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In this study, we aim to explore the effects of two dopamine agonists (levodopa and bromocriptine) and two dopamine antagonists (tiapride and haloperidol) on fear extinction learning. To do so, young and healthy participants (18 to 35 years old) will undergo a three-day fear conditioning paradigm. Fear conditioning is an associative learning paradigm in which an originally neutral stimulus (conditioned stimulus (CS)) elicits fearful responses after being paired with an aversive stimulus (unconditioned stimulus (US)). Once the CS/US association is learned during fear acquisition training, repeated omission of the expected aversive US following CS presentations leads to a progressive decrease of conditioned fear responses (CR), that is extinction learning. In the recent literature, the dopaminergic system is thought to play an important function in mediating fear extinction due to its critical role in reward learning. A fundamental previous discovery was that the reward prediction error driving appetitive learning is signaled by a phasic dopamine increase originating in neurons of the ventral tegmental area (VTA; Schultz, 2016, for review). Because the unexpected omission of the US is rewarding (outcome better than expected), it has been proposed that the reward prediction error driving fear extinction learning is also mediated by dopamine release in the VTA (Kalisch et al., 2019). In humans, the application of levodopa immediately after extinction training augmented consolidation of the extinction memory trace (Gerlicher et al., 2018). Our goal is to assess the effects of dopaminergic and antidopaminergic drugs in extinction learning and recall. The drug will be administered prior to extinction training. Primary physiological outcome measures are changes in pupil size and skin conductance responses.

The relationships between the neurotoxicant manganese (Mn), dopaminergic pathology, and parkinsonism remain unclear. Therefore, we used [11C](N-methyl)benperidol (NMB) positron emission tomography to investigate the associations between Mn exposure, striatal and extrastriatal D2 dopamine receptors (D2R), and motor function in 54 workers with a range of Mn exposure. Cumulative Mn exposure was estimated from work histories, and all workers were examined by a movement specialist and completed a Grooved Pegboard test (GPT). NMB D2R nondisplaceable binding potentials (BPND) were calculated for brain regions of interest. We identified 2 principal components (PCs) in a PC analysis which explained 66.8% of the regional NMB BPND variance (PC1 = 55.4%; PC2 = 11.4%). PC1 was positively correlated with NMB binding in all regions and inversely correlated with age. PC2 was driven by NMB binding in 7 brain regions (all p

Parkinson's disease (PD) is among the most prevalent neurodegenerative diseases. Available evidences support the view of PD as a complex disease, being the outcome of interactions between genetic and environmental factors. In face of diagnosis and therapy challenges, and the elusive PD etiology, the use of alternative methodological approaches for the elucidation of the disease pathophysiological mechanisms and proposal of novel potential therapeutic interventions has become increasingly necessary. In the present study, we first reconstructed the transcriptional regulatory networks (TN), centered on transcription factors (TF), of two brain regions affected in PD, the substantia nigra pars compacta (SNc) and the frontal cortex (FCtx). Then, we used case-control studies data from these regions to identify TFs working as master regulators (MR) of the disease, based on region-specific TNs. Twenty-nine regulatory units enriched with differentially expressed genes were identified for the SNc, and twenty for the FCtx, all of which were considered MR candidates for PD. Three consensus MR candidates were found for SNc and FCtx, namely ATF2, SLC30A9, and ZFP69B. In order to search for novel potential therapeutic interventions, we used these consensus MR candidate signatures as input to the Connectivity Map (CMap), a computational drug repositioning webtool. This analysis resulted in the identification of four drugs that reverse the expression pattern of all three MR consensus simultaneously, benperidol, harmaline, tubocurarine chloride, and vorinostat, thus suggested as novel potential PD therapeutic interventions.

Background Alzheimer’s disease (AD) is the most prevalent form of dementia and represents one of the highest unmet requirements in medicine today. There is shortage of novel molecules entering into market because of poor pharmacokinetic properties and safety issues. Drug repurposing offers an opportunity to reinvigorate the slowing drug discovery process by finding new uses for existing drugs. The major advantage of the drug repurposing approach is that the safety issues are already investigated in the clinical trials and the drugs are commercially available in the marketplace. As this approach provides an effective solution to hasten the process of providing new alternative drugs for AD, the current study shows the molecular interaction of already known antipsychotic drugs with the different protein targets implicated in AD using in silico studies. Result A computational method based on ligand–protein interaction was adopted in present study to explore potential antipsychotic drugs for the treatment of AD. The screening of approximately 150 antipsychotic drugs was performed on five major protein targets (AChE, BuChE, BACE 1, MAO and NMDA) by molecular docking. In this study, for each protein target, the best drug was identified on the basis of dock score and glide energy. The top hits were then compared with the already known inhibitor of the respective proteins. Some of the drugs showed relatively better docking score and binding energies as compared to the already known inhibitors of the respective targets. Molecular descriptors like molecular weight, number of hydrogen bond donors, acceptors, predicted octanol/water partition coefficient and percentage human oral absorption were also analysed to determine the in silico ADME properties of these drugs and all were found in the acceptable range and follows Lipinski’s rule. Conclusion The present study have led to unravel the potential of leading antipsychotic drugs such as pimozide, bromperidol, melperone, anisoperidone, benperidol and anisopirol against multiple targets associated with AD. Benperidol was found to be the best candidate drug interacting with different target proteins involved in AD.

In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n = 39) was composed of obese and nonobese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1-), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1- was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [(11) C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states.

Alterations in dopaminergic circuitry play a critical role in food reward and may contribute to susceptibility to obesity. Ingestion of sweets releases dopamine in striatum, and both sweet preferences and striatal D2 receptors (D2R) decline with age and may be altered in obesity. Understanding the relationships between these variables and the impact of obesity on these relationships may reveal insight into the neurobiological basis of sweet preferences. We evaluated sucrose preferences, perception of sweetness intensity, and striatal D2R binding potential (D2R BPND) using positron emission tomography with a D2R-selective radioligand insensitive to endogenous dopamine, (N-[11C] methyl)benperidol, in 20 subjects without obesity (BMI 22.5 ± 2.4 kg/m2; age 28.3 ± 5.4 years) and 24 subjects with obesity (BMI 40.3 ± 5.0 kg/m2; age 31.2 ± 6.3 years). The groups had similar sucrose preferences, sweetness intensity perception, striatal D2R BPND, and age-related D2R BPND declines. However, both striatal D2R BPND and age correlated with sucrose preferences in subjects without obesity, explaining 52% of their variance in sucrose preference. In contrast, these associations were absent in the obese group. In conclusion, the age-related decline in D2R was not linked to the age-related decline in sweetness preferences, suggesting that other, as-yet-unknown mechanisms play a role and that these mechanisms are disrupted in obesity.

A detailed study of molecular conformation and intermolecular interactions in the experimental crystal structures and general trends observed in the Cambridge Structural Database as well as theoretical calculations were performed to identify the reason for the formation of different crystal structures of two chemically very similar pharmaceutical molecules benperidol and droperidol. The most important difference between both molecules was the weak intermolecular interactions formed by the central ring which therefore was responsible for the formation of different crystal structures. Cross-seeding experiments were performed to check the possibility for the formation of mutually isostructural phases, and theoretical calculations were performed to compare the stability of experimentally observed phases and theoretical isostructural phases by therefore rationalizing the results of the cross-seeding experiments. In cross-seeding crystallizations, three new droperidol phases—an ethanol monosolvate, a dihydrate ...

ObjectiveTo investigate the associations between manganese (Mn) exposure, D2 dopamine receptors (D2Rs), and parkinsonism using [11C](N-methyl)benperidol (NMB) PET.MethodsWe used NMB PET to evaluate 50 workers with a range of Mn exposure: 22 Mn-exposed welders, 15 Mn-exposed workers, and 13 nonexposed workers. Cumulative Mn exposure was estimated from work histories, and movement disorder specialists examined all workers. We calculated NMB D2R nondisplaceable binding potential (BPND) for the striatum, globus pallidus, thalamus, and substantia nigra (SN). Multivariate analysis of covariance with post hoc descriptive discriminate analysis identified regional differences by exposure group. We used linear regression to examine the association among Mn exposure, Unified Parkinson’s Disease Rating Scale motor subsection 3 (UPDRS3) score, and regional D2R BPND.ResultsD2R BPND in the SN had the greatest discriminant power among exposure groups (p < 0.01). Age-adjusted SN D2R BPND was 0.073 (95% confidence interval [CI] 0.022–0.124) greater in Mn-exposed welders and 0.068 (95% CI 0.013–0.124) greater in Mn-exposed workers compared to nonexposed workers. After adjustment for age, SN D2R BPND was 0.0021 (95% CI 0.0005–0.0042) higher for each year of Mn exposure. Each 0.10 increase in SN D2R BPND was associated with a 2.65 (95% CI 0.56–4.75) increase in UPDRS3 score.Conclusions and relevanceNigral D2R BPND increased with Mn exposure and clinical parkinsonism, indicating dose-dependent dopaminergic dysfunction of the SN in Mn neurotoxicity.

Experimental and theoretical characterization and studies of phase transitions and stability of the solvates obtained in solvate screening of the pharmaceutical compound benperidol were performed to rationalize and understand the solvate formation, stability, and phase transitions occurring during their desolvation. The solvate screening revealed that benperidol can form 11 solvates, including two sets of isostructural solvates. The analysis of the solvate crystal structures and molecular properties indicated that benperidol solvate formation is mainly driven by the complications during packing of benperidol molecules in an energetically efficient way in the absence of solvent molecules, as well as by the compensation of an insufficient number of hydrogen bond donor moieties. Analysis of solvate structures, particularly those of isostructural solvates, revealed that both the possible interactions and the size and shape of the solvent molecules were important factors in solvate formation. Stability of the ...

A group effect is generally assumed regarding the prolongation of the QT interval through butyrophenone antipsychotics like haloperidol. Consequently intravenous administration of benperidol is seen critically notwithstanding sparse evidence; thus benperidol and haloperidol were compared regarding their cardiac risk of prolonging the QT interval when administered intravenously for acute sedation of psychotic patients. The QT interval was measured by a 12-lead ECG. For the correction of QT values Bazett’s formula was used. The resulting QTc intervals of the benperidol and the haloperidol group were compared using Mann–Whitney U-test. Our data provide statistical evidence for benperidol being less prone to cause QTc prolongation than haloperidol (p = 0.049). The results of our study indicate a more favourable risk profile of benperidol compared to haloperidol regarding QTc prolongation when administered intravenously.

This chapter describes methods of synthesis, the pharmacological properties, and the use of derivatives of piperidine-based nonfused biheterocycles with C–N and C–C coupling. Piperidine-based nonfused biheterocycles with C–N coupling are presented as a series of drugs such as droperidol, benperidol, timiperone, pimozide, zaldaride, domperidone, and bezitramide—compounds that are effective as antipsychotic agents. Two compounds of this series, benzpiperylon and piperylon, have analgesic and antipyretic properties. Piperidine-based nonfused biheterocycles with C–C coupling are presented by atypical antipsychotic drugs such as risperidone, paliperidone, and iloperidone. Sertindole, a second-generation atypical antipsychotic, and naratriptan, which belongs to a family of triptans, and indicated for the treatment of migraine headaches, are two other representatives of piperidine-based nonfused biheterocycle with C–C coupling.

Previous PET imaging studies have demonstrated mixed findings regarding dopamine D2/D3 receptor availability in obese relative to nonobese humans. Nonspecific D2/D3 radioligands do not allow for separate estimation of D2 receptor (D2R) and D3 receptor (D3R) subtypes of the D2 receptor family, which may play different roles in behavior and are distributed differently throughout the brain. These radioligands are also displaceable by endogenous dopamine, confounding interpretation of differences in receptor availability with differing levels of dopamine release. The present study used PET imaging with the D2R-selective radioligand (N-[(11)C] methyl)benperidol ([(11)C]NMB), which is nondisplaceable by endogenous dopamine, to estimate D2R specific binding (BPND) and its relationship to body mass index (BMI) and age in 15 normal-weight (mean BMI = 22.6 kg/m(2)) and 15 obese (mean BMI = 40.3 kg/m(2)) men and women. Subjects with illnesses or taking medications that interfere with dopamine signaling were excluded. Striatal D2R BPND was calculated using the Logan graphical method with cerebellum as a reference region. D2R BPND estimates were higher in putamen and caudate relative to nucleus accumbens, but did not differ between normal-weight and obese groups. BMI values did not correlate with D2R BPND . Age was negatively correlated with putamen D2R BPND in both groups. These results suggest that altered D2R specific binding is not involved in the pathogenesis of obesity per se and underscore the need for additional studies evaluating the relationship between D3R, dopamine reuptake, or endogenous dopamine release and human obesity.

Deficits in central, subcortical dopamine (DA) signaling may underlie negative symptom severity, particularly anhedonia, in healthy individuals and in schizophrenia. To investigate these relationships, we assessed negative symptoms with the Schedule for the Assessment of Negative Symptoms and the Brief Negative Symptom Scale (BNSS) and self-reported anhedonia with the Scales for Physical and Social Anhedonia (SPSA), Temporal Experience of Pleasure Scale, and Snaith-Hamilton Pleasure Scale in 36 healthy controls (HC), 27 siblings (SIB) of individuals with schizophrenia, and 66 individuals with schizophrenia or schizoaffective disorder (SCZ). A subset of participants (N = 124) were genotyped for DA-related polymorphisms in genes for DRD4, DRD2/ANKK1, DAT1, and COMT, which were used to construct biologically-informed multi-locus genetic profile (MGP) scores reflective of subcortical dopaminergic signaling. DA receptor type 2 (D2R) binding was assessed among a second subset of participants (N = 23) using PET scans with the D2R-selective, non-displaceable radioligand (N-[11C]methyl)benperidol. Higher MGP scores, reflecting elevated subcortical dopaminergic signaling capacity, were associated with less negative symptom severity, as measured by the BNSS, across all participants. In addition, higher striatal D2R binding was associated with less physical and social anhedonia, as measured by the SPSA, across HC, SIB, and SCZ. The current preliminary findings support the hypothesis that subcortical DA function may contribute to negative symptom severity and self-reported anhedonia, independent of diagnostic status.

In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n = 39) was composed of obese and nonobese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1-), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1- was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [(11) C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states.

Alterations of striatal and extrastriatal concentrations of the dopaminergic D2 receptor family, including subtypes D2 (D2R) and D3 (D3R), may play a role in the pathophysiology or treatment of movement and psychiatric disorders including Parkinson disease (Kaasinen et al., 2000a; Kaasinen et al., 2003; Smith and Villalba, 2008), dystonia (Karimi et al., 2011; Perlmutter et al., 1997), Huntington's disease (Pavese et al., 2003), restless legs syndrome (Cervenka et al., 2006; Connor et al., 2009), schizophrenia (Kegeles et al., 2010), social phobia (Schneier et al., 2000) and Tourette syndrome (Gilbert et al., 2006; Steeves et al., 2010). PET imaging with dopamine receptor radioligands provides an in vivo method to investigate such alterations. The most commonly used PET radioligands for the measurement of the D2 family of receptors include [11C] raclopride, [18F]fallypride and [11C]FLB 457. However, the disadvantages of using these radioligands is that they have near equal affinity for both D2R and D3R subtypes (Elsinga et al., 2006; Halldin et al., 1995; Mukherjee et al., 1999) and competition from endogenous dopamine may alter their uptake and retention in brain (Chou et al., 2000; Cropley et al., 2008; Dewey et al., 1992; Dewey et al., 1993; Montgomery et al., 2007; Riccardi et al., 2006; Seeman et al., 1989). These characteristics can be exploited in some experimental designs to measure endogenous dopamine release, but confound interpretation of specific binding levels since the PET measurement may reflect both the binding potential of D2R and D3R subtypes and levels of endogenous dopamine. Although pharmacologic distinction between D2R and D3R subtypes of the dopamine D2 receptor family has been accomplished only recently, the DNA and mRNA that code for these proteins are quite distinct (Chien et al., 2010; Gingrich and Caron, 1993; Sokoloff et al., 1990). Post-mortem radioligand receptor autoradiography of D2R and D3R in the human brain reveal different receptor binding site patterns throughout the brain (Beaulieu and Gainetdinov, 2011; Hall et al., 1996a, b; Murray et al., 1994). Receptor distribution and mRNA expression levels in humans and rodents as determined by receptor autoradiography and in situ hybridization indicate that D2R is distributed heterogeneously throughout the brain; high levels of D2R occur in the dorsal striatum and pole of the nucleus accumbens as well as extrastriatal and cortical regions whereas D3R is highly distributed in limbic areas including the shell of the nucleus accumbens (Hall et al., 1996a, b; Missale et al., 1998; Sokoloff et al., 1992b; Vallone et al., 2000, Xu et al., 2010). However, recent autoradiography data from aged human brains demonstrate that D3R are distributed extensively throughout the striatum (Xu et al., 2011). Therefore, interpretation of previous D2/D3R distribution ratio reports should be viewed with caution; conflicting findings such as these indicate the need for in vivo study of D2R and D3R with PET radioligands specific for D2R or D3R in humans. The differences in regional binding patterns of the D2R subtypes indicate that D2R and D3R likely play different roles in reward, cognition, movement and psychiatric disorders. For example, abnormalities in striatal D3R may play a key role in the pathophysiology of dystonia (Karimi et al., 2011). Notably, antipsychotic drugs have a higher affinity for D2R over D3R (Civelli et al., 1993; Sokoloff et al., 1992), suggesting a larger role for the D2R subtype in neuropsychiatric disorders, or, alternatively, that the D3 subtype may represent a relatively unexplored therapeutic target for D3-selective antagonist antipsychotics. Currently, the relatively modestly D3-preferring PET radiotracer and dopamine agonist [11C]-PHNO has been used to measure D3 specific receptor types (Gallezot et al., 2011; Girgis et al., 2011; Tziortzi et al., 2011). Improved distinction between D2R and D3R binding in striatal and extrastriatal regions via PET imaging would provide a valuable clinical research tool for in vivo study of neuropsychiatric disorders. [18F]N-methylbenperidol ([18F]NMB) is a PET radioligand developed to measure D2R. It is an analog of the dopamine receptor antagonist benperidol of the butyrophenone structural class, has been clinically used as an antipsychotic drug (Reynolds, 1993), and has high affinity and selectivity for D2R (Karimi et al., 2011; Moerlein et al., 1995;, Suehiro et al., 1990). These latter characteristics have made butyrophenones compounds of interest in the search for PET dopamine receptor radioligands (Arnett et al., 1986; Moerlein et al, 1986, 1992, 1995; Suehiro et al., 1990). Selectivity of [18F]NMB and its analogues for D2 receptors over D1, serotonergic and adrenergic receptors has been demonstrated in vivo in baboon and in vitro in mice by unaltered striatal uptake after pretreatment with unlabeled receptor-specific antagonists and by displacement with unlabeled D2 antagonists (Arnett et al., 1985; Moerlein et al., 1995, 1997; Suehiro et al., 1990) [18F]NMB has more than 200-fold higher affinity for D2R than D3R, as recently demonstrated by in vitro radioligand binding assays in transfected cells that express D2 and D3 receptors (Karimi et al., 2011). [18F]NMB reversibly binds to D2R's (Moerlein et al., 1995, 1997; Suehiro et al., 1990) and resists competition from endogenous dopamine release, as demonstrated by lack of displacement by high dose intravenous amphetamine (Moerlein et al., 1997). Thus, [18F]NMB is an excellent candidate radioligand for unambiguous PET quantification of the D2R subtype in brain. Previous research demonstrated [18F]NMB's ability to specifically bind to D2R in striatum (Antenor-Dorsey et al., 2008; Karimi et al., 2011). However, PET measures of extrastriatal D2R specific binding with [18F]NMB has not yet been quantified. Given the importance of extrastriatal D2R binding in neuropsychiatric and movement disorders, it is necessary to determine whether PET using [18F]NMB can reliably measure D2R specific binding in these regions. We now report such PET imaging studies in healthy adults.

A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D(₂-like) dopamine receptors. These compounds also share structural elements with the classical D(₂-like) dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (7) were found to (a) bind to the D₂ receptor subtype with high affinity (K(i) values0.3 nM), (b) exhibit50-fold D₂ versus D₃ receptor binding selectivity and (c) be partial agonists at both the D₂ and D₃ receptor subtype.

In the present study, the binding potential (BP) of the D2 receptor radioligand ( 18 F)N-methyl-benperidol (( 18 F)FMB) was determined with in vivo saturation binding analysis using either cerebellum or parietal cortex as reference region. For the purpose of validation, BP additionally was determined in the same set of animals by computing the equilibrium ratios of the distribution volumes (V3''). With in vivo saturation binding analysis, the striatal BP as obtained with a cortical estimate for the free and non-specifically bound radioligand fell short of the BP as obtained with a cerebellar estimate by 70%. Similarly, with the equilibrium distribution volume method, the employment of a cortical REF led to a striatal V3'', which was 30% lower than the V3'' obtained with a cerebellar REF. The BP determined with in vivo saturation binding analysis and a cerebellar REF provided a closer approximation to the BP previously obtained with in vitro autoradiography relative to the BP determined with in vivo saturation binding analysis and a cortical REF. Findings show that in vivo saturation binding analysis is a feasible approach to obtain receptor binding parameters if scanner characteristics or other technical limitations preclude the kinetic modelling of binding data. However, caution should be exerted in choosing the reference tissue with regard to the intended investigation.

Plasma levels of prolactin (PRL) and the butyrophenone neuroleptic benperidol (BPD) were closely followed 0 to 48 h after acute application of 6 mg BPD as intravenous injection, orally as liquid, and orally as tablets in 12 schizophrenic patients using a partially randomized cross over design. Drug concentrations showed application specific pharmacokinetic behavior with complete elimination within 48 h. All three applications led to a biphasic PRL response with pronounced initial plasma PRL peaks returning to baseline levels within 48 h. The results suggest that after acute neuroleptic challenge BPD plasma levels as low as 2-3 ng/ml can be sufficient for complete depletion of pituitary PRL stores. This initial peak was followed by a PRL plateau about twice above pretreatment values indicating doubling of the PRL synthesis and secretion independent of supraeffective actual BPD concentrations. The PRL plateau persisted as long as BPD concentrations were above those levels which triggered the initial PRL response. As compared with the time of maximum concentrations (tmax) for BPD, the PRL tmax was later after i.v. injection, equal after liquid application, and earlier after tablet administration leading to pronounced application specific differences in shape, direction, and position of resulting hysteresis curves. Plasma levels of homovanillic acid (HVA) were not affected by BPD treatment. The PRL and HVA levels registered after acute doses of BPD indicated that the hormone responses were most likely the result of acute depletion of PRL stores and subsequent stimulation of hormone synthesis whereas it seemed unlikely that dopaminergic activities were relevant.

The frequency of postoperative nausea and vomiting following common ocular operations was studied in 110 male and 125 female patients anaesthetized by four different techniques: N2O- O2-relaxant anaesthesia, neurolept analgesia, N2O-O2-halothane anaesthesia, and local anaesthesia with 2% mepivacaine. There were no significant differences between these various techniques in regard to the frequency of nausea and vomiting, although local anaesthesia seemed to give the best results in this respect. In the second part of the study, the antiemetic effect of dehydrobenzperidol was studied in 127 male and 175 female patients. A dose of 2.5 mg of this drug was effective in preventing postoperative vomiting both after N2O-O2-relaxant anaesthesia and, more distinctly, after local anaesthesia.

N-([(11)C]methyl)benperidol ([(11)C]NMB) can be used for positron emission tomography (PET) measurements of D(2)-like dopamine receptor binding in vivo. We report the absorbed radiation dosimetry of i.v.-administered (11)C-NMB, a critical step before applying this radioligand to imaging studies in humans.Whole-body PET imaging with a CTI/Siemens ECAT 953B scanner was done in a male and a female baboon. After i.v. injection of 444-1221 MBq of (11)C-NMB, sequential images taken from the head to the pelvis were collected for 3 h. Volumes of interest (VOIs) were identified that entirely encompassed small organs (whole brain, striatum, eyes, and myocardium). Large organs (liver, lungs, kidneys, lower large intestine, and urinary bladder) were sampled by drawing representative regions within the organ volume. Time-activity curves for each VOI were extracted from the PET, and organ residence times were calculated by analytical integration of a multi-exponential fit of the time-activity curves. Human radiation doses were estimated using OLINDA/EXM 1.0 and the standard human model.Highest retention was observed in the blood and liver, each with total residence times of 1.5 min. The highest absorbed radiation doses were to the heart (10.5 μGy/MBq) [DOSAGE ERROR CORRECTED] and kidney (9.19 μGy/MBq), [DOSAGE ERROR CORRECTED] making these the critical organs for [(11)C]NMB. A heart absorption of 50 mGy would result from an injected dose of 4,762 MBq [(11)C]NMB.Thus, this study suggests that up to 4,762 MBq of [(11)C]NMB can be safely administered to human subjects for PET studies. Total body dose and effective dose for [(11)C]NMB are 2.82 μGy/MBq [DOSAGE ERROR CORRECTED] and 3.7 mSv/kBq, respectively.

Preclinical Safety Pharmacology (PSP) attempts to anticipate adverse drug reactions (ADRs) during early phases of drug discovery by testing compounds in simple, in vitro binding assays (that is, preclinical profiling). The selection of PSP targets is based largely on circumstantial evidence of their contribution to known clinical ADRs, inferred from findings in clinical trials, animal experiments, and molecular studies going back more than forty years. In this work we explore PSP chemical space and its relevance for the prediction of adverse drug reactions. Firstly, in silico (computational) Bayesian models for 70 PSP-related targets were built, which are able to detect 93% of the ligands binding at IC(50) < or = 10 microM at an overall correct classification rate of about 94%. Secondly, employing the World Drug Index (WDI), a model for adverse drug reactions was built directly based on normalized side-effect annotations in the WDI, which does not require any underlying functional knowledge. This is, to our knowledge, the first attempt to predict adverse drug reactions across hundreds of categories from chemical structure alone. On average 90% of the adverse drug reactions observed with known, clinically used compounds were detected, an overall correct classification rate of 92%. Drugs withdrawn from the market (Rapacuronium, Suprofen) were tested in the model and their predicted ADRs align well with known ADRs. The analysis was repeated for acetylsalicylic acid and Benperidol which are still on the market. Importantly, features of the models are interpretable and back-projectable to chemical structure, raising the possibility of rationally engineering out adverse effects. By combining PSP and ADR models new hypotheses linking targets and adverse effects can be proposed and examples for the opioid mu and the muscarinic M2 receptors, as well as for cyclooxygenase-1 are presented. It is hoped that the generation of predictive models for adverse drug reactions is able to help support early SAR to accelerate drug discovery and decrease late stage attrition in drug discovery projects. In addition, models such as the ones presented here can be used for compound profiling in all development stages.

PET studies have provided mixed evidence regarding central D2/D3 dopamine receptor binding and its relationship with obesity as measured by body mass index (BMI). Other aspects of obesity may be more tightly coupled to the dopaminergic system. We characterized obesity-associated behaviors and determined if these related to central D2 receptor (D2R) specific binding independent of BMI. Twenty-two obese and 17 normal-weight participants completed eating- and reward-related questionnaires and underwent PET scans using the D2R-selective and nondisplaceable radioligand (N-[11C]methyl)benperidol. Questionnaires were grouped by domain (eating related to emotion, eating related to reward, non-eating behavior motivated by reward or sensitivity to punishment). Normalized, summed scores for each domain were compared between obese and normal-weight groups and correlated with striatal and midbrain D2R binding. Compared to normal-weight individuals, the obese group self-reported higher rates of eating related to both emotion and reward (p p = 0.06) and lower non-food reward behavior (p p p

A procedure for the reliable production of the novel PET D2 receptor ligand (N-[11C]methyl)benperidol ([11C]NMB) is described. The method is based on N-methylation of benperidol using [11C]methyl iodide from the PETtrace MeI MicroLab, with product purification via normal-phase HPLC. Batch yields of 2.5±0.9 GBq (68±25 mCi) of [11C]NMB are routinely (n=16) obtained, with a radiochemical purity >98% and an average specific activity of over 40.7 TBq (1100 Ci)/mmol. The overall radiosynthesis, purification, and pre-release quality control testing is accomplished within 50 minutes. The procedure described herein produces a radiopharmaceutical product that is suitable for D2 receptor studies using PET or microPET imaging.

Wir berichten uber eine selten zu beobachtende Leukopenieneigung unter Monotherapie mit zwei Butyrophenon-Neuroleptika (Haloperidol und Benperidol) bei einer akut behandlungsbedurftigen Patientin mit schizophrener Psychose. Weiterhin stellen wir unseren pharmakotherapeutischen Behandlungsansatz dar, der die relativ kurze Eliminationshalbwertszeit von Benperidol bei “Intervallgabe” jeden 2. Tag nutzt. Hierunter kam es neben einer Verbesserung des psychopathologischen Befundes zu einer Erholung des weisen Blutbildes.

Background: Animal and postmortem studies indicate that neuroleptic therapy may induce D 2 dopamine receptor up-regulation in the basal ganglia. Methods: To address this phenomenon in a clinical study, we investigated the D 2 dopamine receptor binding in 15 DSM-III-R schizophrenics in the drug-naive state and 3 days after completion of a standardized neuroleptic therapy (benperidol 12–16 mg/day, for 25 days) using single photon emission computed tomography (SPECT). SPECT scans were obtained 2 hours after intravenous injection of 185 MBq 123 I-iodobenzamide. For analysis, basal ganglia to frontal cortex (BG/FC) ratios were calculated and the patient sample was subgrouped into patients with a favorable versus a poor treatment response. Results: Neuroleptic treatment led to decreased BG/FC ratios in patients with a favorable response, but increased ratios in the poor responders (df = 1, F = 4.1, p = .06). Changes of BG/FC ratios were significantly correlated with extrapyramidal side effects but not with neurological soft signs. Conclusions: Our findings suggest that neuroleptic therapy may induce D 2 dopamine receptor up-regulation in a subgroup of patients characterized by poor treatment response and pronounced extrapyramidal side effects.

Radiation absorbed doses due to IV administration of [18F](N-methyl) benperidol ([18F]NMB) were estimated by whole-body PET imaging of nonhuman primates. Time-activity curves were obtained for nine compartments (striatum, eyes, heart, lungs, liver, gallbladder, intestines, kidneys, bladder) by using dynamic PET scans of three different baboons given the radiotracer. These time-activity curves were used to calculate the residence times of radioactivity in these tissues. Human absorbed dose estimates were calculated using the updated MIRDOSE 3 S values and assuming the same biodistribution. Based on an average of three studies, the critical organs were the lower large intestine, gallbladder, and liver, receiving doses of 585, 281, and 210 mrad/mCi, respectively. The brain received a dose of 13 mrad/mCi; other organs received doses between 32-77 mrad/mCi. These results indicate that up to 8.5 mCi of [18F]NMB can be safely administered to human subjects for PET studies of D2 receptor binding.

Previous PET imaging studies have demonstrated mixed findings regarding dopamine D2/D3 receptor availability in obese relative to nonobese humans. Nonspecific D2/D3 radioligands do not allow for separate estimation of D2 receptor (D2R) and D3 receptor (D3R) subtypes of the D2 receptor family, which may play different roles in behavior and are distributed differently throughout the brain. These radioligands are also displaceable by endogenous dopamine, confounding interpretation of differences in receptor availability with differing levels of dopamine release. The present study used PET imaging with the D2R-selective radioligand (N-[(11)C] methyl)benperidol ([(11)C]NMB), which is nondisplaceable by endogenous dopamine, to estimate D2R specific binding (BPND) and its relationship to body mass index (BMI) and age in 15 normal-weight (mean BMI = 22.6 kg/m(2)) and 15 obese (mean BMI = 40.3 kg/m(2)) men and women. Subjects with illnesses or taking medications that interfere with dopamine signaling were excluded. Striatal D2R BPND was calculated using the Logan graphical method with cerebellum as a reference region. D2R BPND estimates were higher in putamen and caudate relative to nucleus accumbens, but did not differ between normal-weight and obese groups. BMI values did not correlate with D2R BPND . Age was negatively correlated with putamen D2R BPND in both groups. These results suggest that altered D2R specific binding is not involved in the pathogenesis of obesity per se and underscore the need for additional studies evaluating the relationship between D3R, dopamine reuptake, or endogenous dopamine release and human obesity.

In this study, pKa values of some ionizable butyrophenones, namely, benperidol, droperidol, and haloperidol were determined using by the dependence of the retention factor on pH of the mobile phase. The effect of the mobile phase composition on the ionization constant was studied by measuring the pKa at different methanol-water mixtures, ranging between 50 and 65% (v/v) using an LC-UV method. Additionally, a simple, accurate, precise, and fully validated analytical method for the simultaneous and individual determination of benperidol, droperidol, and haloperidol in their dosage forms was developed. Butyrophenones were exposed to thermal, photolytic, hydrolytic, and oxidative stress conditions, and the stressed samples were detected by the proposed method. © 2013 Copyright Taylor and Francis Group, LLC.

PET imaging studies of the role of the dopamine D2 receptor family in movement and neuropsychiatric disorders are limited by the use of radioligands that have near-equal affinities for D2 and D3 receptor subtypes and are susceptible to competition with endogenous dopamine. By contrast, the radioligand [¹⁸F]N-methylbenperidol ([¹⁸F]NMB) has high selectivity and affinity for the D2 receptor subtype (D2R) and is not sensitive to endogenous dopamine. Although [¹⁸F]NMB has high binding levels in striatum, its utility for measuring D2R in extrastriatal regions is unknown. A composite MR-PET image was constructed across 14 healthy adult participants representing average NMB uptake 60 to 120 min after [¹⁸F]NMB injection. Regional peak radioactivity was identified using a peak-finding algorithm. FreeSurfer and manual tracing identified a priori regions of interest (ROI) on each individual's MR image and tissue activity curves were extracted from coregistered PET images. [¹⁸F]NMB binding potentials (BP(ND) s) were calculated using the Logan graphical method with cerebellum as reference region. In eight unique participants, extrastriatal BP(ND) estimates were compared between Logan graphical methods and a three-compartment kinetic tracer model. Radioactivity and BP(ND) levels were highest in striatum, lower in extrastriatal subcortical regions, and lowest in cortical regions relative to cerebellum. Age negatively correlated with striatal BP(ND) s. BP(ND) estimates for extrastriatal ROIs were highly correlated across kinetic and graphical methods. Our findings indicate that PET with [¹⁸F]NMB measures specific binding in extrastriatal regions, making it a viable radioligand to study extrastriatal D2R levels in healthy and diseased states.

Pharmacokinetics and bioavailability of benperidol were determined in 13 schizophrenic patients after acute administration of 6 mg benperidol as an intravenous (i.v.) bolus injection, orally as liquid, and orally as tablets using a partially randomized cross-over design. Drug plasma levels were determined by high performance liquid chromatography with electrochemical detection and subjected to model independent pharmacokinetic analyses. After i.v. dosing the geometric means (mean-g) were 3.2 min for the distribution half-life, 5.80 h for the elimination half-life (t1/2 beta), 4.21 l/kg for the distribution volume, 7.50 h for the mean residence time (MRT), and 0.50 l/(h*kg) for the clearance. After oral administration as liquid and as tablet mean-g data for the time lag until the first appearance of measurable plasma concentrations were 0.33 and 1.1 h, mean-g t1/2 beta values were 5.5 and 4.7 h, respectively, mean-g tmax data were 1.0 h and 2.7 h, mean-g MRT values were 8.44 and 8.84 h, and mean-g Cmax maxvalues were 10.2 and 7.3 ng/ml. Differences between liquid and tablet administration were statistically significant for time lag, tmax, and Cmax. Mean-g absolute bioavailabilities were computed as 48.6% after liquid and 40.2% after tablet administration respectively. All parameters studied exhibited large intersubject variation. The plasma concentrations of the presumed metabolite "reduced benperidol" were found to be very low.

Based on the direct nucleophilic aromatic substitution described previously for [ 18 F ]N- methylspiperone the butyrophenone neuroleptics benperidol, droperidol, fluanisone and haloperidol were labelled with fluorine-18. The n.c.a. aromatic nucleophilic NO2 → 18F substitution takes place in the presence of the moderately basic cryptate system consisting of Kryptofix® 2.2.2., potassium oxalate and potassium carbonate. The one step labeling reaction was performed in different solvents and is equally successful in dimethylsulfoxide, dimethylformamide or dimethylacetamide yielding 25–35% (EOS) within a reaction time of 5–30 min in the range of 140–160°C at analytical activity levels.

The routine production of the D2 receptor-binding radioligand [11C]NMB has been optimized. Uncorrected batch yields of 62–105 mCi of [11C]NMB are obtained within 35 minutes EOB, with a specific activity exceeding 500 Ci/mmol and a radiochemical purity exceeding 95%. PET imaging of baboons shows rapid, specific localization of [11C]NMB to cerebral D2 receptor-rich tissue of primate brain. The specific localization of the radioligand is altered by drug challenge or pathological conditions, indicating utility of the ligand for human application.

3N-(2′-[ 18 F]Fluoroethyl)benperidol ([ 18 F]FEB) an 18 F-labeled analogue of the D 2 antagonist benperidol, was evaluated as a tracer for positron emission tomography (PET). PET imaging of a living baboon showed that the fluorinated ligand rapidly localized in vivo within D 2 receptor-rich brain tissue, with selective retention lasting over 2 h after tracer injection. Pretreatment of the animal with unlabeled D 2 -specific antagonist eticlopride (4 mg/kg, i.v.) 1 h before [ 18 F]FEB completely abolished the selective disposition of the radioligand, whereas the regional cerebral blood flow, blood volume and peripheral metabolism/protein binding of [ 18 F]FEB were not changed. Tracer localization when the baboon was pretreated with unlabeled ketanserin (0.55 mg/kg, i.v.) or SCH 23390 (1.1 mg/kg, i.v.) was identical to that for the control case, indicating that the [ 18 F]FEB did not bind to S 2 of D 1 receptors in vivo. [ 18 F]FEB has advantages compared to previously used PET tracers, and may be an excellent radioligand for non-invasive study of D 2 receptor binding.

In the present study, the binding potential (BP) of the D2 receptor radioligand [18F]N-methyl-benperidol (FMB) was determined with in vivo saturation binding analysis using either cerebellum or parietal cortex as reference region. For the purpose of validation, BP additionally was determined in the same set of animals by computing the equilibrium ratios of the distribution volumes (V 3 ”). In a different set of animals, BP moreover was determined with in vitro storage phosphor autoradiography. With in vivo saturation binding analysis, the striatal BP as obtained with a cortical estimate for the free and non-specifically bound radioligand fell short of the BP as obtained with a cerebellar estimate by 70%. Similarly, with the equilibrium distribution volume method, the employment of a cortical REF led to a striatal V 3 ”, which was 30% lower than the V 3 ” obtained with a cerebellar REF. The BP determined with in vivo saturation binding analysis and a cerebellar REF provided a closer approximation to the autoradiographically obtained BP as the BP determined with in vivo saturation binding analysis and a cortical REF. Findings show that in vivo saturation binding analysis is a feasible approach to obtain receptor binding parameters if scanner characteristics or other technical limitations preclude the the kinetic modelling of binding data. However, caution should be exerted in choosing the reference tissue with regard to the intended investigation.

Es handelt sich bei der Arbeit um eine metaanalytische Evaluation dreier seit langer Zeit und insbesondere in Deutschland oft verwendeter Antipsychotika wie sie bei der Behandlung akuter und chronischer schizophrener Psychosen gebraucht werden. Mit nur einer randomisierten klinischen Doppelblindstudie lässt sich über Benperidol keine sichere Aussage über die Wirksamkeit treffen. Bei Perazin handelt es sich möglicherweise um ein altes, konventionelles Neuroleptikum mit einem atyposchen Wirkungsprofil. In die Metaanalyse zu Perphenazin konnten 25 RCTs eingeschlossen werden, wobei Perphenazin der neuen Generation der Antipsychotika nicht unterlegen zu sein scheint. This dissertation is a meta-analytic evaluation of three different antipsychotics which have been used in Germany for the treatment of schizophrenic episodes for about 40 years. As there is only one RCT available, no secure conclusion can be drawn regarding Benperidol. Perazine might have an atypical side-effect profile, but bigger studies are needed for a proof. The meta-analysis about Perphenazine includes 25 studies and no significant inferiority to atypical neuroleptics could be found.

By the application of 123([123I]IBZM), an iodine-labelled dopamine D2-receptor antagonist, brain D2 receptors in humans can be visualized with single photon emission computed tomography (SPECT). The ratio of IBZM binding to striatal regions versus binding to frontal cortex (ST/FC ratio) provided a semiquantitative measurement of D2 receptor binding in the striatum. This study investigated the relationship between receptor occupancy and plasma prolactin levels in 12 male patients treated with haloperidol, benperidol or clozapine. Prolactin levels were positively correlated with D2 receptor occupancy, reflecting at least in part a comparable dopamine receptor antagonism in different dopaminergic pathways.

A recent investigation showed that intracerebral radioactivity concentrations can reliably be quantified in vivo with a small-animal PET device. The purpose of the current study was to investigate the binding characteristics of the D(2) receptor radioligand (18)F-(3-N-methyl)benperidol ((18)FMB) in rat striatum by determining receptor density (B(max)) and affinity (K(d)) in vivo. For validation, K(d) and B(max) additionally were determined in vitro using storage phosphor autoradiography.Striatal radioactivity was measured with PET in 8 Sprague-Dawley rats after injection of (18)FMB in increasing specific activities. Free radioligand concentrations were estimated from cortical radioactivity concentrations and were subtracted from striatal radioactivity concentrations to obtain specific binding. In vitro saturation experiments were performed on 7 further rats according to the isotopic dilution method. Specific binding was determined by both subtraction of (18)FMB binding in the presence of raclopride and subtraction of cortical radioactivity concentrations from total radioligand binding. Saturation binding curves were obtained by plotting specifically bound radioligand concentrations against free radioligand concentrations and were evaluated with regression analysis.PET yielded a K(d) of 6.2 nmol/L and a B(max) of 16 fmol/mg for the striatal D(2) receptor. In vitro, K(d) and B(max) amounted to 4.4 nmol/L and 84.1 fmol/mg (subtraction of (18)FMB binding in the presence of raclopride), respectively, and 7.9 nmol/L and 70.1 fmol/mg (subtraction of cortical radioactivity concentrations), respectively.K(d) values measured with PET and autoradiography agreed and corresponded to inhibition constants obtained in previous in vitro studies. B(max) values lay within the same order of magnitude. The results of in vitro saturation binding analyses also agreed, irrespective of the mode of determination of free radioligand concentrations. Thus, B(max) and K(d) may be determined with PET in analogy to the evaluation of in vitro binding data by regression analysis of bound-versus-free ligand concentrations. Our results show that small-animal tomographs are valuable tools for the in vivo characterization of receptor radioligands as an alternative to autoradiography.

Unilateral destruction of the substantia nigra by local application of 6-hydroxydopamine (6-OHDA) serves as an animal model for Parkinson's disease. In this study, the changes in neostriatal dopamine D(2) receptor density were investigated with a small animal positron emission tomograph (PET) before and after 6-OHDA lesion. PET scans were performed in 14 rats after injection of the D(2) receptor radioligand [(18)F] N-methylbenperidol. After the first scan (day 0), nigrostriatal pathways were lesioned by unilateral injections of 6-OHDA. Further PET scans were performed on days 2 and 14 post-lesion. For both striata, B(max) values were determined from saturation binding curves with non-linear regression analysis. In the striatum ipsilateral to the lesion, B(max) initially amounted to 19.3+/-1. 9 fmol/mg (mean+/-SD) and increased to 19.7+/-2.2 and 29.9+/-5.7 fmol/mg on days 2 and 14 post-lesion, respectively. Contralateral B(max) values increased from 19.2+/-2 fmol/mg prior to the lesion to 21.2+/-2.9 and 28.6+/-5.7 fmol/mg on days 2 and 14, respectively. On day 14, the ipsilateral saturation binding curve differed from the ipsilateral pre-lesion curve (P=0.04; F test). When the contralateral pre-lesion saturation binding curve was compared with the contralateral post-lesion curve on day 14, a P value of 0.08 was obtained. This first serial in vivo imaging study of 6-OHDA-lesioned rats showed a time-dependent increase in striatal D(2) receptor density on both sides, the increase being more pronounced ipsilateral to the lesion. This result implies that compensatory mechanisms in the intact hemisphere contribute to regenerative processes following nigrostriatal dopaminergic denervation. Overall, our findings show the feasibility of repetitive in vivo studies of striatal receptor density with a small animal tomograph. Moreover, the applied in vivo saturation binding technique provides a versatile method for the quantification of time-dependent changes in the concentration of receptor binding sites.

Background Benperidol is a relatively old antipsychotic drug, marketed since 1966, used in Germany for 30 years, but also available in Belgium, Greece, Italy, the Netherlands and the UK. Benperidol is a butyrophenone antipsychotic, with the highest neuroleptic potency in terms of D2 receptor blockade. Those taking it are, therefore, reputed to be at high risk of extrapyramidal side effects, but benperidol's unusual profile may render it of value to subgroups of people with schizophrenia. Objectives To examine the clinical effects and safety of benperidol for those with schizophrenia and schizophrenia-like psychoses. Search strategy The reviewers searched the Cochrane Schizophrenia Group's register (January 2001) which includes relevant randomised controlled trials from the bibliographic databases Biological Abstracts, CINAHL, The Cochrane Library, EMBASE, MEDLINE, PsycLIT, LILACS, PSYNDEX, Sociological Abstracts and Sociofile. We also searched the references of all included studies and contacted pharmaceutical companies and authors of included studies in order to identify further trials. Selection criteria Randomised controlled trials that compared benperidol with other treatments for people with schizophrenia and/or schizophrenia-like psychoses. Data collection and analysis Citations and, where possible, abstracts were independently inspected by two reviewers and papers were ordered, re-inspected and quality assessed. We independently extracted data but excluded data if loss to follow up was greater than 50%. For homogeneous dichotomous data, we calculated the relative risk (RR), the 95% confidence interval (CI) and, where appropriate, the number needed to treat/harm (NNT/H), on an intention-to-treat basis. Main results We identified only one unpublished poorly randomised controlled trial (N=40, duration 30 days, comparison perphenazine). Although benperidol was inferior to perphenazine (1 RCT, N=40, global state no better or worse RR 8.0 CI 2.1 to 30, NNH 1.4 CI 1 to 2) poor reporting suggests that an overestimate of effect is likely. It was not possible to report other outcomes. Reviewer's conclusions Currently, there are insufficient data from randomised trials to assess the clinical effects of benperidol. This interesting compound merits further research.

Animal and post mortem studies indicate that neuroleptic therapy may induce D2-dopamine receptor upregulation in the basal ganglia. To address this phenomenon in a clinical study, we investigated the D2-dopamine receptor binding in 15 DSM-III-R schizophrenics in the drug-naive state and three days after completion of a standardized neuroleptic therapy (benperidol 12-16 mg/d for 25 days) using single photon emission computed tomography (SPECT). SPECT scans were obtained 2 h after intravenous injection of 185 MBq 123I-IBZM. For analysis, basal ganglia to frontal cortex (BG/FC) ratios were calculated and the patient sample was subgrouped into patients with a favourable versus a poor treatment response. Neuroleptic treatment led to decreased BG/FC ratios in patients with a favourable response, but increased ratios in the poor responders (df = 1, F = 4.1, p = 0.06). Changes of BG/FC ratios were significantly correlated with extrapyramidal side effects, but not with neurological soft signs (NSS). Our findings indicate that neuroleptic therapy induces D2-dopamine receptor upregulation in a subgroup of patients characterized by poor treatment response and pronounced extrapyramidal side effects.

In this study, we investigated experimentally the effects of different activation procedures on both motor and psychic symptoms in of 11 in-patients with acute neuroleptic-induced akathisia using the Hillside and Barnes akathisia rating scales and videotape rating technique. Motor activation was achieved by finger tapping. Cognitive activation tasks consisted of sequences of mental calculations which were designed either to be easy to perform or to produce stress due to a given time limit or to more difficult calculation operations, respectively. Motor as well as psychic symptoms of akathisia decreased during both motor and simple cognitive activation without stress. By contrast, stress-producing calculation tasks led to an increase in motor and psychic symptoms immediately following the task performance. These possibly specific effects of activation procedures on symptoms might be useful in differentiating acute neuroleptic-induced akathisia from other neuroleptic-induced and extrapyramidal movement disorders.