Winter birth, urbanicity and immigrant status predict psychometric schizotypy dimensions in adolescents.

BACKGROUND: Urbanicity, immigration and winter-birth are stable epidemiological risk factors for schizophrenia, but their relationship to schizotypy is unknown. This is a first examination of the association of these epidemiological risk factors with positive schizotypy, in nonclinical adolescents, controlling for a range of potential and known confounders. METHODS: We collected socio-demographics, life-style, family and school circumstances, positive schizotypy dimensions and other personality traits from 445 high school pupils (192 males, 158 immigrants) from 9 municipalities in Athens and Heraklion, Greece, which covered a range of host population and migrant densities. Using multivariate hierarchical linear regressions models, we estimated the association of schizotypy dimensions with: (1) demographics of a priori interest (winter-birth, immigrant status, urban characteristics), including family financial and mental health status; (2) factors resulting from principal component analysis (PCA) of the demographic and personal data; (3) factors resulting from PCA of the personality questionnaires. RESULTS: Adolescent women scored higher on schizotypy than men. High anxiety/neuroticism was the most consistent and significant predictor of all schizotypy dimensions in both sexes. In the fully adjusted models, urbanicity predicted magical thinking and unusual experiences in women, while winter-birth and immigration predicted paranoid ideation and unusual experiences respectively in men. CONCLUSIONS: These results support the continuum hypothesis and offer potential insights in the nature of risk conferred by winter-birth, urbanicity and immigration and the nature of important sex differences. Controlling for a wide range of potential confounding factors increases the robustness of these results and confidence that these were not spurious associations.

Pregnancy, perinatal and postpartum complications as determinants of postpartum depression: the Rhea mother-child cohort in Crete, Greece.

AIMS: Few epidemiological studies evaluated associations between perinatal complications and maternal mood at the early postpartum period and the findings are inconsistent. We aimed at investigating a wide range of complications during pregnancy, at delivery, and at the early postpartum period as determinants of postpartum depression (PPD) at 8 weeks postpartum. METHODS: A total of 1037 women who enrolled in the Rhea mother-child cohort in Crete, Greece participated in the present study. Information on pregnancy, perinatal and postpartum complications was obtained from clinical records or by questionnaires. Postpartum depressive symptoms were assessed at 8 weeks postpartum using the Edinburgh Postnatal Depression Scale (EPDS). Multivariable linear and logistic regression models were fit to estimate the association between pregnancy, perinatal and postpartum complications and maternal depressive symptoms, adjusting also for potential confounders. RESULTS: The prevalence of women with probable depression (EPDS score ≥ 13) was 13.6% at 8 weeks postpartum. Gestational hypertension and/or preeclampsia (ß coefficient 1.86, 95% CI: 0.32, 3.41) and breastfeeding difficulties (ß coefficient 0.77, 95% CI: 0.02, 1.53) were significantly associated with higher PPD symptoms. Sleep patterns during pregnancy, such as sleep deprivation (OR = 3.57, 95% CI: 1.91, 6.67) and snoring (OR = 1.81, 95% CI: 1.11, 2.93), and breastfeeding duration less than 2 months (OR = 1.77, 95% CI: 1.19, 2.64) were significantly associated with increase in the odds for PPD. Some other complications, such as unplanned pregnancy and hospitalisation during pregnancy were also associated with EPDS score, but these associations were explained by socio-demographic characteristics of the mother. CONCLUSIONS: We found that several pregnancy, perinatal and postpartum complications may have an adverse effect on maternal mood at the early postpartum period. These findings have considerable implications for developing effective prevention and early psychoeducational intervention strategies for women at risk of developing PPD.

Maternal screening for early postnatal vulnerability.

Research has highlighted the wide impact of maternal mental health problems during and beyond the postpartum period and the public health role of community health professionals in early detection of women who may be at risk. This paper aims to describe, explore and test an a priori hypothesised conceptual model of postnatal experience, identifying the relationships between postnatal mental vulnerability and postnatal adjustment to maternal roles and attitudes, marital/partner-relationship and sense of coherence. Three validated self-report questionnaires (WAST, MAMA, SOC) measuring the variables of the encompassing framework and EPDS were administered in random order. The conceptual models were tested using the software IBM SPSS Statistics and LISREL and the tests performed were: Student's ttest, chi-square tests, Explanatory factor analysis using a Varimax rotation Principal Components Method, Confirmatory analysis -known as structural equation modelling- of principal components. Psychometric scores indicate high correlation between WAST, MAMA, SOC and EPDS. An exploratory factor analysis confirmed the role of SOC, specific MAMA subscales (maternal roles and attitudes, body image, sex, breasts, nausea) and WAST (relationship tension and emotional and physical abuse) subscales (KMO measure of sampling adequacy=0.735 and Bartlett's test of sphericity=184,786, df=36, p<0.0005). The latent variables confirmed with SEM were marital relationship, maternity experience and self-efficacy (Chi-square=28.45, df=24, P-value=0.24, RMSEA=0.046 p<0.05). Marital Relationship (Factor I: Eigenvalue=3.066) concerning lack of or disappointment with partner support, poor marital relationship and emotional/physical abuse has been associated with high levels of postpartum anxiety and depression. Maternity Experience (Factor II: Eigenvalue=1.280) representing postnatal roles and attitudes towards their infant can be as useful as mood changes for evaluation of mothers. Self-Efficacy (Factor III: Eigen- value=3.144) and especially attitudes regarding body image, sex and coping resources and options of dealing with the stressor, has been demonstrated that serve as a mediator or buffer for psychological distress. The results of this study have implications for the prevention and intervention of postnatal adjustment difficulties both of which need to be intensified in order to minimise perinatal mental vulnerability.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

The effects of the CACNA1C rs1006737 A/G on affective startle modulation in healthy males.

BACKGROUND: The CACNA1C rs1006737 risk A allele has been associated with affective psychoses and functional studies indicate that it is associated with increased hippocampal/amygdala activity during emotional face-processing. Here we studied the impact of the risk A allele on affective startle modulation. METHODS: Hundred and ninety-four healthy males stratified for their CACNA1C rs1006737 genotype (GG:111, GA:67, AA:16) were presented with 18 pleasant, 18 unpleasant and 18 neutral pictures with acoustic probes (104 dB) occurring during 12 pictures in each affective category. Baseline startle was assessed during blank screens. State mood was self-rated on arrival, pre- and post-test and the emotional valence and arousal of affective pictures at post-test. RESULTS: Relative to the other genotypes, risk A allele homozygotes presented with higher anxiety/negative affect at pre-test, reduced and exaggerated physiological responses to the pleasant and negative pictures respectively, negative affect with reduced arousal at post-test and rated the affective pictures as less arousing and inconsistently to their physiological responses (all P<0.05). Sustained contextual negative mood predicted reduced baseline and affective startle reactivity in the AA group. CONCLUSIONS: Healthy homozygous males for the risk A allele appear to have marked contextual sensitivity, affective reactivity akin to anxiety and depression and inefficient emotional appraisal. Our findings provide phenotypic detail of the CACNA1C AA genotype in non-symptomatic individuals, which suggest primary effects in emotional circuitry, consistent with previously documented alterations in hippocampal/amygdala processing.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

Maternal personality traits and risk of preterm birth and fetal growth restriction.

BACKGROUND/AIMS: Maternal personality may increase vulnerability to stress, which could lead to an unfavourable intrauterine environment to the fetus. We sought to investigate the impact of maternal personality traits on adverse birth outcomes such as preterm birth, and fetal growth restriction in the mother-child cohort study (RHEA Study) in Crete, Greece 2007-2009. METHODS: Five hundred and eighty pregnant women participating in "Rhea" cohort study completed the Eysenck Personality Questionnaire-Revised (EPQ-R) at 28-32 weeks of gestation. Information on anthropometric measures at birth was obtained from the hospital delivery logs and medical records. Fetal growth restriction was based on a customized model, and multivariate logistic regression models were used adjusting for confounders. RESULTS: A per unit increase in the EPQ Neuroticism scale increased the risk for fetal weight growth restriction by 9% [odds ratio (OR)=1.09, 95 percent CI: 1.01, 1.19)], and for fetal head circumference growth restriction by 6% [OR=1.06, 95 percent CI: 1.01, 1.18] after adjusting for maternal age, education, origin, marital status, working status, pre-pregnancy BMI, delivery type, parity, smoking, and alcohol intake during pregnancy. CONCLUSIONS: Maternal neuroticism, which predisposes to negative mood, may be a risk factor for fetal growth restriction.

Sub-optimal parenting is associated with schizotypic and anxiety personality traits in adulthood.

Part of the variation in personality characteristics has been attributed to the child-parent interaction and sub-optimal parenting has been associated with psychiatric morbidity. In the present study, an extensive battery of personality scales (Trait Anxiety Inventory, Behavioural Inhibition/Activation System questionnaire, Eysenck Personality Questionnaire-Revised, Temperament and Character Inventory, Schizotypal Traits Questionnaire, Toronto Alexithymia Scale) and the Parental Bonding Instrument (PBI) were administered in 324 adult healthy males to elucidate the effects of parenting on personality configuration. Personality variables were analysed using Principal Component Analysis (PCA) and the factors "Schizotypy", "Anxiety", "Behavioural activation", "Novelty seeking" and "Reward dependence" were extracted. Associations between personality factors with PBI "care" and "overprotection" scores were examined with regression analyses. Subjects were divided into "parental style" groups and personality factors were subjected to categorical analyses. "Schizotypy" and "Anxiety" were significantly predicted by high maternal overprotection and low paternal care. In addition, the Affectionless control group (low care/high overprotection) had higher "Schizotypy" and "Anxiety" compared with the Optimal Parenting group (high care/low overprotection). These results further validate sub-optimal parenting as an important environmental exposure and extend our understanding on the mechanisms by which it increases risk for psychiatric morbidity.

Threat and anxiety affect visual contrast perception.

Threat cues activate the visual cortex and are detected faster than neutral cues as evidenced by functional brain imaging during viewing of visual threat and neutral stimuli. The functional visual processes underlying these phenomena have not been determined. Pattern visual evoked potentials were elicited in a baseline and a verbal threat condition with two stimulus contrasts in subjects with high and low trait anxiety. Threat reduced the latency of the early P100 wave in the low but not the high anxious group. The reduction was greater with increasing stimulus contrasts. The dependence of the P100 latency on trait anxiety is reminiscent of the Yerkes-Dodson inverted U-shape curve, which relates anxiety to behavioural responses. These results show that threat affects perceptual processes and suggest that data based on the effects of threat in visual search studies should be reappraised to include acceleration of contrast perception.

Modafinil treatment of amphetamine abuse in adult ADHD.

Substance abuse is a frequent co-morbid condition of adult attention deficit hyperactivity disorder (ADHD). Treatment with conventional psychostimulants in adult ADHD with co-morbid stimulant abuse may be problematic. In this study, we report the case of a patient with adult ADHD with co-morbid amphetamine abuse who was treated successfully with the non-stimulant alertness-promoting drug modafinil. The drug resolved both the inattention/hyperactivity symptoms as well as the amphetamine abuse. Modafinil may be a suitable candidate treatment for adults with ADHD and stimulant abuse.

Prepulse inhibition of the startle reflex depends on the catechol O-methyltransferase Val158Met gene polymorphism.

BACKGROUND: Recent evidence suggests that dopamine (DA) agonist-induced disruption of prepulse inhibition (PPI) depends on basal PPI values, in a manner that suggests an inverted U-shaped relationship between PPI and prefrontal DA levels. This is the first study to examine possible genetic determinants of PPI and the catechol O-methyltransferase (COMT) Val158Met polymorphism, the main catabolic pathway of released DA in the prefrontal cortex (PFC). METHOD: PPI was measured in 93 healthy males presented with 75-dB and 85-dB prepulses at 60-ms and 120-ms prepulse-pulse intervals. Subjects were grouped according to their COMT status into a Val/Val, a Val/Met and a Met/Met group. RESULTS: ANOVAs showed that at all prepulse and interval conditions, Val/Val individuals had the lowest PPI, Met/Met the highest, and Val/Met were intermediate. CONCLUSIONS: These results suggest that PPI is regulated by DA neurotransmission in the PFC and its levels depend on the COMT Val158Met gene polymorphism. These findings enhance the value of the PPI paradigm in examining individual variability of early information processing in healthy subjects and psychiatric disorders associated with changes in PFC DA activity and attentional deficits such as schizophrenia.

The fear-inhibited light reflex: importance of the anticipation of an aversive event.

RATIONALE: It has been shown previously that the amplitude of the pupillary light reflex response decreases when subjects anticipate an aversive stimulus (i.e. electric shock), compared to periods when subjects are resting ('fear-inhibited light reflex'). OBJECTIVE: To compare the effects of the anticipation of an electric shock (putative aversive event) and of an acoustic stimulus (putative neutral event) on the light reflex. METHODS: Twelve healthy volunteers participated in a training session and an experimental session. Pupil diameter was monitored with infra-red binocular television pupillometry. The experimental session consisted of 14 blocks of 3 light stimuli. 'Relaxation' (no anticipation) and 'anticipation' (electrical or acoustic stimulus) blocks alternated. Mood and feelings were self-rated on visual analogue scales. RESULTS: The anticipation of the electrical stimulus was associated with increases in initial pupil diameter and subjectively rated 'anxiety' and 'alertness', and a decrease in the amplitude of the pupillary light reflex response, whereas anticipation of the acoustic stimulus was associated with increases in initial pupil diameter and subjective 'alertness' only. CONCLUSIONS: The increase in initial pupil diameter is related to the anticipation of any stimulus, whereas the decrease in the amplitude of the light reflex response is associated with the aversiveness of the anticipated stimulus.

Relationship of the 'fear-inhibited light reflex' to the level of state/trait anxiety in healthy subjects.

RATIONALE: It has been shown that the amplitude of the pupillary light reflex response decreases when subjects anticipate an aversive stimulus (i.e. electric shock), compared to periods when subjects are resting ('fear-inhibited light reflex'). OBJECTIVE: To examine whether the sensitivity of the pupillary light reflex to the threat of an electric shock is related to the pre-existing levels of state and trait anxiety. METHODS: Thirty-two healthy volunteers participated in one experimental session. The possibility of an electric shock to the wrist was signalled by a tone. There were six blocks of three light stimuli: three SAFE blocks (no tone applied) and three THREAT blocks (tone applied). The State-Trait Anxiety Inventory was completed at the beginning and at the end of each session. RESULTS: There was a positive correlation between the state anxiety scores and the within-subject (SAFE-THREAT) difference in light reflex amplitude (P<0.05). There was no significant correlation between the trait anxiety scores and the within-subject differences in light reflex amplitude. CONCLUSIONS: Individual differences in state anxiety associated with the threat of an electric shock are reflected in the amplitude of the pupillary light reflex response. This observation strengthens the validity of the fear-inhibited light reflex as a model of human anxiety.

Comparison of the antidepressants reboxetine, fluvoxamine and amitriptyline upon spontaneous pupillary fluctuations in healthy human volunteers.

RATIONALE: Spontaneous fluctuations in the size of the pupil in darkness are a recognised index of "sleepiness". OBJECTIVE: To evaluate the effects of single oral doses of three antidepressants: reboxetine (4 mg), a selective noradrenaline reuptake inhibitor, fluvoxamine (100 mg), a selective serotonin reuptake inhibitor, and amitriptyline (100 mg), a tricyclic antidepressant of known sedative property, upon spontaneous pupillary fluctuations in healthy male volunteers (n=16). METHODS: Using the recently developed pupillographic sleepiness test (PST), resting pupil diameter was recorded and two measures of pupillary fluctuations were obtained: total power obtained from a fast Fourier transform and spectral analysis, and the pupillary unrest index (PUI), a cumulative measure of changes in pupil size. Subjects also rated themselves on a battery of visual analogue scales for "alertness", "anxiety" and "contentedness". RESULTS: Resting pupil diameter was enhanced by reboxetine, but remained unaffected by the other two antidepressants. Amitriptyline, consistent with its sedative property, increased the total power of pupillary fluctuations and showed a tendency to increase PUI. These pupillary effects of amitriptyline were paralleled by reduced scores on the "alertness", "contentedness" and "anxiety" self ratings. Neither fluvoxamine nor reboxetine affected pupillary fatigue waves or subjective ratings of "alertness". Reboxetine caused a small reduction in subjectively rated "anxiety". CONCLUSIONS: The mydriatic effect of reboxetine may be due to noradrenaline reuptake blockade in the iris and/or in the central nervous system. The enhancement of pupillary fatigue waves by the sedative antidepressant amitriptyline, but not by the non-sedative antidepressants fluvoxamine and reboxetine, indicates that the PST is a suitable quantitative objective test for the detection of drug-induced changes in the level of arousal.

Comparison of the effects of diazepam on the fear-potentiated startle reflex and the fear-inhibited light reflex in man.

It has been shown previously that the amplitude of the acoustic startle reflex is enhanced, and the amplitude of the light reflex reduced, when subjects anticipate an aversive event, compared to periods when subjects are resting ('fear-potentiated startle reflex' and 'fear-inhibited light reflex'). We examined whether the anxiolytic diazepam would reverse the effects of threat on the startle and pupillary reflexes. Twelve male volunteers participated in three weekly sessions in which they received oral treatment with placebo, diazepam 5 mg and diazepam 10 mg, according to a balanced crossover double-blind design. One hour after ingestion of the treatments, miotic responses to light pulses and electromyographic responses of the orbicularis oculi muscle to sound pulses were elicited during alternating periods in which the threat of an electric shock (electrodes attached to the subject's wrist) was present (THREAT) and absent (SAFE). The THREAT condition was associated with a significant increase in the amplitude of the electromyographic (EMG) response, a significant reduction of the miotic response amplitude, and an increase in self-rated anxiety. Diazepam attenuated all these effects of THREAT. Diazepam did not affect the amplitude of the miotic response under the SAFE condition, but did suppress the EMG response under this condition. These results confirm the validity of the fear-potentiated startle reflex and fear-inhibited light reflex as laboratory models of human anxiety, and reveal some differences between the effects of diazepam on the two reflexes.

Comparison of the effects of venlafaxine, paroxetine and desipramine on the pupillary light reflex in man.

RATIONALE: The time-course of the pupillary light reflex response is determined by the successive activation of the parasympathetic and sympathetic innervations of the iris, the latency and the amplitude reflecting parasympathetic and the recovery time mainly sympathetic activity. OBJECTIVE: To compare the effects of single doses of three antidepressants (venlafaxine: serotonin/noradrenaline reuptake inhibitor, paroxetine: selective serotonin reuptake inhibitor, and desipramine: tricyclic antidepressant) on resting pupil diameter and the pupillary light reflex response. METHODS: Fifteen healthy male volunteers participated in five weekly sessions, each of which was associated with one treatment (venlafaxine 75 mg or 150 mg, paroxetine 20 mg, desipramine 100 mg, or placebo) according to a double-blind, double-dummy, balanced, cross-over design. An infrared binocular television pupillometer was used for the recording of the resting pupil diameter and the pupillary light reflex in darkness, in previously dark-adapted eyes. Resting pupil diameter in darkness was recorded before and after treatment. The pupillary light reflex was elicited after treatment, with six light flashes (green, 565 nm peak wavelength) of 200 ms duration and of incremental illuminance (measured in the plane of the cornea): 3.0 x 10(-3) 8.5 x 10(-3) 2.5 x 10(-2), 7.0 x 10(-2), 0.18, 0.43 mW cm(-2). The parameters studied were: latency, amplitude and 75% recovery time. RESULTS: Analyses of variance followed by post hoc tests (least significant difference test or Dunnett's test; P < 0.05) revealed that both doses of venlafaxine produced a significant increase in resting pupil diameter, decrease in amplitude and shortening of the 75% recovery time of the light reflex response; venlafaxine 150 mg prolonged the latency, while the other treatments had no significant effects. CONCLUSIONS: The increase in resting pupil diameter could be indicative of parasympathetic inhibition and/or sympathetic activation. The shortening of the recovery time of the light reflex response is consistent with sympathetic potentiation resulting from noradrenaline uptake blockade in the iris. The prolongation of the latency and decrease of the amplitude of the light reflex response are indicative of a parasympatholytic effect of venlafaxine. However, as venlafaxine has negligible affinity for muscarinic cholinoceptors, this effect cannot be attributed to the blockade of cholinoceptors in the iris. A possible explanation for this finding is that it reflects a central rather than a peripheral effect of the drug: the blockade of noradrenaline uptake in the brain could lead to the potentiation of the noradrenergic inhibition of central parasympathetic (Edinger-Westphal) neurones. These results demonstrate the ability of therapeutically relevant single doses of venlafaxine to potentiate noradrenergic responses in man, consistent with the blockade of noradrenaline uptake.

The effects of clonidine on the fear-inhibited light reflex.

We have shown previously that pupil diameter increases and the amplitude of the pupillary light reflex is reduced when subjects are under threat of an aversive event (electric shock), and that light reflex amplitude correlates negatively with subjective anxiety. Furthermore, we have shown that the threat-induced reduction in light reflex amplitude is sensitive to the effect of the anxiolytic drug diazepam. We have suggested that the 'fear-inhibited light reflex' paradigm could be used as a laboratory model of human anxiety. In the present study, we examined whether a single oral dose (200 microg) of the sedative-sympatholytic drug clonidine would antagonize the effects of threat on the pupillary light reflex. Twelve healthy male volunteers participated in two sessions separated by seven days in which they ingested clonidine 200 mg or placebo in a double-blind, balanced, cross-over design. Light stimuli (0.43 mW/cm2, 200 msec) were generated by a green (peak wavelength 565 nm) light-emitting diode, and pupil diameter was monitored by computerized binocular infrared television pupillometry in the dark. The light reflex response was recorded during either the anticipation of a shock ('threat' blocks) or periods in which no shocks were anticipated ('safe' blocks). The shock was a single square wave current pulse (1.5 mA, 50 msec) applied to the median nerve at the end of the experiment. Following each 'threat' or 'safe' block, subjects rated their anxiety using visual analogue scales. Two-factor ANOVA (treatment x condition) showed that clonidine treatment antagonized both the threat-induced increase in pupil diameter and the threat-induced reduction in light reflex amplitude. These effects, however, were not threat-specific since clonidine also reduced pupil diameter and enhanced light reflex amplitude in the 'safe' condition. Clonidine also reduced subjective alertness but not subjective anxiety in the 'threat' condition. These findings suggest that the mutual antagonism between clonidine and threat is likely to reflect the opposite effects of the two variables on the central noradrenergic control of pupillary functions, rather than a specific anxiolytic effect.

Comparison of the effects of moclobemide and selegiline on tyramine-evoked mydriasis in man.

AIMS: To examine the feasibility of using the human iris in vivo for the assessment of the interaction between tyramine and monoamine oxidase (MAO) inhibitors. To examine the relative roles of the two forms of MAO in terminating the response to sympathomimetic amines in the iris, by comparing the effects of single oral doses of moclobemide, a selective MAO-A inhibitor, and selegiline, a selective MAO-B inhibitor, on mydriatic responses to tyramine. METHODS: Twelve healthy male volunteers participated in three monthly sessions, each associated with ingestion of one capsule (moclobemide 450 mg, selegiline 10 mg, or placebo), according to a double-blind, balanced, cross-over design. Tyramine hydrochloride eye-drops (75 mM, 2 x 10 microl) were instilled three times in the left conjuctival sac at 40 min intervals. Pupil diameter was monitored with a binocular infrared television pupillometer before and for 4.5 h after ingestion of the capsule. The pupillary response to tyramine was expressed as the area under the pupil diameter x time curve (arbitrary units). A blood sample was taken before and 2 h after ingestion of the capsule, for the assay of platelet MAO-B activity, and plasma 3,4-dihydroxyphenylglycol (DHPG) concentration, an index of MAO-A activity. Platelet MAO activity was assayed radiochemically, using [14C]-phenylethylamine as substrate, and plasma DHPG by high performance liquid chromatography (h.p.l.c.). The results were analysed using analysis of variance with repeated measures, followed by Bonferroni's corrected t-test, using a significance criterion of P < 0.05. RESULTS: Both moclobemide and selegiline, compared with placebo, caused significant miosis in the right (untreated) eye. The changes in pupil diameter (mm +/- s.e. mean) from the pretreatment measurement were: placebo -0.09 +/- 0.07, moclobemide -0.52 +/- 0.09, selegiline -0.26 +/- 0.1. The mydriatic response to tyramine was potentiated by moclobemide, compared with the response recorded in the presence of placebo. The responses to tyramine (arbitrary units +/- s.e. mean) were: placebo 77.08 +/- 11.65, moclobemide 140.25 +/- 18.9, selegiline 72.75 +/- 12.35. Both moclobemide and selegiline significantly reduced platelet MAO activity, compared with placebo. The changes in platelet MAO activity (nmol h(-1) mg(-1) protein +/- s.e. mean) from the pretreatment level were: placebo 0.5 +/- 0.62, moclobemide -6.7 +/- 0.66, selegiline -17.7 +/- 0.87. Moclobemide significantly reduced plasma DHPG concentration, compared with placebo. The changes in plasma DHPG concentration (nmol l(-1) +/- s.e. mean) from the pretreatment level were: placebo -0.01 +/- 0.24, moclobemide -4.98 +/- 0.32, selegiline -0.51 +/- 0.26. CONCLUSIONS: The potentiation of tyramine-evoked mydriasis by moclobemide is likely to reflect the inhibition of MAO-A activity in the iris, consistent with the activity of this enzyme in sympathetic nerve terminals. The lack of effect of selegiline on tyramine-evoked mydriasis argues against a role of MAO-B in terminating the effects of sympathomimetic amines in the iris. The effects of the two drugs on platelet MAO activity and plasma DHPG concentration are in agreement with previous reports and consistent with the relative selectivity of moclobemide for MAO-A and of selegiline for MAO-B. The miosis caused by the two MAO inhibitors is likely to be due to a central sympatholytic action of the drugs.

Sensitivity of the fear-inhibited light reflex to diazepam.

We have shown previously that pupil diameter increases and the amplitude of the pupillary light reflex is reduced when subjects are under threat of an aversive event (electric shock), and that light reflex amplitude correlates negatively with subjective anxiety. We have suggested that the "fear-inhibited light reflex" paradigm could be used as a laboratory model of human anxiety. In the present study, we examined whether two doses (5 mg and 10 mg) of the anxiolytic drug diazepam would antagonize the effects of threat on the pupillary light reflex. Twelve healthy male volunteers participated in three weekly sessions, each associated with one of three treatments (diazepam 5 mg or 10 mg or placebo) in a double-blind, balanced, cross-over design. The light reflex was recorded during either the anticipation of a shock ("threat" blocks) or periods in which no shocks were anticipated ("safe" blocks). At the end of each "threat" or "safe" block, subjects rated their anxiety using visual analogue scales. Two-factor ANOVA (treatment x condition) showed that diazepam treatment antagonized the effect of threat on light reflex amplitude in a dose-dependent manner but it did not affect the threat-induced increase in pupil diameter. Diazepam had no effect on the pupillary light reflex in the "safe" condition. Diazepam also reduced subjective anxiety and alertness in the threat condition. These results show the sensitivity of the threat-induced reduction of light reflex amplitude to anxiolytic drugs, and provide further evidence for the utility of the fear-inhibited light reflex paradigm as a laboratory model of human anxiety.

Altered pupillary size and darkness and light reflexes in Alzheimer's disease.

The purpose was to compare resting pupil diameter in darkness and light, and the pupillary darkness and light reflexes between a group of patients with Alzheimer's disease and a group of healthy old people. Nine medication free patients with Alzheimer's disease and nine healthy control subjects, matched for sex and age with the patients, participated. There were six men and three women and the median age was 72 years in both groups. Pupil diameter was monitored with an infrared television pupillometer. Resting pupil diameter was smaller in the Alzheimer's disease group (P = 0.041, in darkness). The amplitude and the maximum dilatation velocity of the darkness reflex were smaller for the Alzheimer's disease group (maximum dilatation velocity P < 0.002). The amplitude and the 75% recovery time of the light reflex response were reduced in the Alzheimer's disease group (P < 0.002 and P = 0.034 respectively). There was no difference in the latency of the reflex response between the two groups. The reduced pupil size and diminished darkness reflex in the Alzheimer's disease group are consistent with a sympathetic deficit in the patients. The reduction in light reflex amplitude and recovery time are likely to be secondary to the grossly diminished pupil size in the patient group. The lack of any change in light reflex latency in the patients with Alzheimer's disease argues against an afferent defect. The pupillary changes in patients with Alzheimer's disease are qualitatively the same as those seen in healthy old people and are consistent with the notion of "accelerated aging" in Alzheimer's disease.