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Lyn S Pilowsky

Publications and source records attributed to Lyn S Pilowsky.

16 recordsLinked to original sources
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

A bolus/infusion paradigm for the novel NMDA receptor SPET tracer [123I]CNS 1261.

We have previously performed quantitative kinetic modeling of [(123)I]CNS 1261, a new SPET ligand for the MK801 intrachannel site of the NMDA receptor. We now report a bolus-infusion protocol, which eliminates the need for arterial blood sampling. Dynamic SPET scanning and venous blood sampling were performed in 7 healthy volunteers. Good agreement was obtained between kinetic and equilibrium analysis. SPET scanning with a bolus-infusion protocol is a valid method to estimate the total volume of distribution for [(123)I]CNS 1261 in clinical populations.

Adult↗
PubMed2004

A prospective study of impairment in glucose control caused by clozapine without changes in insulin resistance.

OBJECTIVE: This prospective study examines the effect of clozapine on glucose control and insulin sensitivity. METHOD: Glucose homeostasis was measured in nine female and 11 male patients with schizophrenia (mean age=30.5 years, SD=7.4) before clozapine treatment and after a mean of 2.5 months (SD=0.95) of clozapine treatment. Oral glucose tolerance and insulin levels were measured. Insulin resistance level was measured by the homeostasis model assessment. RESULTS: Eleven (55%) of the patients developed abnormal glucose control; the mean age of these patients was 30.2 (SD=7.1), and five were women. Patients' insulin resistance at baseline (mean insulin resistance level=3.88, SD=2.93) was unaffected by clozapine. Mean fasting and 2-hour glucose levels significantly increased by 0.55 mmol/liter and 1.4 mmol/liter, respectively. There was no correlation between change in body mass index and change in fasting glucose levels. CONCLUSIONS: Clozapine impairs glucose control within 4 months of treatment, independent of changes in insulin sensitivity and body mass index.

Adult↗
PubMed2003

Radioiodinated SB 207710 as a radioligand in vivo: imaging of brain 5-HT4 receptors with SPET.

Single-photon emission tomography (SPET) and positron emission tomography (PET), when coupled to suitable radioligands, are uniquely powerful for investigating the status of neurotransmitter receptors in vivo. The serotonin subtype-4 (5-HT(4)) receptor has discrete and very similar distributions in rodent and primate brain. This receptor population may play a role in normal cognition and memory and is perhaps perturbed in some neuropsychiatric disorders. SB 207710 [(1-butyl-4-piperidinylmethyl)-8-amino-7-iodo-1,4-benzodioxan-5-carboxylate] is a selective high-affinity antagonist at 5-HT(4) receptors. We explored radioiodinated SB 207710 as a possible radioligand for imaging 5-HT(4) receptors in vivo. Rats were injected intravenously with iodine-125 labelled SB 207710, euthanised at known times and dissected to establish radioactivity content in brain tissues. Radioactivity entered brain but cleared rapidly and to a high extent from blood and plasma. Between 45 and 75 min after injection, the ratios of radioactivity concentration in each of 12 selected brain tissues to that in receptor-poor cerebellum correlated with previous measures of 5-HT(4) receptor density distribution in vitro. The highest ratio was about 3.4 in striatum. SB 207710 was labelled with iodine-123 by an iododestannylation procedure. A cynomolgus monkey was injected intravenously with [(123)I]SB 207710 and examined by SPET. Maximal whole brain uptake of radioactivity was 2.3% of the injected dose at 18 min after radioligand injection. Brain images acquired between 9 and 90 min showed high radioactivity uptake in 5-HT(4) receptor-rich regions, such as striatum, and low uptake in receptor-poor cerebellum. At 169 min the ratio of radioactivity concentration in striatum to that in cerebellum was 4.0. In a second SPET experiment, the cynomolgus monkey was pretreated with a selective 5-HT(4) receptor antagonist, SB 204070, at 20 min before [(123)I]SB 207710 injection. Radioactivity in all brain regions was reduced almost to the level in cerebellum by 176 min after radioligand injection. These findings show that [(123)I]SB 207710 is an effective radioligand for imaging brain 5-HT(4) receptors in vivo.

Animals↗
PubMed2003

Depressive episodes in stable schizophrenia: critical evaluation of the DSM-IV and ICD-10 diagnostic criteria.

Depressive episodes are a common and potentially severe occurrence in schizophrenia but are poorly recognised by psychiatrists. Coherent diagnostic criteria are necessary to improve diagnosis and treatment of these conditions. To evaluate the usefulness of the ICD-10 category of post-schizophrenic depression (PSD) and the DSM-IV category of postpsychotic depressive disorder of schizophrenia (PDDS), 80 clinically stable schizophrenic outpatients were evaluated with two independent measures of depression, a dimensional measure and a categorical measure. One rater applied the DSM-IV criteria for major depressive episodes (MDE), and the other applied the Calgary Depression Scale for Schizophrenia, the Positive and Negative Syndrome Scale, and the Extrapyramidal Symptoms Rating Scale. Thirteen patients (16.3%) met criteria for MDE. All of them met the DSM-IV PDDS research criteria, but only two patients matched the ICD-10 PSD criteria, which require that the episode occurred in the 12 months after the last psychotic episode. There was no significant difference in the incidence of depressive episodes within 12 months after an acute psychotic episode and outside this time period. The data suggest that depressive episodes in schizophrenia are not restricted to the first year following the psychotic episode. Useful criteria for depressive episodes in schizophrenia should avoid a temporal relation with the psychotic episode.

Adult↗
PubMed2003

Kinetic modelling of [123I]CNS 1261--a potential SPET tracer for the NMDA receptor.

N-(1-napthyl)-N'-(3-[(123)I]-iodophenyl)-N-methylguanidine ([(123)I]CNS 1261) is a novel SPET ligand developed for imaging the NMDA receptor intra-channel MK 801/PCP/ketamine site. Data was acquired in 7 healthy volunteers after bolus injection of [(123)I]CNS 1261. Kinetic modeling showed reversible tracer binding. Arterial and venous time-activity curves overlapped after 90 min. The rank order of binding was: Thalamus > striatum > cortical regions > white matter. This distribution concurs with [(11)C]-ketamine and [(18)F]-memantine PET studies. These data provide a methodological basis for further direct in vivo challenge studies.

Adult↗
PubMed2003

Analysis of D2 dopamine receptor occupancy with quantitative SPET using the high-affinity ligand [123I]epidepride: resolving conflicting findings.

Recent studies of limbic cortical dopamine D(2) receptor occupancy by clozapine using high-affinity PET and SPET radioligands have produced conflicting findings. It has been suggested that these divergent findings are due to between-study differences in the method used to estimate D(2) receptor-binding potential. We compared different methods for estimating striatal and temporal cortical D(2) receptor occupancy with high-affinity tracers. In vivo experimental SPET data, obtained with [(123)I]epidepride were analysed with reference tissue kinetic modeling and with the ratio method, applied to data corresponding to short (60 min) and long (240 min) acquisition times. Dopamine D(2) receptor occupancy by the atypical antipsychotic drug risperidone was evaluated. Simulation experiments were also performed, comparing occupancy values obtained for different receptor densities in relation to different data acquisition times. The simulation results revealed that previously published data regarding errors in occupancy estimation by analysis of time activity data acquired for 60 min cannot be extrapolated to studies performed over 240 min. The ratio method provided accurate temporal cortical D(2) receptor occupancy values when applied to data from a late time period, but underestimated the occupancy with earlier data. In striatum, both the late data ratio method and reference tissue kinetic modeling using all data underestimated D(2) receptor occupancy. However, more accurate analyses of striatal D(2) occupancy still showed selective limbic/cortical occupancy by risperidone. Our results substantiate the previous [(123)I]epidepride findings of high temporal cortical occupancy by other atypical antipsychotic drugs and suggest that a potential source of conflicting findings might be short scanning times imposed by [(11)C]FLB 457, leading to underestimation of temporal cortical D(2) receptor occupancy by this method.

Algorithms↗
PubMed2003

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 (approximately 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.

Adult↗
PubMed2003

Changes in regional cerebral blood flow with venlafaxine in the treatment of major depression.

OBJECTIVE: Neuroimaging studies reveal abnormalities of regional cerebral blood flow (rCBF) in major depression. In this study the authors prospectively investigated rCBF and clinical response to venlafaxine, a novel antidepressant. METHOD: A trial of venlafaxine was performed with seven patients referred with ICD-10 major depression. At entry and 6-week follow-up, the Beck Depression Inventory and Hamilton Depression Rating Scale were administered and rCBF was measured by means of single photon emission computed tomography with [(99m)Tc]hexamethylpropyleneamine oxime. Blood flow changes were explored with statistical parametric mapping. RESULTS: The subjects showed significant improvement after treatment. Statistical parametric mapping analysis revealed increased rCBF bilaterally in the thalamus and decreased rCBF in the left occipital lobe, right cerebellum, and temporal cortex bilaterally. CONCLUSIONS: These data confirm limbic cortical rCBF changes associated with effective antidepressant treatment.

Adult↗
PubMed2003

Is regionally selective D2/D3 dopamine occupancy sufficient for atypical antipsychotic effect? an in vivo quantitative [123I]epidepride SPET study of amisulpride-treated patients.

OBJECTIVE: Atypical antipsychotic drug treatment is clinically effective with a low risk of extrapyramidal symptoms. Explanations for the mechanism underlying this beneficial therapeutic profile of atypical over typical antipsychotic agents include 1) simultaneous antagonism of dopamine D(2) and serotonin 5-HT(2A) receptors or 2) selective action at limbic cortical dopamine D(2)-like receptors with modest striatal D(2) receptor occupancy. Amisulpride is an atypical antipsychotic drug with selective affinity for D(2)/D(3) dopamine receptors and provides a useful pharmacological model for examining these hypotheses. The authors' goal was to evaluate whether treatment with amisulpride results in "limbic selective" D(2)/D(3) receptor blockade in vivo. METHOD: Five hours of dynamic single photon emission tomography data were acquired after injection of [(123)I]epidepride (approximately 150 MBq). Kinetic modeling was performed by using the simplified reference region model to obtain binding potential values. Estimates of receptor occupancy were made relative to a healthy volunteer comparison group (N=6). RESULTS: Eight amisulpride-treated patients (mean dose=406 mg/day) showed moderate levels of D(2)/D(3) receptor occupancy in the striatum (56%), and significantly higher levels were seen in the thalamus (78%) and temporal cortex (82%). CONCLUSIONS: Treatment with amisulpride results in a similar pattern of limbic cortical over striatal D(2)/D(3) receptor blockade to that of other atypical antipsychotic drugs. This finding suggests that modest striatal D(2) receptor occupancy and preferential occupancy of limbic cortical dopamine D(2)/D(3) receptors may be sufficient to explain the therapeutic efficacy and low extrapyramidal symptom profile of atypical antipsychotic drugs, without the need for 5-HT(2A) receptor antagonism.

Adult↗
PubMed2003

[Glutamatergic hypothesis of schizophrenia].

Schizophrenia is a devastating psychiatric disorder whose pathophysiology has not been fully clarified yet. Although dopamine dysfunction in schizophrenia is unequivocal, there are many evidences suggesting the involvement of the glutamatergic system. This paper briefly describes some basic knowledge regarding the functioning of the glutamatergic receptors with emphasis on the N-methyl-D-aspartate (NMDA) receptors. Presents evidence for glutamatergic dysfunction in schizophrenia, more specifically NMDA receptor hypofunction. Finaly the paper discusses the interaction between the dopaminergic and the glutamatergic systems; in special how hyperdopaminergic state found in schizophrenia can be associated to glutamatergic dysfunctions.

Humans↗
PubMed2002

D-fenfluramine-evoked serotonergic responses in olanzapine-treated schizophrenic patients.

Antagonist activity at the 5-HT(2) receptor may contribute to the therapeutic efficacy of atypical antipsychotics in schizophrenia. This neuroendocrine study examined the in vivo functional serotonergic (5-HT) activity of the atypical antipsychotic olanzapine. We examined central 5-HT(2) responses by measuring the serum prolactin (PRL) over 5 h in response to 30 mg of D-fenfluramine (DFEN) in two groups of male schizophrenic patients. Blunted PRL responses to DFEN indicate functional 5-HT(2) receptor antagonism. Seven patients treated with olanzapine at a mean (S.D.) dose of 13.1 (4.6) for a mean of 28 weeks were compared with a matched group of eight patients who had received no antipsychotic treatment for at least 2 weeks. Baseline PRL levels did not differ significantly in the two patient groups and were within the normal range. The olanzapine-treated patients showed a significantly lower maximal DFEN-evoked PRL response and a significantly lower group x time overall PRL release compared with the untreated patient group. We have previously demonstrated a similar degree of functional in vivo 5-HT(2) antagonism with the atypical antipsychotic clozapine. This study thus suggests that this activity may not contribute to the unique clinical efficacy of clozapine.

Adult↗
PubMed2002

Typical antipsychotic drugs -- D(2) 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.

Adult↗