Development of a brief screen for violence risk (V-RISK-10) in acute and general psychiatry: An introduction with emphasis on findings from a naturalistic test of interrater reliability.

Most violence risk assessment scales were originally developed for use in forensic settings at the time of discharge or release of patients into the community after long-term treatment. However, there is a considerable need for specialized, brief and structured risk assessment tools to inform risk decisions in short-term psychiatric treatment. The present study reports on research findings from the development and implementation of the violence risk screening-10 (V-RISK-10) in two acute psychiatric settings in Norway. The 10-item screen is easy to use, time-saving and may be used for screening of violence risk during hospital stay and after discharge into the community. Prospective validation studies of the screen concerning inpatient and post-release community violence have been conducted. Although data analyses are not yet complete, preliminary findings indicate that the screen has good predictive validity. This suggests that the screen is a promising tool in short-term acute psychiatric settings. However, the importance of reliability in mental health data and tests is well recognized, and a screen with good predictive validity is not worth much if clinicians are unable to agree on the scoring of one and the same patient. In this article we report results from a naturalistic interrater reliability investigation that involved 25 mental health professionals and 73 acute psychiatric patients. V-RISK-10 scoring was accomplished by two raters for each patient. The interrater reliability value for total scores was acceptable. Variations pertaining to the individual V-RISK-10 item, patient characteristics and rater characteristics are discussed.

Cholinergic mechanisms in pain and analgesia.

There is now substantial evidence that acetylcholinesterase inhibitors and muscarinic receptor agonists increase the pain threshold after both systemic and spinal administration. In rats, physostigmine gave a significant dose-dependent increase in latency times in the tail immersion test following intrathecal administration. The effect was antagonized with atropine. Neostigmine gave more prolonged latencies as did the muscarinic receptor agonist carbachol. Spinal cholinergic pathways for antinociception interacted with the spinal opioid and adrenergic nerve tracts. No cross-tolerance to the selective alpha 2-adrenoreceptor agonist guanfacine or to morphine was seen in rats tolerant of spinal carbachol antinociception. The mechanism of spinal cholinergic antinociception is not known but a muscarinic interneuron may explain the interactions with other neurotransmitters. Clinically, the centrally active cholinesterase inhibitor physostigmine has been shown to give postoperative pain relief although of short duration. Severe neurogenic pain has been successfully treated with physostigmine or distigmine.

Chemical principles of chelate therapy in neurotoxicology.

The chemical significance of heavy metals in biology arises from their ability to form bonds with metal-binding substances. These bonds are tighter than ordinary ionic bonds and partly of a covalent nature. Metal-binding substances, many of which act by complex formation, play an important role in the regulation of uptake into cells of trace heavy metals. In biology metal-binding substances predominantly act by: Removal of metal ions from cells, i.e. antidotes to mask or remove toxic metal ions that have accidentally been ingested. Imposition of the metal ion into cells in a concentration above normal, e.g. the mechanism of action of many bactericides and fungicides. The fundamental requirements concerning the complex formation capacity of the complexing agent, as well as the toxicity and pharmacokinetics of the complexing agent and complex must be considered before use in medicine as e.g. antidotes. Easily obtained excretion of the complexing agent as well as of the complex is essential to avoid unwanted side effects. The importance of this requirement is demonstrated by alternative treatment regimens in thallotoxicosis.

Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(beta-11C) DOPA and PET.

BACKGROUND: The aim of the present study was to investigate dopamine synthesis in the brain of drug-free schizophrenic patients, not only in the striatum but also in extrastriatal areas like the prefrontal cortex, brain areas that for a long time has been in focus of interest in the pathophysiology of schizophrenia. METHODS: PET was performed in 12 drug-free (10 drug-naive) psychotic schizophrenic patients and 10 healthy volunteers matched for age and gender using 11C-labelled L-DOPA as the tracer. The time-radioactivity curve from occipital cortex (located within Brodman area 17 and 18) was used as input function to calculate L-DOPA influx rate, Ki images, that were matched to a common brain atlas. A significant overall increase of the Ki values was found in the schizophrenic group as compared with healthy controls. RESULTS: In particular, significantly higher Ki were found in the schizophrenic patients compared to the controls in the caudate nucleus, putamen and in parts of medial prefrontal cortex (Brod 24). The Ki value reflect an increased utilization of L-DOPA, presumably due to increased activity of the amino acid decarboxylate enzyme. CONCLUSIONS: The results indicate that the synthesis of dopamine is elevated within the striatum and parts of medial prefrontal cortex in schizophrenia.

A comparison of 11C-labeled L-DOPA and L-fluorodopa as positron emission tomography tracers for the presynaptic dopaminergic system.

11C-labeled 3,4-Dihydroxy-phenyl-L-alanine (L-DOPA) and L-fluorodopa were used as tracers for the functional state of the presynaptic dopamine system in anesthetized monkeys with positron emission tomography. The radiotracer disposition in brain tissue and plasma were studied and effects induced by pharmacologic challenges were evaluated. 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) increased the striatal influx rate constant, e.g., striatal K(i) for L-[beta-11C]DOPA, but it induced no effect on the K(i)-value using L-[beta-11C]-6-fluorodopa. Studies of radiolabeled tracer and metabolites in plasma showed substantial differences between the two tracers. At baseline conditions, 60% unchanged L-[beta-11C]DOPA was detected in plasma 50 minutes after tracer injection and the 3-O-methylated fraction accounted for 25% of total radioactivity. For L-[beta-11C]-6-fluorodopa, the relation was inverse; about 25% unchanged tracer and 60% 3-O-methyl metabolite were present in plasma after 50 minutes. A site-specific 11C-labeling in the carboxylic position in the molecules revealed a significant specific retention of radioactivity in striatum with L-[car-boxy-11C]-6-fluorodopa but not with L-[carboxy-11C]DOPA. The 3-O-methyl metabolite of L-DOPA is known to pass the blood-brain barrier and may interfere with the calculation of the K(i)value using a brain reference region. Thus, extensive 3-O-methylation in circulation of the fluorinated analog could obscure the detectability of potential functional change in striatal K(i) of the tracer when using a reference tissue model for calculation.

Tacrine restores cholinergic nicotinic receptors and glucose metabolism in Alzheimer patients as visualized by positron emission tomography.

Three patients with Alzheimer's disease, a 68-year-old woman with mild dementia and 2 men (aged 64 and 72 years) with moderate dementia were treated orally with the cholinesterase inhibitor tacrine (tetrahydroaminoacridine), 80 mg daily, for several months. The patients were investigated using positron emission tomography (PET) prior to, and after 3 weeks and 3 months of treatment. The PET studies involved a multi-tracer system consisting of [18F]-fluoro-deoxy-glucose (18F-FDG) (tracer for glucose metabolism); 11C-butanol (cerebral blood flow) and (S)(-)- and (R)(+)-[N-11C-methyl]-nicotine (nicotinic receptors; cholinergic neural activity). Tacrine treatment increased the uptake of 11C-nicotine to the brain. Significant reduced difference in uptake between the two enantiomers (S)(-)- and (R)(+)11C-nicotine was observed in the frontal and temporal cortices after tacrine treatment in all three patients. The kinetic analysis indicated increased binding of (S)(-)11C-nicotine in brain compatible with a restoration of nicotinic cholinergic receptors. The most pronounced effect was observed after 3 weeks and 3 months treatment in the patient with mild dementia. An increase in cerebral glucose utilization was found in the 68-year-old patient with mild dementia but also slightly in the 64-year-old man with moderate dementia when treated with tacrine for 3 months. Tacrine administration did not affect cerebral blood flow. The PET data obtained after 3 weeks of tacrine treatment was paralleled by improvement in neuropsychological performance. This study shows in vivo by PET neurochemical effects induced in brain by treatment with tacrine to Alzheimer patients. Intervention with tacrine in the early course of the disease might be necessary for clinical improvement.

Relation of sedation and amnesia to plasma concentrations of midazolam in surgical patients.

The kinetics and dynamics of midazolam were investigated in 20 female patients undergoing lower abdominal surgery. The relation between the plasma concentrations of midazolam and pharmacokinetic end points was evaluated after an intravenous infusion regimen in 10 patients given an epidural anesthetic. The remaining 10 patients were anesthetized with a totally intravenous anesthetic technique with midazolam and alfentanil. The effect was assessed by means of a rating scale divided into degree of sedation and amnesia. A good correlation was found between plasma level of midazolam and pharmacodynamic response. The relation between the quantal response data and the plasma concentration was represented by an s-shaped concentration-effect curve. Despite similar kinetics of midazolam in the two groups, the postoperative drowsiness was more pronounced in the group receiving total intravenous anesthesia. The concomitant administration of alfentanil shifted the concentration-effect curve regarding sedation to the left.

Central nervous system effects of subdissociative doses of (S)-ketamine are related to plasma and brain concentrations measured with positron emission tomography in healthy volunteers.

Plasma concentrations, maximum regional brain concentrations, and specific regional binding in the brain after administration of 0, 0.1, and 0.2 mg/kg doses of (S)-ketamine were measured in a randomized, double-blind, crossover study in five volunteers and were related to induced effects such as analgesia, amnesia, and mood changes. Specific binding in the brain was assessed by simultaneous administration of (S)-[N-methyl-11C]ketamine quantified by positron emission tomography. High radioactivities in the brain corresponded to regional distribution of N-methyl-D-aspartate receptor complexes. A significant and dose-dependent reduction of binding was measured as a result of displacement of (S)-[N-methyl-11C]ketamine. Memory impairment and psychotomimetic effects were related to dose, plasma concentration 4 minutes after administration, and decreased regional binding of (S)-ketamine in the brain and were consistently seen at plasma and maximum regional brain (S)-ketamine concentrations higher than 70 and 500 ng/ml, respectively. The magnitude of specific binding of (S)-ketamine, measured with positron emission tomography, can be related directly to drug effects.

Levodopa-induced changes in synaptic dopamine in patients with Parkinson's disease as measured by [11C]raclopride displacement and PET.

Changes in striatal binding of [11C]raclopride, a dopamine D2 receptor antagonist, induced by acute levodopa administration, were evaluated with PET in 10 patients with idiopathic Parkinson's disease (PD). The patients were scanned on two occasions: drug-free and 15 minutes after a 5-minute intravenous infusion of 3 mg/kg levodopa. Levodopa administration produced reductions in striatal [11C]raclopride uptake index with a rostrocaudal gradient. The most pronounced reduction was found in the posterior putamen (to 82% of baseline), followed by the anterior putamen (to 88% of baseline) and the caudate nucleus (to 94% of baseline). The magnitude of [11C]raclopride uptake index reduction correlated with drug-free disability. Moreover, in four hemiparkinsonian patients, a reduction in [11C]raclopride uptake index was measured in the putamen contralateral to the parkinsonian symptoms. The present results demonstrate a positive correlation between striatal dopaminergic nerve-terminal deficiency and the capacity for levodopa to increase synaptic dopamine and displace [11C]raclopride binding, which corresponds to an accelerated amine turnover in dopamine-depleted striatal tissue. We therefore suggest that dopaminergic degeneration in PD is paralleled by a progressive acceleration of amine turnover. This mechanistic consequence of nigrostriatal degeneration, the selective restoration of synaptic dopaminergic neurotransmission in denervated striatal subregions, may explain the effectiveness of levodopa in producing symptomatic benefits in early PD. However, we also suggest that in the vastly denervated striatum, as in advanced PD, an excessive acceleration of amine turnover results in swings in levodopa-induced synaptic dopamine levels that are far beyond normal. This phenomenon most likely plays a key role in the pathogenesis underlying the development of motor-response complications in PD.

Positron emission tomography and brain monoamine neurotransmission -- entries for study of drug interactions.

Monoamine neurotransmission is a complicated process with interactions between individual neurotransmitter pathways, multiple receptors with different responses and a variety of feedback loops regulating neurotransmitter synthesis, release, reuptake and effect on receptors. The system is further affected by a range of enzymes with co-factors controlling synthesis and degradation of monoamines. Positron emission tomography (PET) has evolved to a very versatile tool for the in vivo imaging and characterisation of physiology and biochemistry. The basis for its expansion during the last years has been a rapid development of labelling methods, allowing a range of tracer molecules to be generated and used in human and research animal studies. The most important PET radionuclide is (11)C with a short half-life of approximately 20 minutes. This radionuclide is ideal for the labelling of organic molecules and for multi-tracer applications in research and drug development studies. PET has been used for a range of explorative studies on the monoamine neurotransmission, as exemplified by studies on the expression of dopamine and serotonin receptors as well as the rate of dopamine and serotonin synthesis. The present article gives examples of studies where PET has been used for the characterization of monoamine transmitter systems in experimental animals and in humans, both in healthy individuals and in patients with diseases affecting neurotransmission.

Effect of apomorphine infusion on dopamine synthesis rate relates to dopaminergic tone.

The effects of apomorphine on the striatal L-[11C]DOPA influx rate was examined in anaesthetized Rhesus monkeys using positron emission tomography (PET). In comparison with baseline conditions, the addition of a continuous infusion of apomorphine produced decreases in the striatal L-[11C]DOPA influx rate in all the monkeys examined. The effect of apomorphine infusion also showed a dose-dependent trend. In individual monkeys, the magnitude of the effect showed a baseline dopaminergic tone-dependency; that is, the effect of apomorphine was most pronounced in monkeys with high baseline influx rates, and in monkeys with lower baseline values apomorphine induced a weaker effect. Studies of radiolabeled tracer and radiolabeled metabolites formed in plasma confirmed that apomorphine infusion did not induce any change in the peripheral elimination or metabolite formation of L-[11C]DOPA. The decreased striatal L-[11C]DOPA influx rate induced by apomorphine was interpreted as an agonist effect on dopamine autoreceptors regulating the dopamine synthesis rate. The observation of a baseline dopaminergic tone-dependent effect is in agreement with earlier results showing this influence on the striatal influx rate as measured with the tracer L-[11C]DOPA. A priori, it can be established that L-[11C]DOPA and PET provide a method not only to study the structural integrity of the presynaptic dopaminergic system but also to study the homeostasis-regulating mechanisms of this neurotransmitter system in vivo. The ability to measure condition-dependent effects in individuals should be of great importance in determining specific pathophysiological mechanisms underlying degenerative and functional disorders affecting the dopaminergic system.

Effects of the substituted (S)-3-phenylpiperidine (-)-OSU6162 on PET measurements of [11C]SCH23390 and [11C]raclopride binding in primate brains.

The substituted (S)-3-phenylpiperidine (-)-OSU6162 belongs to a novel class of functional modulators of dopaminergic systems. In vivo, (-)-OSU6162 has a unique stabilising profile on dopaminergic functions. In vitro this compound exhibits low affinity for the dopamine D2 receptor, but due to its similarity to neuroleptics on brain dopaminergic neurochemistry and different postsynaptic effects it has been characterised as a preferential dopamine autoreceptor antagonist. To further clarify the effects of (-)-OSU6162 on the postjunctional nigrostriatal dopaminergic system, dopamine receptor binding was measured in rhesus monkeys (Macaca mulatta) by positron emission tomography (PET) using the D1 and D2 dopamine receptor radioligands [11C]SCH23390 and [11C]raclopride respectively, before and during continuous intravenous infusions of(-)-OSU6162. Additionally, the test-retest variability of sequential [11C]SCH23390 scans was estimated. Following the administration of (-)-OSU6162, [11C]raclopride binding in striatum was dose-dependently decreased with a 76% reduction occurring after 3.0 mg/kg per h continuous infusion. Whereas (-)-OSU6162 in the lower doses had no effect on [11C]SCH23390 binding, the highest dose, 3.0 mg/kg per h, increased [11C]SCH23390 binding, which may indicate a potentiating effect on D1 dopamine receptor mediated functions. Thus, in contrast to the conditions in vitro, (-)-OSU6162 produces a high displacement of raclopride from D2 receptors in vivo.

Clinical pharmacokinetics of cholinesterase inhibitors.

This review deals mainly with the pharmacokinetics of the reversible quaternary cholinesterase inhibitors neostigmine, pyridostigmine and edrophonium, which are mainly used to antagonise non-depolarising neuromuscular blockade in general anaesthesia and in the symptomatic treatment of myasthenia gravis. Only in the last few years, since the introduction of highly sensitive and selective analytical procedures based on gas and liquid chromatography, have proper pharmacokinetic studies of these drugs become possible. Rapid cooling and addition of internal standard to samples before freezing are important precautions in view of the poor stability of the cholinesterase inhibitors in plasma and blood. Plasma clearances of the reversible quaternary cholinesterase inhibitors are in the range 0.5 to 1.0 L/h/kg and their apparent volumes of distribution range from 0.5 to 1.7 L/kg. Accordingly, the drugs have short plasma elimination half-lives, in the order of 30 to 90 minutes. One to two hours after oral administration of 60 mg pyridostigmine, peak plasma concentrations of 40 to 60 micrograms/L are observed, whereas the plasma concentrations of neostigmine after a 30 mg oral dose are only 1 to 5 micrograms/L. The oral bioavailability of these hydrophilic ionised compounds is low: that of pyridostigmine is approximately 10% and the value for neostigmine is even lower. In spite of the short elimination half-life of pyridostigmine, intraindividual variations in plasma concentration during a dose interval are small in myasthenic patients receiving oral maintenance therapy, probably as a result of slow absorption from the gastrointestinal tract. Severely impaired renal function has been shown to prolong the elimination of neostigmine and pyridostigmine, while methylcellulose has been reported to inhibit the absorption of the latter drug completely. Other pharmacokinetic drug interactions suggested so far do not seem to be of clinical significance. Although a positive correlation has been demonstrated between the plasma concentrations of these drugs and their pharmacological effects as measured by a decrement in muscle response to repetitive nerve stimulation in a single muscle, this relationship is less clear when a global evaluation of muscular function in myasthenia gravis is used. Pharmacokinetic studies of the tertiary reversible cholinesterase inhibitor physostigmine, an important tool in experimental cholinergic neuropharmacology, are still in their initial stages. This drug too is characterised by a short plasma elimination half-life of 20 to 30 minutes.(ABSTRACT TRUNCATED AT 400 WORDS)

Patient-controlled analgesic therapy, Part II: Individual analgesic demand and analgesic plasma concentrations of pethidine in postoperative pain.

20 survival patients were allowed to self-administer small intravenous doses of pethidine to relieve pain after major abdominal surgery. Pethidine injections were given by means of a programmable drug injector. Pethidine consumption varied from 12 to 50mg/h with a mean +/- SD of 26 +/- 10mg/h. The mean measured plasma concentration of pethidine during self-administration was 551 +/- 182 ng/ml, with a range of 132 to 896 ng/ml. Minimum effective concentrations averaged 455 +/- 174 ng/ml. Individual pethidine consumption and mean plasma concentrations did not differ between men and women, and were not correlated to variations in age, anthropometric factors, plasma clearance or elimination rate constant for pethidine. Individual consumption of pethidine was consistent, with stable plasma concentrations throughout most of the trial period. Pseudo-steady-state plasma concentrations of pethidine were established and maintained at widely different levels. 19 of the 20 patients obtained subjectively satisfactory analgesia.

Patient-controlled analgesic therapy. Part I: Pharmacokinetics of pethidine in the per- and postoperative periods.

The influence of anaesthesia and surgery on the pharmacokinetics of pethidine (meperidine) was studied in 12 patients. Plasma pethidine concentrations in central venous blood collected during anaesthesia and the ensuing postoperative hours were by gas chromatography with electron capture detection. Postoperative analgesia was accomplished by patient-controlled intravenous administration of small doses of pethidine. The NONLIN program was used to calculate pharmacokinetic parameters for each individual. A single dose study of pethidine kinetics was carried out in all patients 3 to 5 days postoperatively. Mean +/- SD for peroperative Vd area was 4.3 +/- 1.7L/kg and for the elimination half-life was 6.1 +/- 3.6h. In the postoperative period Vdarea was 3.2 +/- 0.8L/kg and the elimination half-life was 3.2 +/- 1.4h. Plasma clearance increased from a peroperative value of 8.9 +/- 1.9 ml/min/kg to a postoperative value of 12 +/- 3.0 ml/min/kg. The changes in elimination half-life and plasma clearance are significant. The postoperative pharmacokinetics of pethidine were in accordance with those reported for healthy volunteers. The fraction of unbound pethidine was significantly reduced postoperatively - from 0.26 +/- 0.10 (peroperatively) to 0.18 +/- 0.10 (3 to 5 days later).

Patient-controlled analgesic therapy, Part IV: pharmacokinetics and analgesic plasma concentrations of morphine.

The influence of anaesthesia and surgery on the pharmacokinetics of morphine was studied in 10 patients. Plasma concentrations of morphine were assayed by gas chromatography with electron capture detection. All patients were studied on the day of surgery and again 3 to 7 days later. Mean +/- SD for peroperative Vd(area) was 6.3 +/- 3.6 L/kg and for the terminal half-life was 3.8 +/- 2.3 h. In the postoperative period, Vd(area) decreased to 3.7 +/- 1.4L/kg and the terminal half-life to 2.2 +/- 1.1 h. Plasma clearance (Clp) remained constant, peroperative Clp being 20 +/- 7.0 ml/min/kg and postoperative Clp 21 +/- 6.0 ml/min/kg. Postoperative pain was relieved by patient-controlled administration of intravenous doses of morphine by means of a programmable drug injector. The mean morphine consumption was 2.6 +/- 1.2 mg/h, which produced a mean plasma concentration of 21 +/- 12 ng/ml with a calculated mean minimum effective concentration (MEC) of 16 +/- 9 ng/ml. In 1 patient, temporary hypercapnia was seen during a period of hypovolaemia. Analgesia was considered satisfactory by all patients.

Patient-controlled analgesic therapy, Part III: pharmacokinetics and analgesic plasma concentrations of ketobemidone.

The effects of anaesthesia and surgery on the pharmacokinetics of ketobemidone were studied in 12 patients. Plasma ketobemidone concentrations were assayed with a mass-fragmentographic method. The peroperative Vd(area) was 5.9 +/- 2.6L/kg and the terminal half-life was 3.9 +/- 1.7 h. In the postoperative period Vd(area) decreased to 3.7 +/- 0.4L/kg and the terminal half-life to 2.1 +/- 0.4 h. Plasma clearance (Clp) did not change significantly, peroperative Clp being 18 +/- 4.3 ml/min/kg and postoperative Clp being 22 +/- 7.5 ml/min/kg. The pharmacokinetics of ketobemidone were not influenced by the addition of a spasmolytic agent in the commercial combination ketobemidone preparation 'Ketogin'. Postoperative pain was relieved in 15 patients by patient-controlled intravenous administration of ketobemidone by means of a programmable drug injector. The mean ketobemidone consumption was 2.3 +/- 0.8 mg/h, which produced a mean plasma concentration of 28 +/- 11 mg/ml. Pseudosteady-state plasma concentrations of ketobemidone were established with a mean minimum effective concentration (MEC) of 25 +/- 11 ng/ml. Ketobemidone 'plain' and 'Ketogin' did not differ significantly in these respects. Analgesia was considered by all patients to be satisfactory.

Behavioral effects after intrathecal administration of cholinergic receptor agonists in the rat.

Behavioral effects of nicotine and cytisine, and the cholinesterase inhibitors physostigmine and 9-amino-1,2,3,4-tetrahydroacridine (THA), administered intrathecally (IT) at the lumbar level in the rat have been evaluated. Antinociceptive dose relationships were established using the tail immersion test. Total activity, locomotion and rearing were also measured in computerized test boxes. The nicotinic receptor antagonist, mecamylamine, and the muscarinic receptor antagonist, atropine, were used to study the selectivity of the effects. Physostigmine and THA significantly decreased total activity, locomotion and rearing as compared to control animals. The motor effects of physostigmine were completely antagonized only partly. Mecamylamine had no antagonistic effect. Nicotine did not affect any activity parameter. Cytisin reduced total activity and locomotion 1-6 min after dose. IT physostigmine, 15 micrograms, increased tail immersion latency for 30 min. No significant increase in response latency in this test was observed after the IT administration of nicotine or THA, whereas cytisine elicited a small increase. The IT administration of THA, nicotine and cytisine was also associated with gnawing, vocalization and hyperactivity and in the case of THA, diarrhoea. These effects were blocked by mecamylamine. Physostigmine antinociception as well as the behavioral effects including total activity, locomotion and rearing caused by physostigmine and by THA are most probably due to an action on spinal muscarinic receptors. Nicotinic receptors do not seem to be involved in spinal antinociception. Some aversive behavioral effects caused by the IT administration of nicotinic receptor agonists could, however, be attenuated by the spinal administration of the antagonist mecamylamine, which may indicate the involvement of nicotinic receptors in afferent sensory transmission.

Receptor binding of N-(methyl-11C) clozapine in the brain of rhesus monkey studied by positron emission tomography (PET).

By means of positron emission tomography the uptake and kinetics of N-(methyl-11C)clozapine in different brain regions have been studied in Rhesus monkeys. 11C-clozapine rapidly entered the brain and maximum radioactive uptake was seen 5-12 min after administration. Highest uptake was measured in the striatum. Other regions with an uptake higher than in the cerebellum were thalamus and mesencephalon. The radioactivity from different brain regions decreased with an elimination half-life of about 5 h and parallelled the plasma kinetics of unlabelled clozapine. The striatum/cerebellum ratio of 11C-clozapine-derived radioactivity remained constant during the period studied and did not change after pretreatment with atropine. In contrast, the striatum/cerebellum ratio was somewhat lower after pretreatment with N-methylspiperone (NMSP), indicating competition for the same binding sites in the striatum. After pretreatment with increasing doses of clozapine, a dose-dependent protection of binding sites in the striatum for 11C-NMSP was seen. It is concluded that clozapine is more loosely bound to dopamine receptors in the striatum than N-methylspiperone and that the kinetics of clozapine in the brain parallel that in the plasma. The binding properties of clozapine within the brain may explain some of the clinical properties of the drug.

Striatal and frontal cortex binding of 11-C-labelled clozapine visualized by positron emission tomography (PET) in drug-free schizophrenics and healthy volunteers.

The binding of 11C-labelled clozapine in the brain was studied in three drug-free schizophrenic patients and in three healthy volunteers. High radioactivities were found in the striatum and in the frontal cortex. The rate constant k3, which is proportional to receptor association rate and the number of receptors, was lower in the frontal cortex compared to the striatum. No obvious difference between the two brain areas was seen for the dissociation rate constant from the receptors (k4). Two schizophrenic patients were reexamined after pretreatment with haloperidol, one after 6 weeks of treatment with a low oral dose, the other one after an IV injection 1 h before 11C-clozapine was given. After haloperidol pretreatment, the binding of 11C-clozapine in striatum and frontal cortex was reduced, more pronounced in the striatum, indicating competition for D-2 dopamine binding sites. Our finding indicates that clozapine has an affinity for a receptor population in the frontal cortex that is predominantly not of the dopamine-D2 type. This feature might be of importance for the unique clinical profile of the drug.