A Novel Psychosocial Intervention for Motivational Negative Symptoms in Schizophrenia: Combined Motivational Interviewing and CBT.

OBJECTIVE: Negative symptoms are a primary cause of disability in schizophrenia for which there are no established pharmacotherapies. This study evaluated a novel psychosocial intervention that combined two evidence-based practices-motivational interviewing and cognitive-behavioral therapy (MI-CBT)-for the treatment of motivational negative symptoms. METHODS: Seventy-nine participants with schizophrenia and moderate to severe negative symptoms were included in a randomized controlled trial comparing the 12-session MI-CBT treatment with a mindfulness control condition. Participants were assessed at three time points through the study period, which included 12 weeks of active treatment and 12 weeks of follow-up. The primary outcome measures were motivational negative symptoms and community functioning; the secondary outcomes included a posited biomarker of negative symptoms: pupillometric response to cognitive effort. RESULTS: Compared with the control group, participants in the MI-CBT group showed significantly greater improvements in motivational negative symptoms over the acute treatment period. Their gains relative to baseline were maintained at follow-up, although the differential benefit relative to control subjects was attenuated. There were nonsignificant effects toward improvements in community functioning and differential change in the pupillometric markers of cognitive effort. CONCLUSIONS: The results show that combining motivational interviewing with CBT yields improvements in negative symptoms, a feature of schizophrenia generally thought of as resistant to intervention. Motivational negative symptoms not only responded to the novel treatment, but the gains were maintained over the follow-up period. Implications for future studies and for improving the generalization of the negative symptom gains to daily functioning domains are discussed.

Heritability of acoustic startle magnitude and latency from the consortium on the genetics of schizophrenia.

BACKGROUND: Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed. Schizophrenia subjects exhibit slowed latency compared to healthy controls. One prior publication reported significant heritability of latency. The current study was undertaken to replicate and extend this solitary finding in a larger cohort. METHODS: Schizophrenia probands, their relatives, and control subjects from the Consortium on the Genetics of Schizophrenia (COGS-1) were tested in a paradigm to ascertain magnitude, latency, and prepulse inhibition of startle. Trial types in the paradigm were: pulse-alone, and trials with 30, 60, or 120 ms between the prepulse and pulse. Comparisons of subject groups were conducted with ANCOVAs to assess startle latency and magnitude. Heritability of startle magnitude and latency was analyzed with a variance component method implemented in SOLAR v.4.3.1. RESULTS: 980 subjects had analyzable startle results: 199 schizophrenia probands, 456 of their relatives, and 325 controls. A mixed-design ANCOVA on startle latency in the four trial types was significant for subject group (F(2,973) = 4.45, p = 0.012) such that probands were slowest, relatives were intermediate and controls were fastest. Magnitude to pulse-alone trials differed significantly between groups by ANCOVA (F(2,974) = 3.92, p = 0.020) such that controls were lowest, probands highest, and relatives intermediate. Heritability was significant (p < 0.0001), with heritability of 34-41% for latency and 45-59% for magnitude. CONCLUSION: Both startle latency and magnitude are significantly heritable in the COGS-1 cohort. Startle latency is a strong candidate for being an endophenotype in schizophrenia.

High Quality of Care Persists With Shifting Depression Services From VA Specialty to Integrated Primary Care.

BACKGROUND/OBJECTIVE: Offering depression collaborative care services in primary care (PC) settings can reduce use of nonintegrated mental health care resources and improve mental health care access, particularly for vulnerable PC patients. Tests of effects on depression care quality, however, are needed. We examined overall quality of depression care and tested whether increasing clinic engagement in Veterans Affairs (VA)'s Primary Care-Mental Health Integration (PC-MHI) services was associated with differences in depression care quality over time. METHODS: We conducted a retrospective longitudinal cohort study of 80,136 Veterans seen in 26 Southern California VA PC clinics (October 1, 2008-September 30, 2013). Using multilevel regression models adjusting for year, clinic, and patient characteristics, we predicted effects of clinic PC-MHI engagement (ie, percent of PC patients receiving PC-MHI services) on 3 VA-developed longitudinal electronic population-based depression quality measures among Veterans newly diagnosed with depression (n=12,533). RESULTS: Clinic PC-MHI engagement rates were not associated with significant depression care quality differences. Across all clinics, average rates of follow-up within 84 or 180 days were, 66.4% and 74.5%, respectively. Receipt of minimally appropriate treatment was 80.5%. Treatment probabilities were significantly higher for vulnerable PC patients (homeless: 4.5%, P=0.03; serious mental illness: 15.2%, P<0.001), than for otherwise similar patients without these characteristics. CONCLUSIONS/POLICY IMPLICATIONS: Study patients treated in PC clinics with greater PC-MHI engagement received similarly high quality depression care, and even higher quality for vulnerable patients. Findings support increasing use of PC-MHI models to the extent that they confer some advantage over existing services (eg, access, patient satisfaction) other than quality of care.

Double-Blind, Sham-Controlled, Pilot Study of Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Trigeminal nerve stimulation (TNS), a minimal-risk noninvasive neuromodulation method, showed potential benefits for attention-deficit/hyperactivity disorder (ADHD) in an unblinded open study. The present blinded sham-controlled trial was conducted to assess the efficacy and safety of TNS for ADHD and potential changes in brain spectral power using resting-state quantitative electroencephalography. METHOD: Sixty-two children 8 to 12 years old, with full-scale IQ of at least 85 and Schedule for Affective Disorders and Schizophrenia-diagnosed ADHD, were randomized to 4 weeks of nightly treatment with active or sham TNS, followed by 1 week without intervention. Assessments included weekly clinician-administered ADHD Rating Scales (ADHD-RS) and Clinical Global Impression (CGI) scales and quantitative electroencephalography at baseline and week 4. RESULTS: ADHD-RS total scores showed significant group-by-time interactions (F1,228 = 8.12, p = .005; week 4 Cohen d = 0.5). CGI-Improvement scores also favored active treatment (χ21,168 = 8.75, p = .003; number needed to treat = 3). Resting-state quantitative electroencephalography showed increased spectral power in the right frontal and frontal midline frequency bands with active TNS. Neither group had clinically meaningful adverse events. CONCLUSION: This study demonstrates TNS efficacy for ADHD in a blinded sham-controlled trial, with estimated treatment effect size similar to non-stimulants. TNS is well tolerated and has minimal risk. Additional research should examine treatment response durability and potential impact on brain development with sustained use. CLINICAL TRIAL REGISTRATION INFORMATION: Trigeminal Nerve Stimulation for ADHD; http://clinicaltrials.gov/; NCT02155608.

Changing Patterns of Mental Health Care Use: The Role of Integrated Mental Health Services in Veteran Affairs Primary Care.

OBJECTIVE: Aiming to foster timely, high-quality mental health care for Veterans, VA's Primary Care-Mental Health Integration (PC-MHI) embeds mental health specialists in primary care and promotes care management for depression. PC-MHI and patient-centered medical home providers work together to provide the bulk of mental health care for primary care patients with low-to-moderate-complexity mental health conditions. This study examines whether increasing primary care clinic engagement in PC-MHI services is associated with changes in patient health care utilization and costs. METHODS: We performed a retrospective longitudinal cohort study of primary care patients with identified mental health needs in 29 Southern California VA clinics from October 1, 2008 to September 30, 2013, using electronic administrative data (n = 66,638). We calculated clinic PC-MHI engagement as the proportion of patients receiving PC-MHI services among all primary care clinic patients in each year. Capitalizing on variation in PC-MHI engagement across clinics, our multivariable regression models predicted annual patient use of 1) non-primary care based mental health specialty (MHS) visits, 2) total mental health visits (ie, the sum of MHS and PC-MHI visits), and 3) health care utilization and costs. We controlled for year- and clinic-fixed effects, other clinic interventions, and patient characteristics. RESULTS: Median clinic PC-MHI engagement increased by 8.2 percentage points over 5 years. At any given year, patients treated at a clinic with 1 percentage-point higher PC-MHI engagement was associated with 0.5% more total mental health visits (CI, 0.18% to 0.90%; P = .003) and 1.0% fewer MHS visits (CI, -1.6% to -0.3%; P = .002); this is a substitution rate, at the mean, of 1.5 PC-MHI visits for each MHS visit. There was no PC-MHI effect on other health care utilization and costs. CONCLUSIONS: As intended, greater clinic engagement in PC-MHI services seems to increase realized accessibility to mental health care for primary care patients, substituting PC-MHI for MHS visits, without increasing acute care use or total costs. Thus, PC-MHI services within primary care clinics may improve mental health care value at the patient population level. More research is needed to understand the relationship between clinic PC-MHI engagement and clinical quality of mental health care.

Primary Care-Mental Health Integration in the VA: Shifting Mental Health Services for Common Mental Illnesses to Primary Care.

OBJECTIVE: Primary care-mental health integration (PC-MHI) aims to increase access to general mental health specialty (MHS) care for primary care patients thereby decreasing referrals to non-primary care-based MHS services. It remains unclear whether new patterns of usage of MHS services reflect good mental health care. This study examined the relationship between primary care clinic engagement in PC-MHI and use of different MHS services. METHODS: This was a retrospective longitudinal cohort study of 66,638 primary care patients with mental illnesses in 29 Southern California Veterans Affairs clinics (2008-2013). Regression models used clinic PC-MHI engagement (proportion of all primary care clinic patients who received PC-MHI services) to predict relative rates of general MHS visits and more specialized MHS visits (for example, visits for serious mental illness services), after adjustment for year and clinic fixed effects, other clinic interventions, and patient characteristics. RESULTS: Patients were commonly diagnosed as having depression (35%), anxiety (36%), and posttraumatic stress disorder (22%). For every 1 percentage point increase in a clinic's PC-MHI engagement rate, patients at the clinic had 1.2% fewer general MHS visits per year (p<.001) but no difference in more specialized MHS visits. The reduction in MHS visits occurred among patients with depression (-1.1%, p=.01) but not among patients with psychosis; however, the difference between the subsets was not statistically significant. CONCLUSIONS: Primary care clinics with greater engagement in PC-MHI showed reduced general MHS use rates, particularly for patients with depression, without accompanying reductions in use of more specialized MHS services.

Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension.

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.

Integrated Primary Medical-Behavioral Health Care for Adolescent and Young Adult Depression: Predictors of Service Use in the Youth Partners in Care Trial.

Objectives: Depression, a chronic and disabling condition, frequently has its first onset during adolescence, underscoring the value of early effective treatment and prevention. Integrated medical-behavioral health care provides one strategy for improving treatment access for adolescents and young adults (AYA). Methods: This study examined predictors of accessing treatment in a multisite randomized controlled trial evaluating an integrated collaborative care intervention aimed at improving access to evidence-based depression treatment through primary health care, compared with usual care. Results: The integrated care intervention was able to overcome barriers to care associated with an initial reluctance to pursue active treatment and older age. Service use was low in both conditions among less acculturated/non-English-speaking families. Conclusions: Results support the value of integrated medical-behavioral health care for improving rates of care. Findings highlight mechanisms by which integrated care may lead to improved rates of care and outcomes for AYA, an underserved and understudied group.

Validation of mismatch negativity and P3a for use in multi-site studies of schizophrenia: characterization of demographic, clinical, cognitive, and functional correlates in COGS-2.

Mismatch negativity (MMN) and P3a are auditory event-related potential (ERP) components that show robust deficits in schizophrenia (SZ) patients and exhibit qualities of endophenotypes, including substantial heritability, test-retest reliability, and trait-like stability. These measures also fulfill criteria for use as cognition and function-linked biomarkers in outcome studies, but have not yet been validated for use in large-scale multi-site clinical studies. This study tested the feasibility of adding MMN and P3a to the ongoing Consortium on the Genetics of Schizophrenia (COGS) study. The extent to which demographic, clinical, cognitive, and functional characteristics contribute to variability in MMN and P3a amplitudes was also examined. Participants (HCS n=824, SZ n=966) underwent testing at 5 geographically distributed COGS laboratories. Valid ERP recordings were obtained from 91% of HCS and 91% of SZ patients. Highly significant MMN (d=0.96) and P3a (d=0.93) amplitude reductions were observed in SZ patients, comparable in magnitude to those observed in single-lab studies with no appreciable differences across laboratories. Demographic characteristics accounted for 26% and 18% of the variance in MMN and P3a amplitudes, respectively. Significant relationships were observed among demographically-adjusted MMN and P3a measures and medication status as well as several clinical, cognitive, and functional characteristics of the SZ patients. This study demonstrates that MMN and P3a ERP biomarkers can be feasibly used in multi-site clinical studies. As with many clinical tests of brain function, demographic factors contribute to MMN and P3a amplitudes and should be carefully considered in future biomarker-informed clinical studies.

Cortical substrates and functional correlates of auditory deviance processing deficits in schizophrenia.

Although sensory processing abnormalities contribute to widespread cognitive and psychosocial impairments in schizophrenia (SZ) patients, scalp-channel measures of averaged event-related potentials (ERPs) mix contributions from distinct cortical source-area generators, diluting the functional relevance of channel-based ERP measures. SZ patients (n = 42) and non-psychiatric comparison subjects (n = 47) participated in a passive auditory duration oddball paradigm, eliciting a triphasic (Deviant-Standard) tone ERP difference complex, here termed the auditory deviance response (ADR), comprised of a mid-frontal mismatch negativity (MMN), P3a positivity, and re-orienting negativity (RON) peak sequence. To identify its cortical sources and to assess possible relationships between their response contributions and clinical SZ measures, we applied independent component analysis to the continuous 68-channel EEG data and clustered the resulting independent components (ICs) across subjects on spectral, ERP, and topographic similarities. Six IC clusters centered in right superior temporal, right inferior frontal, ventral mid-cingulate, anterior cingulate, medial orbitofrontal, and dorsal mid-cingulate cortex each made triphasic response contributions. Although correlations between measures of SZ clinical, cognitive, and psychosocial functioning and standard (Fz) scalp-channel ADR peak measures were weak or absent, for at least four IC clusters one or more significant correlations emerged. In particular, differences in MMN peak amplitude in the right superior temporal IC cluster accounted for 48% of the variance in SZ-subject performance on tasks necessary for real-world functioning and medial orbitofrontal cluster P3a amplitude accounted for 40%/54% of SZ-subject variance in positive/negative symptoms. Thus, source-resolved auditory deviance response measures including MMN may be highly sensitive to SZ clinical, cognitive, and functional characteristics.

Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS.

BACKGROUND: Startle inhibition by weak prepulses (PPI) is studied to understand the biology of information processing in schizophrenia patients and healthy comparison subjects (HCS). The Consortium on the Genetics of Schizophrenia (COGS) identified associations between PPI and single nucleotide polymorphisms in schizophrenia probands and unaffected relatives, and linkage analyses extended evidence for the genetics of PPI deficits in schizophrenia in the COGS-1 family study. These findings are being extended in a 5-site "COGS-2" study of 1800 patients and 1200 unrelated HCS to facilitate genetic analyses. We describe a planned interim analysis of COGS-2 PPI data. METHODS: Eyeblink startle was measured in carefully screened HCS and schizophrenia patients (n=1402). Planned analyses of PPI (60 ms intervals) assessed effects of diagnosis, sex and test site, PPI-modifying effects of medications and smoking, and relationships between PPI and neurocognitive measures. RESULTS: 884 subjects met strict inclusion criteria. ANOVA of PPI revealed significant effects of diagnosis (p=0.0005) and sex (p<0.002), and a significant diagnosis×test site interaction. HCS>schizophrenia PPI differences were greatest among patients not taking 2nd generation antipsychotics, and were independent of smoking status. Modest but significant relationships were detected between PPI and performance in specific neurocognitive measures. DISCUSSION: The COGS-2 multi-site study detects schizophrenia-related PPI deficits reported in single-site studies, including patterns related to diagnosis, prepulse interval, sex, medication and other neurocognitive measures. Site differences were detected and explored. The target COGS-2 schizophrenia "endophenotype" of reduced PPI should prove valuable for identifying and confirming schizophrenia risk genes in future analyses.

Demand and modality of directed attention modulate "pre-attentive" sensory processes in schizophrenia patients and nonpsychiatric controls.

BACKGROUND: Mismatch negativity (MNN) and P3a are event related potential (ERP) measures of early sensory information processing. These components are usually conceptualized as being "pre-attentive" and therefore immune to changes with variations in attentional functioning. This study aimed to determine whether manipulations of attention influence the amplitudes and latencies of MMN and P3a and, if so, the extent to which these early sensory processes govern concurrent behavioral vigilance performance in schizophrenia patients and normal subjects. METHODS: Schizophrenia patients (SZ; n = 20) and Nonpsychiatric Control Subjects (NCS; n = 20) underwent auditory ERP testing to assess MMN and P3a across 4 EEG recording sessions in which attentional demand (low vs. high) and sensory modality of directed attention (visual vs. auditory) were experimentally varied. RESULTS: Across conditions, SZ patients exhibited deficits in MMN and P3a amplitudes. Significant amplitude and latency modulation were observed in both SZ and NCS but there were no group-by-condition interactions. The amount of MMN amplitude attenuation from low- to high-demand tasks was significantly associated with increased vigilance performance in both SZ and NCS groups (r = -0.67 and r = -0.60). Several other robust associations were also observed among neurophysiologic, clinical and cognitive variables. CONCLUSIONS: Attentional demand and modality of directed attention significantly influence the amplitude and latencies of "pre-attentive" ERP components in both SZ and NCS. Deficits in MMN and P3a were not "normalized" when attention was directed to the auditory stimuli in schizophrenia patients. The adaptive modulation of early sensory information processing appears to govern concurrent attentional task performance. The temporal window reflecting automatic sensory discrimination as indexed as MMN and P3a may serve as a gateway to some higher order cognitive operations necessary for psychosocial functioning.