Morphine reduced perceived anger from neutral and implicit emotional expressions.

The µ-opioid system modulates responses to pain and psychosocial stress and mediates non-social and social reward. In humans, the µ-opioid agonist morphine can increase overt attention to the eye-region and visual exploration of faces with neutral expressions. However, little is known about how the human µ-opioid system influences sensitivity to and appraisal of subtle and explicit cues of social threats and reward. Here, we examined the effects of selective µ-opioid stimulation on perception of anger and happiness in faces with explicit, neutral or implicit emotion expressions. Sixty-three healthy adults (32 females) attended two sessions where they received either placebo or 10 mg per oral morphine in randomised order under double-blind conditions. Based on the known µ-opioid reduction of pain and discomfort, as well as reports suggesting that the non-specific partial agonist buprenorphine or the non-specific antagonist naltrexone affect appraisal of social emotional stimuli, we hypothesised that morphine would reduce threat sensitivity and enhance perception of happy facial expressions. While overall perception of others' happiness was unaffected by morphine treatment, morphine reduced perception of anger in stimuli with neutral and implicit expressions without affecting perception of explicit anger. This effect was statistically unrelated to gender, subjective drug effects, mood and autism trait measures. The finding that a low dose of µ-agonist reduced the propensity to perceive anger in photos with subtle facial expressions is consistent with the notion that µ-opioids mediate social confidence and reduce sensitivity to threat cues.

Posttraumatic stress disorder and partner-specific social cognition: a pilot study of sex differences in the impact of arginine vasopressin.

Posttraumatic stress disorder (PTSD) is associated with problems in intimate relationships, partly due to deficits in social cognition. In this study, the role of arginine vasopressin (AVP) in the link between PTSD and partner-specific social cognition was examined. Participants were 24 individuals from 12 heterosexual couples in which at least one partner exhibited clinically significant PTSD symptoms. Attention to partner expressions of anger was examined as an indicator of distress and need for affiliative behaviors to repair the relationship bond. AVP administration improved the speed of men's attentional engagement with their partners' expressions of anger and alleviated the negative impact of PTSD on this social cognitive process. Further, men's morning urinary AVP levels were negatively correlated with their PTSD severity. No such effects were found among women or for attention to unfamiliar men's or women's anger expressions. Thus, the AVP system may function in the relationship problems associated with PTSD.

Oxytocin in postnatally depressed mothers: its influence on mood and expressed emotion.

BACKGROUND: Postnatal depression is common and negatively affects the mother-baby relationship; oxytocin has been found to have positive effects on parenting behavior. We hypothesize that intranasal administration of oxytocin to mothers with depression will influence their parenting related expressed emotion, creating a better basis for sensitive parenting. METHODS: Twenty-five postnatally depressed mothers with infants less than one year participated in a randomized, double-blind, placebo controlled within-subject clinical study in 2011. Mothers attended an out-patient perinatal psychiatry setting in NSW, Australia. They received 24 IU of oxytocin alternating with placebo approximately one week apart in random order, prior to completing outcome measures. The outcome measures were the Five Minute Speech Sample, the Self-Assessment Manikin and the Controlled Oral Word Association Test. RESULTS: In the oxytocin condition mothers were sadder (p=.01), and they more often initially described their babies as difficult (p=.038), but they reported that the quality of their relationship with their infant was more positive (p=.036). LIMITATIONS: Despite an adequate sample size to answer our central hypothesis, a larger sample may have elucidated a moderating effect of childhood trauma. CONCLUSION: Oxytocin did not make depressed mothers happier but their perception of the relationship with their baby improved. Treatment with intranasal oxytocin might show some unwanted side-effects in depressed individuals.

Effects of delta-9-tetrahydrocannabinol on evaluation of emotional images.

There is growing evidence that drugs of abuse alter processing of emotional information in ways that could be attractive to users. Our recent report that Δ9-tetrahydrocannabinol (THC) diminishes amygdalar activation in response to threat-related faces suggests that THC may modify evaluation of emotionally-salient, particularly negative or threatening, stimuli. In this study, we examined the effects of acute THC on evaluation of emotional images. Healthy volunteers received two doses of THC (7.5 and 15 mg; p.o.) and placebo across separate sessions before performing tasks assessing facial emotion recognition and emotional responses to pictures of emotional scenes. THC significantly impaired recognition of facial fear and anger, but it only marginally impaired recognition of sadness and happiness. The drug did not consistently affect ratings of emotional scenes. THC's effects on emotional evaluation were not clearly related to its mood-altering effects. These results support our previous work, and show that THC reduces perception of facial threat. Nevertheless, THC does not appear to positively bias evaluation of emotional stimuli in general.

Storm in a coffee cup: caffeine modifies brain activation to social signals of threat.

Caffeine, an adenosine A1 and A(2A) receptor antagonist, is the most popular psychostimulant drug in the world, but it is also anxiogenic. The neural correlates of caffeine-induced anxiety are currently unknown. This study investigated the effects of caffeine on brain regions implicated in social threat processing and anxiety. Participants were 14 healthy male non/infrequent caffeine consumers. In a double-blind placebo-controlled crossover design, they underwent blood oxygenation level-dependent functional magnetic resonance imaging (fMRI) while performing an emotional face processing task 1 h after receiving caffeine (250 mg) or placebo in two fMRI sessions (counterbalanced, 1-week washout). They rated anxiety and mental alertness, and their blood pressure was measured, before and 2 h after treatment. Results showed that caffeine induced threat-related (angry/fearful faces > happy faces) midbrain-periaqueductal gray activation and abolished threat-related medial prefrontal cortex wall activation. Effects of caffeine on extent of threat-related amygdala activation correlated negatively with level of dietary caffeine intake. In concurrence with these changes in threat-related brain activation, caffeine increased self-rated anxiety and diastolic blood pressure. Caffeine did not affect primary visual cortex activation. These results are the first to demonstrate potential neural correlates of the anxiogenic effect of caffeine, and they implicate the amygdala as a key site for caffeine tolerance.

Effect of escitalopram on the processing of emotional faces.

Serotonin has been implicated in the neurobiology of depressive and anxiety disorders, but little is known about its role in the modulation of basic emotional processing. The aim of this study was to determine the effect of the selective serotonin reuptake inhibitor, escitalopram, on the perception of facial emotional expressions. Twelve healthy male volunteers completed two experimental sessions each, in a randomized, balanced order, double-blind design. A single oral dose of escitalopram (10 mg) or placebo was administered 3 h before the task. Participants were presented to a task composed of six basic emotions (anger, disgust, fear, happiness, sadness, and surprise) that were morphed between neutral and each standard emotion in 10% steps. Escitalopram facilitated the recognition of sadness and inhibited the recognition of happiness in male, but not female faces. No drug effect on subjective measures was detected. These results confirm that serotonin modulates the recognition of emotional faces, and suggest that the gender of the face can have a role in this modulation. Further studies including female volunteers are needed.

Effect of escitalopram on the processing of emotional faces

Serotonin has been implicated in the neurobiology of depressive and anxiety disorders, but little is known about its role in the modulation of basic emotional processing. The aim of this study was to determine the effect of the selective serotonin reuptake inhibitor, escitalopram, on the perception of facial emotional expressions. Twelve healthy male volunteers completed two experimental sessions each, in a randomized, balanced order, double-blind design. A single oral dose of escitalopram (10 mg) or placebo was administered 3 h before the task. Participants were presented to a task composed of six basic emotions (anger, disgust, fear, happiness, sadness, and surprise) that were morphed between neutral and each standard emotion in 10 percent steps. Escitalopram facilitated the recognition of sadness and inhibited the recognition of happiness in male, but not female faces. No drug effect on subjective measures was detected. These results confirm that serotonin modulates the recognition of emotional faces, and suggest that the gender of the face can have a role in this modulation. Further studies including female volunteers are needed.

Serotonergic and noradrenergic modulation of emotion processing by single dose antidepressants.

Serotonergic and noradrenergic pathways are the main targets of antidepressants. Their differential effects on emotion processing-related brain activation are, however, to be further characterized. We aimed at elucidating the neural sites of action of an acute differential serotonergic and noradrenergic influence on an emotion-processing task, which was earlier shown to be associated with depressiveness. In a single-blind pseudo-randomized crossover study, 21 healthy subjects (16 subjects finally included in the analysis) participated to ingest a single dose at three time points of either 40 mg citalopram, a selective serotonin-reuptake inhibitor, 8 mg reboxetine, a selective noradrenaline-reuptake inhibitor, or placebo 2-3 h before functional magnetic resonance imaging (fMRI). During fMRI, subjects performed a task comprising the anticipation and perception of pictures of either 'known' (positive, negative, neutral) or 'unknown' valence (randomly 50% positive or negative). In direct comparison with citalopram and with placebo, reboxetine increased brain activity in the medial thalamus. Citalopram modulated certain prefrontal and insular areas more prominently. Other frontal and parieto-occipital areas were modulated by both drugs. In conclusion, the functional network involved in emotional information processing could be modulated by the acute application of selective noradrenergic and serotonergic drugs revealing a noradrenergic effect in thalamic and frontal areas, and a prefrontal and insular focus of serotonergic modulation. These findings could have implications for future selection criteria concerning personalized antidepressant medication in depression.

Effectiveness, safety, and tolerability of lisdexamfetamine dimesylate in children with attention-deficit/hyperactivity disorder: an open-label, dose-optimization study.

OBJECTIVE: The aim of this study was to assess the effectiveness and safety of lisdexamfetamine dimesylate (LDX) in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: This was a 7-week, open-label study evaluating 20, 30, 40, 50, 60, or 70 mg/day LDX in 318 children aged 6-12 years with ADHD. The ADHD Rating Scale IV (ADHD-RS-IV) was the primary efficacy assessment. Secondary measures included the Clinical Global Impressions-Improvement (CGI-I), Expression and Emotion Scale for Children (EESC), and Behavior Rating Inventory of Executive Function (BRIEF). Safety assessments included treatment-emergent adverse events (TEAEs), vital signs, and electrocardiograms. RESULTS: At end point, mean (standard deviation [SD]) improvement from baseline in ADHD-RS-IV total score was 28.6 (10.9) (p < 0.0001). Most subjects (89.9%) were rated "improved" (i.e., CGI-I 1 or 2). Improvements from baseline were observed in the EESC total and subscale scores (p < or = 0.0002). LDX treatment resulted in significant improvement on the Global Executive Composite, Behavioral Regulation, and Metacognition indices of the BRIEF (p < 0.0001). TEAEs (incidences > or =10%) were decreased appetite, decreased weight, irritability, insomnia, headache, upper abdominal pain, and initial insomnia. CONCLUSIONS: LDX was effective and generally well tolerated with a safety profile consistent with long-acting stimulant use. There was overall improvement in ADHD symptoms and executive function measures and no worsening of emotional expression measures. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00500071.

Adverse reactions to methylphenidate treatment for attention-deficit/hyperactivity disorder: structure and associations with clinical characteristics and symptom control.

BACKGROUND: Methylphenidate (MPH)-related adverse events are well characterized. Their predictors and their relationship with therapeutic effects are less well understood. Here we examine these issues in relation to two long-acting formulations. METHOD: Comparison of Methylphenidates in the Analog Classroom Setting (COMACS) was made in a large (n = 184) placebo-controlled trial comparing Equasym XL/Metadate CD, Concerta, and placebo (PLA) using a Laboratory School protocol. Therapeutic effects were measured using direct observation, scores on a simple math productivity task and parent ratings. Parents also completed the Barkley Stimulant Side Effect Rating Scale (BSSERS). RESULTS: The BSSERS had six factors: Emotionality, sleep/appetite, disengaged, dizzy, uninterested, and aches. Treatment effects were seen only for emotionality (which improved) and sleep and appetite (which worsened). Adverse events were not predictable from personal and clinical characteristics of patients. Sleep/appetite adverse events were not associated with therapeutic effects. Improvements in attention-deficit/hyperactivity disorder (ADHD) and emotionality were correlated. DISCUSSION: The results support a narrow conceptualization of MPH adverse events with problems restricted to appetite and sleep. These effects were not predictable on the basis of available information and may be due to an underlying mechanism rather distinct from those determining therapeutic effects.

Involuntary emotional expression disorder in Alzheimer's disease - psychopharmacotherapy aspects.

Involuntary emotional expression disorder (IEED) is syndrome characterized with relatively stereotypical episodes of uncontrollable crying and/or laughing. Additionally, this syndrome can include irritability, anger and frustration. This syndrome is common among a number of neurologic diseases like patients with a stroke or traumatic brain injury (TBI), patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), as well as dementias such as Alzheimer's disease (AD), and motor disorders such as Parkinson's disease (PD). IEED is very common but misdiagnosed and consequently undertreated. Prevalence of IEED in AD is between 15-39%. Recent controlled clinical studies suggest that dextromethorphan (DM) and quinidine (Q) is an effective treatment for IEED. United States Food and Drug Administration (FDA) has accepted for filing and review its New Drug Application (NDA) for Zenvia (dextromethorphan hydrobromide and quinidine sulfate capsules) for the treatment of IEED. In Republic of Croatia current treatment involves antidepressants (tricyclic and selective serotonin reuptake inhibitors), antipsychotic agents, anxiolytics, antidementives and mood stabilizers. New promising treatment can reduce the frequency of episodes and improve the quality of life of patients and their families and caregivers.

Noradrenergic enhancement of amygdala responses to fear.

Multiple lines of evidence implicate the basolateral amygdala (BLA) and the noradrenergic (norepinephrine, NE) system in responding to stressful stimuli such as fear signals, suggesting hyperfunction of both in the development of stress-related pathologies including anxiety disorders. However, no causative link between elevated NE neurotransmission and BLA hyperresponsiveness to fear signals has been established to date in humans. To determine whether or not increased noradrenergic tone enhances BLA responses to fear signals, we used functional magnetic resonance imaging (fMRI) and a strategy of pharmacologically potentiating NE neurotransmission in healthy volunteers. 18 subjects were scanned two times on a facial emotion paradigm and given either a single-dose placebo or 4 mg of the selective NE reuptake inhibitor reboxetine 2 h prior to an fMRI session. We found that reboxetine induced an amygdala response bias towards fear signals that did not exist at placebo baseline. This pharmacological effect was probabilistically mapped to the BLA. Extrapolation of our data to conditions of traumatic stress suggests that disinhibited endogenous NE signaling could serve as a crucial etiological contributor to post-traumatic stress disorder (PTSD) by eliciting exaggerated BLA responses to fear signals.

Effects of acute alcohol consumption on processing of perceptual cues of emotional expression.

Alcohol consumption has been associated with increases in aggressive behaviour. However, experimental evidence of a direct association is equivocal, and mechanisms that may underlie this relationship are poorly understood. One mechanism by which alcohol consumption may increase aggressive behaviour is via alterations in processing of emotional facial cues. We investigated the effects of acute alcohol consumption on sensitivity to facial expressions of emotion. Participants attended three experimental sessions where they consumed an alcoholic drink (0.0, 0.2 or 0.4 g/kg), and completed a psychophysical task to distinguish expressive from neutral faces. The level of emotion in the expressive face varied across trials the threshold at which the expressive face was reliably identified and measured. We observed a significant three-way interaction involving emotion, participant sex and alcohol dose. Male participants showed significantly higher perceptual thresholds for sad facial expressions compared with female participants following consumption of the highest dose of alcohol. Our data indicate sex differences in the processing of facial cues of emotional expression following alcohol consumption. There was no evidence that alcohol altered the processing of angry facial expressions. Future studies should examine effects of alcohol expectancy and investigate the effects of alcohol on the miscategorisation of emotional expressions.

The effects of modafinil, caffeine, and dextroamphetamine on judgments of simple versus complex emotional expressions following sleep deprivation.

Cognitive abilities such as vigilance, attention, memory, and executive functioning can be degraded significantly following extended periods of wakefulness. Although much evidence suggests that sleep-loss induced deficits in alertness and vigilance can be reversed or mitigated by stimulants such as caffeine, it is not clear how these compounds may affect other higher level cognitive processes such as emotional perception and judgment. Following 47 h of sleep deprivation, the study examined the effect of three stimulant medications (modafinil 400 mg, dextroamphetamine 20 mg, caffeine 600 mg) or placebo on the ability of 54 healthy participants to discriminate and label simple emotional expressions versus complex affect blends (created by morphing photographs of two different affective facial expressions). For simple affective faces, neither sleep loss nor stimulant medications made any difference on the accuracy of judgments. In contrast, for complex emotion blends, all three stimulant medications significantly improved the ability to discriminate subtle aspects of emotion correctly relative to placebo, but did not differ from one another. These findings suggest that all three stimulant medications are effective at restoring some aspects of subtle affective perception.

Long-chain n-3 polyunsaturated fatty acids decrease feelings of anger in substance abusers.

It has been suggested that low levels of n-3 polyunsaturated fatty acids (PUFAs) play a role in the pathophysiology of some psychiatric disorders. In light of the existence of strong associations between high-frequency and high-severity aggressive behaviors and substance use disorders and of our observation that substance abusers have poor dietary habits, the possibility that the administration of supplements of n-3 PUFAs would decrease their anger levels was explored. A lifelong history of aggressive behaviors and problems with the law was obtained in 24 patients. Thirteen patients received on a daily basis capsules containing 3 g of n-3 PUFAs (EPA+DHA). Eleven patients received placebo capsules. The trial was double-blind, randomized, and lasted 3 months. An anger scale was administered at baseline and every month thereafter. Six PUFA group patients and eight placebo group patients were followed for an additional 3 months after treatment discontinuation. Four patients in each group had a history of assaultive behavior. The baseline fish and n-3 PUFA intakes of these eight patients were significantly lower than those of the non-aggressive patients. When given for 3 months, n-3 PUFAs were superior to placebo in diminishing anger scores. Scores remained decreased for 3 months following treatment discontinuation. These data provide further support for emerging evidence indicating that supplementation with long-chain n-3 PUFAs could be beneficial in the treatment of some individuals with aggressive tendencies.

Amygdala activation modulated by levodopa during emotional recognition processing in healthy volunteers: a double-blind, placebo-controlled study.

A critical role of dopaminergic systems in emotional processing has been revealed by several animal and clinical studies in Parkinson disease and schizophrenia. We conducted a study with functional magnetic resonance imaging (fMRI) in 13 healthy volunteers to test the dopaminergic modulation on amygdala response to emotional processing and to evaluate if it was the result of a direct action on amygdalar nuclei or indirect modulation via medial prefrontal cortex projecting on amygdala.A placebo-controlled crossover experimental design was used. Subjects received either levodopa (100 mg) or placebo in 2 fMRI sessions. Amygdala activation was evaluated during a facial emotion recognition test.The statistical comparison between placebo versus levodopa situations revealed a significant reduction in activation of right amygdala during the levodopa fMRI session. The functional connectivity analysis revealed only a change of correlated activations between right and left amygdala, and not medial prefrontal cortex, after levodopa administration. Our results suggest that administration of levodopa to healthy volunteers impairs the amygdalar activation. It supports the hypothesis that amygdala activation follows an inverted U-shaped curve in relation to dopamine (DA) concentration. The results of the functional connectivity seem to suggest a dopaminergic action on amygdalar nuclei rather than a modulation of medial prefrontal cortex on amygdala.

Participation of the cannabinoid system in the regulation of emotional-like behaviour.

The endocannabinoid system has been involved in the control of several neurophysiological and behavioural responses. Indeed, recent studies have suggested that the cannabinoid system could represent an important substrate for the control of emotional behaviour, and further research would probably help to identify new promising therapeutic targets. This paper reviews the results obtained in different animal models used to investigate emotional states after the manipulation of the endocannabinoid system. Cannabinoid compounds can induce anxiogenic- and anxiolytic-like responses in rodents depending on the experimental conditions. Studies using knockout mice lacking the CB1 cannabinoid receptors have shown the participation of this receptor in several behavioural responses including anxiety- and depressive-like states. Furthermore, the endocannabinoid system regulates the hypothalamic-pituitary adrenal axis, which is involved in providing an appropriate response to stressful situations. Recent studies have also demonstrated that the endocannabinoids can function as retrograde messengers, modulating the release of different neurotransmitter, including opioids, GABA and cholecystokinin that have been classically involved in the control of anxiety-like responses. All this recent information has further clarified the role played by the endogenous cannabinoid system in the control of emotional behaviour and provides data to support a new possible therapeutic use of cannabinoid compounds.

Apomorphine effects on emotional modulation of the startle reflex in rats.

RATIONALE: Emotional modulation of the startle reflex in the rat may be used to assess whether activation of dopamine receptors specifically increases hedonia, incentive, fear or arousal. OBJECTIVES: The objective of the study is to determine the effects of apomorphine (0.8 mg/kg s.c.) on the startle reflex of rats (72 male Sprague-Dawley rats) exposed to one of three affective conditions. These conditions were negative affective stimulus (exposure to cat smell), positive affective stimulus (availability of a 20% sucrose solution), neutral stimulus (no additional affective stimulus) and one of two appetitive "drive" states (food deprived or non-food deprived). METHODS: The startle response (whole-body flinch response) was measured after presentation of a range of intensities of acoustic stimuli (65-120 dB, 40-ms duration white noise). The resulting sigmoidal stimulus intensity-response magnitude (SIRM) curves were fitted using a logistic regression procedure, and features of these functions were abstracted for analysis. RESULTS: Maximal startle amplitudes were increased by the negative affect (fear) stimulus in non-food-deprived rats and decreased by the positive affect stimulus in food-deprived rats. Apomorphine mimicked the effects of food deprivation under both affect conditions, but also produced an effect in food-deprived rats similar to that of the positive affect condition. CONCLUSIONS: The results are consistent with both a positive incentive effect and a direct hedonic action of apomorphine, but inconsistent with a role in general arousal. In addition, a method of analysing SIRM functions with logistic regressions is introduced as a useful means of standardising startle reflex measurements.

Contextual control over the expression of fear in rats conditioned under a benzodiazepine.

RATIONALE: Benzodiazepines disrupt fear conditioning, but this disruption is context-specific; if rats have been conditioned under a benzodiazepine, their fear is recovered if they are tested in a different context. The present experiments investigated how the conditioning context controls fear in rats conditioned under a benzodiazepine. OBJECTIVES: The experiments had three aims: (1) to replicate the finding that fear is recovered when rats are tested in a different context, (2) to test whether the conditioning context reduces fear generally or only for the specific stimulus conditioned in that context and (3) to test whether latent inhibition of the conditioning context reduces its control over fear. METHODS: Rats were injected with the benzodiazepine midazolam (1.25 mg/kg) or saline and exposed to a conditioned stimulus (CS) and shock in a distinctive chamber. Latent inhibition of the chamber was induced by extensively preexposing the rats to the chamber. The day after conditioning, fear was assessed by presenting the CS while rats were in either the conditioning chamber or a different chamber. RESULTS: The midazolam-induced reduction of fear was reversed (i.e. fear was partially recovered) if rats were tested in the different context, and was completely prevented if the conditioning context had been latently inhibited. These two effects were not additive since, when the conditioning context had been latently inhibited, rats showed less fear in the different context than in the conditioning context. CONCLUSIONS: We argue that midazolam does not disrupt conditioning, but imbues the conditioning context with control over retrieval of the CS-shock association. In this regard, the effects of midazolam closely parallel those of extinction.

Fluoxetine treatment of anger attacks: a replication study.

"Anger attacks" are outbursts of anger which are accompanied by intense autonomic arousal and are clearly inappropriate to the situation in which they occur. The Anger Attacks Questionnaire, designed to assess these attacks, was administered to 164 consecutive patients (78 men and 86 women; mean age, 40.5 +/- 11.0 years) diagnosed as having major depression with the Structured Clinical Interview for DSM-III-R. These patients were treated openly with fluoxetine, 20 mg/day for 8 weeks, and the prevalence of anger attacks was assessed before and after treatment. At baseline, 64 (39%) (26 men and 38 women) of these patients reported having anger attacks according to our criteria. Forty-one (64%) of the 64 depressed patients with anger attacks at baseline did not report anger attacks following fluoxetine treatment, while 7 (7%) of the 100 patients who did not have anger attacks at baseline reported these attacks following treatment, with this difference being statistically significant (chi 2 = 22.7, p < .0005).