Bernard G.C. Sabbe

Drug-induced stimulation and suppression of action monitoring in healthy volunteers.

RationaleAction monitoring has been studied extensively by means of measuring the error-related negativity (ERN). The ERN is an event-related potential (ERP) elicited immediately after an erroneous response and is thought to originate in the anterior cingulate cortex (ACC). Although the ACC has a central role in the brain, only a few studies have been performed to investigate directly the effects of drugs on action monitoring. A recent theory argues that the mesencephalic dopamine system carries an error signal to the ACC, where it generates the ERN.MethodsERPs and behavioral measurements were obtained from 12 healthy volunteers performing an Eriksen Flankers task. On each of the 4 test days, the stimulant d-amphetamine, the sedative lorazepam, the antidepressant mirtazapine, or a placebo was orally administered in a double-blind, four-way crossover design.ResultsThe indirect dopamine agonist amphetamine led to a strong enlargement of ERN amplitudes without affecting reaction times. Lorazepam and mirtazapine both showed slowing of responses, but only lorazepam led to reduced ERN amplitudes.ConclusionsAdministration of amphetamine leads to stimulated action monitoring, reflected in increased ERN amplitudes. This result provides evidence for dopaminergic involvement in action monitoring and is in line with differences in ERN amplitude found in neuropsychiatric disorders also suggesting dopaminergic involvement. The different effects for lorazepam and mirtazapine are probably caused by the neurobiological characteristics of these two types of sedation. Action monitoring is suppressed after administration of lorazepam, because the GABAergic pathways directly inhibit ACC functioning, whereas the histaminergic pathways of mirtazapine do not innervate the ACC directly.

Effects of antipsychotic and antidepressant drugs on action monitoring in healthy volunteers.

Humans need to monitor their actions continuously to detect errors as fast as possible and to adjust their performance to prevent future errors. This process of action monitoring can be investigated by measuring the error-related negativity (ERN), an ERP component elicited immediately after an error. In the current study, we investigated action monitoring after administration of the classic antipsychotic haloperidol (2.5 mg), the atypical antipsychotic olanzapine (10 mg), and the antidepressant paroxetine (20 mg), a selective serotonin reuptake inhibitor. Healthy volunteers (N = 14) were administered the three compounds and placebo in a randomized, double-blind, single-dose, four-way cross-over design. All participants performed a speeded two-choice reaction task, while event-related potentials and behavioral measurements were obtained. Both haloperidol and olanzapine significantly reduced ERN amplitudes. After paroxetine, the ERN was not different from placebo. N2 congruency effects were not affected by treatment condition. Only olanzapine demonstrated behavioral effects, namely a slowing of responses, an increase in error rates, and the absence of performance adjustments. The attenuated ERNs after the dopamine antagonist haloperidol are in line with the presumed role of dopamine in action monitoring. Haloperidol is thought to block dopaminergic signaling, thus reducing ERN amplitudes. On the other hand, the effects of olanzapine are mainly caused by its sedative side effects, leading to a decline in motivation and appraisal of errors. Finally, the absence of any effects after paroxetine suggests that serotonin transmission does not play a direct role in regulating mechanisms related to action monitoring.

Action monitoring and depressive symptom reduction in major depressive disorder.

INTRODUCTION Action monitoring has been reported to be disturbed in Major Depressive Disorder (MDD). Well-known markers for this action monitoring process are the error negativity/error-related negativity (Ne/ERN) and error positivity (Pe), both event-related potentials (ERP) generated in the anterior cingulate cortex. This study aims to explore the impact of symptom severity reduction on the Ne/ERN and Pe in MDD. METHODS Behavioural and ERP measurements were obtained in 15 MDD patients during performance on a speeded flankers task during the early stages of a depressive episode and compared with those recorded after 7 weeks of treatment. The same schedule was used in 15 healthy controls. RESULTS Whereas overall Ne/ERN and Pe peak amplitudes did not improve from sessions 1 to 2 in the patients, positive correlations emerged between between-session changes in symptom severity and Ne/ERN amplitudes. No such correlations were observed for the Pe. ERP amplitudes in the controls also remained unchanged between both sessions. Significant group differences were observed between MDD patients and controls for the Pe, but not for the Ne/ERN. CONCLUSIONS Whereas a clear association was observed between the level of symptom reduction and the level of improvement in Ne/ERN amplitudes in a MDD sample, no overall Ne/ERN enhancements were observed during symptom remission. Subsequent research is needed to further investigate the possible impact of depressive symptom reduction on the action monitoring in MDD. Several factors that might explain the absence of Ne/ERN group differences between patients and healthy controls in the current sample will also be discussed.

Acute effects of the ampakine farampator on memory and information processing in healthy elderly volunteers.

Ampakines act as positive allosteric modulators of AMPA-type glutamate receptors and facilitate hippocampal long-term potentiation (LTP), a mechanism associated with memory storage and consolidation. The present study investigated the acute effects of farampator, 1-(benzofurazan-5-ylcarbonyl) piperidine, on memory and information processes in healthy elderly volunteers. A double-blind, placebo-controlled, randomized, cross-over study was performed in 16 healthy, elderly volunteers (eight male, eight female; mean age 66.1, SD 4.5 years). All subjects received farampator (500 mg) and placebo. Testing took place 1 h after drug intake, which was around Tmax for farampator. Subjects performed tasks assessing episodic memory (wordlist learning and picture memory), working and short-term memory (N-back, symbol recall) and motor learning (maze task, pursuit rotor). Information processing was assessed with a tangled lines task, the symbol digit substitution test (SDST) and the continuous trail making test (CTMT). Farampator (500 mg) unequivocally improved short-term memory but appeared to impair episodic memory. Furthermore, it tended to decrease the number of switching errors in the CTMT. Drug-induced side effects (SEs) included headache, somnolence and nausea. Subjects with SEs had significantly higher plasma levels of farampator than subjects without SEs. Additional analyses revealed that in the farampator condition the group without SEs showed a significantly superior memory performance relative to the group with SEs. The positive results on short-term memory and the favorable trends in the trail making test (CTMT) are interesting in view of the development of ampakines in the treatment of Alzheimers disease and schizophrenia.

Cognitive and Psychomotor Effects of Risperidone in Schizophrenia and Schizoaffective Disorder

OBJECTIVE The aim of this review was to discuss data from double-blind, randomized controlled trials (RCTs) that have investigated the effects of oral and long-acting injectable risperidone on cognitive and psychomotor functioning in patients with schizophrenia or schizoaffective disorder. METHODS PubMed/MEDLINE and the Institute of Scientific Information Web of Science database were searched for relevant English-language double-blind RCTs published between March 2000 and July 2008, using the terms schizophrenia, schizoaffective disorder, cognition, risperidone, psychomotor, processing speed, attention, vigilance, working memory, verbal learning, visual learning, reasoning, problem solving, social cognition, MATRICS, and long-acting. Relevant studies included patients with schizophrenia or schizoaffective disorder. Cognitive domains were delineated at the Consensus Conferences of the National Institute of Mental Health-Measurement And Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS). The tests employed to assess each domain and psychomotor functioning, and the within-group and between-group comparisons of risperidone with haloperidol and other atypical antipsychotics, are presented. The results of individual tests were included when they were individually presented and interpretable for either drug; outcomes that were presented as cluster scores or factor structures were excluded. RESULTS A total of 12 articles were included in this review. Results suggested that the use of oral risperidone appeared to be associated with within-group improvements on the cognitive domains of processing speed, attention/vigilance, verbal and visual learning and memory, and reasoning and problem solving in patients with schizophrenia or schizoaffective disorder. Risperidone and haloperidol seemed to generate similar beneficial effects (on the domains of processing speed, attention/vigilance, [verbal and nonverbal] working memory, and visual learning and memory, as well as psychomotor functioning), although the results for verbal fluency, verbal learning and memory, and reasoning and problem solving were not unanimous, and no comparative data on social cognition were available. Similar cognitive effects were found with risperidone, olanzapine, and quetiapine on the domains of verbal working memory and reasoning and problem solving, as well as verbal fluency. More research is needed on the domains in which study results were contradictory. For olanzapine versus risperidone, these were verbal and visual learning and memory and psychomotor functioning. No comparative data for olanzapine and risperidone were available for the social cognition domain. For quetiapine versus risperidone, the domains in which no unanimity was found were processing speed, attention/vigilance, nonverbal working memory, and verbal learning and memory. The limited available reports on risperidone versus clozapine suggest that: risperidone was associated with improved, and clozapine with worsened, performance on the nonverbal working memory domain; risperidone improved and clozapine did not improve reasoning and problem-solving performance; clozapine improved, and risperidone did not improve, social cognition performance. Use of long-acting injectable risperidone seemed to be associated with improved performance in the domains of attention/vigilance, verbal learning and memory, and reasoning and problem solving, as well as psychomotor functioning. The results for the nonverbal working memory domain were indeterminate, and no clear improvement was seen in the social cognition domain. The domains of processing speed, verbal working memory, and visual learning and memory, as well as verbal fluency, were not assessed. CONCLUSIONS The results of this review of within-group comparisons of oral risperidone suggest that the agent appeared to be associated with improved functioning in the cognitive domains of processing speed, attention/vigilance, verbal and visual learning and memory, and reasoning and problem solving in patients with schizophrenia or schizoaffective disorder. Long-acting injectable risperidone seemed to be associated with improved functioning in the domains of attention/vigilance, verbal learning and memory, and reasoning and problem solving, as well as psychomotor functioning, in patients with schizophrenia or schizoaffective disorder.

Stereotypy in schizophrenia

OBJECTIVES In schizophrenia, stereotypy is observed, a symptom characterized by repetitive, functionless motor behaviour. Whereas cognitive dysfunctioning is known to remain stable throughout the illness, less is known about the course of the motor symptoms. The Zeigeversuch [Mittenecker, E., 1953. Perseveration und Persönlichkeit: 1. Teil: experimentelle Untersuchungen. Z. Exp. Angew. Psychol. 1, 5-31], which entails the generation of a random sequence of button presses, was claimed to capture stereotypy. We used a newly designed computerized version of the Zeigeversuch, the Stereotypy Test Apparatus (STA) to evaluate the evolution of STA performance through the course of the illness. METHODS To assess stereotyped and perseverative behaviour, 58 schizophrenic inpatients and 48 healthy controls performed the STA and the Wisconsin Card Sorting Test (WCST), respectively, as well as several other traditional neuropsychological tests and the Symbol Digit Substitution Test (SDST) on a writing digitizer. RESULTS The STA correlated only weakly with the WCST and SDST measures but not with the cognitive or motor slowing on the SDST, nor with the other cognitive measures. Stereotyped and perseverative idiosyncrasies both seem to increase in the course of the illness, in contrast with other cognitive dysfunctions. However, whereas perseveration is already present in the early stages of the illness, stereotyped behaviour only manifests itself in the later stages of schizophrenia. Failure of cognitive inhibition may result in an activation of prepotent stereotyped responses captured by the STA.

Ziprasidone Vs Olanzapine in Recent-Onset Schizophrenia and Schizoaffective Disorder: Results of an 8-Week Double-Blind Randomized Controlled Trial

INTRODUCTION Head-to-head comparisons of antipsychotics have predominantly included patients with chronic conditions. The aim of the present study was to compare the efficacy and tolerability of ziprasidone and olanzapine in patients with recent-onset schizophrenia. METHODS The study was an 8-week, double-blind, parallel-group, randomized, controlled multicenter trial (NCT00145444). Seventy-six patients with schizophreniform disorder, schizophrenia or schizoaffective disorder (diagnosis < 5 y), and a maximum lifetime antipsychotic treatment < 16 weeks participated in the study. Efficacy of ziprasidone (80-160 mg/d) and olanzapine 10-20 mg was measured using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression (CGI) Scale, the Calgary Depression Scale for Schizophrenia (CDSS), and the Heinrich Quality of Life Scale (HQLS); tolerability assessments included laboratory assessments, body weight, and electroencephalogram. RESULTS Olanzapine (n = 34) and ziprasidone (n = 39) showed equal efficacy as measured by the PANSS, CDSS, CGI, and HQLS. However, mean weight gain was significantly higher in the olanzapine group (6.8 vs 0.1 kg, P < .001). Ziprasidone was associated with decreasing levels of triglycerides, cholesterol, and transaminases, while these parameters increased in the olanzapine group (all P values < .05). There were no significant differences in fasting glucose and prolactin levels or in cardiac or sexual side effects. Patients on ziprasidone used biperiden for extrapyramidal side effects more frequently (P < .05). DISCUSSION The results of this study indicate that ziprasidone and olanzapine have comparable therapeutic efficacy but differ in their side effect profile. However, there is a risk of a type II error with this sample size. Clinically significant weight gain and laboratory abnormalities appear early after initiating treatment and are more prominent with olanzapine, while more patients on ziprasidone received anticholinergic drugs to treat extrapyramidal symptoms.

Effect of Modafinil on Impulsivity and Relapse in Alcohol Dependent Patients: A Randomized, Placebo-Controlled Trial

Poor impulse control plays an important role in the development, course and relapse of substance use disorders. Therefore, improving impulse control may represent a promising approach in the treatment of alcohol dependence. This study aimed to test the effect of modafinil on impulse control and alcohol use in alcohol dependent patients (ADP) in a randomized, double-blind, placebo-controlled trial. Eighty-three abstinent ADP were randomized to 10 weeks modafinil (300 mg/d) or placebo. Alcohol use was quantified using the timeline follow-back method and was assessed until 6 months after treatment discontinuation. Impulsivity was assessed using self-report questionnaires (Barratt Impulsiveness Scale; State Impulsivity questionnaire) and neurocognitive tasks (Stop Signal Task; Delay Discounting Task) administered before, during and after treatment. Modafinil significantly improved self-report measures of state impulsivity, but had no effect on percentage of abstinent days or percentage of heavy drinking days, nor on the behavioral measures of impulsivity. However, subgroup analysis revealed that modafinil prolonged the time to relapse (p=.022) and tended to increase the percentage of abstinent days (p=.066) in ADP with poor response inhibition at baseline, whereas modafinil increased the percentage of heavy drinking days (p=.003) and reduced the percentage of abstinent days (p=.002) in patients with better baseline response inhibition. Overall results do not favor the use of modafinil in order to reduce relapse or relapse severity in ADP, and caution is required in prescribing modafinil to a non-selected sample of ADP. Further research on the effect of modafinil in ADP with poor baseline response inhibition is warranted.

The impact of perfectionism and anxiety traits on action monitoring in major depressive disorder

Perfectionism and anxiety features are involved in the clinical presentation and neurobiology of major depressive disorder (MDD). In MDD, cognitive control mechanisms such as action monitoring can adequately be investigated applying electrophysiological registrations of the error-related negativity (ERN) and error positivity (Pe). It is also known that traits of perfectionism and anxiety influence ERN amplitudes in healthy subjects. The current study explores the impact of perfectionism and anxiety traits on action monitoring in MDD. A total of 39 MDD patients performed a flankers task during an event-related potential (ERP) session and completed the multidimensional perfectionism scale (MPS) with its concern over mistakes (CM) and doubt about actions (DA) subscales and the trait form of the State Trait Anxiety Inventory. Multiple regression analyses with stepwise backward elimination revealed MPS-DA to be a significant predictor (R2:0.22) for the ERN outcomes, and overall MPS (R2:0.13) and MPS-CM scores (R2:0.18) to have significant predictive value for the Pe amplitudes. Anxiety traits did not have a predictive capacity for the ERPs. MPS-DA clearly affected the ERN, and overall MPS and MPS-CM influenced the Pe, whereas no predictive capacity was found for anxiety traits. The manifest impact of perfectionism on patients’ error-related ERPs may contribute to our understanding of the action-monitoring process and the functional significance of the Pe in MDD. The divergent findings for perfectionism and anxiety features also indicate that the wide range of various affective personality styles might exert a different effect on action monitoring in MDD, awaiting further investigation.

The relationship between impulsivity and craving in alcohol dependent patients

RationaleImpulsivity and craving are both associated with higher relapse rates and a worse prognosis in patients with a substance use disorder, but the relationship between these two phenomena has been largely ignored in the field of alcohol use disorders.ObjectivesThe primary aim of this study was to investigate the relationship between different dimensions of impulsivity and different forms of self-reported craving. Additionally, the influence of the severity of alcohol dependence on impulsivity, craving, and on their relationship was exploed.MethodsImpulsivity and craving levels were investigated in 87 abstinent alcohol-dependent (AD) patients using a broad range of self-report questionnaires and behavioral impulsivity measures. Alcohol use was measured by means of the timeline followback method.ResultsHigher scores of emotional craving (Alcohol Urge Questionnaire—AUQ) were significantly related to higher self-reported impulsivity (Barratt Impulsiveness Scale, version 11) and to higher cognitive impulsivity (information sampling task). Additionally, exploratory analyses suggest that these relationships are more pronounced in severe AD patients compared to less severe AD patients. No significant relationships were found between emotional craving (AUQ) and motor impulsivity (stop signal task) or delay discounting and between obsessive-compulsive craving (Obsessive Compulsive Drinking Scale) and measures of impulsivity.ConclusionsEmotional craving is related to self-reported impulsivity and to cognitive impulsivity. These relationships seem to be more pronounced in AD patients with severe alcohol dependence. Further research is needed to explore the effect of this relationship on treatment outcome and relapse.