Choosing the right dose of antipsychotics in schizophrenia: lessons from neuroimaging studies

Despite vast clinical experience with antipsychotics, there is no broad consensus on the doses of these substances that should be administered. Currently, most antipsychotics are administered empirically according to clinical dose-finding studies, in which arbitrarily selected doses were tested to find the "most efficient" dose range in a patient population, with no regard for the molecular effects of the tested drug. Brain imaging studies using nuclear medical techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), can now provide a rationale for doses, directly derived from the central effects of the drugs on neurotransmitter receptors measured in vivo. PET results indicate that occupancy of at least 65% of dopamine D(2) receptors is needed for clinical response to antipsychotics, and that occupancy rates exceeding 72 and 78% are associated with a high risk for elevation of prolactin levels and motor adverse effects, respectively. For example, clinical studies with haloperidol do not point to an advantage of dosages exceeding 5 mg/day. The relevance of D(2) receptor occupancy for drug administration is also borne out by studies relating the effects of antipsychotics to their D(2) receptor occupancy in relevant animal models. Taken together, neuroimaging and clinical studies, as well as animal models, provide a rationale for the use of relatively low doses of typical antipsychotics and equivalent doses of novel antipsychotics. The lower risk of adverse effects with appropriate doses of antipsychotics may further enhance compliance and outcome. This seems to be particularly important in individuals experiencing a first episode of schizophrenia, as they appear to be especially responsive to pharmacotherapy and quite sensitive to adverse effects.     

Increased dopamine D2 receptor binding after long-term treatment with antipsychotics in humans: a clinical PET study

RATIONALE: Dopamine D2 receptor upregulation in the striatum is regularly seen in response to the administration of traditional antipsychotics in animal experiments. This is associated with hyperactivity and, for this reason, D2 receptor upregulation has long been postulated as central to tardive dyskinesia (TD). OBJECTIVE: Using positron emission tomography (PET), the present study attempted to determine whether antipsychotic-induced D2 receptor up-regulation also occurs in humans. METHODS: The long-term effects of traditional and novel antipsychotics on dopamine D2 receptors were investigated in nine subjects meeting DSM-IV criteria for schizophrenia who were deemed eligible for temporary treatment washout. Subjects had been treated with traditional antipsychotics (haloperidol n=3, perphenazine n=1) and novel antipsychotics (risperidone n=3, olanzapine n=2) in the moderate to high dosage range. Fourteen days after treatment withdrawal, the binding potentials (BPs) of dopamine D2 receptors were measured using 11[C] raclopride. The obtained BPs were compared to the BPs from antipsychotic-naive control subjects with schizophrenia. RESULTS: There was a significant increase in the D2 BP in both groups combined that reached 34%. The increases in the D2 BPs in the groups treated with conventional and novel antipsychotics were 37% and 31%, respectively. Significantly, the patients showing the highest degree of D2 receptor upregulation (98%) developed severe and persistent TD shortly after being started on a new antipsychotic with low affinity for D2 receptors. CONCLUSION: This study demonstrates for the first time, using in vivo neuroreceptor imaging, that dopamine D2 receptor binding is increased after long-term treatment with antipsychotics in humans. The data suggest that both traditional and novel antipsychotics with high affinity for dopamine D2 receptors are associated with a substantial increase in D2 receptor binding. The present data in humans agree well with animal data that implicate D2 receptor-mediated mechanisms in motor hyperactivity.     

Fundamentals of positron emission tomography and applications in preclinical drug development

Positron emission tomography (PET) is a nuclear imaging technique that can dynamically image trace amounts of positron-labeled radiopharmaceuticals in vivo. Tracer concentrations can be determined quantitatively, and by application of appropriate tracer kinetic models, the rates of a wide range of different biological processes can be measured noninvasively in humans. PET has been used as a research tool for more than 25 years and has also found clinical applications, particularly in oncology, neurological disorders, and cardiovascular disease. Recently, there has been tremendous interest in applying PET technology to in vivo small-animal imaging. Significant improvements in the imaging technology now permit a wide range of PET studies in mice and rats, using compact, relatively low-cost, dedicated small-animal PET scanners. This article reviews the fundamental basis of PET imaging and discusses the development of small-animal PET scanners and their possible application in preclinical drug development.     

Dopamine D2 receptor occupancy and clinical effects: a systematic review and pooled analysis

Positron emission tomography (PET) studies proposed a therapeutic window of D2 receptor occupancy (65%-80%) of antipsychotics for the treatment of schizophrenia in young adults. However, this conclusion has been drawn from clinical PET studies using small sample sizes (<20). Prospective PET studies that measured D2 occupancy levels and assessed extrapyramidal side effects (EPS) and/or treatment response induced by antipsychotics (excluding partial agonists) were identified, using MEDLINE and EMBASE (last search: March 2010). Individual subjects were divided into 2 groups based on EPS status (ie, presence or lack of newly emergent EPS) and treatment response (ie, a ≥ 25% or ≥ 50% reduction in the Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale). To evaluate the performance of this binary classification, sensitivity, specificity, and accuracy of consecutive cutoff points in the D2 occupancy were calculated: Accuracy = (True Positive + True Negative) / Total N. Twelve studies, including a total of 82 subjects, were included in our analyses. The cutoff points associated with 0.5 or greater in both sensitivity and specificity with the greatest accuracy were 77% to 78% for EPS, 60% for a 25% or greater symptom reduction, and 72% for a 50% or greater symptom reduction. These findings support the presence of a therapeutic window of 60% to 78% D2 occupancy of antipsychotics in young adults with schizophrenia and may suggest the presence of a continuum of effectiveness with increasing occupancy within this therapeutic window.     

Dopamine transporter in vitro binding and in vivo imaging in the brain.

Much research interest has lately been focused on the dopamine transporter function in brain. Recent findings indicate that dopamine reuptake is more like a highly regulated than a constitutive determinant of dopamine clearance. Positron emission tomography (PET) and single-photon emission tomography (SPET) offer unique methods to study dopamine transporter function. Results from in vivo PET and SPET studies correspond well with in vitro studies performed on post mortem human brain tissue. Considering some of the variances between in vitro and in vivo receptor binding phenomena it may be that the role of a compound to alter binding to monoamine uptake sites in vitro does not indicate its potential to affect monoamine transporters after administration in vivo. This discrepancy may be better understood taking into account recent studies indicating the possibility of a rapid regulation of transporter function and surface expression. Furthermore, the dopamine transporter is a fruitful target for CNS drug discovery. Fundamental nature of drug actions in vivo may be studied using demonstrated in vitro and in vivo imaging methods.     

Non-invasive methods to study drug disposition: positron emission tomography. Detection and quantification of brain receptors in man

Positron emission tomography (PET) has been used mostly for the study of brain blood flow and metabolism in normal controls and in a variety of neurological and psychiatric conditions. With the appropriate radiotracers, PET also allows non-invasive imaging and quantification of a growing list of neuroreceptors, the target of most psychotropic drugs. For example, 11C-carfentanil and 11C-diprenorphine, two potent opiate ligands, have been used to label opiate receptors in vivo in man. Methods have been developed to quantify receptor studies with PET in terms of receptor density and affinity. PET is a unique tool that now allows measurement of receptor occupancy in vivo and could be used by the pharmacologist to optimize drug treatment.     

Risk of osteoporosis and fracture incidence in patients on antipsychotic medication

INTRODUCTION: In patients suffering from schizophrenia and bipolar disorder, antipsychotics are the mainstay of treatment worldwide. By blocking D(2) brain mesolimbic receptors, antipsychotics are believed to reduce and control psychotic experiences, but recent evidence has suggested that they may also have adverse effects on bone mineral architecture and fracture incidence. AREAS COVERED: This study reviews current literature surrounding the use of antipsychotics and their effects on bone homeostasis. The primary medical search engines used for the study are Ovid MEDLINE (1950 - April 2010), EMBASE (1988 - April 2010) and PsychINFO (1987 - April 2010) databases. EXPERT OPINION: Typical antipsychotics, in addition to the atypical antipsychotics risperidone and amisulpride, have been shown to increase serum prolactin levels in in vivo human studies. Results from animal and human in vitro and in vivo studies have demonstrated that high concentrations of prolactin have been shown to adversely affect bone cell metabolism and accelerate the rate bone mineral density loss, thereby increasing fracture risk. Increasing awareness of the side effect profile of antipsychotic medications on bone metabolism may prompt clinicians to screen patients at high risk of antipsychotic-induced osteoporosis and provide treatment, which may reduce the incidence of potentially avoidable fractures.     

The value of single photon emission tomography in psychopharmacology

Functional neuroimaging with SPET and PET offers the opportunity to visualize brain function either in terms of blood flow and metabolism or receptor function using specific ligands. SPET is a more widely available and cheaper technology than PET. Continuously developing and being refined, this technology will help the understanding of brain function generally and of brain dysfunction in psychiatric disorders specifically. SPET may also be used to study how these measures of brain function change with pharmacological intervention. Receptor imaging allows the study of drug-receptor interactions in vivo. As yet, the precise role and value of these techniques have not been established, but they do provide complementary tools to structural imaging and may ultimately provide prognostic information and facilitate refinement of the pharmacotherapeutic rationale underlying clinical practice.     

No regional difference in dopamine D2 receptor occupancy by the second-generation antipsychotic drug risperidone in humans: a positron emission tomography study

The effects of antipsychotic drugs have generally been considered to be mediated by blockade of dopamine D2 receptors. The concept of limbic and cortical selectivity of second-generation antipsychotics, i.e. higher dopamine D2 receptor occupancy in the cerebral cortices than in the striatum, has been suggested to explain their clinical efficacy with lower incidence of extrapyramidal side-effects. In this study, regional distribution of dopamine D2 receptor occupancy by risperidone was determined in order to elucidate the limbic and cortical selectivity of second-generation antipsychotics. Striatal and extrastriatal dopamine D2 receptor binding at baseline and after oral administration of 2 mg risperidone were measured in ten healthy men by positron emission tomography (PET) using different tracers with different affinity for the receptors, [11C]raclopride and [11C]FLB 457, respectively. Striatal and extrastriatal occupancies of dopamine D2 receptors were calculated for each brain region. Occupancies of dopamine D2 receptors were about 70% and 60% in the striatum and extrastriatum, respectively. A simulation study showed that non-negligible specific binding in the reference region (cerebellum), could cause systemic underestimation of occupancy in [11C]FLB 457 PET studies, indicating that occupancies in both the striatum and extrastriatum may not have differed. Among the extrastriatal regions including limbic and neocortical regions, no significant regional differences in dopamine D2 receptor occupancy were observed. Thus, limbic and cortical selectivity was not observed by one of the second-generation antipsychotics, risperidone.     

Discriminative stimulus properties of antipsychotics.

Drug discrimination methodology has been used in a number of ways to analyze the actions of novel and putative novel antipsychotics in vivo. Recent studies suggest (a) in contrast to earlier theorizing, antagonism of the low-dose d-amphetamine stimulus in rats may not be an effective screen for novel antipsychotics; (b) dopamine D2-like agonists and antagonists, some of which are putative antipsychotics, can be studied in vivo as discriminative cues, although there is a pressing need for more selective drugs that differentiate the various members of the D2 family. (c) antagonism of the cue induced by the noncompetitive NMDA antagonist MK-801, which has been proposed as a possible screen for clozapine-like compounds, may be an unreliable assay; and (d) the clozapine stimulus is probably a compound cue (a drug "mixture"), which can be used to screen for novel clozapine-like antipsychotics, although the precise receptor mechanisms involved in mediating the clozapine stimulus, and its direct relevance to the antipsychotic action of clozapine remains to be proven conclusively.     

Monitoring interactions at ATP-dependent drug efflux pumps

Chemotherapeutic treatment of cancer patients is often unsuccessful, due to the involvement of various mechanisms, leading to multidrug resistance (MDR). In this review, I describe the mechanisms involved in MDR. Furthermore, results obtained by imaging of P-glycoprotein (P-gp) and the multidrug resistance associated protein (MRP) are reviewed. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) are unique techniques to study P-gp- and MRP-mediated transport. The radiopharmaceutical (99m)Tc-sestamibi is a substrate for both P-gp and MRP. This tracer has been used for tumor imaging in clinical studies, and to visualize blockade of P-gp mediated transport after modulation of the P-gp pump. Other (99m)Tc-radiopharmaceuticals such as (99m)Tc- tetrofosmin and several (99m)Tc-Q-complexes are also substrates for P-gp. Until now, for these compounds only results from in vitro and animal studies are available. For quantification of P-gp mediated transport with PET in vivo, several agents, such as [(11)C]colchicine, [(11)C]verapamil and [(11)C]daunorubicin have been evaluated. In vivo results suggest that these radiopharmaceuticals can be used to image P-gp function in tumors. (124)I and (76)Br radiolabeled doxorubicin analogues are also useful to examine P-gp mediated transport. Leukotrienes are specific substrates for MRP. Therefore, N-[(11)C]acetyl-leukotriene E4 provides the opportunity to study MRP function non-invasively. Results obtained with this radiopharmaceutical in MRP(2) mutated GY/TR- rats indicate visualization of MRP-mediated transport. This tracer enables to study MRP transport function abnormalities in vivo such as in Dubin-Johnson patients, who are MRP(2) gene deficient. In conclusion, it is feasible to study the functionality of MDR transporters in vivo, both with SPECT and with PET. Such imaging techniques may become an important factor in the development of novel chemotherapeutic drugs.     

Imaging Alzheimer's disease pathology: one target, many ligands

Over the past five years there has been a surge of interest in using positron emission tomography (PET) to determine the in vivo density of the senile plaque, a key pathological feature of Alzheimer's disease. The development of the tracers [(11)C]-PIB, [(11)C]-SB13 and [(18)F]-FDDNP has coincided with drug strategies aimed at altering the brain metabolism of amyloid-beta peptides. The evolution of these novel ligands serves not only as an excellent example of how rapidly imaging technologies can progress but also as a reminder that the fundamental biological knowledge, which is necessary to fully interpret the PET data, can be left trailing behind.     

正电子发射断层显像在药物研究和开发中的应用

正电子发射断层显像（PET）是通过探测某些超短寿命放射性核素放射出的正电子与介质中的负电子发生碰撞（即“湮灭”）过程中,产生的一对方向相反、能量均为511KeV的光子的数量实现的一种定量、多维影像技术。它主要用于研究生物体（活体）的主要器官（或组织）在完成其生理功能过程中所伴随的生物化学反应。也可用于直接研究某些药物在生物活体内的生物学行为、疗效和毒性,因此,在药物研究开发中具有广泛的应用前景。本文简要综述了正电子发射断层显像技术的仪器和原理、正电子发射断层显像用放射性标记化合物、在药物研究和开发中的应用及其局限性。     

Application of cardiac molecular imaging using positron emission tomography in evaluation of drug and therapeutics for cardiovascular disorders

The incidence of cardiovascular disease is increasing with the aging population. This has stimulated a need for innovative means to evaluate and develop therapeutic strategies intended to improve patient care. Positron emission tomography (PET) imaging is an advanced nuclear imaging technology. The advantage of PET over other non-invasive imaging modalities is its ability to accurately measure tissue concentrations of specific radiolabeled compounds. These radioligands can be used as molecular probes to quantify physiological processes and the effects of therapy. Molecular imaging with PET has been applied to evaluate new and established drugs and therapies, as well as their effects on physiological parameters. New radiolabeled receptor ligands will also allow in vivo pharmacokinetic studies following drug treatment, yielding insights into drug delivery, optimal drug occupancy, and mechanism of action at the receptor level. These exciting tissue pharmacokinetic data could revolutionize evaluation of drug therapies in cardiovascular diseases. In addition, serial evaluations of these processes are now possible in both animals and humans permitting sensitive means to evaluate disease progression and therapies. New tools for imaging such as PET/CT and small animal PET broaden the potential of PET in drug evaluation. This review will describe the accuracy of PET as a non-invasive modality to quantify various parameters, and the application of PET in evaluating new and established therapies. This paper will also review the application of receptor ligand imaging and the principles of using surrogate physiological end-points in early drug development and evaluation.     

PET and SPET molecular imaging: focus on serotonin system

Emission tomography techniques and, in particular, positron emission tomography (PET) enable the in vivo study of several physiological and neurochemical variables in human subjects using methods originally developed for quantitative autoradiography. In particular, PET allows one to evaluate in human subjects: (a) the effect of specific neurochemical challenges on regional brain function at rest or under activation; (b) the activity of neurotransmitters and the regional expression of specific molecular targets during pathology including their modulation by drug treatment; (c) the kinetics of drug disposition and activity directly in the target organ. This is of primary interest in the field of biological psychiatry and in psychoactive drugs development, where it is particularly difficult to reproduce human diseases using animal models in view of the peculiarity of this field and the large heterogeneity of each psychiatric illness also inside the same clinical definition. The aim of this paper is to review the principal strategies and the main results of the use of PET or single photon emission tomography (SPET) molecular imaging for the in vivo study of serotonin receptors and the main results obtained from their application in the study of major depression.     

Benefit-risk assessment of atypical antipsychotics in the treatment of schizophrenia and comorbid disorders in children and adolescents.

Evidence on the efficacy and safety of atypical antipsychotics in children and adolescents with schizophrenia is limited. The purpose of this review is to assess the published data on the use of atypical antipsychotics in children and adolescents with schizophrenia alone and with comorbid disorders, and to establish benefit-risk guidelines for clinicians.Risperidone, olanzapine and clozapine were found to be effective in the treatment of aggression and mania. Risperidone, and possibly also olanzapine, may be the drugs of choice in children with comorbid tic disorders. Ziprasidone has some monoamine reuptake inhibition properties and may be administered as an augmenting agent in children and adolescents with schizophrenia and comorbid anxiety and mood disorders.Compared with the typical antipsychotics, the atypical drugs seem to be more effective, better tolerated and lead to better patient adherence. Importantly, the atypical antipsychotics have a lower propensity to induce extrapyramidal symptoms and a potential (shown so far only in adults) to improve cognitive function and inhibit suicidal behaviour (especially clozapine). Yet, the adverse effects associated with these agents, especially weight gain, which may also have long-term effects, can lead to non-compliance in the young population. In children and adolescents receiving clozapine, olanzapine and quetiapine (but not ziprasidone, which does not have a pro-appetite effect), particularly those with obesity or a family history of diabetes mellitus, fasting blood glucose and lipid levels must be monitored frequently. Weight gain might be better controlled when the children and their parents are properly informed about this adverse effect and diet is regulated. Another major disadvantage of the atypical antipsychotics, especially risperidone, is their association with hyperprolactinaemia, which can lead to hypogonadism-induced osteoporosis, galactorrhoea, gynaecomastia, irregular menstruation and sexual dysfunction, all seen also with typical antipsychotics. Other atypical antipsychotics, namely olanzapine and ziprasidone, have been reported to be prolactin sparing in adults, but may not be completely devoid of hyperprolactinaemic effects in children and adolescents. Thus, prolactin levels should be assessed routinely in young patients treated with atypical antipsychotics. Further, children and adolescents with hyperprolactinaemia-related effects should be switched to a prolactin-sparing agent, such as quetiapine. All atypical antipsychotics may induce sedation and they are not devoid of extrapyramidal symptoms (especially risperidone). The use of typical antipsychotics has been limited to patients who are resistant to atypical antipsychotics, intolerant to their adverse effects, or require injections or depot preparations.Further double-blind, placebo-controlled trials and long-term safety assessments are needed before definitive conclusions can be reached about the place of atypical antipsychotics in the therapeutic armamentarium of childhood-onset schizophrenia.     

Synthesis and evaluation of [N-methyl-11C]N-desmethyl-loperamide as a new and improved PET radiotracer for imaging P-gp function

[(11)C]Loperamide has been proposed for imaging P-glycoprotein (P-gp) function with positron emission tomography (PET), but its metabolism to [N-methyl-(11)C] N-desmethyl-loperamide ([(11)C]dLop; [(11)C]3) precludes quantification. We considered that [(11)C]3 might itself be a superior radiotracer for imaging brain P-gp function and therefore aimed to prepare [(11)C]3 and characterize its efficacy. An amide precursor (2) was synthesized and methylated with [(11)C]iodomethane to give [(11)C]3. After administration of [(11)C]3 to wild-type mice, brain radioactivity uptake was very low. In P-gp (mdr-1a(-/-)) knockout mice, brain uptake of radioactivity at 30 min increased about 3.5-fold by PET measures, and over 7-fold by ex vivo measures. In knockout mice, brain radioactivity was predominantly (90%) unchanged radiotracer. In monkey PET experiments, brain radioactivity uptake was also very low but after P-gp blockade increased more than 7-fold. [(11)C]3 is an effective new radiotracer for imaging brain P-gp function and, in favor of future successful quantification, appears free of extensive brain-penetrant radiometabolites.     

PET in psychopharmacology.

Emission tomography techniques and, in particular, positron emission tomography (PET) enable the in vivo study of several physiological and neurochemical variables in human subjects using methods originally developed for quantitative autoradiography. In particular, PET allows one to evaluate in human subjects: (a) the effect of specific neurochemical challenges on regional brain function at rest or under activation; (b) the activity of neurotransmitters and the regional expression of specific molecular targets during pathology including their modulation by drug treatment; (c) the kinetics of drug disposition and activity directly in the target organ. This is of primary interest in the field of biological psychiatry and in psychoactive drugs development, where it is particularly difficult to reproduce human diseases using animal models in view of the peculiarity of this field and the large heterogeneity of each psychiatric illness also inside the same clinical definition. The aim of this paper is to review the principal strategies and the main results of the use of PET in psychopharmacology.     

The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia.

Schizophrenia has been linked to abnormal dopamine function, recently to excessive amphetamine-induced release of striatal dopamine, and also to pathology of prefrontal cortical neurons. It has been hypothesized that prefrontal pathology is a primary condition that leads to dopamine dysregulation. We evaluated in vivo the relationship between neuronal integrity in dorsolateral prefrontal cortex, assessed as N-acetylaspartate (NAA) relative concentrations measured with proton magnetic resonance spectroscopic imaging, and amphetamine-induced release of striatal dopamine, assessed with 11C-raclopride Positron Emission Tomography (PET) in patients with schizophrenia and in healthy subjects. In the patients, NAA measures in dorsolateral prefrontal cortex selectively predicted striatal displacement of 11C-raclopride after amphetamine infusions (rho = -0.76, p < .02). In contrast, NAA measures in other cortical regions and in healthy subjects did not show any correlation. These results support the hypothesis that in schizophrenia neuronal pathology of dorsolateral prefrontal cortex is directly related to abnormal subcortical dopamine function.     

长期使用抗精神病药对精神分裂症患者认知功能的影响研究

目的:探讨长期使用典型和非典型抗精神病药对精神分裂症患者认知功能的影响。方法:对45例持续服用典型或非典型抗精神病药10年以上的精神分裂症患者,使用蒙特利尔认知评估量表(MoCA)、简易智能精神状态量表(MMSE)和简明精神病评定量表(BPRS)检测患者目前的认知功能和精神症状。结果:典型和非典型抗精神病药或两型药物联用患者之间的MoCA、MMSE、BPRS差异不显著。结论:长期治疗的精神分裂症患者,认知功能损害与药物因素的相关性不明显,可能与疾病的结局相关。MoCA可作为非急性期精神分裂症患者认知功能的评定工具。