Short-term quetiapine treatment alters the use of reinforcement signals during risky decision-making and promotes the choice of negative expected values in healthy adult males.

Effective decision-making can involve using environmental signals about the possible good and bad outcomes, and their probabilities, to select optimal actions. Problematic decision-making in psychiatric disorders, and particularly bipolar illness, may result from disrupted use of these reinforcement cues, leading to actions that reflect or precipitate pathological changes in mood. Previous experiments indicate that the processing of reinforcement cues while selecting between risky actions can be influenced by dopamine and serotonin activity. Quetiapine is an atypical antipsychotic agent with a complex pharmacology, including antagonist actions at 5-HT2A and, to a lesser extent, D2 receptors. Here, we investigated the effects of (short-term) treatment with quetiapine on the risky decision-making of healthy human adults. Twenty participants received 150 mg of quetiapine XL for 7 d, whereas 20 age- and IQ-matched participants received a placebo. On the eighth day, all participants completed a risky decision-making task that involved making a series of choices between two simultaneously presented gambles that differed in the magnitudes of their possible gains and losses, and the probabilities with which these outcomes were delivered. Quetiapine treatment was associated with a marked tendency to choose options with negative expected values compared with placebo treatment in male but not female participants. Our results demonstrate that antagonism of serotonin and dopamine receptor activity can alter the way individuals use information about gains and losses when selecting between risky actions, possibly reflecting gender-specific differences in risk attitudes. These effects may be beneficial by correcting decision-making biases that feature in mood disorders.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Lack of effect of tyrosine depletion on mood in recovered depressed women.

The role of dopamine (DA) pathways in the pathophysiology of depressive disorder is poorly understood. However, because DA plays a key role in motivational behavior, it is important to study in a disorder characterized by anhedonia, lack of energy and psychomotor retardation. A recently developed dietary manipulation ('tyrosine (TYR) depletion') offers a novel method to assess the role of DA in major depression. We studied 15 euthymic women with a past history of recurrent depression, who received a 74 g amino-acid drink lacking TYR and phenylalanine (PHE) (TYR-free) and a balanced (BAL) amino acid drink on two separate occasions in a double-blind, random-order, crossover design. Plasma prolactin levels rose following the TYR-free drink relative to the balanced mixture, while performance on a spatial recognition memory task was impaired. However, relative to the BAL drink, the TYR-free drink did not lower objective or subjective measures of mood. We conclude that as in healthy volunteers, TYR depletion in euthymic subjects, with a past history of major depression, attenuated DA function, as reflected in increased plasma prolactin levels and decreased spatial memory performance. However ratings of depression were unaffected, suggesting that disruption of dopaminergic function by this manipulation does not induce a lowering of mood in individuals vulnerable to depression.

The effects of acute tyrosine and phenylalanine depletion on spatial working memory and planning in healthy volunteers are predicted by changes in striatal dopamine levels.

RATIONALE: Dopamine (DA) is considered important in the modulation of tasks of spatial working memory. However, the findings from studies in humans to date are mixed. While this may be due to the characteristics of the tasks used, it is also possible that these findings are explained by variable central effects of the manipulations used. OBJECTIVE: To test the effects of acute tyrosine and phenylalanine depletion (TPD, which reduces synthesis and release of brain DA) on cognitive function and relate changes in performance accuracy to the central effects of TPD measured with [11C]raclopride positron emission tomography (PET). METHODS: Fourteen participants were given tests of spatial working memory, planning, verbal memory span and trial-and-error learning after acute TPD, seven of whom also received PET scans to measure changes in striatal DA levels. RESULTS: Although TPD produced a clear reduction in tyrosine and phenylalanine availability to the brain, no impairments on any of the cognitive tests were observed. However, changes in spatial working memory and planning accuracy after TPD showed a highly significant relationship with the changes in striatal DA levels. CONCLUSIONS: Our findings suggest that the effects of TPD on spatial working memory and planning may be unreliable due to the variability of the changes in brain DA levels achieved with this manipulation.

Reduction of brain dopamine concentration with dietary tyrosine plus phenylalanine depletion: an [11C]raclopride PET study.

OBJECTIVE: Extracellular dopamine concentrations were estimated through measurement of [(11)C]raclopride binding with positron emission tomography after dietary manipulation of the dopamine precursors tyrosine and phenylalanine. METHOD: Healthy male subjects were scanned on two occasions: once after receiving a balanced amino acid drink and once after receiving a drink mixture from which tyrosine and phenylalanine were omitted. RESULTS: Dietary tyrosine and phenylalanine depletion increased [(11)C]raclopride binding in the striatum by a mean of 6%. The change in [(11)C]raclopride binding correlated significantly with the fall in the ratio of tyrosine and phenylalanine to large neutral amino acids. CONCLUSIONS: This is the first demonstration of an effect of a dietary manipulation on brain dopamine release in humans. This result provides support for the further investigation of the role of dietary manipulations in the treatment of neuropsychiatric disorders.

Repetitive transcranial magnetic stimulation to right prefrontal cortex does not modulate the psychostimulant effects of amphetamine.

Preliminary evidence indicates lateralized efficacy of repetitive transcranial magnetic stimulation (rTMS) in the treatment of mood disorders. Right-sided prefrontal cortex (PFC) stimulation has been reported to treat symptoms of mania. The acute effect of amphetamine serves as a model of mania in healthy individuals, hence rTMS to right PFC was hypothesized to attenuate the psychostimulant action of amphetamine in healthy volunteers. Eighteen subjects received rTMS to right PFC or right parietal cortex (PAR), or sham stimulation, in a randomized between-subjects design. Following rTMS subjects received i.v. amphetamine (0.15 mg/kg). Intravenous amphetamine induced robust subjective (visual analogue scales) and objective (blood pressure, sustained attention) effects, but the extent of the effects was not modulated by right PFC stimulation. Though this dose cannot refute the efficacy of rTMS in treating mania, it indicates that any therapeutic mechanism of action is unlikely to be through modulation of dopamine function.

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

RATIONALE: Varenicline is the most effective drug for smoking cessation, but its use decreased because of reports of depressogenic side effects. However, because smoking and smoking cessation on their own are associated with depression, it remains unclear whether reported depressogenic effects are attributable to varenicline, or to smoking, and/or smoking cessation themselves. OBJECTIVES: Previously, we observed no depressogenic effects of varenicline on a psychological level. In the present study, we aimed at investigating potential depressogenic effects of the partial nicotinergic acetylcholine receptor agonist varenicline on a biological level. A possible pathway would be an effect of varenicline on the hypothalamic-pituitary-adrenal (HPA) axis, considering the relation between the HPA axis and (1) the cholinergic system and (2) depression. METHODS: In a randomized, double-blind design, we administered varenicline or placebo for 7 days (0.5 mg/day first 3 days, then 1 mg/day) to healthy never-smoking subjects, thereby eliminating bias by (previous) smoking status. We used repeated measures (before and after treatment) of the salivary free cortisol awakening response to measure HPA axis activity and flexibility. RESULTS: Salivary cortisol data of 34 subjects were included in the analysis. Results showed no effect of varenicline on height (F1,32 = 0.405; P = 0.529) or shape (F2,31 = 0.110; P = 0.164) of the cortisol awakening response. CONCLUSIONS: Results do not suggest depressogenic effects of varenicline on the HPA axis. Although this does not preclude other biological depressogenic effects of varenicline, it seems that concerns about effects of varenicline on the HPA axis should not limit its potential to treat nicotine and related addictions.

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.

Short-term NK1 receptor antagonism and emotional processing in healthy volunteers.

BACKGROUND: Despite early promise in phase II, the performance of the NK1 receptor antagonist aprepitant in subsequent clinical trials has been disappointing. Healthy volunteer models of emotional processing offer a potential means by which novel drugs can be screened prior to clinical trials. Here, we consider the effect of 7 days of treatment with aprepitant in such a model. METHOD: Healthy volunteers (n = 32) were randomised to receive 7-day treatment with aprepitant (125 mg) or placebo. On the seventh day, participants completed a battery of tasks measuring emotional processing previously demonstrated to be sensitive to conventional antidepressant drugs. The tasks included facial expression recognition, emotional categorisation and memory, attentional dot-probe and emotion potentiated startle task. RESULTS: Aprepitant abolished the emotionally potentiated startle effect and increased recognition memory for emotionally positive versus negative stimuli. In addition, the drug decreased attention to negative relative to positive emotional stimuli on the masked version of the dot-probe task. These effects were seen in the absence of any change in subjective mood. There were no effects on emotional categorisation, recall or on facial expression recognition. CONCLUSION: These results suggest that NK1 receptor antagonism does affect some aspects of emotional processing and, in particular, that it has anxiolytic-like effects. The profile of effects reported here is, however, more limited than that found in response to conventional antidepressant treatment, and this may explain disappointing results at clinical trial. Healthy volunteer models of emotional processing may be useful in closing the gap between preclinical and clinical trials.

Low-dose tryptophan depletion in recovered depressed women induces impairments in autobiographical memory specificity.

BACKGROUND: Depressed patients perform poorly on tests of autobiographical memory specificity (AMS); this may have negative consequences for other important cognitive abilities, delays recovery from mood episodes, and, in recovered patients, may mediate vulnerability to future episodes. Although the cognitive mechanisms underlying AMS deficits are beginning to be understood, the neurobiological mechanisms remain unclear. Serotonin is implicated in both depression and long-term memory; therefore, temporary lowering of brain serotonin function via acute tryptophan depletion (ATD) offers a means of studying the role of serotonin in autobiographical memory specificity. MATERIALS AND METHODS: In this study, 24 previously depressed women underwent low-dose ATD or sham depletion and completed tests of initial and delayed memory, recollection- and familiarity-based recognition, and AMS. RESULTS: ATD did not differentially affect state mood. Compared with sham depletion, ATD impaired immediate recall on the Auditory Verbal Learning Test. Although ATD did not differentially impair recollection- and familiarity-based recognition, it did slow recognition of positive words. ATD also reduced autobiographical memory specificity in response to negative cue words. DISCUSSION: The results confirm previous findings that low-dose ATD can reinstate depression-congruent biases in cognition without causing depressive mood in vulnerable populations. The ATD-induced reduction in memory specificity suggests that serotonergic dysfunction may mediate depressive deficits in autobiographical memory; the interaction of cognitive and neurobiological vulnerability mechanisms is discussed.

Tyrosine depletion alters cortical and limbic blood flow but does not modulate spatial working memory performance or task-related blood flow in humans.

Dopamine appears critical in regulating spatial working memory (SWM) within the PFC of non-human primates; however findings in humans are less clear. Recent studies of the effects of global depletion of dopamine via acute tyrosine/phenylalanine depletion (TPD) on SWM task performance have yielded inconsistent results, which may be partly related to task differences. These previous studies do not address whether TPD can directly impair PFC functioning. The current study investigated the effects of TPD on (1) regional cerebral blood flow (rCBF) during a SWM n-back task using H(2) (15)O Positron Emission Tomography (PET), and (2) behavioural performance on three different SWM tasks. Ten healthy males were scanned twice: once following a placebo (balanced) amino acid mixture and once following an equivalent mixture deficient in tyrosine/phenylalanine (TPD condition). Participants completed two additional delayed-response tasks to examine whether differences in response demands influenced TPD effects on performance. TPD resulted in widespread increases in rCBF, with maximum increases in the region of the parahippocampal gyrus bilaterally, left inferior frontal gyrus, and the putamen. TPD related rCBF reductions were observed in the medial frontal gyrus bilaterally, right inferior temporal gyrus and the pons. Despite widespread changes in blood flow following TPD, no specific effects on SWM neural networks or task performance were observed. The use of three different SWM tasks suggests that task differences are unlikely to account for the lack of effects observed. These findings question the capacity of TPD to consistently modulate dopamine function and SWM neural networks in humans.