Decrease of cocaine, but not heroin, self-administration and relapse by the tyrosine kinase inhibitor masitinib in male Sprague Dawley rats.

RATIONALE: Accumulating evidence shows that cocaine, and also heroin, influence several tyrosine kinases, expressed in neurons and in non-neuronal populations such as microglia, astrocytes and mast-cells. Drug-induced activation of mast cells both triggers inflammatory processes in the brain mediated by the glial cells they activate, and facilitates histamine release which may directly influence the dopamine system. Thus, by triggering the activation and degranulation of mast cells dependent on the tyrosine kinase c-kit and Fyn, the latter being also involved in NMDA-dependent synaptic plasticity, cocaine and heroin may indirectly influence the neural mechanisms that mediate their reinforcing properties. Masitinib, a novel tyrosine kinase inhibitor with high selectivity for c-Kit, Fyn and Lyn, may alter the aberrant consequences of the activation of these tyrosine kinases by cocaine and heroin. OBJECTIVE: We investigated in rats the effect of a chronic oral treatment with masitinib (20 mg/kg) on the reinforcing and motivational properties of self-administered cocaine (250 µg/infusion) and heroin (40 µg/infusion). METHODS: Three different cohorts of rats were trained instrumentally to respond for cocaine, heroin or food under continuous reinforcement. In each group, we assessed the influence of chronic daily treatment with masitinib on the maintenance of instrumental responding and intake and the motivation for the reinforcer. Thus, masitinib and vehicle-treated rats were challenged to adapt to high behavioural demand, to respond under a progressive ratio schedule of reinforcement and to reinstate instrumental responding after extinction and/or abstinence. RESULTS: Masitinib selectively decreased cocaine intake, the motivation for cocaine and the subsequent propensity to respond for cocaine under extinction, while having no effect on instrumental responding for heroin or food. CONCLUSION: The present findings suggest masitinib, a drug with proven efficacy in CNS disorders, could represent a novel treatment for cocaine addiction provided its influence on the reinforcing and incentive properties of the drug is confirmed.

From impulses to maladaptive actions: the insula is a neurobiological gate for the development of compulsive behavior.

Impulsivity is an endophenotype of vulnerability for compulsive behaviors. However, the neural mechanisms whereby impulsivity facilitates the development of compulsive disorders, such as addiction or obsessive compulsive disorder, remain unknown. We first investigated, in rats, anatomical and functional correlates of impulsivity in the anterior insular (AI) cortex by measuring both the thickness of, and cellular plasticity markers in, the AI with magnetic resonance imaging and in situ hybridization of the immediate early gene zif268, respectively. We then investigated the influence of bilateral AI cortex lesions on the high impulsivity trait, as measured in the five-choice serial reaction time task (5-CSRTT), and the associated propensity to develop compulsivity as measured by high drinking levels in a schedule-induced polydipsia procedure (SIP). We demonstrate that the AI cortex causally contributes to individual vulnerability to impulsive-compulsive behavior in rats. Motor impulsivity, as measured by premature responses in the 5-CSRTT, was shown to correlate with the thinness of the anterior region of the insular cortex, in which highly impulsive (HI) rats expressed lower zif268 mRNA levels. Lesions of AI reduced impulsive behavior in HI rats, which were also highly susceptible to develop compulsive behavior as measured in a SIP procedure. AI lesions also attenuated both the development and the expression of SIP. This study thus identifies the AI as a novel neural substrate of maladaptive impulse control mechanisms that may facilitate the development of compulsive disorders.

In search of predictive endophenotypes in addiction: insights from preclinical research.

Drug addiction is widely recognized to afflict some but not all individuals by virtue of underlying risk markers and traits involving multifaceted interactions between polygenic and external factors. Remarkably, only a small proportion of individuals exposed to licit and illicit drugs develop compulsive drug-seeking behavior, maintained in the face of adverse consequences and associated detrimental patterns of drug intake involving extended and repeated bouts of binge intoxication, withdrawal and relapse. As a consequence, research has increasingly endeavored to identify distinctive neurobehavioral mechanisms and endophenotypes that predispose individuals to compulsive drug use. However, research in active drug users is hampered by the difficulty in categorizing putatively causal behavioral traits prior to the initiation of drug use. By contrast, research in experimental animals is often hindered by the validity of approaches used to investigate the neural and psychological mechanisms of compulsive drug-seeking habits in humans. Herein, we survey and discuss the principal findings emanating from preclinical animal research on addiction and highlight how specific behavioral endophenotypes of presumed genetic origin (e.g. trait anxiety, novelty preference and impulsivity) differentially contribute to compulsive forms of drug seeking and taking and, in particular, how these differentiate between different classes of stimulant and non-stimulant drugs of abuse.

Risk assessment and receiver operating characteristic curves.

Risk assessment is now regarded as a necessary competence in psychiatry. The area under the curve (AUC) statistic of the receiver operating characteristic curve is increasingly offered as the main evidence for accuracy of risk assessment instruments. But, even a highly statistically significant AUC is of limited value in clinical practice.

Suicide attempts in a prospective cohort of patients with schizophrenia treated with sertindole or risperidone.

The incidence of suicide attempts (fatal and non-fatal) was analysed in a prospective cohort of patients with schizophrenia randomly assigned to sertindole (4905 patients) or risperidone (4904 patients) in a parallel-group open-label study with blinded classification of outcomes (the sertindole cohort prospective study--SCoP). The total exposure was 6978 and 7975 patient-years in the sertindole and risperidone groups, respectively. Suicide mortality in the study was low (0.21 and 0.28 per 100 patients per year with sertindole and risperidone, respectively). The majority (84%) of suicide attempts occurred within the first year of treatment. Cox's proportional hazards model analysis of the time to the first suicide attempt, reported by treating psychiatrists and blindly reviewed by an independent expert group according to the Columbia Classification Algorithm of Suicide Assessment (both defining suicide attempts by association of suicidal act and intent to die), showed a lower risk of suicide attempt for sertindole-treated patients than for risperidone-treated patients. The effect was statistically significant with both evaluation methods during the first year of randomized treatment (hazard ratios [95% CI]: 0.5 [0.31-0.82], p=0.006; and 0.57 [0.35-0.92], p=0.02, respectively). With classification by an independent safety committee using a broader definition including all incidences of intentional self-harm, also those without clear suicidal intent, the results were not significant. A history of previous suicide attempts was significantly associated with attempted suicides in both treatment groups.

Safety of sertindole versus risperidone in schizophrenia: principal results of the sertindole cohort prospective study (SCoP).

OBJECTIVE: To explore whether sertindole increases all-cause mortality or cardiac events requiring hospitalization, compared with risperidone. METHOD: Multinational randomized, open-label, parallel-group study, with blinded classification of outcomes, in 9858 patients with schizophrenia. RESULTS: After 14147 person-years, there was no effect of treatment on overall mortality (sertindole 64, risperidone 61 deaths, Hazard Ratio (HR) = 1.12 (90% CI: 0.83, 1.50)) or cardiac events requiring hospitalization [sertindole 10, risperidone 6, HR = 1.73 (95% CI: 0.63, 4.78)]: Of these, four were considered arrhythmia-related (three sertindole, one risperidone). Cardiac mortality was higher with sertindole (Independent Safety Committee (ISC): 31 vs. 12, HR=2.84 (95% CI: 1.45, 5.55), P = 0.0022; Investigators 17 vs. 8, HR=2.13 (95% CI: 0.91, 4.98), P = 0.081). There was no significant difference in completed suicide, but fewer sertindole recipients attempted suicide (ISC: 68 vs. 78, HR=0.93 (95% CI: 0.66, 1.29), P = 0.65; Investigators: 43 vs. 65, HR=0.67 (95% CI: 0.45, 0.99), P = 0.044). CONCLUSION: Sertindole did not increase all-cause mortality, but cardiac mortality was higher and suicide attempts may be lower with sertindole.

Analyses of mortality risk in patients with dementia treated with galantamine.

OBJECTIVE: To analyze mortality data from patients with Alzheimer's disease (AD), Alzheimer's plus cerebrovascular disease (AD + CVD) or vascular dementia (VaD). METHODS: (1) Meta-analysis of mortality data from double-blind, placebo-controlled, randomized trials; and (2) recontact study to collect additional longer term mortality data from previous galantamine trial participants. RESULTS (META-ANALYSIS): Across 12 trials (< or =6 months duration), there was no increased risk of mortality associated with the use of galantamine (n = 4116) compared with that of placebo (n = 2386) (OR galantamine/placebo: 0.67, 95% CI 0.41-1.10). RESULTS (RECONTACT STUDY): Median survival was 79 months for patients with AD (n = 478) and 59 months for patients with AD + CVD (n = 180) or VaD (n = 145). Prolonged galantamine treatment (> vs < or =6 months) was not associated with decreased survival time (75 vs 61 months respectively; P = 0.02). Cox regression analyses were consistent with the Kaplan-Meier analyses. CONCLUSIONS: We found no short-term or longer term evidence of increased risk of mortality associated with the use of galantamine in patients with AD, AD + CVD or VaD.

Drug addiction and the memory systems of the brain.

We review drug addiction from the perspective of the hypothesis that drugs of abuse interact with distinct brain memory systems. We focus on emotional and procedural forms of memory, encompassing Pavlovian and instrumental conditioning, both for action-outcome and for stimulus-response associations. Neural structures encompassed by these systems include the amygdala, hippocampus, nucleus accumbens, and dorsal striatum. Additional influences emanate from the anterior cingulate and prefrontal cortex, which are implicated in the encoding and retrieval of drug-related memories that lead to drug craving and drug use. Finally, we consider the ancillary point that chronic abuse of many drugs may impact directly on neural memory systems via neuroadaptive and neurotoxic effects that lead to cognitive impairments in which memory dysfunction is prominent.

Psychological effects of chemical weapons: a follow-up study of First World War veterans.

BACKGROUND: Chemical weapons exercise an enduring and often powerful psychological effect. This had been recognized during the First World War when it was shown that the symptoms of stress mimicked those of mild exposure to gas. Debate about long-term effects followed the suggestion that gassing triggered latent tuberculosis. METHOD: A random sample of 103 First World War servicemen awarded a war pension for the effects of gas, but without evidence of chronic respiratory pathology, were subjected to cluster analysis using 25 common symptoms. The consistency of symptom reporting was also investigated across repeated follow-ups. RESULTS: Cluster analysis identified four groups: one (n=56) with a range of somatic symptoms, a second (n=30) with a focus on the respiratory system, a third (n=12) with a predominance of neuropsychiatric symptoms, and a fourth (n=5) with a narrow band of symptoms related to the throat and breathing difficulties. Veterans from the neuropsychiatric cluster had multiple diagnoses including neurasthenia and disordered action of the heart, and reported many more symptoms than those in the three somatic clusters. CONCLUSIONS: Mild or intermittent respiratory disorders in the post-war period supported beliefs about the damaging effects of gas in the three somatic clusters. By contrast, the neuropsychiatric group did not report new respiratory illnesses. For this cluster, the experience of gassing in a context of extreme danger may have been responsible for the intensity of their symptoms, which showed no sign of diminution over the 12-year follow-up.

The effects of social class and dental attendance on oral health.

The relationship between socio-economic status (SES) and oral health is well-established. We investigated whether the association between SES and the number of sound teeth in adults is explained by dental attendance patterns, in turn determined by the effect of SES on barriers to dental attendance. Data on 3817 participants from the 1998 Adult Dental Health Survey in the UK were analyzed. Using structural equation modeling, we found a model with 4 factors (aging, SES, attendance-profile, and barriers-to-dental-attendance) providing an adequate fit to the covariance matrix of the 9 covariates. The final model suggests that the association between SES and the number of sound teeth in adults in the UK is partially explained by the pathway [SES --> barriers-to-dental-attendance --> dental-attendance-profile --> number-of-sound-teeth]. A direct relationship, SES --> number-of-sound-teeth, is also significant.

An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition.

Alpha5IA is a compound that binds with equivalent subnanomolar affinity to the benzodiazepine (BZ) site of GABA(A) receptors containing an alpha1, alpha2, alpha3, or alpha5 subunit but has inverse agonist efficacy selective for the alpha5 subtype. As a consequence, the in vitro and in vivo effects of this compound are mediated primarily via GABA(A) receptors containing an alpha5 subunit. In a mouse hippocampal slice model, alpha5IA significantly enhanced the burst-induced long-term potentiation of the excitatory postsynaptic potential in the CA1 region but did not cause an increase in the paroxysmal burst discharges that are characteristic of convulsant and proconvulsant drugs. These in vitro data suggesting that alpha5IA may enhance cognition without being proconvulsant were confirmed in in vivo rodent models. Hence, alpha5IA significantly enhanced performance in a rat hippocampal-dependent test of learning and memory, the delayed-matching-to-position version of the Morris water maze, with a minimum effective oral dose of 0.3 mg/kg, which corresponded to a BZ site occupancy of 25%. However, in mice alpha5IA was not convulsant in its own right nor did it potentiate the effects of pentylenetetrazole acutely or produce kindling upon chronic dosing even at doses producing greater than 90% occupancy. Finally, alpha5IA was not anxiogenic-like in the rat elevated plus maze nor did it impair performance in the mouse rotarod assay. Together, these data suggest that the GABA(A) alpha5-subtype provides a novel target for the development of selective inverse agonists with utility in the treatment of disorders associated with a cognitive deficit.

Incidence and distribution of first-episode mania by age: results from a 35-year study.

BACKGROUND: Few epidemiological studies have investigated incidence by age or age at onset distributions for mania or bipolar disorder. The current study aimed to determine these in a defined area in south-east London, over a 35-year period. METHOD: All cases of first-episode mania presenting to psychiatric services in Camberwell, south-east London, between 1965 and 1999 were identified. Incidence rates by age, using 5-year age-at-onset bands, were estimated and the structure of the age-at-onset distribution for first-episode mania was investigated using finite mixture distributions (admixture analysis). RESULTS: The incidence of DSM-IV bipolar I disorder (BP I), first manic episode peaked in early adult life (16.38/100,000 population per year in the 21-25 years band) with a much smaller peak in mid-life. A two-component normal mixture distribution fitted age at onset better than either a single normal distribution or a three-component mixture, implying the existence of early and later onset subgroups. The early onset group had a stronger family history of bipolar disorder, and showed more acute, severe and atypical symptoms during their first manic episode. CONCLUSIONS: The incidence of mania peaks in early adult life but there is clear evidence of early and later onset subgroups which may represent different forms of disorder.

Acquisition of instrumental conditioned reinforcement is resistant to the devaluation of the unconditioned stimulus.

The associative mechanisms responsible for the efficacy of Pavlovian stimuli during first- and second-order conditioning have been extensively studied, but little is known about the representations underlying instrumental conditioned reinforcement. The present study investigated the associative structure underlying conditioned reinforcement, by employing an unconditioned stimulus (US) devaluation procedure on a commonly used instrumental task: the acquisition of a new response with conditioned reinforcement. Whilst US-directed behaviour was abolished following devaluation, the conditioned stimulus acting as a conditioned reinforcer supported the acquisition of instrumental responding. In this preparation then, the conditioned reinforcer appears to be impervious to devaluation of its associated US, suggesting that the underlying representation maintaining behaviour is independent of the current value of the US and may reflect the activation of a central appetitive motivational state.

Computerized, interactive, multimedia cognitive-behavioural program for anxiety and depression in general practice.

BACKGROUND: Cognitive-behavioural therapy (CBT) brings about significant clinical improvement in anxiety and depression, but therapists are in short supply. We report the first phase of a randomized controlled trial of an interactive multimedia program of cognitive-behavioural techniques, Beating the Blues (BtB), in the treatment of patients in general practice with anxiety, depression or mixed anxiety/depression. METHOD: One hundred and sixty-seven adults suffering from anxiety and/or depression and not receiving any form of psychological treatment or counselling were randomly allocated to receive, with or without medication, BtB or treatment as usual (TAU). Measures were taken on five occasions: prior to treatment, 2 months later, and at 1, 3 and 6 months follow-up using the Beck Depression Inventory, Beck Anxiety Inventory and Work and Social Adjustment Scale. RESULTS: Patients who received BtB showed significantly greater improvement in depression and anxiety compared to TAU by the end of treatment (2 months) and to 6 months follow-up. Symptom reduction was paralleled by improvement in work and social adjustment. There were no interactions of BtB with concomitant pharmacotherapy or duration of illness, but evidence, on the Beck Anxiety Inventory only, of interaction with primary care practice. Importantly, there was no interaction between the effects of BtB and baseline severity of depression, from which we conclude that the effects of the computer program are independent of starting level of depression. CONCLUSIONS: These results demonstrate that computerized interactive multimedia cognitive-behavioural techniques under minimal clinical supervision can bring about improvements in depression and anxiety, as well as in work and social adjustment, with and without pharmacotherapy and in patients with pre-treatment illness of durations greater or less than 6 months. Thus, our results indicate that wider dissemination of cognitive-behavioural techniques is possible for patients suffering from anxiety and/or depression.

Nucleus accumbens dopamine depletion impairs both acquisition and performance of appetitive Pavlovian approach behaviour: implications for mesoaccumbens dopamine function.

The involvement of mesoaccumbens dopamine in adaptive learning and behaviour is unclear. For example, dopamine may act as a teaching signal to enable learning, or more generally modulate the behavioural expression, or selection, of an already-learned response. The present study investigated the involvement of the mesoaccumbens dopamine system in a fundamental form of learning: Pavlovian conditioning. In this case, the temporal association of a previously neutral visual stimulus and a biologically significant unconditioned stimulus (US), subsequently led to the production of the conditioned response (CR) of discriminated approach behaviour directed toward the conditioned stimulus (CS+), relative to a control (CS-) stimulus. 6-hydroxydopamine lesions of the nucleus accumbens (NAcc), leading to approximately 80% reductions in tissue dopamine, were made at varying time points in four experimental groups of rats, either before or subsequent to the acquisition of the CR. NAcc dopamine depletion produced long-term neuroadaptations in dopamine function 2 months after surgery, and profoundly impaired discriminated Pavlovian approach regardless of when the lesion was made. Thus, NAcc dopamine not only plays a role in conditioned behavioural activation, but also in making the appropriate discriminated response i.e. the direction of response. Further, acquisition lesions produced a far greater impact on discriminated approach than performance lesions. This difference in lesion-induced impairment implies that mesoaccumbens dopamine may play differential roles in the learning and performance of preparatory Pavlovian conditioning.

Searching for a Gulf War syndrome using cluster analysis.

BACKGROUND: Gulf veterans report medically unexplained symptoms more frequently than non-Gulf veterans did. We examined whether Gulf and non-Gulf veterans could be distinguished by their patterns of symptom reporting. METHOD: A k-means cluster analysis was applied to 500 randomly sampled veterans from each of three United Kingdom military cohorts of veterans; those deployed to the Gulf conflict between 1990 and 1991; to the Bosnia peacekeeping mission between 1992 and 1997; and military personnel who were in active service but not deployed to the Gulf (Era). Sociodemographic, health variables and scores for ten symptom groups were calculated. RESULTS: The gap statistic indicated the five-group solution as one that provided a particularly informative description of the structure in the data. Cluster 1 consisted of low scores for all symptom groups. Cluster 2 had veterans with highest symptom scores for musculoskeletal symptoms and high scores for psychiatric symptoms. Cluster 3 had high scores for psychiatric symptoms and marginally elevated scores for the remaining nine groups symptom groups. Cluster 4 had elevated scores for musculoskeletal symptoms only and cluster 5 was distinguishable from the other clusters in having high scores in all symptom groups, especially psychiatric and musculoskeletal. CONCLUSION: The findings do not support the existence of a unique syndrome affecting a subgroup of Gulf veterans but emphasize the excess of non-specific self-reported ill health in this group.