Pregnenolone-progesterone-allopregnanolone pathway as a potential therapeutic target in first-episode antipsychotic-naïve patients with schizophrenia.

Neurosteroids are both endogenous and exogenous steroids that rapidly alter neuronal excitability through interactions with ligand-gated ion channels and other cell surface receptors. They are originated from cholesterol and have important implications for schizophrenia (SZ) pathophysiology and treatment strategies. Specifically, pregnenolone (PREG), progesterone (PROG) and allopregnanolone (ALLO) exhibit similar psychotropic properties.

Clinical psychopathology in youth at familial high risk for psychosis.

Aim: While the course of psychopathology has been explored from an index mental health diagnosis onwards, there are few detailed, prospective studies of the occurrence of clinical psychopathology in youth with familial risk for severe mental illnesses such as psychosis. We sought to describe the appearance of Axis I psychopathology in a unique sample of adolescents with a family history of schizophrenia (FHR).

Methods: One hundred and sixty two first- and second-degree relatives (mean age 15.

Association of sFlt-1 and worsening psychopathology in relatives at high risk for psychosis: A longitudinal study.

Background: Angiogenic dysfunction and abnormalities in psychopathology and brain structure have been reported in schizophrenia, but their relationships are mostly unknown. We recently demonstrated that sFlt-1, anti-angiogenic factor, was significantly elevated in patients at familial high-risk for psychosis (FHR). We hypothesized that elevated sFlt-1 correlates with baseline and longitudinal changes in psychopathology, cognition, and brain structure.

Angiogenic and immune signatures in plasma of young relatives at familial high-risk for psychosis and first-episode patients: A preliminary study.

Schizophrenia (SZ) is a heterogeneous disorder that presents in adolescence, persists into adulthood, and has many clinical features. Recent evidence suggests that abnormalities in inflammatory, neurotrophic, and angiogenic processes may play a role in the etiology of SZ. The identification of molecular biomarkers early in the course of disease is crucial to transforming diagnostic and therapeutic avenues.

Sleep spindle deficits in antipsychotic-naïve early course schizophrenia and in non-psychotic first-degree relatives.

Introduction: Chronic medicated patients with schizophrenia have marked reductions in sleep spindle activity and a correlated deficit in sleep-dependent memory consolidation. Using archival data, we investigated whether antipsychotic-naïve early course patients with schizophrenia and young non-psychotic first-degree relatives of patients with schizophrenia also show reduced sleep spindle activity and whether spindle activity correlates with cognitive function and symptoms.

Method: Sleep spindles during Stage 2 sleep were compared in antipsychotic-naïve adults newly diagnosed with psychosis, young non-psychotic first-degree relatives of schizophrenia patients and two samples of healthy controls matched to the patients and relatives.

Longitudinal treatment outcome of African American and Caucasian patients with first episode psychosis.

The purpose of our analyses to examine the outcome differences between African American and Caucasian first-episode psychotic patients over the course of one year, to explore the interactive effects of gender, diagnosis, and race on treatment outcome. A consecutive series of patients (N=199) were recruited into our study from the inpatient and outpatient services at a psychiatric clinic. Global functioning, positive, negative, affective, and depression symptoms and treatment adherence were assessed at baseline prior to treatment and during follow-up up to one year.

Multivariate prediction of emerging psychosis in adolescents at high risk for schizophrenia.

Background: Accurate prediction of psychosis development in high-risk populations is an important but thus far elusive goal. Of the many diverse etiologic and risk factors identified thus far, few have been combined into prospective multivariate risk ascertainment models. We tested the predictive power of familial, neurobiological, socioenvironmental, cognitive and clinical risk factors through an integrative biopsychosocial model for emerging psychosis in young relatives at familial risk for schizophrenia.

Associations between purine metabolites and clinical symptoms in schizophrenia.

Background: The antioxidant defense system, which is known to be dysregulated in schizophrenia, is closely linked to the dynamics of purine pathway. Thus, alterations in the homeostatic balance in the purine pathway may be involved in the pathophysiology of schizophrenia.

Methodology/principal Findings: Breakdown products in purine pathway were measured using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system for 25 first-episode neuroleptic-naïve patients with schizophrenia at baseline and at 4-weeks following initiation of treatment with antipsychotic medication.

Sleep correlates of cognition in early course psychotic disorders.

Background: Slow waves and sleep spindles, the main oscillations during non-rapid eye movement sleep, have been thought to be related to cognitive processes, and are impaired in psychotic disorders. Cognitive impairments, seen early in the course of psychotic disorders, may be related to alterations in these oscillations, but few studies have examined this relationship.

Method: Twenty seven untreated patients with a recently diagnosed psychotic disorder had polysomnographic sleep studies and neuro-cognitive testing.

Working memory and attention deficits in adolescent offspring of schizophrenia or bipolar patients: comparing vulnerability markers.

Background: Working memory deficits abound in schizophrenia and attention deficits have been documented in schizophrenia and bipolar disorder. Adolescent offspring of patients may inherit vulnerabilities in brain circuits that subserve these cognitive domains. Here we assess impairments in offspring of schizophrenia (SCZ-Offspring) or bipolar (BP-Offspring) patients compared to controls (HC) with no family history of mood or psychotic disorders to the second degree.

3-Hydroxykynurenine and clinical symptoms in first-episode neuroleptic-naive patients with schizophrenia.

One branch of the tryptophan catabolic cascade is the kynurenine pathway, which produces neurotoxic [3-hydroxykynurenine (3-OHKY), quinolinic acid] and neuroinhibitory (kynurenic acid) compounds. Kynurenic acid acts as a competitive antagonist at the glycine site of N-methyl-d-asparate receptors at high concentrations and as a non-competitive antagonist on the α7-nicotinic acetylcholine receptor at low concentrations. Kynurenine compounds also influence cognitive functions known to be disrupted in schizophrenia.

Abnormalities of the corpus callosum in non-psychotic high-risk offspring of schizophrenia patients.

Alterations in the structure of the corpus callosum (CC) have been observed in schizophrenia. Offspring of schizophrenia parents have 10-15 times higher risk for developing schizophrenia. We examined CC volume in offspring at genetic high-risk (HR) subjects.

Progressive alterations of the auditory association areas in young non-psychotic offspring of schizophrenia patients.

Background: Schizophrenia may involve progressive alterations of structure and hemispheric lateralization of auditory association areas (AAA) within the superior temporal gyrus. These alterations may be greater in male patients. It is unclear if these deficits are state-dependent or whether they predate illness onset and reflect familial diathesis.

Gray matter loss in young relatives at risk for schizophrenia: relation with prodromal psychopathology.

The maturation of neocortical regions mediating social cognition during adolescence and young adulthood in relatives of schizophrenia patients may be vulnerable to heritable alterations of neurodevelopment. Prodromal psychotic symptoms, commonly emerging during this period in relatives, have been hypothesized to result from alterations in brain regions mediating social cognition. We hypothesized these regions to show longitudinal alterations and these alterations to predict prodromal symptoms in adolescent and young adult relatives of schizophrenia patients.

Grey matter and cognitive deficits in young relatives of schizophrenia patients.

Grey-matter volumetric and cognitive deficits in young, high-risk relatives of schizophrenia patients may be vulnerability markers of the illness. Although these markers may be correlated, it is unclear if their distributions in relatives overlap. We examined convergence of these markers in 94 young first and second-degree relatives (HR) and 81 healthy controls.

Premorbid cognitive deficits in young relatives of schizophrenia patients.

Neurocognitive deficits in schizophrenia (SZ) are thought to be stable trait markers that predate the illness and manifest in relatives of patients. Adolescence is the age of maximum vulnerability to the onset of SZ and may be an opportune "window" to observe neurocognitive impairments close to but prior to the onset of psychosis. We reviewed the extant studies assessing neurocognitive deficits in young relatives at high risk (HR) for SZ and their relation to brain structural alterations.

Homeostatic imbalance of purine catabolism in first-episode neuroleptic-naïve patients with schizophrenia.

Background: Purine catabolism may be an unappreciated, but important component of the homeostatic response of mitochondria to oxidant stress. Accumulating evidence suggests a pivotal role of oxidative stress in schizophrenia pathology.

Methodology/principal Findings: Using high-pressure liquid chromatography coupled with a coulometric multi-electrode array system, we compared 6 purine metabolites simultaneously in plasma between first-episode neuroleptic-naïve patients with schizophrenia (FENNS, n = 25) and healthy controls (HC, n = 30), as well as between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment.

Do inter-regional gray-matter volumetric correlations reflect altered functional connectivity in high-risk offspring of schizophrenia patients?

Background: Schizophrenia patients and their relatives show aberrant functional connectivity in default network regions (DRs) such as the medial prefrontal, lateral temporal, cingulate and inferior parietal cortices and executive regions such as the dorsolateral prefrontal cortex (DLPFC). Gray-matter volumetric alterations may be related to these functional connectivity deficits. Also, gray-matter volume inter-regional correlations may reflect altered inter-regional functional connectivity.

Longitudinal alterations of executive function in non-psychotic adolescents at familial risk for schizophrenia.

Genetic diathesis to schizophrenia may involve alterations of adolescent neurodevelopment manifesting as cognitive deficits. Brain regions mediating executive function (fronto-striatal circuits) develop during adolescence while those supporting elementary aspects of attention (e.g.

Decreased BDNF in patients with antipsychotic naïve first episode schizophrenia.

Objective: Brain-derived neurotrophic factor (BDNF) is a key factor known to mediate neuronal proliferation, differentiation, survival and response to stress. Decreases in BDNF levels have been reported in schizophrenia, but studies in treatment naïve patients are few. Herein we report on serum BDNF levels in a series of patients with first-episode treatment naïve psychoses in comparison to age matched healthy controls.

Cognitive enhancement therapy for early-course schizophrenia: effects of a two-year randomized controlled trial.

Objective: The early application of cognitive rehabilitation may afford long-term functional benefits to patients with schizophrenia. This study examined the two-year effects of an integrated neurocognitive and social-cognitive rehabilitation program, cognitive enhancement therapy (CET), on cognitive and functional outcomes in early-course schizophrenia.

Methods: Early-course outpatients (mean+/-SD illness duration=3.

Verbal fluency deficits and altered lateralization of language brain areas in individuals genetically predisposed to schizophrenia.

Alterations of verbal fluency may correlate with deficits of gray matter volume and hemispheric lateralization of language brain regions like the pars triangularis (PT) in schizophrenia. Examining non-psychotic individuals at high genetic risk (HR) for schizophrenia may clarify if these deficits represent heritable trait markers or state dependent phenomena. We assessed adolescent and young adult HR subjects (N=60) and healthy controls (HC; N=42) using verbal fluency tests and Freesurfer to process T1-MRI scans.

Striatal metabolic alterations in non-psychotic adolescent offspring at risk for schizophrenia: a (1)H spectroscopy study.

In vivo proton ((1)H) Magnetic Resonance spectroscopy ((1)H MRS) has shown abnormalities in young first-episode patients with schizophrenia. It is unclear whether these abnormalities reflect trait related vs. state related alterations in schizophrenia.

Do premorbid impairments predict emergent 'prodromal' symptoms in young relatives at risk for schizophrenia?

Aims: Individuals at risk for developing schizophrenia (SZ) in the future frequently exhibit subtle behavioural and neurobiological abnormalities in their childhood. A better understanding of the role of these abnormalities in predicting later onset of 'prodromal' symptoms or psychosis may help in early identification of SZ.

Methods: In an ongoing prospective follow-up study of young genetically at-risk relatives of patients with SZ, we studied the prevalence of problems in premorbid social adjustment and childhood psychopathology and examined their relationship with the presence and progression of 'prodromal' symptoms of SZ.