The differential effects of chlorpromazine and haloperidol on latent inhibition in healthy volunteers.

Latent inhibition (LI) is a measure of reduced learning about a stimulus to which there has been prior exposure without any consequence. It therefore requires a comparison between a pre-exposed (PE) and a non-pre-exposed (NPE) condition. Since, in animals, LI is disrupted by amphetamines and enhanced by antipsychotics, LI disruption has been proposed as a measure of the characteristic attentional deficit in schizophrenia: the inability to ignore irrelevant stimuli. The findings in humans are, however, inconsistent. In particular, a recent investigation suggested that since haloperidol disrupted LI in healthy volunteers, and LI was normal in non-medicated patients with schizophrenia, the previous findings in schizophrenic patients were entirely due to the negative effects of their medication on LI (Williams et al., 1998). We conducted two studies of antipsychotic drug effects on auditory LI using a within-subject, parallel group design in healthy volunteers. In the first of these, single doses of haloperidol (1 mg. i.v.) were compared with paroxetine (20 mg p.o.) and placebo, and in the second, chlorpromazine (100 mg p.o.) was compared with lorazepam (2 mg. p.o.) and placebo. Eye movements, neuropsychological test performance (spatial working memory (SWM), Tower of London and intra/extra dimensional shift, from the CANTAB test battery) and visual analogue rating scales, were also included as other measures of attention and frontal lobe function. Haloperidol was associated with a non-significant reduction in LI scores, and dysphoria/akathisia (Barnes Akathisia Rating Scale) in three-quarters of the subjects. The LI finding may be explained by increased distractibility which was indicated by an increase in antisaccade directional errors in this group. In contrast, LI was significantly increased by chlorpromazine but not by an equally sedative dose of lorazepam (both drugs causing marked decreases in peak saccadic velocity). Paroxetine had no effect on LI, eye movements or CANTAB neuropsychological test performance. Haloperidol was associated with impaired SWM, which correlated with the degree of dysphoria/akathisia, but no other drug effects on CANTAB measures were detected. We conclude that the effect of antipsychotics on LI is both modality and pharmacologically dependent and that further research using a wider range of antipsychotic compounds is necessary to clarify the cognitive effects of these drugs, and to determine whether there are important differences between them.

Effects of amisulpride, risperidone and chlorpromazine on auditory and visual latent inhibition, prepulse inhibition, executive function and eye movements in healthy volunteers.

In view of the evidence that cognitive deficits in schizophrenia are critically important for long-term outcome, it is essential to establish the effects that the various antipsychotic compounds have on cognition, particularly second-generation drugs. This parallel group, placebo-controlled study aimed to compare the effects in healthy volunteers (n = 128) of acute doses of the atypical antipsychotics amisulpride (300 mg) and risperidone (3 mg) to those of chlorpromazine (100 mg) on tests thought relevant to the schizophrenic process: auditory and visual latent inhibition, prepulse inhibition of the acoustic startle response, executive function and eye movements. The drugs tested were not found to affect auditory latent inhibition, prepulse inhibition or executive functioning as measured by the Cambridge Neuropsychological Test Battery and the FAS test of verbal fluency. However, risperidone disrupted and amisulpride showed a trend to disrupt visual latent inhibition. Although amisulpride did not affect eye movements, both risperidone and chlorpromazine decreased peak saccadic velocity and increased antisaccade error rates, which, in the risperidone group, correlated with drug-induced akathisia. It was concluded that single doses of these drugs appear to have little effect on cognition, but may affect eye movement parameters in accordance with the amount of sedation and akathisia they produce. The effect risperidone had on latent inhibition is likely to relate to its serotonergic properties. Furthermore, as the trend for disrupted visual latent inhibition following amisulpride was similar in nature to that which would be expected with amphetamine, it was concluded that its behaviour in this model is consistent with its preferential presynaptic dopamine antagonistic activity in low dose and its efficacy in the negative symptoms of schizophrenia.

Design of potent GlyT1 inhibitors: In vitro and in vivo profiles

Inhibitors of Gly transporter type-1 (GlyT1) for the treatment of schizophrenia have been pursued on the basis of the NMDA receptor (R) hypofunction hypothesis, which stems largely from the observation that NMDAR antagonists induce symptoms that more closely mimic those characteristic of schizophrenia than do other classes of psychotic agents. GlyT1 is responsible for uptake of synaptic Gly, an NMDAR co-agonist amino acid, in neuronal populations throughout the forebrain. GlyT1 inhibition thereby potentiates NMDAR activity by increasing synaptic Gly levels. Correspondingly, a large body of data suggests that GlyT1 inhibitors likely confer more comprehensive symptom alleviation than current antipsychotics. To date, a number of small-molecule GlyT1 inhibitors have been reported by the pharmaceutical industry. Developments in the discovery and characterization of GlyT1 inhibitors are discussed in this review.

Psychotropic medications and the transition into care:a national data linkage study

Objectives
To determine whether excessive and often inappropriate or dangerous psychotropic drug dispensing to older adults is unique to care homes or is a continuation of community treatment.

Design
Population-based data-linkage study using prescription drug information.

Setting
Northern Ireland's national prescribing database and care home information from the national inspectorate.

Participants
Two hundred fifty thousand six hundred seventeen individuals aged 65 and older.

Measurements
Prescription information was extracted for all psychotropic drugs included in the British National Formulary (BNF) categories 4.1.1, 4.1.2, and 4.2.2 (hypnotics, anxiolytics, and antipsychotics) dispensed over the study period. Repeated cross-sectional analysis was used to monitor changes in psychotropic drug dispensing over time.

Results
Psychotropic drug use was higher in care homes than the community; 20.3% of those in care homes were dispensed an antipsychotic in January 2009, compared with 1.1% of those in the community. People who entered care had higher use of psychotropic medications before entry than those who did not enter care, but this increased sharply in the month of admission and continued to rise. Antipsychotic drug dispensing increased from 8.2% before entry to 18.6% after entering care (risk ratio (RR) = 2.26, 95% confidence interval (CI)=1.96–2.59) and hypnotic drug dispensing from 14.8% to 26.3% (RR=1.78, 95% CI=1.61–1.96).

Conclusion
A continuation of high use before entry cannot wholly explain the higher dispensing of psychotropic drugs to individuals in care homes. Although drug dispensing is high in older people in the community, it increases dramatically on entry to care. Routine medicine reviews are necessary in older people and are especially important during transitions of care.

Assessment of factors that influence physician decision making regarding medication use in patients with dementia at the end of life

Objective
This study aimed to evaluate the extent to which patient-related factors and physicians' country of practice (Northern Ireland [NI] and the Republic of Ireland [RoI]) influenced decision making regarding medication use in patients with end-stage dementia.

Methods
The study utilised a factorial survey design comprising four vignettes to evaluate initiating/withholding or continuing/discontinuing specific medications in patients with dementia nearing death. Questionnaires and vignettes were mailed to all hospital physicians in geriatric medicine and to all general practitioners (GPs) in NI (November 2010) and RoI (December 2010), with a second copy provided 3 weeks after the first mailing. Logistic regression models were constructed to examine the impact of patient-related factors and physicians' country of practice on decision making. Significance was set a priori at p ≤ 0.05. Free text responses to open questions were analysed qualitatively using content analysis.

Results
The response rate was 20.6% (N = 662) [21.1% (N = 245) for GPs and 52.1% (N = 38) for hospital physicians in NI, 18.3% (N = 348) for GPs and 36.0% (N = 31) for hospital physicians in RoI]. There was considerable variability in decision making about initiating/withholding antibiotics and continuing/discontinuing the acetylcholinesterase inhibitor and memantine hydrochloride, and less variability in decision making regarding statins and antipsychotics. Patient place of residence and physician's country of practice had the strongest and most consistent effects on decision making although effect sizes were small.

Conclusions
Further research is required into other factors that may impact upon physicians' prescribing decisions for these vulnerable patients and to clarify how the factors examined in this study influence prescribing decisions.

Psychotropic prescribing patterns among adolescents in Northern Ireland presenting with psychotic symptoms during a 5-year period

Objective: To report new prescriptions of psychotropic medications among adolescents presenting with new onset psychotic symptoms during a 5-year period.
Methods: The Northern Ireland Early Onset Psychosis Study is a naturalistic longitudinal observational study of patients with an early onset first psychotic episode. All patients aged <18 years presenting to specialist mental health services across Northern Ireland with new onset psychotic symptoms between 2001 and 2006 were recruited (n = 113). Clinical case notes were analysed retrospectively for details of subsequent treatment with psychotropic medications.
Results: A total of 100 patients (88.5%) were prescribed some form of psychotropic medication. Over three-quarters of patients received an antipsychotic as their first medication. Risperidone (45.8%), olanzapine (24.0%) and chlorpromazine (12.5%) were the most commonly prescribed first-line antipsychotic medications. Of a total of 160 antipsychotic prescriptions,81 (50.6%) were off-label. Prescriptions were most likely to have been deemed off-label owing to medications not being licensed in under-18s (71.6% of off-label prescriptions) but other reasons were medications being used outsidelicensed age ranges (23.5%) and outside licensed indications (4.9%).
Conclusions: This is the first study examining psychotropic prescribing patterns in a complete sample of all children and adolescents presenting with early onset psychotic episodes in a single geographical area. The observation of risperidoneas the most commonly prescribed antipsychotic was in keeping with previous studies in child and adolescent populations. Rates of off-label prescribing were lower than previously observed although our study was the first to investigateoff-label prescribing solely in children and adolescents presenting with psychotic symptoms.