R.C. Oude Voshaar

Determinants of serum brain-derived neurotrophic factor

BACKGROUNDnBrain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of growth factors and affects the survival and plasticity of neurons in the adult central nervous system. The high correlation between cortical and serum BDNF levels has led to many human studies on BDNF levels in various populations, however knowledge about determinants that influence BDNF is lacking.nnnAIMSnTo gain insight into the factors that influence BDNF levels in humans.nnnMETHODSnIn 1168 people aged 18 through 65, free of antidepressants and current psychiatric disease, from the Netherlands study of depression and anxiety four categories of determinants (sampling, sociodemographics, lifestyle indicators and diseases) were measured as well as BDNF level. We used univariate analyses as well as multivariate linear regression analyses in particular to determine which of the possible determinants significantly influenced serum BDNF levels.nnnRESULTSnThe mean BDNF level was 8.98ng/ml (SD 3.1ng/ml) with a range from 1.56ng/ml through 18.50ng/ml. Our final multivariate regression analysis revealed that a non-fasting state of blood draw (β=-.067; p=.019), later measurement (β=-.065; p=.022), longer sample storage (β=-.082; p=.004) and being a binge drinker (β=-.063; p=.035) all resulted in attenuated BDNF levels. This was in contrast to smoking (β=.098; p=.001) and living in an urban area (β=.109; p<.001), which resulted in increased BDNF levels. Moreover we found that older subjects also had higher BDNF levels, but this only applied to women (β=.226; p<.001).nnnCONCLUSIONSnFuture studies on serum levels of BDNF in humans should correct for the time of blood withdrawal, storage, urbanicity, age, sex, smoking status and food and alcohol intake.

Predictors of long-term benzodiazepine abstinence in participants of a randomized controlled benzodiazepine withdrawal program

Objective: To identify predictors of resumed benzodiazepine use after participation in a benzodiazepine discontinuation trial. Method: We performed multiple Cox regression analyses to predict the long-term outcome of a 3-condition, randomized, controlled benzodiazepine discontinuation trial in general practice. Results: Of 180 patients, we completed follow-up for 170 (94%). Of these, 50 (29%) achieved long-term success, defined as no use of benzodiazepines during follow-up. Independent predictors of success were as follows: offering a taper-off program with group therapy (hazard ratio [HR] 2.4; 95% confidence interval [CI], 1.5 to 3.9) or without group therapy (HR 2.9; 95%CI, 1.8 to 4.8); a lower daily benzodiazepine dosage at the start of tapering off (HR 1.5; 95%CI, 1.2 to 1.9); a substantial dosage reduction by patients themselves just before the start of tapering off (HR 2.1; 95%CI, 1.4 to 3.3); less severe benzodiazepine dependence, as measured by the Benzodiazepine Dependence Self-Report Questionnaire Lack of Compliance subscale (HR 2.4; 95%CI, 1.1 to 5.2); and no use of alcohol (HR 1.7; 95%CI, 1.2 to 2.5). Patients who used over 10 mg of diazepam equivalent, who had a score of 3 or more on the Lack of Compliance subscale, or who drank more than 2 units of alcohol daily failed to achieve long-term abstinence. Conclusions: Benzodiazepine dependence severity affects long-term taper outcome independent of treatment modality, benzodiazepine dosage, psychopathology, and personality characteristics. An identifiable subgroup needs referral to specialized care.

Big Five personality and depression diagnosis, severity and age of onset in older adults

BACKGROUNDnPersonality may play an important role in late-life depression. The aim of this study is to examine the association between the Big Five personality domains and the diagnosis, severity and age of onset of late-life depression.nnnMETHODSnThe NEO-Five Factor Inventory (NEO-FFI) was cross-sectionally used in 352 depressed and 125 non-depressed older adults participating in the Netherlands Study of Depression in Older Persons (NESDO). Depression diagnosis was determined by the Composite International Diagnostic Interview (CIDI). Severity of depression was assessed by the Inventory of Depressive Symptomatology (IDS). Logistic and linear regression analyses were applied. Adjustments were made for sociodemographic, cognitive, health and psychosocial variables.nnnRESULTSnBoth the presence of a depression diagnosis and severity of depression were significantly associated with higher Neuroticism (OR=1.35, 95% CI=1.28-1.43 and B=1.06, p<.001, respectively) and lower Extraversion (OR=.79, 95% CI=.75-.83; B=-.85, p<.001) and Conscientiousness (OR=.86, 95% CI=.81.-.90; B=-.86, p<.001). Earlier onset of depression was significantly associated with higher Openness (B=-.49, p=.026).nnnLIMITATIONSnDue to the cross-sectional design, no causal inferences can be drawn. Further, current depression may have influenced personality measures.nnnCONCLUSIONSnThis study confirms an association between personality and late-life depression. Remarkable is the association found between high Openness and earlier age of depression onset.

Hypothalamic–pituitary–adrenal axis activity in older persons with and without a depressive disorder

BACKGROUNDnAltered functioning of the hypothalamic-pituitary-adrenal axis (HPA-axis) has been associated with depression, but findings have been inconsistent. Among older depressed persons, both hyperactivity and hypo-activity of the HPA-axis were demonstrated. However, most studies were population-based studies, with single cortisol measurements, lacking insight into diurnal patterns of HPA-axis functioning. We aim to provide insight into functioning of the HPA-axis, assessed by various salivary cortisol samples, in depressed older adults and non-depressed controls.nnnMETHODSnData were derived from the Netherlands Study of Depression in Older Persons. Cortisol levels of older persons without a lifetime diagnosis of depression and/or anxiety (n=109) were compared with older persons with a 6-month major depression diagnosis (n=311). ANCOVA analyses and random coefficient analysis on the four morning cortisol samples were performed. A possible U-shaped association between cortisol and depression status was examined.nnnRESULTSnDepressed older persons showed higher morning cortisol levels at awakening (T1) and a less dynamic awakening response compared to non-depressed older persons. Dexamethasone suppression did not differ across groups. No U-shaped association between HPA-axis activity and depression was observed.nnnCONCLUSIONnWe demonstrated a hypercortisolemic state and a diminished ability to respond to the stress of awakening among depressed older persons. Previously it was shown, that hypercortisolemic states may indicate a lifelong biological vulnerability for depression. Our findings expand on previous literature by demonstrating that in older persons the HPA-axis may become less responsive to stress, culminating in a further dysregulation of the diurnal cortisol-rhythm, superimposed on - possibly lifelong - hypercortisolemic states.

A brief cognitive-behavioral intervention for treating depression and panic disorder in patients with noncardiac chest pain: a 24-week randomized controlled trial

Most patients with noncardiac chest pain experience anxiety and depressive symptoms. Commonly they are reassured and referred back to primary care, leaving them undiagnosed and untreated. Some small studies have suggested efficacy of 12 cognitive behavioral therapy (CBT) sessions. Our aim was to examine efficacy of brief CBT in reducing anxiety and depressive symptoms in patients with noncardiac chest pain and comorbid panic and/or depressive disorders.

Paradoxical embolization: a potential cause of cerebral damage in Alzheimer's disease?

Abstract Background: There are considerable overlaps between vascular dementia and Alzheimers disease (AD), with a suggestion that cerebrovascular disease (CVD) contributes to the neurodegenerative pathology of AD. Paradoxical embolization of venous emboli into the systemic circulation through a venous to arterial circulation shunt (v-aCS), the most commonly a patent foramen ovale (PFO), is known to cause cryptogenic stroke in younger people. We reviewed the potential role of paradoxical embolization in AD. Methods: A review of the literature on paradoxical embolization in neurological disorders and techniques to detect v-aCS and PFO, supplemented by data from our own studies. Results: Before our research, the role of paradoxical embolism in dementia had not been studied. The potential role of embolization in cerebral damage was highlighted by studies in patients undergoing coronary artery bypass or carotid surgery. Paradoxical embolization was found to occur in patients with cryptogenic stroke, migraine, decompression sickles and during hip surgery. The methods for detecting v-aCS or PFO had not been standardized. We found significant v-aCS (equivalent to PFO) in 32% of AD patients compared with 22% of controls, but the study was not sufficiently powered to test the statistic significance of this difference. In AD, there was evidence of an association between significant v-aCS and the severity of white matter hyperintensities on magnetic resonance imaging (MRI). Conclusion: Paradoxical embolization through a v-aCS may be a potentially preventable or treatable cause of CVD in AD.

Large normal-range TBP and ATXN7 CAG repeat lengths are associated with increased lifetime risk of depression

Depression is one of the most prevalent and debilitating psychiatric disorders worldwide. Recently, we showed that both relatively short and relatively long cytosine–adenine–guanine (CAG) repeats in the huntingtin gene (HTT) are associated with an increased risk of lifetime depression. However, to what extent the variations in CAG repeat length in the other eight polyglutamine disease-associated genes (PDAGs) are associated with depression is still unknown. We determined the CAG repeat sizes of ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7, TBP, ATN1 and AR in two well-characterized Dutch cohorts—the Netherlands Study of Depression and Anxiety and the Netherlands Study of Depression in Older Persons—including 2165 depressed and 1058 non-depressed individuals—aged 18–93 years. The association between PDAG CAG repeat size and the risk for depression was assessed via binary logistic regression. We found that the odds ratio (OR) for lifetime depression was significantly higher for individuals with >10, compared with subjects with ≤10, CAG repeats in both ATXN7 alleles (OR=1.90, confidence interval (CI) 1.26–2.85). For TBP we found a similar association: A CAG repeat length exceeding the median in both alleles was associated with an increased risk for lifetime depression (OR=1.33, CI 1.00–1.76). In conclusion, we observed that carriers of either ATXN7 or TBP alleles with relatively large CAG repeat sizes in both alleles had a substantially increased risk of lifetime depression. Our findings provide critical evidence for the notion that repeat polymorphisms can act as complex genetic modifiers of depression.

Antidepressants differentially related to 1,25-(OH)(2) vitamin D-3 and 25-(OH) vitamin D-3 in late-life depression

A low plasma 25-OH vitamin D3 level is a universal risk factor for a wide range of diseases and has also been implicated in late-life depression. It is currently unknown whether the biologically active form of vitamin D, that is, 1,25-(OH)2 vitamin D3, is also decreased in late-life depression, or whether vitamin D levels correlate with specific depression characteristics. We determined plasma 25-OH vitamin D3, 1,25-(OH)2 vitamin D3 and parathormone levels in 355 depressed older persons and 124 non-depressed comparison subjects (age⩾60 years). Psychopathology was established with the Composite International Diagnostic Interview 2.1, together with potential confounders and depression characteristics (severity, symptom profile, age of onset, recurrence, chronicity and antidepressant drug use). Adjusted for confounders, depressed patients had significantly lower levels of 25-OH vitamin D33 (Cohen’s d =0.28 (95% confidence interval: 0.07–0.49), P=0.033) as well as 1,25-(OH)2 vitamin D3 (Cohen’s d =0.48 (95% confidence interval: 0.27–0.70), P<0.001) than comparison subjects. Of all depression characteristics tested, only the use of tricyclic antidepressants (TCAs) was significantly correlated with lower 1,25-(OH)2 vitamin D3 levels (Cohen’s d =0.86 (95% confidence interval: 0.53–1.19), P<0.001), but not its often measured precursor 25-OH vitamin D3. As vitamin D levels were significantly lower after adjustment for confounders, vitamin D might have an aetiological role in late-life depression. Differences between depressed and non-depressed subjects were largest for the biologically active form of vitamin D. The differential impact of TCAs on 25-OH vitamin D3 and 1,25-(OH)2 vitamin D3 levels suggests modulation of 1-α-hydroxylase and/or 24-hydroxylase, which may in turn have clinical implications for biological ageing mechanisms in late-life depression.

A BRIEF COGNITIVE-BEHAVIORAL INTERVENTION FOR TREATING DEPRESSION AND PANIC DISORDER IN PATIENTS WITH NONCARDIAC CHEST PAIN: A 24-WEEK RANDOMIZED CONTROLLED TRIAL: Research Article: A Brief Cognitive-Behavioral Intervention

Most patients with noncardiac chest pain experience anxiety and depressive symptoms. Commonly they are reassured and referred back to primary care, leaving them undiagnosed and untreated. Some small studies have suggested efficacy of 12 cognitive behavioral therapy (CBT) sessions. Our aim was to examine efficacy of brief CBT in reducing anxiety and depressive symptoms in patients with noncardiac chest pain and comorbid panic and/or depressive disorders.

P01-362 - Dress induced by anti-epileptic drugs in the elderly population: delay in recognition

Background In the eldery population anti-epileptic drugs (AED) are used in epilepsy, neuralgiform pain, psychiatric disorders and behavioral problems in dementia. The prevalence of AED- treatment in the community is 1%; among nursing home residents 10%. A complex of adverse effects, known as Drug Reaction Eosinophilia and Systemic Symptoms (DRESS), is associated with several drugs, in particular AED. The incidence of DRESS syndrome is estimated between 1 in 1000 and 1 in 10000. DRESS syndrome has a high mortality rate (around 10%), primarily due to doctors delay in recognition. Case reports As AED-induced DRESS syndrome is rarely described in elderly patients, we describe two with dementia-related behavioural problems, treated with carbamazepine. Both patients developed severe rash, eosinophilia and fever after three weeks of administration. Patient 1 also developed anemia, diarrhoea and delirium; Patient 2 suffered from a severe edema of arms and face. Initially the clinical presentation of inflammatory and hypersensitivity symptoms was attributed to several diseases and/or medication other than carbamazepine. After recognition of DRESS by carbamazepine and stopping this drug, both patients fully recovered. Conclusions Recognition of DRESS syndrome induced by AED is difficult as the condition is rare, symptoms occur 1 to 8 weeks after start of treatment; there may be slow progression and similarity with infections and neoplastic disorders exists. Withdrawal of the offending drug is the primary treatment of the DRESS syndrome and patients relatives must be informed since the incidence of the DRESS syndrome is higher amongst first- degree relatives.