Pituitary volume and clinical trajectory in young relatives at risk for schizophrenia.

BACKGROUND: Stress and vulnerability likely interact to play a major role in psychosis. While much has been written about the neural diathesis-stress model in psychosis and its clinical risk states, little is known about HPA axis biomarkers in non-help-seeking individuals at familial high risk (FHR). We sought to prospectively measure pituitary volume (PV) in adolescents and young adults at FHR for schizophrenia and to follow their emerging sub-clinical psychotic symptoms and clinical trajectories. METHOD: Forty healthy controls and 38 relatives of patients with schizophrenia or schizoaffective disorder were identified in Pittsburgh, USA. PV was derived from baseline 1.5 T magnetic resonance imaging. Chapman's schizotypy scales were acquired at baseline, and structured clinical interviews for DSM-IV-TR Axis I diagnoses were attempted annually for up to 3 years. RESULTS: Seven individuals converted to psychosis. PV did not differ between FHR and control groups overall. Within the FHR group, PV was positively correlated with Chapman's positive schizotypy (Magical Ideation and Perceptual Aberration) scores, and there was a significant group × PV interaction with schizotypy. PV was significantly higher in FHR subjects carrying any baseline Axis I diagnosis (p = 0.004), and higher still in individuals who went on to convert to psychosis (p = 0.0007). CONCLUSIONS: Increased PV is a correlate of early positive schizotypy, and may predict trait vulnerability to subsequent psychosis in FHR relatives. These preliminary findings support a model of stress-vulnerability and HPA axis activation in the early phases of psychosis.

Altered interactions of tryptophan metabolites in first-episode neuroleptic-naive patients with schizophrenia.

Schizophrenia is characterized by complex and dynamically interacting perturbations in multiple neurochemical systems. In the past, evidence for these alterations has been collected piecemeal, limiting our understanding of the interactions among relevant biological systems. Earlier, both hyper- and hyposerotonemia were variously associated with the longitudinal course of schizophrenia, suggesting a disturbance in the central serotonin (5-hydroxytryptamine (5-HT)) function. Using a targeted electrochemistry-based metabolomics platform, we compared metabolic signatures consisting of 13 plasma tryptophan (Trp) metabolites simultaneously between first-episode neuroleptic-naive patients with schizophrenia (FENNS, n=25) and healthy controls (HC, n=30). We also compared these metabolites between FENNS at baseline (BL) and 4 weeks (4w) after antipsychotic treatment. N-acetylserotonin was increased in FENNS-BL compared with HC (P=0.0077, which remained nearly significant after Bonferroni correction). N-acetylserotonin/Trp and melatonin (Mel)/serotonin ratios were higher, and Mel/N-acetylserotonin ratio was lower in FENNS-BL (all P-values<0.0029), but not after treatment, compared with HC volunteers. All three groups had highly significant correlations between Trp and its metabolites, Mel, kynurenine, 3-hydroxykynurenine and tryptamine. However, in the HC, but in neither of the FENNS groups, serotonin was highly correlated with Trp, Mel, kynurenine or tryptamine, and 5-hydroxyindoleacetic acid (5HIAA) was highly correlated with Trp, Mel, kynurenine or 3-hydroxykynurenine. A significant difference between HC and FENNS-BL was further shown only for the Trp-5HIAA correlation. Thus, some metabolite interactions within the Trp pathway seem to be altered in the FENNS-BL patients. Conversion of serotonin to N-acetylserotonin by serotonin N-acetyltransferase may be upregulated in FENNS patients, possibly related to the observed alteration in Trp-5HIAA correlation. Considering N-acetylserotonin as a potent antioxidant, such increases in N-acetylserotonin might be a compensatory response to increased oxidative stress, implicated in the pathogenesis of schizophrenia.

Delta sleep deficits in schizophrenia: evidence from automated analyses of sleep data.

BACKGROUND: Several, though not all, polysomnographic studies that use conventional visual scoring techniques show delta sleep deficits in schizophrenia. Delta sleep (in particular, > or = 1- to 2-Hz frequency range), mediated by thalamocortical circuits, is postulated to be abnormal in schizophrenia. We investigated whether deficits in delta sleep occur in schizophrenia and whether these are primarily related to the illness or are epiphenomena of previous medication use or illness chronicity. METHODS: We compared 30 unmedicated schizophrenic patients and 30 age- and sex-matched controls for sleep data evaluated by visual scoring as well as automated period amplitude analyses and power spectral analyses. RESULTS: Schizophrenic patients had reduced visually scored delta sleep. Period amplitude analyses showed significant reductions in delta wave counts but not rapid eye movement counts; power spectral analyses showed reductions in delta as well as theta power. Delta spectral power was also reduced in the subset of 19 neuroleptic-naive, first-episode schizophrenic patients compared with matched controls. Delta deficits were more pronounced in the greater than 1- to 2-Hz frequency range. CONCLUSIONS: Delta sleep deficits that occur in schizophrenia may be related to the primary pathophysiological characteristics of the illness and may not be secondary to previous neuroleptic use. Automated sleep quantification by means of period amplitude and power spectral analyses can complement the use of conventional visual scoring for understanding electrophysiological abnormalities in psychiatric disorders.

Frontostriatal measurement in treatment-naive children with obsessive-compulsive disorder.

BACKGROUND: Abnormalities in frontostriatal circuits have been implicated in obsessive-compulsive disorder (OCD). Although OCD commonly emerges during childhood or adolescence, few studies have examined frontostriatal anatomy in psychotropic-naive children with OCD near the onset of illness to determine the possible role of atypical developmental processes in this disorder. METHODS: Magnetic resonance imaging scans from 19 children with OCD who had not been exposed to psychotropic drugs, aged 7 to 18 years, and 19 case-matched healthy control subjects were analyzed to determine the volumes of the following structures: prefrontal cortex, striatum (caudate and putamen), lateral and third ventricles, and intracranial volume. RESULTS: Patients with OCD had significantly smaller striatal volumes and significantly larger third ventricle volumes than controls, but did not differ in prefrontal cortical, lateral ventricular, or intracranial volumes. Striatal volumes were inversely correlated with OCD symptom severity but not illness duration. CONCLUSIONS: Our findings provide new evidence of abnormalities of the striatum in pediatric OCD. These results are preliminary, given the small sample size.

Magnetic resonance imaging and spectroscopy in offspring at risk for schizophrenia: preliminary studies.

1. Studies of first-degree relatives of persons with schizophrenia provide an opportunity to characterize risk factors for the development of this illness. In this report the authors will provide preliminary data from an ongoing study of neurobiological alterations in the offspring of schizophrenia patients. 2. A series of offspring of schizophrenic patients (OS) were compared with age and sex matched healthy controls (HC) without psychiatric history in first degree relatives on psychiatric, volumetric Magnetic Resonance Imaging (MRI) of whole brain and proton Magnetic Resonance Spectroscopy (1H MRS) evaluations of the ventral prefrontal cortex. 3. Compared with HC group, high risk subjects had reduced left amygdala volume, enlarged third ventricular volume, and smaller overall brain volume. 4. 1H MRS studies showed a trend for decreased NAA/choline ratios in the anterior cingulate region in the OS group as compared to HC subjects. 5. Follow-up studies of these subjects are needed to confirm the predictive value of these measures for future emergence of schizophrenia in subjects at risk for this illness.

A longitudinal study of EEG sleep in schizophrenia.

Several abnormalities in sleep architecture have been described in schizophrenia. However, the question of whether sleep electroencephalographic (EEG) changes are influenced by treatment and phase of illness remains unclear. To examine the longitudinal stability of sleep data, we compared baseline sleep measures with measures obtained approximately 4 weeks and 1 year after the beginning of treatment in a series of schizophrenic patients. At the 4-week assessment, sleep continuity measures improved significantly; a modest increase in rapid eye movement (REM) latency was seen, but no other changes were found in sleep architecture. At the 1-year assessment, REM latency, REM time, and average automated REM counts increased. No significant changes were seen for slow-wave sleep (SWS) parameters at 1-year follow-up. These findings suggest that SWS parameters are relatively stable during follow-up, while REM parameters seem to change, perhaps in relation to phase of illness and treatment. SWS alterations may, at least in part, reflect more invariant, perhaps trait-related alterations in schizophrenia.

Oculomotor delayed response abnormalities in young offspring and siblings at risk for schizophrenia.

Individuals with schizophrenia are know to demonstrate cognitive and behavioral difficulties, particularly alterations in executive functions, including working memory. It is unclear whether these deficits reflect trait-related vulnerability to schizophrenia indicators and can be assessed by studying nonpsychotic relatives of patients with schizophrenia. In this study, we used an oculomotor delayed response (ODR) paradigm to examine spatial working memory in 37 "high-risk" child and adolescent offspring and siblings (age range=6-25 years) of patients with schizophrenia or schizoaffective disorder. Compared with 37 age- and sex-matched healthy controls (age range=6-23 years), high-risk subjects showed nonsignificantly greater errors in the ODR task at longer delay intervals. Statistical analyses suggested that performance improved with age in healthy control subjects, whereas it worsened with age in high-risk subjects. In both groups, the ODR errors were generally associated with poorer sustained attention (Continuous Performance Test: visuospatial d prime), somewhat poorer executive function (Wisconsin Card Sorting Test), and elevated Heinrichs-Buchanan neurological soft signs scores. These findings indicate the presence of spatial working memory abnormalities in individuals at risk for schizophrenia. Furthermore, these abnormalities may be progressive in nature. The ODR task is a valuable indicator of prefrontal cortical function and spatial working memory and may be a potentially valuable marker for familial risk of schizophrenia.

Sleep EEG changes in psychotic disorders: gender and age effects.

The aim of this study was to examine gender-related differences in electroencephalographic (EEG) sleep in inpatients with psychotic disorders. We investigated the effects of gender and age as well as gender-by-age interactions on sleep continuity, architecture and intranight distributions in 38 male and 23 female patients with functional psychoses. No gender effects were seen for any sleep parameters. However, older psychotic males had less slow-wave sleep than older psychotic females. On the other hand, female psychotic patients showed a significant decline in automated REM counts with age. It is possible that gender-related differences in neurodevelopment and/or aging could account for these findings.

Prefrontal membrane phospholipid metabolism of child and adolescent offspring at risk for schizophrenia or schizoaffective disorder: an in vivo 31P MRS study.

In vivo (31)P magnetic resonance spectroscopy ((31)P MRS) studies have shown abnormal membrane phospholipid metabolism in the prefrontal cortex (PF) in the early course of schizophrenia. It is unclear, however, whether these alterations also represent premorbid risk indicators in schizophrenia. In this paper, we report in vivo (31)P MRS data on children and adolescents at high risk (HR) for schizophrenia. In vivo (31)P MRS studies of the PF were conducted on 16 nonpsychotic HR offspring of parents with schizophrenia or schizoaffective disorder, and 37 age-matched healthy comparison (HC) subjects. While 11 of the HR subjects had evidence of Axis I psychopathology (HR-P), five HR subjects had none (HR-NP). We quantified the freely mobile phosphomonoester (PME) and phosphodiester (PDE) levels reflecting membrane phospholipid precursors and breakdown products, respectively, and the relatively broad signal underlying PDE and PME peaks, comprised of less mobile molecules with PDE and PME moieties (eg, synaptic vesicles and phosphorylated proteins). Compared to HC subjects, HR subjects had reductions in freely mobile PME; the differences were accounted for mainly by the HR-P subjects. Additionally, HR-P subjects showed increases in the broad signal underlying the PME and PDE peaks in the PF. To conclude, these data demonstrate new evidence for decreased synthesis of membrane phospholipids and possibly altered content or the molecular environment of synaptic vesicles and/or phosphoproteins in the PF of young offspring at risk for schizophrenia. Follow-up studies are needed to examine the predictive value of these measures for future emergence of schizophrenia in at-risk individuals.