Adjunctive glycine in the treatment of obsessive-compulsive disorder in adults.

BACKGROUND: Recent preclinical findings, case reports and non-blinded studies have suggested that glutamatergic interventions may be efficacious for Obsessive-Compulsive Disorder (OCD). METHODS: We enrolled 24 adult outpatients with OCD on stabilized treatment regimens in a double-blind trial of adjunctive glycine, an NMDA glutamate receptor agonist. Participants were randomly assigned 1:1 to either placebo or glycine titrated to 60g/day, with follow-up visits scheduled at 4, 8 and 12 weeks. Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was the principal outcome measure. RESULTS: Regimen non-adherence, principally related to complaints about the taste and/or nausea, resulted in only 14 individuals who were evaluable by predetermined criteria. Those receiving glycine (n=5) experienced a mean decrease of 6.04 points in Y-BOCS score, compared with a 1.00 point decrease for those receiving placebo (n=9). Using a hierarchical linear model, compared with placebo, individuals who received glycine had an average 0.82 decrease in Y-BOCS score for each week they remained in the study, not quite reaching statistical significance (p=0.053). Two of those receiving glycine were responders, versus none receiving placebo (p=0.11, ns, Fisher exact). Despite the dropouts, two participants were known to have subsequently continued taking glycine through their regular treating psychiatrist for over a year. CONCLUSIONS: The glycine condition approached efficacy for treatment of OCD in this study, with the high dropout rate related to problems with palatability and small sample size the principal caveats. This may indicate a new strategy for treatment of OCD, although confirmatory studies are clearly needed. (ClinicalTrials.gov NCT00405535.).

Mismatch negativity (MMN) to spatial deviants and behavioral spatial discrimination ability in the etiology of auditory verbal hallucinations and thought disorder in schizophrenia.

Persistent auditory verbal hallucinations (AVH) in schizophrenia are increasingly tied to dysfunction at the level of auditory cortex. AVH may reflect in part misattribution of internally generated thoughts to external spatial locations. Here, we investigated the association between persistent AVH and spatial localization abilities assessed both behaviorally and by mismatch negativity (MMN) to location deviants. METHODS: Spatial- and tonal- discrimination abilities were assessed in patients (n=20) and controls (n=20) using free-field tones. MMN was assessed to spatial-location-, pitch- and duration-deviants. AVH and thought disorder were assessed using clinical evaluation. RESULTS: As predicted, patients showed significant reductions in behavioral spatial-discrimination (p<0.0001) and tone-matching (p<0.001) ability, along with impaired MMN generation to location (p<0.03) and pitch (p<0.05) deviants. Hallucinating (AVH+) and non-hallucinating (AVH-) subjects showed similar deficits in location MMN to left-hemifield stimuli (p<0.0001 vs. control). By contrast, AVH- patients differed significantly from controls (p=0.009) and AVH+ patients (p=0.018) for MMN to right-lateral hemifield (left auditory cortex) stimuli, whereas AVH+ patients showed paradoxically preserved MMN generation (p=0.99 vs. controls). Severity of thought disorder correlated with impaired spatial discrimination, especially to right-hemifield stimuli (p=0.013), but did not correlate significantly with MMN or tone matching deficits. CONCLUSION: These findings demonstrate a significant relationship between auditory cortical spatial localization abilities and AVH susceptibility, with relatively preserved function of left vs. right auditory cortex predisposing to more severe AVH, and support models that attribute persistent AVH to impaired source-monitoring. The findings suggest new approaches for therapeutic intervention for both AVH and thought disorder in schizophrenia.

Differences in PTSD prevalence and associated risk factors among World Trade Center disaster rescue and recovery workers.

OBJECTIVE: This study compared the prevalence and risk factors of current probable posttraumatic stress disorder (PTSD) across different occupations involved in rescue/recovery work at the World Trade Center site. METHOD: Rescue and recovery workers enrolled in the World Trade Center Health Registry who reported working at the World Trade Center site (N=28,962) were included in the analysis. Interviews conducted 2-3 years after the disaster included assessments of demographic characteristics, within-disaster and work experiences related to the World Trade Center, and current probable PTSD. RESULTS: The overall prevalence of PTSD among rescue/recovery workers was 12.4%, ranging from 6.2% for police to 21.2% for unaffiliated volunteers. After adjustments, the greatest risk of developing PTSD was seen among construction/engineering workers, sanitation workers, and unaffiliated volunteers. Earlier start date and longer duration of time worked at the World Trade Center site were significant risk factors for current probable PTSD for all occupations except police, and the association between duration of time worked and current probable PTSD was strongest for those who started earlier. The prevalence of PTSD was significantly higher among those who performed tasks not common for their occupation. CONCLUSIONS: Workers and volunteers in occupations least likely to have had prior disaster training or experience were at greatest risk of PTSD. Disaster preparedness training and shift rotations to enable shorter duration of service at the site may reduce PTSD among workers and volunteers in future disasters.

Asthma diagnosed after 11 September 2001 among rescue and recovery workers: findings from the World Trade Center Health Registry.

BACKGROUND: Studies have consistently documented declines in respiratory health after 11 September 2001 (9/11) among surviving first responders and other World Trade Center (WTC) rescue, recovery, and clean-up workers. OBJECTIVES: The goal of this study was to describe the risk of newly diagnosed asthma among WTC site workers and volunteers and to characterize its association with WTC site exposures. METHODS: We analyzed 2003-2004 interview data from the World Trade Center Health Registry for workers who did not have asthma before 9/11 (n = 25,748), estimating the risk of newly diagnosed asthma and its associations with WTC work history, including mask or respirator use. RESULTS: Newly diagnosed asthma was reported by 926 workers (3.6%). Earlier arrival and longer duration of work were significant risk factors, with independent dose responses (p < 0.001), as were exposure to the dust cloud and pile work. Among workers who arrived on 11 September, longer delays in the initial use of masks or respirators were associated with increased risk of asthma; adjusted odds ratios ranged from 1.63 [95% confidence interval (CI), 1.03-2.56) for 1 day of delay to 3.44 (95% CI, 1.43-8.25) for 16-40 weeks delay. CONCLUSIONS: The rate of self-reported newly diagnosed asthma was high in the study population and significantly associated with increased exposure to the WTC disaster site. Although we could not distinguish appropriate respiratory protection from inappropriate, we observed a moderate protective effect of mask or respirator use. The findings underscore the need for adequate and timely distribution of appropriate protective equipment and the enforcement of its use when other methods of controlling respiratory exposures are not feasible.

Elevated maternal interleukin-8 levels and risk of schizophrenia in adult offspring.

OBJECTIVE: Many studies have implicated prenatal infection in the etiology of schizophrenia. Cytokines, a family of soluble polypeptides, are critically important in the immune response to infection and in other inflammatory processes. The goal of this study was to determine whether second-trimester levels of four cytokines-interleukin-8 (IL-8), interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)-are higher in the mothers of offspring who later developed schizophrenia spectrum disorders than in matched comparison subjects. METHOD: The authors conducted a nested case-control study of maternal serum cytokine levels in a large birth cohort, born 1959-1967. Cases (N=59) were subjects diagnosed with schizophrenia spectrum disorders (mostly schizophrenia and schizoaffective disorder) who had available second-trimester maternal serum samples. Comparison subjects (N=105) were members of the birth cohort, had not been diagnosed with a schizophrenia spectrum disorder or major affective disorder, and were matched to subjects with schizophrenia for date of birth, gender, length of time in the cohort, and availability of maternal sera. Maternal second-trimester serum levels of IL-8, IL-1beta, IL-6, and TNF-alpha were determined by sandwich enzyme-linked immunosorbent assay. RESULTS: The second-trimester IL-8 levels in mothers of offspring with schizophrenia spectrum disorders were significantly higher than those of the mothers of comparison subjects. There were no differences between subjects with schizophrenia and comparison subjects with respect to maternal levels of IL-1beta, IL-6, or TNF-alpha. CONCLUSIONS: Using prospectively collected prenatal sera in a large and well-characterized birth cohort, the authors have documented a significant association between maternal IL-8 level during the second trimester and risk of schizophrenia spectrum disorders in the offspring. These findings provide further support for a substantive role of in utero infection or inflammation in the etiology of schizophrenia. Moreover, these results may have important implications for elucidating the mechanisms by which disrupted fetal development raises the risk of this disorder.

Male pseudohermaphroditism: long-term quality of life outcome in five 46,XY individuals reared female.

We assessed the adult quality of life of five medical chart-selected genetic males (ages 29-34 years) assigned and reared as females due to ambiguity of the external genitalia. All five were treated following the traditional method proposed by John Money and colleagues in 1955, commonly referred to as the "optimal gender policy". The adult follow-up assessment included physical and endocrinological evaluation, completion of self-report questionnaires, and a semi-structured interview assessing gender identity, sexual experience and orientation. Quality of life domains assessed by questionnaire included health-related issues, satisfaction with health-care management, emotional distress, and relationship satisfaction. Vaginoplasty in four out of five patients was initially unsuccessful. Four patients had periodic lapses in adherence to hormone replacement therapy. Gender role behavior across development was masculine relative to norms for women. All participants reported a female gender identity without a history of gender dysphoria. The majority of participants (four of five) reported being sexually active and in long-term relationships (three heterosexual, one homosexual). Current emotional adaptation and health-related quality of life are within the normal range for four participants. Sex assignment of 46,XY individuals with ambiguous genitalia as females is compatible with a positive quality of life.

Differential relationships of mismatch negativity and visual p1 deficits to premorbid characteristics and functional outcome in schizophrenia.

BACKGROUND: Mismatch negativity (MMN) and visual P1 are established event-related potential (ERP) markers of impaired auditory and visual sensory function in schizophrenia. Differential relationships of these measures with premorbid and present function and with clinical course have been noted previously in independent cohorts, but measures have not yet been compared within the same patient group. METHODS: Twenty-six schizophrenia patients and 19 control subjects participated in a simultaneous visual and auditory ERPs experiment. Attended visual ERPs were obtained to low- and high-spatial frequency stimuli. Simultaneously, MMN was obtained to unattended pitch, duration, and intensity deviant stimuli. Premorbid function, symptom, and global outcome measures were obtained as correlational measures. RESULTS: Patients showed substantial P1 reductions to low- but not high-spatial frequency stimuli, unrelated to visual acuity. Patients also exhibited reduced MMN to all deviant types. No significant correlations were observed between visual ERPs and premorbid or global outcome measures or illness duration. In contrast, MMN amplitude correlated significantly and independently with premorbid educational achievement, cognitive symptoms, global function, and illness duration. The MMN to duration versus other deviants was differentially reduced in individuals with poor premorbid function. CONCLUSIONS: Visual and auditory ERP measures are differentially related to the pathophysiology of schizophrenia. Visual deficits correlate poorly with functional measures and illness duration and serve primarily as trait vulnerability markers. The MMN deficits are independently related to premorbid function and illness duration, suggesting independent neurodevelopmental and neurodegenerative contributions. The lack of correlation between auditory and visual ERPs in schizophrenia suggests contributions from divergent underlying neurophysiological processes.

Spatial localization deficits and auditory cortical dysfunction in schizophrenia.

BACKGROUND: Schizophrenia is associated with deficits in the ability to discriminate auditory features such as pitch and duration that localize to primary cortical regions. Lesions of primary vs. secondary auditory cortex also produce differentiable effects on ability to localize and discriminate free-field sound, with primary cortical lesions affecting variability as well as accuracy of response. Variability of sound localization has not previously been studied in schizophrenia. METHODS: The study compared performance between patients with schizophrenia (n = 21) and healthy controls (n = 20) on sound localization and spatial discrimination tasks using low frequency tones generated from seven speakers concavely arranged with 30° separation. RESULTS: For the sound localization task, patients showed reduced accuracy (p = 0.004) and greater overall response variability (p = 0.032), particularly in the right hemifield. Performance was also impaired on the spatial discrimination task (p = 0.018). On both tasks, poorer accuracy in the right hemifield was associated with greater cognitive symptom severity. Better accuracy in the left hemifield was associated with greater hallucination severity on the sound localization task (p = 0.026), but no significant association was found for the spatial discrimination task. CONCLUSION: Patients show impairments in both sound localization and spatial discrimination of sounds presented free-field, with a pattern comparable to that of individuals with right superior temporal lobe lesions that include primary auditory cortex (Heschl's gyrus). Right primary auditory cortex dysfunction may protect against hallucinations by influencing laterality of functioning.

Posttraumatic stress symptoms, PTSD, and risk factors among lower Manhattan residents 2-3 years after the September 11, 2001 terrorist attacks.

Manhattan residents living near the World Trade Center may have been particularly vulnerable to posttraumatic stress disorder (PTSD) after the September 11, 2001 (9/11) terrorist attacks. In 2003-2004, the authors administered the PTSD Checklist to 11,037 adults who lived south of Canal Street in New York City on 9/11. The prevalence of probable PTSD was 12.6% and associated with older age, female gender, Hispanic ethnicity, low education and income, and divorce. Injury, witnessing horror, and dust cloud exposure on 9/11 increased risk for chronic PTSD. Postdisaster risk factors included evacuation and rescue and recovery work. The results indicate that PTSD is a continued health problem in the local community. The relationship between socioeconomic status and PTSD suggests services must target marginalized populations. Followup is necessary on the course and long-term consequences of PTSD.

Growth trajectory during early life and risk of adult schizophrenia.

BACKGROUND: Growth abnormalities have been suggested as a precursor to schizophrenia, but previous studies have not assessed growth patterns using repeated measures. AIMS: To assess the association between early life/later childhood growth patterns and risk of schizophrenia. METHODS: Using prospectively collected data from a birth cohort (born 1959-1967), measurements of height, weight and body mass index (BMI) were analysed to compare growth patterns during early life and later childhood between 70 individuals with schizophrenia-spectrum disorder (SSD) and 7710 without. RESULTS: For women, growth in the SSD group was approximately 1 cm/year slower during early life (P < 0.01); no association was observed for men. Later childhood growth was not associated with SSD. Weight patterns were not associated with SSD, whereas slower change in BMI was observed among the SSD group during later childhood. CONCLUSIONS: The association between slower growth in early life and schizophrenia in women suggests that factors responsible for regulating growth might be important in the pathogenesis of the disorder.

Surveillance for World Trade Center disaster health effects among survivors of collapsed and damaged buildings.

PROBLEM/CONDITION: Survivors of collapsed or damaged buildings from the attack on the World Trade Center (WTC) were among those most exposed to injury hazards, air pollution, and traumatic events. REPORTING PERIOD: This report summarizes data from health outcomes collected during interviews conducted from September 5, 2003, to the close of the World Trade Center Health Registry (WTCHR) enrollment on November 20, 2004. DESCRIPTION OF SYSTEM: WTCHR will be used to monitor periodically the mental and physical health of 71,437 enrollees for 20 years. The analysis is limited to 8,418 adult survivors of collapsed buildings (n = 5,095) and buildings with major or moderate damage (n = 3,323), excluding those who were involved in rescue and recovery. RESULTS: A total of 62.4% of survivors of collapsed or damaged buildings were caught in the dust and debris cloud that resulted from the collapse of the WTC towers, and 63.8% experienced three or more potentially psychologically traumatizing events. Injuries were common (43.6%), but few survivors reported injuries that would have required extensive treatment. More than half (56.6%) of survivors reported experiencing new or worsening respiratory symptoms after the attacks, 23.9% had heartburn/reflux, and 21.0% had severe headaches. At the time of the interview, 10.7% of building survivors screened positive for serious psychological distress (SPD) using the K6 instrument. After multiple adjustments, data indicated that survivors caught in the dust and debris cloud were more likely to report any injuries (adjusted odds ratio [AOR] = 3.9; p< or =0.05); any respiratory symptom (AOR = 2.7; p< or =0.05); severe headaches (AOR = 2.0; p< or =0.05); skin rash/irritation (AOR = 1.7; p< or =0.05); hearing problems or loss (AOR = 1.7; p< or =0.05); heartburn (AOR = 1.7; p< or =0.05); diagnosed stroke (AOR = 5.6; p< or =0.05); self-reported depression, anxiety, or other emotional problem (AOR = 1.4; p< or =0.05); and current SPD (AOR = 2.2; p< or =0.05). Adjustment for SPD did not diminish the observed associations between dust cloud exposure and physical health outcomes. Building type and time of evacuation were associated with injuries on September 11, 2001 and reported symptoms; building type (collapsed versus damaged) also was associated with mental distress. INTERPRETATION: Two to three years after September 11, survivors of buildings that collapsed or that were damaged as a result of the WTC attack reported substantial physical and mental health problems. The long-term ramifications of these effects are unknown. Many survivors were caught directly in the dust and debris of collapsing towers, a dense cloud of particulate matter that might have produced or exacerbated these health effects. PUBLIC HEALTH ACTION RECOMMENDED: Long-term follow-up of building survivors and all other persons enrolled in WTCHR should be maintained, with particular attention to those persons exposed to the dust cloud. Some of these findings might lead to building designs that can minimize injury hazards.