The relevance of social anxiety for understanding social functioning and facial emotion recognition in individuals at clinical high-risk for psychosis.

AIM: Individuals at clinical high risk (CHR) for psychosis often experience poor social functioning and impaired facial emotion recognition (FER); however, the impact of frequently comorbid symptoms upon these processes is underexplored. In particular, social anxiety is characteristic of this population and also related to poor social functioning and FER biases, such as misinterpreting neutral faces as negative or threatening; however, little is known about how social anxiety relates to these processes in CHR individuals. The present study examined the overlap of social anxiety, social functioning, and FER accuracy and bias. METHOD: Participants (CHR N = 62, healthy controls N = 52) completed the self-report Social Interaction Anxiety Scale (SIAS), Penn Emotion Recognition-40 (ER-40) behavioural task, and interviewer-rated Global Functioning Scale-Social (GFS-S). The ER-40 was used to assess both FER accuracy (e.g., overall number of correct responses) and bias (e.g., mislabelling neutral faces as angry). RESULTS: Consistent with previous research, relative to controls, CHR participants had more social anxiety (d = -1.07), poorer social functioning (d = -1.62), and performed more poorly on the FER task (e.g., d = -.37). Within CHR participants, social anxiety was related to an anger detection bias (r = .28), above and beyond positive symptom severity, which in turn was related to FER accuracy (r = .26) and social functioning (r = -.28). CONCLUSION: These findings suggest that ongoing work examining social processes within CHR individuals needs to account for social anxiety and that social anxiety may be a useful preventive intervention target.

Chronic stress, structural exposures and neurobiological mechanisms: A stimulation, discrepancy and deprivation model of psychosis.

Chronic stress exposure has been established as a key vulnerability factor for developing psychotic disorders, including schizophrenia. A structural, or systems level perspective, has often been lacking in conceptualizations of chronic stress for psychotic disorders. The current review thus identified three subtypes of structural exposures. Stimulation exposures included urban environments, population density and crime exposure, with intermediary mechanisms of lack of safety and high attentional demands. Underlying neural mechanisms included threat neural circuits. Discrepancy exposures included environmental ethnic density, income inequality, and social fragmentation, with intermediary mechanisms of lack of belonging and social exclusion, and neural mechanisms including the oxytocin system. Deprivation exposures included environments lacking socioeconomic, educational, or material resources, with intermediary mechanisms of lack of needed environmental enrichment, and underlying neural mechanisms of over-pruning and protracted PFC development. Delineating stressor etiology at the systems level is a necessary step in reducing barriers to effective interventions and health policy.

Assessing Developmental Environmental Risk Factor Exposure in Clinical High Risk for Psychosis Individuals: Preliminary Results Using the Individual and Structural Exposure to Stress in Psychosis-Risk States Scale.

INTRODUCTION: Exposure to cumulative environmental risk factors across development has been linked to a host of adverse health/functional outcomes. This perspective incorporating information regarding exposure at differing developmental periods is lacking in research surrounding individuals at Clinical High Risk (CHR) for developing a psychotic disorder. METHODS: CHR individuals (n = 35) and healthy volunteers (n = 28) completed structured clinical interviews as well as our group's newly developed Individual and Structural Exposure to Stress in Psychosis-risk-states (ISESP) interview. Lifetime cumulative scores were calculated, and severity of stress was reported for multiple developmental periods/ages. Group differences were tested, and associations with current symptom domains were examined. RESULTS: Significant group differences were not observed for lifetime cumulative events, though CHR trended toward endorsing more events and greater stress severity. For stress severity across development, there were trending group differences for the 11-13 age range, and significant group differences for the 14-18 age range; notably, comparisons for earlier time points did not approach statistical significance. Associations between negative symptoms and cumulative severity of exposure were observed. DISCUSSION: Results suggest exploring exposure to cumulative environmental risk factors/stressors and stress severity across developmental periods is generally informative and possibly specifically so for predictive models and diathesis-stress psychosis risk conceptualizations.

Effects of acute and chronic treatment with fluoxetine on stress-induced hyperthermia in telemetered rats and mice.

Preclinical and clinical evidence suggests that anxiolytic effects are observed after chronic administration of the selective serotonin reuptake inhibitor fluoxetine. In contrast, acute treatment may increase signs of anxiety. The present study examined the effects of acute and chronic administration of fluoxetine on a physiological measure of anxiety, stress-induced hyperthermia, in rats and mice using radiotelemetry to record core temperature and locomotor activity and ethologically relevant stressors to evoke the hyperthermic response. In both species, the benzodiazepine agonist chlordiazepoxide reduced stress-induced hyperthermia at doses (5 mg/kg i.p. rat, 10 mg/kg p.o. mouse) that had no significant effect on locomotor activity. Similarly, in both species, chronic (21 days) treatment with fluoxetine attenuated the hyperthermic response without significantly affecting locomotor activity. However, acute fluoxetine elicited species-specific effects. Thus in mice, stress-induced hyperthermia and activity were unaffected by fluoxetine (20 mg/kg p.o.) consistent with a lack of anxiolytic or anxiogenic activity. In contrast, in rats, fluoxetine (10 mg/kg i.p.) caused a significant baseline hypothermia in the absence of stress, confounding further interpretation. In conclusion, stress-induced hyperthermia in mice was unaffected by acute treatment and significantly reduced by chronic treatment with fluoxetine. However, in rats chronic administration of fluoxetine significantly reduced stress-induced hyperthermia while the effects of acute treatment were confounded by a decrease in body temperature in the absence of stress. Together, these observations support the view that chronic administration of fluoxetine is anxiolytic; however, the stress-induced hyperthermia assay does not reveal anxiogenic effects of acute administration of fluoxetine in rats or mice.

Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines.

The GABA(A) receptor subtypes responsible for the anxiolytic effects of nonselective benzodiazepines (BZs) such as chlordiazepoxide (CDP) and diazepam remain controversial. Hence, molecular genetic data suggest that alpha2-rather than alpha3-containing GABA(A) receptors are responsible for the anxiolytic effects of diazepam, whereas the anxiogenic effects of an alpha3-selective inverse agonist suggest that an agonist selective for this subtype should be anxiolytic. We have extended this latter pharmacological approach to identify a compound, 4,2'-difluoro-5'-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-á]pyridin-3-yl]biphenyl-2-carbonitrile (TP003), that is an alpha3 subtype selective agonist that produced a robust anxiolytic-like effect in both rodent and non-human primate behavioral models of anxiety. Moreover, in mice containing a point mutation that renders alpha2-containing receptors BZ insensitive (alpha2H101R mice), TP003 as well as the nonselective agonist CDP retained efficacy in a stress-induced hyperthermia model. Together, these data show that potentiation of alpha3-containing GABA(A) receptors is sufficient to produce the anxiolytic effects of BZs and that alpha2 potentiation may not be necessary.

Inhibition of acute nociceptive responses in rat spinal cord by a bradykinin B1 receptor antagonist.

This study used behavioural and in vivo electrophysiological paradigms to examine the effects of systemic and spinal administration of a bradykinin B1 receptor antagonist, compound X, on acute nociceptive responses in the rat. In behavioural experiments, compound X significantly increased the latency to withdraw the hindpaw from a radiant heat source after both intravenous and intrathecal administration, without affecting motor performance on the rotarod. In electrophysiological experiments, both intravenous and direct spinal administration of compound X attenuated the responses of single dorsal horn neurones to noxious thermal stimulation of the hindpaw. These data show that the antinociceptive effects of a bradykinin B1 receptor antagonist are mediated, at least in part, at the level of the spinal cord and suggest a role for spinal bradykinin B1 receptors in acute nociception.

Substance P (neurokinin 1) receptor antagonists enhance dorsal raphe neuronal activity.

Substance P receptor [neurokinin 1 (NK1] antagonists (SPAs) represent a novel mechanistic approach to antidepressant therapy with comparable clinical efficacy to selective serotonin reuptake inhibitors (SSRIs). Because SSRIs are thought to exert their therapeutic effects by enhancing central serotonergic function, we have examined whether SPAs regulate neuronal activity in the dorsal raphe nucleus (DRN), the main source of serotonergic projections to the forebrain. Using in vivo electrophysiological techniques in the guinea pig, we found that administration of the highly selective NK1 receptor antagonist 1-(5-[[(2R,3S)-2-([(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-phenyl)morpholin-4-yl]methyl]-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine (L-760735) caused an increase in DRN neuronal firing rate. However, unlike chronic treatment with fluoxetine, there was no detectable 5-HT1A autoreceptor desensitization. In vitro electrophysiological investigation showed that these effects were not mediated by a direct action in the DRN, an observation supported by immunocytochemical analysis that identified the lateral habenula (LHb) as a more likely site of action. Subsequently, we found that local application of L-760735 into the LHb increased firing in the DRN, which, together with our data showing that L-760735 increased metabolic activity in the cingulate cortex, amygdala, LHb, and DRN, indicates that the effects of L-760735 may be mediated by disinhibition of forebrain structures acting via a habenulo raphe projection. These findings support other evidence for an antidepressant profile of SPAs and suggest that regulation of DRN neuronal activity may contribute to their antidepressant mechanism of action but in a manner that is distinct from monoamine reuptake inhibitors.