the day of the interview, and self-reported information on family history of depressive disorders was obtained. Eight persons (16%; 95% CI: 7%, 29%) were in the midst of a major depressive episode, 4 of these also reported a previous episode of depression. Seven of the 8 persons with an ongoing major depressive episode met the criteria for melancholia. Three persons (6%) met the criteria for dysthymia, and 6 persons (12%) had previous episode(s) of depression, without being currently depressed. The 17 (33%; 95% CI: 21%, 48%) persons with ongoing and/or previous depressive disorder had increased HbA1c (8.5%; 95% CI: 7.6%, 9.4%) compared to those without depressive disorders (7.9%; 95% CI: 7.5%, 8.3%), although the difference did not reach statistical significance. Conclusions: Persons with type 1 diabetes had a high prevalence of depressive disorders, mainly depressive episodes that also met the criteria for melancholia, a subtype often considered a more serious and “biologic” form of depression. We were not able to demonstrate that persons with depressive disorders had poorer regulated diabetes compared to those without depressive disorders

Cyclothymic temperament: Associations with ADHD, other psychopathology, and medical morbidity in the general population

Under embargo until: 2020-08-19Background: Cyclothymic temperament (CT) is an affective disposition often preceding bipolar disorder (BD), and is the most common affective temperament in patients with BD. In depressed patients, CT is a predictor for developing a bipolar course. In a clinical sample of adults with BD and attention deficit hyperactivity disorder (ADHD), CT was associated with higher loads of psychiatric symptoms, somatic comorbidity, impairment, and higher morbidity among first-degree relatives. We aimed to investigate the morbidity and occupational functioning of persons with CT in the general population. Methods: Randomly recruited Norwegian adults (n = 721) were assessed with a 21-item cyclothymic subscale from the TEMPS Autoquestionnaire. Self-reported data were collected on psychiatric symptoms, comorbidity, educational and occupational level, and known family morbidity. Results: Thirteen percent had CT associated with an increased prevalence of ADHD, BD, high scores on the Mood Disorder Questionnaire (MDQ), and childhood and adulthood ADHD symptoms. CT was found in 75% (p < .001) of the bipolar participants, and in 68% (p < .001) of those with a positive MDQ score. CT was associated with more anxiety/depression, substance and alcohol problems, lower educational and occupational levels, and having a first-degree relative with anxiety/depression, alcohol problems, ADHD, and BD. Limitations: The CT subscale alone might include overlapping features with cyclothymic, anxious, irritable, and depressed temperaments, thus increasing the prevalence estimate of CT. Conclusions: CT is a strong predictor of occupational failure and associated with more psychiatric impairment in the participants and their families. CT should be assessed in both mood disorder and ADHD patients.acceptedVersio

Complexity and variability analyses of motor activity distinguish mood states in Bipolar Disorder

Changes in motor activity are core symptoms of mood episodes in bipolar disorder. The manic state is characterized by increased variance, augmented complexity and irregular circadian rhythmicity when compared to healthy controls. No previous studies have compared mania to euthymia intra-individually in motor activity. The aim of this study was to characterize differences in motor activity when comparing manic patients to their euthymic selves. Motor activity was collected from 16 bipolar inpatients in mania and remission. 24-h recordings and 2-h time series in the morning and evening were analyzed for mean activity, variability and complexity. Lastly, the recordings were analyzed with the similarity graph algorithm and graph theory concepts such as edges, bridges, connected components and cliques. The similarity graph measures fluctuations in activity reasonably comparable to both variability and complexity measures. However, direct comparisons are difficult as most graph measures reveal variability in constricted time windows. Compared to sample entropy, the similarity graph is less sensitive to outliers. The little-understood estimate Bridges is possibly revealing underlying dynamics in the time series. When compared to euthymia, over the duration of approximately one circadian cycle, the manic state presented reduced variability, displayed by decreased standard deviation (p = 0.013) and augmented complexity shown by increased sample entropy (p = 0.025). During mania there were also fewer edges (p = 0.039) and more bridges (p = 0.026). Similar significant changes in variability and complexity were observed in the 2-h morning and evening sequences, mainly in the estimates of the similarity graph algorithm. Finally, augmented complexity was present in morning samples during mania, displayed by increased sample entropy (p = 0.015). In conclusion, the motor activity of mania is characterized by altered complexity and variability when compared within-subject to euthymia.publishedVersio

Objective assessment of motor activity in a clinical sample of adults with attention-deficit/hyperactivity disorder and/or cyclothymic temperament

Background Most research on patterns of motor activity has been conducted on adults with mood disorders, but few studies have investigated comorbid attention-deficit/hyperactivity disorder (ADHD) or temperamental factors that may influence the clinical course and symptoms. Cyclothymic temperament (CT) is particularly associated with functional impairment. Clinical features define both disorders, but objective, biological markers for these disorders could give important insights with regard to pathophysiology and classification. Methods Seventy-six patients, requiring diagnostic evaluation of ADHD, mood or anxiety disorders were recruited. A comprehensive diagnostic evaluation, including the CT scale of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego – Auto-questionnaire (TEMPS-A), neuropsychological tests and actigraphy, was performed. ADHD was diagnosed according to the DSM-IV criteria. There was a range of different conditions in this clinical sample, but here we report on the presence of CT and ADHD in relation to motor activity. Twenty-nine healthy controls were recruited. We analyzed motor activity time series using linear and nonlinear mathematical methods, with a special focus on active and inactive periods in the actigraphic recordings. Results Forty patients fulfilled the criteria for ADHD, with the remainder receiving other psychiatric diagnoses (clinical controls). Forty-two patients fulfilled the criteria for CT. Twenty-two patients fulfilled the criteria for ADHD and CT, 18 patients met the criteria for ADHD without CT, and 15 patients had neither. The ratio duration of active/inactive periods was significantly lower in patients with CT than in patients without CT, in both the total sample, and in the ADHD subsample. Conclusions CT is associated with objectively assessed changes in motor activity, implying that the systems regulating motor behavior in these patients are different from both healthy controls and clinical controls without CT. Findings suggest that actigraphy may supplement clinical assessments of CT and ADHD, and may provide an objective marker for CT.publishedVersio

The effect of electroconvulsive therapy (ECT) on serum tryptophan metabolites

Background: Prior studies suggest that activation of the tryptophan catabolism via the kynurenine pathway by proinflammatory cytokines may be involved in the pathophysiology of depression. Electroconvulsive therapy (ECT) is an effective treatment for major depression (MD) with immunomodulation as one of the proposed modes of action. Objective: The aim of this study was to investigate serum concentrations of tryptophan and kynurenine pathway metabolites in MD patients and healthy controls, and to explore the effect of ECT on components of the kynurenine pathway. Methods: The study included 27 moderately to severely depressed patients referred to ECT. Blood samples were collected prior to treatment and after the completed ECT-series. Baseline samples were also collected from 14 healthy, age- and sex-matched controls. Serum concentrations of tryptophan, kynurenine, 3-hydroxykynurenine (HK), kynurenic acid (KA), xanthurenic acid (XA), anthranilic acid (AA), 3-hydroxyanthranilic acid (HAA), quinolinic acid (QA), picolinic acid (Pic), pyridoxal 5′-phosphat (PLP), riboflavin, neopterin and cotinine were measured. Results: Patients with MD had lower levels of neuroprotective kynurenine-pathway metabolites (KA, XA and Pic) and lower metabolite ratios (KA/Kyn and KA/QA) reflecting reduced neuroprotection compared to controls. The concentration of the inflammatory marker neopterin was increased after ECT, along with Pic and the redox active and immunosuppressive metabolite HAA. Conclusion: In this pilot study, we found increased concentrations of inflammatory marker neopterin and putative neuroprotective kynurenine metabolites HAA and Pic in MD patients after ECT. Further research in larger cohorts is required to conclude whether ECT exerts its therapeutic effects via changes in the kynurenine pathway.publishedVersio

Neurocognitive profiles in treatment-resistant bipolar I and bipolar II disorder depression

Background The literature on the neuropsychological profiles in Bipolar disorder (BD) depression is sparse. The aims of the study were to assess the neurocognitive profiles in treatment-resistant, acutely admitted BD depression inpatients, to compare the neurocognitive functioning in patients with BD I and II, and to identify the demographic and clinical illness characteristics associated with cognitive functioning. Methods Acutely admitted BD I (n = 19) and BD II (n = 32) inpatients who fulfilled the DSM-IV-TR criteria for a major depressive episode were tested with the MATRICS Consensus Cognitive Battery (MCCB), the Wechsler Abbreviated Scale of Intelligence, the National Adult Reading Test, and a battery of clinical measures. Results Neurocognitive impairments were evident in the BD I and BD II depression inpatients within all MCCB domains. The numerical scores on all MCCB-measures were lower in the BD I group than in the BD II group, with a significant difference on one of the measures, category fluency. 68.4% of the BD I patients had clinically significant impairment (>1.5 SD below normal mean) in two or more domains compared to 37.5% of the BD II patients (p = 0.045). A significant reduction in IQ from the premorbid to the current level was seen in BD I but not BD II patients. Higher age was associated with greater neurocognitive deficits compared to age-adjusted published norms. Conclusions A high proportion of patients with therapy-resistant BD I or II depression exhibited global neurocognitive impairments with clinically significant severity. The cognitive impairments were more common in BD I compared to BD II patients, particularly processing speed. These findings suggest that clinicians should be aware of the severe neurocognitive dysfunction in treatment-resistant bipolar depression, particularly in BD I.publishedVersio

Diurnal variation of motor activity in adult ADHD patients analyzed with methods from graph theory

Attention-deficit /hyperactivity disorder (ADHD) is a common neurodevelopmental syndrome characterized by age-inappropriate levels of motor activity, impulsivity and attention. The aim of the present study was to study diurnal variation of motor activity in adult ADHD patients, compared to healthy controls and clinical controls with mood and anxiety disorders. Wrist-worn actigraphs were used to record motor activity in a sample of 81 patients and 30 healthy controls. Time series from registrations in the morning and evening were analyzed using measures of variability, complexity and a newly developed method, the similarity algorithm, based on transforming time series into graphs. In healthy controls the evening registrations showed higher variability and lower complexity compared to morning registrations, however this was evident only in the female controls. In the two patient groups the same measures were not significantly different, with one exception, the graph measure bridges. This was the measure that most clearly separated morning and evening registrations and was significantly different both in healthy controls and in patients with a diagnosis of ADHD. These findings suggest that actigraph registrations, combined with mathematical methods based on graph theory, may be used to elucidate the mechanisms responsible for the diurnal regulation of motor activity.publishedVersio

Anterior cingulate gamma-aminobutyric acid concentrations and electroconvulsive therapy

Objective The anticonvulsant hypothesis posits that ECT’s mechanism of action is related to enhancement of endogenous anticonvulsant brain mechanisms. Results of prior studies investigating the role of the inhibitory neurotransmitter gamma‐aminobutyric acid (“GABA+”, GABA and coedited macromolecules) in the pathophysiology and treatment of depression remain inconclusive. The aim of our study was to investigate treatment‐responsive changes of GABA+ in subjects with a depressive episode receiving electroconvulsive therapy (ECT). Methods In total, 41 depressed subjects (DEP) and 35 healthy controls (HC) were recruited at two independent sites in Norway and the USA. MEGA‐PRESS was used for investigation of GABA+ in the anterior cingulate cortex. We assessed longitudinal and cross‐sectional differences between DEP and HC, as well as the relationship between GABA+ change and change in depression severity and number of ECTs. We also assessed longitudinal differences in cognitive performance and GABA+ levels. Results Depressive episode did not show a difference in GABA+ relative to HC (t71 = −0.36, p = .72) or in longitudinal analysis (t36 = 0.97, p = .34). Remitters and nonremitters did not show longitudinal (t36 = 1.12, p = .27) or cross‐sectional differences in GABA+. GABA+ levels were not related to changes in antidepressant response (t35 = 1.12, p = .27) or treatment number (t36 = 0.05, p = .96). An association between cognitive performance and GABA+ levels was found in DEP that completed cognitive effortful testing (t18 = 2.4, p = .03). Conclusion Our results failed to support GABA as a marker for depression and abnormal mood state and provide no support for the anticonvulsant hypothesis of ECT. ECT‐induced change in GABA concentrations may be related to change in cognitive function.publishedVersio

Towards Adaptive Technology in Routine Mental Healthcare

This paper summarizes the information technology-related research findings after 5 years with the INTROducing Mental health through Adaptive Technology project. The aim was to improve mental healthcare by introducing new technologies for adaptive interventions in mental healthcare through interdisciplinary research and development. We focus on the challenges related to internet-delivered psychological treatments, emphasising artificial intelligence, human-computer interaction, and software engineering. We present the main research findings, the developed artefacts, and lessons learned from the project before outlining directions for future research. The main findings from this project are encapsulated in a reference architecture that is used for establishing an infrastructure for adaptive internet-delivered psychological treatment systems in clinical contexts. The infrastructure is developed by introducing an interdisciplinary design and development process inspired by domain-driven design, user-centred design, and the person based approach for intervention design. The process aligns the software development with the intervention design and illustrates their mutual dependencies. Finally, we present software artefacts produced within the project and discuss how they are related to the proposed reference architecture. Our results indicate that the proposed development process, the reference architecture and the produced software can be practical means of designing adaptive mental health care treatments in correspondence with the patients’ needs and preferences. In summary, we have created the initial version of an information technology infrastructure to support the development and deployment of Internet-delivered mental health interventions with inherent support for data sharing, data analysis, reusability of treatment content, and adaptation of intervention based on user needs and preferences.publishedVersio

The Pharmacogenomics of Bipolar Disorder study (PGBD): Identification of genes for lithium response in a prospective sample

Background: Bipolar disorder is a serious and common psychiatric disorder characterized by manic and depressive mood switches and a relapsing and remitting course. The cornerstone of clinical management is stabilization and prophylaxis using mood-stabilizing medications to reduce both manic and depressive symptoms. Lithium remains the gold standard of treatment with the strongest data for both efficacy and suicide prevention. However, many patients do not respond to this medication, and clinically there is a great need for tools to aid the clinician in selecting the correct treatment. Large genome wide association studies (GWAS) investigating retrospectively the effect of lithium response are in the pipeline; however, few large prospective studies on genetic predictors to of lithium response have yet been conducted. The purpose of this project is to identify genes that are associated with lithium response in a large prospective cohort of bipolar patients and to better understand the mechanism of action of lithium and the variation in the genome that influences clinical response. Methods/Design: This study is an 11-site prospective non-randomized open trial of lithium designed to ascertain a cohort of 700 subjects with bipolar I disorder who experience protocol-defined relapse prevention as a result of treatment with lithium monotherapy. All patients will be diagnosed using the Diagnostic Interview for Genetic Studies (DIGS) and will then enter a 2-year follow-up period on lithium monotherapy if and when they exhibit a score of 1 (normal, not ill), 2 (minimally ill) or 3 (mildly ill) on the Clinical Global Impressions of Severity Scale for Bipolar Disorder (CGI-S-BP Overall Bipolar Illness) for 4 of the 5 preceding weeks. Lithium will be titrated as clinically appropriate, not to exceed serum levels of 1.2 mEq/L. The sample will be evaluated longitudinally using a wide range of clinical scales, cognitive assessments and laboratory tests. On relapse, patients will be discontinued or crossed-over to treatment with valproic acid (VPA) or treatment as usual (TAU). Relapse is defined as a DSM-IV manic, major depressive or mixed episode or if the treating physician decides a change in medication is clinically necessary. The sample will be genotyped for GWAS. The outcome for lithium response will be analyzed as a time to event, where the event is defined as clinical relapse, using a Cox Proportional Hazards model. Positive single nucleotide polymorphisms (SNPs) from past genetic retrospective studies of lithium response, the Consortium on Lithium Genetics (ConLiGen), will be tested in this prospective study sample; a meta-analysis of these samples will then be performed. Finally, neurons will be derived from pluripotent stem cells from lithium responders and non-responders and tested in vivo for response to lithium by gene expression studies. SNPs in genes identified in these cellular studies will also be tested for association to response. Discussion: Lithium is an extraordinarily important therapeutic drug in the clinical management of patients suffering from bipolar disorder. However, a significant proportion of patients, 30–40 %, fail to respond, and there is currently no method to identify the good lithium responders before initiation of treatment. Converging evidence suggests that genetic factors play a strong role in the variation of response to lithium, but only a few genes have been tested and the samples have largely been retrospective or quite small. The current study will collect an entirely unique sample of 700 patients with bipolar disorder to be stabilized on lithium monotherapy and followed for up to 2 years. This study will produce useful information to improve the understanding of the mechanism of action of lithium and will add to the development of a method to predict individual response to lithium, thereby accelerating recovery and reducing suffering and cost.publishedVersio