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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Reduced arterial compliance in patients with psychiatric diagnoses.

BACKGROUND: Peripheral arterial compliance is a measure of elasticity of the arteries that has been found to be a robust predictor of prevalent arteriosclerosis as well as incident stroke and myocardial infarction. Psychiatric diagnoses and second generation antipsychotics may contribute to cardiovascular risk and stroke, but effects on peripheral arterial compliance are unknown. This study compared peripheral arterial compliance in healthy male controls to male patients with psychiatric diagnoses who were treated with quetiapine or risperidone or off antipsychotics at time of testing. METHODS: The groups consisted of 63 patients with mental illness taking quetiapine, risperidone, or no antipsychotics. There were 111 males in the control group. Mean thigh and calf arterial compliance among four groups were compared by ANCOVA, adjusting for body mass index and Framingham Risk Score. All patients were also compared to the control group. Compliance was measured with a computerized plethysmography device. RESULTS: Patients (n=63) had significantly lower arterial compliance in both thigh and calf than the controls. Arterial compliance in the calf was significantly lower in the subgroups of quetiapine (n=16) and risperidone (n=19) treated, and in unmedicated (n=28) patients than in controls. In the thigh, patients taking either quetiapine or risperidone had significantly lower arterial compliance than controls. These subgroups did not differ from each other in arterial compliance. CONCLUSION: The presence of psychiatric diagnoses is associated with reduced arterial compliance. A large study may be required to measure any specific affects of antipsychotics such as quetiapine and risperidone on compliance compared to controls.

Versatility of fear-potentiated startle paradigms for assessing human conditioned fear extinction and return of fear.

Fear conditioning methodologies have often been employed as testable models for assessing learned fear responses in individuals with anxiety disorders such as post-traumatic stress disorder (PTSD) and specific phobia. One frequently used paradigm is measurement of the acoustic startle reflex under conditions that mimic anxiogenic and fear-related conditions. For example, fear-potentiated startle is the relative increase in the frequency or magnitude of the acoustic startle reflex in the presence of a previously neutral cue (e.g., colored shape; termed the conditioned stimulus or CS+) that has been repeatedly paired with an aversive unconditioned stimulus (e.g., airblast to the larynx). Our group has recently used fear-potentiated startle paradigms to demonstrate impaired fear extinction in civilian and combat populations with PTSD. In the current study, we examined the use of either auditory or visual CSs in a fear extinction protocol that we have validated and applied to human clinical conditions. This represents an important translational bridge in that numerous animal studies of fear extinction, upon which much of the human work is based, have employed the use of auditory CSs as opposed to visual CSs. Participants in both the auditory and visual groups displayed robust fear-potentiated startle to the CS+, clear discrimination between the reinforced CS+ and non-reinforced CS-, significant extinction to the previously reinforced CS+, and marked spontaneous recovery. We discuss the current results as they relate to future investigations of PTSD-related impairments in fear processing in populations with diverse medical and psychiatric histories.

El trastorno de estrés postraumático puede asociarse a un deterioro de la inhibición del temor: relación con la gravedad de los síntomas / Posttraumatic stress disorder may be associated with impaired fear inhibition: Relation to symptom severity

Uno de los problemas clave que se plantean en el trastorno de estrés postraumático (TEPT) es la incapacidad de inhibir el temor, incluso estando en unas condiciones seguras. Los fundamentos neurales que subyacen en el temor son clínicamente relevantes pero no se conocen bien. En este estudio se evaluó la potenciación y la inhibición del temor con el empleo del sobresalto potenciado por el temor en un procedimiento de discriminación condicionada (AX+/BX–). Nuestra hipótesis fue que los pacientes con TEPT mostrarían una potenciación del temor normal, pero con un deterioro de su inhibición. Se estudió a 28 voluntarios sanos y 27 pacientes con TEPT (14 con síntomas actuales bajos, 13 con síntomas actuales altos) a los que se presentó un conjunto de luces de colores (ensayos AX) emparejadas con chorros de aire aversivos en la garganta, y una serie diferente de luces (ensayos BX) presentadas sin chorros de aire. A continuación se les presentaron conjuntamente A y B (ensayos AB) con objeto de determinar si B inhibía la potenciación del temor que se producía con A. Todos los grupos mostraron una potenciación clara del temor, por cuanto la magnitud del sobresalto fue significativamente mayor en los ensayos AX que en los ensayos con ruido solo. Sin embargo, el grupo de TEPT de síntomas altos no mostró una inhibición del temor: estos pacientes mostraban una potenciación del temor en los ensayos AB significativamente superior a la de los controles y a la de los pacientes con TEPT de síntomas bajos (AU)

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 highsymptom 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 (AU)

Risk of lipid abnormality with haloperidol, olanzapine, quetiapine, and risperidone in a Veterans Affairs population.

Second-generation antipsychotics can cause lipid elevations at a greater rate than older typical antipsychotics. This risk may not be equivalent amongst the second-generation antipsychotics. We conducted a computerized, retrospective, nonrandomized, case-control analysis of 6331 patients receiving antipsychotics. For each patient, the first prescription for at least 60 continuous days for four antipsychotics [haloperidol (HALD), olanzapine (OLANZ), quetiapine (QUET), or risperidone (RISP)] was analyzed for total cholesterol, low-density lipoprotein, high-density lipoprotein (HDL), and triglycerides (TGL). Mean HDL was lower during OLANZ treatment than with RISP (P = 0.03) or QUET (P = 0.001). TGL were higher during OLANZ (P = 0.0007) or QUET treatment (P = 0.006) than RISP. In dichotomous analyses, odds ratios on the percentage of participants having abnormal cholesterol (P = 0.0003), low-density lipoprotein (P = 0.001), or TGL (P = 0.0001) during medication were in the order: OLANZ > QUET > RISP > HALD. For HDL, the results were less robust but the percentage of participants were in the order: OLANZ>RISP = HALD = QUET. In treatment-emergent analyses of patients without lipid abnormalities during an unmedicated baseline period, there was a greater risk of developing new HDL abnormality with OLANZ than RISP (P<0.05). In conclusion, treatment with RISP or HALD was associated with a more favorable lipid profile than with OLANZ or QUET.

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.

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.

Conditioned fear extinction and reinstatement in a human fear-potentiated startle paradigm.

The purpose of this study was to analyze fear extinction and reinstatement in humans using fear-potentiated startle. Participants were fear conditioned using a simple discrimination procedure with colored lights as the conditioned stimuli (CSs) and an airblast to the throat as the unconditioned stimulus (US). Participants were extinguished 24 h after fear conditioning. Upon presentation of unsignaled USs after extinction, participants displayed significant fear reinstatement. In summary, these procedures produced robust fear-potentiated startle, significant CS+/CS- discrimination, within-session extinction, and significant reinstatement. This is the first demonstration of fear extinction and reinstatement in humans using startle measures.