摘要:

The σ receptor was originally proposed to be a subtype of the opioid receptor. However, it is now clear that σ receptors are unique non-opioid, non-phencyclidine brain proteins. Two types of σ receptor exist, the σ-1 receptor and the σ-2 receptor. σ-1 receptors have been cloned and their distribution, physiological functions and roles in signal transduction were recently characterised. Certain sex hormones in the brain (neurosteroids) are known to interact with σ-1 receptors. σ-1 receptors regulate glutamate NMDA receptor function and the release of neurotransmitters such as dopamine. They are thus proposed to be involved in learning and memory as well as in certain neuropsychiatric disorders.Selective σ-1 receptor ligands have been suggested to represent a new class of therapeutic agents for neuropsychiatric disorders, although none have yet been introduced into therapeutic use. Early studies showed that psychotomimetic benzomorphans, as well as several antipsychotics, can bind to σ-1 receptors. As a result of these findings, σ-1 receptor ligands have been proposed as being of potential use in the treatment of schizophrenia. Nevertheless, the relationship of σ-1 receptors to the underlying pathogenesis of schizophrenia is still unclear. σ-1 receptor ligands have failed to improve acute psychotic symptoms of schizophrenia in clinical trials, but, interestingly, a few studies have shown an improvement in negative symptoms in schizophrenic patients.A number of preclinical studies have shown that selective agonists of σ-1 receptors affect higher-ordered brain functions such as learning and memory, cognition and mood. These studies indicate that σ-1 receptor agonists may exert therapeutic effects in depression and senile dementia. Indeed, the σ-1 receptor agonist igmesine, has been shown to improve depression in a clinical trial. The most distinctive feature of the action of σ-1 receptor ligands is their ‘modulatory’ role. In behavioural studies of depression and memory, they exert beneficial effects only when brain functions are perturbed.Given the recently accumulated preclinical and clinical data, it is time to reconstruct the concept of σ-1 receptors and the associated pathophysiological conditions that ligands of these receptors target. This would allow clinical trials to be performed more efficiently, and the results may confirm a long-speculated possibility that σ-1 receptor ligands represent a new class of therapeutic agents for neuropsychiatric disorders.

ISSN:1172-7047    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

The management of insomnia in patients experiencing chronic pain requires careful evaluation, good diagnostic skills, familiarity with cognitive-behavioural interventions and a sound knowledge of pharmacological treatments. Sleep disorders are characterised by a circular interrelationship with chronic pain such that pain leads to sleep disorders and sleep disorders increase the perception of pain. Sleep disorders in individuals with chronic pain remain under-reported, under-diagnosed and under-treated, which may lead – together with the individual’s emotional, cognitive and behavioural maladaptive responses – to the frequent development of chronic sleep disorders. The moderately positive relationship between pain severity and sleep complaints, and the specificity of pain-related arousal and mediating variables such as depression, illustrate that insomnia in relation to chronic pain is multifaceted and poorly understood. This may explain the limited success of the available treatments.This article discusses the evaluation of patients with chronic pain and insomnia and the available pharmacological and nonpharmacological interventions to manage the sleep disorder. Non-pharmacological interventions should not be considered as single interventions, but in association with one another. Some non-pharmacological interventions especially the cognitive and behavioural approaches, can be easily implemented in general practice (e.g. stimulus control, sleep restriction, imagery training and progressive muscle relaxation). Hypnotics are routinely prescribed in the medically ill, regardless of their adverse effects; however, their long-term efficacy is not supported by robust evidence. Antidepressants provide an interesting alternative to hypnotics, since they can improve pain perception as well as sleep disorders in selected patients. Sedative antipsychotics can be considered for sleep disturbances in those patients exhibiting psychotic features, or for those with contraindications to benzodiazepines. Low doses of sedative antipsychotics may improve chronic insomnia in the elderly. However, no intervention is likely to be effective unless a good physician-patient relationship is developed.

ISSN:1172-7047    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

The risk of ‘hangover’ effects, e.g. residual daytime sleepiness and impairment of psychomotor and cognitive functioning the day after bedtime administration, is one of the main problems associated with the use of hypnotics. However, the severity and duration of these effects varies considerably between hypnotics and is strongly dependent on the dose administered.This article reviews epidemiological evidence on the effect of hypnotics on patients’ risk for accidents such as traffic accidents, falls and hip fractures (i.e. end-points for residual effects). Information on the duration and severity of residual effects of 11 hypnotics (flunitrazepam, flurazepam, loprazolam, lormetazepam, midazolam, nitrazepam, temazepam, triazolam, zaleplon, zolpidem and zopiclone) was derived from expert ratings, a meta-analysis and actual driving studies. Epidemiological studies show that the risks of an accident increase with increasing half-life of the hypnotic, but that the use of hypnotics with a short half-life, such as triazolam, zopiclone and zolpidem, can also be associated with increased risks. A summary of results from experimental studies should enable prescribing clinicians to compare residual effects of the various hypnotics at different doses and select the one considered most favourable in this respect for the individual patient. This information should also enable them to inform patients more adequately about the likelihood and duration of residual effects of a specific hypnotic dose.

ISSN:1172-7047    

出版商:ADIS    

年代:2004

数据来源: ADIS

摘要:

ObjectiveCitalopram, a highly potent SSRI, is effective in the treatment of depressive disorders and obsessive-compulsive disorder (OCD); however, very few studies have reported concentration-effect relationships for SSRIs. The aim of this study was to investigate the relationship between citalopram concentrations and clinical response in patients with OCD.Methods and study designFifteen patients (aged 18−65 years) with a DSM-IV diagnosis of OCD were included in this open-label, single-blind study. Citalopram was started at a dosage of 20 mg/day; the dosage was increased to a maximum of 60 mg/day by the third week, on the basis of clinical need and tolerability. The dosage then remained unchanged until the end of the 10-week study. Clinical assessments were made at baseline, weekly for the first four weeks and then at weeks 6, 8 and 10. The assessment scales used were the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), the Clinical Global Impression Scale (CGI) and the Hamilton Depression Rating Scale (HDRS). Plasma citalopram concentrations were determined using a high performance liquid chromatography method after solid phase extraction.ResultsOne patient was withdrawn from the study because of poor compliance. Of the 14 patients who completed the study, nine did not meet the treatment response criterion of an improvement of >25% from the baseline total Y-BOCS score and a score of ≤3 for the global improvement item of the CGI (these patients were termed non-responders), while five did (responders). There were no differences in the main demographic and baseline clinical variables between responders and non-responders. Steady-state citalopram concentrations were similar in the two groups, suggesting that the anti-obsessional effects of citalopram were not related to pharmacokinetic differences between responders and non-responders. There was no linear relationship between steady-state citalopram concentrations and response. The citalopram concentrations and Y-BOCS scores of individual responders obtained at baseline and various study timepoints showed a sigmoid relationship when analysed using the Emax(maximum change in Y-BOCS score) model, with a mean EC50value (drug concentration that elicits 50% of the Emax) of 152 μg/L, whereas a similar analysis of the non-responders generated a flat line.ConclusionThe results of this preliminary study suggest that plasma citalopram concentrations may be related to the clinical response in responders, but do not seem to account for the lack of clinical effect in non-responders. These data, as well as the usefulness of the model in relating plasma concentrations to response, even after repeated administration, need to be validated by further investigations.

ISSN:1172-7047    

出版商:ADIS    

年代:2004

数据来源: ADIS