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The first generation of genome-wide association studies (GWA studies) for psychiatric disorders has led to new insights regarding the genetic architecture of these disorders. We now start to realize that a larger number of genes, each with a small contribution, are likely to explain the heritability of psychiatric diseases. The contribution of a large number of genes to complex traits can be analyzed with genome-wide profiling. In a discovery sample, a genetic risk profile for depression was defined based on a GWA study of 1738 adult cases and 1802 controls. The genetic risk scores were tested in two population-based samples of elderly participants. The genetic risk profiles were evaluated for depression and anxiety in the Rotterdam Study cohort and the Erasmus Rucphen Family (ERF) study. The genetic risk scores were significantly associated with different measures of depression and explained up to ∼0.7% of the variance in depression in Rotterdam Study and up to ∼1% in ERF study. The genetic score for depression was also significantly associated with anxiety explaining up to 2.1% in Rotterdam study. These findings suggest the presence of many genetic loci of small effect that influence both depression and anxiety. Remarkably, the predictive value of these profiles was as large in the sample of elderly participants as in the middle-aged samples. [ABSTRACT FROM AUTHOR]

A recently developed oral serotonergic challenge test consisting of 5-Hydroxytryptophane (5-HTP, 200 mg) combined with carbidopa (CBD, 100 mg + 50 mg) exhibited dose-related neuroendocrine responsiveness and predictable pharmacokinetics. However, its applicability is limited by nausea and vomiting. A randomized, double-blind, placebo-controlled, four-way crossover trial was performed in 12 healthy male volunteers. The 5-HTP/CBD-challenge was combined with two oral anti-emetics (granisetron, 2 mg or domperidone, 10 mg) to investigate its reliability when side-effects are suppressed. The neuroendocrine response (serum cortisol and prolactin), the side-effect profile [Visual Analogue Scale Nausea (VAS)] and vomiting subjects per treatment were the main outcome measures. Compared to 5-HTP/CBD/placebo, 5-HTP/CBD/ granisetron had no impact on cortisol [% change with 95% confidence interval: -7.1% (18.9; 6.5)] or prolactin levels [-9.6% (-25.1; 9.1)]; 5-HTP/CBD/domperidone increased cortisol [+13.0% (-4.2; 33.4)], and increased prolactin extensively [+336.8% (245.7; 451.9)]. Compared to placebo, VAS Nausea increased non-significantly with granisetron [+7.6 mm (-1.3; 16.5)], as opposed to domperidone [+16.2 mm (7.2; 25.2)] and 5-HTP/CBD/placebo [+14.7 mm (5.5; 23.8)]. No subjects vomited with granisetron, compared to two subjects treated with 5-HTP/CBD/placebo and five subjects with domperidone. Compared with 5-HTP/CBD/placebo, granisetron addition decreased Cmax of 5-HTP statistically significantly different (from 1483 to 1272 ng/ml) without influencing AUC0-∞. Addition of granisetron to the combined 5-HTP/CBD challenge suppresses nausea and vomiting without influencing the neuroendocrine response or pharmacokinetics, enhancing its clinical applicability in future psychiatric research and drug development. [ABSTRACT FROM AUTHOR]

The neuropeptide vasopressin is centrally involved in the regulation of social behaviour and response to stress. We previously found support for a subcategory of depression defined by above-normal plasma vasopressin (AVP) concentration. This subcategory is validated by a positive family history of depression and correlating plasma AVP and cortisol concentrations. The data support the validity of above-normal plasma AVP concentration as a genetically determined biological marker for a subcategory of depression. The aim of the present study was to test whether above-normal plasma AVP concentration in depression is related to personality characteristics reflecting a specific social behaviour style. The data of 78 patients from a previously investigated sample were reanalysed. Fifty-eight patients were available after 2 years, 15 of whom with initially above-normal plasma AVP. The dimensions of the Temperament and Character Inventory (TCI) were scored, with particular focus on the dimensions of Cooperativeness (CO) and Reward-dependence (RD). Normative subjects and other depressed subjects were used as controls. After full remission, patients with initially above-normal AVP had low CO compared with normal and patient controls. During depression, these patients had both low CO and low RD compared with normal controls and low RD compared with patient controls. Low CO is a presumably premorbid trait and reduced RD a state-dependent characteristic in depression with above-normal plasma AVP. The low CO further supports the validity of above-normal plasma AVP concentration as a genetically determined biological marker for a subcategory of depression. [ABSTRACT FROM AUTHOR]

5-hydroxytryptophan (5-HTP) is a direct 5-hydroxytryptamine (5-HT) precursor used to assess central serotonergic function. Its use has been limited by a narrow window between neuroendocrine changes and side effects, and variable kinetics related to inconsistent administration modes. By combining 5-HTP with carbidopa (CBD), increased bioavailability for brain penetration and decreased peripheral side effects would be expected, due to reduced peripheral decarboxylation of 5-HTP to 5-HT. A doubleblind, placebo-controlled, single rising dose, four-way crossover trial with placebo randomisation was performed in 15 healthy male volunteers to investigate the neuroendocrine dose-response relationship at various 5-HTP levels; the tolerability and subjective effects of oral 5-HTP at 100, 200 and 300mg combined with CBD and the pharmacokinetic properties of the 5-HTP/CBD-challenge. Dose-dependent increases in average cortisol concentrations were observed. Mean response (area-under-thecurve) over the first 4 hours (SD): 172.0nmol/L (22.3) for placebo, 258.3nmol/L (72.6) for 100mg, 328.47nmol/L (84.6) for 200mg and 387.3nmol/L (82.4) for 300mg 5-HTP. Similar dose-dependent increases for prolactin were seen while adreno-corticotrophic hormone response was more variable. 5-HTP kinetics were adequately described using a one-compartment model with first-order absorption and a lag time (mean oral clearance 28 L/h ± interindividual coefficient of variation 31%). Nausea and vomiting occurred dose-dependently as most frequent side effects, resulting in dose-related dropout of 6.6% at 100mg and 45.5% at 300mg 5-HTP. Orally administered 5-HTP combined with CBD is an effective serotonergic challenge test, exhibiting dose-related plasma concentrations and neuroendocrine responsiveness. Frequent occurrence of nausea and vomiting limits the applicability of this challenge at 5-HTP doses above 100mg. [ABSTRACT FROM AUTHOR]

Background: Contrary to short-term use, long-term benzodiazepine use is undesirable. Nevertheless, its prevalence is high. To prevent long-term use, it is important to know which short-term users are at risk of becoming long-term users.Objectives: The purpose of the present study was to identify patient-related factors of long-term versus short-term use of benzodiazepines.Methods: A cross-sectional study was carried out in family practices among users of benzodiazepines with regard to DSM-IV diagnosis, coping and psychosocial characteristics,. In a multivariate logistic regression analysis, long-term use of benzodiazepines was the dependent variable.Results: A total of 164 short-term and 158 long-term benzodiazepine users participated in the study. Having a DSM-IV disorder and psychiatric co-morbidity, being older, less educated, lonely and using more avoidance coping behaviour was associated with long-term use of benzodiazepines compared with short-term use.Conclusion: The associations found point to possibilities to reduce long-term benzodiazepine use, for example if patients with these characteristics are treated with the alternatives to benzodiazepines or are monitored closely for a short period after being prescribing benzodiazepines. [ABSTRACT FROM AUTHOR]

Background: Benzodiazepine withdrawal programmes have never been experimentally compared with a nonintervention control condition.Aims: To evaluate the efficacy and feasibility of tapering off long-term benzodiazepine use in general practice, and to evaluate the value of additional group cognitive-behavioural therapy (CBT).Method: A 3-month randomised, 3-month controlled trial was conducted in which 180 people attempting to discontinue long-term benzodiazepine use were assigned to tapering off plus group CBT, tapering off alone or usual care.Results: Tapering off led to a significantly higher proportion of successful discontinuations than usual care (62% nu. 21%). Adding group CBT did not increase the success rate (58% v. 62%). Neither successful discontinuation nor intervention type affected psychological functioning. Both tapering strategies showed good feasibilityin general practice.Conclusions: Tapering off is a feasible and effective way of discontinuing long-term benzodiazepine use in general practice. The addition of group CBT is of limited value. [ABSTRACT FROM AUTHOR]

Background: Many patients with depression take benzodiazepine drugs long term despite the absence of continuing therapeutic value.Aims: To evaluate a treatment programme involving gradual discontinuation with or without simultaneous selective serotonin reuptake inhibitor (SSRI) prescribing and to determine the long-term outcome after benzodiazepine withdrawal.Method: Patients went through three phases - change to an equivalent dose of diazepam; subsequent randomisation to either 20 mg of paroxetine or placebo; and gradual reduction of diazepam in depression-free patients - with a follow-up after 2 or 3 years.Results: A total of 230 patients were recruited and 75% in the paroxetine group and 61% in the placebo group were successfully treated after 6 weeks (P:=0.067). After 2 or 3 years 13% of patients were still benzodiazepine free: 26% of those who had successfully tapered off benzodiazepine and 6% of the total group.Conclusions: Transfer to diazepam followed by gradual withdrawal is an effective way of discontinuing chronic benzodiazepine use. The addition of SSRI treatment is of limited value. [ABSTRACT FROM AUTHOR]