Dopaminergic drug treatment remediates exaggerated cingulate prediction error responses in obsessive-compulsive disorder.

RATIONALE: Patients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function. OBJECTIVE: In this study, we investigate potential dopaminergic dysfunction during reward processing in the context of OCD. METHODS: We studied OCD patients (n = 18) and controls (n = 18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of a dopamine receptor agonist, pramipexole 0.5 mg; a dopamine receptor antagonist, amisulpride 400 mg; and placebo. We fitted a Q-learning computational model to fMRI prediction error responses; group differences were examined in anterior cingulate and nucleus accumbens regions of interest. RESULTS: There were no significant group, drug, or interaction effects in the number of correct choices; computational modeling suggested a marginally significant difference in learning rates between groups (p = 0.089, partial ƞ2 = 0.1). In the imaging results, there was a significant interaction of group by drug (p = 0.013, partial ƞ2 = 0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p = 0.014, partial ƞ2 = 0.26, 1-ß error probability = 0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD. CONCLUSIONS: Our data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.

Effects of risperidone, amisulpride and nicotine on eye movement control and their modulation by schizotypy.

RATIONALE: The increasing demand to develop more efficient compounds to treat cognitive impairments in schizophrenia has led to the development of experimental model systems. One such model system combines the study of surrogate populations expressing high levels of schizotypy with oculomotor biomarkers. OBJECTIVES: We aimed (1) to replicate oculomotor deficits in a psychometric schizotypy sample and (2) to investigate whether the expected deficits can be remedied by compounds shown to ameliorate impairments in schizophrenia. METHODS: In this randomized double-blind, placebo-controlled study 233 healthy participants performed prosaccade (PS), antisaccade (AS) and smooth pursuit eye movement (SPEM) tasks after being randomly assigned to one of four drug groups (nicotine, risperidone, amisulpride, placebo). Participants were classified into medium- and high-schizotypy groups based on their scores on the Schizotypal Personality Questionnaire (SPQ, Raine (Schizophr Bull 17:555-564, 1991)). RESULTS: AS error rate showed a main effect of Drug (p < 0.01), with nicotine improving performance, and a Drug by Schizotypy interaction (p = 0.04), indicating higher error rates in medium schizotypes (p = 0.01) but not high schizotypes under risperidone compared to placebo. High schizotypes had higher error rates than medium schizotypes under placebo (p = 0.03). There was a main effect of Drug for saccadic peak velocity and SPEM velocity gain (both p ≤ 0.01) indicating impaired performance with risperidone. CONCLUSIONS: We replicate the observation of AS impairments in high schizotypy under placebo and show that nicotine enhances performance irrespective of group status. Caution should be exerted in applying this model as no beneficial effects of antipsychotics were seen in high schizotypes.

Brain functional connectivity in stimulant drug dependence and obsessive-compulsive disorder.

There are reasons for thinking that obsessive-compulsive disorder (OCD) and drug dependence, although conventionally distinct diagnostic categories, might share important cognitive and neurobiological substrates. We tested this hypothesis directly by comparing brain functional connectivity measures between patients with OCD, stimulant dependent individuals (SDIs; many of whom were non-dependent users of other recreational drugs) and healthy volunteers. We measured functional connectivity between each possible pair of 506 brain regional functional MRI time series representing low frequency (0.03-0.06 Hz) spontaneous brain hemodynamics in healthy volunteers (N=18), patients with OCD (N=18) and SDIs (N=18). We used permutation tests to identify i) brain regions where strength of connectivity was significantly different in both patient groups compared to healthy volunteers; and ii) brain regions and connections which had significantly different functional connectivity between patient groups. We found that functional connectivity of right inferior and superior orbitofrontal cortex (OFC) was abnormally reduced in both disorders. Whether diagnosed as OCD or SDI, patients with higher scores on measures of compulsive symptom severity showed greater reductions of right orbitofrontal connectivity. Functional connections specifically between OFC and dorsal medial pre-motor and cingulate cortex were attenuated in both patient groups. However, patients with OCD demonstrated more severe and extensive reductions of functional connectivity compared to SDIs. OCD and stimulant dependence are not identical at the level of brain functional systems but they have some important abnormalities in common compared with healthy volunteers. Orbitofrontal connectivity may serve as a human brain systems biomarker for compulsivity across diagnostic categories.

Amisulpride-induced acute akathisia in OCD: an example of dysfunctional dopamine-serotonin interactions?

We report about a clinical observation in a well-characterized group of patients with obsessive-compulsive disorder (OCD) during an experimental medicine study in which a single dose of amisulpride (a selective D2/3 antagonist) was administered. Almost half of the OCD patients, in particular those with less severe obsessive-compulsive symptoms, experienced acute akathisia in response to the amisulpride challenge. This unexpectedly high incidence of akathisia in the selective serotonin reuptake inhibitor (SSRI)-treated patients with OCD suggests that individual differences in dopamine-serotonin interactions underlie the clinical heterogeneity of OCD, and may thus explain the insufficiency of SSRI monotherapy in those patients not experiencing a satisfactory outcome in symptom reduction. We further speculate about the neuropathology possibly underlying this clinical observation and outline a testable hypothesis for future molecular imaging studies.

A validation of cognitive biomarkers for the early identification of cognitive enhancing agents in schizotypy: a three-center double-blind placebo-controlled study.

A number of compounds aimed at improving cognition in schizophrenia have failed to demonstrate efficacy in Phase 2 clinical trials. Translational studies using biomarkers in surrogate populations, such as schizotypy, could be used to assess the efficacy of novel compounds. In this study, we aimed to validate the sensitivity and inter-site reliability of cognitive biomarkers (working memory (N-back), spatial working memory (SWM) and verbal fluency (VF) tasks) to detect the schizotypy phenotype and its reversal by psychotropic drugs. Healthy volunteers scoring high or average on a schizotypal personality measure (122 in each group) were randomized to receive a single dose of risperidone, amisulpride, nicotine or placebo in a double-blind, between-subject design. We found evidence for a poorer performance on N-back and VF tasks in the high schizotypy group, replicating previous research. This effect was counteracted by amisulpride on N-back: it improved working memory in high schizotypy group but impaired the controls. A similar pattern was seen in SWM and VF. We interpret this finding in the light of the dopamine enhancing action of amisulpride when given in low doses. In contrast, risperidone impaired both groups and nicotine had a beneficial effect for the low baseline performers only. These effects were consistent across sites. These data demonstrates the utility of biomarkers in detecting the effect of schizotypy and its reversal by drugs that enhance dopamine and cholinergic function. Studies using similar design could help the early assessment of potential of compounds designed to improve cognition in schizophrenia.

Response perseveration in stimulant dependence is associated with striatal dysfunction and can be ameliorated by a D(2/3) receptor agonist.

BACKGROUND: Compulsivity is a hallmark of drug addiction and in animal models is measured by consecutive incorrect responses to a previously rewarded stimulus during reversal learning. The aim of this study was to measure behavioral and neural markers of compulsivity in stimulant-dependent individuals and to test whether these markers could be modulated by treatment with drugs targeting the dopamine system. METHODS: In a randomized, double-blind, placebo-controlled, crossover design, stimulant-dependent individuals (SDIs; n = 18) and healthy volunteers (n = 18) received single doses of dopamine D(2/3) receptor antagonist (amisulpride, 400 mg) and agonist (pramipexole, 0.5 mg) drugs. To examine compulsivity and its dopaminergic modulation more generally, patients with obsessive-compulsive disorder (OCD; n = 18) were also included in the study. RESULTS: SDIs made significantly more perseverative responses to the previously correct stimulus immediately following reversal, compared with both healthy volunteers and patients with OCD. Across all participants, the number of perseverative errors was negatively correlated with functional activation in right fronto-striato-parietal networks-in particular, the right caudate nucleus. In SDIs, perseveration-related caudate activation was abnormally reduced in the placebo condition, but the dopamine D(2/3) agonist pramipexole normalized both perseverative responding and related activation of the right caudate. CONCLUSIONS: Perseveration during reversal learning was associated specifically with stimulant dependence rather than with compulsive behaviors more generally. The beneficial effects of a dopamine agonist drug challenge on both behavior and associated brain activation in SDIs may indicate new avenues for pharmacologic treatment in stimulant dependence.

Validation of experimental medicine methods in psychiatry: the P1vital approach and experience.

In the pharmaceutical industry deciding whether to progress a compound to the next stage of development or choosing between compounds in a development portfolio is laden with risk. This is particularly true of compounds developed to treat CNS disorders. The use of pre-clinical models in CNS drug development is well established but these models often lack predictive validity and many compounds fail when they reach the target patient group. Bridging the gap between pre-clinical CNS models and patient studies, P1vital's objective is to develop human volunteer models that will enable rapid, accurate and reliable decision making about which compounds to progress into patient trials. The research strategy of P1vital and its academic research network is to focus on science that progresses the development of clinical efficacy models. As part of this strategy P1vital established a CNS Experimental Medicine Consortium with members from both academic research and the pharmaceutical industry. This consortium is unique in that experimental medicine models initially developed through academic research are selected for further validation in a process that is managed by the Pharma members of the P1vital CNS Experimental Medicine Consortium steering (PEM) committee. The P1vital consortium is very much a work in progress. However, since its inception in 2007 the consortium has successfully delivered results from five clinical studies in four therapeutic areas namely, anxiety, cognitive disorders, schizophrenia and depression.

Impaired visuospatial associative memory and attention in obsessive compulsive disorder but no evidence for differential dopaminergic modulation.

RATIONALE: Patients with obsessive compulsive disorder (OCD) demonstrate impaired cognition in some selected domains. Although serotoninergic dysfunction has been implicated in OCD, recent evidence suggests that dopamine may play a role as well. OBJECTIVE: The aim of the study was to evaluate learning and working memory in OCD and to determine the effects of dopaminergic manipulations on these capacities. METHODS: Visuospatial associative memory and spatial and verbal working memory were examined in 18 nondepressed patients with OCD and 18 matched healthy controls. The study further investigated whether acute administration of dopamine D2/D3 receptor agonist and antagonist would differentially modulate cognition in OCD. Each participant underwent the cognitive battery three times in a randomized double-blind, placebo-controlled crossover design. RESULTS: Significant impairments in patients compared with controls were noted on the Cambridge Neuropsychological Test Automated Battery (CANTAB) paired associates learning (PAL) and a measure of sustained attention (rapid visual information processing, RVIP) that persisted across all sessions, with deficient strategy in the CANTAB spatial working memory task in the first session alone. Although the dopamine D2/D3 agonist, pramipexole, led to poorer performance on the PAL and RVIP tasks, no differential effects were noted between the two groups. No significant effects were noted for the D2/D3 antagonist, amisulpride. CONCLUSIONS: The results are consistent with a specific associative memory deficit in OCD that remained robust despite possible practice effects and compensatory strategies and point to abnormal medial temporal lobe involvement in OCD in addition to the previously implicated frontostriatal loops, with no clear evidence of D2 receptor mediation.

Influence of compulsivity of drug abuse on dopaminergic modulation of attentional bias in stimulant dependence.

CONTEXT: There are no effective pharmacotherapies for stimulant dependence but there are many plausible targets for development of novel therapeutics. We hypothesized that dopamine-related targets are relevant for treatment of stimulant dependence, and there will likely be individual differences in response to dopaminergic challenges. OBJECTIVE: To measure behavioral and brain functional markers of drug-related attentional bias in stimulant-dependent individuals studied repeatedly after short-term dosing with dopamine D(2)/D(3) receptor antagonist and agonist challenges. DESIGN: Randomized, double-blind, placebo-controlled, parallel-groups, crossover design using pharmacological functional magnetic resonance imaging. SETTING: Clinical research unit (GlaxoSmithKline) and local community in Cambridge, England. PARTICIPANTS: Stimulant-dependent individuals (n = 18) and healthy volunteers (n = 18). INTERVENTIONS: Amisulpride (400 mg), pramipexole dihydrochloride (0.5 mg), or placebo were administered in counterbalanced order at each of 3 repeated testing sessions. MAIN OUTCOME MEASURES: Attentional bias for stimulant-related words was measured during functional magnetic resonance imaging by a drug-word Stroop paradigm; trait impulsivity and compulsivity of dependence were assessed at baseline by questionnaire. RESULTS: Drug users demonstrated significant attentional bias for drug-related words, which was correlated with greater activation of the left prefrontal and right cerebellar cortex. Attentional bias was greater in people with highly compulsive patterns of stimulant abuse; the effects of dopaminergic challenges on attentional interference and related frontocerebellar activation were different between high- and low-compulsivity subgroups. CONCLUSIONS: Greater attentional bias for and greater prefrontal activation by stimulant-related words constitute a candidate neurocognitive marker for dependence. Individual differences in compulsivity of stimulant dependence had significant effects on attentional bias, its brain functional representation, and its short-term modulation by dopaminergic challenges.

The Irritability Questionnaire: a new scale for the measurement of irritability.

Irritability is an important symptom in patients with neuropsychiatric disorders. It is a major source of distress to patients and their carers and can lead to social and family dysfunction. Despite this, there has been little systematic research on irritability in psychiatry. The development of an instrument that captures the various components of irritability is a prerequisite to more detailed research in this area. The aim of this study was to design a scale to measure irritable mood and to explore its nature and subtypes. Following a review of the literature and examination of current theories in affective neuroscience, a new self-rating questionnaire was developed covering a range of subjective experiences, judgements and behaviours deemed to encompass the components of irritability. The items were rated along intensity and frequency dimensions. The questionnaire was administered to patients with affective disorders (n=22), Huntington's disease (n=23), Alzheimer's disease (n=19) and a control group (n=46). The new questionnaire shows good reliability and validity. Preliminary differences in irritability were identified between the diagnostic groups.

Obsessive-compulsive disorder: boundary issues.

The boundaries between obsessive-compulsive disorder (OCD) and other neuropsychiatric disorders remain unresolved and may well differ from one disorder to another. Endophenotypes are heritable, quantitative traits hypothesized to more closely represent genetic risk for complex polygenic mental disorders than overt symptoms and behaviors. They may have a role in identifying how closely these disorders are associated with another and with other mental disorders with which they share major comorbidity. This review maps the nosological relationships of OCD to other neuropsychiatric disorders, using OCD as the prototype disorder and endophenotype markers, such as cognitive, imaging, and molecular data as well as results from demographic, comorbidity, family, and treatment studies. Despite high comorbidity rates, emerging evidence suggests substantial endophenotypic differences between OCD and anxiety disorders, depression, schizophrenia, and addictions, though comparative data is lacking and the picture is far from clear. On the other hand, strong relationships between OCD, Tourette syndrome, body dysmorphic disorder, hypochondriasis, grooming disorders, obsessive-compulsive personality disorder, and pediatric autoimmune neuropsychiatric disorders associated with streptococcus are likely. Studies designed to delineate the cause, consequences, and common factors are a challenging but essential goal for future research in this area.