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Biomedical subjects

Lyn S Pilowsky

Publications and source records attributed to Lyn S Pilowsky.

At least 19 recordsLinked to original sources
PubMed2007

Role of processing speed and depressed mood on encoding, storage, and retrieval memory functions in patients diagnosed with schizophrenia.

The role of various types of slowing of processing speed, as well as the role of depressed mood, on each stage of verbal memory functioning in patients diagnosed with schizophrenia was investigated. Mixed lists of high- and low-frequency words were presented, and immediate and delayed free recall and recognition were required. Two levels of encoding were studied by contrasting the relatively automatic encoding of the high-frequency words and the more effortful encoding of the low-frequency words. Storage was studied by contrasting immediate and delayed recall. Retrieval was studied by contrasting free recall and recognition. Three tests of motor and cognitive processing speed were administered as well. Regression analyses involving the three processing speed measures revealed that cognitive speed was the only predictor of the recall and recognition of the low-frequency words. Furthermore, slowing in cognitive speed accounted for the deficit in recall and recognition of the low-frequency words relative to a healthy control group. Depressed mood was significantly associated with recognition of the low-frequency words. Neither processing speed nor depressed mood was associated with storage efficiency. It is concluded that both cognitive speed slowing and depressed mood impact on effortful encoding processes.

Brain↗
PubMed2007

Schizophrenia: more evidence for less glutamate.

Evaluation of: Hahn CJ, Hoau-Yan W, Dan-Sung C et al. Altered neuregulin 1-erbB4 signaling contributes to NMDA receptor hypofunction in schizophrenia. Nat. Med. 12, 824-828 (2006). Schizophrenia may be associated with deficits in glutamate transmission at the N-methyl-D-aspartate (NMDA) receptor complex. Recent work has shown that neuregulin 1 (NRG1) acts via ErbB4 receptors to inhibit NMDA receptor currents. This is important given that NRG1 is a convincing susceptibility gene in schizophrenia. Hahn and colleagues add to our knowledge of NRG1 modulation of NMDA receptors and show intriguing differences between control and schizophrenic brains. NMDA receptors in the schizophrenic prefrontal cortex showed smaller responses to exogenously applied NMDA/glycine. Furthermore, NMDA receptors in tissue from schizophrenic patients appeared to be more sensitive to the inhibitory effects of a fixed dose of NRG1. In agreement, the ErbB4-PSD-95-NMDA complex was more tightly coupled in schizophrenic brains and NRG1-mediated stimulation of ErbB4 was markedly enhanced. These findings underscore the importance of NMDA receptors in schizophrenia and support therapeutic strategies aimed at boosting glutamate transmission.

Animals↗
PubMed2006

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.

Adult↗
PubMed2006

Towards NR2B receptor selective imaging agents for PET-synthesis and evaluation of N-[11C]-(2-methoxy)benzyl (E)-styrene-, 2-naphthyl- and 4-trifluoromethoxyphenylamidine.

Three potent and selective 11C-labelled NR2B antagonists have been synthesized and evaluated as PET ligands. The brain uptake of the compounds in mice varied substantially and was dominated by metabolism. One compound was found to have favourable uptake and retention in the brain, as well as a binding pattern consistent with the expression of the target receptor as measured by in vitro autoradiography. However, the metabolism of the compounds tested was too rapid to allow for in vivo imaging.

Amidines↗
PubMed2006

Closing in on the AMPA receptor: synthesis and evaluation of 2-acetyl-1-(4'-chlorophenyl)-6-methoxy-7-[11C]methoxy-1,2,3,4-tetrahydroisoquinoline as a potential PET tracer.

2-Acetyl-1-(4'-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline, one of the most potent non-competitive AMPA antagonists described to date, has been labelled with carbon-11 and tritium and evaluated as a potential ligand for in vivo imaging of AMPA receptors using PET. The carbon-11 labelled compound showed good initial brain uptake in rats, but with rapid clearance and relatively homogenous distribution. In saturation binding studies, the tritiated racemic ligand was found to be highly potent with a Kd of 14.8+/-1.8 nM. We conclude that the low receptor density labelled with this compound, its rapid clearance from the CNS and low specific binding makes it unsuitable as an in vivo PET imaging agent for AMPA receptors.

Animals↗
PubMed2006

[123I]TPCNE--a novel SPET tracer for the sigma-1 receptor: first human studies and in vivo haloperidol challenge.

[123I]TPCNE (1(trans-[123I]iodopropen-2-yl)-4-[(4-cyanophenoxy)methyl] piperidine; Ki = 0.67 nM; log P = 3.36) is a novel sigma-1 receptor SPET ligand. In this study, we developed an optimized labeling method for [123I]TPCNE and investigated the kinetics, binding characteristics, and whole-body distribution of this tracer for the first time in humans. We also performed a challenge with the sigma-1 receptor antagonist haloperidol against [123I]TPCNE. Seven healthy volunteers were recruited. Dynamic brain SPET scans were performed following i.v. administration of 185 MBq [123I]TPCNE in all seven subjects. Three of the subjects were given oral haloperidol (2.5 mg) approximately 1 h before the scan. The dynamic data were analyzed with both reversible and irreversible compartmental models.[123I]TPCNE showed high uptake in brain and liver. All non-haloperidol-treated subjects showed a high whole-brain uptake (average: 8.7% of injected activity). No significant clearance of the tracer was seen up to 30 h post injection. In the haloperidol-treated subjects, the time-activity curves clearly demonstrated clearance of the tracer from the brain. Regional radioactivity concentrations were reduced by haloperidol from 42% in the cerebellum to 73% in the thalamus.[(123)I]TPCNE demonstrated high brain uptake, with highest binding found in the posterior cingulate. A region in which binding was unaffected by haloperidol pretreatment could not be identified, and the time-activity data were best described by an irreversible model.

Adult↗
PubMed2006

Ketamine displaces the novel NMDA receptor SPET probe [(123)I]CNS-1261 in humans in vivo.

[(123)I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intra-channel PCP/ketamine/MK-801 site of the N-methyl-d-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intra-channel PCP/ketamine/MK-801 site) on [(123)I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [(123)I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [(123)I]CNS-1261 V(T) in most of the brain regions examined (P<.05). [(123)I]CNS-1261 appears to be a specific ligand in vivo for the intra-channel PCP/ketamine/MK-801 NMDA binding site.

Adult↗
PubMed2006

Processing speed: a strong predictor of verbal memory performance in schizophrenia.

The role of slowing of processing speed in verbal memory impairment in patients with schizophrenia was investigated. Forty-one patients with schizophrenia and 41 healthy control subjects were administered a verbal memory task involving free recall of three lists of words, which varied in their degree of semantic organization. Standard processing speed tests were administered as well. Regression analyses were conducted on the number of words recalled in each list. A global processing speed measure was a significant predictor of the recall of each list in patients. Patients were very significantly impaired in the recall of the three lists relative to healthy controls. However, when the processing speed measure was entered in the regression, the significance of diagnosis was considerably reduced for one of the lists, with no semantic organization, and eliminated for the other two lists which contained semantic organization. These findings suggest that slowing in processing speed is an important contributor to verbal memory impairment in patients with schizophrenia. The possible role of various specific slowing functions is discussed.

Adult↗
PubMed2006

The relationship between prolactin levels and glucose homeostasis in antipsychotic-treated schizophrenic patients.

OBJECTIVES: To determine if prolactin levels are associated with glucose-insulin homeostasis in antipsychotic-treated patients with schizophrenia. METHOD: Prolactin levels and glucose homeostasis (quantified using oral glucose tolerance testing, insulin measurement, and homeostasis model assessment) were measured in 15 patients with elevated prolactin levels secondary to antipsychotic treatment of schizophrenia (mean age, 30.4 years; SD, 5.3 years). The effect of reducing prolactin levels by switching patients' antipsychotic treatment to clozapine was ascertained by performing the measures before and after the switch to clozapine. RESULTS: There was no significant correlation between prolactin and glucose-insulin measures at baseline. There was a large reduction in prolactin (593 mIU/L) after switching to clozapine, but this was not associated with changes in glucose-insulin measures. CONCLUSIONS: Prolactin is not a significant determinant of glucose-insulin homeostasis in patients taking antipsychotics for schizophrenia. There was no benefit from lowering prolactin levels using clozapine. This could be because prolactin does not have a major effect on glucose homeostasis or that the effects of prolactin reduction are countered by clozapine.

Adult↗
PubMed2006

Antipsychotic drug action: targets for drug discovery with neurochemical imaging.

Schizophrenia is a serious lifelong mental illness for which current treatments may only be partially effective. All antipsychotic medications available at present are thought to exert their main antipsychotic effect through antagonism of dopamine D2 receptors. Clozapine is the most effective antipsychotic drug currently available, but it can cause serious side effects, including agranulocytosis and diabetes. Pharmacologic factors that distinguish clozapine from other antipsychotic drugs have been studied to try to develop safer drugs with similar efficacy to clozapine. These have met with limited success. Neurochemical imaging techniques, such as positron emission tomography, single photon emission tomography and magnetic resonance spectroscopy, have been used to study antipsychotic drug action in living human subjects. These techniques shed a great deal of light on the mechanisms of antipsychotic action and have revealed a number of novel targets for future drug development in schizophrenia. Next-generation antipsychotic medications will aim to improve on the efficacy and tolerability of currently available medications. The authors believe that they are likely to achieve this through drug action at non-D2 sites. Future research and drug development, including the development of medications to prevent progression from the prepsychotic stage to schizophrenia, will rely heavily on neurochemical imaging methods at all stages in the drug-discovery pipeline.

Animals↗
PubMed2005

Non-uniform blockade of intrastriatal D2/D3 receptors by risperidone and amisulpride.

RATIONALE: Atypical antipsychotic drugs have been shown to preferentially affect extrastriatal (mesolimbic) D2/D3 receptors over those within the striatum (nigrostriatal). The striatum does not contain exclusively nigrostriatal dopamine tracts, however. The caudate nucleus and ventral parts of the striatum primarily contain limbic and associative dopamine pathways more relevant to psychosis. OBJECTIVES: We tested the hypothesis that two pharmacologically distinct atypical antipsychotic drugs, amisulpride and risperidone, would preferentially occupy of D2/D3 dopamine receptors in limbic and associative regions of the striatum. METHODS: Eight amisulpride-treated patients, six risperidone-treated patients and six age- and sex-matched healthy controls were recruited. Dynamic SPET studies were performed after bolus injection of [123I]epidepride. Binding potential (BP) images were generated using a modified Logan method and aligned between subjects. Regions of interest (ROIs) were placed around head of caudate and putamen bilaterally on an average BP map derived from aligned control images. These ROIs were then applied user-independently to the BP maps for each subject to calculate BP for head of caudate and putamen. Mean occupancy of D2/D3 receptors in each ROI was determined by reference to the drug-free healthy volunteer group. Occupancy values for head of caudate and putamen were compared using paired Student's t test. RESULTS: D2/D3 receptor occupancy was 42% in caudate and 31% in putamen for risperidone (t=5.9, df=11, p=0.0001) and 51% in caudate and 37% in putamen for amisulpride (t=11.1, df=15, p<0.0001). CONCLUSIONS: Amisulpride and risperidone both show selective occupancy for limbic and associative D2/D3 receptors within the striatum.

Adult↗
PubMed2005

Impact of schizophrenia and chronic antipsychotic treatment on [123I]CNS-1261 binding to N-methyl-D-aspartate receptors in vivo.

BACKGROUND: Antipsychotic drugs modulate N-methyl-D-aspartate (NMDA) receptor function in animals. The novel single photon emission tomography (SPET) radiotracer [123I]CNS-1261 binds to the PCP/MK-801 intrachannel site of the NMDA receptor, allowing the noninvasive estimation of NMDA receptor activity in living humans. We used [123I]CNS-1261 to determine whether binding to the NMDA receptor intrachannel PCP/MK-801 site is affected by schizophrenia or by treatment with typical antipsychotics and clozapine in vivo. METHODS: Three groups of schizophrenia patients were recruited-drug free (n = 5), typical antipsychotic treated (n = 7), and clozapine treated (n = 9)-as well as a control group of healthy normal volunteers (n = 13). All underwent [123I]CNS-1261 SPET scanning. Total volume of distribution of [123I]CNS-1261 was determined within predefined user-independent regions of interest after alignment of all images to a common template. RESULTS: There was no apparent difference in total volume of distribution of [123I]CNS-1261 in drug-free patients relative to healthy control subjects. A nonsignificant reduction in total volume of distribution was observed in typical antipsychotic treated patients. A significant decline in total volume of distribution of [123I]CNS-1261 was observed in all examined brain regions in the clozapine-treated patient group relative to healthy control subjects (p < .005). CONCLUSIONS: Clozapine treatment resulted in a global reduction in [123I]CNS-1261 binding to the NMDA receptor intrachannel PCP/MK-801 site in vivo. This supports an effect of the drug on glutamatergic systems that could be exploited for future antipsychotic drug discovery.

Adult↗
PubMed2005

Word frequency effects on free recall and recognition in patients with schizophrenia.

BACKGROUND: Word frequency paradigms have been used repeatedly in healthy populations to help understand the functioning of verbal memory. We investigated the word frequency effects in a sample of patients with schizophrenia, assuming these data may shed light on certain encoding processes. METHODS: Two mixed lists of high- and low-frequency words were presented to 46 patients with schizophrenia and 43 healthy control subjects. List learning was followed by free recall and recognition in immediate and delayed conditions. RESULTS: Overall the high-frequency words were better recalled, whereas the low-frequency words were better recognised. The lack of interaction with diagnosis indicates that these effects were equivalent in both groups. In immediate recognition, the discrimination deficit for the high-frequency words in patients tended to be increased relative to that for the low-frequency words, suggesting greater impairment in the encoding of those words. CONCLUSION: It is argued that the encoding of the distinct low-frequency words is less efficient in patients, but qualitatively unimpaired. By contrast, the familiar words might be more difficult for patients to encode, as they are more easily confused with other common words stored in long-term memory.

Adult↗
PubMed2005

Hallucinations, negative symptoms, and response bias in a verbal recognition task in schizophrenia.

Several studies have reported an association between hallucinations and tendency to make false alarms in acoustic signal detection tasks. Previous work on patients with schizophrenia has suggested that false recognitions and other types of memory error were positively associated with hallucinations and inversely associated with certain negative symptoms of withdrawal. In this study, 40 patients with schizophrenia were administered a word recognition task. Mixed lists of high- and low-frequency words were presented, then the target words had to be recognized among distractors in immediate and delayed recognition conditions. Hallucination scores were correlated with an increased bias toward false recognitions of nonpresented words. Affective flattening tended to be correlated with a reduced bias toward false recognitions. Anhedonia was significantly correlated with a reduced response bias. Hallucinations and anhedonia therefore presented an opposite association with the response bias. The influence of word frequency and delay on this association is discussed.

Adult↗
PubMed2004

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.

Acoustic Stimulation↗
PubMed2004

Prolactinemia is uncoupled from central D2/D3 dopamine receptor occupancy in amisulpride treated patients.

RATIONALE: Atypical antipsychotic drugs are classically associated with lower propensity to extrapyramidal symptoms (EPS) and hyperprolactinemia than typical antipsychotic drugs. It has not been clarified why some atypical antipsychotic drugs, such as amisulpride, induce prolactin plasma concentration (PRL) elevation, but little EPS. Previous studies have found an association between striatal D2/D3 receptor occupancy and PRL in typical antipsychotic treated patients suggesting that PRL is a marker of central D2/D3 receptors blockade. OBJECTIVE: We have evaluated the relationship between PRL and central (striatum, temporal cortex and thalamus) D2/D3 receptor occupancy in amisulpride treated schizophrenic patients. METHODS: Single photon emission tomography (SPET) and [123I]-epidepride were used to determine D2/D3 receptor occupancy in eight amisulpride treated patients. PRL was measured concurrently with the scans. RESULTS: The mean PRL was 1166 (range 499-1892 mIU/l) for a mean amisulpride dose of 406 mg/day (range 150-600 mg/day). Amisulpride plasma concentration and central D2/D3 receptor occupancy were positively correlated (r=0.83-0.89, df=4, P<0.05). No significant correlations were observed between PRL and amisulpride (daily dose or plasma concentration, P>0.05), or between PRL and central D2/D3 receptor occupancy (P>0.05). CONCLUSIONS: Our findings show that amisulpride-induced hyperprolactinemia is uncoupled from central D2/D3 receptor occupancy. Amisulpride has poor blood-brain barrier penetration and reaches much higher concentration at the pituitary, which is outside the blood-brain barrier. Higher D2/D3 receptor occupancy at the pituitary gland than at central regions is a possible explanation for amisulpride PRL elevation with low EPS. Further studies evaluating pituitary D2/D3 receptor occupancy in vivo are necessary to confirm this hypothesis.

Adult↗
PubMed2004

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.

Antipsychotic Agents↗