The role of 5-HT in response inhibition and re-engagement.

In animal and human research, the neurotransmitter serotonin (5-HT) has been implicated in inhibitory control. Using functional magnetic resonance imaging (fMRI), the present study investigated the acute effects of pharmacological modulation of the serotonergic system on brain activation during response inhibition and re-engagement in healthy human volunteers. In a randomized double-blind placebo-controlled cross-over design 14 men received either a single oral dose of the selective serotonin reuptake inhibitor (SSRI) escitalopram (10mg) or a placebo. At the time of the expected plasma peak concentration, participants performed a stop-change task during fMRI. Escitalopram did not affect behavioural performance, since the main effect did not reveal significant differences between reaction times of go-, stop- or change-trials. During successful response inhibition, escitalopram, however, was associated with enhanced brain activation in right prefrontal cortex, right supplementary/pre-motor and bilateral cingulate cortex, and subcortical regions. During inhibition failures, escitalopram also modulated a broad network of brain regions, including anterior cingulate, right parietal cortex, right orbitofrontal cortex, and areas in right temporal cortex and subcortical regions. During response re-engagement escitalopram increased brain activation in right inferior frontal gyrus and precuneus as well as in left middle temporal gyrus. The results implicate the involvement of 5-HT in neural regulation of response inhibition and re-engagement. This study also provides evidence that 5-HT affects both action restraint and action cancellation through modulation of activation of brain areas. The results support the view for a fronto-striatal circuitry for response inhibition in conjunction with serotonin.

Vulnerability to psychotogenic effects of ketamine is associated with elevated D2/3-receptor availability.

Previous positron emission tomography (PET) studies employing competition paradigms have shown either no change or substantial declines in striatal [(11)C]-raclopride binding after challenge with psychotogenic doses of the N-methyl-D-aspartate antagonist ketamine. We sought to probe the relationship between the severity of ketamine-induced psychotic symptoms and altered dopamine D(2/3) receptor availability throughout brain using the high affinity ligand [(18)F]-fallypride (FP). PET recordings were obtained in a group of 10 healthy, young male volunteers, in a placebo condition, and in the course of an infusion with ketamine at a psychotomimetic dose. Administration of the Positive and Negative Syndrome Scale and the Thought and Language Index in both conditions revealed a substantial emergence of mainly negative symptoms of schizophrenia, persisting until the end of the 3 h PET recordings. The baseline FP binding in cortex, caudate nucleus and other brain regions was highly predictive of the individual severity of psychotic symptoms in the ketamine condition. However, there was no evidence of ketamine-evoked reductions in FP binding. In the context of earlier findings, we speculate that high baseline D(2/3)-receptor availability may impart benefits with regard to cognitive flexibility, but increases the risk of maladaptive information processing in the face of environmental stresses and challenges.

Serotonergic modulation of response inhibition and re-engagement? Results of a study in healthy human volunteers.

OBJECTIVE: Cognitive functions dependent on the prefrontal cortex, such as the ability to suppress behavior (response inhibition) and initiate a new one (response re-engagement) is important in the activities of daily life. Central serotonin (5-HT) function is thought to be a critical component of these cognitive functions. In recent studies, 5-HT failed to affect stop-signal reaction time (SSRT), a fundamental process in behavioral inhibition. We were interested if response inhibition and re-engagement are influenced through central 5-HT activity as mediated via the 5-HT transporter. METHODS: Here, using a stop-change task, we investigated the effects of acute and repeated treatment with 10 mg escitalopram, a selective 5-HT reuptake inhibitor, in 36 healthy human volunteers on response inhibition and re-engagement in a randomized, double-blind, placebo-controlled study with cross-over design. RESULTS: Results do not show an influence of escitalopram on response inhibition or response re-engagement as we did not find differences in SSRT or change reaction time (CRT). CONCLUSIONS: These findings support the results of previous studies suggesting that 5-HT is not critical in inhibition of already initiated responses and response re-engagement. We hypothesize that results are due to different forms of behavioral inhibition and 5-HT may critical to other forms.

Differential effects of escitalopram on attention: a placebo-controlled, double-blind cross-over study.

RATIONALE: The role of serotonin (5-HT) in attention is not fully understood yet. OBJECTIVE: We aimed to investigate whether attention is modulated after treatment with escitalopram, a selective serotonin reuptake inhibitor (SSRI). METHODS: We administered 10 mg of escitalopram to 20 healthy subjects in a placebo-controlled, double-blind cross-over design for 1 day or to another 20 participants for a period of 7 days. Attention was assessed at time of plasma peak escitalopram concentration using the computerised Attention Network Test (ANT), which is a combined flanker and cued reaction time task. RESULTS: The results showed differential effects of serotonergic manipulation on attention depending on sequence of intake. For the acute treatment, we found significant differences between escitalopram and placebo for all warning conditions dependent of sequence of intake: participants receiving escitalopram as first treatment showed significant slower reaction times in all warning conditions as compared with placebo while participants receiving escitalopram as second treatment showed significant faster reaction times as compared with placebo. For the sub-chronic treatment, we found significant differences between escitalopram and placebo depending on sequence of intake, but only for the flanker condition: participants receiving escitalopram first had significant slower reaction times in incongruent trials with escitalopram as compared with placebo while participants starting with placebo had significant shorter reaction times in incongruent trials with escitalopram. CONCLUSIONS: Thus, the results showed a differential effect of escitalopram in cognition, especially in attention, and are discussed with regard to an interaction between serotonin and familiarity with the attention test.

Basal prolactin values correlate with response to reboxetine treatment in major depression, but not with response to citalopram.

Little is known about variables that might predict outcome in major depression. Recently, basal prolactin values (BPV) have been suggested to predict response to treatment with tricyclic antidepressive drugs. In order to examine whether BPV predict response to selective mono-aminergic therapy, 24 in-patients with major depression were treated in a single-masked, randomised study using the most selective noradrenergic or serotonergic reuptake inhibitors available for antidepressant treatment, i.e. reboxetine and citalopram. A significant correlation between BPV and treatment response to reboxetine was found, but not between BPV and response to citalopram. As BPV are influenced by noradrenergic activity, it can be hypothesized that depressed patients with comparatively high BPV have a relatively high noradrenergic function. This might explain why in our study depressed patients with the highest BPV responded strongest to selective noradrenergic treatment with reboxetine. As measurement of BPV is simple, further studies are suggested to examine the possible clinical value of the link between prolactin, noradrenergic function in major depression and treatment response.

The astroglial protein S100B and visually evoked event-related potentials before and after antidepressant treatment.

RATIONALE: S100B is an astrocytic, calcium-binding protein which in nanomolar concentrations has neuroprotective and regenerating effects on neurons and glial cells. Increased levels have been shown to be positively correlated with therapeutic response in major depression. Event-related potentials (ERP) have been reported to be impaired in depressed patients. OBJECTIVES: The aim of our study was to assess the relationship between S100B and visually evoked ERP in depression. METHODS: ERP and S100B serum concentration were studied in 18 patients with major depression, before and after 4 weeks of antidepressant treatment. RESULTS: The S100B concentration in patients was increased at intake and after 4 weeks of treatment compared to healthy controls. Initially increased P3-latency normalized and P2-latency significantly decreased after 4 weeks of treatment, although only in patients with clearly elevated initial S100B levels (mean plus 2 SD of the healthy controls). CONCLUSION: The neuroregenerative activity of moderately increased S100B levels in major depression might be a factor contributing to a decrease of prolonged ERP parameters in major depression during antidepressant treatment.