Age-of-onset (AO) seems to be a phenotypic variable with a strong genetic component and therefore useful in molecular analysis of bipolar disorder (BP). A debate about the cut-off point for defining early AO has developed over the last few years. Using an Expectation-Maximization algorithm Bellivier et al. (2001) found the best fit for a model with three onset-groups, proposing the age 20-21 as cut-off for early onset, while using the same algorithm Kennedy et al. (2005) found the best fit for a two onset-group model with age 40 as cut-off with an incidence peak for mania in the age-band 21-25. Based on segregation analysis, we proposed a two AO-group model with cut-off age 25 for early onset (Grigoroiu-Serbanescu et al. 2001). The present study aimed at investigating the best AO-model in 500 Romanian BPI and 1458 German BPI patients using commingling analysis (SAGEv6.01-software) (Elston et al, 2009). The best model was selected according to Akaike's Information Criterion (AIC).

The two AO-group and three AO-group models provided similar AIC-values both in the Romanian and the German sample. The Romanian early-onset group (40% cases) had means around 18 years, SDs=6-7, while in the German early-onset group the mean AO was around 20 years (SDs=9-11) (50% cases). Thus the cut-off for early-onset (X +1SD) was different.

Our results overlapped with the findings of Kennedy et al (2005) showing that two-curve and three-curve AO mixtures similarly fit the AO-distribution in BPI disorder and the cut-offs for early-onset differ by sample.

To evaluate open-label treatment with olanzapine in patients with borderline personality disorder (BPD).

In two concurrent studies, patients received 12 weeks of open-label olanzapine after completing 12-weeks of double-blind treatment with either olanzapine or placebo. Open-label olanzapine dosing started at 2.5 or 5mg/day and could be increased up to 20mg/day (Study 1) or 15mg/day (Study 2).

Mean ZAN-BPD total scores decreased from approximately 17 points to approximately 8-10 points during the acute phase. After 12 weeks of open-label olanzapine treatment, mean ZAN-BPD total scores were approximately 6-7 points. Patients treated with placebo during the acute phase and then open-label olanzapine showed changes in weight, prolactin, and other laboratory values similar in magnitude to those seen in acutely olanzapine-treated patients. Patients treated with olanzapine during the acute phase showed smaller changes in weight and laboratory values during the open-label extension.

Overall BPD symptom severity was low by the end of the open-label olanzapine treatment period. The types of treatment emergent adverse events appeared to be consistent with those seen previously in patients treated with olanzapine. The direction and magnitude of effects on safety measures depended on the treatment received during the prior double-blind period.

Neuropsychological deficits are considered endophenotypes for schizophrenia, because they are not only found in patients but also in many of their unaffected relatives, albeit in attenuated form. It is not yet clear which of these deficits in relatives are related to genetic or to environmental causes. We tested effects of inferred genetic liability for schizophrenia on neurocognitive variables to address this problem.

Twenty-eight patients with schizophrenia, 129 non-affected biological parents and 143 matched controls were assessed with an extensive neuropsychological test battery including tests of attention, memory, executive functioning and motor soft signs. Twenty-two parents had an ancestral history of schizophrenia and therefore were hypothesized to be more likely than their spouses without such a history (n = 17) to carry a genetic risk for schizophrenia.

Unaffected parents of schizophrenic patients showed significant deficits in a wide array of neuropsychological tasks and task domains. However, comparison of more likely and less likely carriers of illness-related genes showed specifically attentional and executive functioning, but not memory, to vary with degree of inferred genetic loading.

Attentional and executive (frontal) impairments vary with genetic loading for schizophrenia and can be considered true endophenotypes for this disorder. Consequently, these functions are particularly suited to evaluate the functional impact of candidate genes for schizophrenia in future studies.

We examined the efficacy and safety of flexibly-dosed olanzapine for the treatment of borderline personality disorder (BPD).

In this 12-week double-blind trial, patients 18-65 years of age with a diagnosis of DSM-IV BPD received olanzapine (2.5-20mg/day; N=155) or placebo (N=159). The primary efficacy measure was the change from baseline to last-observation carried forward endpoint (LOCF) on the Zanarini Rating Scale for BPD (ZAN-BPD) total score. Rate of response and time to response were also examined, with response defined as a >=50% reduction in ZAN-BPD total score.

Mean baseline ZAN-BPD total scores were indicative of moderate symptom severity (olanzapine 17.01 vs. placebo 17.70, p=0.156). Both treatment groups showed significant improvements in overall symptom severity, based on mean changes from baseline to LOCF endpoint in ZAN-BPD total score, but did not differ in the magnitude of improvement at endpoint (olanzapine -6.56 vs. placebo -6.25, p=.661). Response rates did not differ between treatment groups (olanzapine 64.7% vs. placebo 53.5%, p=.062); however, time to response was significantly shorter for the olanzapine treatment group (p=.022). Treatment-emergent adverse events reported significantly more frequently among olanzapine-treated patients included somnolence, sedation, increased appetite and weight increase. Mean weight change from baseline to endpoint was significantly different for olanzapine- relative to placebo-treated patients (2.86vs. -0.35kg, p<.001).

Both the olanzapine- and placebo-treated patients showed significant but not statistically different improvement on overall symptoms of borderline personality disorder. The types of adverse events observed with olanzapine treatment were similar to those seen previously in adult populations.

Neurocognitive and functional neuroimaging studies point to frontal lobe abnormalities in schizophrenia. Molecular and behavioural genetic studies suggest that the frontal lobe is under significant genetic influence. We carried out structural magnetic resonance imaging (MRI) of the frontal lobe in monozygotic (MZ) twins concordant or discordant for schizophrenia and healthy MZ control twins.

The sample comprised 21 concordant pairs, 17 discordant affected and 18 discordant unaffected twins from 19 discordant pairs, and 27 control pairs. Groups were matched on sociodemographic variables. Patient groups (concordant, discordant affected) did not differ on clinical variables. Volumes of superior, middle, inferior and orbital frontal gyri were calculated using the Cavalieri principle on the basis of manual tracing of anatomic boundaries. Group differences were investigated covarying for whole-brain volume, gender and age.

Results for superior frontal gyrus showed that twins with schizophrenia (i.e. concordant twins and discordant affected twins) had reduced volume compared to twins without schizophrenia (i.e. discordant unaffected and control twins), indicating an effect of illness. For middle and orbital frontal gyrus, concordant (but not discordant affected) twins differed from non-schizophrenic twins. There were no group differences in inferior frontal gyrus volume.

These findings suggest that volume reductions in the superior frontal gyrus are associated with a diagnosis of schizophrenia (in the presence or absence of a co-twin with schizophrenia). On the other hand, volume reductions in middle and orbital frontal gyri are seen only in concordant pairs, perhaps reflecting the increased genetic vulnerability in this group.

We examined the efficacy and safety of low vs. moderate olanzapine doses for the treatment of borderline personality disorder (BPD) in the largest controlled clinical trial ever conducted in this population.

This 12-week, double-blind trial involved patients 18-65 years with a diagnosis of DSM-IV BPD randomized to receive 2.5mg/day olanzapine (N=150), 5-10mg/day olanzapine (N=148), or placebo (N=153). The primary efficacy measure was the change from baseline-to-endpoint (last-observation-carried-forward) on the Zanarini Rating Scale for BPD (ZAN-BPD) total score. Rate of response and time-to-response were also examined (response defined as a >=50% reduction in ZAN-BPD total score).

Mean baseline ZAN-BPD total scores ranged from 17.01 to 17.42, indicating moderate symptom severity. Treatment with OLZ5-10 was associated with significantly greater mean change from baseline-to-endpoint in ZAN-BPD total score than placebo (-8.50 vs. -6.79, p=.010). Response rates were significantly higher for OLZ5-10 (73.6%) than for OLZ2.5 (60.1%, p=.018) and placebo (57.8%, p=.006). Time-to-response was significantly shorter for OLZ5-10 than placebo (p=.028). Treatment-emergent adverse events seen more frequently in the olanzapine groups included somnolence, increased appetite, and weight gain. Mean weight change from baseline-to-endpoint was 2.09kg for OLZ 2.5, 3.17kg for OLZ5-10, and 0.02kg for placebo.

The results of this study suggest that moderate doses of olanzapine (5-10mg/day) are effective in the treatment of overall borderline psychopathology. Also, the types of adverse events observed with olanzapine treatment were similar to those seen previously in adult populations.

Significant alterations of cardiac autonomic function were shown for patients with schizophrenia and their first-degree relatives, implying a genetic association. Cardio-respiratory function, although a core physiological regulatory component, has never been assessed.

To test the hypothesis of altered patterns of breathing in patients with acute schizophrenia, we assessed breathing rate, rhythm and depth, as well as heart rate variability (HRV) and cardio-respiratory coupling in patients (n = 23), their first-degree relatives (n = 20) and controls (n = 30). Control subjects were matched for age, gender, smoking and physical fitness, and were investigated a second time by means of a stress task to identify stress-related changes of cardio-respiratory function.

Patients breathe faster (p < .001) and shallower (p < .001) than controls most pronouncedly during exhalation. Patients' breathing is characterized by an increased amount of middle- (p < .001), high- (p < .001), and very high fluctuations (p < .001). These measures correlated with positive symptoms. Shallow breathing of patients is mirrored by a smaller tidal volume (p < .001) without variability changes. Cardio-respiratory coupling was reduced in patients only, while HRV was decreased in patients and healthy relatives.

Changes of respiratory regulation and decreased cardio-respiratory coupling mirror profound alterations of core physiological function. In contrast to HRV changes, respiratory alterations were observed in patients only and might reflect arousal in acutely ill patients. This assumption is supported by observed changes of breathing and cardiac regulation in healthy subjects during stress. Findings are of high relevance for other research areas such as functional imaging.

Based on the vulnerability–stress model, we aimed to (1) determine new onset of depression in individuals who had not shown evidence of depression at baseline (5 years earlier) and (2) identify social, psychological, behavioral, and somatic predictors.

Longitudinal data of N = 10 036 participants (40–79 years) were evaluated who had no evidence of depression at baseline based on Patient Health Questionnaire (PHQ-9), no history of depression, or intake of antidepressants. Multivariate logistic regression models were used to predict the onset of depression.

Prevalence of new cases of depression was 4.4%. Higher rates of women (5.1%) than men (3.8%) were due to their excess incidence <60 years of age. Regression analyses revealed significant social, psychological, behavioral, and somatic predictors: loneliness [odds ratio (OR) 2.01; 95% confidence interval (CI) 1.48–2.71], generalized anxiety (OR 2.65; 1.79–3.85), social phobia (OR 1.87; 1.34–2.57), panic (OR 1.67; 1.01–2.64), type D personality (OR 1.85; 1.47–2.32), smoking (OR 1.35; 1.05–1.71), and comorbid cancer (OR 1.58; 1.09–2.24). Protective factors were age (OR 0.88; 0.83–0.93) and social support (OR 0.93; 0.90–0.95). Stratified by sex, cancer was predictive for women; for men smoking and life events. Entered additionally, the PHQ-9 baseline score was strongly predictive (OR 1.40; 1.34–1.47), generalized anxiety became only marginally, and panic was no longer predictive. Other predictors remained significant, albeit weaker.

Psychobiological vulnerability, stress, and illness-related factors were predictive of new onset of depression, whereas social support was protective. Baseline subclinical depression was an additional risk weakening the relationship between anxiety and depression by taking their overlap into account. Vulnerability factors differed between men and women.