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Rare genomic disorders (RGDs) confer elevated risk for neurodevelopmental psychiatric disorders. In this era of intense genomics discoveries, the landscape of RGDs is rapidly evolving. However, there has not been comparable progress to date in scalable, harmonized phenotyping methods. As a result, beyond associations with categorical diagnoses, the effects on dimensional traits remain unclear for many RGDs. The nature and specificity of RGD effects on cognitive and behavioral traits is an area of intense investigation: RGDs are frequently associated with more than one psychiatric condition, and those studied to date affect, to varying degrees, a broad range of developmental and cognitive functions. Although many RGDs have large effects, phenotypic expression is typically influenced by additional genomic and environmental factors. There is emerging evidence that using polygenic risk scores in individuals with RGDs offers opportunities to refine prediction, thus allowing for the identification of those at greatest risk of psychiatric illness. However, translation into the clinic is hindered by roadblocks, which include limited genetic testing in clinical psychiatry, and the lack of guidelines for following individuals with RGDs, who are at high risk of developing psychiatric symptoms. The Genes to Mental Health Network (G2MH) is a newly funded National Institute of Mental Health initiative that will collect, share, and analyze large-scale data sets combining genomics and dimensional measures of psychopathology spanning diverse populations and geography. The authors present here the most recent understanding of the effects of RGDs on dimensional behavioral traits and risk for psychiatric conditions and discuss strategies that will be pursued within the G2MH network, as well as how expected results can be translated into clinical practice to improve patient outcomes.

High comorbidity among psychiatric disorders suggests that they may share underlying neurobiological deficits. Abnormalities in cortical thickness and volume have been demonstrated in clinical samples of adults, but less is known when these structural differences emerge in youths. The purpose of this study was to examine the association between dimensions of psychopathology and brain structure.The authors studied 1,394 youths who underwent brain imaging as part of the Philadelphia Neurodevelopmental Cohort. Dimensions of psychopathology were constructed using a bifactor model of symptoms. Cortical thickness and volume were quantified using high-resolution 3-T MRI. Structural covariance networks were derived using nonnegative matrix factorization and analyzed using generalized additive models with penalized splines to capture both linear and nonlinear age-related effects.Fear symptoms were associated with reduced cortical thickness in most networks, and overall psychopathology was associated with globally reduced gray matter volume across all networks. Structural covariance networks predicted psychopathology symptoms above and beyond demographic characteristics and cognitive performance.The results suggest a dissociable relationship whereby fear is most strongly linked to reduced cortical thickness and overall psychopathology is most strongly linked to global reductions in gray matter volume. Such results have implications for understanding how abnormalities of brain development may be associated with divergent dimensions of psychopathology.

Objective: Chromosome 22q11.2 deletion syndrome is a neurogenetic disorder associated with high rates of schizophrenia and other psychiatric conditions. The authors report what is to their knowledge the first large-scale collaborative study of rates and sex distributions of psychiatric disorders from childhood to adulthood in 22q11.2 deletion syndrome. The associations among psychopathology, intellect, and functioning were examined in a subgroup of participants. Method: The 1,402 participants With 22q11.2 deletion syndrome, ages 6-68 years, were assessed for psychiatric disorders with validated diagnostic instruments. Data on intelligence and adaptive functioning were available for 183 participants ages 6 to 24 years. Results: Attention deficit hyperactivity disorder (ADHD) was the most frequent disorder in children (37.10%) and was overrepresented in males. Anxiety disorders were more prevalent than mood disorders at all ages, but especially in children and adolescents. Anxiety and unipolar mood disorders were overrepresented in females. Psychotic disorders were present in 41% of adults over age 25. Males did not predominate in psychotic or autism spectrum disorders. Hierarchical regressions in the subgroup revealed that daily living skills were predicted by the presence of anxiety disorders. Psychopathology was not associated with communication or socialization skills. Conclusions: To the authors' knowledge, this is the largest study of psychiatric morbidity in 22q11.2 deletion syndrome. It validates previous findings that this condition is one of the strongest risk factors for psychosis. Anxiety and developmental disorders were also prevalent. These results highlight the need to monitor and reduce the long-term burden of psychopathology in 22q11.2 deletion syndrome.

A major barrier to developing treatments for negative symptoms has been measurement concerns with existing assessment tools. Fulfilling the top recommendation of the National Institute of Mental Health's Consensus Development Conference on Negative Symptoms, the Clinical Assessment Interview for Negative Symptoms (CAINS) was developed using an iterative, empirical approach, and includes items assessing motivation, pleasure, and emotion expression. The authors employed multiple analytic techniques to develop the CAINS and here provide final development and validation results.The CAINS structure, interrater agreement, test-retest reliability, and convergent and discriminant validity were assessed in a large and diverse sample of 162 outpatients with schizophrenia or schizoaffective disorder recruited from four sites.Three items with poor psychometric properties were removed, resulting in a 13-item CAINS. The CAINS factor structure was replicated, demonstrating two modestly correlated scales: expression (four items) and motivation/pleasure (nine items). The scales demonstrated good internal consistency, test-retest stability, and interrater agreement. Strong convergent validity was demonstrated by linkages with other negative symptom measures, self-report scales of sociality, pleasure, and motivation, and coded facial expressions. Discriminant validity was shown by independence from depression, medication side effects, and cognition. Notably, the CAINS scales were related to real-world vocational, independent living, and social/familial functioning.The CAINS is an empirically developed and evaluated measure of negative symptoms. Findings indicate that the CAINS is brief yet comprehensive and employable across a wide range of research and clinical contexts.

This study assessed the relationship between symptoms and cognitive measures at intake and functional outcome 2-8 years later (average 3 years) in first-episode and previously treated schizophrenia patients.A composite cognitive score was assessed at intake to determine the influence of cognition on later functional outcome. At intake and follow-up, positive and negative symptoms were assessed with the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms, and affective symptoms were assessed with the Hamilton Depression Rating Scale. Level of function in seven domains (social function, occupational function, independent living, symptom severity, fullness of life, extent of psychiatric hospitalization, and overall level of function) at intake and follow-up was assessed with the Strauss-Carpenter Level of Function scale. The contributions of sex, education, and duration of illness to functional outcome were also examined.The results indicated that symptoms at intake had distinct patterns of prognostic significance for functional outcome in previously treated patients, compared with first-episode patients. In addition, male and female patients differed in the degree to which initial symptoms were correlated with later function.Initial level of function, symptoms, sex, education, and duration of illness are all important predictors for functional outcome in patients with schizophrenia.

Anatomical and functional deficits of the olfactory neural system have been identified in patients with schizophrenia. Since olfactory structures develop in conjunction with both the palate and ventral forebrain, the authors hypothesized that schizophrenia patients might have structural abnormalities of the nasal cavity, which could represent specific markers of embryological dysmorphogenesis underlying schizophrenia.A measurement of nasal volume was acquired by acoustic rhinometry for 40 male schizophrenia patients and 24 healthy male comparison subjects.The patients had smaller posterior nasal volumes than the comparison subjects but did not differ in anterior nasal volumes. This difference persisted after covarying for height and smoking history.The lower observed posterior nasal volume likely reflects a specific developmental craniofacial abnormality. This finding confirms an early disruption in embryological development in males with schizophrenia and may represent a genetic or environmental "first hit" that leaves the individual vulnerable to subsequent pathology.

Objective: Neuropsychological studies have demonstrated verbal episodic memory deficits in schizophrenia during word encoding and retrieval. This study examined neural substrates of memory in an analysis that controlled for successful retrieval. Method: Event-related blood-oxygenlevel-dependent (BOLD) functional magnetic resonance imaging (fMRI) was used to measure brain activation during word encoding and recognition in 14 patients with schizophrenia and 15 healthy comparison subjects. An unbiased multiple linear regression procedure was used to model the BOLD response, and task effects were detected by contrasting the signal before and after stimulus onset. Results: Patients attended during encoding and had unimpaired reaction times and normal response biases during recognition, but they had lower recognition discriminability scores, compared with the healthy subjects. Analysis of contrasts was restricted to correct items. Previous findings of a deficit in bilateral prefrontal cortex activation during encoding in patients were reproduced, but patients showed greater parahippocampal activation rather than deficits in temporal lobe activation. During recognition, left dorsolateral prefrontal cortex activation was lower in the patients and right anterior prefrontal cortex activation was preserved, as in the authors’ previous study using positron emission tomography. Successful retrieval was associated with greater right dorsolateral prefrontal cortex activation in the comparison subjects, whereas orbitofrontal, superior frontal, mesial temporal, middle temporal, and inferior parietal regions were more active in the patients during successful retrieval. Conclusions: The pattern of prefrontal cortex underactivation and parahippocampal overactivation in the patients suggests that functional connectivity of dorsolateral prefrontal and temporal-limbic structures is disrupted by schizophrenia. This disruption may be reflected in the memory strategies of patients with schizophrenia, which include reliance on rote rehearsal rather than associative semantic processing.

Objective: The authors used color photographs of emotional and neutral expressions to investigate recognition patterns of five universal emotions in schizophrenia. Method: Twenty-eight stable outpatients with schizophrenia (19 men and nine women) and 61 healthy subjects (29 men and 32 women) completed an emotion discrimination test that presented mild and extreme intensities of happy, sad, angry, fearful, disgusted, and neutral faces, balanced for gender and ethnicity. Analyses evaluated accuracy of identifying emotions as a function of intensity, diagnosis, and gender of poser and rater. Results: Patients performed worse than comparison subjects on recognition of all emotions and neutral faces combined, including mild and extreme expressions. For specific emotions, patients performed worse on recognition of fearful, disgusted, and neutral expressions. For all emotions except disgust, recognition of extreme intensity was better than recognition of mild intensity. However, patients showed less benefit from increased intensity for all emotions combined, and the difference was most pronounced for fear. Thus, patients were more impaired than healthy comparison subjects in identifying high-intensity expressions, even though this was an easier task than identifying low-intensity expressions. In the comparison of patterns of errors, patients and healthy subjects differed only in misattributions of neutral expressions; patients overattributed disgusted expressions and underattributed happy expressions. Conclusions: Patients with schizophrenia were impaired in overall emotion recognition, particularly fear and disgust, and did not benefit from increased emotional intensity. Error patterns indicate that patients misidentified neutral cues as negatively valenced.

Objective: Olfactory deficits in patients with schizophrenia, including those of odor identification, detection threshold sensitivity, discrimination, and memory, have been well described. Deficits in emotional perception, processing, and experience have also been reported, with anhedonia being one of the core features. While anatomical connections testify to the relationship between olfaction and emotion, there has been little investigation of the hedonic properties of odors in schizophrenia. This study examined intensity and hedonic judgments in patients with schizophrenia to determine whether these functions were differentially impaired. Method: Suprathreshold scaling of odor intensity and pleasantness was acquired by using the Suprathreshold Amyl Acetate Odor Intensity and Odor Pleasantness Rating Test given to 30 patients (15 men and 15 women) with a DSM-IV diagnosis of schizophrenia and 30 age- and sexmatched healthy comparison subjects. Results: Despite virtually identical ratings of odor intensity, male patients were impaired in the assignment of odor pleasantness to amyl acetate. This gender-specific diagnostic group difference was not explained by variability in symptom severity or negative/positive symptoms. The impact of smoking status and general cognitive impairment on this deficit was also insignificant. Conclusions: Findings reveal a genderspecific disruption in the ability to attribute appropriate hedonic valence to odors in male patients with schizophrenia. This difficulty in identifying the hedonic valence of odors, despite intact intensity ratings, is consistent with clinical observations of anhedonia and points to a neural substrate that might contribute to the emotional disturbances seen in patients with schizophrenia.

There is a substantial genetic contribution to schizophrenia but no way to readily identify individuals at risk. Biological abnormalities reflecting greater genetic vulnerability may be discovered by examining healthy family members of patients with schizophrenia. There is evidence that olfactory impairments are common in patients. The authors previously reported that patients have abnormal olfactory bulbs, assessed by magnetic resonance imaging (MRI). This study examined olfactory bulbs in patients' relatives to determine whether low bulb volume represents an endophenotypic marker of genetic vulnerability.Olfactory psychophysical measures and MRI scans of olfactory bulbs were acquired from 19 healthy first-degree relatives, 20 healthy comparison subjects with similar age and gender distributions, and the 11 patient probands of these relatives. Olfactory bulb volumes were measured by using a reliable region-of-interest procedure.The patients had impaired ability to detect odors and had lower olfactory bulb volumes than the comparison subjects. Although the family members had normal olfactory ability, they exhibited low right bulb volume. The patients had smaller left, but not right, olfactory bulbs than their own healthy relatives.The findings in family members suggest that structural abnormalities of the olfactory system in schizophrenia may partly reflect preexisting genetic vulnerability to illness. Preliminary analyses suggest that right olfactory bulb volume may serve as an endophenotypic marker of genetic vulnerability, while left bulb volume may reflect overt disease among individuals who share genetic vulnerability. Bulb abnormalities in patients are consistent with reports of cellular abnormalities affecting peripheral olfactory receptor neurons.

Emotion processing deficits are notable in schizophrenia. The authors evaluated cerebral blood flow response in schizophrenia patients during facial emotion processing to test the hypothesis of diminished limbic activation related to emotional relevance of facial stimuli.Fourteen patients with schizophrenia and 14 matched comparison subjects viewed facial displays of happiness, sadness, anger, fear, and disgust as well as neutral faces. Functional magnetic resonance imaging was used to measure blood-oxygen-level-dependent signal changes as the subjects alternated between tasks of discriminating emotional valence (positive versus negative) and age (over 30 versus under 30) of the faces with an interleaved crosshair reference condition.The groups did not differ in performance on either task. For both tasks, healthy participants showed activation in the fusiform gyrus, occipital lobe, and inferior frontal cortex relative to the resting baseline condition. The increase was greater in the amygdala and hippocampus during the emotional valence discrimination task than during the age discrimination task. In the patients with schizophrenia, minimal focal response was observed for all tasks relative to the resting baseline condition. Contrasting patients and comparison subjects on the emotional valence discrimination task revealed voxels in the left amygdala and bilateral hippocampus in which the comparison subjects had significantly greater activation.Failure to activate limbic regions during emotional valence discrimination may explain emotion processing deficits in patients with schizophrenia. While the lack of limbic recruitment did not significantly impair simple valence discrimination performance in this clinically stable group, it may impact performance of more demanding tasks.

OBJECTIVE: The authors’ goal in this study was to compare the size of olfactory bulbs of patients with schizophrenia and those of healthy subjects.METHOD: Magnetic resonance imaging scans of olfactory bulbs were obtained from 26 patients with schizophrenia and 22 healthy comparison subjects. A reliable region of interest procedure was used to measure olfactory bulb volume.RESULTS: Patients exhibited 23% smaller bilateral bulb volume than comparison subjects, independent of acute clinical, demographic, or treatment measures. Bulb volume correlated with odor detection sensitivity in healthy subjects but not in patients with schizophrenia.CONCLUSIONS: Patients with schizophrenia exhibit structural olfactory deficits as well as functional olfactory deficits. The olfactory system may be a model system in which to study the neurobiology of the disorder.

OBJECTIVE The purpose of this study was to characterize the neuropsychiatric profile of elderly patients with schizophrenia and establish a patient registry for prospective ante-mortem and post-mortem studies. METHOD Medical records of all chronically institutionalized patients in eight state hospitals who were over the age of 65 and had a chart diagnosis of schizophrenia (N = 528) were reviewed. Of the potential subjects, 192 were excluded because of clinical histories inconsistent with a diagnosis of schizophrenia, 56 because of insufficient information to establish a psychiatric diagnosis, and 122 because of family members' refusal to give consent for autopsy in the event of death. To date, 81 of the remaining 158 patients have undergone neuropsychiatric evaluation with standard assessment instruments. RESULTS Mini-Mental State scores of the 81 patients indicated severe dementia, and Functional Assessment Scale scores showed that patients required assistance with activities of daily living. All patients were rated as severely ill on the Brief Psychiatric Rating Scale. Ratings on the Scale for the Assessment of Negative Symptoms and the Scale for the Assessment of Positive Symptoms indicated a predominance of negative symptoms over positive. Of 30 patients who have died to date, research autopsies have been conducted on 26. CONCLUSIONS Establishing a well characterized, prospective patient registry for clinicopathologic studies of schizophrenia is feasible but labor intensive. Diagnosis of schizophrenia with a high degree of confidence can be achieved by means of detailed chart review and assessment of current neuropsychiatric functioning with standard rating instruments. These data provide a basis for correlations of clinicopathologic factors.