Catecholamine-Mediated Increases in Gain Enhance the Precision of Cortical Representations.

UNLABELLED: Neurophysiological evidence suggests that neuromodulators, such as norepinephrine and dopamine, increase neural gain in target brain areas. Computational models and prominent theoretical frameworks indicate that this should enhance the precision of neural representations, but direct empirical evidence for this hypothesis is lacking. In two functional MRI studies, we examine the effect of baseline catecholamine levels (as indexed by pupil diameter and manipulated pharmacologically) on the precision of object representations in the human ventral temporal cortex using angular dispersion, a powerful, multivariate metric of representational similarity (precision). We first report the results of computational model simulations indicating that increasing catecholaminergic gain should reduce the angular dispersion, and thus increase the precision, of object representations from the same category, as well as reduce the angular dispersion of object representations from distinct categories when distinct-category representations overlap. In Study 1 (N = 24), we show that angular dispersion covaries with pupil diameter, an index of baseline catecholamine levels. In Study 2 (N = 24), we manipulate catecholamine levels and neural gain using the norepinephrine transporter blocker atomoxetine and demonstrate consistent, causal effects on angular dispersion and brain-wide functional connectivity. Despite the use of very different methods of examining the effect of baseline catecholamine levels, our results show a striking convergence and demonstrate that catecholamines increase the precision of neural representations. SIGNIFICANCE STATEMENT: Norepinephrine and dopamine are among the most widely distributed and ubiquitous neuromodulators in the mammalian brain and have a profound and pervasive impact on cognition. Baseline catecholamine levels tend to increase with increasing task engagement in tasks involving perceptual decisions, yet there is currently no direct evidence of the specific impact of these increases in catecholamine levels on perceptual encoding. Our results fill this void by showing that catecholamines enhance the precision of encoding cortical object representations, and by suggesting that this effect is mediated by increases in neural gain, thus offering a mechanistic account of our key finding.

Catecholaminergic Neuromodulation Shapes Intrinsic MRI Functional Connectivity in the Human Brain.

UNLABELLED: The brain commonly exhibits spontaneous (i.e., in the absence of a task) fluctuations in neural activity that are correlated across brain regions. It has been established that the spatial structure, or topography, of these intrinsic correlations is in part determined by the fixed anatomical connectivity between regions. However, it remains unclear which factors dynamically sculpt this topography as a function of brain state. Potential candidate factors are subcortical catecholaminergic neuromodulatory systems, such as the locus ceruleus-norepinephrine system, which send diffuse projections to most parts of the forebrain. Here, we systematically characterized the effects of endogenous central neuromodulation on correlated fluctuations during rest in the human brain. Using a double-blind placebo-controlled crossover design, we pharmacologically increased synaptic catecholamine levels by administering atomoxetine, an NE transporter blocker, and examined the effects on the strength and spatial structure of resting-state MRI functional connectivity. First, atomoxetine reduced the strength of inter-regional correlations across three levels of spatial organization, indicating that catecholamines reduce the strength of functional interactions during rest. Second, this modulatory effect on intrinsic correlations exhibited a substantial degree of spatial specificity: the decrease in functional connectivity showed an anterior-posterior gradient in the cortex, depended on the strength of baseline functional connectivity, and was strongest for connections between regions belonging to distinct resting-state networks. Thus, catecholamines reduce intrinsic correlations in a spatially heterogeneous fashion. We conclude that neuromodulation is an important factor shaping the topography of intrinsic functional connectivity. SIGNIFICANCE STATEMENT: The human brain shows spontaneous activity that is strongly correlated across brain regions. The factors that dynamically sculpt these inter-regional correlation patterns are poorly understood. Here, we test the hypothesis that they are shaped by the catecholaminergic neuromodulators norepinephrine and dopamine. We pharmacologically increased synaptic catecholamine levels and measured the resulting changes in intrinsic fMRI functional connectivity. At odds with common understanding of catecholamine function, we found (1) overall reduced inter-regional correlations across several levels of spatial organization; and (2) a remarkable spatial specificity of this modulatory effect. Our results identify norepinephrine and dopamine as important factors shaping intrinsic functional connectivity and advance our understanding of catecholamine function in the central nervous system.

Evaluating the Responsiveness to Therapeutic Change with Routine Outcome Monitoring: A Comparison of the Symptom Questionnaire-48 (SQ-48) with the Brief Symptom Inventory (BSI) and the Outcome Questionnaire-45 (OQ-45).

Assessment of psychological distress is important, because it may help to monitor treatment effects and predict treatment outcomes. We previously developed the 48-item Symptom Questionnaire (SQ-48) as a public domain self-report psychological distress instrument and showed good internal consistency as well as good convergent and divergent validity among clinical and non-clinical samples. The present study, conducted among psychiatric outpatients in a routine clinical setting, describes additional psychometric properties of the SQ-48. The primary focus is on responsiveness to therapeutic change, which to date has been rarely examined within psychiatry or clinical psychology. Since a questionnaire should also be stable when no clinically important change occurs, we also examined test-retest reliability within a test-retest design before treatment (n = 43). A pre-treatment/post-treatment design was used for responsiveness to therapeutic change, comparing the SQ-48 with two internationally widely used instruments: the Brief Symptom Inventory (n = 97) and the Outcome Questionnaire-45 (n = 109). The results showed that the SQ-48 has excellent test-retest reliability and good responsiveness to therapeutic change, without significant differences between the questionnaires in terms of responsiveness. In sum, the SQ-48 is a psychometrically sound public domain self-report instrument that can be used for routine outcome monitoring, as a benchmark tool or for research purposes. Copyright © 2015 John Wiley & Sons, Ltd. Key Practitioner Message The SQ-48 is developed as a public domain self-report questionnaire, in line with growing efforts to develop clinical instruments that are free of charge. The SQ-48 has excellent test-retest reliability and good responsiveness to therapeutic change or patient progress. There were no significant differences in terms of responsiveness between the SQ-48 and BSI or OQ-45. The SQ-48 can be used as a routine evaluation outcome measure for quality assurance in clinical practice. Providing feedback on patient progress via outcome measures could contribute to the enhancement of treatment outcomes.

Age-related characteristics of outpatients with anxiety disorders: the Leiden routine outcome monitoring study.

OBJECTIVE: It has been hypothesised that clinically important age-related differences between adults with anxiety disorders exist; this study aims to elucidate these differences. METHODS: We analysed data from 1950 outpatients diagnosed with DSM-IV-TR anxiety disorders treated at a Dutch hospital or affiliated mental healthcare centres. Three age-groups (young- (18-25; n = 435), mid- (26-40; n = 788) and older adult (41-65; n = 727)) were compared with regard to social demographic characteristics, diagnostic characteristics, anxiety symptom profile, general psychiatric symptom profile and generic health status, in addition, linear analyses were carried out with age as a continuous variable. RESULTS: Average age was 36.48 years (SD 11.71), 62.8% were female. Significant associations with age emerged for gender, employment, education level, living situation, observed depression, agoraphobia (AP), social phobia, aches and pains, inner tension, sleep, interpersonal sensitivity, observed hostility, physical functioning, role limitations due to physical problems, vitality and bodily pain in categorical and continuous analyses. Self reported hostility was only significant in group-wise comparisons; role limitations due to emotional problems were only significant in linear analyses (all at p < .001). CONCLUSIONS: This study identified clinically relevant differences between younger and older adult outpatients with anxiety disorders. Clinicians should take these findings into account, as they may support treatment.

The Neurobiological Mechanisms of Gamma-Hydroxybutyrate Dependence and Withdrawal and Their Clinical Relevance: A Review.

OBJECTIVE: x03B3;-Hydroxybutyrate (GHB) has gained popularity as a drug of abuse. In the Netherlands the number of patients in treatment for GHB dependence has increased sharply. Clinical presentation of GHB withdrawal can be life threatening. We aim, through this overview, to explore the neurobiological pathways causing GHB dependency and withdrawal, and their implications for treatment choices. METHODS: In this work we review the literature discussing the findings from animal models to clinical studies focused on the neurobiological pathways of endogenous but mainly exogenous GHB. RESULTS: Chronic abuse of GHB exerts multifarious neurotransmitter and neuromodulator effects on x03B3;-aminobutyric acid (GABA), glutamate, dopamine, serotonin, norepinephrine and cholinergic systems. Moreover, important effects on neurosteroidogenesis and oxytocin release are wielded. GHB acts mainly via a bidirectional effect on GABAB receptors (GABABR; subunits GABAB1 and GABAB2), depending on the subunit of the GIRK (G-protein-dependent ion inwardly rectifying potassium) channel involved, and an indirect effect of the cortical and limbic inputs outside the nucleus accumbens. GHB also activates a specific GHB receptor and ß1-subunits of α4-GABAAR. Reversing this complex interaction of neurobiological mechanisms by the abrupt cessation of GHB use results in a withdrawal syndrome with a diversity of symptoms of different intensity, depending on the pattern of GHB abuse. CONCLUSION: The GHB withdrawal symptoms cannot be related to a single mechanism or neurological pathway, which implies that different medication combinations are needed for treatment. A single drug class, such as benzodiazepines, gabapentin or antipsychotics, is unlikely to be sufficient to avoid life-threatening complications. Detoxification by means of titration and tapering of pharmaceutical GHB can be considered as a promising treatment that could make polypharmacy redundant.

Aberrant CYP2D6 metabolizer phenotypes do not show increased frequency in patients undergoing ECT after antidepressant therapy.

We investigated the accumulation of aberrant CYP2D6 genotypes and predicted metabolizer phenotypes (ultrarapid metabolizer, intermediate metabolizer and poor metabolizer) potentially affecting the antidepressant treatment response in depressive patients indicated for electroconvulsive therapy (ECT) compared with patients with a single episode of depression. Seventy-six Dutch White patients with unipolar or bipolar treatment-resistant depression who underwent ECT were genotyped using the Amplichip CYP450 Test for CYP2D6. Two hundred and eight patients with a single episode of unipolar or bipolar depression were used as controls. No difference was observed in the prevalence of CYP2D6 phenotypes (poor metabolizer, intermediate metabolizer, extensive metabolizer and ultrarapid metabolizer) between the ECT and the control patients (5.3, 38.7, 56.0 and 0.0% vs. 6.4, 51.0, 42.6 and 0.0%, respectively). The types of depression (odds ratio = 0.33, P = 0.018) and age (odds ratio = 1.55 for a 10-year increase, P < 0.001), but not CYP2D6 phenotype or activity score were associated with the response to antidepressant treatment. In conclusion, preemptive genotyping for CYP2D6 currently appears to have no clinical implications in treatment-resistant depressive patients indicated for ECT.

Musicians seeking psychiatric help: a preliminary study of psychiatric characteristics.

Musicians are at increased risk for mental disorders, in particular performance anxiety. Likely causes are high levels of occupational stress, special personality traits, and coping skills. In this cross-sectional study, routine outcome monitoring (ROM) data on clinical and psychosocial characteristics were collected from the first 50 musicians visiting our outpatient psychiatric clinic for performing artists and were compared to those of a large sample of psychiatric outpatients (n=1,498) and subjects from the general population. Of the musician outpatients, 82% (n=41) met the criteria of an Axis I psychiatric disorder. Performance anxiety could not be accurately diagnosed with the MINI-plus, and in a few cases it masked different psychiatric disorders. Musician outpatients scored significantly better on functional scales despite their Axis I disorder, with equal scores on scales measuring distress compared to general outpatients. Musicians displayed significantly higher mean scores on the DAPP-sf subscale measuring narcissistic personality traits than general outpatients and non-patient controls (p=0.001). Diagnostic challenges, in particular regarding performance anxiety, of musicians seeking psychiatric care are thoroughly discussed. Musicians with psychiatric disorders may constitute a group of patients with specific characteristics who may benefit from specialized psychiatric care, and health professionals should be aware of the high prevalence of psychiatric disorders in musicians.

Predicting outcome of depression using the depressive symptom profile: the Leiden Routine Outcome Monitoring Study.

BACKGROUND: To investigate the predictive value of items for individual depressive symptoms measured with the self-rated Beck Depression Inventory-Revised (BDI-II) self-report scale on outcome in a large naturalistic cohort of depressive outpatients. METHODS: We used a cohort of 1,489 adult patients aged 18-65 years with major depressive disorder or dysthymic disorder established with the MINI-Plus diagnostic interview. All patients had a routine outcome monitoring baseline measurement in 2004-2009, with a maximum of 2 years follow-up. We used multivariable Cox regression models to predict remission (MADRS < 10; where MADRS stands for Montgomery-Åsberg Depression Rating Scale) and response (≥50% improvement), and adjusted for clinical and demographic characteristics (i.e. marital status, level of education, working status, comorbid anxiety, avoidant and borderline personality traits, and suicidality) that were identified as predictors in earlier studies. RESULTS: Of the 21 BDI-II items, the items "pessimism" and "loss of energy" independently predicted for both remission and response. For pessimism, the hazard ratio (HR) for remission was 0.81 (95% confidence interval [CI]: 0.73-0.89, P < .001) and for loss of energy, the HR was 0.81 (95% CI: 0.72-0.92, P = .001). CONCLUSIONS: These findings of robust prediction of poor outcome by baseline items of "pessimism" and "loss of energy" in a naturalistic treatment setting may help clinicians to identify depressive patients in need for additional or alternative therapeutic approaches.

Reference values for generic instruments used in routine outcome monitoring: the Leiden Routine Outcome Monitoring Study.

INTRODUCTION: The Brief Symptom Inventory (BSI), Mood & Anxiety Symptom Questionnaire -30 (MASQ-D30), Short Form Health Survey 36 (SF-36), and Dimensional Assessment of Personality Pathology-Short Form (DAPP-SF) are generic instruments that can be used in Routine Outcome Monitoring (ROM) of patients with common mental disorders. We aimed to generate reference values usually encountered in 'healthy' and 'psychiatrically ill' populations to facilitate correct interpretation of ROM results. METHODS: We included the following specific reference populations: 1294 subjects from the general population (ROM reference group) recruited through general practitioners, and 5269 psychiatric outpatients diagnosed with mood, anxiety, or somatoform (MAS) disorders (ROM patient group). The outermost 5% of observations were used to define limits for one-sided reference intervals (95th percentiles for BSI, MASQ-D30 and DAPP-SF, and 5th percentiles for SF-36 subscales). Internal consistency and Receiver Operating Characteristics (ROC) analyses were performed. RESULTS: Mean age for the ROM reference group was 40.3 years (SD=12.6) and 37.7 years (SD=12.0) for the ROM patient group. The proportion of females was 62.8% and 64.6%, respectively. The mean for cut-off values of healthy individuals was 0.82 for the BSI subscales, 23 for the three MASQ-D30 subscales, 45 for the SF-36 subscales, and 3.1 for the DAPP-SF subscales. Discriminative power of the BSI, MASQ-D30 and SF-36 was good, but it was poor for the DAPP-SF. For all instruments, the internal consistency of the subscales ranged from adequate to excellent. DISCUSSION AND CONCLUSION: Reference values for the clinical interpretation were provided for the BSI, MASQ-D30, SF-36, and DAPP-SF. Clinical information aided by ROM data may represent the best means to appraise the clinical state of psychiatric outpatients.

Prevalence, demographic and clinical characteristics of body dysmorphic disorder among psychiatric outpatients with mood, anxiety or somatoform disorders.

AIMS: To describe the prevalence, demographic and clinical characteristics of body dysmorphic disorder (BDD) compared with other psychiatric outpatients with a mood, anxiety or somatoform disorder. METHOD: Outpatients referred for treatment of a mood, anxiety or somatoform disorder were routinely assessed at intake. A structured interview (MINI-Plus), observer-based and self-rating instruments were administered by an independent assessor. RESULTS: Among our sample of 3798 referred patients, 2947 patients were diagnosed with at least one DSM-IV mood, anxiety or somatoform disorder. Of these patients 1.8% (n = 54) met the diagnostic criteria for BDD. In comparison with other outpatients, patients with BDD were on average younger, less often married and were more often living alone. Highly prevalent comorbid diagnoses were major depression (in 46.3% of cases), social anxiety disorder (in 35.2% of cases) and obsessive-compulsive disorder (OCD) (in 16.7% of cases). Furthermore, patients with BDD had higher scores on the Clinical Global Impression of Severity (CGI-S) as well as lower scores on the Short Form 36 social role functioning. CONCLUSION: BDD is frequently associated with depression, social phobia and OCD. Patients with BDD have more distress and more impaired interpersonal functioning.

Long-term outcome of bipolar depressed patients receiving lamotrigine as add-on to lithium with the possibility of the addition of paroxetine in nonresponders: a randomized, placebo-controlled trial with a novel design.

OBJECTIVE: In two previous manuscripts, we described the efficacy of lamotrigine versus placebo as add-on to lithium (followed by the addition of paroxetine in nonresponders) in the short-term treatment of bipolar depression. In this paper we describe the long-term (68 weeks) outcome of that study. METHODS: A total of 124 bipolar depressed patients receiving lithium were randomized to addition of lamotrigine or placebo. After eight weeks, paroxetine was added to nonresponders for another eight weeks. Responders continued medication and were followed for up to 68 weeks or until a relapse or recurrence of a depressive or manic episode. RESULTS: After eight weeks, the addition of lamotrigine to lithium was significantly more efficacious than addition of placebo, while after addition of paroxetine in nonresponders both groups further improved with no significant difference between groups at week 16. During follow-up the efficacy of lamotrigine was maintained: time to relapse or recurrence was longer for the lamotrigine group [median time 10.0 months (confidence interval: 1.1-18.8)] versus the placebo group [3.5 months (confidence interval: 0.7-7.0)]. CONCLUSION: In patients with bipolar depression, despite continued use of lithium, addition of lamotrigine revealed a continued benefit compared to placebo throughout the entire study.

Dynamic time warp analysis of individual symptom trajectories in depressed patients treated with electroconvulsive therapy.

BACKGROUND: Although electroconvulsive therapy (ECT) effectively improves severity scores of depression, its effects on its individual symptoms has scarcely been studied. We aimed to study which depressive symptom trajectories dynamically cluster together in individuals as well as groups of patients during ECT using Dynamic Time Warp (DTW) analysis. METHODS: We analysed the standardized weekly scores on the 25-item abbreviated version of the Comprehensive Psychopathological Rating Scale (CPRS) in depressed patients before and during their first six weeks of ECT treatment. DTW analysis was used to analyse the (dis)similarity of time series of items scores at the patient level (300 'DTW distances' per patient) as well as on the group level. Hierarchical cluster, network, and Distatis analyses yielded symptom dimensions. RESULTS: We included 133 patients, 64.7% female, with an average age of 60.4 years (SD 15.1). Individual DTW distance matrices and networks revealed marked differences in hierarchical and network clusters among patients. Based on cluster analyses of the aggregated matrices, four symptom clusters emerged. In patients who reached remission, the average DTW distance between their symptoms was significantly smaller than non-remitters, reflecting denser symptom networks in remitters than non-remitters (p=0.04). LIMITATIONS: The assessments were done only weekly during the first six weeks of ECT treatment. The use of individual items of the abbreviated CPRS may have led to measurement error as well as floor and ceiling effects. CONCLUSION: DTW offers an efficient new approach to analyse symptom trajectories within individuals as well as groups of patients, aiding personalized medicine of psychopathology.

Testing for response shift in treatment evaluation of change in self-reported psychopathology amongst secondary psychiatric care outpatients.

OBJECTIVES: If patients change their perspective due to treatment, this may alter the way they conceptualize, prioritize, or calibrate questionnaire items. These psychological changes, also called "response shifts," may pose a threat to the measurement of therapeutic change in patients. Therefore, it is important to test the occurrence of response shift in patients across their treatment. METHODS: This study focused on self-reported psychological distress/psychopathology in a naturalistic sample of 206 psychiatric outpatients. Longitudinal measurement invariance tests were computed across treatment in order to detect response shifts. RESULTS: Compared with before treatment, post-treatment psychopathology scores showed an increase in model fit and factor loading, suggesting that symptoms became more coherently interrelated within their psychopathology domains. Reconceptualization (depression/mood) and reprioritization (somatic and cognitive problems) response shift types were found in several items. We found no recalibration response shift. CONCLUSION: This study provides further evidence that response shift can occur in adult psychiatric patients across their mental health treatment. Future research is needed to determine whether response shift implies an unwanted potential bias in treatment evaluation or a desired cognitive change intended by treatment.

Treatment consumption and treatment re-enrollment in GHB-dependent patients in The Netherlands.

BACKGROUND: The objective of this study was to assess treatment consumption and re-enrollment in treatment in patients with gamma-hydroxybutyrate (GHB)-dependence in Dutch Addiction Treatment Centers (ATCs) in comparison with other addictions. METHODS: A cohort-study using nationwide administrative data from regular Dutch ATCs associated with the Dutch National Alcohol and Drugs Information System (LADIS), covering an estimated 95% of ATCs. We selected in- and out-patients with alcohol, drug and/or behavioral addictions with a first treatment episode in 2008-2011 and consecutive treatments until 2013 (n=71,679). Patients still in treatment at that date (n=3686; 5.1%), forensic patients (n=1949; 2.7%) and deceased patients (n=570; 0.8%) were excluded, leaving 65,474 patients (91.3%). Of those, 596 (0.9%) patients had GHB dependence. We analyzed number of treatment contacts, treatment duration, admissions and admission duration of the first treatment episode, and re-enrollment (defined as having started a second treatment episode in the study period). RESULTS: GHB-dependent patients showed the highest number of treatment contacts, duration of treatment and chance of being admitted. Re-enrollment rates were 2-5 times higher in GHB-dependent patients than other patients with adjusted HR of other addictions ranging from 0.18 (95% confidence interval [CI]: 0.15-0.21) to 0.53 (95% CI: 0.47-0.61). CONCLUSIONS: This study demonstrates high levels of treatment consumption and high rates of treatment re-enrollment in GHB-dependent patients. These findings highlight the urgency of developing effective relapse prevention interventions for GHB-dependent patients.

Pharmacological Treatment in γ-Hydroxybutyrate (GHB) and γ-Butyrolactone (GBL) Dependence: Detoxification and Relapse Prevention.

The misuse of γ-hydroxybutyrate (GHB) for recreational purposes has resulted in an increase in GHB-related problems such as intoxications, dependence and withdrawal in several countries in Europe, Australia and the US over the last decade. However, prevalence rates of misuse of GHB and its precursor, γ-butyrolactone (GBL), are still relatively low. In this qualitative review paper, after a short introduction on the pharmacology of GHB/GBL, followed by a summary of the epidemiology of GHB abuse, an overview of GHB dependence syndrome and GHB/GBL withdrawal syndrome is provided. Finally, the existing literature on management of GHB detoxification, both planned and unplanned, as well as the available management of GHB withdrawal syndrome, is summarized. Although no systematic studies on detoxification and management of withdrawal have been performed to date, general recommendations are given on pharmacological treatment and preferred treatment setting.

Concordance between self-reported and observer-rated anxiety severity in outpatients with anxiety disorders: The Leiden routine outcome monitoring study.

OBJECTIVES: Anxiety severity measures can be self-report or observer-rated. Although mostly these measures concur, they can diverge markedly. We examined concordance between two anxiety scales: the observer-rated Brief Anxiety Scale (BAS) and the self-report Brief Symptom Inventory 12-item version (BSI-12), and described associations between patient characteristics and discordance. DESIGN: The study used an observational design, using prospective data from 2,007 outpatients with DSM-IV-TR panic disorder with or without agoraphobia, agoraphobia without panic, social phobia, and/or generalized anxiety disorder. METHODS: Overall agreement was described using Pearson's product-moment correlation coefficient. Associations between patient characteristics and discordance (defined as |Z-BAS-Z-BSI-12| ≥ 1) were evaluated with univariable and multivariable multinomial logistic regression analyses. RESULTS: Overall correlation between BAS and BSI-12 was positive and strong (r = .59). Discordance occurred in 24.8% of patients ([Z-BAS ≥ Z-BSI-12 + 1] = 12.2%; [Z-BAS ≤ Z-BSI-12 - 1]  = 12.6%). Patients with higher observed than self-reported anxiety severity did not differ from concordant patients. Patients with lower observed than self-reported anxiety severity more often had panic disorder, less often had social phobia, and had higher scores on cluster B and C personality characteristics than concordant patients. Lower observed than self-reported anxiety severity was best predicted by panic disorder, social phobia, and affective lability. CONCLUSIONS: Results demonstrate that the use of a single source of information gives a one-sided view of pathology. A multimethod approach is highly preferable, as this allows for assessment across different domains and through multiple sources of information, and as such, provides clinicians with vital information. PRACTITIONER POINTS: When assessing anxiety severity, the use of self-report measures provides additional information to observer-rated measures. In patients who have strong cluster B and C personality traits, anxiety severity might be overlooked, even by trained observers. The use of a multimethod assessment strategy is preferable in anxiety severity assessment.

The effect of atomoxetine on random and directed exploration in humans.

The adaptive regulation of the trade-off between pursuing a known reward (exploitation) and sampling lesser-known options in search of something better (exploration) is critical for optimal performance. Theory and recent empirical work suggest that humans use at least two strategies for solving this dilemma: a directed strategy in which choices are explicitly biased toward information seeking, and a random strategy in which decision noise leads to exploration by chance. Here we examined the hypothesis that random exploration is governed by the neuromodulatory locus coeruleus-norepinephrine system. We administered atomoxetine, a norepinephrine transporter blocker that increases extracellular levels of norepinephrine throughout the cortex, to 22 healthy human participants in a double-blind crossover design. We examined the effect of treatment on performance in a gambling task designed to produce distinct measures of directed exploration and random exploration. In line with our hypothesis we found an effect of atomoxetine on random, but not directed exploration. However, contrary to expectation, atomoxetine reduced rather than increased random exploration. We offer three potential explanations of our findings, involving the non-linear relationship between tonic NE and cognitive performance, the interaction of atomoxetine with other neuromodulators, and the possibility that atomoxetine affected phasic norepinephrine activity more so than tonic norepinephrine activity.

Detoxification with titration and tapering in gamma-hydroxybutyrate (GHB) dependent patients: The Dutch GHB monitor project.

BACKGROUND AND AIMS: Gamma-hydroxybutyrate (GHB) detoxification procedures have been insufficiently studied for effectiveness and safety. Based on case reports, benzodiazepines are generally regarded as first-choice agents in GHB detoxification. Detoxification by titration and tapering (DeTiTap) with pharmaceutical GHB in an open-label consecutive case series of 23 GHB-dependent patients showed to be feasible, effective and safe. This study further explored the feasibility, effectiveness and safety of this detoxification procedure in a large group of patients. METHOD: A large observational multicenter study was carried out in six addiction treatment centers in the Netherlands. GHB-dependent inpatients (229 unique patients, 274 admissions) were titrated on and tapered off with pharmaceutical GHB. RESULTS: Successful detoxification was achieved in 85% of cases. Detoxification was carried out in 12.5days in most patients. The DeTiTap procedure proved to be feasible and significantly reduced the experienced withdrawal symptoms and craving (p≤0.001). Several symptoms were found to influence the course of subjective withdrawal symptoms. During detoxification, psychological symptoms such as depression, anxiety, and stress decreased (p≤0.05). The main complications were hypertension and anxiety. Six patients were sent to the general hospital for observation, but all six were able to continue detoxification in the addiction treatment centers. Most patients (69%) relapsed within three months after detoxification. CONCLUSIONS: The DeTiTap procedure using pharmaceutical GHB seems a safe alternative to benzodiazepines as a GHB detoxification procedure. However, the high relapse rates warrant further investigation.

Effects of clonidine and scopolamine on multiple target detection in rapid serial visual presentation.

RATIONALE: The specific role of neuromodulator systems in regulating rapid fluctuations of attention is still poorly understood. OBJECTIVES: In this study, we examined the effects of clonidine and scopolamine on multiple target detection in a rapid serial visual presentation task to assess the role of the central noradrenergic and cholinergic systems in temporal attention. METHOD: Eighteen healthy volunteers took part in a crossover double-dummy study in which they received clonidine (150/175 µg), scopolamine (1.2 mg), and placebo by mouth in counterbalanced order. A dual-target attentional blink task was administered at 120 min after scopolamine intake and 180 min after clonidine intake. The electroencephalogram was measured during task performance. RESULTS: Clonidine and scopolamine both impaired detection of the first target (T1). For clonidine, this impairment was accompanied by decreased amplitudes of the P2 and P3 components of the event-related potential. The drugs did not impair second-target (T2) detection, except if T2 was presented immediately after T1. The attentional blink for T2 was not affected, in line with a previous study that found no effect of clonidine on the attentional blink. CONCLUSIONS: These and other results suggest that clonidine and scopolamine may impair temporal attention through a decrease in tonic alertness and that this decrease in alertness can be temporarily compensated by a phasic alerting response to a salient stimulus. The comparable behavioral effects of clonidine and scopolamine are consistent with animal studies indicating close interactions between the noradrenergic and cholinergic neuromodulator systems.