Deep psychophysiological phenotyping of adolescents and adults with 22q11.2 deletion syndrome: a multilevel approach to defining core disease processes.

BACKGROUND: 22q11.2 deletion syndrome (22q11.2DS) is the most common chromosomal interstitial-deletion disorder, occurring in approximately 1 in 2000 to 6000 live births. Affected individuals exhibit variable clinical phenotypes that can include velopharyngeal anomalies, heart defects, T-cell-related immune deficits, dysmorphic facial features, neurodevelopmental disorders, including autism, early cognitive decline, schizophrenia, and other psychiatric disorders. Developing comprehensive treatments for 22q11.2DS requires an understanding of both the psychophysiological and neural mechanisms driving clinical outcomes. Our project probes the core psychophysiological abnormalities of 22q11.2DS in parallel with molecular studies of stem cell-derived neurons to unravel the basic mechanisms and pathophysiology of 22q11.2-related psychiatric disorders, with a primary focus on psychotic disorders. Our study is guided by the central hypothesis that abnormal neural processing associates with psychophysiological processing and underlies clinical diagnosis and symptomatology. Here, we present the scientific background and justification for our study, sharing details of our study design and human data collection protocol. METHODS: Our study is recruiting individuals with 22q11.2DS and healthy comparison subjects between the ages of 16 and 60 years. We are employing an extensive psychophysiological assessment battery (e.g., EEG, evoked potential measures, and acoustic startle) to assess fundamental sensory detection, attention, and reactivity. To complement these unbiased measures of cognitive processing, we will develop stem-cell derived neurons and examine neuronal phenotypes relevant to neurotransmission. Clinical characterization of our 22q11.2DS and control participants relies on diagnostic and research domain criteria assessments, including standard Axis-I diagnostic and neurocognitive measures, following from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and the North American Prodrome Longitudinal Study (NAPLS) batteries. We are also collecting measures of autism spectrum (ASD) and attention deficit/hyperactivity disorder (ADHD)-related symptoms. DISCUSSION: Studying 22q11.2DS in adolescence and adulthood via deep phenotyping across multiple clinical and biological domains may significantly increase our knowledge of its core disease processes. Our manuscript describes our ongoing study's protocol in detail. These paradigms could be adapted by clinical researchers studying 22q11.2DS, other CNV/single gene disorders, or idiopathic psychiatric syndromes, as well as by basic researchers who plan to incorporate biobehavioral outcome measures into their studies of 22q11.2DS.

Effects of Oxytocin on Emotion Recognition in Schizophrenia: A Randomized Double-Blind Pilot Study.

BACKGROUND: Schizophrenia (SCZ) is a neurodevelopmental disorder that leads to poor social function. Oxytocin (OXT), a neuropeptide involved in social cognition, is a potential therapeutic agent for alleviating social dysfunction. Therefore, we investigated the effects of intranasal oxytocin (IN-OXT) on emotional processes in experimental interactive social contexts in individuals with SCZ. METHODS: In a male-only parallel randomized placebo-controlled double-blind trial, we investigated the effects of IN-OXT (24 IU) on visual fixation on pictures of faces and emotion recognition in an interactive ball-tossing game that probed processing of social and nonsocial stimuli. RESULTS: Intranasal oxytocin enhanced the recognition of emotions during an emotion-based ball-tossing game. This improvement was specific to the game that included social cue processing. Intranasal oxytocin did not affect eye gaze duration or gaze dwell time on faces in these patients. CONCLUSIONS: An acute low dose of IN-OXT had a modest effect on social cue processing and was limited to emotion recognition. Higher doses and long-term trials targeting emotional processing in SCZ may lead to improved social function.

Polygenic risk scores differentiate schizophrenia patients with toxoplasma gondii compared to toxoplasma seronegative patients.

Schizophrenia (SCZ) is an etiologically heterogeneous disease with genetic and environmental risk factors (e.g., Toxoplasma gondii infection) differing among affected individuals. Distinguishing such risk factors may point to differences in pathophysiological pathways and facilitate the discovery of individualized treatments. Toxoplasma gondii (TOXO) has been implicated in increasing the risk of schizophrenia. To determine whether TOXO-positive individuals with SCZ have a different polygenic risk burden than uninfected people, we applied the SCZ polygenic risk score (SCZ-PRS) derived from the Psychiatric GWAS Consortium separately to the TOXO-positive and TOXO-negative subjects with the diagnosis of SCZ as the outcome variable. The SCZ-PRS does not include variants in the major histocompatibility complex. Of 790 subjects assessed for TOXO, the 662 TOXO-negative subjects (50.8% with SCZ) reached a Bonferroni corrected significant association (p = 0.00017, R2 = 0.023). In contrast, the 128 TOXO-positive individuals (53.1% with SCZ) showed no significant association (p = 0.354) for SCZ-PRS and had a much lower R2 (R2 = 0.007). To account for Type-2 error in the TOXO-positive dataset, we performed a random sampling of the TOXO-negative subpopulation (n = 130, repeated 100 times) to simulate equivalent power between groups: the p-value was <0.05 for SCZ-PRS 55% of the time but was rarely (6% of the time) comparable to the high p-value of the seropositive group at p > 0.354. We found intriguing evidence that the SCZ-PRS predicts SCZ in TOXO-negative subjects, as expected, but not in the TOXO-positive individuals. This result highlights the importance of considering environmental risk factors to distinguish a subgroup with independent or different genetic components involved in the development of SCZ.

Acute stress disorder versus chronic posttraumatic stress disorder: inhibition of fear as a function of time since trauma.

BACKGROUND: Previous work has shown that inhibition of fear is impaired in posttraumatic stress disorder (PTSD) resulting from both civilian and combat trauma. The purpose of the present study was to investigate the inhibition of learned fear in traumatized individuals diagnosed with either acute stress disorder (ASD) or PTSD. This is the first study to use a conditioned inhibition paradigm with traumatized individuals within a month of trauma exposure. We hypothesized that impaired fear inhibition would be evident in PTSD, but not ASD. METHOD: Using established translational, psychophysiological methods including fear-potentiated startle, and skin conductance, we examined fear acquisition, stimulus discrimination, and the transfer of learned safety in a Croatian population with ASD or PTSD. This cross-sectional study included three age-matched groups: healthy nontrauma controls (n = 27), a group with chronic PTSD (10 or more years since trauma exposure, n = 24), and a group with ASD (30 days or less since trauma exposure, n = 27). RESULTS: The presence of trauma-related psychopathology, whether acute or chronic, was associated with an impaired ability to transfer learned safety based on fear-potentiated startle measures, while healthy control subjects showed significant fear inhibition in the presence of the safety cue compared to the danger cue, F(1,26) = 12.64, P = .001. CONCLUSIONS: These data expand our previously observed findings of PTSD-associated fear inhibition deficits by demonstrating that trauma-related impairments in safety learning are evident within 30 days of trauma exposure.

Prevalence of childhood physical and sexual abuse in veterans with psychiatric diagnoses.

We examined the prevalence of childhood (≤ 18 years) physical and sexual abuse reported among patients admitted to the psychiatric inpatient service and the differential rates of this abuse associated with psychiatric diagnoses. This study consisted of a retrospective chart review of 603 patients admitted to a psychiatric ward during a period of 1 year at Atlanta Veterans Affairs Medical Center who had data on childhood physical and sexual abuse. The prevalence of reported childhood physical or sexual abuse in this inpatient clinical population was 19.4% (117/603). The prevalence of reported physical abuse was 22.6% (19/84) in the women and 12.0% (62/519) in the men (p = 0.008); the prevalence of sexual abuse was 33.3% (28/84) in the women and 7.7% (40/519) in the men (p < 0.0001). More patients with depressive disorders reported sexual abuse than did those without these disorders. More patients with posttraumatic stress disorder (PTSD) reported physical and sexual abuse than did those without these disorders. Stratifying by race, sex, and diagnoses, multivariate analyses showed that the women with PTSD had a greater likelihood to report physical abuse (p = 0.03) and sexual abuse histories (p = 0.008) than did the women without PTSD. The men with substance-induced mood disorder (p = 0.01) were more likely to report physical abuse compared with the men without substance-induced mood disorder. Screening for abuse in patients with depressive disorders and PTSD is warranted to tailor individualized treatments for these patients. More research is needed to better understand the potential implications of childhood abuse on psychiatric diagnoses.

Psychophysiological treatment outcomes: Corticotropin-releasing factor type 1 receptor antagonist increases inhibition of fear-potentiated startle in PTSD patients.

After exposure to a traumatic event, a subset of people develop post-traumatic stress disorder (PTSD). One of the key deficits in PTSD is regulation of fear, and impaired inhibition of fear-potentiated startle (FPS) has been identified as a potential physiological biomarker specific to PTSD. As part of a larger clinical trial, this study investigated the effects of a CRF receptor 1 antagonist, GSK561679, on inhibition of fear-potentiated startle during a conditional discrimination fear-conditioning paradigm, termed AX+/BX-. Prior research using this paradigm has demonstrated deficits in inhibition of conditioned fear in several PTSD populations. The randomized, double-blind, placebo-controlled clinical trial compared fear inhibition between female PTSD participants taking 350 mg/day GSK561679 (n = 47 pre- and 29 post-treatment) and patients taking a placebo pill (n = 52 pre- and 30 post-treatment) daily for 6 weeks. There was no significant difference between the two groups in their acquisition of fear or discrimination between threat and safety cues, and no pre-post-treatment effect on these measures. However, there was a significant effect of treatment on inhibition of FPS during the AB trials in the AX+/BX- transfer test (p < 0.05). While all PTSD participants showed typical impairments in fear inhibition prior to treatment, GSK561679 enhanced fear inhibition post-treatment, independent of clinical effects. The current study suggests that CRF receptor 1 antagonism may have specific effects within neural circuitry mediating fear inhibition responses, but not overall symptom presentation, in PTSD.

Posttraumatic stress disorder may be associated with impaired fear inhibition: relation to symptom severity.

One of the central problems in posttraumatic stress disorder (PTSD) is the inability to suppress fear even under safe conditions. The neural underpinnings of fear are clinically relevant but poorly understood. This study assessed fear potentiation and fear inhibition using fear-potentiated startle in a conditional discrimination procedure (AX+/BX-). We hypothesized that patients with PTSD would show normal fear potentiation and impaired fear inhibition. Subjects comprised 28 healthy volunteers and 27 PTSD patients (14 with low current symptoms, 13 with high current symptoms) who were presented with one set of colored lights (AX trials) paired with aversive air blasts to the throat, and a different series of lights (BX trials) presented without air blasts. We then presented A and B together (AB trials) to see whether B would inhibit fear potentiation to A. All groups showed robust fear potentiation in that they had significantly greater startle magnitude on AX trials than on noise-alone trials. However, the high-symptom PTSD group did not show fear inhibition: these subjects had significantly greater fear potentiation on the AB trials than both the controls and the low-symptom PTSD patients.

Timing of extinction relative to acquisition: a parametric analysis of fear extinction in humans.

Fear extinction is a reduction in conditioned fear following repeated exposure to the feared cue in the absence of any aversive event. Extinguished fear often reappears after extinction through spontaneous recovery. Animal studies suggest that spontaneous recovery can be abolished if extinction occurs within minutes of acquisition. However, a limited number of human extinction studies have shown that short interval extinction does not prevent the return of fear. For this reason, we performed an in-depth parametric analysis of human fear extinction using fear-potentiated startle. Using separate single-cue and differential conditioning paradigms, participants were fear conditioned and then underwent extinction either 10 min (Immediate) or 72 hr (Delayed) later. Testing for spontaneous recovery occurred 96 hr after acquisition. In the single cue paradigm, the Immediate and Delayed groups exhibited differences in context, but not fear, conditioning. With differential conditioning, there were no differences in context conditioning and the Immediate group displayed less spontaneous recovery. Thus, the results remain inconclusive regarding spontaneous recovery and the timing of extinction and are discussed in terms of performing translational studies of fear in humans.

Childhood Physical and Sexual Abuse Predicts Suicide Risk in a Large Cohort of Veterans.

OBJECTIVE: To examine whether childhood physical and sexual abuse is a significant predictor of suicide risk in veterans. METHODS: This study was a retrospective chart review of 4,709 patients admitted to a psychiatric ward (August 2004 through July 2014) at the Atlanta Veterans Affairs Medical Center (VAMC). Sociodemographic and clinical data and history of childhood (aged ≤ 18 years) physical and sexual abuse were obtained from the patients' electronic health records. Suicide risk data of patients who attempted and completed suicide were obtained from the Atlanta VAMC suicide high-risk team. Binary logistic regressions with maximum likelihood estimation method were used to examine the association of demographic (age, sex, marital status, race, service) and clinical (psychiatric diagnoses, number of hospital admissions, and length of stay) variables and childhood physical and sexual abuse and type with suicide behavior. RESULTS: The combination of childhood physical and sexual abuse, number of admissions to a psychiatric inpatient unit, and major depressive disorder (MDD) were the best predictors of enhanced suicide risk (P < .001). This combination accounted for 9.9% variance in suicide risk and correctly classified 83% of cases into respective suicide versus nonsuicide risk groups. Additional significant predictors were bipolar disorder (P < .001) and cocaine use disorder (P = .02). Surprisingly, diagnosis of schizophrenia predicted a reduced risk. CONCLUSIONS: To our knowledge, this study is the first to shed light on the interaction of childhood physical and sexual abuse and suicide risk in a large cohort of veterans. In the final model, childhood physical and sexual abuse, number of psychiatric admissions, and MDD were the best predictors of increased suicide risk. Schizophrenia was a protective factor in this veteran cohort.

Relation of neurological soft signs to psychiatric symptoms in schizophrenia.

INTRODUCTION: Although several studies have identified abnormal rates of neurological soft signs (NSS) as a manifestation of CNS dysfunction in schizophrenia, differences in sample populations have contributed to a discrepancy in empirical findings. Furthermore, little is known about the potential of NSS to predict a clinical response to antipsychotic medications. The present study tests the associations between NSS and schizophrenia symptomatology and examines NSS as a potential marker for predicting treatment response. METHODS: Nineteen unmedicated male schizophrenia patients were treated prospectively with haloperidol for six weeks. The subjects were assessed for pre and post-treatment NSS and schizophrenia symptomatology (Brief Psychiatric Rating Scale, BPRS). RESULTS: NSS at baseline were significantly associated with baseline symptoms on the Positive, Negative, and Psychological Discomfort BPRS subscales. NSS showed a strong trend toward improvement during six weeks of a prospective haloperidol trial. Hierarchical linear regression analyses indicated that more severe baseline NSS predicted poorer response to haloperidol treatment as measured by post-treatment BPRS Total subscale scores. DISCUSSION: NSS at untreated baseline are associated with baseline symptom severity, and elevated NSS are predictive of a smaller degree of improvement in symptoms after antipsychotic treatment. These findings are consistent with the hypothesis that NSS are linked to the neuropathology that underlies schizophrenia symptomatology and course.

Evaluating the Effect of the Changes in FDA Guidelines for Clozapine Monitoring.

BACKGROUND: Concerns exist that clozapine is underutilized in the management of treatment-resistant schizophrenia. Although a 2015 change in the US Food and Drug Administration (FDA) monitoring recommendations lowered the threshold of the absolute neutrophil count for treatment interruption from 1,500/µL to 1,000/µL and removed white blood cell count thresholds from the monitoring algorithm, the implications of this policy change on clozapine interruptions remain unknown. METHODS: We analyzed outpatient prescribing records for antipsychotic medications in the Veterans Integrated Service Network 7 (VISN 7) database between 1999 and 2012 to assess the potential impact of the recent changes in FDA neutropenia monitoring recommendations on clozapine treatment discontinuation. We evaluated results of complete blood count monitoring to compare percentages of patients who developed or would have developed ≥ 1 hematologic event under the previous and current FDA guidelines in the first year following initiation of clozapine. RESULTS: From a cohort of 14,620 patients with schizophrenia (ICD-9-295.x), 246 patients received clozapine treatment (1.7%). No agranulocytosis was observed during the study period. Under the former recommendations, 5 patients in the clozapine initiation cohort (n = 160, 3.1%; 95% CI, 0.43-5.83) qualified for treatment interruption during the first year of clozapine treatment, while only 1 patient (0.6%) qualified under the current recommendations. Under the former recommendations, hematologic events occurred at a similar rate for individuals taking and not taking clozapine. CONCLUSIONS: While clozapine remains an underused medication, the new FDA monitoring guidelines are likely to substantially reduce the percentage of patients who meet criteria for clozapine-associated hematologic events requiring treatment interruption. This decrease may reduce the clinical burden of managing patients on clozapine and therefore increase the number of individuals treated with this uniquely effective medication. However, prospective studies of individuals treated under the new guidelines are needed to fully assess safety of the FDA's change.

Contingency awareness and fear inhibition in a human fear-potentiated startle paradigm.

Fear-potentiated startle is defined as an increase in the magnitude of the startle reflex in the presence of a stimulus that was previously paired with an aversive event. It has been proposed that a subject's awareness of the contingencies in the experiment may affect fear-potentiated startle. The authors adapted a conditional discrimination procedure (AX+/BX-), previously validated in animals, to a human fear-potentiated startle paradigm in 50 healthy volunteers. This paradigm allows for an assessment of fear-potentiated startle during threat conditions as well as inhibition of fear-potentiated startle during safety conditions. A response keypad was used to assess contingency awareness on a trial-by-trial basis. Both aware and unaware subjects showed fear-potentiated startle. However, awareness was related to stimulus discrimination and fear inhibition.

A preliminary study of the effects of cigarette smoking on prepulse inhibition in schizophrenia: involvement of nicotinic receptor mechanisms.

BACKGROUND: Schizophrenics exhibit deficits in prepulse inhibition (PPI) of the startle response, and have high rates of cigarette smoking. We evaluated the effects of cigarette smoking on PPI deficits in schizophrenia, and the role of nicotinic acetylcholine receptors (nAChRs) in mediating cigarette smoking-related PPI enhancement. METHODS: PPI was assessed at baseline, after overnight abstinence, and after smoking reinstatement during three separate test weeks in nicotine-dependent schizophrenia (n=15) and control (n=14) smokers pre-treated with the nAChR antagonist mecamylamine (MEC; 0.0, 5.0 or 10.0 mg/day). RESULTS: PPI was comparable between schizophrenia and control smokers after ad lib cigarette smoking. Overnight smoking abstinence significantly reduced PPI, while smoking reinstatement reversed abstinence-induced worsening of PPI deficits in schizophrenia. However, acute abstinence and reinstatement did not alter PPI in controls. PPI enhancement by smoking reinstatement in schizophrenia was dose-dependently blocked by MEC, whereas MEC had no effect on PPI in control smokers. CONCLUSIONS: These results suggest that: 1) Non-deprived smokers with schizophrenia have comparable levels of PPI to non-deprived smoking controls; 2) In schizophrenia, PPI is impaired by smoking abstinence and improved by acute smoking reinstatement, and; 3) enhancement of PPI by cigarette smoking in schizophrenia is mediated by stimulation of central nAChRs. Our findings may contribute to understanding the increased vulnerability to nicotine dependence in schizophrenia, with implications for treatment of PPI deficits in this disorder.

Medication status affects the relationship of symptoms to prepulse inhibition of acoustic startle in schizophrenia.

Inhibition of the acoustic startle response by a smaller preliminary nonstartling stimulus is termed prepulse inhibition (PPI). Schizophrenia patients have impairments in PPI that may not fully normalize even when they are clinically stable on medication, particularly typical antipsychotics. There is evidence that more severe symptoms are associated with more severe PPI abnormalities, but the effect of antipsychotics on this relationship is not clear. Seventy-three male schizophrenia patients underwent acoustic startle and PPI testing. Symptom ratings were performed using the Brief Psychiatric Rating Scale (BPRS) and its subscales. Fifty-two subjects were treated with antipsychotic medication at time of testing; 21 were unmedicated. For all subjects, PPI was negatively correlated with the BPRS psychological discomfort subscale but not with BPRS total symptoms, BPRS positive symptoms or BPRS negative symptoms. For medicated subjects analyzed separately, there were no correlations with BPRS total scores or any subscales. For the unmedicated subjects analyzed separately, there were significant correlations of lower PPI with greater severity of BPRS total symptoms, positive symptoms and the psychological discomfort subscale. These data indicate that more severe symptoms are associated with lower PPI, but that medication status is an important factor in the relationship between symptom severity and sensorimotor gating.

Predictors of Calf Arterial Compliance in Male Veterans With Psychiatric Diagnoses.

BACKGROUND: Peripheral arterial compliance (PAC) is a measure of the ability of the vascular tree to dilate in response to a pressure wave. Reduced PAC is seen in patients with psychiatric diagnoses and has been associated with increased risk for stroke, myocardial infarction, and mortality. The objective of this pilot study was to identify predictors of reduced PAC in subjects with psychiatric diagnoses. METHODS: Male psychiatric subjects (N = 77) were studied in a cross-sectional study of medication effects on PAC conducted from August 2005 to February 2010. Calf and thigh compliance were modeled in separate linear regressions. The models were adjusted for age, race, smoking status, presence or absence of the metabolic syndrome, current treatment with a statin, diagnosis of schizophrenia or schizoaffective disorder, current antipsychotic treatment, and body mass index (BMI). RESULTS: Of the 77 subjects (mean ± SD age of 53.7 ± 8.8 years), 41 were white, 36 were black, and 27 were diagnosed with schizophrenia or schizoaffective disorder (DSM-IV criteria). Fifty participants were being treated with an antipsychotic medication, while the remaining 27 were off of antipsychotics for at least 2 months. Our model explained 27% of the variance in calf compliance. Black subjects had reduced calf compliance compared to white subjects (P = .02). Having metabolic syndrome was associated with reduced PAC at a trend level (P < .08), and BMI (P = .004) and BMI2 (P = .011) were significant predictors of calf compliance. Schizophrenia versus other psychiatric diagnoses and antipsychotic treatment were not significantly associated with calf compliance. CONCLUSIONS: In this pilot study, significant predictors of calf compliance were race (black vs white) and BMI. PAC is a noninvasive measure that may be a predictor of cardiovascular risk in psychiatric patients. The reduced PAC seen in patients with psychiatric diagnoses does not appear to be directly related to their diagnosis or antipsychotic treatment but rather to other characteristics inherent to the subject. Future studies are warranted to better understand the pathophysiology of PAC including but not limited to inflammation in psychiatric patients.

Fear potentiation and fear inhibition in a human fear-potentiated startle paradigm.

BACKGROUND: The inability to suppress excessive fear or anxiety is a significant clinical problem. In the laboratory, extinction is a preferred method for the study of fear inhibition; however, in this paradigm the same stimulus causes both elicitation (excitation) and inhibition of fear, making it difficult to know whether an experimental manipulation that affects extinction does so by affecting one or both of these processes. For this reason, we sought to develop a behavioral procedure in humans that would render a stimulus primarily inhibitory. METHODS: We adapted a conditional discrimination procedure (AX+/BX-), previously validated in animals, to a human fear-potentiated startle paradigm. Forty-one healthy volunteers were presented with one set of colored lights paired with the delivery of aversive airblasts to the throat (AX+) and a different series of lights presented without airblasts (BX-). RESULTS: Participants exhibited fear potentiation to AX+, discrimination between AX+ and BX-, and transfer of fear inhibition to A in an AB compound test but not in an AC compound test. CONCLUSIONS: We believe this procedure will advance clinical research on fear disorders, such as posttraumatic stress disorder and phobias, by providing an effective and relatively independent measure of fear potentiation and fear inhibition.

Effect of treatment status on prepulse inhibition of acoustic startle in schizophrenia.

RATIONALE: The acoustic startle response is inhibited when the startling stimulus is preceded by a weaker non-startling acoustic stimulus. This phenomenon, termed prepulse inhibition of acoustic startle (PPI), is impaired in schizophrenics compared to normal controls. To date, there is conflicting evidence regarding whether PPI impairments improve with antipsychotic treatment. OBJECTIVES: To examine the effect of medication status on PPI in schizophrenic subjects. METHODS: First, we performed acoustic startle testing on 16 schizophrenic subjects when they were acutely decompensated off medication and later after they were stabilized on antipsychotic treatment. Second, in a between-group design, we tested 21 schizophrenic subjects off medication, 16 subjects on atypical neuroleptics, and 27 subjects on typical neuroleptics. RESULTS: In both the test-retest study and the between-group study, ANOVAs revealed no significant changes in startle to pulse alone stimuli, habituation of startle to pulse alone stimuli, PPI, latency to response onset, or latency to response peak between the treatment conditions. CONCLUSIONS: Our results do not support the hypothesis that impaired sensorimotor gating in schizophrenia improves with antipsychotic treatment. Rather, impaired gating persists despite symptomatic improvement on medication.

Effects of D-cycloserine on negative symptoms in schizophrenia.

INTRODUCTION: The negative and cognitive symptoms of schizophrenia are poorly responsive to neuroleptic treatment. Glutamatergic dysfunction may mediate some of these symptoms. Low dose D-cycloserine (DCS) is a partial agonist at the glycine site of the NMDA-associated receptor complex, noncompetitively enhancing NMDA neurotransmission. Prior studies suggest a beneficial effect of DCS on negative symptoms and cognition. This treatment trial was initiated to confirm and extend these findings. METHODS: Twenty-two male schizophrenic subjects displaying prominent negative symptoms who were stabilized on typical neuroleptics completed the study. A randomized double-blind parallel group design was used to compare the effects of 50 mg p.o. QD of DCS to placebo over 4 weeks. The two subject groups did not differ significantly in age, age of onset of illness or time on current neuroleptic treatment. Symptoms were rated by means of the SANS, BPRS and Abrams and Taylor rating scale. Cognition was assessed with the Sternberg Memory Test and the Continuous Performance Test. RESULTS: Both medication groups improved over the 4 weeks of treatment. However, there were no significant differences between the DCS and placebo group on any symptom rating. DCS effects on cognition did not differ from placebo. DISCUSSION: This study did not detect improvement in negative symptoms or cognitive performance with DCS treatment that has been found in some prior studies. This negative finding may be attributed to small sample size, relatively short duration of treatment and the overall modest effect of DCS. Future studies of DCS should be adequately powered to detect a small to medium effect size and should provide for a longer treatment phase than was used in this study in order to avoid a type II error.

A randomized, double-blind evaluation of D-cycloserine or alprazolam combined with virtual reality exposure therapy for posttraumatic stress disorder in Iraq and Afghanistan War veterans.

OBJECTIVE: The authors examined the effectiveness of virtual reality exposure augmented with D-cycloserine or alprazolam, compared with placebo, in reducing posttraumatic stress disorder (PTSD) due to military trauma. METHOD: After an introductory session, five sessions of virtual reality exposure were augmented with D-cycloserine (50 mg) or alprazolam (0.25 mg) in a double-blind, placebo-controlled randomized clinical trial for 156 Iraq and Afghanistan war veterans with PTSD. RESULTS: PTSD symptoms significantly improved from pre- to posttreatment across all conditions and were maintained at 3, 6, and 12 months. There were no overall differences in symptoms between D-cycloserine and placebo at any time. Alprazolam and placebo differed significantly on the Clinician-Administered PTSD Scale score at posttreatment and PTSD diagnosis at 3 months posttreatment; the alprazolam group showed a higher rate of PTSD (82.8%) than the placebo group (47.8%). Between-session extinction learning was a treatment-specific enhancer of outcome for the D-cycloserine group only. At posttreatment, the D-cycloserine group had the lowest cortisol reactivity and smallest startle response during virtual reality scenes. CONCLUSIONS: A six-session virtual reality treatment was associated with reduction in PTSD diagnoses and symptoms in Iraq and Afghanistan veterans, although there was no control condition for the virtual reality exposure. There was no advantage of D-cycloserine for PTSD symptoms in primary analyses. In secondary analyses, alprazolam impaired recovery and D-cycloserine enhanced virtual reality outcome in patients who demonstrated within-session learning. D-cycloserine augmentation reduced cortisol and startle reactivity more than did alprazolam or placebo, findings that are consistent with those in the animal literature.

Treatment compliance in veterans administration schizophrenia spectrum patients treated with risperidone long-acting injectable.

Risperidone is the first of the second-generation antipsychotics available in a long-acting injectable form (RLAI). This form of delivery has proven efficacy and safety in the treatment of schizophrenia. However, outcome studies in 'real-world' clinical samples are lacking. We carried out a retrospective study using a computerized repository of clinical data from eight Veterans Affairs Medical Centers. Compliance with outpatient medication and metabolic monitoring frequency was evaluated in schizophrenia spectrum patients during treatment with oral risperidone (RispPO) and after switch to RLAI. Propensity scores were computed during baseline when both groups were on RispPO, and the two groups were matched on propensity scores. Matching on propensity score was successful: 132 RispPO patients were well matched to 132 RLAI patients during the RispPO Baseline Period. Days until medication discontinuation were longer in the RLAI group (679.2±499.3) than the RispPO group (403.7±365.1, P<0.0001). Days late for receiving medication were significantly shorter during the RLAI treatment (5.6±6.2) than the RispPO treatment (8.2±8.6, P<0.004). Metabolic monitoring frequency was significantly greater for patients switched to RLAI for patients maintained on RispPO treatment. Outpatient medication compliance is enhanced during treatment with RLAI compared with treatment with RispPO, as is the rate of monitoring for metabolic measures.