Parental age effects on odor sensitivity in healthy subjects and schizophrenia patients.

A schizophrenia phenotype for paternal and maternal age effects on illness risk could benefit etiological research. As odor sensitivity is associated with variability in symptoms and cognition in schizophrenia, we examined if it was related to parental ages in patients and healthy controls. We tested Leukocyte Telomere Length (LTL) as an explanatory factor, as LTL is associated with paternal age and schizophrenia risk. Seventy-five DSM-IV patients and 46 controls were assessed for detection of PEA, WAIS-III for cognition, and LTL, assessed by qPCR. In healthy controls, but not schizophrenia patients, decreasing sensitivity was monotonically related to advancing parental ages, particularly in sons. The relationships between parental aging and odor sensitivity differed significantly for patients and controls (Fisher's R to Z: χ(2) = 6.95, P = 0.009). The groups also differed in the association of odor sensitivity with cognition; lesser sensitivity robustly predicted cognitive impairments in patients (<0.001), but these were unassociated in controls. LTL was unrelated to odor sensitivity and did not explain the association of lesser sensitivity with cognitive deficits.Parental aging predicted less sensitive detection in healthy subjects but not in schizophrenia patients. In patients, decreased odor sensitivity strongly predicted cognitive deficits, whereas more sensitive acuity was associated with older parents. These data support separate risk pathways for schizophrenia. A parental age-related pathway may produce psychosis without impairing cognition and odor sensitivity. Diminished odor sensitivity may furthermore be useful as a biomarker for research and treatment studies in schizophrenia. © 2015 Wiley Periodicals, Inc.

Olfactory performance segregates effects of anhedonia and anxiety on social function in patients with schizophrenia.

BACKGROUND: Social dysfunction is common among individuals with schizophrenia. While often attributed to anhedonia, social dysfunction could also result from unrecognized anxiety. We examined the contributions of anhedonia and anxiety to social function using olfactory function to examine whether the domains had separate underpinnings. METHODS: We assessed anhedonia, anxiety and social function as well as olfactory function in well-characterized patients with schizophrenia or schizoaffective disorder and healthy controls. RESULTS: We included 56 patients and 37 controls in our study. Patients exhibited significantly higher levels of anhedonia and anxiety than controls, and the domains were highly correlated in patients. The combination of anhedonia and anxiety more strongly predicted social dysfunction than either measure alone. Smell identification was differentially related to the symptoms, with better performance predicting less anhedonia but more social fear in male patients. LIMITATIONS: The use of self-report measures precludes differentiation between recollected or recounted experience. Aside from smell identification and odour threshold, additional measures of olfaction may be considered for future studies. CONCLUSION: Anhedonia and anxiety were strongly correlated and both negatively impacted social function. The olfactory biomarker results support the conclusion that these domains are separate. Social function in patients with schizophrenia may improve with interventions for anxiety, even in the presence of marked negative symptoms.

Gut and oral microbiome modulate molecular and clinical markers of schizophrenia-related symptoms: A transdiagnostic, multilevel pilot study.

Although increasing evidence links microbial dysbiosis with the risk for psychiatric symptoms through the microbiome-gut-brain axis (MGBA), the specific mechanisms remain poorly characterized. In a diagnostically heterogeneous group of treated psychiatric cases and nonpsychiatric controls, we characterized the gut and oral microbiome, plasma cytokines, and hippocampal inflammatory processes via proton magnetic resonance spectroscopic imaging (1H-MRSI). Using a transdiagnostic approach, these data were examined in association with schizophrenia-related symptoms measured by the Positive and Negative Syndrome Scale (PANSS). Psychiatric cases had significantly greater heterogeneity of gut alpha diversity and an enrichment of pathogenic taxa, like Veillonella and Prevotella, in the oral microbiome, which was an accurate classifier of phenotype. Cases exhibited significantly greater positive, negative, and general PANSS scores that uniquely correlated with bacterial taxa. Strong, positive correlations of bacterial taxa were also found with cytokines and hippocampal gliosis, dysmyelination, and excitatory neurotransmission. This pilot study supports the hypothesis that the MGBA influences psychiatric symptomatology in a transdiagnostic manner. The relative importance of the oral microbiome in peripheral and hippocampal inflammatory pathways was highlighted, suggesting opportunities for probiotics and oral health to diagnose and treat psychiatric conditions.

Olfactory acuity is associated with mood and function in a pilot study of stable bipolar disorder patients.

OBJECTIVES: Olfactory dysfunction is described in several neuropsychiatric disorders but there is little research on olfactory processing in bipolar disorder. METHODS: We assessed odor detection threshold (sensitivity) and smell identification test scores, along with symptoms, cognition, and social function in 20 DSM-IV bipolar disorder patients and 44 control subjects. RESULTS: The patient and control groups had similar demographic measures, intelligence, and mean olfaction scores, but significantly differed in social domains, including adjustment, function, and anxiety. Odor detection sensitivity showed significantly opposite correlations for the depressive and manic mood domains in bipolar disorder (r to z = 2.83, p = 0.005). Depressive symptoms were related to increased sensitivity (the ability to detect odors at a lower concentration) and mania symptoms were related to decreased sensitivity for odor detection. Increased sensitivity for odor detection also predicted significantly better employment (r = -0.642, p = 0.024), whereas less sensitivity was associated with social avoidance (r = 0.702, p =0.024) and social fear (r = 0.610, p = 0.046). CONCLUSIONS: Diminished odor detection sensitivity predicted mania and social avoidance, whereas more sensitive odor detection predicted more depressive symptoms but better employment functioning in bipolar disorder patients. Odor acuity may be an illness state marker of mood syndromes in bipolar disorder. Alternatively, differences in odor acuity may identify heterogeneous subgroups within the bipolar spectrum. Longitudinal assessments in a large, sex-stratified sample are needed to understand the implications of odor sensitivity in patients with bipolar disorder.

Olfaction and cognition in schizophrenia: sex matters.

Cognitive and olfactory deficits occur in schizophrenia, but little is known whether sex modifies these deficits. We examined the relationship between olfaction and cognition in 55 schizophrenia patients and 32 healthy controls. Patients and controls demonstrated significant differences performing cognitive tasks. In patients, sex modified all relationships of odor identification to cognition. Female patients showed significantly stronger trends than male patients correlating better smell identification with higher scores on intelligence, memory, and attention, whereas their correlations of odor identification with executive functioning contradicted those of male patients. Odor acuity significantly correlated with several cognitive measures, especially in male patients, in whom better acuity was generally associated with better cognition. Female patients again differed significantly from males; odor acuity correlations with cognitive measures were weaker, or contradicted, those of male patients. These findings indicate significant sex differences in olfactory processing in schizophrenia. Combining the sexes in research analyses may obscure important differences.

Patient-reported exposures and outcomes link the gut-brain axis and inflammatory pathways to specific symptoms of severe mental illness.

We developed a "gut-brain-axis questionnaire" (GBAQ) to obtain standardized person-specific "review of systems" data for microbiome-gut-brain-axis studies. Individual items were compared to PANSS symptom measures using dimensional, transdiagnostic and traditional categorical approaches. METHOD: Forty psychotic participants, independent of diagnoses, and 42 without psychosis (18 nonpsychotic affective disorders, 24 healthy controls) completed the GBAQ and underwent research diagnostic and symptom assessments. The PANSS scales and its dysphoric mood, autistic preoccupation and activation factors were computed. RESULTS: Transdiagnostic analyses robustly linked psychosis severity to constipation (p<.001), and Negative (p=.045) and General Psychopathology scores (p=.016) with bowel hypomotility. Activation factor scores predicted numbers of psychiatric (p=.009) and medical conditions (p=.003), BMI (p=.003), skin (p<.001) and other conditions. Categorical analyses comparing psychotic, nonpsychotic and control groups revealed behavioral differences: cigarette smoking (p=.013), alcohol use (p=.007), diet (p's <.05), exercise (p<.001). All subjects accurately self-reported their diagnosis. CONCLUSIONS: The GBAQ is a promising tool. Transdiagnostic analyses associated psychotic symptoms to gut hypomotility, indicative of low gut vagal tone, consistent with reduced cardiovagal activity in psychosis. Activation, similar to delirium symptoms, predicted medical comorbidity and systemic inflammatory conditions. Group level comparisons only showed behavioral differences. Underpinnings of psychiatric disorders may include reduced gut vagal function, producing psychosis, and systemic inflammation, impacting risks for psychotic and nonpsychotic conditions.

An integrative study of the microbiome gut-brain-axis and hippocampal inflammation in psychosis: Persistent effects from mode of birth.

The mechanism producing psychosis appears to include hippocampal inflammation, which could be associated with the microbiome-gut-brain-axis (MGBS). To test this hypothesis we are conducting a multidisciplinary study, herein described. The procedures are illustrated with testing of a single subject and group level information on the impact of C-section birth are presented. METHOD: Study subjects undergo research diagnostic interviews and symptom assessments to be categorized into one of 3 study groups: psychosis, nonpsychotic affective disorder or healthy control. Hippocampal volume and metabolite concentrations are assessed using 3-dimensional, multi-voxel H1 Magnetic Resonance Imaging (MRSI) encompassing all gray matter in the entire hippocampal volume. Rich self-report information is obtained with the PROMIS interview, which was developed by the NIH Commons for research in chronic conditions. Early trauma is assessed and cognition is quantitated using the MATRICS. The method also includes the most comprehensive autonomic nervous system (ANS) battery used to date in psychiatric research. Stool and oral samples are obtained for microbiome assessments and cytokines and other substances are measured in blood samples. RESULTS: Group level preliminary data shows that C-section birth is associated with higher concentrations of GLX, a glutamate related hippocampal neurotransmitter in psychotic cases, worse symptoms in affective disorder cases and smaller hippocampal volume in controls. CONCLUSION: Mode of birth appears to have persistent influences through adulthood. The methodology described for this study will define pathways through which the MGBA may influence the risk for psychiatric disorders.

Ineffective risk-reward learning in schizophrenia.

The underpinnings of poor decision-making in schizophrenia could reflect excessively risky or inhibited behaviors. This study employed the Balloon Analogue Risk Task (BART) to compare decision-making in schizophrenia cases to that of healthy controls. Individuals with schizophrenia performed significantly differently across three trials, failing to improve their performance as shown by the control group. In the control group, cognitive ability, measured with the Wechsler Adult Intelligence Scale (WAIS-III) showed that Perceptual Organization scores predicted Average Inflations per Trial, Total Balloon Pops, and Total Earnings. Although the schizophrenia cases failed to learn, group performance on the BART was not associated with cognitive ability, but regression analyses showed 41.4% of average inflations per trial were explained by Excitement, Delusions, Emotional Withdrawal, and Poor Rapport; total balloon pops were only explained by emotional withdrawal and Total Earnings were reduced by Delusions, Excitement and Poor Rapport. Only healthy participants demonstrated a relation between cognitive ability performance improvement across trials. Schizophrenia cases showed less risk-taking, and earned significantly less money overall. Identifying the determinants of poor decision-making could inform interventions and possible treatments to improve their function and perhaps be of relevance to public safety if decisions are overly risky.

Normal sexual dimorphism in theory of mind circuitry is reversed in Schizophrenia.

The ability to mentalize, or theory of mind (ToM), is sexually dimorphic in humans and impaired in schizophrenia. This sex-stratified study probed cognitive (indexed by intelligence) and affective (indexed by olfactory tasks) contributions to ToM performance in 37 individuals with schizophrenia and 31 healthy controls. The schizophrenia group showed impairments in mental state identification and inferring intentions compared to controls. Higher intelligence was correlated with mental state identification and inferring intentions in healthy females, whereas better smell identification was associated with mental state identification in healthy males. Conversely, higher intelligence was associated with mental state identification and inferring intentions in schizophrenia males, while better smell identification was correlated with mental state identification in schizophrenia females. These findings suggest that for ToM circuitry, the cognitive influences in healthy females and affective influences in healthy males are reversed in schizophrenia and may be displaced to lower circuitries by disease pathology. Symptom associations with emotion and cognition are also dimorphic, plausibly due to similar pathology superimposed on normal sex-specific circuitries. Males appear to rely on limbic processing for ToM, and disruption to this circuitry may contribute to development of negative symptoms. These findings highlight the importance of utilizing sex-stratified designs in schizophrenia research.

Factor Structure of the Positive and Negative Syndrome Scale (PANSS) Differs by Sex.

Although the Positive and Negative Syndrome Scale (PANSS) is widely used in clinical research, factor analytic studies of the scale have been inconsistent and questions remain about the underlying factor structure of schizophrenia symptoms. The purpose of this study was to examine whether the factor structure of the PANSS differs in men and women with schizophrenia. Principal components analysis (PCA) with equamax rotation was used to examine the factor structure of the PANSS separately in 124 males and 74 females with schizophrenia-related psychoses. In males, a four-factor structure was identified: 1) Negative, 2) Cognitive, 3) Positive, and 4) Hostility. In females, a four-factor structure also emerged: 1) Negative, 2) Cognitive, 3) Positive, and 4) Depression. The most notable difference between the male and female PCAs was the presence of a depression factor in the females and a hostility factor in males. These results support sex differences in the factor structure of schizophrenia symptoms, which has important implications for clinical research.

Maternal household crowding during pregnancy and the offspring's risk of schizophrenia.

BACKGROUND: Animal models of schizophrenia suggest a link between maternal crowding during pregnancy and increased risk of the offspring to develop physiological, developmental, and behavioral abnormalities that are comparable to those observed in schizophrenia. We tested the hypothesis that a similar link is present in humans. METHOD: We investigated whether prenatal exposure to household crowding was associated with the risk of schizophrenia in a sub-cohort of the Jerusalem Perinatal Study (JPS) consisting 11,015 individuals born between 1964 and 1976. During these years mothers participated in face to face interviews in early pregnancy. The prenatal and birth data, including the number of rooms and individuals living in the mothers' household, was cross-linked with the Israel Psychiatric Registry by ministry personnel. RESULTS: 104 schizophrenia cases were identified in the cohort. Offspring who, while in utero, their mother resided in a household with five or more individuals had RR of 1.47 (95% CI: 0.99-2.16, p=0.05) to develop schizophrenia, compared to those whose mother resided with four or fewer individuals. However, when adjusted for paternal age, the RR was reduced to 1.18 (95% CI: 0.76-1.84, p=0.46). The number of rooms in the household and the household crowding during pregnancy did not significantly impact the offspring's risk to develop schizophrenia. CONCLUSION: The link between maternal household crowding during pregnancy and the offspring's risk of schizophrenia was explained primarily by the impact of paternal age. The authors discuss the results in view of findings from animal and human studies.

Frequent Comorbidity and Predictors of Social Anxiety in Persons With Schizophrenia: A Retrospective Cohort Study.

OBJECTIVE: To determine if symptoms of social anxiety are distinct from negative symptoms of schizophrenia. METHOD: Fifty-three patients with schizophrenia or schizoaffective disorder (diagnosed per DSM-IV criteria) and 37 healthy controls were examined with the Liebowitz Social Anxiety Scale (LSAS) for social anxiety disorder and for the severity of social anxiety. The Positive and Negative Syndrome Scale (PANSS) and the Chapman scales for physical and social anhedonia were also administered. Data were collected from 2005 to 2010 from inpatient and outpatient research centers at the New York State Psychiatric Institute, New York. RESULTS: Social anxiety disorder was elevated more than 10-fold in schizophrenia patients than in controls (37.7% of patients vs 2.9% of controls, P ≤ .001). Social anxiety and social fear were unrelated to the PANSS with few exceptions. A family history of psychosis was also a significant independent predictor of social anxiety as measured by LSAS total (P = .004) and the social fear subscale (P = .007). CONCLUSIONS: These data confirm social anxiety disorder as a prominent comorbid disorder in patients with schizophrenia. Future studies should focus on treatment trials of this phenomenon. Social anxiety cannot be explained by the negative symptomatology of the disease. This study suggests that a family history of psychosis is a significant predictor of social anxiety.

Rare variants in the neurotrophin signaling pathway implicated in schizophrenia risk.

Multiple lines of evidence corroborate impaired signaling pathways as relevant to the underpinnings of schizophrenia. There has been an interest in neurotrophins, since they are crucial mediators of neurodevelopment and in synaptic connectivity in the adult brain. Neurotrophins and their receptors demonstrate aberrant expression patterns in cortical areas for schizophrenia cases in comparison to control subjects. There is little known about the contribution of neurotrophin genes in psychiatric disorders. To begin to address this issue, we conducted high-coverage targeted exome capture in a subset of neurotrophin genes in 48 comprehensively characterized cases with schizophrenia-related psychosis. We herein report rare missense polymorphisms and novel missense mutations in neurotrophin receptor signaling pathway genes. Furthermore, we observed that several genes have a higher propensity to harbor missense coding variants than others. Based on this initial analysis we suggest that rare variants and missense mutations in neurotrophin genes might represent genetic contributions involved across psychiatric disorders.

Paternal age and sporadic schizophrenia: evidence for de novo mutations.

Schizophrenia is an etiologically heterogeneous syndrome. It has a strong genetic component and exists in clinically indistinguishable familial and nonfamilial (sporadic) forms. A significant role for de novo genetic mutations in genetic schizophrenia vulnerability is suggested by a strong monotonic increase in schizophrenia risk with advancing paternal age. However, an alternative explanation for the paternal age effect in schizophrenia is that childbearing is delayed in fathers who themselves have genetic schizophrenia vulnerability. In this study, we compared paternal birth ages between patient groups with familial (n = 35) and sporadic (n = 68) patients with DSM-IV schizophrenia from an inpatient schizophrenia research unit. If later age of fathering children is related to having some genetic schizophrenia vulnerability, then paternal birth age should be later in familial schizophrenia cases than in sporadic cases, and any association of father's age and schizophrenia risk in offspring would be a spurious finding, unrelated to etiology. However, if de novo mutations cause sporadic schizophrenia, then patients without a family history of schizophrenia would have older fathers than familial patients. We found that patients without a family history of schizophrenia had significantly older fathers (4.7 years) than familial patients; so later childbirth was not attributable to parental psychiatric illness. These findings support the hypothesis that de novo mutations contribute to the risk for sporadic schizophrenia.

Schizophrenia risk and paternal age: a potential role for de novo mutations in schizophrenia vulnerability genes.

How schizophrenia (SZ) is maintained at roughly 1% of the population despite diminished reproduction is one puzzle currently facing researchers. De novo mutations were first proposed over half a century ago as a source for new SZ genes. Current evidence linking advancing paternal age to SZ risk makes revisiting this hypothesis important. Advancing paternal age is the major source of new mutations in the human population. This article will examine potential mechanisms whereby parental age may impact new mutations, as well as review recent data supporting such a hypothesis.

Low vitamin D levels predict clinical features of schizophrenia.

Vitamin D plays crucial roles in neuroprotection and neurodevelopment, and low levels are commonly associated with schizophrenia. We considered if the association was spurious or causal by examining the association of Vitamin D with Leukocyte Telomere Length (LTL), a marker of cellular aging. Vitamin D levels in 22 well-characterized schizophrenia cases were examined with respect to symptoms, cognition, and functioning. LTL was assessed using quantitative polymerase chain reaction (qPCR). The results showed that 91% (20) had deficient or insufficient Vitamin D levels, which were associated with excitement and grandiosity, social anhedonia, and poverty of speech. Sex-specific analyses showed strong associations of hypovitamintosis D to negative symptoms and decreased premorbid adjustment in males, and to lesser hallucinations and emotional withdrawal, but increased anti-social aggression in females. In females LTL was furthermore associated with Vitamin D levels. This study demonstrates a relationship of low vitamin D levels with increased cellular aging in females. It is also the first study to demonstrate potential sex-specific profiles among schizophrenia cases with hypovitaminosis.

Point-of-Care HbA1c Testing with the A1cNow Test Kit in General Practice Dental Clinics: A Pilot Study Involving Its Accuracy and Practical Issues in Its Use.

With millions of at-risk people undiagnosed with pre-diabetes and diabetes, there is a need to identify alternate screening sites for out-of-range glucose values. We examined practical issues and accuracy (relative to High Performance Liquid Chromatography testing in a laboratory) in the use of the A1cNow point of care device for this screening in general practice dental clinics at a large University-based Dental College. Health care professionals obtained evaluable readings for only 70% of the subjects, even after two attempts, and its use according to manufacturer's instructions was often challenging in the busy environment of the dental clinic. At thresholds for pre-diabetes and diabetes established by the American Diabetes Association, sensitivities of the A1cNow kit relative to the HPLC method were 91.9% and 100%, respectively. However, specificities for pre-diabetes and diabetes were 66.7% and 82.4%, respectively, indicating many false positive results. A better strategy for diabetes screening may involve a laboratory-based analysis approach that is patient- and provider-friendly, with minimal burden to the dental team.

Olfactory processing, sex effects and heterogeneity in schizophrenia.

INTRODUCTION: Smell identification deficits are associated with negative symptoms in schizophrenia, particularly in males. Far less information is known about the relationship of odor detection sensitivity (acuity) and negative symptoms in schizophrenia, and currently there is a dearth in sex-stratified research specifically examining odor sensitivity and smell identification. METHODS: Fifty-eight individuals with schizophrenia and 42 healthy comparison subjects were assessed on tests of odor sensitivity, smell identification and cognition. Negative symptoms were assessed with the Positive and Negative Syndrome Scale and the Schedule for the Deficit Syndrome. RESULTS: In healthy males, increased odor detection sensitivity predicted better smell identification scores. In contrast, male schizophrenia patients showed a significant inverse relationship, in which increased odor sensitivity predicted lower smell identification scores. Odor sensitivity and smell identification were unrelated in both schizophrenia and healthy females. Olfactory processing was strongly linked to negative symptoms, but the relationships differed by sex. Emotional expression deficits were related to odor detection hypersensitivity in female patients, whereas smell identification deficits predicted these emotional deficits in male cases. CONCLUSION: Sex differences in olfactory functioning were identified in healthy subjects and in schizophrenia patients. Smell identification was related to negative symptoms in males with schizophrenia, whereas odor detection sensitivity predicted these features in females. Sex differences should be considered in future analyses that employ odor stimuli for neuropsychiatric research.

Sensitivity of ICD-10 diagnosis of psychotic disorders in the Israeli National Hospitalization Registry compared with RDC diagnoses based on SADS-L.

OBJECTIVE: The Israeli National Psychiatric Hospitalization Registry is a nationwide list of all psychiatric hospitalizations in the country and has been widely used as a source of data for psychiatric research. This study assessed the sensitivity of the diagnosis of psychotic disorders ( International Statistical Classification of Diseases, 10th Revision [ ICD-10 ] F20.0-F29.9) and schizophrenia ( ICD-10 F20.0-F20.9) in the Registry. METHOD: Registry discharge diagnoses of psychotic disorders ( ICD-10 F20.0-F29.9) and schizophrenia ( ICD-10 F20.0-F20.9) were compared with research diagnoses derived from best-estimate procedures based on Research Diagnostic Criteria (RDC) using structured clinical research interviews, hospital records, and family information. RESULTS: Out of 169 patients meeting RDC for psychotic disorder, 150 also had a diagnosis of psychotic disorders in the Registry, yielding a sensitivity of 0.89. Re-running this analysis for the narrow definition of schizophrenia identified 94 patients who were diagnosed with schizophrenia using RDC; 82 of those patients also had a diagnosis of schizophrenia in the Registry, yielding a sensitivity of 0.87. CONCLUSION: In 87% to 89% of cases with psychotic disorders or with schizophrenia, Registry diagnoses agreed with RDC diagnoses, a rate of agreement comparable with those of other, similar registries. Because a large number of analyses derived from this and similar national registries will be published in the coming years, this constitutes relevant information.