Emotion-potentiated Startle Research Articles

Effects of short-term quetiapine treatment on emotional processing, sleep and circadian rhythms

Quetiapine is an atypical antipsychotic that can stabilise mood from any index episode of bipolar disorder. This study investigated the effects of seven-day quetiapine administration on sleep, circadian rhythms and emotional processing in healthy volunteers. Twenty healthy volunteers received 150 mg quetiapine XL for seven nights and 20 matched controls received placebo. Sleep-wake actigraphy was completed for one week both pre-dose and during drug treatment. On Day 8, participants completed emotional processing tasks. Actigraphy revealed that quetiapine treatment increased sleep duration and efficiency, delayed final wake time and had a tendency to reduce within-day variability. There were no effects of quetiapine on subjective ratings of mood or energy. Quetiapine-treated participants showed diminished bias towards positive words and away from negative words during recognition memory. Quetiapine did not significantly affect facial expression recognition, emotional word categorisation, emotion-potentiated startle or emotional word/faces dot-probe vigilance reaction times. These changes in sleep timing and circadian rhythmicity in healthy volunteers may be relevant to quetiapine's therapeutic actions. Effects on emotional processing did not emulate the effects of antidepressants. The effects of quetiapine on sleep and circadian rhythms in patients with bipolar disorder merit further investigation to elucidate its mechanisms of action.

Acute fluoxetine modulates emotional processing in young adult volunteers.

Fluoxetine is generally regarded as the first-line pharmacological treatment for young people, as it is believed to show a more favourable benefit:risk ratio than other antidepressants. However, the mechanisms through which fluoxetine influences symptoms in youth have been little investigated. This study examined whether acute administration of fluoxetine in a sample of young healthy adults altered the processing of affective information, including positive, sad and anger cues. A total of 35 male and female volunteers aged between 18 and 21 years old were randomized to receive a single 20 mg dose of fluoxetine or placebo. At 6 h after administration, participants completed a facial expression recognition task, an emotion-potentiated startle task, an attentional dot-probe task and the Rapid Serial Visual Presentation. Subjective ratings of mood, anxiety and side effects were also taken pre- and post-fluoxetine/placebo administration. Relative to placebo-treated participants, participants receiving fluoxetine were less accurate at identifying anger and sadness and did not show the emotion-potentiated startle effect. There were no overall significant effects of fluoxetine on subjective ratings of mood. Fluoxetine can modulate emotional processing after a single dose in young adults. This pattern of effects suggests a potential cognitive mechanism for the greater benefit:risk ratio of fluoxetine in adolescent patients.

Emotion potentiated startle in fragile X syndrome.

Social avoidance and anxiety are prevalent in fragile X syndrome (FXS) and are potentially mediated by the amygdala, a brain region critical for social behavior. Unfortunately, functional brain resonance imaging investigation of the amygdala in FXS is limited by the difficulties experienced by intellectually impaired and anxious participants. We investigated the relationship between social avoidance and emotion-potentiated startle, a probe of amygdala activation, in children and adolescents with FXS, developmental disability without FXS (DD), and typical development. Individuals with FXS or DD demonstrated significantly reduced potentiation to fearful faces than a typically developing control group (p < .05). However, among individuals with FXS, social avoidance correlated positively with fearful-face potentiation (p < .05). This suggests that general intellectual disability blunts amygdalar response, but differential amygdala responsiveness to social stimuli contributes to phenotypic variability among individuals with FXS.

Effects of short-term varenicline administration on emotional and cognitive processing in healthy, non-smoking adults: a randomized, double-blind, study.

Varenicline is an effective and increasingly prescribed drug for smoking cessation, but has been associated with depressive symptoms and suicidal behavior. However, it remains unclear whether those changes in mood and behavior are directly related to varenicline use, or caused by smoking cessation itself or reflects depression and suicidality rates in smokers, independent of treatment. To investigate the influence of varenicline on mood and behavior independent of smoking and smoking cessation, we assessed the effects of varenicline on emotional processing (a biomarker of depressogenic effects), emotion-potentiated startle reactivity, impulsivity (linked with suicidal behavior), and cognitive performance in non-smoking subjects. We used a randomized, double-blind design, in which we administered varenicline or placebo to healthy subjects over 7 days (0.5 mg/day first 3 days, then 1 mg/day). Cognitive and emotional processing was assessed by a battery of computerized tasks and recording of emotion-potentiated startle response. A total of 41 subjects were randomized, with 38 subjects included in the analysis. The varenicline group did not differ from placebo in terms of negative biases in emotional processing or mood. However, compared with placebo, the varenicline group scored higher on working and declarative memory. In conclusion, short-term varenicline use did not influence negative biases in emotional processing or impulsivity in non-smoking subjects, thereby not supporting direct depressogenic or suicidal risk behavior-inducing effects. In contrast, varenicline may have cognitive-enhancing effects.

Effect of d-amphetamine on emotion-potentiated startle in healthy humans: implications for psychopathy and antisocial behaviour

An emerging literature associates increased dopaminergic neurotransmission with altered brain response to aversive stimuli in humans. The direction of the effect of dopamine on aversive motivation, however, remains unclear, with some studies reporting increased and others decreased amygdala activation to aversive stimuli following the administration of dopamine agonists. Potentiation of the startle response by aversive foreground stimuli provides an objective and directional measure of emotional reactivity and is considered useful as an index of the emotional effects of different drugs. We investigated the effects of two doses of D-amphetamine (5 and 10 mg), compared to placebo, for the first time to our knowledge, using the affect-startle paradigm. The study employed a between-subjects, double-blind design, with three conditions: 0 mg (placebo), and 5 and 10 mg D-amphetamine (initially n = 20/group; final sample: n = 18, placebo; n = 18, 5 mg; n = 16, 10 mg). After drug/placebo administration, startle responses (eyeblinks) to intermittent noise probes were measured during viewing of pleasant, neutral and unpleasant images. Participants' general and specific impulsivity and fear-related personality traits were also assessed. The three groups were comparable on personality traits. Only the placebo group showed significant startle potentiation by unpleasant, relative to neutral, images; this effect was absent in both 5- and 10-mg D-amphetamine groups (i.e. the same effect of D-amphetamine observed at different doses in different people). Our findings demonstrate a reduced aversive emotional response under D-amphetamine and may help to account for the known link between the use of psychostimulant drugs and antisocial behaviour.

Using an experimental medicine model to understand the antidepressant potential of the N-Methyl-D-aspartic acid (NMDA) receptor antagonist memantine

There is growing interest in the role of the glutamatergic system both in depression and as a novel target for treatments. Preclinical studies suggested that the non-competitive N-Methyl-D-aspartic acid (NMDA) receptor antagonist memantine might have antidepressant properties, but a randomised controlled trial failed to support this. A healthy volunteer model of emotional processing was used to assess the neuropsychological profile of action of memantine. Healthy volunteers (n=32) were randomised to receive a single dose of memantine (10 mg) or placebo, and subsequently completed a battery of tasks measuring emotional processing, including facial expression recognition, emotional memory, dot-probe and emotion-potentiated startle tasks, as well as working and verbal memory. Memantine treated volunteers showed an increased emotion-potentiated startle, and a reduced bias for negative items in emotional recognition memory. There were no effects of the drug on any other aspect of emotional or non-emotional information processing. These results suggest that a single dose of memantine produces an early anxiogenic response in the emotion-potentiated startle similar to that seen following a single dose of the selective serotonin reuptake inhibitor, citalopram. However, the overall profile of effects is more limited than that which might be expected in response to a conventional antidepressant.

The common adolescent bipolar phenotype shows positive biases in emotional processing

Bipolar disorder is associated with abnormalities in emotional processing that persist into periods of remission. However, studies of euthymic bipolar disorder patients may be confounded by the experience of mood episodes and medication. We therefore assessed an adolescent group for vulnerability markers associated with the bipolar phenotype. The Mood Disorder Questionnaire (MDQ) is a screening tool for bipolar disorder that targets mood-elevation symptoms. We selected 32 high-scoring students (≥ 7 symptoms) with the adolescent bipolar phenotype and 30 low-scoring controls (≤ 3 symptoms) and screened them with the Mini International Neuropsychiatric Interview-Plus for bipolar disorder and other psychiatric disorders. We investigated emotional processing by assessing facial expression recognition, emotional memory, emotion-potentiated startle, and a dot-probe task. Of the high-MDQ participants, 12 were in remission from bipolar disorder defined by DSM-IV-TR and interview (bipolar II disorder/bipolar disorder not otherwise specified) and 3 from major depressive disorder. High-MDQ participants had higher levels of neuroticism, low mood, and lifetime anxiety comorbidity and alcohol dependence compared with low-MDQ participants. The high-MDQ group showed facilitated recognition of surprised and neutral facial expressions and enhanced processing of positive versus negative information in emotional recognition memory and emotion-potentiated startle. There were no effects on emotional categorisation/recall memory or attentional bias in the dot-probe task. These results suggest that students with the common adolescent bipolar phenotype show positive emotional processing biases despite increased levels of neuroticism, low mood, and anxiety. Such effects may represent a psychological vulnerability marker associated with the bipolar phenotype.

Agomelatine facilitates positive versus negative affective processing in healthy volunteer models

Agomelatine is a new antidepressant with a novel profile of pharmacological action. The clinical efficacy of agomelatine has been established in major depression, but its actions on emotional bias are unknown. Consequently, the current experimental study assessed the effect of agomelatine on emotional processing in healthy volunteers using an Emotional Test Battery shown to be sensitive to serotonin and noradrenaline reuptake inhibitors. Volunteers were randomized to receive placebo, 25 mg or 50 mg of agomelatine over a 7-day period in a double-blind parallel groups design. Emotional processing (n = 48) was assessed on the morning of day 8 using the Emotional Test Battery which included facial expression recognition, emotional memory, attentional visual probe and emotion-potentiated startle. Mood and subjective state were monitored before and during treatment. Agomelatine (25 mg) decreased subjective ratings of sadness, reduced recognition of sad facial expressions, improved positive affective memory and reduced the emotion-potentiated startle response. The results show that agomelatine has more selective effects on the processing of social facial cues than conventional antidepressants, which could contribute to less blunting of emotional experience. The study highlights the potential value of volunteer models in drug development for screening and profiling of novel antidepressants.

Dissociable effects of acute antidepressant drug administration on subjective and emotional processing measures in healthy volunteers

We have previously shown that single doses of serotonin-selective and noradrenaline-selective antidepressant agents produce positive biases in measures of emotional processing in healthy volunteers. The aim of the present study was to confirm and extend this finding by studying the effects of a single dose of the selective serotonin and noradrenaline re-uptake inhibitor, duloxetine. Healthy volunteers were randomly allocated to double-blind administration of either duloxetine 60 mg orally or placebo. Participants then completed a battery of emotional-processing tasks measuring facial expression recognition, emotional memory and emotion-potentiated startle. Subjective state was measured using visual analogue scales throughout the test period. Duloxetine enhanced the recognition of both disgusted and happy facial expressions and increased memory intrusions for positive personality characteristics in the free recall test. There were no significant effects on startle responses. However, duloxetine was not well tolerated and was associated with a high level of negative subjective effects. Despite the induction of negative subjective effects after duloxetine administration, some positive effects on emotional processing were seen in line with acute administration of serotonin-selective and noradrenaline-selective antidepressant agents. These results confirm the induction of fast changes in emotional processing in healthy volunteer groups and suggest a mechanism by which antidepressants may act in depression. Further studies are required to assess whether positive effects on emotional processing are more selective at a lower dose of duloxetine.

A single dose of citalopram increases fear recognition in healthy subjects

We have previously shown that a single dose of intravenous citalopram in healthy volunteers enhances the detection of fearful facial expressions, suggesting an effect of acute selective serotonin re-uptake inhibitor (SSRI) treatment on the processing of anxiety-related stimuli. The aim of the present study was to confirm and extend this finding by studying the effects of a single dose of oral citalopram on a range of tasks designed to assess different aspects of emotional processing. A total of 32 healthy volunteers were randomly allocated to double-blind treatment with either citalopram 20 mg orally or placebo. Participants then completed a series of tasks assessing emotional aspects of attention (visual-probe task), perception (categorization of facial affect), memory (emotional memory task) and reactivity to threat (emotion potentiated startle). Relative to placebo-treated subjects, participants treated with citalopram demonstrated improved recognition of fearful faces and increased baseline startle response. However, the citalopram group also showed an attentional bias towards positive words. Our data suggest that acute oral citalopram increases the processing of anxiety-related stimuli in healthy volunteers. This mechanism could underlie the known tendency of SSRIs to increase anxiety in patients early in treatment. Our data also suggests that some of the positive biases in emotional processing produced by SSRI treatment might be detectable at the beginning of treatment.

Highly neurotic never-depressed students have negative biases in information processing

Cognitive theories associate depression with negative biases in information processing. Although negatively biased cognitions are well documented in depressed patients and to some extent in recovered patients, it remains unclear whether these abnormalities are present before the first depressive episode. High neuroticism (N) is a well-recognized risk factor for depression. The current study therefore compared different aspects of emotional processing in 33 high-N never-depressed and 32 low-N matched volunteers. Awakening salivary cortisol, which is often elevated in severely depressed patients, was measured to explore the neurobiological substrate of neuroticism. High-N volunteers showed increased processing of negative and/or decreased processing of positive information in emotional categorization and memory, facial expression recognition and emotion-potentiated startle (EPS), in the absence of global memory or executive deficits. By contrast, there was no evidence for effects of neuroticism on attentional bias (as measured with the dot-probe task), over-general autobiographical memory, or awakening cortisol levels. These results suggest that certain negative processing biases precede depression rather than arising as a result of depressive experience per se and as such could in part mediate the vulnerability of high-N subjects to depression. Longitudinal studies are required to confirm that such cognitive vulnerabilities predict subsequent depression in individual subjects.

Tryptophan supplementation induces a positive bias in the processing of emotional material in healthy female volunteers

The serotonin precursor L-tryptophan (TRP) is available as a nutritional supplement and is licensed as an antidepressant in a number of countries. However, evidence of its efficacy as the primary treatment for depression is limited, and the direct action of TRP on the symptoms of depression and anxiety has not been well-characterised. The present study assessed whether TRP induces cognitive changes opposite to the negative biases found in depression and characteristic of those induced by serotonergic antidepressants in healthy volunteers. Thirty eight healthy volunteers were randomised to receive 14 days double-blind intervention with TRP (1 g 3x a day) or placebo. On the final day, emotional processing was assessed using four tasks: facial expression recognition, emotion-potentiated startle, attentional probe and emotional categorisation and memory. TRP increased the recognition of happy facial expressions and decreased the recognition of disgusted facial expressions in female, but not male, volunteers. TRP also reduced attentional vigilance towards negative words and decreased baseline startle responsivity in the females. These findings provide evidence that TRP supplementation in women induces a positive bias in the processing of emotional material that is reminiscent of the actions of serotonergic antidepressants. This highlights a key role for serotonin in emotional processing and lends support to the use of TRP as a nutritional supplement in people with mild depression or for prevention in those at risk. Future studies are needed to clarify the effect of tryptophan on these measures in men.