The NMDA receptor partial agonist d-cycloserine does not enhance motor learning.

RATIONALE: There has recently been increasing interest in pharmacological manipulations that could potentially enhance exposure-based cognitive behaviour therapy for anxiety disorders. One such medication is the partial NMDA agonist d-cycloserine. It has been suggested that d-cycloserine enhances cognitive behaviour therapy by making learning faster. While animal studies have supported this view of the drug accelerating learning, evidence in human studies has been mixed. We therefore designed an experiment to measure the effects of d-cycloserine on human motor learning. METHODS: Fifty-four healthy human volunteers were randomly assigned to a single dose of 250mg d-cycloserine versus placebo in a double-blind design. They then performed a motor sequence learning task. RESULTS: D-cycloserine did not increase the speed of motor learning or the overall amount learnt. However, we noted that participants on d-cycloserine tended to respond more carefully (shifting towards slower, but more correct responses). CONCLUSION: The results suggest that d-cycloserine does not exert beneficial effects on psychological treatments via mechanisms involved in motor learning. Further studies are needed to clarify the influence on other cognitive mechanisms.

[Episodes of apparent transient loss of consciousness: disorders a cardiologist should not ignore]. / Le perdite transitorie di coscienza solo apparenti: affezioni che il cardiologo non dovrebbe ignorare.

Affections such as psychogenic (functional) pseudosyncope and cataplexy are characterized by transient attacks without impairment of consciousness, but with loss of postural control and unresponsiveness. Therefore, these disorders should be differentiated from syncope and should not be ignored by the cardiologist, who is usually a reference point for patients with syncope or suspected syncope. Clinical findings that suggest psychogenic pseudosyncope include frequent attacks always in the presence of audience, a fall to the ground that may develop slowly enough to allow the patient to stagger and break the fall before hitting the floor, prolonged attacks (>10 min), many psychosomatic symptoms as the clinical context. In most cases, the differential diagnosis should be made with neurally mediated syncope; to this end, tilt test appears to be very useful. Cataplexy is a relevant symptom of narcolepsy; the differential diagnosis between cataplexy and syncope should be made only when symptoms of narcolepsy are mild. Clinical findings that suggest cataplexy include an emotional trigger - above all if the emotion is positive -, an "unreal" fall similar to that observed in patients with psychogenic pseudosyncope, repeated attacks in a daytime, symptoms of narcolepsy as the clinical context. Since cataleptic attacks are triggered by emotion, in most cases the differential diagnosis should be made with vasovagal syncope; a positive emotion as a trigger suggests a cataleptic attack.

A role beyond learning for NMDA receptors in reward-based decision-making-a pharmacological study using d-cycloserine.

N-methyl-D-aspartate (NMDA) receptors are known to fulfill crucial functions in many forms of learning and plasticity. More recently, biophysical models, however, have suggested an additional role of NMDA receptors in evidence integration for decision-making, going beyond their role in learning. We designed a task to study the role of NMDA receptors in human reward-guided learning and decision-making. Human participants were assigned to receive either 250 mg of the partial NMDA agonist d-cycloserine (n=20) or matching placebo capsules (n=27). Reward-guided learning and decision-making were assessed using a task in which participants had to integrate learnt and explicitly shown value information to maximize their monetary wins and minimize their losses. To tease apart the effects of NMDA on learning and decision-making we used simple learning models. D-cycloserine shifted decision-making towards a more optimal integration of the learnt and the explicitly shown information, in the absence of a direct learning effect. In conclusion, our results reveal a distinct role for NMDA receptors in reward-guided decision-making. We discuss these findings in the context of NMDA's roles in neuronal super-additivity and as crucial for evidence integration for decisions.

Combined NK1 antagonism and serotonin reuptake inhibition: effects on emotional processing in humans.

BACKGROUND: Synergistic effects of NK1 receptor antagonism combined with serotonin reuptake inhibition have been reported in preclinical models. GSK424887 is a selective competitive antagonist of the human NK1 receptor and inhibitor of the serotonin transporter. However, its actions in human models of depression have not been assessed. METHODS: This study explored the effects of acute administration of GSK424887 compared to placebo in healthy male volunteers. The selective serotonin reuptake inhibitor (SSRI) citalopram was used as a positive control. A battery of emotional processing tasks was given at the peak time of drug effect. RESULTS: GSK424887 enhanced attentional vigilance in the dot-probe task to both positive and negative stimuli. By contrast, citalopram enhanced perception of angry, sad and happy facial expressions and increased positive bias in the facial expression recognition task. Neither drug significantly affected emotion potentiated startle responses or emotional memory. CONCLUSIONS: These results suggest that acute administration of GSK424887 modulated some aspects of emotional processing but these effects were not similar to those seen previously with antidepressant agents. This was the first use of the battery of emotional processing tasks in a Phase 1 study. Repeated administration of the test and active control drugs may be needed to reliably characterise their effects.

Attentional bias in untreated panic disorder.

The role of attentional biases in panic disorder has been well characterised. However, recent studies suggest an important effect of antidepressant and anxiolytic drugs on cognitive bias and most studies have included medicated patients in their sample. This study therefore examined cognitive bias in an untreated sample of participants with panic disorder (PD). A sample of 23 untreated participants with panic disorder with or without agoraphobia (PPD) and 22 healthy controls (HC) were tested with a Facial Expression Recognition task featuring different emotional intensities, a Faces Dot Probe task, a Self Beliefs task and an Emotional Stroop task. PPD showed exaggerated attentional biases to negative face and word stimuli in two different paradigms and endorsed more panic-related and negative self-attributions. They also showed enhanced perception of facial expressions of sadness. These tasks are sensitive to cognitive bias in a community-based sample of untreated PD participants. Attentional biases in panic disorder cannot be explained by the use of medication in this group and may therefore play a critical role in the underlying pathogenesis of the disorder.

Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients.

OBJECTIVE: Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers. The current study investigates the effects of Epo on the neural and cognitive response to emotional facial expressions in depressed patients. METHOD: Nineteen acutely depressed patients were randomized to receive Epo (40,000 IU) or saline intravenously in a double-blind, parallel-group design. On day 3, we assessed neuronal responses to fearful and happy faces using functional magnetic resonance imaging and measured facial expression recognition after the scan. RESULTS: Epo reduced neural response to fearful vs. happy faces in the amygdala and hippocampus, and to fearful faces vs. baseline in superior temporal and occipitoparietal regions 3 days after administration in acutely depressed patients. This was accompanied by a specific reduction in the recognition of fear in Epo-treated patients after the scan similar to the effects on face recognition seen with antidepressant drug treatment. CONCLUSIONS: The present findings are similar to the effects of conventional antidepressants in acutely depressed patients and opposite to hypervigilance to negative facial expressions in depression. This highlights a potential antidepressant mechanism and warrants further investigation of Epo as a new candidate compound for treatment of depression.

Acoustic startle response in panic disorder.

The amygdala and the limbic system are important in inducing a fear reaction; if this "fear network" is involved in panic disorder, panic patients might be more sensitive to fear stimuli than healthy subjects. We compared the startle response with an aversive stimulus in a sample of 29 patients with panic disorder and a sample of 29 healthy controls. The intensity of the startle response, induced by a series of aversive loud (100 dB) sounds, was measured by skin conductance recording in each subject. No statistically significant differences between the two groups were found in either the baseline level of skin conductance or in the response to the stimuli. Nonetheless, panic patients reported significantly higher levels of baseline anxiety measured by the State-Trait Anxiety Inventory. In conclusion, our data do not support the hypothesis that patients with panic disorder are characterised by a hyperreactivity, as measured by the skin conductance response, to fearful sudden stimuli or, at least, to those delivered to the auditory system.

Effect of acute antidepressant administration on negative affective bias in depressed patients.

OBJECTIVE: Acute administration of an antidepressant increases positive affective processing in healthy volunteers, an effect that may be relevant to the therapeutic actions of these medications. The authors investigated whether this effect is apparent in depressed patients early in treatment, prior to changes in mood and symptoms. METHOD: In a double-blind, placebo-controlled, between-groups randomized design, the authors examined the effect of a single 4-mg dose of the norepinephrine reuptake inhibitor reboxetine on emotional processing. Thirty-three depressed patients were recruited through primary care clinics and the community and matched to 31 healthy comparison subjects. Three hours after dosing, participants were given a battery of emotional processing tasks comprising facial expression recognition, emotional categorization, and memory. Ratings of mood, anxiety, and side effects were also obtained before and after treatment. RESULTS: Depressed patients who received placebo showed reduced recognition of positive facial expressions, decreased speed in responding to positive self-relevant personality adjectives, and reduced memory for this positive information compared to healthy volunteers receiving placebo. However, this effect was reversed in patients who received a single dose of reboxetine, despite the absence of changes in subjective ratings of mood or anxiety. CONCLUSIONS: Antidepressant drug administration modulates emotional processing in depressed patients very early in treatment, before changes occur in mood and symptoms. This effect may ameliorate the negative biases in information processing that characterize mood and anxiety disorders. It also suggests a mechanism of action compatible with cognitive theories of depression.

Effects of erythropoietin on emotional processing biases in patients with major depression: an exploratory fMRI study.

INTRODUCTION: Erythropoietin (Epo) has neurotrophic effects and may be a novel therapeutic agent in the treatment of depression. We have found antidepressant-like effects of Epo on emotional processing and mood in healthy volunteers. OBJECTIVE: The current study aimed to explore the effects of Epo on the neural processing of emotional information in depressed patients. MATERIALS AND METHODS: Seventeen patients with acute major depressive disorder were randomised to receive Epo (40,000 IU) or saline iv in a double-blind, parallel-group design. On day 3, we assessed neural responses to positive, negative and neutral pictures during fMRI followed by picture recall after the scan. Mood and blood parameters were assessed at baseline and on day 3. RESULTS: Epo reduced neural response to negative vs. positive pictures 3 days post-administration in a network of areas including the hippocampus, ventromedial prefrontal and parietal cortex. After the scan, Epo-treated patients showed improved memory compared with those that were given placebo. The effects occurred in the absence of changes in mood or haematological parameters, suggesting that they originated from direct neurobiological actions of Epo. CONCLUSIONS: These findings are similar to the effects of conventional antidepressants and opposite to the negative biases in depression. The central effects of Epo therefore deserve further investigation as a potential antidepressant mechanism.

Is there an association between depression and cardiovascular mortality or sudden death?

The results of many studies and recent meta-analyses strongly suggest that depression is a risk factor for total and cardiovascular mortality, both in the general population and in patients with known heart disease. By contrast, the association between depression and sudden death or cardiac arrest has received little attention. This issue has been investigated in three recent studies; two were carried out in the general population and showed depression to be a independent risk factor for sudden death. The other study was carried out in patients with acute myocardial infarction (AMI); the adjusted relative risk (RR) of sudden death was significantly increased in depressed patients but, after adjustment for dyspnea/fatigue (a common symptom for heart disease and depression), the RR was no longer statistically significant. However, when the cognitive-affective depressive symptoms were examined separately from the somatic ones (dyspnea/fatigue, etc.), there was a clear trend for an association between cognitive-affective symptoms and sudden death. Because a risk factor can be defined as 'independent' only in a multivariate analysis in which variables are dichotomized, the presence of common symptoms between heart disease and depression represents a very difficult problem. However, taken together, the results of studies carried out in the general population and in patients with AMI strongly suggest that depression is a significant risk factor for sudden death.

Antipanic efficacy of paroxetine and polymorphism within the promoter of the serotonin transporter gene.

Serotonin selective reuptake inhibitors (SSRIs) are the drugs of choice in the treatment of panic disorder (PD). The serotonin transporter (5-HTT) is a prime target for SSRIs. A functional polymorphism within the promoter region of the 5-HTT gene, leading to different transcriptional efficiency, was repeatedly reported to influence the response to SSRIs in mood disorders while the response of patients with OCD seems unrelated. We tested the hypothesis that allelic variation of the 5-HTT promoter could be related to the antipanic response to paroxetine. In total, 92 patients with PD completed a treatment with a variable dose of paroxetine for 12 weeks. The severity of panic-phobic symptomatology was measured before the beginning of the treatment and after 12 weeks. Allelic variation in each subject was determined using a PCR-based method. Both homozygotes for the long variant (l/l) of the 5-HTT promoter and heterozygotes (l/s) showed a better response to paroxetine than homozygotes for the short variant (s/s) (chi(2)=6.9, p<0.03). This result emerged in the whole sample, but was related only to female patients (chi(2)=7.6, p<0.02). The presence of the long allelic variant was associated with a better response of panic attacks while was not significantly associated with the response of anticipatory anxiety or phobic avoidance. In conclusion, paroxetine efficacy in PD seems to be related to allelic variation within the promoter of the 5-HTT gene in female subjects. This gender effect might be related to the genomic effects of sex hormones. Understanding the interaction between gender and genes coding for structures target of psychotropic drugs could help to individualize the pharmacological treatment of PD.

Lack of relationship between CO2 reactivity and serotonin transporter gene regulatory region polymorphism in panic disorder.

Changes in the function of the serotonergic system influence both panic phobic symptoms and carbon dioxide (CO2) reactivity in patients with panic disorder. Schmidt et al. [2000: J Abnorm Psychol 109(2):308-320] recently reported a predictive role of the genetic variants of the 5-HTTLPR on the fearful response to CO2 in healthy controls. We tested the hypothesis that the heterogeneity of CO2 reactivity in patients with panic disorder could be related to the allelic variation of the 5-HTT promoter. Ninety-five patients with panic disorder were challenged with 35% CO2. 5-HTTLPR allelic variation in each subject was determined using a PCR-based method. There were no differences for all the measures of CO2 reactivity among the genotype groups. CO2 reactivity of patients with panic disorder seems not to be influenced by the genetic variants of the 5-HTTLPR; this finding does not support a role for the serotonin transporter in the etiopathogenesis of CO2 reactivity in panic disorder.