VA Desert Pacific Healthcare Network

Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies. A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

The impairments now called negative symptoms have long been noted as common features of schizophrenia, and the concept of negative symptoms itself has a long history.1,2 Patients who exhibit significant negative symptoms have particularly poor function and quality of life,3–8 and this aspect of schizophrenia has been proposed as a separate domain with distinctive pathophysiological and therapeutic implications since at least 1974.9 Despite the attention these problems receive, no drug has received Food and Drug Administration (FDA) approval for an indication of negative symptoms, and available data indicate that second-generation antipsychotic medications have not met early hopes for a highly effective treatment for alleviation of negative symptoms.10 Because of limited progress in the development of effective treatments for negative symptoms, under the auspices of the National Institute of Mental Health (NIMH), Drs. Steve Marder, Wayne Fenton, William T. Carpenter, Jr, and Brian Kirkpatrick initiated a process to examine issues that may interfere with treatment development. The NIMH had previously focused attention on impaired cognition as a therapeutic target with the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) project. The success of the MATRICS process suggested similar progress could be made in the area of negative symptoms and provided a possible model for proceeding in the area of negative symptoms. Marder, Fenton, Carpenter, and Kirkpatrick organized a consensus development conference, which was held at the NIMH Neuroscience Center in Rockville, Maryland, on January 26–27, 2005. Those attending are listed in the appendix. The mission statement of the meeting was: To review the data relating to the existence of separate domains within negative symptoms, as a prerequisite for choosing appropriate measures of these domains in clinical trials. To initiate a process for developing or identifying widely acceptable, evidence-based measures and methodologies needed to establish the efficacy of treatments that target negative symptoms. Prior to the meeting, the organizers asked experts to address a series of questions: What are the separate components of negative symptoms? Are they independent, or components of the same latent construct? Which aspect of each domain belongs to the negative symptom construct? Does this area need a separate assessment? What is the best assessment method for clinical trials? Since research has suggested that both negative symptoms and cognitive impairments were significant determinants of poor outcome in schizophrenia, an additional set of questions related to the relationship between these domains of psychopathology was also addressed at the conference: Which aspects of cognition are part of the negative symptom construct? Which are independent? Which are uncertain? Articles that more fully address the topics of these presentations can be found in this issue of Schizophrenia Bulletin. Those articles address regulatory issues and negative symptoms,11 negative symptoms as a therapeutic target,12 the factor structure of negative symptoms,13 restricted affect,14 anhedonia,15 and the relationship between negative symptoms and cognitive impairment.16 At the conference other presentations were also made: Wayne Fenton spoke on “Meeting Goals and Objectives: The NIMH Perspective,” Robert Buchanan on “Summary of the MATRICS Process,” William Carpenter, Jr, on “Study Design and the “Pseudospecificity' Problem,” Michael Green on “Social Cognition,” Nancy Andreasen on “Alogia,” and Jeffrey Cummings on “Apathy.” Conference participants achieved consensus on 11 points. 1. Negative symptoms constitute a distinct therapeutic indication area. One purpose of this first statement is to encourage those involved in treatment development to target negative symptoms as a primary outcome variable in treatment trials. Historically, the main strategy for drug development has been to target “positive” psychotic symptoms (hallucinations, delusions, and disorganization) and hope that antipsychotic efficacy will extend to other aspects of schizophrenia, including negative symptoms. The underlying assumption of this approach is that positive and negative symptoms share an underlying pharmacology and hence will have a similar treatment response. The relative lack of success in developing pharmacological treatments for negative symptoms suggests this strategy is not sufficient and brings into question the assumption of a common neuropharmacology. 2. Negative symptoms and cognitive impairments represent separate domains. Aspects of interaction and overlap may be defined in the future, but documentation of substantial separation is available in current data. There is some evidence for a relationship between cognitive impairment and negative symptoms. (For further discussion of this issue, see the accompanying article by Harvey et al.16) The question therefore arose whether negative symptoms and cognitive impairment constitute separate therapeutic indications. Two lines of argument suggest that negative symptoms represent a distinct therapeutic target. First, the relationship between negative symptoms and cognitive impairment is weak and varies with the domain of cognitive impairment. The second line of argument is related to the third point of consensus. 3. Negative symptoms have face validity as disease manifestations and represent loss or diminution of normal functions. The cognitive impairment associated with schizophrenia has become an important focus of treatment trials in large part because of the relationship between cognitive impairment and both level of function in the community and quality of life.17 Improvement in function and quality of life constitute the principal purpose of treatment, but cognitive impairment has an indirect relationship to impairment of significance to the patient's life. In contrast, many negative symptoms have face validity as treatment targets, as they represent a loss of normal function and/or a decrease in the quality of life that can be readily recognized by clinicians and family members. 4. Persistent and clinically significant negative symptoms are an unmet therapeutic need in a large proportion of cases. Review of the prevalence of negative symptoms sufficiently severe to merit therapeutic intervention would be useful. Longitudinal studies, which provide information on the persistence of negative symptoms, would be especially informative. Data from treatment trials, which are usually presented as group averages, do not translate easily into estimates of the percentage of patients with a particular degree of severity. A review of existing literature, including both epidemiological and clinic-based studies, might yield a reasonable estimate of the percentage of patients meeting a criterion for significant negative symptoms, but additional studies may be needed. 5. The distinction between primary and secondary negative symptoms is not essential for the purpose of testing therapeutics for negative symptoms, if a design is used that both selects subjects with persistent negative symptoms and controls for principal sources of secondary negative symptoms. Primary negative symptoms are those that are part of the disease process itself, that is, are not secondary to such factors as depression, drug-induced akinesia, or a suspicious withdrawal.18 Patients with primary negative symptoms can be distinguished from other patients with negative symptoms with good reliability, and with considerable evidence for the validity of that distinction.19 In clinical samples patients with primary negative symptoms represent about 20–25% of patients, whereas in population-based samples approximating incidence samples, they comprise 15–20% of schizophrenia patients. These figures provide a floor for estimates of the percentage of patients whose negative symptoms are sufficiently severe to merit therapeutic intervention. The evidence showing differences in the pathophysiology of primary versus secondary negative symptoms19 suggests that a treatment first shown to be effective for persistent negative symptoms may not prove to be effective for primary negative symptoms. However, most studies of the treatment of negative symptoms will probably focus on patients with both primary and secondary negative symptoms, in order to maximize the number of patients eligible for a treatment trial, and if an appropriate study design is used, this is a reasonable strategy. 6. The paradigmatic design for clinical trials of persistent negative symptoms would include clinically stable patients whose negative symptoms persist with adequate antipsychotic drug treatment. This would be a double-blind, placebo-controlled comparison of parallel groups, in which the putative negative symptom treatment is administered as a co-medication with a second-generation antipsychotic. Many antipsychotics have been shown to improve the negative symptoms of patients who enter a clinical trial during an exacerbation of their positive symptoms. In this context, an improvement in negative symptoms has an ambiguous interpretation, as dysphoria and psychotic symptoms can exacerbate negative symptoms, and if dysphoria or psychotic symptoms should improve at the same time that negative symptoms improve, it is not clear that there has been a direct effect on negative symptoms.20 This issue is sometimes called the “pseudospecificity problem.” An improvement of negative symptoms in clinically stable patients, whose psychotic symptoms have been treated to a usual clinical standard and do not change significantly, would allow an unambiguous interpretation. The rationale for parallel groups is to avoid an ambiguous interpretation due to carryover effects. 7. The paradigmatic design for a co-administered drug is less satisfactory when testing a broad spectrum antipsychotic agent, that is, one that may have superior efficacy for both positive and negative symptoms. If subjects have achieved maximum antipsychotic drug response, the patient population described above for the paradigmatic design above may be appropriate. In such a study, superiority for negative symptoms would be established if the experimental treatment's advantage were limited to negative symptoms, with psychosis and other key symptoms remaining stable and similar to the comparator drug. If an experimental drug is superior in multiple symptom domains, including negative symptoms, a superior efficacy claim may be appropriate, but an indication for negative symptoms may be problematic because of a lack of specificity. The topic of an antipsychotic with superior efficacy for both positive and negative symptoms—a “broad spectrum” antipsychotic (BSA)—was the focus of considerable discussion at the conference. There was agreement that a BSA would be desirable, but the group could not envision or reach consensus on a design that, in a single study, could both establish superior efficacy for psychotic symptoms and avoid the problem of pseudospecificity discussed under point 6, above. There was consensus that, at present, the only way to establish superior efficacy for negative symptoms is with a study in which dysphoria, psychosis, sedation, and extrapyramidal symptoms, which can exacerbate negative symptoms, do not change. Because the interpretation of studies in which a drug simultaneously exhibited superior efficacy for both positive and negative symptoms cannot escape the pseudospecificity problem, FDA approval for a separate indication for negative symptoms would be unlikely. However, a “superior efficacy” claim might be approved. Laughren and Levin of the FDA discuss this issue further in their accompanying article.11 These considerations are not intended to serve as a disincentive for the development of a BSA. Even without an approved indication for negative symptoms, a drug labeling of “superior efficacy” should not be a disincentive, and other solutions to the pseudospecificity problem may be found. Alternative designs deserve further consideration, such as treatment of negative symptoms in a schizoid group without psychotic symptoms, or in a validated human model of primary negative symptoms, should such a model be developed. 8. Within negative symptoms, the definition of a clinically meaningful effect size needs further review. Given the current poor therapeutic results, which means that few patients improve with treatment in the absence of a change in psychotic and depressive symptoms, it is difficult to judge the meaning of a particular effect size. Both clinical experience and correlations with other measures of level of function and quality of life are lacking. 9. The length of a clinical trial will vary with the purpose of a trial. Proof of concept studies may be brief. Preliminary efficacy studies may be 4–12 weeks. Registration trials are likely to be substantially longer (in the range of 6 months), in order to document persistent efficacy. Registration trials are those used to support an application for approval of a therapeutic indication in package inserts and advertising for a drug marketed in the United States. 10. As currently understood, the domains of negative symptoms include blunted affect, alogia, asociality, anhedonia, and avolition. There are substantial correlations across these domains, but they may have separate neurobiological substrates and may represent separate therapeutic targets. The structure of relationships among these domains and their predictive validity require further study. The relationship among the domains of negative symptoms is an important issue for treatment trials. It is unusual for negative symptom domains to be analyzed separately in the context of clinical trials or other studies. If the domains of negative symptoms consistently respond to treatment in a similar manner, detailed assessment of all the domains would be unnecessary. On the other hand, if the domains respond differently to treatment, assessment of a single domain, or use of a combined negative symptom score, might conceal meaningful improvement in a single domain, leading to a false negative finding. (See the accompanying articles in this issue for further discussion of the relationships among negative symptom domains.) This issue also has implications for the development of animal models. If the negative symptom domains have a single or very similar underlying pharmacology, a valid model of one domain may provide accurate predictions about the treatment response of all negative symptoms. However, if the domains have significant differences in their neuropharmacological substrates, predictions based on a model for one domain may be misleading with regard to other domains. Psychometric studies offer important but limited information on this issue. The evidence reviewed during the consensus conference suggested that although these domains are intercorrelated and/or load onto a single factor, there may also be an important degree of independence within groups of these domains. Specifically, there is evidence that blunted affect and poverty of speech comprise a separable grouping or factor, while anhedonia, asociality, and avolition may comprise another. (See the accompanying articles in this issue.) Consideration of social cognition led to the conclusion that as usually defined, it is not part of the negative symptom construct. “Social cognition” refers to the mental operations underlying social interactions, which include the ability and capacity to perceive the intentions and dispositions of others.21 Most of the social cognitive research in schizophrenia has focused on emotion processing, theory of mind, social perception, social knowledge, and attributional bias. Asociality, which is a domain of negative symptoms, refers to a withdrawal from social contact that derives from indifference or lack of desire to have social contact. Other domains were considered in the discussion of negative symptoms, and this point should not be construed to represent a consensus that no other domains should in the future be included in the concept of negative symptoms. 11. The structure of the Scale for the Assessment of Negative Symptoms (SANS)22,is preferred to that of the Positive and Negative Symptom Scale (PANSS)23in that several negative symptom constructs are ascertained, with multiple items related to each. However, the PANSS, SANS, and perhaps other assessment approaches are appropriate for application in current clinical trials. The SANS has played an important role in the study of negative symptoms. Its inclusion of more than 1 item improves the psychometric properties of the scale. Although an instrument with multiple domains and multiple items in each domain should be considered preferable when negative symptoms are the primary focus of a clinical trial, important and valid information can result from the use of other instruments. At the Consensus Development Conference, there was also agreement on 3 recommendations that were intended to facilitate future work on the development of treatments for negative symptoms. 1. Development of a new instrument that included the 5 agreed-upon domains would advance work in this area. Such an instrument needs to be applicable in both in-patient and outpatient clinical trials and needs to be sensitive to change. The negative symptom domains need to be clearly defined for the purposes of instrument development. This task is also essential to encourage development of preclinical models and laboratory-based, human assessments of negative symptoms, and to stimulate translation from neuroscience to the clinical study of negative symptoms. Much of the conference focused on the SANS, which was considered the most important negative symptom rating scale. The SANS was thought to have certain weaknesses, especially the inclusion of items that were not considered to belong to the negative symptom construct, specifically items related to inappropriate affect, attentional impairment, and poverty of content of speech.24 As revision of the SANS seemed desirable, there was also general agreement that a careful reconsideration of items for the 5 domains was justified. For instance, in the area of anhedonia, the concept of appetitive and consummatory aspects of anhedonia has been extended to the study of schizophrenia15; in a negative symptom rating scale it may be desirable to distinguish between these 2 aspects of anhedonia. In the area of asociality, a measure of the subject's desire for relationships is currently absent from most rating scales, but this is a prominent feature in some patients with schizophrenia and appears to be strongly related to other negative symptoms.25,26 2. There is a need to establish a framework, leadership, and financing to accomplish the following: a. form a work group for the development of a negative symptom instrument for clinical trials; b. test the instrument and assess its reliability and psychometric properties; and c. test the instrument in a clinical trial to assess its sensitivity to change. NIMH has made a commitment to serve as a convening body in support of the process envisioned in this point. Marder and Kirkpatrick will organize a working group that would develop the instrument. Marder will also organize a second group composed of senior figures in the field who will provide oversight for the process but will not be involved in the details of instrument development. Participation of representatives from the pharmaceutical industry will be important, as it is hoped that drug companies will use the resulting instrument. 3. There is also a need to establish a framework to promote the identification and testing of drugs for a negative symptom indication. It is likely that this process would be similar to the MATRICS process for drug discovery for the treatment of cognitive impairment in schizophrenia. Prior to the conference, the organizers judged that the conference should not attempt to review the neurobiology of negative symptoms, as this would be such a formidable undertaking that doing so would interfere with the principal goals of the conference, namely, to consider the measurement and definition of negative symptoms. In discussions of this third recommendation, a group composed of experts in clinical treatments and basic neuroscientists was envisioned. The MATRICS process, which has a similar group, was seen as the model for this group. Again, participation by the pharmaceutical industry was envisioned because of the important role of drug companies in developing treatments for patients with schizophrenia. The treatment of the negative symptoms of schizophrenia is generally disappointing, but patients with negative symptoms, whether or not these symptoms are primary, suffer a disproportionate amount of impairment. The hope of those attending the conference was that pointing out areas of consensus and recommending processes for future work would facilitate the development of treatments for negative symptoms. The NIMH decision to continue to support the instrument development and drug identification processes is very promising in this regard. Nancy Andreasen, M.D., of and the of of Maryland, of Maryland, Robert M.D., of Maryland, William T. Carpenter, M.D., of Maryland, Jeffrey M.D., of National Institute of Mental Health Steve M.D., of Wayne Fenton, M.D., National Institute of Mental Health M.D., of Maryland, Michael of M.D., of of Robert National Institute of Mental Health William of M.D., Institute M.D., of Brian M.D., of Maryland, of M.D., Food and Drug Administration Robert M.D., Food and Drug Administration M.D., Steve Marder, M.D., of National Institute of Mental Health Goals and Objectives: The NIMH Wayne Fenton, and Negative Symptoms Negative Symptoms as a Steve Marder, of the MATRICS Robert Design and the William Carpenter, structure and Cognition Michael Nancy Andreasen, M.D., Brian M.D., William Are Negative Symptoms and Jeffrey FDA

Deficits in the ability to perceive facial and vocal emotion expression are common in schizophrenia. However, relatively little is known about how such deficits might affect functional outcomes. This prospective study examined cross-sectional and longitudinal relationships between perception of emotion and aspects of psychosocial functioning, including family relationships, social relationships, work functioning, and independent living/self-care in 94 clinically stabilized schizophrenia outpatients from five community-based rehabilitation programs. Emotion perception (facial emotion, voice emotion, and affect perception) and psychosocial outcome (Strauss and Carpenter Outcome Scale and Role Functioning Scale) were assessed at baseline and after 12 months of psychosocial rehabilitation. Significant associations were found between perception of emotion and work functioning/independent living both cross-sectionally and prospectively over the 12 months. Causal explanatory models suggested that perception of emotion might cause work functioning/independent living outcome over 1 year. The results remained significant when conceptual disorganization was statistically controlled. We did not find differences between men and women in the correlations between emotion perception and work functioning/independent living. Associations between social functioning/family relationships and perception of emotion were not significant. These findings suggest that emotion processing is a key determinant of work functioning/independent living for individuals with serious mental illness.

Despite effective pharmacological treatments for psychotic symptoms (eg, hallucinations, delusions), functional outcomes for people with psychotic disorders are often disappointing. Although it is not included in the diagnostic criteria for psychotic disorders, cognitive impairment is one of the strongest determinants of community functioning in this clinical population, and thus it is an important target for intervention. In this review, we discuss the major areas of research regarding impaired cognition in psychotic illness. The specific topics covered include: (i) the prevalence of cognitive impairment in psychotic disorders; (ii) the profile and magnitude of cognitive impairment in psychotic disorders; (iii) the developmental course of cognitive impairment; (iv) the longitudinal stability of cognitive impairment; and (v) treatment approaches to improve cognitive performance in people with psychotic disorders. .

STUDY OBJECTIVES: To test the role of task difficulty in the cerebral compensatory response after total sleep deprivation (TSD). DESIGN: Subjects performed a modified version of Baddeley's logical reasoning task while undergoing functional magnetic resonance imaging twice: once after normal sleep and once following 35 hours of TSD. The task was modified to parametrically manipulate task difficulty. SETTING: Inpatient General Clinical Research Center and outpatient functional magnetic resonance imaging center. PATIENTS OR PARTICIPANTS: 16 young adults (7 women; mean age, 27.6 +/- 6.1 years; education, 15.4 +/- 1.8 years) were included in the final analyses. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Behaviorally, subjects performed the same after TSD as while well rested. Neuroimaging data revealed a linear increase in cerebral response with a linear increase in task demands in several brain regions after normal sleep. Even stronger linear responses were found after TSD in several brain regions, including bilateral inferior parietal lobes, bilateral temporal cortex, and left inferior and dorsolateral prefrontal cortex. CONCLUSIONS: Task difficulty facilitates the cerebral compensatory response observed following TSD. Compensation manifests as both new regions that did not show significant responses to task demands in the well-rested condition, as well as stronger responses within regions typically underlying task performance. The possible significance of these 2 types of responses should be explored further, as should the importance of the parietal lobes for cognitive performance after TSD.

Research has shown that prevention programming can improve community health when implemented well. There are examples of successful prevention in local communities, however many continue to face significant challenges, demonstrating a gap between science and practice. Common strategies within the United States to address this gap are available (e.g., trainings), but lack outcomes. Building community capacity to implement high quality prevention can help communities achieve positive health outcomes, thereby narrowing the gap. While there is ample research on the efficacy of evidence-based programs, there is little on how to improve community capacity to improve prevention quality. In order to narrow the gap, a new model of research-one based in Community Science-is suggested that improves the latest theoretical understanding of community capacity and evaluates technologies designed to enhance it. In this article, we describe this model and suggest a research agenda that can lead to improved outcomes at the local level.

BACKGROUND: Collaborative-care management is an evidence-based practice for improving depression outcomes in primary care. The Department of Veterans Affairs (VA) has mandated the implementation of collaborative-care management in its satellite clinics, known as Community Based Outpatient Clinics (CBOCs). However, the organizational characteristics of CBOCs present added challenges to implementation. The objective of this study was to evaluate the effectiveness of evidence-based quality improvement (EBQI) as a strategy to facilitate the adoption of collaborative-care management in CBOCs. METHODS: This nonrandomized, small-scale, multisite evaluation of EBQI was conducted at three VA Medical Centers and 11 of their affiliated CBOCs. The Plan phase of the EBQI process involved the localized tailoring of the collaborative-care management program to each CBOC. Researchers ensured that the adaptations were evidence based. Clinical and administrative staff were responsible for adapting the collaborative-care management program for local needs, priorities, preferences and resources. Plan-Do-Study-Act cycles were used to refine the program over time. The evaluation was based on the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) Framework and used data from multiple sources: administrative records, web-based decision-support systems, surveys, and key-informant interviews. RESULTS: Adoption: 69.0% (58/84) of primary care providers referred patients to the program. Reach: 9.0% (298/3,296) of primary care patients diagnosed with depression who were not already receiving specialty care were enrolled in the program. Fidelity: During baseline care manager encounters, education/activation was provided to 100% (298/298) of patients, barriers were assessed and addressed for 100% (298/298) of patients, and depression severity was monitored for 100% (298/298) of patients. Less than half (42.5%, 681/1603) of follow-up encounters during the acute stage were completed within the timeframe specified. During the acute phase of treatment for all trials, the Patient Health Questionnaire (PHQ9) symptom-monitoring tool was used at 100% (681/681) of completed follow-up encounters, and self-management goals were discussed during 15.3% (104/681) of completed follow-up encounters. During the acute phase of treatment for pharmacotherapy and combination trials, medication adherence was assessed at 99.1% (575/580) of completed follow-up encounters, and side effects were assessed at 92.4% (536/580) of completed follow-up encounters. During the acute phase of treatment for psychotherapy and combination trials, counseling session adherence was assessed at 83.3% (239/287) of completed follow-up encounters. Effectiveness: 18.8% (56/298) of enrolled patients remitted (symptom free) and another 22.1% (66/298) responded to treatment (50% reduction in symptom severity). Maintenance: 91.9% (10/11) of the CBOCs chose to sustain the program after research funds were withdrawn. CONCLUSIONS: Provider adoption was good, although reach into the target population was relatively low. Fidelity and maintenance were excellent, and clinical outcomes were comparable to those in randomized controlled trials. Despite the organizational barriers, these findings suggest that EBQI is an effective facilitation strategy for CBOCs. TRIAL REGISTRATION: Clinical trial # NCT00317018.

Social visual engagement difficulties are hallmark early signs of autism (ASD) and are easily quantified using eye tracking methods. However, it is unclear how these difficulties are linked to atypical early functional brain organization in ASD. With resting state fMRI data in a large sample of ASD toddlers and other non-ASD comparison groups, we find ASD-related functional hypoconnnectivity between 'social brain' circuitry such as the default mode network (DMN) and visual and attention networks. An eye tracking-identified ASD subtype with pronounced early social visual engagement difficulties (GeoPref ASD) is characterized by marked DMN-occipito-temporal cortex (OTC) hypoconnectivity. Increased DMN-OTC hypoconnectivity is also related to increased severity of social-communication difficulties, but only in GeoPref ASD. Early and pronounced social-visual circuit hypoconnectivity is a key underlying neurobiological feature describing GeoPref ASD and may be critical for future social-communicative development and represent new treatment targets for early intervention in these individuals.

INTRODUCTION: 22q11.2 deletion syndrome (22q11DS) represents one of the largest known genetic risk factors for psychosis, yet the neurobiological mechanisms underlying symptom development are not well understood. Here we conducted a cross-sectional study of 22q11DS to decompose cortical volume into its constituent parts, cortical thickness (CT) and surface area (SA), which are believed to have distinct neurodevelopmental origins. METHODS: High-resolution T1-weighted scans were collected on 65 participants (31 22q11DS, 34 demographically comparable typically developing controls, 10-25 years old). Measures of cortical volume, CT, and SA were extracted from regions of interest using the FreeSurfer image analysis suite. Group differences and age-related trajectories in these structures, as well as their association with psychotic symptomatology, were assessed. RESULTS: Relative to controls, 22q11DS participants showed bilateral volumetric reductions in the inferior temporal cortex, fusiform gyrus, anterior cingulate, superior parietal cortex, and cuneus, which were driven by decreased SA in these regions. 22q11DS participants also had increased volumes, driven by increased CT, in bilateral insula regions. 22q11DS youth had increased CT in frontal regions, particularly middle frontal and medial orbitofrontal cortices. A pattern of age-associated cortical thinning was observed in typically developing controls in brain regions associated with visual and sensory information-processing (i.e., left pericalcarine cortex and fusiform gyrus, right lingual and postcentral cortices). However, this relationship was disrupted in 22q11DS participants. Finally, correlational analyses revealed that increased CT in right medial orbitofrontal cortex was associated with increased positive symptom severity in 22q11DS. CONCLUSION: Differential disruptions of CT and SA in distinct cortical regions in 22q11DS may indicate abnormalities in distinct developmental neural processes. Further, neuroanatomic abnormalities in medial frontal brain structures disproportionately affected in idiopathic schizophrenia were associated with psychotic symptom severity in 22q11DS youth, suggesting that disrupted biological processes in these cortical regions may underlie development of psychotic symptoms, both in 22q11DS and in the broader population.

Empathic deficits have been linked to poor functioning in schizophrenia, but this work is mostly limited to self-report data. This study examined whether performance-based empathy measures account for incremental variance in social competence and social attainment above and beyond self-reported empathy, neurocognition, and clinical symptoms. Given the importance of working memory in theoretical models of empathy and in the prediction of functioning in schizophrenia, we also examined whether empathy mediates the relationship between working memory and functioning. Sixty outpatients and 45 healthy controls were compared on performance-based measures of 3 key components of empathic responding, including facial affect perception, emotional empathy (affective responsiveness), and cognitive empathy (emotional perspective-taking). Participants also completed measures of self-reported empathy, neurocognition, clinical symptoms, and social competence and attainment. Patients demonstrated lower accuracy than controls across the 3 performance-based empathy measures. Among patients, these measures showed minimal relations to self-reported empathy but significantly correlated with working memory and other neurocognitive functions as well as symptom levels. Furthermore, cognitive empathy explained significant incremental variance in social competence (∆R (2) = .07, P < .05) and was found to mediate the relation between working memory and social competence. Performance-based measures of empathy were sensitive to functionally relevant disturbances in schizophrenia. Working memory deficits appear to have an important effect on these disruptions in empathy. Empathy is emerging as a promising new area for social cognitive research and for novel recovery-oriented treatment development.

This article reviews the extant twin studies employing magnetic resonance imaging data (MRI), with an emphasis on studies of population-based samples. There have been approximately 75 twin reports using MRI, with somewhat under half focusing on typical brain structure. Of these, most are samples of adults. For large brain regions such as lobar volumes, the heritabilities of large brain volumes are consistently high, with genetic factors accounting for at least half of the phenotypic variance. The role of genetics in generating individual differences in the volumes of small brain regions is less clear, mostly due to a dearth of information, but rarely because of disagreement between studies. Multivariate analyses show strong genetic relationships between brain regions. Cortical regions involved in language, executive function, and emotional regulation appear to be more heritable than other areas. Studies of brain shape also show significant, albeit lower, genetic effects on population variance. Finally, there is evidence of significant genetically mediated relationships between intelligence and brain structure. At present, the majority of twin imaging studies are limited by sample sizes small by the standards of behavioral genetics; nevertheless the literature at present represents a pioneering effort in the pursuit of answers to many challenging neurobiological questions.

Abstract Background and Aims Alcohol use disorders (AUDs) are common among people with chronic hepatitis C (HCV) and accelerate the development of fibrosis and cirrhosis caused by HCV. Baclofen, a gamma‐aminobutyric acid (GABA) beta‐receptor agonist, differs from medications for AUDs currently approved by the United States Food and Drug Administration (FDA), as it is metabolized primarily through the kidneys. The primary outcome of this study was to compare baclofen with a placebo in the percentage of days abstinent from alcohol. Design A double‐blind, placebo‐controlled randomized trial. Setting Hepatology clinics in four separate US Veteran Affairs Medical Centers in the United States. Participants One hundred and eighty Veteran men and women older than 18 years with chronic HCV, a comorbid AUD and current alcohol use. Intervention and Comparator Oral baclofen was given at dosages of 0 (placebo) or 30 mg/day over 12 weeks with concomitant manual‐guided counseling. Measurements The primary measurement was percentage of days abstinent during the 12‐week study period between the baclofen and placebo groups [measured by time‐line follow‐back (TLFB)]. Secondary measurements were the percentage of Veterans who achieved complete abstinence, the percentage of Veterans who achieved no heavy drinking between weeks 4 and 12 of the study, alcohol craving, anxiety, depression and post‐traumatic stress disorder (PTSD). Findings Primary outcome: compared with placebo, baclofen did not improve the percentage of days abstinent. For all subjects there were significant reductions from baseline to 12 weeks in percentage of days abstinent from 37.0% [standard error (SE) = 2.7] to 68.6% (SE = 2.8, F (1151.1) = 66.1, P &lt; 0.001). However, there was no statistically significant difference between groups for change in percentage of days abstinent over the 12‐week study period [absolute difference 1.3% (−9.1 to 1.7%), F (1152.6) = 0.005, P = 0.95]. Secondary outcomes: Of subjects who completed the first 4 weeks of the study, 8.9% (15 of 168) achieved complete abstinence; 10.1% (nine of 89) in the placebo group and 7.6% (six of 79) in the baclofen group [χ 2 (1) = 0.33, odds ratio (OR) = 0.73 (0.24–2.15)]. The percentage of no heavy drinking for all subjects between weeks 4 and 12 was 20.2% (34 of 168), but no statistically significant differences were found between placebo 15.7% (14 of 89) and baclofen 25.3% (20 of 79) [χ 2 (1) = 2.38, OR = 1.82 (0.85–3.90)]. There were significant reductions for all subjects in all other secondary variables over the course of the study, but no differences between groups. Measures of various biomarkers of alcohol use did not change significantly throughout the course of the study for either the baclofen or placebo groups. Conclusions Baclofen administered at 30 mg/day does not appear to be superior to placebo in increasing abstinence or in reducing alcohol use, cravings for alcohol or anxiety among people with alcohol use disorder.

BACKGROUND: The Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first "wave" (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS "wave" (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients. METHODS: PPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, "wave" (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness. RESULTS: ANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across "waves" (p<0.0004). Strict response criteria excluded almost 39% of all subjects, disproportionately impacting specific subgroups; ANOVA in this smaller cohort confirmed no significant effect of "wave" or "wave x diagnosis" interaction, and a significant effect of diagnosis (p<0.002). Antipsychotic-free, early-illness patients had particularly robust PPI deficits. DISCUSSION: Schizophrenia-linked PPI deficits were replicable across two multi-site "waves" of subjects collected over 3.5years. Strict response criteria disproportionately excluded older, male, non-Caucasian patients with low-normal hearing acuity. These findings set the stage for genetic analyses of PPI using the combined COGS wave 1 and 2 cohorts.

Evidence for abnormal brain function as measured with diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) and cognitive dysfunction have been observed in inter-episode bipolar disorder (BD) patients. We aimed to create a joint statistical model of white matter integrity and functional response measures in explaining differences in working memory and processing speed among BD patients. Medicated inter-episode BD (n=26; age=45.2±10.1 years) and healthy comparison (HC; n=36; age=46.3±11.5 years) participants completed 51-direction DTI and fMRI while performing a working memory task. Participants also completed a processing speed test. Tract-based spatial statistics identified common white matter tracts where fractional anisotropy was calculated from atlas-defined regions of interest. Brain responses within regions of interest activation clusters were also calculated. Least angle regression was used to fuse fMRI and DTI data to select the best joint neuroimaging predictors of cognitive performance for each group. While there was overlap between groups in which regions were most related to cognitive performance, some relationships differed between groups. For working memory accuracy, BD-specific predictors included bilateral dorsolateral prefrontal cortex from fMRI, splenium of the corpus callosum, left uncinate fasciculus, and bilateral superior longitudinal fasciculi from DTI. For processing speed, the genu and splenium of the corpus callosum and right superior longitudinal fasciculus from DTI were significant predictors of cognitive performance selectively for BD patients. BD patients demonstrated unique brain-cognition relationships compared to HC. These findings are a first step in discovering how interactions of structural and functional brain abnormalities contribute to cognitive impairments in BD.

AIMS: To determine the efficacy of motivational enhancement therapy (MET) on alcohol use in patients with the hepatitis C virus (HCV) and an alcohol use disorder (AUD). DESIGN: Randomized, single-blind, controlled trial comparing MET to a control education condition with 6-month follow-up. SETTING: Patients were recruited from hepatitis clinics at the Minneapolis, Minnesota and Portland, Oregon Veterans Affairs Health Care Systems, USA. PARTICIPANTS AND INTERVENTION: Patients with HCV, an AUD and continued alcohol use (n = 139) were randomized to receive either MET (n = 70) or a control education condition (n = 69) over 3 months. MEASUREMENTS: Data were self-reported percentage of days abstinent from alcohol and number of standard alcohol drinks per week 6 months after randomization. FINDINGS: At baseline, subjects in MET had 34.98% days abstinent, which increased to 73.15% at 6 months compared to 34.63 and 59.49% for the control condition. Multi-level models examined changes in alcohol consumption between MET and control groups. Results showed a significant increase in percentage of days abstinent overall (F(1120.4) = 28.04, P < 0.001) and a significant group × time effect (F(1119.9) = 5.23, P = 0.024) with the MET group showing a greater increase in percentage of days abstinent at 6 months compared with the education control condition. There were no significant differences between groups for drinks per week. The effect size of the MET intervention was moderate (0.45) for percentage of days abstinent. CONCLUSION: Motivational enhancement therapy (MET) appears to increase the percentage of days abstinent in patients with chronic hepatitis C, alcohol use disorders and ongoing alcohol use.

Previous fMRI research has found altered brain response after total sleep deprivation (TSD), with TSD effects moderated by task difficulty. Specific models of the impact of sleep deprivation and task difficulty on brain response have yet to be developed. Differences in networks of fMRI measured brain response during verbal encoding in sleep deprived and well-rested individuals were examined with structural equation modeling (SEM). During fMRI scanning, 23 healthy volunteers memorized words either easy or difficult to recall, 12 (well-rested) and 36 hours (sleep deprived) after awaking. A priori models that linked specified regions of interest were evaluated, with the focus on the extent to which two left parietal regions interacted with the left inferior frontal gyrus (Model 1) or with the right inferior frontal gyrus (Model 2). Task difficulty, not TSD, determined which model fit the brain response data; Model 2 fit best for hard words before and after TSD, whereas Model 1 fit best for easy words. TSD altered the patterns of interaction within each of the best fitting models: prefrontal interactions with the left inferior parietal lobe were diminished and intra-parietal interactions increased. Sleep deprivation and item difficulty produce different effects on brain networks involved in verbal learning.

Numerous studies have demonstrated that collaborative care (care management) for depression improves outcomes, yet few clinics have implemented this evidence-based practice. To promote adoption of this best practice, our objective was to describe the steps needed to tailor collaborative care models for local needs, resources, and priorities while maintaining fidelity to the evidence base. Based on lessons learned from 2 multisite Veterans Affairs implementation studies conducted in 2 different clinical, organizational, and geographic contexts, we describe in detail the steps needed to adapt an evidence-based collaborative care program for depression for local context while maintaining highly fidelity to the research evidence. These steps represent a detailed checklist of decisions and action items that can be used as a tool to plan the implementation of a collaborative care model for depression. We also identify other tools (eg, decision support systems, suicide risk assessment) and resources (eg, training materials) that will support implementation efforts. These implementation tools should help clinicians and administrators develop informed strategies for rolling out collaborative care models for depression.

Targeted cognitive training (TCT) of auditory processing enhances higher-order cognition in schizophrenia patients. TCT performance gains can be detected after 1 training session. As a prelude to a potential clinical trial, we assessed a pharmacological augmentation of cognitive therapy (PACT) strategy by testing if the psychostimulant, amphetamine, augments TCT gains in auditory processing speed (APS) in schizophrenia patients and healthy subjects (HS). HS and schizophrenia patients were tested in a screening session (test 1), followed by a double-blind crossover design (tests 2-3), comparing placebo vs amphetamine (10 mg; 7 d between tests). On each test day, 1 hour of Posit Science "Sound Sweeps" training was bracketed by 2- to 4-minute pre- and post-training assessments of APS. Training consisted of a speeded auditory time-order judgment task of successive frequency modulation sweeps. Auditory system "learning" (APS post- vs pre-training) was enhanced by amphetamine (main effect of drug: P < .002; patients: d = 0.56, P < .02; HS: d = 0.39, nonsignificant), and this learning was sustained for at least 1 week. Exploratory analyses assessed potential biomarker predictors of sensitivity to these effects of amphetamine. Amphetamine enhances auditory discrimination learning in schizophrenia patients. We do not know whether gains in APS observed in patients after 1 hour of TCT predict clinical benefits after a full course of TCT. If amphetamine can enhance the therapeutic effects of TCT, this would provide strong support for a "PACT" treatment paradigm for schizophrenia.

OBJECTIVE: Individuals with the hepatitis C virus (HCV) have high rates of both chronic pain and substance use disorder (SUD). Despite high comorbidity, there are limited data available on effective methods of treatment for co-occurring chronic pain and SUD. In this study, we sought to develop and conduct preliminary testing of an integrated cognitive-behavior therapy (CBT) for chronic pain and SUD in patients with HCV. DESIGN: Descriptive, including pretreatment, posttreatment, and follow-up testing. SETTING AND PATIENTS: Outpatient clinic as part of one VA Medical Center. PARTICIPANTS: Veterans with chronic pain, SUD, and HCV. INTERVENTION: Eight-session integrated group CBT for chronic pain and SUD in patients with HCV. METHODS: Participants completed standardized measures of pain, function, depression severity, and alcohol and substance use at baseline, post-treatment, and 3-month follow-up. RESULTS: Generalized estimating equations identified improvements in pain interference, reducing cravings for alcohol and other substances, and decreasing past-month alcohol and substance use. The proportion of participants who met diagnostic criteria for current SUD demonstrated a four-fold decrease over the course of the study from 24% at baseline to 15% at post-treatment and 6% at 3-month follow-up. On response to a global impression of change, 94% of participants noted improvement from baseline. CONCLUSIONS: Results from this pilot study suggest that a customized CBT for patients with both chronic pain and SUD (CBT-cp.sud) may be beneficial in improving important pain and addiction-related outcomes in patients with HCV. Larger scale investigations of this intervention appear warranted.

Currently approved treatments for schizophrenia only minimally affect the cognitive features of the illness that are the most closely related to disability. Hence, there is now considerable effort to repurpose drugs for schizophrenia, and to seek agents that can improve cognition by targeting receptor systems other than the dopaminergic system. The results of these studies have been mixed thus far; however, this continues to be a high-priority area of schizophrenia research and an important unmet need.