Judith Haffmans

Long-term cortisol in bipolar disorder: associations with age of onset and psychiatric co-morbidity.

INTRODUCTION Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is hypothesized to play a role in the pathogenesis of bipolar disorder (BD). Conflicting results have been reported when saliva or serum was used to measure cortisol levels. A recently developed method is to measure cortisol in scalp hair, with 1cm of scalp hair representing 1 month. We studied whether there are differences in long-term hair cortisol levels between BD patients and healthy individuals and whether there are associations between hair cortisol and disease characteristics. METHODS Hair samples were collected in 100 BD patients and 195 healthy controls. Long-term cortisol levels were determined in 3 cm hair segments. Saliva samples were collected on two consecutive evenings. Documented disease characteristics were disease state, age of onset and psychiatric co-morbidity. RESULTS Hair cortisol levels were not statistically different in BD patients compared to healthy controls (p=0.233) and were not associated with the disease state at the moment of sample collection (p=0.978). In the subgroup of patients with age of onset ≥ 30 years, hair cortisol levels were significantly elevated compared to the subgroup with age of onset <30 years and to healthy controls (p=0.004). Psychiatric co-morbidity was associated with elevated cortisol levels (44.87 versus 31.41 pg/mg hair; p=0.021), with the exclusion of panic disorder, which was associated with decreased cortisol levels (22.13 versus 34.67 pg/mg hair; p=0.019). CONCLUSIONS Elevated long-term cortisol levels might play a role in a subgroup of patients with BD. There may be differences in pathogenesis of younger and older onset BD suggesting two different disease entities.

Serum BDNF Concentrations Show Strong Seasonal Variation and Correlations with the Amount of Ambient Sunlight

Earlier findings show seasonality in processes and behaviors such as brain plasticity and depression that in part are regulated by Brain-Derived Neurotrophic Factor (BDNF). Based on this we investigated seasonal variation in serum BDNF concentrations in 2,851 persons who took part in the Netherlands Study of Depression and Anxiety (NESDA). Analyses by month of sampling (monthly n’s >196) showed pronounced seasonal variation in serum BDNF concentrations (P<.0001) with increasing concentrations in the spring-summer period (standardized regression weight (ß) = 0.19, P<.0001) and decreasing concentrations in the autumn-winter period (ß = −0.17, P<.0001). Effect sizes [Cohen’s d] ranged from 0.27 to 0.66 for monthly significant differences. We found similar seasonal variation for both sexes and for persons with a DSM-IV depression diagnosis and healthy control subjects. In explorative analyses we found that the number of sunshine hours (a major trigger to entrain seasonality) in the week of blood withdrawal and the 10 weeks prior to this event positively correlated with serum BDNF concentrations (Pearson’s correlation coefficients ranged: 0.05 – 0.18) and this could partly explain the observed monthly variation. These results provide strong evidence that serum BDNF concentrations systematically vary over the year. This finding is important for our understanding of those factors that regulate BDNF expression and may provide novel avenues to understand seasonal dependent changes in behavior and illness such as depression. Finally, the findings reported here should be taken into account when designing and interpreting studies on BDNF.

Functional polymorphism of the glucocorticoid receptor gene associates with mania and hypomania in bipolar disorder

OBJECTIVES In affective disorders, dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis is a frequently observed phenomenon. Subtle changes in glucocorticoid receptor (GR) functioning caused by polymorphisms of the GR gene (NR3C1) may be at the base of the altered reaction of the HPA axis to stress and subsequently related to the development and course of affective disorders. The aim of our study is to evaluate associations between GR gene polymorphisms and bipolar disorder (BD). METHODS In this study, 245 patients with BD were interviewed to confirm diagnosis and BD subtype. Data on medication use and sociodemographic details were also collected. The control group consisted of 532 healthy blood donors, from which data on sex and age were collected. To perform genotyping, blood was collected from all patients and healthy controls. RESULTS A trend was found for a protective effect of the exon 9beta polymorphism (p = 0.14) and the TthIIII polymorphism (p < 0.05) on the manifestation of the disease. These effects were significantly influenced by male gender for both polymorphisms. Patients with BD and the A/G variant in exon 9beta had significantly fewer manic and hypomanic episodes than noncarriers (p < 0.05). No further associations were found with the other investigated GR gene polymorphisms and BD. These findings were not corrected for multiple comparisons. CONCLUSIONS We conclude that the exon 9beta polymorphism and the TthIIII polymorphism of the GR gene may be associated with a protective effect on the clinical manifestation and course in patients with BD. Furthermore, no associations were found between the other studied GR gene polymorphisms and this disease.

Glucocorticoid and mineralocorticoid receptor polymorphisms and clinical characteristics in bipolar disorder patients.

INTRODUCTION The hypothalamus-pituitary-adrenal (HPA)-axis is often found to be dysregulated in bipolar disorder (BD) while stress and changes in day-night rhythms can trigger a new mood episode. Genetic variants of the glucocorticoid receptor (GR)- and mineralocorticoid receptor (MR)-gene influence both the reactivity of the stress-response and associate with changes in mood. In this study we tested the hypothesis that these polymorphisms associate with different clinical characteristics of BD. METHODS We studied 326 outpatients with BD and performed GR genotyping of the TthIIII, ER22/23EK, N363S, BclI, and 9β polymorphisms, as well as MR genotyping of the 2G/C and I180V variants. All patients were interviewed for clinical characteristics. RESULTS Seasonal patterns of hypomania are related to the BclI haplotype and the TthIIII+9β haplotype of the GR gene (respectively, crude p=.007 and crude p=.005). Carriers of the ER22/23EK polymorphism had an almost 8 years earlier onset of their first (hypo)manic episode than non-carriers (crude p=.004, after adjustment p=.016). No evidence for a role of the MR in modifying clinical manifestations was found. CONCLUSION Polymorphisms of the GR-gene are factors which influence some clinical manifestations of BD, with respect to seasonal pattern of (hypo)mania and age of onset.

Effects of mood state on divided attention in patients with bipolar disorder: Evidence for beneficial effects of subclinical manic symptoms

A relatively small number of studies have been dedicated to the differential effects of the current mood state on cognition in patients with a bipolar disorder (BD). The aim of the current study was to investigate the effect of current mood state on divided attention (DA) performance, and specifically examine possible beneficial effects of the (hypo-) manic state. Over a maximum period of 24 months, medication use, divided attention test (a subtest of the Test for Attentional Performance (TAP)) was assessed every 6 months in 189 outpatients with BD. Data were analyzed with multilevel regression analysis (i.e. linear mixed models). DA performance varied considerable over time within patients. Corrected for psychotropic medication a significant quadratic relationship between manic symptoms and DA performance was found, with mild hypomanic symptoms having a positive influence on divided attention scores and moderate to severe manic symptoms having a negative influence. No association between depressive symptoms and DA performance was found. In future research on mania and cognition as well as in the clinical practice both the beneficial and negative effects of mania should be taken into account.

Five-Year Mental Health Care Use by Patients Referred to Collaborative Care or to Specialized Care

OBJECTIVE This study compared long-term use of mental health care by two groups of patients who had common mental disorders in the Netherlands-those treated in a collaborative care setting and those referred to off-site specialized mental health services if indicated. METHODS The study was a retrospective analysis of use of mental health care over five years by 139 patients who participated in a cluster-randomized parent study. The parent study involved 27 general practitioners (GPs) who provided either collaborative care or usual care. In the collaborative care condition, a mental health professional worked on site at the GPs practice and was available to provide short-term treatment. In the usual-care condition, the GP referred the patient to off-site specialized mental health services if indicated; if not indicated, the GP provided usual care. The two treatment groups were compared on the number of mental health care contacts and total treatment duration, the proportion that initiated a new treatment episode after termination of the initial treatment, and time to new treatment. RESULTS Patients in the collaborative care condition received about half the number of mental health care contacts as those in the usual-care condition, and no differences were found in the rate of initiation of new treatment episodes after initial treatment, time to new treatment, and total treatment duration. CONCLUSIONS Referral of patients with common mental disorders to collaborative mental health care as a first intervention led to fewer contacts with a mental health care professional over the long term, compared with referral to specialized mental health care.

Antipsychotics switching strategies in real life: A longitudinal study in clinical practice

Background and Objectives: Switching antipsychotics (APs) in the treatment of mental ilnesses such as schizophrenia is common practice for clinicians as well as a transitional moment associated with the possibility of adverse events and recurrence of psychoses. As in recent years, AP switching strategies have received more attention, a number of authors have recommended transitions with overlapping drug dosage regimens in time (such as tapering, cross-tapering, plateau switching) over abrupt switches. However, there is a paucity of data documenting how clinicians are switching APs in real life. Moreover, the question if recently recommended switching strategies are converted into everyday practice is still very much unanswered. The present investigation aims to study if indeed there is a preference for tapered approaches over abrupt switching. Methods: In a retrospective longitudinal descriptive study, electronic prescription data from a large clinical psychiatric setting in the Netherlands were collected for the year 2007. Timelines of medication regimens were constructed for individual patients, enabling to identify transitions between APs. As patients could have been subjected to multiple switches in a given time period, transitions were expressed as episodes. Abrupt switches were defined as switches having no overlap in time. Results: From a total of 5322 AP prescriptions involving 1465 patients, a total of 180 episodes (associated with 158 patients) were identified where APs were switched. Of these 180 episodes, 110 (61%) involved abrupt transitions. 70 episodes (39%) had overlap in time with an average taper length of 16.1 (SEM 1.6) days. Conclusions: In the majority of cases in the studied clinical setting, APs are switched abruptly

Prediction of mental health services use one year after regular referral to specialized care versus referral to stepped collaborative care

Referral to collaborative mental health care within the primary care setting is a service concept that has shown to be as effective as direct referral to specialized mental health care for patients with common mental disorders. Additionally it is more efficient in terms of lower mental health services use. This post-hoc analysis examines if treatment intensity during 1-year of follow-up can be predicted prospectively by baseline characteristics. With multilevel multivariate regression analyses baseline characteristics were examined as potential predictors of visit counts. Results showed that only the enabling factors service concept and referral delay for treatment had a significant association with mental health visit counts, when outcome was dichotomized in five or more visits. Inclusion of the outcome variable as a count variable confirmed the predictive value of service concept and referral delay, but added marital status as a significant predictor. Overall, enabling factors (service concept and referral delay) seem to be important and dominant predictors of mental health services use.

A pilot study of bright light therapy in schizophrenia.

Negative symptoms and episodes of major depressive disorder in patients with schizophrenia are common and there is an overlap in symptoms. Unfortunately, there is no effective primary treatment for negative symptoms yet. Depressive disorder in patients with schizophrenia is associated with a decreased quality of life and an increased risk of psychotic relapses. Previous research has shown that Bright Light Therapy (BLT) has a positive impact on negative symptoms of patients with schizophrenia. Our aim was to investigate the feasibility and the effect of Bright Light Therapy in a severely ill population of patients who were admitted to a closed ward. This pilot study was a single center, open label add-on trial with two control groups and included 20 patients. RESULTS Neither negative nor positive symptoms were affected. However, there was a trend towards increase on the general psychopathology scale of the Positive And Negative Syndrome Scale in the BLT group. BLT did not change daily mood ratings. One participant from the BLT group was withdrawn from the study due to a manic state possibly triggered by BLT. Patients participating in our study did not benefit from BLT. It was an additional burden on the participants and worsened general psychopathology at a follow-up. Based on this study, we did not find any beneficial effect of BLT for patients with schizophrenia.