Comparing 7-year outcome of early antipsychotic dose-reduction/discontinuation (DR) with maintenance treatment (MT) on remission, relapse and recovery in remitted first episode psychosis (FEP).

FEP patients (N=128) symptomatically remitted for 6m during their first treatment year who completed an 18 months trial comparing MT and DR were followed-up at 7 years. Symptomatic remission criteria were adopted from Andreasen et al., functional remission criteria were based on a functioning scale. Recovery was defined as meeting both criteria sets. MT or DR strategy, and baseline parameters were entered in a logistic regression analysis with symptom and functional remission and recovery at 7-years follow-up as dependent variables.

103 patients consented to participate. DR-patients showed twice the recovery-rate of MT-patients (40% against 18%), odds ratio 3.5 (P=.014). Symptomatic remission-rates were equal (69% and 67%). Better DR recovery-rates were attributable to higher functional remission-rates (46% vs. 20%) in DR. Predictors of recovery were DR, baseline living together and less severe negative symptoms. During the last 2 years of follow-up the mean daily dose in haloperidol equivalents was 2.20mg in DR vs. 3.60mg in MT (P=.031).

Relapse-rates were initially higher in DR but leveled at 3 years; 61.5% relapsed in DR and 68.6% in MT in 7 years.

DR of antipsychotics during early stages of remitted FEP significantly improved 7-years outcome in terms of recovery and functional remission compared to maintenance treatment. Though initially relapse-rates in GD were higher, these equaled those in MT from 3 years to the end of the study.

Despite therapeutic advances, unipolar depression and bipolar disorder are among the most debilitating psychiatric disorders. Unfortunately, lacking knowledge about the underlying pathophysiology limit early identification and indicated prevention efforts. Therefore, early characterization of the ‘prodromal” (subsyndromal) stages of depression and, especially, bipolar mania have attracted increasing attention, especially in youth, given the early age of first depression and bipolar disorder symptom onset.

Review of phenomenological manifestations of the prodromal stages preceding syndromal unipolar depression and bipolar disorder, including antecedent and comorbid conditions.

While offspring mood disorder studies are ongoing, clinical ‘high-risk” mood disorder research is relatively new. So far, retrospective and early prospective data suggest that a clinical prodrome exits in a sizeable patient group of patients subsequently developing unipolar depression and bipolar disorder. Moreover, phenomenologically, the early clinical depression or mania prodrome includes character traits that may become more pronounced, non-specific symptoms of decreasing role and social functioning, as well as subthreshold depressive and/or attenuated (hypo)mania-like symptoms (especially mood swings/lability, racing thoughts and sleep abnormalities). Frequent comorbidities that overlap with mood disorder criteria, the fact that several concurrent supratheshold symptoms can coexist that are still subthreshold for the full mood disorder and the episodicity of emerging as well as full mood symptoms are complicate the identification of the mood disorder prodrome.

Data suggest that a relevant proportion of patients ultimately developing unipolar depression or bipolar disorder presents with a clinically identifiable depressive or (hypo)mania ‘prodromal” symptom stage that may enable indicated prevention. Prospective clinical and biological risk marker studies, utilizing specific instruments that target at-risk phenomenology are needed to advance the clinical high-risk and prevention approach for mood disorders.

After two decades of research, prevention of psychosis becomes increasingly accepted in clinical psychiatry. However, there are still unmet scientific and clinical needs. Therefore, guidance for prediction as well as prevention is required, reflecting their current capabilities, but also their requirements and limitations.

Evaluating the current state of risk estimation and prevention.

Developing clinical recommendations for the prediction and prevention of psychosis.

42 samples, mainly defined by ultra-high risk criteria and/or the basic symptoms criterion ‘COGDIS‘, were included into meta-analyses of prevention, 15 studies into meta-analyses of prevention.

The pooled conversion rate at >4-year follow-up was 37.0% in UHR and 61.3% in COGDIS samples. The 12-month pooled risk ratio was 0.44, the NNT 10. Psychosocial functioning seemed not to improve, however results were inconclusive due to methodological issues of the trials. Both meta-analyses indicated age related differences.

Several recommendations were developed to guide prediction and prevention, emphasizing age-adapted strategies; details will be presented and discussed during the symposium.

Regarding future steps to further improve prediction and thus prevention, neurocognitive and neurobiological parameters of information processing, i.e. mismatch negativity, P300 and processing speed, as well as support vector machine based analysis of structural MRI seem to be most promising. Furthermore, with regard to current developmental models of psychotic disorders, risk should be conceptualized as dynamically modulated over time and thus presumably non-linearly related to future outcome. Therefore, studies need to consider the fluid interplay of risk and resilience factors to advance prediction significantly.

An association between Toxoplasma gondii (T. gondii) and schizophrenia has been shown by a meta-analysis showing a significant Odds Ratio (OR) of 2.7. Currently, several studies have looked at the association between T. gondii and other psychiatric disorders as well, rendering exploration of diagnostic specificity possible. Furthermore, questions remain on the timing and nature of the infection.

A systematic search was performed to identify relevant studies of all major psychiatric disorders versus healthy controls in relation to T. gondii infection. Methodological quality, heterogeneity and risk of bias were assessed.

A total of 2866 studies were found, from which 51 studies were finally included. Significant ORs were found for Schizophrenia, Bipolar Disorder, OCD and Addiction, but not for Major Depression. Further exploration of the association between T. gondii and schizophrenia, yielded a significant association of seropositivity before onset of psychosis and with high antibody titers. A decline of the association was found when baseline exposure in the healthy control population increased.

These findings suggest that T. gondii infection is not merely associated with psychosis and that in schizophrenia a reactivation of a latent T. gondii infection occurs. Several hypotheses remain open about the nature of this association.

Immune mechanisms have been implicated in the pathogenesis of schizophrenia. This has lead to clinical trials of re-purposing drugs with off-target anti-inflammatory actions. They include the antibiotic minocycline and simvastatin (HMP-Co reductase inhibitor), which decrease microglial activation, and ondansetron a 5-HT3-receptor antagonist that has limited effects on cytokine production. This presentation will address their efficacy and mechanism of action.

1) Update on trials with minocycline including our own positive finding on negative symptoms (PMID: 16959472)

2) Present new results with ondansetron and simvastatin summarised below.

Ondansetron (8mg) and simvastatin (40mg) vs placebos in 2x2 design (PMID: 23782463). Patients aged 18-65, stable treatment, DSM IV schizophrenia-related diagnosis. PANSS and cognition at 0,3,6 months.

The four cells of the 2x2 design contained 302 patients. The interaction between ondansetron and simvastatin was significant at p=.006 reflecting the lower scores in the 3 active treatment groups than in the P+P group. Ondansetron improved verbal (p=.007) and visual list learning (p=.02) with no other treatment effects on cognition.

Minocycline appears to benefit negative symptoms in early psychosis with a minor effect on cognition. Simvastatin had limited effects in our patients with established schizophrenia but its anti-inflammatory effects could be worth investigating in early psychosis. Ondansetron has a significant effect on new learning, which might be expected from its 5-HT3 antagonist properties. This may underlie a benefit on negative symptoms reported by others and us.

Infidelity is usually defined as the action or state of being unfaithful to a spouse or other sexual partner. Being unfaithful in general terms may mean more than just being unfaithful sexually, but also being unfaithful emotionally and psychologically. Nevertheless, infidelity is mostly defined in terms of being unfaithful sexually. In modern civilization, a sexual/marital relationship is defined in monogamous terms. However, historically, most cultures have been polygynous. Most species are socially monogamous (males and females pair to breed or raise offspring), but not sexually monogamous (97% of mammals are not monogamous, among primates only gibbons are predominantly monogamous, gorillas are polygynous and chimpanzee do not pair at all)). The reason for most humans being monogamous is unclear, it may be a reflection of societal, religious and moral pressures.

To examine possible biological determinants of monogamy and infidelity.

Literature review

Infidelity is fairly prevalent, reported more frequently by males than by females. The literature presents numerous reported ‘causes,‘ such as sexual dissatisfaction, partner incompatibility, liberal values and sexual permissiveness. Some authors propose a biological side to infidelity, for example a brain system which is purely ‘sex drive” (dopamine vs. oxytocin), or evolutionary factors such as access to high quality genes. Biological factors of infidelity in humans are not well studied.

Humans are not exclusively monogamous. Infidelity may have some biological underpinning (genetics, brain chemistry), but it seems to be modified/moderated by societal, cultural, religious and other factors.

Childhood trauma (CT) is known to impact brain structure and function and is a major risk factor for most of the psychiatric conditions. However, there are few multimodal studies allowing an integrated perspective. Our goal was thus to study the effects of CT on the limbic network using multimodal MRI.

We obtained multimodal MRI (T1, diffusion weighted, and resting state fMRI) data from 55 healthy subjects. We performed correlational analyses between Childhood Trauma Questionnaire (CTQ) subscores and anatomo-functional measurements of the limbic network (hippocampal and amygdala volumes, functional connectivity between hippocampus or amygdala with ventromedial prefrontal cortex and fractional anisotropy (FA) in the Uncinate Fasciculus (UF).

Significant associations of CTQ subscores were found with changes in limbic anatomy, functional and structural connectivity. We observed a positive correlation between CTQ subscores and left amygdala volumes, negative correlations with right amygdala and hippocampus (bilateral) volumes as well negative correlations with left prefrontal-amygdala functional connectivity and with FA in right UF fibers.

The present study provides new evidences that childhood adversity may be associated with structure and connectivity of the limbic system. Future longitudinal studies may be valuable to further understand the timing effects of CT on the limbic structures and also to obtain a more precise insight about the relation among CT, limbic alterations and the etiology of psychiatric disorders.

Brain derived neurotrophic factor (BDNF) is important for brain development and plasticity, and here we tested if the functional BDNF val66met variant modulates the association between high levels of childhood trauma, cognitive function, and brain abnormalities in psychoses. Serotonin transporter gene (5-HTTLPR) variants and childhood trauma were also investigated together with cognitive function in psychosis.

A total of 323 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited. A history of childhood trauma was obtained using the Childhood Trauma Questionnaire. BDNF val66met, 5-HTTLPR, and BDNF RNA were analyzed using standardized procedures. A subsample of n=108 underwent MRI scanning, and the FreeSurfer was used to obtain measures of hippocampal subfield. Cognitive function was assessed through a comprehensive, standardized neuropsychological test battery.

Additive effects were observed between a history of childhood trauma and BDNF val66met, in the direction of met carriers with high levels of childhood trauma having the lowest BDNF mRNA levels. Moreover, met carriers reporting high levels of childhood trauma had significantly reduced hippocampal subfield volumes of CA2/3 and CA4 dentate gyrus, as well as reduced cognitive function. Lastly, we observed a significant interaction between homozygotic s-carriers of the serotonin transporter gene 5-HTTLPR variants exposed to high levels of childhood trauma and poorer cognitive functioning, compared to patients with low trauma and ll- or sl- carriers.

Our results need replication but underline the importance of investigating childhood trauma and its interaction with genetic markers when studying cognitive abnormalities in psychotic disorders.

Previous research revealed substantial relations between the experience of childhood adversities and the development of borderline personality disorders (BPD) in adulthood. However, research about antecedents of adolescent BPD is still in its beginnings. Moreover, there is an ongoing controversy regarding transgenerational effects of childhood adversities and potential mediators.

We aim to investigate transgenerational effects of parental childhood experiences on the development of adolescent BPD within the next generation. Hereby, we are focusing on the investigation of differential effects of maternal and paternal experiences of childhood adversities on adolescent BPD and on underlying mechanisms.

We consecutively recruited 91 female inpatients (Mage = 15.6 years) from the Department of Child and Adolescent Psychiatry, University Hospital Heidelberg, as well as 87 mothers and 59 fathers. Childhood adversities were assessed for parents and adolescents with the German Childhood Experiences of Care and Abuse Questionnaire, adolescent BPD by means of structured clinical interviews (SKID II).

Our results are in favor of a transgenerational effect of parental childhood adversities on the development of adolescent BPD. This effect turned out to be stronger for paternal than for maternal childhood adversities. Moreover, paternal childhood adversities revealed to be related to experiences of childhood adversities within the next generation.

Our results underline the importance of taking the family environment into consideration when developing prevention and treatment programs for adolescent BPD.