Hugh M. Jones

Optimizing limbic selective D2/D3 receptor occupancy by risperidone: a [123I]-epidepride SPET study.

Selective action at limbic cortical dopamine D2-like receptors is a putative mechanism of atypical antipsychotic efficacy with few extrapyramidal side effects. Although risperidone is an atypical antipsychotic with high affinity for D2 receptors, low-dose risperidone treatment is effective without inducing extrapyramidal symptoms. The objective was to test the hypothesis that treatment with low-dose risperidone results in ‘limbic selective’ D2/D3 receptor blockade in vivo. Dynamic single photon emission tomography (SPET) sequences were obtained over 5 hours after injection of [123I]-epidepride (∼150 MBq), using a high-resolution triple-headed brain scanner (Marconi Prism 3000XP). Kinetic modelling was performed using the simplified reference region model to obtain binding potential values. Estimates of receptor occupancy were made relative to a normal volunteer control group (n = 5). Six patients treated with low-dose risperidone (mean = 2.6 mg) showed moderate levels of D2/D3 occupancy in striatum (49.9%), but higher levels of D2/D3 occupancy in thalamus (70.8%) and temporal cortex (75.2%). Occupancy values in striatum were significantly different from thalamus (F (1,4) = 26.3, p < 0.01) and from temporal cortex (F (1,4) = 53.4, p < 0.01). This is the first study to evaluate striatal and extrastriatal occupancy of risperidone. Low dose treatment with risperidone achieves a similar selectivity of limbic cortical over striatal D2/D3 receptor blockade to that of atypical antipsychotics with lower D2/D3 affinity such as clozapine, olanzapine and quetiapine. This finding is consistent with the relevance of ‘limbic selective’ D2/D3 receptor occupancy to the therapeutic efficacy of atypical antipsychotic drugs.

Typical antipsychotic drugs — D2 receptor occupancy and depressive symptoms in schizophrenia

We tested the hypothesis that the degree of striatal dopamine D(2) receptor blockade induced by typical antipsychotic treatment directly correlates with the presence and severity of depressive symptoms in schizophrenia. Clinical and [(123)I]-IBZM single-photon emission tomography (SPET) scan data obtained from 18 typical antipsychotic treated schizophrenic patients was analysed to evaluate the relationship between striatal D(2) receptor occupancy and the depressive subscale of the Brief Psychiatric Rating Scale (BPRS-D). Striatal D(2) receptor occupancy by typical antipsychotic drugs was significantly positively correlated with BPRS-D scores (r=0.52, p=0.025). This study suggests that high striatal dopamine D(2) blockade by typical antipsychotic drugs may contribute to the emergence of depressive symptoms in typical antipsychotic treated schizophrenic patients.

Cortical effects of quetiapine in first-episode schizophrenia: a preliminary functional magnetic resonance imaging study.

BACKGROUND Quetiapine improves both psychotic symptoms and cognitive function in schizophrenia. The neural basis of these actions is poorly understood. METHODS Three subject groups underwent a single functional magnetic resonance imaging (fMRI) session: drug-naive (n = 7) and quetiapine-treated samples of patients with schizophrenia (n = 8) and a healthy control group (n = 8). The fMRI session included an overt verbal fluency task and a passive auditory stimulation task. RESULTS In the verbal fluency task, there was significantly increased activation in the left inferior frontal cortex in the quetiapine-treated patients and the healthy control sample compared with the drug-naive sample. During auditory stimulation, the healthy control group and stably treated group produced significantly greater activation in the superior temporal gyrus than the drug-naive sample. CONCLUSIONS Quetiapine treatment is associated with altered blood oxygen level-dependent responses in both the prefrontal and temporal cortex that cannot be accounted for by improved task performance subsequent to drug treatment.

Temporal context discrimination in patients with schizophrenia: Associations with auditory hallucinations and negative symptoms

BACKGROUND A deficit in remembering the temporal context of events (a type of source memory) has been observed in schizophrenia, and suggested to be associated with positive symptoms. METHODS In order to investigate memory for temporal context, we administered a list discrimination task to a sample of schizophrenia patients and a sample of healthy controls. Participants were required to learn two lists of mixed high- and low-frequency words separated by 10 min, then to remember whether each word had been presented in the first or in the second list. RESULTS The number of misattributions to the wrong list was significantly higher in patients than in healthy controls. However, the group difference was eliminated when recall efficiency was covaried. The number of list misattributions was higher in patients with auditory hallucinations than in the other patients, independently of verbal recall efficiency. By contrast, affective flattening and anhedonia were associated with fewer list misattributions of the high-frequency words. CONCLUSIONS It is suggested that auditory hallucinations are associated with deficit in processing or remembering the temporal context. Conversely, certain negative symptoms are associated with reduced temporal context errors. The possible neural mechanisms involved in temporal context deficit as well as in these specific clinical symptoms are discussed.

Atypical antipsychotic drugs and tardive dyskinesia: relevance of D2 receptor affinity:

Evidence suggests atypical antipsychotic treatment is associated with a lower incidence of tardive dyskinesia (TD) than typical antipsychotic drugs, and is a potential antidyskinetic treatment. We present the case of a middle-aged woman never previously exposed to antipsychotic treatment who developed TD after 6 months of olanzapine monotherapy. Substitution of quetiapine for olanzapine alleviated her TD symptoms. The case demonstrates that atypical antipsychotic drugs have different effects in relation to TD. Potential psychopharmacological mechanisms explaining these differences are discussed, highlighting the importance of D2 receptor occupancy by atypical antipsychotic drugs for TD.

Clinical effectiveness in first-episode patients

Managing patients with first-episode schizophrenia is a challenging task for psychiatrists. Early diagnosis and effective intervention are vital to achieving long-term positive clinical outcomes among first-episode patients. Although these patients are the most responsive to treatment, they are also more susceptible to adverse events. The efficacy and improved tolerability associated with the newer atypical antipsychotics means that these drugs can be used successfully in the treatment and long-term management of schizophrenia from the onset of illness. However, as well as managing the symptoms of the disease, pharmacological treatments need to meet the broader requirements of clinical effectiveness that encompass all of the outcome domains associated with schizophrenia. This article will discuss available data on atypical antipsychotics in first-episode patients and present the primary results from the F1RST (Southwark first-onset psychosis) study, which examined the use of quetiapine for the first-line management of schizophrenia as part of a specialist episode psychosis service.

Visual memory errors in schizophrenic patients with auditory and visual hallucinations

Hallucinations have been found associated with false detection or false recognition of acoustic/verbal material in several studies. We investigated whether they were also linked with false recognition of pictures. Furthermore, an association between hallucinations and deficits in remembering temporal context was observed in previous research on schizophrenia. We investigated whether the association extends to deficits in remembering spatial context. Forty-one patients with schizophrenia underwent a visual memory task. Sixteen mixed black-and-white and colored pictures were presented at different locations. Participants had to recognize the pictures among distractors, then to recall the spatial context of the presentation of the target pictures. Results showed that auditory hallucinations were associated with poor recognition of the colored pictures. When recognition efficiency and negative symptoms were statistically controlled, auditory hallucinations were also associated with increased response bias toward false recognition of nontarget pictures, and with errors in remembering the spatial context. No associations with visual hallucinations emerged. Anhedonia was associated with response bias, in the direction opposite to that of hallucinations. In conclusion, the association between hallucinations and response bias extends across modalities to picture recognition. The association between hallucinations and temporal context impairment extends to spatial context.

Working memory span and motor and cognitive speed in schizophrenia.

ObjectiveThe aim of this study was to investigate the verbal working memory deficit and decrease of motor and cognitive speed in patients with schizophrenia, and to clarify their associations with negative and depressive symptomatology. MethodsForty patients with schizophrenia and 41 healthy control individuals were administered the backward digit span to assess the working memory capacity, along with 3 tests of processing speed. ResultsPatients demonstrated reduced backward digit span, as well as decreased motor and cognitive speed. Regression analyses indicated that the backward digit span was associated with cognitive speed. It was not associated with either negative or depressive symptoms. Decreased processing speed was unrelated to negative symptoms, but the depression score was significantly associated with the cognitive speed measure. ConclusionsWorking memory and processing speed seem to share a cognitive component. Depression, but not negative symptoms, affects processing speed, especially by decreasing cognitive speed.

New targets for antipsychotics.

Atypical antipsychotic drugs have a favorable side effect profile compared with older neuroleptics. Clozapine exhibits superior clinical efficacy in resistant schizophrenia. The neurochemical profile of these atypical agents suggests two distinct strategies in the development of novel antipsychotic drugs. Better-targeted dopaminergic agents may avoid the side effects associated with profound D2 receptor blockade. Current approaches include D3 receptor antagonists and drugs combining partial agonist activity at dopamine autoreceptors with conventional D2 antagonism. The D1 receptor may be a potential target for improving cognitive function in schizophrenia. Secondly drugs acting at glutamate (NMDA) and serotonin (5-HT2A, 5-HT1A, 5-HT2C, 5-HT3) receptors may offer improved treatment particularly against resistant schizophrenic symptoms, as well as improving the side effect profile of antipsychotic drugs. This research in receptor pharmacology is set in the context of theincreasingly recognised importance of the clinical care for patients with first onset schizophrenia and recent developments in pharmacogenomics.