The first step in the validation of a new screen for violence risk in acute psychiatry: The inpatient context.

BACKGROUND: Instruments for evaluating the risk of violence towards others have mostly been developed for assessment of risk for recidivism into violent crime in forensic psychiatry. In general psychiatry there is a considerable need for specialised, brief and structured assessment tools to inform risk decisions. METHOD: The study aimed to validate a brief structured clinical risk assessment screen of inpatient violence (V-RISK-10), a 10-item structured clinical checklist with a good vignette-based interrater reliability (ICC=0.87). In this study it was used for risk assessment of a one-year sample of patients (N=1.017) admitted to two acute psychiatric units. Risk assessments at admission were compared to prospective records of aggressive and violent acts during the hospital stay. RESULTS: Results showed a base rate for aggression of 9%. The predictive validity of the V-RISK-10 was estimated by Receiver Operating Characteristics (ROC). It yielded an area under the curve (AUC) of 0.83, with sensitivity/specificity of 0.81/0.73 and corresponding positive and negative predictive values (PPV/NPV) of 0.24/0.97. The screen was easy-to-use and showed a short completion time. CONCLUSION: Despite promising results further validation studies are required before the V-RISK-10 is adopted into routine clinical practise.

V-RISK-10: validation of a screen for risk of violence after discharge from acute psychiatry.

BACKGROUND: Current violence risk assessment instruments are time-consuming and mainly developed for forensic psychiatry. A paucity of violence screens for acute psychiatry instigated the development and validation of the V-RISK-10. The aim of this prospective naturalistic study was to test the predictive validity of the V-RISK-10 as a screen of violence risk after discharge from two acute psychiatric wards. METHODS: Patients were screened with V-RISK-10 before discharge, and incidents of violence were recorded 3, 6, 9 and 12 months after discharge. A total of 381 of the 1017 patients that were screened completed the follow up. RESULTS: The ROC-AUC values for any violent behaviour were 0.80 and 0.75 (p<0.001) for the 3 and 12 months follow-up periods, respectively, and significant for both genders. The most accurate risk estimates were obtained for severe violence. For persons without a known history of violence prior to the screening, AUCs were 0.74 (p=0.004) and 0.68 (p=0.002). CONCLUSIONS: Results indicate that the V-RISK-10 is a valid and clinically useful screen for violence risk after discharge from acute psychiatry, and even significant for patients without a known previous history of violence.

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.

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.

Use of positron emission tomography in analysing receptor function in vivo.

The non-invasive radiotracer technique positron emission tomography (PET) may provide valuable information in the toxicokinetic-toxicodynamic evaluation of endogenous or toxic environmental compounds. Assessment of mechanism of action of toxins is often difficult to validate. In this respect, PET may offer advantages since it can quantify not only the distribution and kinetics of the radiolabelled toxin in the body, but also the altered rates of physiological or biochemical processes induced by the toxin. It is even possible to validate the body distribution and tissue accumulation of the toxic compound in primates, since linear kinetics can be assumed after administration of the radiolabelled compound in minute amounts without any toxic or physiological effects. Quantitative estimates can be derived with accuracy and high precision. Using a multi-tracer protocol, it is often possible to illuminate both the kinetics and the dynamics of a toxic compound. Long-term effects of different toxins on dopamine receptor function have been evaluated with PET as well as the influence of Parkinson disease medication on pre- and postsynaptic dopaminergic receptor function over the course of the disease. In conclusion, PET may provide very informative insight into complex receptor interactions of both toxic compounds and drugs under development.

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.

Compounds labelled with short-lived beta(+)-emitting radionuclides and some applications in life sciences. The importance of time as a parameter.

Some examples of recent development of the synthesis of compounds labelled with short-lived beta(+)-emitting radionuclides will be discussed with an emphasis on the importance of time in selecting a synthetic strategy. Furthermore the use of such labelled compounds to monitor certain processes in areas within the field of analytical chemistry and in various applications in drug development will be presented.

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.

The anaesthetic potency of propofol in the rat is reduced by simultaneous intravenous administration of lignocaine.

Lignocaine added to the anaesthetic preparation Diprivan reduces propofol induced pain on injection. This effect is due to a drop in pH which decreases the content of propofol in the aqueous phase of the soya bean emulsion. This in turn changes the electrostatic forces in the emulsion and destabilization occurs. The effect of lignocaine on the anaesthetic potency of propofol was validated in a randomized blind study in the rat. The induction dose of 1% propofol mixed with 1% lignocaine (10 + 1) was significantly higher when compared with the induction dose of propofol 1% given after a separate injection of 1% lignocaine (9.4 +/- 5.5 vs. 5.6 +/- 5.2 mg; P < 0.05). The duration of sleep was shorter in rats injected with propofol 1% mixed with lignocaine 1% (10 + 1) compared with those given 1% lignocaine and 1% propofol in separate injections (160 +/- 181 vs. 375 +/- 202 s; P < 0.05). The anaesthetic potency of propofol was not significantly changed by the addition of either saline or hydrochloric acid. The anaesthesia inducing effect was not time-dependent. A similar lower potency was observed for a solution stored for 4 h compared with one freshly prepared, although sleeping time was longer (9.2 +/- 6.8 mg; 428 +/- 110 s) as compared with the 4 h mixture. The results indicate that lignocaine altered the propofol preparation. The reduced anaesthetic potency of propofol after addition of lignocaine is not due to the resultant drop in pH, which is known to occur.

Acidified propofol retains its anaesthetic potency after storage.

The reduction in propofol-induced pain on injection caused by the addition of lignocaine results mainly from a drop in pH, which reduces the concentration of propofol in the aqueous phase of the emulsion. It is not an effect of the local anaesthetic per se. Propofol emulsion mixed with lignocaine destabilizes within hours. We mixed 10 parts of propofol 1% emulsion with one part of 0.0064 M HCl or 0.013 M HCl, respectively. These mixtures were stored for 3 months and compared with a freshly prepared solution of propofol 1% emulsion and saline, in the same proportion, regarding their ability to induce anaesthesia in the rat. There was no significant difference in the amount of propofol required to induce anaesthesia, nor was there any difference in recovery time between the three groups.

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.

NMDA-receptor activity visualized with (S)-[N-methyl-11C]ketamine and positron emission tomography in patients with medial temporal lobe epilepsy.

PURPOSE: To determine whether neurochemical activation of the N-methyl-D-aspartate (NMDA) receptor-gated ion channel shows quantitative changes, measured as binding of 11C-labeled (S)-[N-methyl]ketamine, in patients with medial temporal lobe epilepsy (MTLE). METHODS: Eight patients with MTLE who were evaluated regarding epilepsy surgery underwent positron emission tomography (PET) with (S)-[N-methyl-11C]ketamine. The presurgical investigations included magnetic resonance imaging (MRI), PET with 18F-fluoro-deoxyglucose (18FDG), and seizure monitoring by using video-EEG. The uptake of (S)-[N-methyl-11C]ketamine in the temporal lobe of ictal onset was compared with the contralateral side and correlated to changes in regional glucose metabolism measured by PET with 18FDG. RESULTS: (S)-[N-methyl-11C]ketamine rapidly reached the brain, and high radioactivities were measured in the striatum, thalamic nuclei, and cortical regions. Overall the brain uptake and regional binding potentials of (S)-[N-methyl-11C]ketamine were similar to measurements observed previously in healthy controls. However, 20 min after administration, when blood flow influence was negligible, a side-to-side comparison revealed a 9-34% reduction of tracer radioactivity in the temporal lobes of ictal onset. At earlier times, the differences in binding potentials were less pronounced, 9-21%. The magnitude and distribution of the reduction were similar to the metabolic pattern seen on PET scans with 18FDG. CONCLUSIONS: Radioactivity uptake of intravenously administered (S)-[N-methyl-11C]ketamine was reduced in temporal lobes of ictal in patients with TLE. This may reflect reduced NMDA-receptor density, reduced perfusion, focal atrophy, or other factors.

Absorption of L-DOPA from the proximal small intestine studied in the rhesus monkey by positron emission tomography.

Positron emission tomography (PET) seems to be a valuable method for the understanding of intestinal absorption mechanisms, for simultaneous quantitation of absorption rate and distribution kinetics to the tissues of interest after oral drug delivery. PET was evaluated in three Rhesus monkeys for quantitation of the absorption rate from the gastrointestinal tract and the distribution kinetics into different organs. To obtain optimal standardized conditions for the measurement of absorption the drug was administered via a naso-duodenal catheter directly to the absorption site in the proximal small intestine. l-DOPA was used as study drug given in a suspension together with carbidopa and the radiomarker l-[beta-11C]DOPA. The l-DOPA suspension was given into the duodenum without and after administration of a suspension of six l-amino acids (120 mM) in order to investigate any interaction on the intestinal absorption and distribution of l-DOPA into the liver and brain tissue. Intestinal absorption was in general minor during the first study period and higher together with administered l-amino acids. The somewhat contradictory result with increased absorption when amino acids were present in the intestinal lumen, may be a consequence of increased intestinal motility initiated by the nutrient load.

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.

Conjugate chemistry, iodination and cellular binding of mEGF-dextran-tyrosine: preclinical tests in preparation for clinical trials.

A conjugate with specific binding to the epidermal growth factor receptor, EGFR, and of interest for clinical tests was prepared using mouse epidermal growth factor, mEGF, and dextran. The mEGF was first coupled to dextran by reductive amination in which the free amino group on the N-terminal of mEGF was reacted with the aldehyde group on the reductive end of the dextran chain. The end-end coupled intermediate was further activated by the cyanopyridinium agent CDAP and tyrosines introduced to the dextran part of the conjugate. The mEGF-dextran-tyrosine conjugate was, with high efficiency, iodinated with the chloramine-T method. Approximately 25-35% of the radioactivity could be removed from the conjugate after exposure to protease K while 65-75% of the radioactivity could be removed after exposure to dextranase. Thus, the largest amount of the iodine was on the dextran part of the conjugate. The iodinated mEGF-dextran-tyrosine had EGFR specific binding since the binding to an EGFR rich human glioma cell line could be displaced by an excess of non-radioactive mEGF. The conjugate was to a large extent internalized in these cells and the administrated radioactivity was thereby retained inside the cells for at least up to 50 h.