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Background Major depressive disorder (MDD) is commonly treated with selective serotonin reuptake inhibitors (SSRIs). SSRIs inhibit the serotonin transporter (5-HTT), but the downstream antidepressant mechanism of action of these drugs is poorly understood. The serotonin 1B (5-HT1B) receptor is functionally linked to 5-HTT and 5-HT1B receptor binding and 5-HT1B receptor mRNA is reduced in the raphe nuclei after SSRI administration in primates and rodents, respectively. The effect of SSRI treatment on 5-HT1B receptor binding in patients with MDD has not been examined previously. This positron emission tomography (PET) study aimed to quantify brain 5-HT1B receptor binding changes in vivo after SSRI treatment for MDD in relation to treatment effect. Methods Eight unmedicated patients with moderate to severe MDD underwent PET with the 5-HT1B receptor radioligand [11C]AZ10419369 before and after 3 to 4 weeks of treatment with the SSRI escitalopram 10 mg daily. Depression severity was assessed at time of PET and after 6 to 7 weeks of treatment with the Montgomery-Åsberg Depression Rating Scale. Results We observed a significant reduction in [11C]AZ10419369 binding in a dorsal brainstem (DBS) region containing the median and dorsal raphe nuclei after escitalopram treatment (P  = .036). Change in DBS [11C]AZ10419369 binding correlated with Montgomery-Åsberg Depression Rating Scale reduction after 3-4 (r = 0.78, P  = .021) and 6-7 (r = 0.94, P  < .001) weeks' treatment. Conclusions Our findings align with the previously reported reduction of 5-HT1B receptor binding in the raphe nuclei after SSRI administration and support future studies testing change in DBS 5-HT1B receptor binding as an SSRI treatment response marker. [ABSTRACT FROM AUTHOR]

Background: Positron emission tomography studies examining differences in D1-dopamine receptor binding between control subjects and patients with schizophrenia have been inconsistent, reporting higher, lower, and no difference in the frontal cortex. Exposure to antipsychotic medication has been suggested to be a likely source of this heterogeneity, and thus there is a need for studies of patients at early stages of the disorder who have not been exposed to such drugs., Methods: Here, we compared 17 healthy control subjects and 18 first-episode neuroleptic naive patients with schizophrenia or schizophreniform psychosis using positron emission tomography and the D1-dopamine receptor radioligand [11C]SCH23390., Results: We observed a statistically significant difference in the dorsolateral prefrontal cortex. Contrary to our expectations, patients had less D1-dopamine receptor availability with a moderate effect size. In a Bayesian analysis, we show that the data are over 50 times more likely to have occurred under the decrease as opposed to the increase hypothesis. This effect was not global, as our analysis showed that the null hypothesis was preferred over either hypothesis in the striatum., Conclusions: This investigation represents the largest single sample of neuroleptic-naive patients examined for D1-dopamine receptor availability using PET and suggests a reduction of prefrontal D1-dopamine receptor density in the pathophysiology of schizophrenia. However, further work will be required to reach a consensus., (© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.)

Background: [11C]Cimbi-36 is a serotonin 2A receptor agonist positron emission tomography radioligand that has recently been examined in humans. The binding of agonist radioligand is expected to be more sensitive to endogenous neurotransmitter concentrations than antagonist radioligands. In the current study, we compared the effect of serotonin releaser fenfluramine on the binding of [11C]Cimbi-36, [11C]MDL 100907 (a serotonin 2A receptor antagonist radioligand), and [11C]AZ10419369 (a serotonin 1B receptor partial agonist radioligand with established serotonin sensitivity) in the monkey brain., Methods: Eighteen positron emission tomography measurements, 6 for each radioligand, were performed in 3 rhesus monkeys before or after administration of 5.0 mg/kg fenfluramine. Binding potential values were determined with the simplified reference tissue model using cerebellum as the reference region., Results: Fenfluramine significantly decreased [11C]Cimbi-36 (26-62%) and [11C]AZ10419369 (35-58%) binding potential values in most regions (P < 0.05). Fenfluramine-induced decreases in [11C]MDL 100907 binding potential were 8% to 30% and statistically significant in 3 regions. Decreases in [11C]Cimbi-36 binding potential were larger than for [11C]AZ10419369 in neocortical and limbic regions (~35%) but smaller in striatum and thalamus (~40%). Decreases in [11C]Cimbi-36 binding potential were 0.9 to 2.8 times larger than for [11C]MDL 100907, and the fraction of serotonin 2A receptor in the high-affinity state was estimated as 54% in the neocortex., Conclusions: The serotonin sensitivity of serotonin 2A receptor agonist radioligand [11C]Cimbi-36 was higher than for antagonist radioligand [11C]MDL 100907. The serotonin sensitivity of [11C]Cimbi-36 was similar to [11C]AZ10419369, which is one of the most sensitive radioligands. [11C]Cimbi-36 is a promising radioligand to examine serotonin release in the primate brain., (© The Author 2017. Published by Oxford University Press on behalf of CINP.)

Background: Previous autoradiography studies have suggested a marked interspecies variation in the neuroanatomical localization and expression levels of the neurokinin 3 receptor, with high density in the brain of rat, gerbil, and guinea pig, but at the time offered no conclusive evidence for its presence in the human brain. Hitherto available radioligands have displayed low affinity for the human neurokinin 3 receptor relative to the rodent homologue and may thus not be optimal for cross-species analyses of the expression of this protein., Methods: A novel neurokinin 3 receptor radioligand, [(18)F]Lu AF10628 ((S)-N-(cyclobutyl(3-fluorophenyl)methyl)-8-fluoro-2-((3-[(18)F]-fluoropropyl)amino)-3-methyl-1-oxo-1,2-dihydroisoquinoline-4-carboxamide), was synthesized and used for autoradiography studies in cryosections from guinea pig, monkey, and human brain as well as for positron emission tomography studies in guinea pig and monkey., Results: The results confirmed previous observations of interspecies variation in the neurokinin 3 receptor brain localization with more extensive distribution in guinea pig than in primate brain. In the human brain, specific binding to the neurokinin 3 receptor was highest in the amygdala and in the hypothalamus and very low in other regions examined. Positron emission tomography imaging showed a pattern consistent with that observed using autoradiography. The radioactivity was, however, found to accumulate in skull bone, which limits the use of this radioligand for in vivo quantification of neurokinin 3 receptor binding., Conclusion: Species differences in the brain distribution of neurokinin 3 receptors should be considered when using animal models for predicting human neurokinin 3 receptor pharmacology. For positron emission tomography imaging of brain neurokinin 3 receptors, additional work is required to develop a radioligand with more favorable in vivo properties., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)

Background: Positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. The aim of the present study was to examine and compare the brain exposure of 12 commercially available CNS drugs and one non-CNS drug., Methods: The drugs were radiolabeled with (11)C (t 1/2 = 20.4 minutes) and examined using a high resolution research tomograph. In cynomolgus monkeys, each drug was examined twice. In rhesus monkeys, a first positron emission tomography microdosing measurement was repeated after preadministration with unlabeled drug to examine potential dose-dependent effects on brain exposure. Partition coefficients between brain and plasma (KP) were calculated by dividing the AUC0-90 min for brain with that for plasma or by a compartmental analysis (VT). Unbound KP (KP u,u) was obtained by correction for the free fraction in brain and plasma., Results: After intravenous injection, the maximum radioactivity concentration (C max, %ID) in brain ranged from 0.01% to 6.2%. For 10 of the 12 CNS drugs, C max, %ID was >2%, indicating a preferential distribution to brain. A lower C max, %ID was observed for morphine, sulpiride, and verapamil. K P ranged from 0.002 (sulpiride) to 68 (sertraline) and 7 of 13 drugs had KP u,u close to unity. For morphine, sulpiride, and verapamil, K P u,u was <0.3, indicating impaired diffusion and/or active efflux. Brain exposure at microdosing agreed with pharmacological dosing conditions for the investigated drugs., Conclusions: This study represents the largest positron emission tomography study on brain exposure of commercially available CNS drugs in nonhuman primates and may guide interpretation of positron emission tomography microdosing data for novel drug candidates., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Background: The neurotransmitter norepinephrine has been implicated in psychiatric and neurodegenerative disorders. Examination of synaptic norepinephrine concentrations in the living brain may be possible with positron emission tomography (PET), but has been hampered by the lack of suitable radioligands., Methods: We explored the use of the novel α2C-adrenoceptor antagonist PET tracer [(11)C]ORM-13070 for measurement of amphetamine-induced changes in synaptic norepinephrine. The effect of amphetamine on [(11)C]ORM-13070 binding was evaluated ex vivo in rat brain sections and in vivo with PET imaging in monkeys., Results: Microdialysis experiments confirmed amphetamine-induced elevations in rat striatal norepinephrine and dopamine concentrations. Regional [(11)C]ORM-13070 receptor binding was high in the striatum and low in the cerebellum. After injection of [(11)C]ORM-13070 in rats, mean striatal specific binding ratios, determined using cerebellum as a reference region, were 1.4±0.3 after vehicle pretreatment and 1.2±0.2 after amphetamine administration (0.3mg/kg, subcutaneous). Injection of [(11)C]ORM-13070 in non-human primates resulted in mean striatal binding potential (BP ND) estimates of 0.65±0.12 at baseline. Intravenous administration of amphetamine (0.5 and 1.0mg/kg, i.v.) reduced BP ND values by 31-50%. Amphetamine (0.3mg/kg, subcutaneous) increased extracellular norepinephrine (by 400%) and dopamine (by 270%) in rat striata., Conclusions: Together, these results indicate that [(11)C]ORM-13070 may be a useful tool for evaluation of synaptic norepinephrine concentrations in vivo. Future studies are required to further understand a potential contribution of dopamine to the amphetamine-induced effect., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)

Quetiapine, originally developed as an antipsychotic, demonstrates efficacy in clinical studies of schizophrenia, bipolar mania and depression, major depressive disorder and generalized anxiety disorder. This broad spectrum of efficacy was not predicted from the preclinical pharmacology of quetiapine. Binding studies in vitro show that quetiapine and its major active human metabolite, norquetiapine, have moderate to high affinity for dopamine D2 and serotonin 5-HT2A receptors, while norquetiapine alone has high affinity for the norepinephrine transporter (NET). This positron emission tomography (PET) study measured NET occupancy in human subjects treated with extended-release quetiapine (quetiapine XR) at doses relevant in the treatment of depression. PET measurements using the specific NET radioligand (S,S)-[(18)F]FMeNER-D2 were performed before and after quetiapine XR treatment at 150 and 300 mg/d for 6-8 d in nine healthy males (aged 21-33 yr). Regions of interest were defined for the thalamus, using the caudate as reference region. NET occupancy was calculated using a target:reference region ratio method. Plasma concentrations of quetiapine and norquetiapine were monitored during PET measurements. Following quetiapine XR treatment, the mean NET occupancy in the thalamus was 19 and 35%, respectively, at quetiapine XR doses of 150 and 300 mg/d. The estimated plasma concentration of norquetiapine corresponding to 50% NET occupancy was 161 ng/ml. This is the first demonstration of NET occupancy by an antipsychotic in the human brain. NET inhibition is accepted as a mechanism of antidepressant activity. NET occupancy may therefore contribute to the broad spectrum of efficacy of quetiapine.

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for treatment of psychiatric disorders. The exact mechanism underlying the clinical effects of SSRIs remains unclear, although increased synaptic serotonin concentrations have been hypothesized to be an initial step. [¹¹C]AZ10419369 is a novel 5-HT(1B) receptor selective radioligand, which is sensitive to changes in endogenous serotonin concentrations. To assess whether a single dose of the SSRI escitalopram affects endogenous serotonin concentrations in serotonergic projection areas and in the raphe nuclei (RN), three cynomolgus monkeys and nine human subjects underwent PET examinations with [¹¹C]AZ10419369 at baseline conditions and after escitalopram administration. In monkeys, the binding potential (BP(ND)) was significantly lower post dose compared to baseline in dorsolateral prefrontal cortex, occipital cortex, thalamus, midbrain and RN (p < 0.05). In humans, the BP(ND) tended to decrease in RN post dose (p = 0.08). In all serotonergic projection areas, the BP(ND) was conversely higher post dose compared to baseline. The increase was significant in a combined region of all projection areas (p = 0.01) and in occipital and temporal cortex (p < 0.05). SSRIs are generally assumed to elevate endogenous serotonin concentrations in projection areas, evoking the antidepressant effect. In the present study, a single, clinically relevant, dose of escitalopram was found to decrease serotonin concentrations in serotonergic projection areas in humans. Hypothetically, desensitization of inhibitory serotonergic autoreceptors will cause the serotonin concentration in projection areas to increase over time with chronic administration. Thus, the findings in the present study might aid in understanding the mechanism of SSRIs' delayed onset of clinical effect.

Studies in rodents have shown that psychostimulant drugs such as cocaine and amphetamine cause endorphin release in the brain reward system. There is also evidence for the involvement of the opioid system in human psychostimulant dependence. The acute effects of an i.v. psychostimulant drug on the brain opioid system, however, have not yet been investigated in humans. We hypothesized that an i.v. dose of amphetamine as compared to placebo would cause an opioid release in the human brain reward system, measurable as a reduction of the binding potential of the μ-opioid receptor radioligand [(11)C]carfentanil. Ten healthy young men were examined using positron emission tomography (PET) and [(11)C]carfentanil in three sessions: at baseline; after placebo; after an i.v. amphetamine dose of 0.3 mg/kg bodyweight. The order of amphetamine and placebo was double-blinded and randomized. PET examinations were performed with a Siemens high resolution research tomograph. Data were analysed with the simplified reference tissue model, applying manually drawn regions of interest for every subject. Using repeated measures analysis of variance, we found no significant differences in [(11)C]carfentanil binding potential between amphetamine and placebo conditions in any of the investigated brain regions. In contrast to data from rodent studies and a recent study of oral amphetamine administration in humans, an i.v. dose of amphetamine does not cause any acute opioid release in healthy human subjects. The postulated role of the opioid system in mediating the effects of amphetamine needs to be further investigated in animal models of the disease as well as in patient populations.

The aim of the present clinical positron emission tomography study was to examine if the 5-HTT is a common target, both for tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Serotonin transporter (5-HTT) occupancy was estimated during treatment with TCA, SSRI and mirtazapine in 20 patients in remission from depression. The patients were recruited from out-patient units and deemed as responders to antidepressive treatment. The radioligand [¹¹C]MADAM was used to determine the 5-HTT binding potential. The mean 5-HTT occupancy was 67% (range 28-86%). There was no significant difference in 5-HTT occupancy between TCA (n=5) and SSRI (n=14). 5-HTT affinity correlated with the recommended clinical dose. Mirtazapine did not occupy the serotonin transporter. The results support that TCAs and SSRIs have a shared mechanism of action by inhibition of 5-HTT.

Quetiapine is an established drug for treatment of schizophrenia, bipolar disorder, and major depressive disorder. While initially manufactured as an immediate-release (IR) formulation, an extended-release (XR) formulation has recently been introduced. Pharmacokinetic studies show that quetiapine XR provides a lower peak and more stable plasma concentration than the IR formulation. This study investigated if the pharmacokinetic differences translate into different time curves for central D₂ dopamine receptor occupancy. Eleven control subjects were examined with positron emission tomography (PET) and the radioligand [11C]raclopride. Eight subjects underwent all of the scheduled PET measurements. After baseline examination, quetiapine XR was administered once-daily for 8 d titrated to 300 mg/d on days 5-8, followed by 300 mg/d quetiapine IR on days 9-12. PET measurements were repeated after the last doses of quetiapine XR and IR at predicted times of peak and trough plasma concentrations. Striatal D₂ receptor occupancy was calculated using the simplified reference tissue model. Peak D₂ receptor occupancy was significantly higher with quetiapine IR than XR in all subjects (50 ± 4% and 32 ± 11%, respectively), consistent with lower peak plasma concentrations for the XR formulation. Trough D₂ receptor occupancy was similarly low for both formulations (IR 7 ± 7%, XR 8 ± 6%). The lower peak receptor occupancy associated with quetiapine XR may explain observed pharmacodynamic differences between the formulations. Assuming that our findings in control subjects are valid for patients with schizophrenia, the study supports the view that quetiapine, like the prototype atypical antipsychotic clozapine, may show antipsychotic effect at lower D₂ receptor occupancy than typical antipsychotics.

The increased proportion of the high-affinity state of dopamine D2/3 receptors (D2,high) is assumed to correlate with dopamine hypersensitivity, implying a relationship with psychotic symptoms observed in psychiatric disorders such as schizophrenia. [11C](R)-2-CH3O-N-n-propylnorapomorphine ([11C]MNPA), which has an agonistic property to dopamine D2 receptors (D2Rs), is expected to bind preferentially to D2,high. The occupancy of dopamine D2Rs by antagonists to receptors has not been investigated using [11C]MNPA. We compared dopamine D2R occupancies by risperidone, an antagonist to receptors, between [11C]MNPA and [11C]raclopride to confirm whether risperidone occupies D2,high and D2,low at almost identical proportions. PET studies were performed on 11 healthy men under resting condition and following oral administration of a single dose of risperidone (0.5-2.0 mg). Striatal receptor occupancy for each radioligand was calculated. The relationship between dose or plasma concentration of risperidone and dopamine D2R occupancy was calculated. Striatal dopamine D2R occupancies measured with [11C]MNPA and [11C]raclopride were 22-65% and 24-69%, respectively. In the striatum, ED50 values measured with [11C]MNPA and [11C]raclopride were 0.98 and 1.03 mg, respectively. The striatal ED50 values as calculated from plasma concentration were 9.15 ng/ml and 8.01 ng/ml, respectively. Almost identical occupancies and ED50 values were observed between the two radioligands, indicating that risperidone bound to D2,high and D2,low at almost identical proportions in a dose-dependent manner.

The human serotonin transporter (5-HTT) gene is one of the most extensively studied in psychiatry. A functional polymorphism in the promoter region of the 5-HTT gene (5-HTTLPR) has been associated with several psychiatric disorders as well as anxiety-related personality traits. In search of a mechanistic understanding of the functional implications of 5-HTTLPR, the influence of this polymorphism on regional 5-HT1A receptor density has previously been examined in two positron emission tomography (PET) studies in humans, yielding, however, contradictory results. In the present study, 54 control subjects were examined with [11C]WAY 100635 PET and a battery of cognitive tests. Regional binding potential (BP) of [11C]WAY 100635 to 5-HT1A receptor was calculated for the dorsal raphe nuclei, the hippocampus, the anterior cingulate, the insula, the temporal cortex and the frontal cortex. The influence of 5-HTTLPR genotype on regional 5-HT1A BP and cognitive performance was investigated. No differences in 5-HT1A receptor density between carriers and non-carriers of the S allele were found. Thus, we could not replicate any of the previously reported associations between 5-HTTLPR and 5-HT1A density. There was, however, a highly significant association between 5-HTTLPR genotype and performance in Wisconsin Card Sorting Test; carriers of the S allele had a superior performance compared to the LL carriers. These observations suggest that functional implications of the 5-HTTLPR polymorphism are not likely to be mediated by differences in 5-HT1A expression levels and that other biomarkers must be considered for future investigations at phenotype level.

Animal research has shown a diurnal variation in dopamine neurotransmission, with a reduced release at night. Variations in biomarkers for the dopamine system over the day have, however, not been investigated in human subjects. In this preliminary PET study, we used the radioligands [11C]raclopride and [11C]FLB 457 to determine dopamine D2-receptor binding in 16 human subjects in the morning and evening on the same day. The average difference between morning and evening examinations did not indicate a diurnal effect on D2 receptor availability. However, when age was taken into account in the analysis, a pattern emerged where individuals in the lower age range showed reduced evening binding while in older subjects binding potential increased. The product-moment correlation between morning-evening change and age was statistically significant in insula, medial frontal cortex and rostral anterior cingulate. The findings, if replicated, have direct relevance for applied PET studies and could also prove relevant with regard to age effects on dopamine-related behaviour such as arousal and cognitive performance.

The mechanisms underlying the clinical properties of atypical antipsychotics have been postulated to be mediated, in part, by interactions with the 5-HT2A receptor. Recently, it has been recognized that clinically effective antipsychotic drugs are 5-HT2A receptor inverse agonists rather than neutral antagonists. In the present study, which is part of the clinical development of the novel, selective 5-HT2A receptor inverse agonist ACP-103, we applied positron emission tomography (PET) with the radioligand [11C]N-methylspiperone ([11C]NMSP) to study the relationship between oral dose, plasma level, and uptake of ACP-103 in living human brain. The safety of drug administration was also assessed. Four healthy volunteers were examined by PET at baseline, and after the oral administration of various single doses of ACP-103. Two subjects each received 1, 5, and 20 mg doses, and two subjects each received 2, 10, and 100 mg doses, respectively. ACP-103 was well tolerated. Detectable receptor binding was observed at very low ACP-103 serum levels. Cortical [11C]NMSP binding was found to be dose-dependent and fitted well to the law of mass action. A reduction in binding was detectable after an oral dose of ACP-103 as low as 1 mg, and reached near maximal displacement following the 10-20 mg dose. In conclusion, administration of ACP-103 to healthy volunteers was found to be safe and well tolerated, and single oral doses as low as 10 mg were found to fully saturate 5-HT2A receptors in human brain as determined by PET.

The selective serotonin reuptake inhibitor (SSRI) citalopram (R,S-citalopram) is a racemic compound of two enantiomers. On the basis of in-vitro studies, inhibition of the human serotonin transporter (5-HTT) is achieved by the S-enantiomer (S-citalopram or escitalopram). The aim of the present PET study was to compare 5-HTT occupancy after single equimolar doses (with respect to S-enantiomer) in humans in vivo using R,S-citalopram (20 mg) and S-citalopram (10 mg) using PET and the radioligand [(11)C]MADAM. The design was a single-dose, double-blind, two-way crossover study in eight healthy male subjects. The 5-HTT binding potential at baseline and after single doses of study drugs was used to calculate 5-HTT occupancy in seven brain regions. Serum concentrations of the study drugs were determined in order to calculate the apparent inhibition constant (K(i),(app)), a secondary parameter of interest for the comparison. In all brain regions examined, occupancy was numerically higher after treatment with R,S-citalopram [66+/-19% to 78+/-17% (mean+/-s.d.) depending on the region] than after S-citalopram (59+/-15% to 69+/-13%; overall comparison: F=14.8, d.f.=1, 90, p<0.001). In line with this the apparent inhibition constant was significantly lower for R,S-citalopram than for S-citalopram (overall comparison: F=6.7, d.f.=1, 90, p<0.05). The small but significant difference in occupancy and K(i),(app) found between R,S-citalopram and S-citalopram suggests that not only S-citalopram but also R-citalopram to some degree occupies the 5-HTT in the human brain in vivo.

Several mechanisms have been suggested to account for altered dopaminergic neurotransmission in schizophrenia. The brain is the only organ for which amino-acid transport is limited and competition for transport over the blood-brain barrier (BBB) occurs at physiological plasma concentrations. One line of research suggests that patients with schizophrenia have altered brain levels of the essential amino acid tyrosine, the precursor for the synthesis of dopamine. The most common hypothesis is that less tyrosine is available because of competition with elevated levels of other amino acids. By consequence, the synthesis of dopamine in the brain will decrease. In contrast, another line of evidence suggests a change in the affinity for one of the transport proteins. A limitation of this research has been that the systems for amino-acid transport across the BBB have not been fully characterized at a molecular or functional level. The L system is the major system for transport of tyrosine across cell membranes including the BBB. The A system is also involved in this transport. Earlier in-vitro studies using fibroblasts have demonstrated a normal L system in schizophrenia but nevertheless reduced tyrosine transport. The combination of molecular research, fibroblast techniques, and brain imaging provides a new basis for clinical research on the role of amino-acid membrane transport in schizophrenia.

Since the 1960s, physicians have been aware of electrocardiographic (ECG) abnormalities and cases of sudden death associated with the use of antipsychotic drugs in patients with schizophrenia. Explanations for such deaths have traditionally focused on drug-induced prolongation of the QT interval leading to the development of life-threatening ventricular arrhythmias such as torsade de pointes (TdP). It is now apparent that most conventional and atypical antipsychotics can cause dose-related prolongation of the corrected QT interval (QTc), although there are important differences in the potency of individual agents. This review discusses potential mechanisms underlying QTc prolongation and arrhythmogenesis and examines the evidence for a relationship between antipsychotic drugs and prolongation of the QTc interval. New electrophysiological and epidemiological data are presented which suggest there may not be a clear-cut cause-effect relationship between QTc prolongation and the development of ventricular tachyarrhythmias for all atypical antipsychotics. For at least one of these agents (sertindole), counterbalancing mechanisms may act to reduce the risk of proarrhythmic activity arising as a result of QTc prolongation.

The thalamus is a neuroanatomic structure that has reciprocal connections with several brain regions suggested to be involved in the pathophysiology of schizophrenia. Recent studies have reported structural as well as functional abnormalities of the thalamus in schizophrenia. The aim of the present exploratory study was to examine D2/D3 dopamine receptors in the thalamus as well as the anterior cingulate and the frontal and temporal cortices by using the high-affinity radioligand [11C]FLB 457 and positron emission tomography (3D PET) and to explore the data in relation to disease, age and psychopathology. Nine drug-naive patients with schizophrenia and eight control subjects were examined. Regional binding potential (BP) values were calculated using the simplified reference tissue model. The D2/D3 receptor binding was significantly lower in the right medial thalamus in the schizophrenia patients compared to control subjects. In addition, we found a significant negative age effect on the D2/D3 BP in the frontal and temporal cortex for both groups. There was no significant age effect on the D2/D3 BP in the thalamus or in the anterior cingulate. The result provides additional support to the view that the age effect on D2/D3 receptors differ between brain regions. The preliminary finding of low thalamic D2/D3 BP in patients strengthens the hypothesis that the thalamus is a key region in the pathophysiology of schizophrenia.

Several radiolabelled cocaine analogues have been proposed for brain imaging of the dopamine transporter in research on neuropsychiatric disorders and drug abuse. In a recent positron emission tomography (PET) study we labelled the cocaine analogue ß-CIT-FE with carbon-11 and demonstrated high specific binding in the monkey striatum. In the present study, the selectivity of [11C]ß-CIT-FE binding in the primate brain was examined by pretreatment experiments with reference ligands for the dopamine, serotonin and norepinephrine transporter. In three healthy human subjects the regional binding of [11C]ß-CIT-FE was analysed using equilibrium and kinetic analyses. A Scatchard analysis showed that [11C]ß-CIT-FE bound in a saturable manner yielded a density value of the same order as that reported in vitro. The pharmacological characterization indicated that a high degree of [11C]-CIT-FE binding in the primate striatum represents the dopamine transporter. In human subjects the radioligand provided high brain uptake and reached peak equilibrium within 1 hour after i.v. injection. Different quantitative approaches gave similar values for the binding potential. The results support the view that [11C]ß-CIT-FE is a suitable radioligand for clinical studies of the dopamine transporter. In particular for studies requiring short data acquisition or repeated PET measurements on the same day.

The aim of the present study was to quantify the density and affinity of human extrastriatal dopamine D2 receptors using positron emission tomography (PET). [(11)C]FLB-457, a high-affinity dopamine D2 receptor antagonist with various specific radioactivities (SA) was used. Eight healthy male subjects, age 20-35 yr, participated twice or three times at different SAs (1-279 GBq/ µmol), and serial dynamic scans were performed in the 3D data acquisition mode. The peak of the specific binding was not well defined with high SA due to the flatness of the curves after 60 min but was observed within the PET measurement. In the experiment with low SA, the peak came earlier than that with high SA. Scatchard analysis was performed using the maximal specific binding value (transient equilibrium) and the radioactivity in the cerebellum as free ligand concentration. The highest density was observed in the thalamus (2.3+/-0.6 pmol/ml), followed by the temporal cortex (1.5+/-0.5 pmol/ml), hippocampus (1.4+/-0.5 pmol/ml), parietal cortex (0.9+/-0.4 pmol/ml), frontal cortex (0.8+/-0.2 pmol/ml) and occipital cortex (0.7+/-0.3 pmol/ml). There was no significant difference in K(d) values in these six regions. The present results demonstrate that dopamine D2 receptor densities in the extrastriatal regions were only 2-8% of that in the striatum. Although the density of extrastriatal dopamine D2 receptor was low, significant regional differences were observed in the present study, as reported in postmortem studies.

Individual schizophrenic patients are sometimes reported to benefit from unusually high doses of neuroleptics. Such patients may have poor drug penetration into the brain or ultra-rapid metabolism. Alternately, very high doses may be required to induce occupancy of 5-HT(2) receptors, which have been suggested as mediators of atypical effects. Five schizophrenic patients treated with high doses of fluphenazine decanoate (100-250 mg/wk) and adjunct medications were examined with positron emission tomography and [(11)C]raclopride to measure D(2) receptor occupancy and [(11)C]NMSP to measure 5-HT(2) receptor occupancy. All patients were rated globally as 'markedly' to 'severely' ill and had high scores on all subscales of the Positive and Negative Syndrome Scale for schizophrenia. However, according to retrospective clinical evaluation, there was improved social function and reduced distress following high-dose treatment, an effect that deteriorated after previous explorative dose reduction. Extrapyramidal symptoms were modest. D(2) receptor occupancy was very high (89-97%). 5-HT(2) receptor occupancy was also high (76-105%). Plasma concentrations of fluphenazine were 5-37 nm. No patient had a cytochrome P450 CYP2D6 genotype associated with ultra-rapid drug metabolism. The findings suggest almost complete saturation of D(2) receptors, and do not support poor drug availability in the brain as the basis of the apparent high-dose requirement. The high 5-HT(2) receptor occupancy may have contributed to the apparent clinical improvement and modest degree of EPS. However, it is likely that the treatment used also induced occupancy of other neuroreceptors.

Almost half a century ago, a series of remarkable therapeutic developments occurred and were soon recognised as milestones in the history of medicine. The introduction of lithium, chlorpromazine, imipramine and the monoamine oxidase inhibitors, within a few years of each other, radically altered the prospects for treating serious psychiatric disorders. Until then, electroconvulsive therapy had been the only definitive treatment available. Research on pharmacological agents that alleviate disturbances of mood, cognition and behaviour, was given an impetus that led to quantum expansion in the ensuing years. It has become customary to recount the history of neuropsychopharmacology from that time. Although this is an understandable bias, it ignores much fundamental research in neurophysiology, neurochemistry and pharmacology and clinical experimentation with psychoactive agents that laid the foundations for what was to follow. Nevertheless, neuropsychopharmacology is still a very young discipline. This manifests not only in chronology but in the ferment, rapid shifts in priorities and fluidity of fundamental concepts that are hallmarks of youth. The critical observer cannot but concede the likelihood that tenets held basic to contemporary neuropsychopharmacology could turn out to be substantially overemphasised, unacceptably simplistic or even incorrect, in the relatively near future. Perusal of major papers in the field, published no more than one or two decades ago, confirms this impression. Rather than detracting from the discipline, these attributes are what give neuropsychopharmacology its remarkable allure. There is the distinct feeling that much of what can be known has yet to be discovered. Steps equal to or greater in impact than those of half a century ago, wait to be taken.