An Open-Label Study of Adjunctive Dextromethorphan/Quinidine in Treatment-Resistant Depression.

BACKGROUND: Approximately one third of individuals with major depressive disorder have treatment-resistant depression (TRD). Glutamatergic modulators such as the N -methyl- d -aspartate receptor antagonist ketamine have rapid and robust antidepressant effects, but their use has been limited by accessibility and route of administration. This open-label pilot study assessed the adjunctive antidepressant efficacy of dextromethorphan/quinidine (DM/Q) in TRD. METHODS: Inpatients with TRD (n = 17, 40.8 ± 12.3 years; 9 females/8 males) received adjunctive open-label DM/Q (20 mg/10 mg) up to 3 times daily. The study had no set endpoint; participants were followed until they discontinued DM/Q or were discharged. Montgomery-Asberg Depression Rating Scale (MADRS) scores were obtained at baseline (before DM/Q administration) and regularly during hospitalization. Full response was defined as a ≥50% reduction in baseline MADRS score, partial response as a 25% to 50% decrease in baseline MADRS score, and nonresponse as a <25% reduction or an increase in baseline MADRS score. RESULTS: The 17 inpatients received open-label DM/Q for 5.1 ± 2.7 weeks. Forty-seven percent of participants responded to DM/Q-12% achieved a full response and 35% achieved a partial response. The largest MADRS difference observed at any time point was -6.4 ± 8.4 (-21.0% ± 29.9%), and the MADRS difference observed at time of DM/Q discontinuation or hospital discharge was -4.8 ± 8.4 (-15.9% ± 29.7%). Twenty-four percent of participants experienced a nonserious adverse event; none experienced a serious adverse event. CONCLUSIONS: In this open-label pilot study, 47% of participants responded to adjunctive DM/Q, which was well tolerated. Larger placebo-controlled trials are needed to determine the real-world efficacy of DM/Q.

Assessing geographic disparities in mental health research participation.

BACKGROUND: Large geographic health disparities are well-documented within the U.S. Although approximately 60 million Americans-or roughly 20% of the total U.S. population-live in rural areas, rural residents may be less likely to participate in health research, including mental health research, due to multiple barriers. This retrospective analysis evaluated the urbanity and rurality of inpatient research participants and potential research participants over a five-year period at the Experimental Therapeutics and Pathophysiology Branch (ETPB), NIMH-NIH (Bethesda, Maryland), which conducts experimental medicine and neurobiological research in mood disorders. METHODS: Participant and potential participant zip codes were converted to Rural Urban Commuting Area (RUCA) codes (1-3 urban, 4-10 rural). These results were compared with each other and with U.S. population data. RESULTS: The analysis included 182 research participants and 1864 potential research participants; the former were admitted to an in-person research unit and the latter were screened by phone or online. ETPB research participants had an urban residence rate of 93.4% and a rural residence rate of 6.6%. Potential ETPB research participants had an urban residence rate of 90.9% and a rural residence rate of 9.1%. In comparison, the U.S. urban residence rate is 80% and the rural rate is 20%. CONCLUSION: At the ETPB, both research participants with mood disorders admitted to an in-person research unit and potential research participants screened online or by phone from rural areas were under-represented relative to participants from more urban areas. Further study of research recruitment barriers in rural areas of the U.S is needed.

Reduced Functional Brain Activation and Connectivity During a Working Memory Task in Childhood-Onset Schizophrenia.

OBJECTIVE: Working memory (WM) deficits are consistently reported in schizophrenia and are related to poor functional outcomes. Functional magnetic resonance imaging studies of adult-onset schizophrenia have reported decreased functional activations and connectivity in the WM network, but no prior functional magnetic resonance imaging study has examined WM in childhood-onset schizophrenia (COS). The aim of this study was to examine the neural correlates of WM in COS. METHOD: Adult patients with COS (n = 32, 21.3 ± 1.1 years), nonpsychotic siblings of patients with COS (n = 30, 19.4 ± 0.8 years), and healthy controls (n = 39, 20.0 ± 0.7 years) completed 1- and 2-back WM tasks during 3-T functional magnetic resonance imaging. Functional activation and connectivity analyses were conducted. A separate group of 23 younger patients with COS (17.9 ± 7.4 years) could not perform the tasks after twice completing a standard training and are not included in this report. RESULTS: Patients with COS who were included scored significantly lower than controls on all tasks (p < .001). Patients with COS showed significantly lower activations in the dorsolateral prefrontal cortices, posterior parietal cortices, cerebellum, and caudate and decreased frontoparietal and corticostriatal functional connectivity compared with controls (p < .05, corrected). Siblings had functional activations and connectivity intermediate between those of patients and controls in a similar set of regions (p < .05, corrected). In patients, functional connectivity strength in the left frontoparietal network correlated positively with accuracy scores during the 1-back task (p = .0023, corrected). CONCLUSION: Decreased functional activation and connectivity in the WM network in COS supports pathophysiologic continuity with adult-onset schizophrenia. The low participation rate and accuracy of the patients highlights the disease severity of COS. Hypo-activations and hypo-connectivity were shared by siblings of patients with COS, suggesting COS as a potential endophenotype. CLINICAL TRIAL REGISTRATION INFORMATION: Evaluating Genetic Risk Factors for Childhood-Onset Schizophrenia; http://ClinicalTrials.gov;NCT00001198.

Attenuated resting-state functional connectivity in patients with childhood- and adult-onset schizophrenia.

BACKGROUND: Childhood-onset schizophrenia (COS) is a rare, severe form of the adult-onset disorder (AOS). Our previous resting-state fMRI study identified attenuated functional connectivity in COS compared with controls. Here, we ask whether COS and AOS patients and their siblings exhibit similar abnormalities of functional connectivity. METHODS: A whole-brain, data-driven approach was used to assess resting-state functional connectivity differences in COS (patients/siblings/controls, n: 26/28/33) and AOS (n: 19/28/30). There were no significant differences in age, sex, or head motion across groups in each dataset and as designed, the COS dataset has a significantly lower age than the AOS. RESULTS: Both COS and AOS patients showed decreased functional connectivity relative to controls among a wide set of brain regions (P<0.05, corrected), but their siblings did not. Decreased connectivity in COS and AOS patients showed no amplitude differences and was not modulated by age-at-onset or medication doses. Cluster analysis revealed that these regions fell into two large-scale networks: one sensorimotor network and one centered on default-mode network regions, but including higher-order cognitive areas only in COS. Decreased connectivity between these two networks was notable (P<0.05, corrected) for both patient groups. CONCLUSIONS: A shared pattern of attenuated functional connectivity was found in COS and AOS, supporting the continuity of childhood-onset and adult-onset schizophrenia. Connections were altered between sensorimotor areas and default-mode areas in both COS and AOS, suggesting potential abnormalities in processes of self-monitoring and sensory prediction. The absence of substantial dysconnectivity in siblings indicates that attenuation is state-related.

Lack of Gender-Related Differences in Childhood-Onset Schizophrenia.

OBJECTIVE: Gender differences, including younger age of onset and greater premorbid deficits in men, have been reported in adult-onset schizophrenia. This study comprehensively evaluated gender differences in childhood-onset schizophrenia (COS), a rare variant of the disorder. METHOD: Demographic, premorbid, clinical, familial, and cognitive characteristics, presence of chromosomal abnormalities, and brain magnetic resonance imaging cortical volumes were evaluated in 133 patients with COS. Cortical analyses included age- and gender-matched healthy volunteers (n = 124). RESULTS: Males with COS (n = 72) had a slightly but significantly younger age of onset than females with COS (mean age 9.51 ± 2.28 versus 10.29 ± 1.63 years, t131 = 2.21, p = .03), higher verbal IQ scores (83.00 ± 15.97 versus 75.58 ± 15.10, t89 = 2.24, p = .03), and higher rates of comorbid pervasive developmental disorder (28.17% versus 6.90%, χ(2)1 = 9.54, p < .01) and attention-deficit/hyperactivity disorder (43.86% versus 21.43%, χ(2)1 = 5.40, p = .02). There were no significant gender differences across other demographic, IQ, or clinical measurements, frequency of chromosomal abnormalities, family clinical measurements, premorbid functioning, or in gender-by-disorder interactions for magnetic resonance imaging brain measurements. CONCLUSION: The present comprehensive examination found few remarkable gender differences in COS. Although less striking than that seen in adult-onset schizophrenia, males with COS had a younger age of onset. Attention-deficit/hyperactivity disorder and pervasive developmental disorder rates were high in COS overall, suggesting greater neurodevelopmental vulnerability in COS. However, the gender ratios of these comorbidities in COS mirror those of the general populations, indicating that these gender differences might be unrelated to COS.

Severity of Cortical Thinning Correlates With Schizophrenia Spectrum Symptoms.

OBJECTIVE: This study investigated the relationship between regional cortical gray matter thinning and symptoms of schizophrenia spectrum personality disorders (PDs) in siblings of patients with childhood-onset schizophrenia (COS). METHOD: A total of 66 siblings of patients with COS were assessed for symptoms of schizophrenia spectrum PDs (avoidant, paranoid, schizoid, schizotypal). Structural magnetic resonance images were obtained at approximately 2-year intervals from the siblings and from 62 healthy volunteers matched for age, sex, ethnicity, and handedness. Cortical thickness measures were extracted. Mixed effect regression models were used to test the relationship between symptoms and cortical gray matter thickness in siblings. Cortical thinning was also tested longitudinally in healthy volunteers and siblings. RESULTS: Cortical thinning was found to correlate with symptoms of schizotypal and, to a lesser extent, schizoid PDs. Thinning was most pronounced in the left temporal and parietal lobes and right frontal and parietal regions. Gray matter loss was found to be continuous with that measured in COS. Longitudinal thinning trajectories were found not to differ between siblings and healthy volunteers. CONCLUSION: The present investigation of cortical thinning in siblings of patients with COS indicates that symptoms of schizophrenia spectrum PDs correlate with regional gray matter loss. This finding supports the idea of cortical thinning as a schizophrenia endophenotype.

Disrupted sensorimotor and social-cognitive networks underlie symptoms in childhood-onset schizophrenia.

Schizophrenia is increasingly recognized as a neurodevelopmental disorder with altered connectivity among brain networks. In the current study we examined large-scale network interactions in childhood-onset schizophrenia, a severe form of the disease with salient genetic and neurobiological abnormalities. Using a data-driven analysis of resting-state functional magnetic resonance imaging fluctuations, we characterized data from 19 patients with schizophrenia and 26 typically developing controls, group matched for age, sex, handedness, and magnitude of head motion during scanning. This approach identified 26 regions with decreased functional correlations in schizophrenia compared to controls. These regions were found to organize into two function-related networks, the first with regions associated with social and higher-level cognitive processing, and the second with regions involved in somatosensory and motor processing. Analyses of across- and within-network regional interactions revealed pronounced across-network decreases in functional connectivity in the schizophrenia group, as well as a set of across-network relationships with overall negative coupling indicating competitive or opponent network dynamics. Critically, across-network decreases in functional connectivity in schizophrenia predicted the severity of positive symptoms in the disorder, such as hallucinations and delusions. By contrast, decreases in functional connectivity within the social-cognitive network of regions predicted the severity of negative symptoms, such as impoverished speech and flattened affect. These results point toward the role that abnormal integration of sensorimotor and social-cognitive processing may play in the pathophysiology and symptomatology of schizophrenia.