Steinberg and Durell (1968) revisited: increased rates of First Episode Psychosis following military induction in Greek Army Recruits.

Since the seminal study of Steinbeck and Durell (1968), few epidemiological studies have attempted to replicate whether psychosocial stress precipitates the onset of a first psychotic episode. Our aim was to support or refute the finding of elevated psychosis incidence in the first month of army induction and to examine factors impacting the timing of onset. Data were collected from medical files of 186 army conscripts, hospitalized with a diagnosis of First Episode Psychosis (FEP) between 2005 and 2014 in the Psychiatric Military Hospital in Athens, Greece. FEP rates were at least 4.5 times higher in the first month of military service, compared with any other month. Earlier FEP onset was associated with rural environment at the time of birth, multiple drug use and service away from home. Psychosocial stress precipitates FEP, particularly in those exposed to other risk factors.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

Risk factors and peripheral biomarkers for schizophrenia spectrum disorders: an umbrella review of meta-analyses.

OBJECTIVE: This study aimed to systematically appraise the meta-analyses of observational studies on risk factors and peripheral biomarkers for schizophrenia spectrum disorders. METHODS: We conducted an umbrella review to capture all meta-analyses and Mendelian randomization studies that examined associations between non-genetic risk factors and schizophrenia spectrum disorders. For each eligible meta-analysis, we estimated the summary effect size estimate, its 95% confidence and prediction intervals and the I2 metric. Additionally, evidence for small-study effects and excess significance bias was assessed. RESULTS: Overall, we found 41 eligible papers including 98 associations. Sixty-two associations had a nominally significant (P-value <0.05) effect. Seventy-two of the associations exhibited large or very large between-study heterogeneity, while 13 associations had evidence for small-study effects. Excess significance bias was found in 18 associations. Only five factors (childhood adversities, cannabis use, history of obstetric complications, stressful events during adulthood, and serum folate level) showed robust evidence. CONCLUSION: Despite identifying 98 associations, there is only robust evidence to suggest that cannabis use, exposure to stressful events during childhood and adulthood, history of obstetric complications, and low serum folate level confer a higher risk for developing schizophrenia spectrum disorders. The evidence on peripheral biomarkers for schizophrenia spectrum disorders remains limited.

Shared variance of oculomotor phenotypes in a large sample of healthy young men.

This study used canonical correlation analysis to investigate patterns of shared variance between parameters measured in seven different occulomotor function tasks, namely the visually guided saccade task, the antisaccade task, the closed-loop smooth-pursuit task, the open-loop smooth-pursuit task, and three active visual fixation tasks. These tasks were performed by 2130 young army recruits. Only a small percentage (1-10%) of shared variance existed between sets of parameters for all oculomotor function tasks measured. The most correlated tasks were the visually guided saccade and the antisaccade. The first common factor correlated with speed of performance between these tasks (latency), while the second and third correlated with accuracy of performance. Better performance in active visual fixation tasks correlated with better performance accuracy (lower error rate) and increased speed (lower latency) in the antisaccade and saccade tasks as well as better performance in the closed-loop smooth-pursuit task (increase in gain and decrease in the rate of unwanted saccades during pursuit). Better performance in the closed-loop smooth-pursuit task (increased gain and decreased number of unwanted saccades) also correlated with increased accuracy and increased speed of performing saccades and antisaccades. Finally, the open-loop fixation task had no correlation with all other oculomotor tasks except for a very weak negative correlation with the closed-loop pursuit task where better performance (increased gain) in one correlated with worse performance (decreased gain) in the other. The results of this analysis showed that a small percentage of variance is shared among different oculomotor function tasks. The structure of this shared variance could be used to derive common oculomotor function indices to study their relation to genetic and other sources of inter-subject variation.

Schizophrenia-related RGS4 gene variations specifically disrupt prefrontal control of saccadic eye movements.

BACKGROUND: The gene encoding the regulator of G-protein signaling subtype 4 (RGS4), located on chromosome 1q23-3, has been proposed as a possible susceptibility gene for schizophrenia and has been specifically linked to prefrontal cortical structural and functional integrity. METHOD: The effects of four core single nucleotide polymorphisms (SNPs) within the RGS4 gene on oculomotor parameters in a battery of oculomotor tasks (saccade, antisaccade, smooth eye pursuit, fixation) were investigated in a sample of 2243 young male military conscripts. RESULTS: The risk allele of RGS4SNP18 was found to be associated with two variables of antisaccade performance, increased error rate and variation in the correct antisaccade latency. By contrast, the same allele and also the risk allele of RGS4SNP4 led to an improvement in smooth eye pursuit performance (increased gain). Structural equation modeling confirmed that the combined gene variation of RGS4SNP4 and RGS4SNP18 was a significant predictor of antisaccade but not smooth eye pursuit performance. CONCLUSIONS: These results provide evidence for a specific effect of schizophrenia-related RGS4 genotype variations to prefrontal dysfunction measured by oculomotor indices of performance in normal individuals, further validating the hypothesis that RGS4 is related to prefrontal dysfunction in schizophrenia.

Replication in two independent population-based samples that childhood maltreatment and cannabis use synergistically impact on psychosis risk.

BACKGROUND: There may be biological plausibility to the notion that cannabis use and childhood trauma or maltreatment synergistically increase the risk for later development of psychotic symptoms. To replicate and further investigate this issue, prospective data from two independent population-based studies, the Greek National Perinatal Study (n=1636) and The Netherlands Mental Health Survey and Incidence Study (NEMESIS) (n=4842), were analyzed. METHOD: Two different data sets on cannabis use and childhood maltreatment were used. In a large Greek population-based cohort study, data on cannabis use at age 19 years and childhood maltreatment at 7 years were assessed. In addition, psychotic symptoms were assessed using the Community Assessment of Psychic Experiences (CAPE). In NEMESIS, the Composite International Diagnostic Interview (CIDI) was used to assess psychotic symptoms at three different time points along with childhood maltreatment and lifetime cannabis use. RESULTS: A significant adjusted interaction between childhood maltreatment and later cannabis use was evident in both samples, indicating that the psychosis-inducing effects of cannabis were stronger in individuals exposed to earlier sexual or physical mistreatment [Greek National Perinatal Study: test for interaction F(2, 1627)=4.18, p=0.02; NEMESIS: test for interaction χ2(3)=8.08, p=0.04]. CONCLUSIONS: Cross-sensitivity between childhood maltreatment and cannabis use may exist in pathways that shape the risk for expression of positive psychotic symptoms.

Theory of Mind as a potential trait marker of schizophrenia: a family study.

INTRODUCTION: Although there is some evidence that Theory of Mind (ToM) deficits may be trait markers of schizophrenia it is not clear yet if ToM deficits are primary deficits, that is, to be independent of deficits in general intellectual abilities and executive function. The aim was to examine if ToM deficits may be trait markers of the illness and the effect of cognitive inhibition, general intellectual abilities and depression on ToM abilities of patients with schizophrenia and their unaffected parents. METHODS: We assessed ToM abilities (first-order and second-order ToM stories, The Revised Eyes Test), cognitive inhibition (Stroop Task), general intellectual ability (Standard Progressive Matrices Test Plus) in patients with schizophrenia (N=21) and their unaffected fathers (N=21) and mothers (N=21) in comparison with healthy control families (healthy control males, N=21, healthy control fathers, N=21, healthy control mothers, N=21) RESULTS: Patients showed deficits in first-order ToM tasks but some of these deficits were mediated by general intellectual abilities. Impairments in cognitive inhibition mediated only patients' performance in The Revised Eyes Test. Patients showed deficits in second-order ToM stories independently of deficits in general intellectual abilities and cognitive inhibition. Unaffected parents did not show deficits in first-order ToM tasks, whereas they showed deficits in second-order ToM stories. However, the deficits that unaffected parents showed in second-order ToM stories were mediated by their deficits in general intellectual abilities, and there was an effect of remitted depression on the unaffected mothers' performance. CONCLUSIONS: The results suggest that intact neurocognitive and general intellectual abilities are necessary in order patients and their unaffected parents to pass successfully ToM tasks. Patients and their unaffected parents show ToM deficits but these deficits are not similar. Patients show ToM deficits but these deficits seem to be a component of the pathophysiology of the illness (e.g., deficits in executive function, general intellectual abilities).

Association of serum brain-derived neurotrophic factor and duration of untreated psychosis in first-episode patients with schizophrenia.

BACKGROUND/AIMS: The brain-derived neurotrophic factor (BDNF) levels in serum and the central nervous system are altered in patients with schizophrenia, suggesting that changes in the expression of BDNF might contribute to the disease pathophysiology. Long duration of untreated psychosis (DUP) has been associated with poorer prognosis in patients with schizophrenia. Such a relationship of untreated psychosis to outcome may indicate a neurodegenerative process and may have important implications for understanding the pathophysiology of schizophrenia. METHODS: In this study, we investigated the association between serum BDNF levels and DUP in a sample of drug-naïve patients in their first episode of schizophrenia (FEP). We investigated serum BDNF levels in a sample of 37 drug-naïve FEP patients and 21 matched healthy subjects. RESULTS: The serum BDNF level in the sample of FEP was significantly reduced compared to the healthy subjects (18.87 +/- 8.23 vs. 29.2 +/- 7.73 ng/ml, t = 4.76, d.f. = 57, p = 0.01). A negative correlation was found between serum BDNF levels and DUP in the group of patients (r = -0.346, p = 0.036). CONCLUSIONS: Our findings indicate that low serum BDNF levels at the onset of schizophrenia were associated with a long DUP and this could reflect an acute neurodegenerative reaction during the untreated phase of psychosis.

[Childhood adverse traumatic experiences and schizophrenia].

Εpidemiological research during last decades has demonstrated the association of certain environmental variables with psychosis. Ιn parallel with understanding environmental contributors to schizophrenia, identification of those at high risk of psychosis has become a priority. These risk factors include adverse traumatic experiences, such as discrimination, social environment adversities, bullying, emigration and childhood trauma. For many years the possibility of a relationship of adverse traumatic experiences with schizophrenia was minimized in favor of a biological paradigm. However, there is evidence supporting that childhood adversities is one of the most significant environmental risk factors for psychosis, if not the most significant. Studies have demonstrated the validity and the reliability of retrospective reports of adverse traumatic experiences in psychotic patients. The question on the causal relationship between adverse traumatic experiences and psychosis has been raised for many years, but it has not yet been answered. Researchers have focused on the study of dysfunctional cognitive schemes being formed due to childhood adversities and interpreting the world as unfriendly and threatening. According to social defeat hypothesis, the patients do not experience more stressful life events but they experience them as less controllable. Furthermore, researchers study the mediator psychopathology associated directly with adverse traumatic experiences, such as anxiety, mood, dissociative and adaptation disorders, which possibly predispose to psychosis. Cannabis use and childhood adversities may interact to increase the risk of psychotic symptoms in adolescence, according to research findings. Several publications have positively linked the number of traumatic adverse experiences with the severity of mental health and possibly with high risk of psychosis in a dose-response relationship model. Taking note that it is important to have a plausible hypothesis of the biological mechanisms involved with the relationship between adverse traumatic experiences and psychosis, the putative systems being explored are: (1) the hypothalamus-pituitary-adrenal (HPA) axis because it mediates the principal adaptive response to perceived psychological or physiological stress and (2) the dopamine system, which is considered to be important in the development of psychosis. The biological and environmental risk factors are both important in the etiology of psychosis but the effects of some forms of childhood adversity act largely independently of pre-existing genetic liability to increase the risk of psychosis. A supposed differentiation of psychosis associated with adverse traumatic experiences from the classic neurodegenerative model possibly should be considered seriously by the clinician in order to design the best therapeutic plan.

The development of the Early Intervention in Psychosis (EIP) outpatient unit of Eginition University Hospital into an EIP Network.

Over the past 25 years, in the field of psychosis there is an increased interest in early detection of symptoms and treatment provision for people who are either at Ultra High Risk (UHR) of developing psychosis or with First Episode Psychosis (FEP). Extensive research has proved, that by engaging quickly into treatment and addressing the needs of each case individually, clinical outcomes could be improved substantially. The above evidence-based argument has resulted in the establishment of specialized Early Intervention in Psychosis (EIP) services worldwide. Eginition University Hospital (EUH) in Athens has been providing care for Early Psychosis through a specialized outpatient EIP service since 2012, which receives all early psychosis cases. Initially clinical focus was mainly directed towards UHR cases, since EUH had long been providing standard care for FEP. However, over the last 4 years, the EIP Unit has evolved incrementally into a network of directly linked services, involving the EIP outpatient service, an Inpatient Unit for prompt hospitalization and a Day Clinic for partial hospitalization, to address acute treatment, follow-up and recovery/relapse prevention phases. Diagnostic evaluation is made through specialized instruments along with the typical psychiatric interview. The therapeutic approach follows the international guidelines for EIP, namely symptom-based and phase-specific treatment, which includes supportive counselling, coping strategies and psychoeducation both for subjects and family members, as well as pharmacotherapy when needed and preferably in low doses. Regarding our results, in the first 3 years (3/2012-3/2015) the EIP unit received 26 (60%) UHR subjects and 17 (40%) FEP patients. Over the last 4 years (3/2015-3/2019) the referrals rose to 167 with 35 (21%) UHR and 132 (79%) FEP cases. All of the UHR subjects were from the outset followed by the specialized outpatient EIP service for up to 3 years. As to the FEP patients, seventy-seven (60%) were acutely hospitalized for less than a month, and 10 (8%) attended the Day Clinic for 6 - 12 months, before being referred to the outpatient service. Concluding, the development of the EIP network of specialized services has cohesively enabled a broader therapeutic framework, shifting the clinical focus towards FEP, although UHR subjects are still being assessed systematically. However, there is still considerable work to be done, in order to enhance the full potential of all units and promote the interconnection with potential community settings.

Evidence of advanced parental age linked to sporadic schizophrenia.

Νovel emergence of schizophrenia (SCZ) in its sporadic type has been linked, among many candidate epigenetic factors, with advanced paternal age (PA) and advanced maternal age (MA). The most common hypothesis to the paternal age effect is the increased "de novo mutations" during spermatogenesis, while the maternal age hypothesis, though controversial, is at most based on studies that support higher frequency of perinatal complications. Our sample consisted of 462 subjects with DSM-IV-TR SCZ spectrum disorders from the outpatient unit of Eginition Hospital in Athens, Greece, who were further screened for heritability and were divided in a group of sporadic cases (no reported family history for SCZ related disorders up to 2nd degree relatives) and a group of familial SCZ-spectrum disorder cases (positive reported history for SCZ spectrum). These two groups of patients were compared regarding either paternal or maternal age, while the familial type band was used as a control group. The aim of this retrospective file study was to examine whether advanced parental age may contribute in novel appearance of non-affective psychosis in offspring. Using logistic regression analysis, we found that the risk for the sporadic type, as compared to familial type, showed a significant increase for both advanced MA (OR=4.39, p=0.001) and PA (OR=1.92, p=0.012). After adjusting for confounding effects for the other parent's age and gender, the risk effect for the sporadic type of SCZ remained statistically significant for both advanced MA (OR=4.04, p=0.002) and advanced PA, but with a loss of statistical power (OR=1.72, p=0.049). Few studies have been conducted in Greece concerning the role of parental age in SCZ. Our study is consistent with current literature which indicates that both advanced MA and PA may contribute to an increased risk for emergence of sporadic type of SCZ. Furthermore, it is implied that this risk for the sporadic type as compared to the familial type could be higher for advanced MA than advanced PA. Patients with the sporadic type of SCZ, though clinically indistinguishable from the patients with the familial type of the disorder, may share other pathophysiological underlying mechanisms in which parental age, especially advanced MA, may be a candidate mediator. However, future studies could help clarify the role of both PA and MA in the pathophysiology of the disorder.

[A proposal for the implementation of Early Intervention in Psychosis (EIP) services in Greece: If not now, when?]

The disorders of the psychosis spectrum, with the most severe being schizophrenia, are prevalent and have a great impact on the patients' quality of life. The purpose of this article is to highlight the need for a novel national strategic approach to the management of psychotic disorders in accordance with the international principles of early intervention. Even though outpatient treatment is considered adequate, there is an urgent need to adopt an early and more comprehensive and effective intervention strategy for young patients with psychosis and their families whose clinical and personal needs are clearly not met by the existing infrastructure of our mental health services. This can be accomplished by the legislation and implementation within the national health system of EIP services which on the one hand actively engage community organizations with the purpose of early identification of cases, reduction of the duration of untreated psychosis and on the other, offer assertive community-based support and treatment, based on a multi-disciplinary community team model. The effectiveness of early intervention in psychosis is supported by evidence provided by 9 international RCTs. The results of these programs indicate a superior effect in indexes of quality of life, retention in treatment, psychopathology, judicious use of medication and return to work/school as well as the patient's effective recovery. International experience (Denmark, Norway, Australia, UK, USA, Canada and Italy) and the corresponding prevention programs emphasize the effectiveness of EIP services and thus the patients' reintegration. However, in contrast to Northern European countries, Southern European countries have not yet incorporated EIP services in their national health system. From a financial perspective, EIP services seem to be cost-effective for the national health system, since the economic burden is compensated in the long term through their qualitative benefits. In Greece, specialized services for those young afflicted for the first time by the most serious of mental disorders are non-existent and no local information exists for the patient's outcome and social integration after a first psychotic-episode nor for the financial burden, placed on mental health services. Overall, the implementation of EIP services is expected to have long-term benefits for our country's National Health System as well as for the patients and their families.

Early psychotic experiences: Interventions, problems and perspectives.

Psychotic or psychotic-like experiences and symptoms may precede and be indicative of later psychosis emergence. DSM-5 has introduced Attenuated Psychosis Syndrome (APS) as a condition for further study, arguing for its clinical validity and the need for identifying sub- threshold psychotic states. Early psychosis intervention has an already established role in reducing the Duration of Untreated Psychosis (DUP), delaying psychosis onset and relieving Ultra High Risk (UHR) individuals from their presenting symptoms. Pharmacological and mainly psycho-therapeutical approaches are suggested for this purpose. Cognitive Behavior Therapy (CBT) seems to have clear evidence of favorable outcome concerning transition to psychosis rates, omega-3 fatty acids lower but promising evidence, while low-dose antipsychotic medication or antidepressant treatment may seem beneficial, but it remains unclear if the reported favorable effects persist in the long term and how long intervention in UHR subjects should be given for. Case management and close monitoring based on principles of social psychiatry are considered key elements for the management of UHR individuals. However, the blazing case about early psychosis concerns the accurate specification of the prodromal stage of psychosis, which may set the basis for meaningful and effective early intervention. Although psychometric tools have been developed and provide a common criteria-based recognition method, debate is alive and well regarding "false positive" cases, since most UHR subjects will not finally develop psychosis. Moreover, transition rates to psychosis have been declining over the years, leading to fierce criticism over the validity of the UHR/ APS state and legitimacy of its treatment. On this framework, ethical issues of stigmatizing through unnecessary diagnosing and antipsychotics' prescribing are matters of serious questioning. Clinical heterogeneity and high comorbidity are further implications of the UHR state. Current research emphasizes on improving validity of inclusion criteria and formulating personalised and clinical stage- based intervention strategies. In order to do that, early psychosis recognition and intervention services are established throughout the world, trying to contribute in research by applying clinical, cognitive or neuropsychological criteria. Nevertheless, in the majority of so far conducted studies, samples sizes are considered small and duration of follow-up short, which are limitations yet to overcome. Other scientific voices argue that the UHR state might represent a non-specific risk factor for psychiatric disorders in general and not necessarily for psychosis and tend to examine the UHR and early intervention idea under the prism of subthreshold or early mental distress state. Either way, recognizing and intervening early in emerging psychiatric states, especially in those with psychotic or psychotic-like symptomatology, share indisputable benefits under the broader concept of prevention, setting a strong scientific-clinical rationale for service provision to help-seeking people and the possibility of changing the course for those with vulnerability to psychotic illnesses.

Temperament and character dimensions assessed in general population, in individuals with psychoactive substance dependence and in young male conscripts.

BACKGROUND: In this work we consider Cloninger's psychobiological model, which measures two dimensions of personality: character and temperament. Temperament refers to the biological basis of personality and its characteristics, while character refers to an individual's attitudes towards own self, towards humanity and as part of the universe. METHODS: The Temperament and Character Inventory-Revised-140 (TCI-R-140) was administered to 3 divergent samples: a general population sample, a sample of male conscripts and a sample of individuals attending a substance abuse rehabilitation programme. Score differences among the three samples were assessed controlling for age and gender and reliability coefficients are reported. The latent structure was studied in all samples, using exploratory and confirmatory factor analysis methods (EFA and CFA respectively). RESULTS: The proposed structure was partially replicated via EFA. CFA however indicated less than satisfactory fit, as in previously reported results. To improve the fit, the path diagram was augmented to account for multiple factor complexity, as suggested by the EFA results in all samples. While retaining the original seven-factor structure, the augmented model provided adequate fit. The consistency of the inventory was satisfactory in all samples. Evidence for the construct validity was found in relation to aggression. CONCLUSIONS: This is the first study to conclude in adequate fit, after allowing for the indicators to load on more than one factor within each dimension. While cross-national differences apply, our results were similar (when comparable) with previously reported ones in the literature.

Inter-rater reliability of the Greek version of CAARMS among two groups of mental health professionals.

There is increasing interest within the Greek psychiatric community in the early detection and prevention of psychotic disorders. To support this, there is a need for a valid and reliable tool to identify young people that may be at risk of developing a psychotic disorder. Our team has previously translated the Comprehensive Assessment of At-Risk Mental States (CAARMS). The validity of the CAARMS was ensured by the procedure of translation and the aim of the current study was to estimate the interrater reliability of the CAARMS Greek translation among residents in psychiatry and specialized mental health professionals. 43 mental health workers (27 residents in psychiatry and 16 specialized mental health professionals (i.e. 11 psychiatrists and 5 psychologist) participated in two seminars that covered theoretical information about the ultra high risk concept and training in the CAARMS. During the seminars, 10 vignettes with psychiatric history cases were presented, including healthy, ultra high risk and first episode psychosis. The mean correlated percentage of agreement with the correct answers regarding diagnosis of the presented history cases among all our subjects was 81.42, among specialized mental health professionals 77.88, and among residents 84.46. Intraclass correlation co-efficients were 0.994 for specialized mental health professionals and 0.997 for residents. The translated Greek version of CAARMS presents a satisfying interrater reliability when used by both residents and specialized mental health professionals. Residents declare even higher intraclass correlation co-efficients and mean correlated percentage of agreement than specialized mental health professionals, which indicate that residents are capable of using the CAARMS in early intervention units.

Hippocampal volume reduction in schizophrenia: effects of genetic risk and pregnancy and birth complications.

BACKGROUND: Hippocampal volume reduction has been repeatedly demonstrated in schizophrenia. The relative contribution of genetic and environmental factors to this is unclear. METHODS: To address this question, we compared volumetric measurements of the left and right hippocampus, obtained using stereological methods from brain MRI scans, from two groups of patients with schizophrenia as well as healthy controls (n = 26). Patients (n = 27) in the first group, had no family history of schizophrenia and had experienced severe pregnancy and birth complications (PBCs). The second group comprised of patients (n = 21) without a history of severe PBCs from families multiply affected with schizophrenia. RESULTS: Reduction of the left hippocampal volume was associated with the diagnosis of schizophrenia but was present only in patients with a history of severe PBCs; in this group the smaller hippocampal volume, the earlier the onset of psychosis. CONCLUSIONS: Our findings suggest that environmental factors, in this case severe PBCs, make a significant contribution to hippocampal abnormalities in schizophrenia.

Elevation of D4 dopamine receptor mRNA in postmortem schizophrenic brain.

The D4 dopamine (DA) receptor has been proposed to be a target for the development of a novel antipsychotic drug based on its pharmacological and distribution profile. There is much interest in whether D4 DA receptor levels are altered in schizophrenia, but the lack of an available receptor subtype-specific radioligand made this difficult to quantitate. In this study, we examined whether D4 mRNA levels are altered in different brain regions of schizophrenics compared to controls. Ribonuclease protection assays were carried out on total RNA samples isolated postmortem from frontal cortex and caudate brain regions of schizophrenics and matched controls. 32P-labelled RNA probes to the D4 DA receptor and to the housekeeping gene, glyceraldehyde-3-phosphate dehydrogenase (G3PDH), were hybridised with the RNA samples, digested with ribonucleases to remove unhybridised probe, and separated on 6% sequencing gels. Densitometer analysis on the subsequent autoradiogams was used to calculate the relative optical density of D4 mRNA compared to G3PDH mRNA. Statistical analysis of the data revealed a 3-fold higher level (P<0.011) of D4 mRNA in the frontal cortex of schizophrenics compared to controls. No increase was seen in caudate. D4 receptors could play a role in mediating dopaminergic activity in frontal cortex, an activity which may be malfunctioning in schizophrenia.

Prolactin and thyrotropin responses to ECT after pindolol administration. A placebo controlled study.

The effect of pindolol, a beta-receptor blocker with potent 5-HT1 receptor antagonistic properties, on the prolactin (PRL) and thyrotropin (TSH) responses to electroconvulsive therapy (ECT) was systematically studied in 12 female depressed patients. In a balanced order, crossover design, the patients were given placebo or pindolol 5 mg orally, 1 h prior to bilateral ECT. The last five patients were additionally tested with 10 mg pindolol during the third ECT. Plasma levels of PRL and TSH increased in all three trials, but no consistent effect of pindolol on these hormonal responses could be demonstrated. Pindolol tended to attenuate seizure duration, especially at the 10 mg dose. The participation of 5-HT1 receptor activity in the secretion of PRL and TSH during ECT remains uncertain.