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Effects of stresses associated with extremely preterm birth may be biologically “recorded” in the genomes of individuals born preterm via changes in DNA methylation (DNAm) patterns. Genome-wide DNAm profiles were examined in buccal epithelial cells from 45 adults born at extremely low birth weight (ELBW; ≤1000 g) in the oldest known cohort of prospectively followed ELBW survivors (Mage = 32.35 years, 17 male), and 47 normal birth weight (NBW; ≥2500 g) control adults (Mage = 32.43 years, 20 male). Sex differences in DNAm profiles were found in both birth weight groups, but they were greatly enhanced in the ELBW group (77,895 loci) versus the NBW group (3,424 loci), suggesting synergistic effects of extreme prenatal adversity and sex on adult DNAm profiles. In men, DNAm profiles differed by birth weight group at 1,354 loci on 694 unique genes. Only two loci on two genes distinguished between ELBW and NBW women. Gene ontology (GO) and network analyses indicated that loci differentiating between ELBW and NBW men were abundant in genes within biological pathways related to neuronal development, synaptic transportation, metabolic regulation, and cellular regulation. Findings suggest increased sensitivity of males to long-term epigenetic effects of extremely preterm birth. Group differences are discussed in relation to particular gene functions.
Some studies have shown that alexithymic patients respond poorly to pharmacotherapy and that alexithymia may have a negative impact on the naturalistic course of psychiatric illnesses. The view that alexithymic patients are also less responsive to psychotherapy is often described in the literature, but few empirical studies have examined this issue, with inconsistent results.
We conducted two prospective studies (pre/post/follow-up) with patients with panic disorder and obsessive-compulsive disorder, to evaluate alexithymia as a potential predictor of the outcome of cognitive-behavioral therapy (CBT) including exposure response management. A further aim was to examine the absolute and relative stability of alexithymia.
Regression analyses revealed that alexithymia, as measured with the 20-item Toronto Alexithymia Scale, was related neither to the post-treatment nor to the follow-up outcome. The repeated measures ANOVA showed a significant decrease of alexithymia over time, even after controlling for depression. The high test-retest correlations of alexithymia total and factor scores indicated relative stability of this construct, suggesting that it is a stable personality trait rather than a state-dependent phenomenon in these patients.
The results are encouraging for cognitive-behavior therapists working with alexithymic patients with panic disorder and obsessive-compulsive disorder, since the CBT outcome of these patients does not appear to be negatively affected by alexithymia. Furthermore, some alexithymic characteristics may decrease during CBT, even when the therapy program is not specifically directed to alexithymia. Future controlled studies should examine whether these improvements of alexithymia are due to psychotherapeutic interventions, in particular exposure therapy.
Purpose of this study was to assess subjective well-being in schizophrenia inpatients and to find variables predictive for response and remission of subjective well-being.
The subjective well-being under neuroleptic treatment scale (SWN-K) was used in 232 schizophrenia patients within a naturalistic multicenter trial. Early response was defined as a SWN-K total score improvement of 20% and by at least 10 points within the first 2 treatment weeks, response as an improvement in SWN-K total score of at least 20% and by at least 10 points from admission to discharge and remission in subjective well-being as a total score of more or equal to 80 points at discharge. Logistic regression and CART analyses were used to determine valid predictors of subjective well-being outcome.
Twenty-nine percent of the patients were detected to be SWN-K early responders, 40% fulfilled criteria for response in subjective well-being and 66% fulfilled criteria for remission concerning subjective well-being. Among the investigated predictors, SWN-K early improvement and the educational status were significantly associated with SWN-K response. The SWN-K total score at baseline showed a significant negative predictive value for response. Baseline SWN-K total score, PANSS global subscore, and side effects as well as the educational status were found to be significantly predictive for remission.
Depressive symptoms should be radically treated and side effects closely monitored to improve the patient's subjective well-being. The important influence of subjective well-being on overall treatment outcome could be underlined.
This guidance paper from the European Psychiatric Association (EPA) aims to provide evidence-based recommendations on early intervention in clinical high risk (CHR) states of psychosis, assessed according to the EPA guidance on early detection. The recommendations were derived from a meta-analysis of current empirical evidence on the efficacy of psychological and pharmacological interventions in CHR samples. Eligible studies had to investigate conversion rate and/or functioning as a treatment outcome in CHR patients defined by the ultra-high risk and/or basic symptom criteria. Besides analyses on treatment effects on conversion rate and functional outcome, age and type of intervention were examined as potential moderators. Based on data from 15 studies (n = 1394), early intervention generally produced significantly reduced conversion rates at 6- to 48-month follow-up compared to control conditions. However, early intervention failed to achieve significantly greater functional improvements because both early intervention and control conditions produced similar positive effects. With regard to the type of intervention, both psychological and pharmacological interventions produced significant effects on conversion rates, but not on functional outcome relative to the control conditions. Early intervention in youth samples was generally less effective than in predominantly adult samples. Seven evidence-based recommendations for early intervention in CHR samples could have been formulated, although more studies are needed to investigate the specificity of treatment effects and potential age effects in order to tailor interventions to the individual treatment needs and risk status.
Data about quality of life (QoL) are important to estimate the impact of diseases on functioning and well-being. The present study was designed to assess the association of different aspects of panic disorder (PD) with QoL and to examine the relationship between QoL and symptomatic outcome following brief cognitive-behavioral group therapy (CBGT).
The sample consisted of 55 consecutively recruited outpatients suffering from PD who underwent CBGT. QoL was assessed by the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36) at baseline, post-treatment and six months follow-up. SF-36 baseline scores were compared with normative data obtained from a large German population sample.
Agoraphobia, disability, and worries about health were significantly associated with decreased QoL, whereas frequency, severity and duration of panic attacks were not. Treatment responders showed significantly better QoL than non-responders. PD symptom reduction following CBGT was associated with considerable improvement in emotional and physical aspects of QoL. However, the vitality subscale of the SF-36 remained largely unchanged over time.
Our results are encouraging for cognitive-behavior therapists who treat patients suffering from PD in groups, since decrease of PD symptoms appears to be associated with considerable improvements in QoL. Nevertheless, additional interventions designed to target specific aspects of QoL, in particular vitality, may be useful to enhance patients’ well-being.
Responsiveness of quality of life (QOL) assessments in chronic schizophrenic patients was investigated by a quasi-experimental pilot study. Satisfaction ratings were assessed over five time points with an externally imposed disturbing stimulus at the second time point. Despite a markedly high stability, the disturbance provoked a temporally limited decrease in QOL.
The aim of this guidance paper of the European Psychiatric Association is to provide evidence-based recommendations on the early detection of a clinical high risk (CHR) for psychosis in patients with mental problems. To this aim, we conducted a meta-analysis of studies reporting on conversion rates to psychosis in non-overlapping samples meeting any at least any one of the main CHR criteria: ultra-high risk (UHR) and/or basic symptoms criteria. Further, effects of potential moderators (different UHR criteria definitions, single UHR criteria and age) on conversion rates were examined. Conversion rates in the identified 42 samples with altogether more than 4000 CHR patients who had mainly been identified by UHR criteria and/or the basic symptom criterion ‘cognitive disturbances’ (COGDIS) showed considerable heterogeneity. While UHR criteria and COGDIS were related to similar conversion rates until 2-year follow-up, conversion rates of COGDIS were significantly higher thereafter. Differences in onset and frequency requirements of symptomatic UHR criteria or in their different consideration of functional decline, substance use and co-morbidity did not seem to impact on conversion rates. The ‘genetic risk and functional decline’ UHR criterion was rarely met and only showed an insignificant pooled sample effect. However, age significantly affected UHR conversion rates with lower rates in children and adolescents. Although more research into potential sources of heterogeneity in conversion rates is needed to facilitate improvement of CHR criteria, six evidence-based recommendations for an early detection of psychosis were developed as a basis for the EPA guidance on early intervention in CHR states.
Ghrelin showed antidepressant-like effects in mice. Furthermore, ghrelin influences sleep and the activity of hypothalamic-pituitary-adrenal (HPA) and somatotropic axis in healthy humans as indicated by increased cortisol and growth hormone (GH) plasma levels. Both sleep and the activity of these endocrine axes are disturbed in depression.
To study the effect of ghrelin on psychopathology, sleep and secretion of cortisol and GH in patients with major depression.
Depressive symptoms as assessed by a validated self rating scale (’Befindlichkeits-Skala’, [well-being scale]), secretion profiles of cortisol and GH and sleep-EEGs were determined in 14 unmedicated patients with major depression (7 women) twice, receiving 50 μg ghrelin or placebo at 2200, 2300, 0000, and 0100 hours.
Overall, depressive symptoms did not change significantly after ghrelin administration (placebo: 37 ± 8; ghrelin: 33 ± 10, p = 0.178). However, there was an improvement at trend level in men (placebo: 36 ± 9 to ghrelin: 30 ± 9, p = 0.093) but not in women. In men, ghrelin was associated with less time awake (placebo: 149.0 ± 11.1; ghrelin: 88.0±12.2 min, p = 0.029) and more non-REM sleep (placebo: 263.2 ± 24.1; ghrelin: 304.9 ± 14.1 min, p = 0.027), in women with less REM sleep (placebo: 108.6 ± 15.7; ghrelin: 74.1 ± 13.8 min, p = 0.031) and longer REM latency (placebo: 49.9 ± 6.5; ghrelin: 85.6 ± 14.1 min, p = 0.019). In both sexes, ghrelin caused strong transient increases of GH and cortisol.
Our study may provide an initial indication that ghrelin can exert antidepressant effects in patients with major depression. Ghrelin strongly affected sleep and secretion of GH and cortisol in a partly different way as previously reported in healthy subjects.
RGH-188 is an orally active, potent dopamine D3/D2 receptor antagonist/partial agonist atypical antipsychotic for the treatment of schizophrenia and bipolar mania.
RGH-188 displayed high affinity to human D3 receptors (Ki: 0.085 nM) and approximately six- and thirty-times less affinity to human D2, and 5-HT1A receptors. In various in vitro and in vivo assays RGH-188 behaved either as an antagonist or as a partial agonist on dopamine D3 and D2 receptors.
RGH-188 displayed potent antipsychotic activity (0.1-0.8 mg/kg) in rodent models such as apomorphine-induced climbing, amphetamine- and phencyclidine-induced hypermotility, conditioned avoidance response. It significantly improved the learning performance of rats (0.02-0.2 mg/kg) impaired by scopolamine in a water-labyrinth learning paradigm. RGH-188 showed no EPS liability as it produced no catalepsy up to 100-fold therapeutic range.
In a nonhuman primate positron emission tomography (PET) study using 11C-raclopride RGH-188 occupied striatal D2/D3 receptors in a dose dependent and saturable manner with an ED50 of 7 μg/kg iv. In healthy male subjects multiple administration of 1 mg RGH-188 resulted in over 70% D2/D3 receptor occupancy and the displacement showed correlation with RGH-188 and metabolites plasma levels.
After single administration to healthy volunteers, Tmax for RGH-188 was 3-4 hours and the terminal disposition half-life was 5-6 days. Over the dose range of 0.5-2.5 mg AUC of the parent drug was approximately dose-proportional. Systemic exposure to the pharmacologically active metabolites, desmethyl- and didesmethyl-RGH-188 was 20-30% and 50-200% of that to the parent, respectively.
To examine the predictive validity of early improvement in a naturalistic sample of inpatients and to identify the criterion that best defines early improvement.
Two hundred and forty-seven inpatients who fulfilled ICD-10 criteria for schizophrenia were assessed with the Positive And Negative Syndrome Scale (PANSS) at admission and at biweekly intervals until discharge from hospital. Remission was defined according to the recently proposed consensus criteria, response as a reduction of at least 40% in the PANNS total score from admission to discharge.
Receiver operating characteristic (ROC) analyses showed that early improvement (reduction of the PANSS total score within the first 2 weeks of treatment) predicts remission (AUC = 0.659) and response (AUC = 0.737) at discharge. A 20% reduction in the PANSS total score within the first 2 weeks was the most accurate cut-off for the prediction of remission (total accuracy: 65%; sensitivity: 53%; specificity: 76%), and a 30% reduction the most accurate cut-off for the prediction of response (total accuracy: 76%; sensitivity: 47%; specificity: 90%).
The findings of clinical drug trials that early improvement is a predictor of subsequent treatment response were replicated in a naturalistic sample. Further studies should examine whether patients without early improvement benefit from an early change of antipsychotic medication.
The hypothesis that tardive dyskinesias observed after long-term administration of neuroleptics are due to the formation of free radicals following this medication has prompted studies on the use of vitamin E (α-tocopherol), an antioxidant to treat patients suffering from such side-effects. The present study aimed at reproducing earlier encouraging results in treating 23 patients with vitamin E, using a double-blind crossover design. Inclusion criteria were: duration of tardive dyskinesia for at least 3 months, appearance of the symptoms during neuroleptic treatment or after stopping this kind of medication. The 10 subjects in the first group (Gl) were treated for 14 days with 1 200 mg vitamin E per day and then for 14 days with placebo. For the second group (G2) with 9 subjects, the treatment periods were inversed. The 2 dropouts in each group were not due to experimental problems: there was no complication due to vitamin E intake, or only negligible side-effects. Side-effects were rated on the AIM scale on days 0, 14 and 28. The results of the present study do not confirm earlier reports: there was no significant difference in the therapeutic effect between placebo and vitamin E in any of the groups. However, the fact of taking these symptoms into account in the physician-patient relationship has contributed significantly to a decrease of tardive dyskinesia in both groups, from the beginning until the end of the investigation period, during which both neuroleptic and tranquilizing treatments were kept constant. Further studies should include longer treatment periods with vitamin E or even test the preventive effect of vitamin E in the production of tardive dyskinesia by neuroleptics.