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[123I]IBZM SPECT for imaging of striatal D2 dopamine receptors in 56 schizophrenic patients taking various neuroleptics
Abstract
The purpose of this study was to compare the binding of various typical and atypical neuroleptics to striatal D2 dopamine receptors in schizophrenic patients.
Fifty-six inpatients with schizophrenia, including 14 with schizoaffective disorder and one with schizophreniform disorder, were evaluated. Fourteen patients were neuroleptic free. Single photon emission computed tomography (SPECT) was performed 90 minutes after intravenous injection of [123I]benzamide ([123I]IBZM). Subsequent semiquantitative analysis of D2 receptor binding was done with the use of the basal ganglia (striatum)/frontal cortex (BG/FC) ratio of activity. Clinical symptoms were rated with the Positive and Negative Syndrome Scale and the Hamilton Depression Rating Scale.
The BG/FC ratios in patients taking typical neuroleptics were significantly lower than those in the neuroleptic-free subjects but not lower than those in the patients taking atypical neuroleptics (clozapine, remoxipride). For atypical antipsychotics, a dose-dependent relationship with striatal D2 receptor binding could not be demonstrated. BG/FC ratios were not significantly correlated with clinical symptoms or with duration of illness.
The results indicate that [123I]IBZM SPECT is useful for semiquantitative imaging of striatal D2 dopamine receptors and for estimating their blockade by neuroleptics. Thus, it may improve drug monitoring in psychiatric patients. Furthermore, the findings suggest a complex relationship between the antipsychotic effect of atypical neuroleptics and D2 receptor blockade.
... For example, in patients taking therapeutically effective antipsychotic doses of clozapine, this drug only occupies between 0% and 50% of brain dopamine D2 receptors, as measured by a variety of radioligands using either positron tomography 1,2,[8][9][10][11][12][13] or single photon tomography. [14][15][16][17][18][19] Although the apparently low occupancy of D2 by clozapine might suggest that D2 may not be the major antipsychotic target for clozapine (because clozapine binds to many other neurotransmitter receptors) 20 it is necessary to analyse these low occupancy data in the light of recent evidence showing that the occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. [21][22][23][24][25][26] This latter finding shows that the occupancy is higher when radioligands with higher dissociation constants are used. ...
... It has been consistently claimed that clozapine only occupies between 0% and 50% of brain dopamine D2 receptors, as measured by a variety of radioligands using either positron tomography 1,2,[8][9][10][11][12][13] or single photon tomography. [14][15][16][17][18][19] This is in contrast to the D2 occupancies of 70 -80% for the typical neuroleptics. ...
... This Figure shows that clozapine occupied low levels of D2 receptors, between 0 and 29%, when radiomethylspiperone congeners were used ([ 18 F]methylspiperone, 8 [ 11 C]methylspiperone 11,12 or [ 18 F]fluorethylspiperone 9,10 ), all of which have a dissociation constant of 0.092 nM (this lab, unpublished). 72 Clozapine occupied higher levels of D2 receptors, between 30% and 47%, [14][15][16][17][18][19] when [ 123 I]iodobenzamide was used with its higher dissociation constant of 0.43-0.49 nM. ...
This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions. As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs.
... K Ke ey y w wo or rd ds s: : a at ty yp pi ic ca al l n ne eu ur ro ol le ep pt ti ic cs s; ; d do op pa am mi in ne e D D 2 2 r re ec ce ep pt to or r; ; [ 1 12 23 3 I I] I IB BZ ZM M; ; o ol la an nz za ap pi in ne e; ; S SP PE EC CT T 75-900 mg/day) in comparison to haloperidol has been demonstrated (Brücke et al., 1992;Farde et al., 1992;Pilowsky et al., 1992;Klemm et al., 1996;Nyberg et al., 1996). ...
... Our results are in accordance with a PET study using [ 11 C] raclopride and [ 11 C] NMSP demonstrating a 63% dopamine D 2 receptor occupancy after oral administration of 10 mg olanzapine to healthy controls (Nyberg et al., 1997). Our findings indicate that the dose-response relationship of olanzapine and risperidone is very similar and closer to that of haloperidol than to that of clozapine (Klemm et al., 1996;Dresel et al., 1998Dresel et al., , 1999. ...
... Apparently, the D 2 receptor binding of olanzapine is more pronounced than that of clozapine, especially at doses above 20 mg/daily. This was demonstrated by findings of previous studies (Klemm et al., 1996;Dresel et al., 1998;Kapur et al., 1998;Dresel et al., 1999;Kapur et al., 1999;Tauscher et al., 1999). ...
The aim of this study was to compare the degree of striatal dopamine D2 receptor availability in patients treated with recommended (5-20 mg, mean dose 11.9 +/- 6.3 mg daily) and higher doses (25-40 mg, mean 32.1 +/- 5.6 mg daily) of the novel antipsychotic drug olanzapine by means of [123I] IBZM Single photon emission computed tomography (SPECT). The results were compared to those of a group of 10 untreated, healthy, age- and sex-matched controls. The degree of dopamine D2 receptor occupancy in the patient group was correlated with the presence of extrapyramidal symptoms (EPS). A total of 20 patients who met the DSM III R criteria for schizophrenia or schizoaffective disorder received a clinically effective antipsychotic monotherapy with olanzapine. The mean daily dose of olanzapine ranged from 0.05-0.6 mg/kg body weight. The dopamine D2 receptor binding was reduced in all patients treated with olanzapine. Specific IBZM binding expressed as the [STR-BKG]/BKG ratio ranged from 0.13-0.61 (healthy controls 0.95). The D2 receptor availability revealed an exponential dose-response relationship (r = - 0.85, p < 0.001). The frequency of EPS induced by olanzapine was considerably lower. Only one patient, treated with 40 mg olanzapine, suffered from severe EPS symptoms and had to be given biperiden. There were no significant differences in the presence of EPS symptoms between patients with recommended doses and those with higher doses of olanzapine.
... For REM, the predicted pituitary RO was between 80% and 95% for the dose range of 50-600 mg per day, while in PET studies in humans, striatal RO has been reported to be 60-80% (Klemm et al. 1996). Farde and von Bahr reported 73% and 71% striatal RO in human subjects dosed with REM 100 mg thrice daily or 200 mg twice daily, respectively (Farde and von Bahr 1990). ...
... The significance of predicting plasma prolactin lies in its ability to inform clinical efficacy and extrapyramidal side effects. The RO predicted by the translational PP model is in the same ballpark as that reported in published studies using imaging modalities (Farde and von Bahr 1990;Klemm et al. 1996). Furthermore, a similar approach has been used to predict central RO for PA and RI, respectively (De Ridder 2005;Gomeni et al. 2013). ...
Prolactin release is a side effect of antipsychotic therapy with dopamine antagonists, observed in rats as well as humans. We examined whether two semimechanistic models could describe prolactin response in rats and subsequently be translated to predict pituitary dopamine D2 receptor occupancy and plasma prolactin concentrations in humans following administration of paliperidone or remoxipride. Data on male Wistar rats receiving single or multiple doses of risperidone, paliperidone, or remoxipride was described by two semimechanistic models, the precursor pool model and the agonist–antagonist interaction model. Using interspecies scaling approaches, human D2 receptor occupancy and plasma prolactin concentrations were predicted for a range of clinical paliperidone and remoxipride doses. The predictions were compared with corresponding observations described in literature as well as with predictions from published models developed on human data. The pool model could predict D2 receptor occupancy and prolactin response in humans following single doses of paliperidone and remoxipride. Tolerance of prolactin release was predicted following multiple doses. The interaction model underpredicted both D2 receptor occupancy and prolactin response. Prolactin elevation may be deployed as a suitable biomarker for interspecies translation and can inform the clinical safe and effective dose range of antipsychotic drugs. While the pool model was more predictive than the interaction model, it overpredicted tolerance on multiple dosing. Shortcomings of the translations reflect the need for better mechanistic models.
... Interestingly, lower D 2 receptor occupancy rates have been found for haloperidol in doses ranging from 0.6 to 5 mg (11-37%) (Broich et al. 1992;. It can therefore be concluded that a relatively low dose of a typical antipsychotic already occupies a substantial proportion of D 2 receptors, reflected by the steep decline of the saturation curve (Klemm et al. 1996). At higher doses, either reducing or increasing the dose will alter receptor availability only slightly, since the D 2 receptors are almost saturated. ...
... The atypical antipsychotic agent clozapine consistantly has been demonstrated to reveal a low striatal D 2 receptor occupancy rate, which is related to its favorable profile of lack of EPS. These findings have been obtained by SPECT (Brücke et al. 1992;Pilowsky et al. 1992;Klemm et al. 1996;Küfferle et al. 1996;) as well as with PET imaging techniques (Farde et al. 1992;. In these investigations the striatal D 2 receptor occupancy rates for clozapine ranged from 20-63% using dosages between 300 and 600 mg/day. ...
Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. Since psychopharmacological treatment is thought to act on the underlying biological basis of the disease, brain imaging techniques enable us to understand the mechanism of action of such compounds. Positron emission tomography (PET) as well as single photon emission computerized tomography (SPECT) are important tools used to determine patterns of brain dysfunction and to uncover the mechanism of action for antipsychotic compounds. These techniques allow us to determine striatal D2 receptor as well as cortical 5-HT2A receptor occupancy rates which are linked, at least partly, to clinical efficacy as well as side effect rates. In general it has been shown that atypical antipsychotics have a lower striatal D2 receptor occupancy rate than typical antipsychotics, parallelling the more favorable extrapyramidal side effects of atypical antipsychotics, and as a group effect they have a high 5-HT2A occupancy compared to low rates for typical agents. However, there is no association between striatal D2 receptor occupancy rates and antipsychotic efficacy but 5-HT2A occupancy rates are associated with favorable treatment for depressive symptoms within schizophrenia and improvement of cognitive function. The availability of ligands for measurement of extrastriatal D2 receptors or different 5-HT receptors (e.g. 5-HT1A) will further shed light on the pathophysiology of schizophrenia as well as possible psychopharmacological treatment perspectives.
... [ 123 I]IBZM has been shown to be useful for semi-quantitative imaging of striatal D 2 dopamine receptors and for estimating their blockade by neuroleptics. Thus, it may improve drug monitoring in psychiatric patients [35]. The availability of iodine-123-labeled post-synaptic, and technetium-99m-labeled presynaptic dopaminergic radiotracers, affords the possibility of dual-isotope studies of this important region of the brain. ...
Single photon emission computed tomography (SPECT) has been the cornerstone of nuclear medicine and today it is widely used to detect molecular changes in cardiovascular, neurological and oncological diseases. While SPECT has been available since the 1980s, advances in instrumentation hardware, software and the availability of new radiotracers that are creating a revival in SPECT imaging are reviewed in this paper.
The biggest change in the last decade has been the fusion of CT with SPECT, which has improved attenuation correction and image quality. Advances in collimator design, replacement of sodium iodide crystals in the detectors with cadmium zinc telluride (CZT) detectors as well as advances in software and reconstruction algorithms have all helped to retain SPECT as a much needed and used technology.
Today, a wide spectrum of radiotracers is available for use in cardiovascular, neurology and oncology applications. The development of several radiotracers for neurological disorders is briefly described in this review, including [¹²³I]FP-CIT (DaTSCANTM) available for Parkinson's disease. In cardiology, while technetium-99m labeled tetrofosmin and technetium-99m labeled sestamibi have been well known for myocardial perfusion imaging, we describe a recently completed multicenter clinical study on the use of [¹²³I]mIBG (AdreViewTM) for imaging in chronic heart failure patients. For oncology, while bone scanning has been prevalent, newer radiotracers that target cancer mechanisms are being developed. Technetium-99m labeled RGD peptides have been reported in the literature that can be used for imaging angiogenesis, while technetium-99m labeled duramycin has been used to image apoptosis.
While PET/CT is considered to be the more advanced technology particularly for oncology applications, SPECT continues to be the modality of choice and the workhorse in many hospitals and nuclear medicine centers. The cost of SPECT instruments also makes them more attractive in developing countries where the cost of a scan is still prohibitive for many patients.
... 196 Positron emission and single-photon emission computed tomography studies have shown that in the brain D2 receptor occupancy between 60% and 80% is necessary for a therapeutic effect, while exceeding this threshold is highly likely to generate EPS. 174,197,198 Figure 9. Structures of representative typical and atypical antipsychotics. ...
Viele therapeutisch eingesetzte Arzneistoffe entfalten ihre erwünschte Wirkung über heptahelikale, membranständige Rezeptoren, besser bekannt als G-Protein-gekoppelte Rezeptoren (GPCR). Diese dienen als Überträger externer Signale ins Zellinnere, indem sie zytosolische Effektoren wie G-Proteine oder β-Arrestine aktivieren. Wenn sie an einen aktivierten GPCR gekoppelt sind, können diese Effektorproteine anregende oder hemmende Signalwege in Gang setzen und dadurch spezifische Zellantworten auslösen. Erkenntnisse experimenteller Untersuchungen der letzten drei Jahrzehnte legen nahe, dass individuelle GPCR in der Lage sind, physisch miteinander zu interagieren und so funktionsfähige Rezeptorkomplexe zu bilden, welche man, sofern sie aus zwei unterschiedlichen Rezeptortypen bestehen, als Heterodimere bezeichnet. Typischerweise zeigen derartige Rezeptorverbünde Eigenschaften, die sich wesentlich von denen der entsprechenden Monomere unterscheiden.16,17,23,35 Es ist eine elementare Frage, inwiefern die GPCR-Heteromerisierung, die bisher hauptsächlich in vitro beobachtet und beschrieben wurde, von physiologischer oder pathophysiologischer Relevanz ist. GPCR-Komplexe in Primärgewebe oder sogar in lebenden Organismen nachzuweisen, wäre ein starkes Indiz für deren Beteiligung an pharmakologisch interessanten biochemischen Vorgängen.218 Im Gehirn überschneiden sich die dopaminergen und serotonergen Nervenbahnen vor allem im Striatum, in der Hirnrinde und in den Basalganglien. Aufgrund dessen interagieren beide Neurotransmittersysteme und kontrollieren gemeinsam wichtige neurologische Aufgaben wie die Motorik, die Gemütslage oder die Kognition. Die umfangreich exprimierten Dopamin D2- und Serotonin 5-HT2A-Rezeptoren spielen bei der Vermittlung der Effekte ihrer natürlichen Monoaminliganden eine zentrale Rolle. Bei der Behandlung der Schizophrenie beispielsweise sind die beiden Rezeptoren die Hauptangriffspunkte vieler first-line Antipsychotika.129,192 Darüber hinaus sind 5-HT2AR-D2R-Komplexe in transfizierten Zellen sowie in unterschiedlichen Regionen des Rattenhirns nachgewiesen worden und es hat sich herausgestellt, dass sie aufgrund modulatorischer Wechselwirkungen ein charakteristisches Signalverhalten zeigen.44,226–228 Nachdem 5-HT2AR und D2R wesentliche Komponenten bei der Behandlung neuropsychiatrischer Störungen sind, war es die Motivation dieser Arbeit, Informationen über die Besonderheiten des 5-HT2AR-D2R-typischen Signalverhaltens zu gewinnen und herauszufinden, ob die Bildung von 5-HT2AR-D2R-Heterorezeptorkomplexen zur Dysfunktion neurologischer Mechanismen beiträgt. Nach der Validierung der Interaktion von 5-HT2AR und D2R untersuchten wir 5-HT2AR-D2R-exprimierende Zellen hinsichtlich ihrer G-Protein-vermittelten Signaltransduktion sowie dem möglichen Einfluss Ligand-induzierter β-Arrestin Rekrutierung. Die Ergebnisse gewährten Einblick in die Spezifizität der Interaktionen zwischen 5-HT2AR und D2R innerhalb eines Heterokomplexes. Abschließend wurde in einem Rattenmodell der in vivo Effekt der Stimulation von 5-HT2AR auf das Ausmaß der Heteromerisierung von 5-HT2AR und D2R untersucht. Dieses Tierexperiment stellt erste Daten darüber zu Verfügung, ob die Entwicklung Psychose-ähnlicher Symptome mit der Bildung von 5-HT2AR-D2R-Komplexen in Zusammenhang stehen könnte. Serotonin 5-HT2A-Rezeptor-vermittelte Calciumsignale von 5-HT2AR-D2R-Komplexen Frühere Untersuchungen an NTS1R-D2R-Heterokomplexen, durchgeführt von Thorsten Schäfer, ließen eine inhibitorische Wirkung des D2-Protomers auf NTS1R-vermittelte Calciumsignale vermuten.111,112 Inspiriert durch diese funktionale Rezeptor-Rezeptor-Interaktion untersuchten wir auf dieselbe Art und Weise 5-HT2AR-bezogene, Gq-vermittelte Calciumsignale und einen eventuellen regulatorischen Einfluss co-exprimierter D2R auf diesen Signalweg. Mittels Einzelzellfluoreszenzmikroskopie konnten im Zytosol transient (co-)transfizierter Zellen (HT22, HEK293T) Ligand-induzierte Änderungen der Calciumkonzentrationen beobachtet werden. Unabhängig von der Art des 5-HT2AR-Liganden, der als Stimulus eingesetzt wurde – entweder der nicht-halluzinogene, endogene Agonist Serotonin (5-HT) oder der halluzinogene Agonist DOI –, haben sich die Calciumantworten in 5-HT2AR und D2R co-exprimierenden und 5-HT2AR mono-exprimierenden Zellen nicht unterschieden (Abbildung 64). Eine gleichzeitige Aktivierung oder Inhibition des D2-Protomers hatte keinen Effekt auf das Calciumsignal. Wohingegen D2R die Fähigkeit von NTS1R, intrazelluläres Calcium zu erhöhen, abgeschwächt hat, deuten die Ergebnisse hier an, dass in unseren Testsystemen D2R den 5-HT2AR-vermittelten Gq-Signalweg nicht reguliert. Auf Grundlage dieses vergleichenden Ansatzes kamen wir zu dem Schluss, dass funktionelle Interaktionen zwischen verschiedenen GPCR höchst spezifisch sind und maßgeblich von der Zusammensetzung des Komplexes abhängen. Die Aktivierung der 5-HT2A-Rezeptoren führte interessanterweise zu heterogenen Calciumsignalprofilen (Abbildung 64). Vor allem in den hippokampalen HT22-Zellen, jedoch kaum in HEK293T-Zellen folgten auf den initialen Calciumpeak Oszillationen mit unregelmäßiger Frequenz und Amplitude. Solche Calciumimpulse wurden unabhängig von der Anwesenheit, einer Aktivierung oder Deaktivierung von D2-Rezeptoren beobachtet, was auf ein Signalverhalten deutet, das nicht unmittelbar mit der Heteromerisierung von 5-HT2AR und D2R in Verbindung steht, sondern speziell in einer neuronalen Umgebung spezifisch für 5-HT2AR zu sein scheint. Die Validierung der Interaktion zwischen 5-HT2AR und D2R mittels BRET Durch Messung des Biolumineszenz-Resonanz-Energie-Transfers (BRET) konnten wir zwischen co-exprimierten 5-HT2A- und D2-Rezeptoren physische Interaktionen nachweisen. Genauer gesagt erhielt man in HEK293T-Zellen unter Zuhilfenahme von Rluc8-Donor- und mVenus-Akzeptor-Fusionskonstrukten in BRET-Sättigungs-Assays hyperbolische BRET-Kurven, die die Spezifizität der Interaktion bestätigten. Aufgrund niedriger Expressionslevel der Biosensor-Konstrukte in HT22-Zellen war es mit Schwierigkeiten verbunden, darin die 5-HT2AR-D2R-Interaktion reproduzierbar nachzuweisen. Da jedoch die Ligand-induzierte Calciumantwort in 5-HT2AR-D2R-exprimierenden HT22- und HEK293T-Zellen sehr ähnlich war, ließ die Auswertung der BRET-Daten die Schlussfolgerung zu, dass das Fehlen modulierender Effekte nicht durch die Abwesenheit von 5-HT2AR-D2R-Komplexen bedingt ist. Es wurden weitere BRET-Sättigungs-Assays durchgeführt, um den Einfluss erhöhter Konzentrationen an Dopamin (DA) bzw. Serotonin auf die Interaktion der Protomere zu untersuchen. Weder erhöhten noch verringerten die Agonisten das BRET-Ratio, unabhängig davon, welcher Rezeptor mit dem Donor- oder dem Akzeptorprotein verbunden war. Die unveränderten BRET-Effizienzen deuten auf eine konstitutive Bildung von 5-HT2AR-D2R-Heterorezeptorkomplexen hin, die unabhängig von deren Aktivierung ist. Die Untersuchung Gi-Protein-vermittelter Signale von 5-HT2AR-D2R-Komplexen Es gibt Anhaltspunkte, dass modulatorische Interaktionen innerhalb von GPCR-Komplexen bidirektional gerichtet sein können.97 Nachdem kein Effekt von D2R auf die 5-HT2AR-abhängige Gq-Signaltransduktion gezeigt werden konnte, legten wir den Schwerpunkt auf die Untersuchung der D2R-vermittelten Aktivierung von Gi und ob diese durch 5-HT2AR beeinflusst wurde. Mit Hilfe des zytosolischen BRET-Biosensors CAMYEL wurde in HEK293T-Zellen die Hemmung der Forskolin-stimulierten cAMP-Bildung analysiert. Im 5-HT2AR-D2R-exprimierenden Zustand wurde die durch Dopamin ausgelöste maximale cAMP-Hemmung durch die gleichzeitige Zugabe von Serotonin gesenkt (Abbildung 66). Im Gegensatz dazu wurde die maximale cAMP-Hemmung gesteigert, wenn D2-Rezeptoren durch Dopamin aktiviert und 5-HT2A-Rezeptoren durch den Antagonisten Ketanserin blockiert wurden. In D2R mono-exprimierenden Zellen wurden derartige abschwächende oder verstärkende Effekte nicht beobachtet. Diese wurden daher als Resultat der gleichzeitigen Besetzung beider Protomere von 5-HT2AR-D2R-Komplexen aufgefasst, was im Gesamtzusammenhang betrachtet auf eine negative Beeinflussung der D2R-assoziierten Gi-Signaltransduktion durch das 5-HT2A-Protomer hindeutet. Eine Kombination aus 5-HT und DA war in Gegenwart von YM-254890, einem selektiven Inhibitor von Gαq/11-Proteinen, nicht mehr in der Lage, die maximale cAMP-Inhibition zu verringern (Abbildung 66). Demzufolge scheint aktives Gαq eine entscheidende Rolle dabei zu spielen, die negative Kooperativität innerhalb des 5-HT2AR-D2R-Heterokomplexes zu vermitteln. Gemäß den cAMP-Assays, die ohne Vorstimulation mit Forskolin durchgeführt worden sind, konnte ausgeschlossen werden, dass Gαs-Proteine einen signifikanten Anteil an der inhibitorischen 5-HT2AR-D2R-Wechselwirkung haben. Die Untersuchungen zur Freisetzung intrazellulären Calciums sowie zur Hemmung der cAMP-Akkumulation nach Ligandbindung lieferten Informationen über die in vitro Eigenschaften von 5-HT2AR-D2R-Komplexen. Die Auswirkungen der 5-HT2AR-D2R-Heteromerisierung auf die G-Protein-vermittelte Signaltransduktion, welche sich aus unseren Ergebnissen ableiten lassen, werden in Abbildung 67 veranschaulicht. β-Arrestin-Rekrutierung an 5-HT2AR-D2R-Heterokomplexe Abgesehen vom Einfluss anderer G-Protein-Subtypen auf das modifizierte cAMP-Signal co-aktivierter 5-HT2AR-D2R-Heteromere untersuchten wir anschließend einen möglichen Zusammenhang mit der Agonist-stimulierten Rekrutierung von β-Arrestin-2 an den Komplex. Dazu verwendeten wir mit PK-Sequenzen markierte 5-HT2AR- und D2R-Konstrukte, die es ermöglichten, eine Rekrutierung von β-Arrestin-2 durch Enzymkomplementation und einer nachfolgenden Substratumsetzung nachzuweisen. Wie erwartet induzierten in HEK293-Zellen Serotoninrezeptoragonisten die Rekrutierung von β-Arrestin-2 an monomere 5-HT2A-Rezeptoren und Dopaminrezeptoragonisten die Rekrutierung an monomere D2-Rezeptoren. Interessanterweise erhielten wir für Zellen, die Heterodimere bestehend aus je einem PK-markierten Protomer und einem Wildtyp-Protomer exprimierten, charakteristische β-Arrestin-2-Kopplungsmuster (Abbildung 68). Die selektive Aktivierung des nicht-markierten Protomers führte zu einer geringen, aber messbaren Rekrutierung von β-Arrestin-2 an den Komplex. Um die Spezifizität der beobachteten β-Arrestin-2-Rekrutierung weiter zu analysieren, wurden innerhalb der Heterokomplexe die Wildtyp-Rezeptoren gegen nicht-signalfähige Mutanten ausgetauscht. Hierbei konnte durch Aktivierung des mutierten Protomers keine β-Arrestin-2-Bindung an den Komplex ausgelöst werden. Ob die Stimulation des nicht-markierten Rezeptors dazu führt, dass β-Arrestin-2 an das PK-Fragment des benachbarten Protomers koppelt oder ob eine allosterische Wechselwirkung innerhalb des 5-HT2AR-D2R-Komplexes eine asymmetrische Rekrutierung ermöglicht, lässt sich nicht abschließend beurteilen. Sicher scheint jedoch, dass für das beobachtete Rekrutierungsmuster von β-Arrestin-2 an 5-HT2AR-D2R die Funktionsfähigkeit beider Protomere gegeben sein muss. Der Einfluss akuter serotonerger Behandlung auf die Interaktion von 5-HT2AR und D2R im Rattenhirn Es ist gezeigt worden, dass im zentralen Nervensystem 5-HT2AR und D2R physisch und aller Voraussicht nach auch funktionell miteinander interagieren.228,329 Auf Grundlage dieser Erkenntnisse haben wir Sprague-Dawley-Ratten einer Einzeldosis-Behandlung mit verschiedenen Serotoninrezeptoragonisten unterzogen, was im letzten Abschnitt dieser Arbeit dargelegt wurde. Durch die Simulation einer kurzzeitig erhöhten Aktivität der serotonergen Transmission wollten wir herausfinden, ob eine Aktivierung von 5-HT2A-Rezeptoren die Bildung von 5-HT2AR-D2R-Heterokomplexen in vivo beeinflusst. An fixierten Rattenhirnschnitten des Striatum und der Hirnrinde konnten mit Hilfe des in situ Proximity Ligation Assays (PLA) GPCR-Komplexe identifiziert und anschließend mittels konfokaler Mikroskopie lokalisiert sowie quantifiziert werden. Die PLA-Versuche sowie die mikroskopischen Untersuchungen habe ich während eines Forschungsaufenthaltes im Labor von Prof. Kjell Fuxe am Karolinska Institutet in Stockholm durchgeführt. Im Vergleich zur Kontrollgruppe haben sowohl der halluzinogene 5-HT2AR-Agonist DOI als auch der nicht-halluzinogene 5-HT2AR-Agonist TCB-2 in subkortikalen und kortikalen Regionen die Dichte an 5-HT2AR-D2R-Clustern erhöht, wobei TCB-2 einen leicht stärkeren Effekt zeigte (Abbildung 69). Innerhalb des Striatum konnte DOI, im Gegensatz zu TCB-2, die Anzahl an Komplexen ausschließlich im medialen Teil der Schalenregion des Nucleus accumbens erhöhen. MDL-100907 als selektiver 5-HT2AR-Antagonist war in der Lage, die DOI-Effekte im Striatum sowie im subkortikalen Claustrum aufzuheben, was zu Häufigkeiten der 5-HT2AR-D2R-Heterokomplexe führte, die vergleichbar zu denen der Kontrollgruppe waren. Die DOI-vermittelte Zunahme an 5-HT2AR-D2R-Komplexen in bestimmten Bereichen des Rattenhirns steht demzufolge in Zusammenhang mit der Aktivierung von 5-HT2A-Rezeptoren. Unseren Erkenntnissen entsprechend akkumulieren 5-HT2AR-D2R-Heterodimere in einigen Regionen des Gehirns, in denen ihre Bildung zudem durch spezifische Aktivierung von 5-HT2AR angeregt werden kann. Die Schalenregion des Nucleus accumbens sowie das Claustrum sind an der Steuerung von Emotionen und Bewusstsein beteiligt.341,349 Interessanterweise waren beide Regionen empfindlich gegenüber halluzinogenem DOI. Eine Hochregulation von 5-HT2AR-D2R-Komplexen dort könnte zur Entstehung psychotischer Symptome beitragen, indem dadurch die für eine normale Sinneswahrnehmung erforderliche Informationsverarbeitung beeinträchtigt wird.
... It should be noted that although previous studies have shown the utility of quantifying D 2/3 receptor availability in patients receiving stable antipsychotic treatment in evaluating the relationship with clinical characteristics [53][54][55], the present study has the limitation of being a cross-sectional study without a drug-free time point. Therefore, we could not calculate D 2/3 receptor occupancy by antipsychotics due to the absence of baseline (medication-free) PET data. ...
The purpose of this study was to investigate the relationship between specific symptom severity and D2/3 receptor availability in extrastriatal regions in outpatients with schizophrenia to shed light on the role of extrastriatal dopaminergic neurotransmission in the pathophysiology of symptoms of schizophrenia. Sixteen schizophrenia patients receiving relatively low-dose maintenance atypical antipsychotics and seventeen healthy controls underwent 3-Tesla magnetic resonance imaging and high-resolution positron emission tomography with [(18)F]fallypride. For D2/3 receptor availability, the binding potential with respect to non-displaceable compartment (BPND) was derived using the simplified reference tissue model. The BPND values were lower in patients on antipsychotic treatment than in controls across all regions with large effect sizes (1.03-1.42). The regions with the largest effect size were the substantia nigra, amygdala, and insula. Symptoms of schizophrenia were assessed using a five-factor model of the Positive and Negative Syndrome Scale (PANSS). The region of interest-based analysis showed that PANSS excitement factor score had a significant positive correlation with the [(18)F]fallypride BPND in the insula. The equivalent dose of antipsychotics was not significantly correlated with PANSS factor scores or regional BPND values. The voxel-based analysis also revealed a significant positive association between the PANSS excitement factor and the [(18)F]fallypride BPND in the insula. The present study revealed a significant association between excitement symptom severity and D2/3 receptor availability in the insula in schizophrenia, suggesting a possible important role of D2/3 receptor-mediated neurotransmission in the insula and related limbic system in the pathophysiology of this specific symptom cluster.
... Low striatal D2/D3R availability in patients, either at baseline or due to receptor occupancy by antipsychotics, has been associated with greater negative symptom severity (de Haan et al., 2000; Heinz et al., 1998; Lataster et al., 2011; Martinot et al., 1994; Pickar et al., 1996; Uchida et al., 2009) and dysphoria (Mizrahi et al., 2007). However, it has also been associated with greater positive and less negative symptom severity (Pogarell et al., 2012) and some studies did not show any relationship (Agid et al., 2007; Graff-Guerrero et al., 2009; Kegeles et al., 2008; Klemm et al., 1996; Talvik et al., 2006). Some of the variability in these findings may be due to certain properties of the D2/D3R radioligands used (i.e. ...
... This may also help address conflicting results in the literature regarding the effects of pharmacological drugs on symptoms. For example, there have been conflicting results on whether antipsychotics can ameliorate negative symptoms in schizophrenia (Kane et al., 1988;Fitton and Heel, 1990;Miller et al., 1994;Schooler, 1994;Klemm et al., 1996;Risch, 1996;Rosenheck et al., 1997;Fink-Jensen, 2000;Rueter et al., 2004;Horacek et al., 2006;Tamrakar et al., 2006;Buckley and Stahl, 2007;Curtis et al., 2008). This could be due the fact that negative symptoms in schizophrenia are not monolithic constructs and may vary from individual from another. ...
Mounting evidence shows that brain disorders involve multiple and different neural dysfunctions, including regional brain damage, change to cell structure, chemical imbalance, and/or connectivity loss among different brain regions. Understanding the complexity of brain disorders can help us map these neural dysfunctions to different symptom clusters as well as understand subcategories of different brain disorders. Here, we discuss data on the mapping of symptom clusters to different neural dysfunctions using examples from brain disorders such as major depressive disorder, Parkinson’s disease, schizophrenia, PTSD and Alzheimer’s disease. In addition, we discuss data on the similarities of symptoms in different disorders. Importantly, computational modeling work may be able to shed light on plausible links between various symptoms and neural damage in brain disorders.
... Different atypical antipsychotics have dissociable effects on brain and cognition (Breier et al., 1999;Beninger, 2006). Some argue that most antipsychotics are used to treat psychiatric impairment, including positive symptoms, in schizophrenia, possibly by blocking dopamine receptors in the striatum or hippocampus (Klemm et al., 1996;Risch, 1996;Fink-Jensen, 2000;Rueter et al., 2004;Horacek et al., 2006). Many studies show that some antipsychotics are not effective at treating negative symptoms (Buckley and Stahl, 2007). ...
Introduction:
Schizophrenia is a severe mental disorder with multiple psychopathological domains being affected. Several lines of evidence indicate that cognitive impairment serves as the key component of schizophrenia psychopathology. Although there have been a multitude of cognitive studies in schizophrenia, there are many conflicting results. We reasoned that this could be due to individual differences among the patients (i.e. variation in the severity of positive vs. negative symptoms), different task designs, and/or the administration of different antipsychotics.
Methods:
We thus review existing data concentrating on these dimensions, specifically in relation to dopamine function. We focus on most commonly used cognitive domains: learning, working memory, and attention.
Results:
We found that the type of cognitive domain under investigation, medication state and type, and severity of positive and negative symptoms can explain the conflicting results in the literature.
Conclusions:
This review points to future studies investigating individual differences among schizophrenia patients in order to reveal the exact relationship between cognitive function, clinical features, and antipsychotic treatment.
... Molecular imaging studies with both SPECT (e.g. Brücke et al., 1991Brücke et al., , 1992Klemm et al., 1996;Pilowsky et al., 1993;Volk et al., 1994) and PET (e.g. Baron et al., 1989;Farde et al., 1988;Goyer et al., 1996;Kapur et al., 1996;Nordström et al., 1992Nordström et al., , 1993Wolkin, 1989) have extended the in vitro studies on dopamine receptors and antipsychotics from the 1970s in several crucial ways. ...
The glutamate and dopamine hypotheses are leading theories of the pathoaetiology of schizophrenia. Both were initially based on indirect evidence from pharmacological studies supported by post-mortem findings, but have since been substantially advanced by new lines of evidence from in vivo imaging studies. This review provides an update on the latest findings on dopamine and glutamate abnormalities in schizophrenia, focusing on in vivo neuroimaging studies in patients and clinical high-risk groups, and considers their implications for understanding the biology and treatment of schizophrenia. These findings have refined both the dopamine and glutamate hypotheses, enabling greater anatomical and functional specificity, and have been complemented by preclinical evidence showing how the risk factors for schizophrenia impact on the dopamine and glutamate systems. The implications of this new evidence for understanding the development and treatment of schizophrenia are considered, and the gaps in current knowledge highlighted. Finally, the evidence for an integrated model of the interactions between the glutamate and dopamine systems is reviewed, and future directions discussed.
© The Author(s) 2015.
... Interestingly, Parkinsonian panic coincides with reduced ldopa efficacy and l-dopa induced psychosis. Furthermore, autoradiographic data suggest comparable mesocorticolimbic DA receptor variations (e.g., frontal cortex and nucleus accumbens) in paranoid schizophrenia and Parkinsonian patients experiencing l-dopa psychosis [145,238239240241242243. The saliency of mesocorticolimbic DA/CCK alterations to the promotion of panic in individuals with schizophrenia and Parkinson's disease is obvious. ...
Panic disorder is characterized by a progression of panic symptom severity with repeated attacks. Repeated panic episodes evoke heightened anticipatory anxiety, phobic avoidance and are typically associated with comorbid symptoms of depression. Due to the heterogeneity of the disorder, reliable neurochemical correlates attending panic have not been identified. However, variable neuropeptide interfacing with major and minor transmitter systems may modulate individual vulnerability to panic and account for variable panic profiles. The extensive colocalization of cholecystokinin (CCK) with other neurotransmitters, including dopamine (DA), enkephalin (ENK) and GABA, in specific central sites may influence various aspects of anxiety and panic. The behavioral correlates attending panic likely follow from variable neurochemical release and conditioning/sensitization. Clinicians maintain that recurrent panic attacks are spontaneous (unexpected, uncued) and fail to acknowledge the wealth of information implicating a prominent role for stressful life events in panic. Conditioning and sensitization of both behavior (e.g., fear-motivated) and neurochemical events (e.g., DA and CCK) in response to uncontrollable stressors parallel the diverse heterogeneity of panic amongst clinical samples. Cholecystokinin-4, pentagastrin, lactate acid, and CO2 induce panic attacks that are dependent on subjective history, expectancy measures and panic profiles. Panic disorder is associated with chronic illness and familial sick-role modeling exacerbates the course of the illness. The current review outlines the evidence in support of a conditioning/sensitization model for panic, a model that may explain the variable efficacies of pharmacological interventions.
... ROIs were placed on the two consecutive oblique slices that contained the maximum striatal uptake, and averaged mean counts/pixel of the two slices were used for calculations. Percentage of receptor occupancy (%RO) was calculated as a percentage of change of the uptake ratios obtained during antipsychotic treatment ([S/O]t) related to a mean baseline value ([S/O]b), according to the formulae previously reported (Klemm et al., 1996;Tauscher et al., 2002): ...
There is as yet no definite prognostic marker to determine whether a first-episode psychosis will become schizophrenia or not. The aim of the present study is to address whether the mechanism of sensitization of the subcortical dopaminergic pathway - yielding to an increase of the postsynaptic D2 receptors - may serve as a prognostic marker of clinical outcome in drug naïve patients with a first-episode psychosis, by means of a prospective and multicentric study with untreated first-episode psychosis patients (n=37). 123I-IBZM SPECT was performed at the time of the inclusion in the study, before antipsychotic medication was initiated. One year later, patients were assessed again so as to determine their diagnosis. There was a significant group effect at baseline in D2 Striatal/Frontal (S/F) ratios (F=10.2, p<0.001). Bonferroni posthoc comparisons attested significant differences between diagnosis (p=0.006), and between schizophrenia and control groups (p<0.001) but no differences between non-schizophrenia and control groups (p=0.9). The logistic regression model showed that D2R binding (p=0.02) and PAS (Premorbid Adjustment Scale) adulthood score (p=0.03) were predictive of the final diagnosis (schizophrenia/non-schizophrenia; Nagelkerke R(2)=0.59; X(2)=11.08, p=0.001). These findings replicate previous results on the usefulness of D2R binding as an objective prognostic parameter, together with the evaluation of premorbid adjustment, of the evolution of first-episode psychosis. In this regard, the results may provide a new view in the approach of early and personalized treatment in the debut of a psychosis.
... In a study of Kapur and coworkers, the threshold for antipsychotic effect was suggested to be 65% rather than 70% [19]. An indirect support for a threshold around 65-70% D 2 occupancy is that recommended doses of more recently developed antipsychotic drugs correspond to this occupancy level [17,18,21,22]. However, a few antipsychotic drugs do not seem to fit the therapeutic window, which will be exemplified below. ...
Antipsychotic drugs were introduced in the early 50s on the basis of clinical observations in patients with schizophrenia. Experimental studies later revealed that antagonism at the D(2) dopamine receptor is a common characteristic of all antipsychotic drugs. In the 80s, the advent of brain imaging technologies such as positron emission tomography (PET) allowed for direct noninvasive studies of drug binding in treated patients. The concept receptor occupancy is defined as the fraction (%) of a receptor population that is occupied during treatment with an unlabelled drug. With regard to antipsychotic drugs, the radioligand [(11) C]-raclopride has been the most widely used for binding to the D(2) /D(3) -dopamine receptors. The present review discusses the contribution from molecular imaging to the current understanding of mechanism of action (MoA) of antipsychotic drugs. Consistent initial PET-findings of high D2-receptor occupancy in the striatum of patients responding to different antipsychotic drug treatments provided clinical support for the dopamine hypothesis of antipsychotic drug action. It has subsequently been demonstrated that patients with extrapyramidal syndromes (EPS) have higher occupancy (above 80%) than patients with good response but no EPS (65-80%). The PET-defined interval for optimal antipsychotic drug treatment has been implemented in the evolvement of dose recommendations for classical as well as more recently developed drugs. Another consistent finding is lower D(2) -occupancy during treatment with the prototype atypical antipsychotic clozapine. The MoA of clozapine remains to be fully understood and may include nondopaminergic mechanisms. A general limitation is that currently available PET-radioligands are not selective for any of the five dopamine receptor subtypes. Current attempts at developing such ligands may provide the tools required to refine further the MoA of antipsychotic drugs.
... Landmark in vitro studies in the 1970s showed there was a close relationship between the affinity of antipsychotic drugs for D2 receptors and the clinical potency of the drugs [18;19]. Subsequent ligand imaging studies with both SPECT (eg: [47][48][49][50][51]) and PET (eg: [52][53][54][55][56][57][58]) have demonstrated that all antipsychotic drugs cross the blood-brain-barrier and block D2/3 striatal receptors in vivo at clinically effective doses. These data support the in vitro findings, and have provided the foundation for studies in which the relationship between D2 occupancy and clinical response could be established. ...
Molecular imaging studies have generated important in vivo insights into the etiology of schizophrenia and treatment response. This article first reviews the PET and SPECT evidence implicating dopaminergic dysfunction, especially presynaptic dysregulation, as a mechanism for psychosis. Second, it summarises the neurochemical imaging studies of antipsychotic action, focussing on D2/3 receptors. These studies show that all currently licensed antipsychotic drugs block striatal D2/3 receptors in vivo- a site downstream of the likely principal dopaminergic pathophysiology in schizophrenia- and that D2/3 occupancy above a threshold is required for antipsychotic treatment response. However, adverse events, such as extra-pyramidal side-effects or hyperprolactinemia, become much more likely at higher occupancy levels, which indicates there is an optimal 'therapeutic window' for D2/3 occupancy, and questions the use of high doses of antipsychotic treatment in clinical practice and trials. Adequate D2/3 blockade by antipsychotic drugs is necessary but not always sufficient for antipsychotic response. Molecular imaging studies of clozapine, the one antipsychotic licensed for treatment resistant schizophrenia, have provided insights into the mechanisms underlying its unique efficacy. To link this pharmacology to the phenomenology of the illness, we discuss the role of dopamine in motivational salience and show how i) psychosis could be viewed as a process of aberrant salience, and ii) antipsychotics might provide symptomatic relief by blocking this aberrant salience. Finally, we discuss the implications of these PET and SPECT findings for new avenues of drug development.
... Our results show that when classical neuroleptics were switched to clozapine, striatal and thalamic perfusion decreased. Buchsbaum et al. (1992) and Potkin et al. (1994) reported that clozapine increased striatal metabolism when compared to a drug-free baseline, which may relate to the degree of D 2 blockade induced by clozapine, lower than that produced by classical neuroleptics (Farde et al., 1992;Klemm et al., 1996). Chakos et al. (1995) showed that striatal volume increases with classical neuroleptics and decreases when this treatment is substituted by clozapine. ...
Several studies with functional and structural brain-imaging techniques support the hypothesis that responders and non-responders to clozapine could show a different pattern of cerebral dysfunction. Thirty-nine neuroleptic-refractory schizophrenic patients were studied with 99Tc-labelled hexamethyl-propylene-aminoxime (HMPAO) and SPECT, while on classical neuroleptics and after 6 months of treatment with clozapine. The perfusion differences between responders and non-responders to clozapine were studied in the regions included within the dorsolateral and orbitofrontal fronto-striato-thalamic circuits, as well as the predictive value of these parameters. These values were compared to those of a normal database, and between both treatments within the two groups. On-neuroleptic perfusion in non-responders was lower in the thalamus, basal ganglia and dorsolateral prefrontal cortex. Thalamus and right prefrontal perfusion regions were selected as response predictors by a discriminant analysis. Thalamic and left basal ganglia activities while on neuroleptics were lower only in non-responders with respect to the normal subjects. Perfusion changes were only observed in the responder group in thalamus and basal ganglia. Study of regional perfusion may contribute to the prediction of clozapine response.
... With the development of new neuroimaging techniques, it has become possible to investigate the pharmacodynamic effect of antipsychotic drugs in vivo. Now, the degree of striatal D 2 receptor occupancy in the human brain during treatment with antipsychotic substances can be quantitatively analyzed by means of positron emission tomography (PET) (Farde et al. 1988a) and single photon emission computerized tomography (SPECT) (Brücke et al. 1991(Brücke et al. , 1992Klemm et al. 1996;Küfferle et al. 1996Küfferle et al. , 1997Kasper et al. 1998). ...
We investigated the degree of striatal dopamine-2 (D2) receptor occupancy in six schizophrenic patients receiving clinically effective antipsychotic treatment with olanzapine 10-25 mg/day in comparison to patients treated with clozapine 300-600 mg/day (n = 6) or haloperidol 5-20 mg/day (n = 10). 123I Iodobenzamide (IBZM) and single photon emission computerized tomography (SPECT) were used for the visualization of striatal D2 receptors. For the quantification of striatal D2 receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to that in untreated healthy controls (n = 8) reported earlier. Olanzapine led to a mean striatal D2 receptor occupancy rate of 75% (range 63-85). Haloperidol-treated patients showed dose-dependently (Pearson r = 0.64; P < 0.05) a significantly higher (P < 0.05) mean occupancy rate of 84% (range 67-94). During clozapine treatment, the mean D2 receptor occupancy of 33% (range < 20-49) was significantly lower than with olanzapine (P < 0.005). The higher striatal D2 receptor occupancy of haloperidol was correlated with the incidence and severity of extrapyramidal motor side-effects (EPS). No clinical relevant EPS occurred during treatment with olanzapine or clozapine. There was no correlation between the degree of striatal D2 receptor occupancy and clinical improvement.
... Sabri and Schreckenberger (1997) employing HMPAO-SPECT of the brain reported a positive correlation between the bitemporal rCBF elevation and formal disorders of the mental process in schizophrenic patients, but not in patients with hallucinations or delusions. Klemm et al., (1996) noted a statistically significant hypoperfusion in the temporal region of schizophrenics that correlated with positive symptoms of schizophrenia. Tune et al., (1997) demonstrated an inversive relationship between reduced temporal lobe volume and elevated levels of striatal dopamine D 2 density in schizophrenics. ...
The atypical neuroleptic clozapine induces specific electroencephalogram changes, which have not been investigated using the technique of magnetoencephalography (MEG).
The present study investigated whether spontaneous magnetoencephalographic (MEG) activity in patients treated with clozapine differs from that in patients treated with haloperidol and untreated control subjects.
A 2 x 37 channel biomagnetic system was used to record spontaneous magnetic activity for the frequency ranges (2-6 Hz), (7.5-12 Hz), (12.5-30 Hz) in schizophrenic patients and controls in two trials within 3 weeks. After data acquisition, the processed data were digitally filtered and the spatial distribution of dipoles was determined by a 3-D convolution with a Gaussian envelope. The dipole localisation was calculated by the dipole density plot and the principal component analysis. The target parameters were absolute dipole values and the dipole localisations. The relationship between absolute dipole values, dipole localisations and psychopathological findings (documented by the use of the PANSS, BPRS-scale) during a 3 week period with constant doses of clozapine and haloperidol was investigated using correlation analysis.
Our results lend strong support to the assumption of a significant elevation of absolute dipole values [dipole density maximum (Dmax), dipole number (Dtotal), absolute and relative dipole density] in the fast frequency range (12.5-30 Hz) over the left hemisphere, especially in the temporoparietal region by clozapine. In this area, we found a dipole concentration effect only in patients treated with the atypical neuroleptic, whereas the dipole distribution in patients treated with haloperidol and healthy controls was concentrated in the central region. With regard to the absolute dipole values in the frequency ranges 2-6 Hz (delta, theta) and 7.5-12 Hz (alpha), we found no statistically significant differences between the groups investigated. In the slow frequency range (2-6 Hz) no difference was found between the clozapine and haloperidol group for the dipole localisation, which predominated in the temporoparietal region, in contrast to the central dipole distribution in control subjects.
The results of an increase in beta activity under clozapine demonstrate a smaller reduction in activity in terms of unspecific sensory and motor paradigms in comparison with typical neuroleptics. The temporoparietal concentration of dipoles, in particular over the left half of the brain, might illustrate either their special role in the disease process, or the effects of the medication. The latter possibility was supported by the differing dipole distribution in the clozapine group with a left temporoparietal centre in both frequency ranges, and a deviating central dipole localisation in the fast activity range in the haloperidol group.
... It is a point of great scientific interest to demonstrate which receptors are occupied at clinically effective doses of antipsychotic drugs. In vivo occupancy of dopamine D 2 receptors by remoxipride has been demonstrated in humans using positron emission (30,31) and single photon emission tomographies (PET and SPET, respectively) (11,52). The specific in vivo occupancies of D 2 extrastriatal sites by remoxipride would have been more relevant to the therapeutic antipsychotic action of the drug. ...
Remoxipride is a substituted benzamide that acts as a weak but very selective antagonist of dopamine D2 receptors. It was introduced by Astra (Roxiam) at the end of the eighties and was prescribed as an atypical antipsychotic. This article reviews its putative selective effects on mesolimbic versus nigrostriatal dopaminergic systems. In animals, remoxipride has minimal cataleptic effects at doses that block dopamine agonist-induced hyperactivity. These findings are predictive of antipsychotic activity with a low likelihood of extrapyramidal symptoms. Remoxipride also appears to be effective in more recent animal models of schizophrenia, such as latent inhibition or prepulse inhibition. In clinical studies, remoxipride shows a relatively low incidence of extrapyramidal side effects and its effects on prolactin release are short-lasting and generally mild. The clinical efficacy of remoxipride is similar to that of haloperidol or chlorpromazine. Although its clinical use was severely restricted in 1993, due to reports of aplastic anemia in some patients receiving remoxipride, this drug has been found to exhibit relatively high selectivity for dopamine D2 receptors making remoxipride an interesting tool for neurochemical and behavioral studies.
Background
Al though the prin ci pal brain tar get that all an tipsy chotic drugs at tach to is the do pamine D 2 re cep tor, tra di tional or typi cal an tipsy chot ics, by at tach ing to it, in duce ex tra py r a mi dal signs and symp toms (EPS). They also, by bind ing to the D 2 re cep tor, ele vate se rum pro lac tin. Atypi cal a ntipsy chot ics given in dos ages within the clini cally ef fec tive range do not bring about these adverse clini cal ef fects. To un der stand how these drugs work, it is im por tant to ex am ine the atypical an tipsychot ics' mecha nism of ac tion and how it dif fers from that of the more typi cal drugs.
Method
This re view analy zes the af fini ties, the oc cu pan cies, and the dis so cia tion time- course of vari ous an tipsy chot ics at do pa mine D 2 re cep tors and at se ro tonin (5-HT) re cep tors, both in the test tube and in live pa tients.
Results
Of the 31 an tipsy chot ics ex am ined, the older tra di tional an tipsy chot ics such as tri fluperazine, pi mozide, chlor pro maz ine, fluphe nazine, ha loperi dol, and flupen thixol bind more tightly than dopamine it self to the do pa mine D 2 re cep tor, with dis so cia tion con stants that are lower than that for do pa mine. The newer, atypi cal an tipsy chot ics such as queti apine, re moxi pride, clo zapine, ol a nzap ine, sert in dole, zi pra si done, and amisul pride all bind more loosely than do pa mine to the do pamine D 2 re cep tor and have dis so cia tion con stants higher than that for do pa mine. These tight and loose bind ing data agree with the rates of an tipsy chotic dis so cia tion from the human- cloned D 2 recep tor. For in stance, ra dio ac tive ha loperi dol, chlor pro maz ine, and ra clo pride all dis s o ci ate very slowly over a 30- minute time span, while ra dio ac tive queti apine, clo zap ine, re moxi pride, and amisul pride dis so ci ate rap idly, in less than 60 sec onds. These data also match clini cal brain-imaging find ings that show ha loperi dol re main ing con stantly bound to D2 in hu mans un der go ing 2 posi tron emis sion to mo gra phy (PET) scans 24 hours apart. Con versely, the oc cu pa tion of D 2 by clo zap ine or queti apine has mostly dis ap peared af ter 24 hours.
Conclusion
Atypi cals clini cally help pa tients by tran siently oc cu py ing D 2 re cep tors and then rap idly dis so ci at ing to al low nor mal do pa mine neu ro trans mis sion. This keeps pro lac tin lev els nor mal, spares cog ni tion, and ob vi ates EPS. One the ory of atypi cal ity is that the newer drugs block 5-HT 2A re ceptors at the same time as they block do pa mine re cep tors and that, some how, this serotonin- dopam i n e bal ance con fers atypi cal ity. This, how ever, is not borne out by the re sults. While 5-HT 2A re cep tors are read ily blocked at low dos ages of most atypi cal an tipsy chotic drugs (with the im por tant ex ceptions of re moxi pride and amisul pride, nei ther of which is avail able for use in Can ada) the do s ages at which this hap pens are be low those needed to al le vi ate psy cho sis. In fact, the an tipsy chotic thresh old oc cu pancy of D 2 for an tipsy chotic ac tion re mains at about 65% for both typi cal and atypi cal an tipsychotic drugs, re gard less of whether 5-HT 2A re cep tors are blocked or not. At the same time, the a ntipsy chotic thresh old oc cu pancy of D 2 for elic it ing EPS re mains at about 80% for both typi cal and atypi cal an tipsy chot ics, re gard less of the oc cu pancy of 5-HT 2A re cep tors.
Relevance
The “fast- off-D 2 ” the ory, on the other hand, pre dicts which an tipsy chotic com pounds will or will not pro duce EPS and hy per pro lac ti ne mia and which com pounds pres ent a rela tiv ely low risk for tar dive dyski ne sia. This the ory also ex plains why L- dopa psy cho sis re sponds t o low atypi cal an tipsy chotic dos ages, and it sug gests vari ous in di vidu al ized treat ment strategies.
In addition to probing regional differences in receptor availability, molecular positron emission tomography (PET) is proving useful for investigating perturbations in neurotransmitter networks using interregional correlation analyses. In a multi‐modal imaging study, we examined interregional correlations of dopamine D2/3 receptor availability between striatal and extrastriatal regions using [¹⁸F]fallypride high‐resolution PET in 11 patients with schizophrenia receiving low‐dose maintenance atypical antipsychotics and 14 healthy control subjects, and investigated resting‐state functional connectivity in the same subjects using seed‐based functional magnetic resonance imaging (fMRI) analysis. In the healthy control group, there were no significant correlations between [¹⁸F]fallypride binding potential (BPND) in striatal regions and any cortical areas, whereas the patient group showed significant and widespread inter‐correlations. Correlations between BPND in striatum, amygdala and insula with cortex were significantly higher in patients than in controls. In seed‐based resting‐state fMRI analysis, the healthy controls revealed positive and negative functional connectivity patterns, while patients exhibited a pattern of exclusively positive connectivity. Functional connectivity was significantly higher between striatal regions and extrastriatal areas including cortical regions in patients compared to controls. In this first such report, molecular and functional connectivity between striatal and extrastriatal regions was primarily characterized by increased interregional relationships in treated patients with schizophrenia. The results suggest that the spatial organization of D2/3 receptor availability and related functional connectivity are significantly perturbed in stable outpatients on maintenance antipsychotics. Future studies should include antipsychotic‐naïve patients to determine if these relationships are illness‐related characteristics, or arising due to chronic antipsychotic treatment.
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Die Dopamin (DA)-Hypothese der Schizophrenie geht von einer Überaktivität dopaminerger Neurone aus, welche durch eine vermehrte Ausschöttung von DA oder eine öberschieβende Reaktion des DA-Rezeptors bedingt sein kann. Die antipsychotische Wirkung der Neuroleptika auf der Grundlage des DA-Antagonismus ist ein wichtiger Beleg för diese Hypothese. Umgekehrt können unter Anwendung von Substanzen, die zu einer vermehrten DA-Ausschiittung föhren, wie beispielsweise Amphetamin, Psychose-ahnliche Zustande beobachtet werden.
Die Verlaufsforschung hat in der Psychiatrie u. a. die folgenden Zielsetzungen: Validierung von Krankheitskonzepten, Beschreibung des Krankheitsverlaufs unter gegebenen Behandlungsbedingungen, Subdifferenzierung von Patientengruppen, Suche nach Verlaufsprädiktoren. An der psychiatrischen Klinik der Universität München bestehen besonders günstige Rahmenbedingungen für Verlaufsuntersuchungen, da routinemäßig ein umfassendes Basis- und Befunddokumentationssystem angewandt wird. Im Rahmen dieses Dokumentationssystems werden u.a. umfangreiche Daten zum psychopathologischen Aufnahme- und Entlassungsbefund mit dem AMDP (Arbeitsgemeinschaft für Methodik und Dokumentation in der Psychiatrie)-System erhoben. Die erhobenen Daten dienen einerseits zur Qualitätskontrolle, können aber natürlich auch wissenschaftlichen Zwecken zugeführt werden.
Based on the multifactorial etiopathogenesis of schizophrenia, a multidimensional therapy approach is suggested, in which psychopharmacological and psychosocial methods are combined (Deister and Möller, 1998; Moller and von Zerssen, 1995). The results of controlled group studies show that the efficacy of neuroleptics is very well proven for both treatment of the acute phase and relapse prevention (Möller et al., 2000). Supportive and educational approaches to increase compliance are widely used. Information about the complex causation of the disease and about its treatment requirements and possibilities are of great importance for the patient himself and also for his relatives, among others to increase the compliance.
Non-response to an initial antipsychotic trial emerges frequently in the pharmacological management of schizophrenia. Increasing the dose (high-dose treatment, dose escalation) is an often applied strategy in this regard, but there are currently no meta-analytic data available to ascertain the evidence of this treatment option.
We systematically searched for all randomized controlled trials (RCTs) that compared a dose increase directly to the continuation of standard-dose medication in patients with initial non-response to a prospective standard-dose pharmacotherapy with the same antipsychotic compound. Primary outcome was mean change in the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) total score. Secondary outcomes were positive and negative symptoms, response rates, and attrition rates. Hedges's g and risks ratios were calculated as effect sizes and the influence of the amount of the dose increase was examined by meta-regressions.
Altogether, five trials with 348 patients investigating dose escalation with quetiapine, ziprasidone, haloperidol, and fluphenazine could be included. We did not find any significant difference for the mean PANSS/BPRS score change between the dose-increase and control group, neither for the pooled antipsychotic group nor for the individual antipsychotic drugs. Moreover, there were no between-group differences in positive and negative symptoms, response rates, and drop-out rates. The meta-regressions indicate no significant influence of the different amounts of dose increments on effect sizes.
This meta-analysis suggests no evidence for a dose-escalation of the investigated antipsychotic drugs fluphenazine, haloperidol, quetiapine, and ziprasidone in case of initial non-response to standard-dose pharmacotherapy.
Copyright © 2015 Elsevier B.V. All rights reserved.
Single photon emission computed tomography (SPECT) has been the cornerstone of nuclear medicine and today it is widely used to detect molecular changes in cardiovascular, neurological and oncological diseases. While SPECT has been available since the 1980s, advances in instrumentation hardware, software and the availability of new radiotracers that are creating a revival in SPECT imaging are reviewed in this paper.
The biggest change in the last decade has been the fusion of CT with SPECT, which has improved attenuation correction and image quality. Advances in collimator design, replacement of sodium iodide crystals in the detectors with cadmium zinc telluride (CZT) detectors as well as advances in software and reconstruction algorithms have all helped to retain SPECT as a much needed and used technology.
Today, a wide spectrum of radiotracers is available for use in cardiovascular, neurology and oncology applications. The development of several radiotracers for neurological disorders is briefly described in this review, including [ ¹²³ I]FP-CIT (DaTSCAN TM ) available for Parkinson's disease. In cardiology, while technetium-99m labeled tetrofosmin and technetium-99m labeled sestamibi have been well known for myocardial perfusion imaging, we describe a recently completed multicenter clinical study on the use of [ ¹²³ I] m IBG (AdreView TM ) for imaging in chronic heart failure patients. For oncology, while bone scanning has been prevalent, newer radiotracers that target cancer mechanisms are being developed. Technetium-99m labeled RGD peptides have been reported in the literature that can be used for imaging angiogenesis, while technetium-99m labeled duramycin has been used to image apoptosis.
While PET/CT is considered to be the more advanced technology particularly for oncology applications, SPECT continues to be the modality of choice and the workhorse in many hospitals and nuclear medicine centers. The cost of SPECT instruments also makes them more attractive in developing countries where the cost of a scan is still prohibitive for many patients.
The clinical potencies of antipsychotic drugs are directly related to their affinities for the dopamine D2 receptor. In addition, the concentrations of antipsychotic drugs (given at therapeutic maintenance doses) in the plasma water or in the spinal fluid are almost identical to the antipsychotic dissociation constants at the dopamine D2 receptor. A consistent 70–75% of brain D2 receptors are occupied by antipsychotic drugs, as calculated from the therapeutic concentration and the antipsychotic dissociation constant. The D3 and D4 dopamine receptors, however, are not consistently occupied by antipsychotic drugs, the occupancies being 0–85% for D3, and 0–95% for D4. Human brain imaging also reveals that therapeutic doses of antipsychotic drugs occupy ∼70% of D2 receptors. Between 2 and 4 h after the daily oral dose, clozapine and quetiapine occupy high levels (∼70%) of the dopamine D2 receptors in schizophrenia patients, with lower occupancies at 6 and 12 h. Although clozapine and quetiapine occupy low levels of D2 receptors many hours after the oral dose, the observed fraction of D2 receptors occupied by these drugs, however, depends on the radioligand used, with high occupancy seen when using [11C]raclopride, and low occupancy seen with [11C]methylspiperone (which is tightly bound to D2). This dependence on the radioligand occurs because clozapine and quetiapine are loosely bound to D2. The loose binding of clozapine and quetiapine to D2 permits endogenous dopamine to displace these antipsychotic drugs much more quickly than haloperidol. In addition, the small dose of radioactive raclopride injected (in brain imaging) can displace a little of the D2-bound clozapine. Hence, the observed low level of D2 occupancy by clozapine in patients may arise from a combination of the above three factors – the ligand dependency, the endogenous dopamine, and the displacement by the imaging dose. Parkinsonism and extrapyramidal effects occur with antipsychotics which have a high affinity for D2 and which are, therefore, tightly bound to D2. Clozapine and quetiapine have a low affinity for D2, and, being readily displaced by endogenous dopamine, do not give rise to extrapyramidal effects. Because the loosely bound antipsychotics dissociate from D2 more rapidly, clinical relapse may occur earlier than that found with the tightly bound traditional antipsychotics. The dopamine hypothesis of schizophrenia is supported by the fact that D2 is the main target of antipsychotic action, that monomers of D2 appear elevated in schizophrenia, and that the synaptic levels of dopamine in schizophrenia are at least two-fold higher than in control subjects.
The pathogenesis of schizophrenia is not known, but several causative factor have been proposed, such as the existence of
a genetic defect [1], prenatal infections with viruses [2], structural abnormalities in the brain [3
4], receptor dysfunctions in many neurotransmission or transduction systems [5
6]. Concerning the latter the dopaminergic system has been implicated in schizophrenia for more than four decades. Whereas
in early studies the metabolism of dopamine (DA) was studied, in the last decade the emphasis has been on dopamine receptors
and transduction mechanisms. A major lead in the DA-approach has been the fact that clinically effective antipsychotics in
schizophrenia appear to exert anti-DA-ergic activity, either by inhibiting subtypes of DA-receptors, or by decreasing metabolism
or other aspects of neurotransmission of cerebral DA-containing neurons. These pharmacological properties led to the proposal
of an increased DA-activity in the limbic system in schizophrenia [7-10].
Olanzapine is a new atypical antipsychotic agent that belongs to the same chemical class as clozapine. The pharmacological
efficacy of olanzapine (in contrast to that of risperidone) has been shown to be comparable to that of clozapine, but olanzapine
has the advantage of producing a less pronounced bone marrow depressing effect than clozapine. The specific aims of this study
were (a) to assess dopamine D2/D3 receptor availability in patients treated with olanzapine by means of iodine-123 iodobenzamide [123I]IBZM single-photon emission tomography (SPET), (b) to compare the results with findings of [123I]IBZM SPET in patients under treatment with risperidone and (c) to correlate the results with the occurrance of extrapyramidal
side-effects (EPMS). Brain SPET scans were performed in 20 schizophrenic patients (DSM III R) at 2 h after i.v. administration
of 185 MBq [123I]IBZM. Images were acquired using a triple-head gamma camera (Picker Prism 3000 XP). For semiquantitative evaluation of D2/D3 receptor binding, transverse slices corrected for attenuation were used to calculate specific uptake values [STR–BKG]/BKG
(STR=striatum; BKG=background). The mean daily dose of olanzapine ranged from 0.05 to 0.6 mg/kg body weight. The dopamine
D2/D3 receptor binding was reduced in all patients treated with olanzapine. Specific IBZM binding [STR–BKG]/BKG ranged from 0.13
to 0.61 (normal controls >0.95). The decreased D2/D3 receptor availability revealed an exponential dose-response relationship (r=–0.85, P<0.001). The slope of the curve was similar to that of risperidone and considerably higher than that of clozapine as compared
with the results of a previously published study. EPMS were observed in only one patient, presenting with the lowest D2/D3 availability. The frequency of EPMS induced by olanzapine (5%) was considerably lower than the frequency under risperidone
treatment (40%). Our findings suggest an exponential relationship between the daily dose of olanzapine striatal and decreased
D2/D3 striatal binding availability. The results are consistent with the findings of in vitro experiments reporting a higher D2/D3 receptor affinity and a similar 5HT2 receptor affinity of olanzapine as compared with clozapine. Thus, the decreased tendency to induce EPMS at therapeutic doses
is not due to the limited occupancy of striatal D2/D3 receptors in vivo. Patients are protected from EPMS by other intrinsic effects of the drug, i.e. the combination of both
D2/D3 and 5HT2 receptor antagonism.
Schizophrenia and bipolar disorder remain two of the most severe and difficult to treat psychotic disorders hampered by our poor understanding of their pathologies. The development of typical antipsychotic drugs opened an avenue of investigation through the dopamine D2 receptor in schizophrenia. With the reintroduction of the atypical antipsychotic clozapine came the development of a new generation of atypical agents and hypotheses challenging the centrality of this receptor in explaining antipsychotic effects. Evaluation of these competing theories does not provide sufficient evidence to displace the importance of the dopamine D2 receptor in antipsychotic efficacy, but does raise limitations of it as an explanatory hypothesis. Further, the treatment of other symptom domains in schizophrenia remains relatively neglected and open for the development of novel therapies. Similar to schizophrenia, bipolar disorder presents a diversity of clinical states but unlike schizophrenia, its mainstay of treatment, lithium, has not had a clear receptor target impeding understanding of the disorder's pathology and treatment. This has pushed investigation into other domains emphasising a number of intracellular signalling pathways and glial-neuronal interactions. The heavy genetic loading of bipolar disorder has allowed linkage analyses to identify a number of putative regions, however, the diversity of phenotypes complicates such studies. Polymorphisms of candidate genes have yielded potential leads such as dopamine beta hydroxylase in mood disorder and the serotonin transporter for treatment response. It is anticipated that combining the above approaches may hold promise for the development of more effective treatments.
Recent studies have described a left lateralized striatal asymmetry of D2 dopamine receptors in male patients with schizophrenia. To replicate this finding and to explore its potential functional consequences, we investigated the D2 dopamine receptor system in 23 drug-naive patients with schizophrenia using single photon emission computed tomography (SPELT). Patients were examined in the drug-naive state and 72 h after completing a standardized neuroleptic treatment with benperidol (12–16 mg/day) for 25 days. Each SPELT examination comprised two scans: the first scan was taken 2 h after intravenous injection of 185 MBq [123I]iodobenzamide. After completion of the first scan, patients received benperidol (8 mg) intravenously. The second scan was started 20 min later. For analysis, basal ganglia to frontal cortex ratios were calculated. Fifteen of the 23 patients originally recruited completed the study on day 28. When compared to female patients, male patients showed a left lateralized asymmetry of striatal D2 dopamine receptor binding in the drug-naive state with an almost significant (P = 0.07) sex X hemisphere interaction. In the male patients, benperidol challenge led to a reversal of asymmetry patterns. These findings support previous reports of a left lateralized striatal D2 receptor binding in drug-naive male patients with schizophrenia and suggest that this asymmetry may affect the binding of conventional neuroleptics such as benperidol at the D2 dopamine receptor.
Levels above 75% of striatal dopamine 2 receptor occupancy (D2RO) have been associated with extrapyramidal symptoms (EPS). The aim of the present study is to investigate the relationship between D2RO and EPS in a sample of psychotic patients in current treatment with both typical and atypical antipsychotics. Brain iodine-123-iodobenzamide single photon emission computed tomography ((123)I-IBZM SPECT) was performed in 81 patients taking stable doses of haloperidol, risperidone, olanzapine, quetiapine, clozapine or ziprasidone. First, the degree of D2RO and Positive and Negative Syndrome Scale (PANSS) scores was compared between the group of patients who presented EPS and the group free of EPS. Afterwards, these variables were compared among the different antipsychotic medications. The group with EPS presented means of D2RO significantly higher than the group free of EPS. Significant differences in D2RO were found in clozapine, quetiapine and ziprasidone groups compared with the haloperidol group. No differences were observed between either olanzapine or risperidone and haloperidol. No quetiapine- or clozapine-treated patients developed EPS. Haloperidol and risperidone demonstrated a relationship between striatal D2RO and EPS. The findings suggest that higher D2RO is related to appearance of EPS. Occupancy in the group with EPS was in agreement with previous studies that suggested a high degree of D2RO is necessary for the occurrence of EPS.
The guidelines summarize the current views of the European Association of Nuclear Medicine Neuroimaging Committee (ENC). The aims of the guidelines are to assist nuclear medicine practitioners in making recommendations, performing, interpreting and reporting the results of clinical dopamine D2 receptor SPECT or PET studies, and to achieve a high quality standard of dopamine D2 receptor imaging, which will increase the impact of this technique in neurological practice.The present document is an update of the first guidelines for SPECT using D2 receptor ligands labelled with (123)I [1] and was guided by the views of the Society of Nuclear Medicine Brain Imaging Council [2], and the individual experience of experts in European countries. The guidelines intend to present information specifically adapted to European practice. The information provided should be taken in the context of local conditions and regulations.
L'apprentissage moteur est un type d'apprentissage procédural représenté par l'acquisition progressive d'une habileté motrice ou sensorimotrice. Ce genre d'apprentissage implique des expositions répétées à une tâche ou à une situation invariable. Les substrats anatomiques sous-jacents à l'apprentissage moteur sont de mieux en mieux documentés. Certains auteurs suggèrent que le striatum est impliqué dans un processus de modification des programmes moteurs en fonction des paramètres de la situation. Des résultats obtenus au cours des dernières années suggèrent un rôle déterminant de la dopamine dans ce processus d'apprentissage. Les deux articles proposés dans le cadre de cette thèse visent à préciser ce phénomène en étudiant le rôle du système dopaminergique nigrostrié dans l'apprentissage moteur. Le premier article évalue les capacités d'apprentissage moteur de patients schizophrènes traités soit avec de l'halopéridol (un antipsychotique classique) ou avec de l'olanzapine (un antipsychotique atypique). Les capacités d'apprentissage de ces patients sont évaluées par l'entremise d'une tâche de poursuite rotative. Les résultats obtenus sont mis en relation avec une mesure in vivo du niveau de saturation des récepteurs dopaminergiques D₂ du striatum. Le niveau de saturation des récepteurs dopaminergiques est évalué grâce à un examen tomographique par émission monophotonique (TEMP) couplé à l'administration d'Iodine 123-iodobenzamide (¹²³ I-IBZM). Les résultats obtenus montrent que les capacités d'apprentissage moteur des patients traités avec halopéridol sont affectées en comparaison de celles de sujets contrôles. Aucune différence n'est remarquée lorsque la performance des patients traités avec olanzapine est comparée à celle des sujets du groupe contrôle. Dans le groupe halopéridol, une corrélation significative est observée entre les déficits d'apprentissage moteur et le niveau d'occupation des récepteurs D₂ du striatum. Dans le second article, l'impact de la médication dopaminergique sur les capacités d'adaptation sensorimotrice de patients parkinsoniens est étudié. Les patients sont évalués avec et sans leur régime habituel de lévodopa à un délai test re-test de 24 heures. Cette étude permet de préciser le rôle de la déplétion dopaminergique nigrostriatale. Sur le plan fonctionnel, cette étude s'intéresse également à l'hypothèse d'une implication dopaminergique striatale dans le processus d'inhibition des anciens mouvements au profit des nouveaux, qui sont mieux adaptés. Les résultats obtenus montrent que les patients persistent à effectuer les mouvements anciens lorsqu'ils sont privés de lévodopa. Ces sujets s'adaptent peu à la tâche malgré les essais répétés. Ce phénomène n'apparaît pas si le traitement dopaminergique est réinstauré. De façon générale, les résultats obtenus dans le cadre de ces études montrent un lien direct et un rôle prépondérant de la dopamine striatale dans l'apprentissage de séquences motrices et dans l'adaptation sensorimotrice. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Apprentissage moteur, Apprentissage de séquences motrices, Adaptation sensorimotrice, SPECT, Dopamine, Récepteurs D2, Striatum, Schizophrénie, Maladie de Parkinson, Neuroleptiques, Lévodopa.
Considerable progress has been achieved over the past 15 years in uncovering the biological basis of major psychiatric disorders. Since psychopharmacological treatment is thought tc act on the underlying biological basis of the disease, brain imaging techniques enable us to understand the mechanism of action of such compounds. One important tool used to determine patterns of brain dysfunction and how psychopharmacological agents such as antipsychotic compounds work is single-photon emission computerised tomography (SPECT). This technique allows determination of striatal D(2) receptor occupancy rates, which are associated with the extrapyramidal side effects (EPS) of antipsychotic drugs. Studies have confirmed that atypical antipsychotic agents have lower occupancy rates than typical agents. No association has been found between D(2) receptor occupancy rates n the striatum and antipsychotic efficacy, and it therefore appears that striatal D(2) receptor occupancy rates are not necessary for the antipsychotic effect of such agents in schizophrenia. The availability of more refined radioligands will help us not only to understand the action of antipsychotics but also the pathophysiology of schizophrenia.
Brain SPECT with HMPAO or ECD has-due to its short accumulation period--a rather high time resolution of approx 60 sec. Compared to isopropyl amphetamine (I-123) and FDG-PET, shortlasting interventions may be evaluated by SPECT. Usually, a two-step approach is used, injecting one third of the dose under baseline conditions and two thirds during intervention. The first study is then subtracted from the second study, resulting in a "difference" image which allows to calculate the effect of the intervention. These interventional procedures may include drug, mechanical, and mental intervention as well as ictal, blood pressure and receptor intervention. Moreover, the difference of pCO2 after hyperventilation or hypoventilation may also be used as a stimulus. The above mentioned procedures are described in detail.
Studies have suggested that antipsychotic drug therapy with haloperidol in schizophrenic patients requires an optimal dose that blocks the brain dopamine D2 receptors. We evaluated the effect of different doses of haloperidol on D2 receptor occupancy in schizophrenia.
Three normal subjects and three patients with acute schizophrenia had serial brain SPECT imaging studies (every 5 min) for 3 hr following the injection of [123I]IBZM. The patients had IBZM studies off medication and at different doses (1-10 mg) of haloperidol.
The basal ganglia (BG) were well visualized in normals and in schizophrenics off medication. After haloperidol therapy, SPECT images showed qualitatively diminished activity in the basal ganglia. ROIs were drawn over the basal ganglia and cerebellum (CE). The results were expressed as BG/CE ratios. At 2 hr postinjection of IBZM, the mean BG/CE ratio in normals was 1.75 +/- 0.025. In schizophrenics, the BG/CE ratio off medication was 1.54 +/- 0.12. The BC/CE ratio showed an inverse relationship to haloperidol dose; 1.46 at 1 mg, 1.25 at 4 mg and 1.05 at 10 mg, respectively.
These results demonstrate that IBZM brain SPECT imaging studies are potentially useful to relate the antipsychotic drug D2 receptor occupancy with the administered dose in schizophrenic patients and may ultimately help optimize antipsychotic treatment.
Risperidone is an antipsychotic drug with high affinity at dopamine D2 and serotonin 5-HT2 receptors. Previous clinical studies have proposed that risperidone's pharmacologic profile may produce improved efficacy for negative psychotic symptoms and decreased propensity for extrapyramidal side effects; features shared by so-called 'atypical' neuroleptics. To determine if routine risperidone treatment is associated with a unique degree of D2 receptor occupancy and pattern of clinical effects, we used [123I]IBZM SPECT to determine D2 occupancy in subjects treated with routine clinical doses of risperidone (n = 12) or haloperidol (n = 7). Both risperidone and haloperidol produced D2 occupancy levels between approximately 60 and 90% at standard clinical doses. There was no significant difference between occupancy levels obtained with haloperidol or risperidone. Drug-induced parkinsonism was observed in subjects treated with risperidone (42%) and haloperidol (29%) and was observed at occupancy levels above 60%. Based on these observations, it is concluded that 5-HT2 blockade obtained with risperidone at D2 occupancy rates of 60% and above does not appear to protect against the risk for extrapyramidal side effects.
The recently introduced neuroleptic, risperidone, was expected to block fewer dopamine D2 receptors than typical neuroleptics (e.g., haloperidol), but at comparable potency. The aim of this study was to evaluate the degree of dopamine D2 receptor occupancy in relation to the neuroleptic dosage and to correlate the findings with the presence of extrapyramidal symptoms (EPS). Additionally, the data were compared to previous iodobenzamide (IBZM) SPECT findings in patients treated with other neuroleptics, haloperidol and clozapine.
In 20 patients with schizophrenia [Diagnostic and Statistical Manual of Mental Disorders (Third Edition-Revised)] treated with mean daily doses of risperidone ranging from 0.029 to 0.128 mg/kg body weight, SPECT was performed 2 hr after intravenous injection of 185 MBq 123I-IBZM, a selective dopamine D2 receptor ligand. Striatal IBZM binding was assessed by calculating a striatal/frontal cortex ratio, expressed as a percentage of the control value.
Selective dopamine D2 receptor binding of the ligand was reduced in all treated patients, with binding values ranging from 7% to 68%. The degree of occupancy displayed an exponential dose-response relationship (r = -0.86; p < 0.0001). The slope of the curve was between those of haloperidol and clozapine but was closer and more similar in shape to the curve of haloperidol. Extrapyramidal symptoms were observed in 8 of 20 patients with binding values between 7% and 47%. However, there was no clear relationship between the degree of receptor occupancy and the presence of EPS.
The findings suggest an exponential dose-response relationship between the daily dosage of risperidone and the dopamine D2 receptor occupancy. The blockade of specific striatal IBZM binding found under therapy with risperidone is between those of haloperidol and clozapine. The dose-response curve for risperidone, however, shows greater similarity to that of haloperidol.
Functional neuroimaging techniques including single photon emission computerised tomography (SPECT), positron emission tomography (PET) and functional magnetic resonance imaging (FMRI) can provide insight into the functional connectivity of the human brain in both health and disease, including the effects of aging and drugs on brain function.
Neuroimaging measurement techniques can either be direct, using radio-specific ligands, or indirect, using the neurophysiological consequences of pharmacological interventions. Both approaches can be combined with sensorimotor or cognitive activation to examine the interaction between the targeted receptor function and the sensorimotor or cognitive process implicit in the study design.
Using radionuclides, PET can provide absolute measurement of cerebral blood flow to regions of interest and can measure changes in cerebral metabolism using labelled fluorodeoxyglucose. PET offered the first opportunity to image brain activation caused by a variety of stimuli and hence to measure the effect of drugs on brain activation. PET also enables the study of drug disposition within the brain. SPECT has been used to study relative changes in cerebral blood flow associated with disease processes and also receptor occupancy.
FMRI, by contrast, does not involve ionising radiation and has better spatial and temporal resolution. It is still a relatively new technique and limited by its ability to only measure haemodynamic changes through the blood oxygen level-dependent (BOLD) signal.
The effects of aging on drug responsiveness and the effects of drug treatment of diseases associated with old age are relatively unexplored areas of functional neuroimaging research.
In an attempt to understand the basis of early relapse after antipsychotic withdrawal, the objective of this study was to determine whether the low occupancy of dopamine D2 receptors by clozapine and by quetiapine, as seen by brain imaging, could arise from a rapid release of some of the D2-bound clozapine or quetiapine by the brain imaging compounds and by the action of a physiological concentration of dopamine.
Human cloned D2 receptors were first pre-equilibrated with the [3H]antipsychotic drug, after which raclopride, iodobenzamide, or dopamine (at the physiological concentration in the synapse) was added, and the time course of release of the [3H]antipsychotic from the D2 receptor was measured.
Within 5 minutes, low concentrations of raclopride and iodobenzamide displaced appreciable amounts of [3H]clozapine and [3H]quetiapine from the D2 receptors but, during the course of 1 hour, did not displace any of the other antipsychotic [[3H]ligands. [3H]Clozapine and [3H]quetiapine, moreover, were displaced by dopamine (100 nM) at least 100 times faster than the other antipsychotic [3H]ligands.
Clozapine and quetiapine are loosely bound to the D2 receptor, and the injected radioactive ligand at its peak concentration may displace some of the D2-bound antipsychotic drug, resulting in apparently low D2 occupancies. Therefore, under clinical brain imaging conditions with [11C]raclopride, D2 occupancies by clozapine and by quetiapine may be higher than currently estimated. These considerations may result in high levels of the D2 receptors being occupied by therapeutic doses of clozapine or quetiapine. The rapid release of clozapine and quetiapine from D2 receptors by endogenous dopamine may contribute to low D2 receptor occupancy and to early clinical relapse upon withdrawal of these medications.
Clozapine is an atypical antipsychotic drug, which is claimed to have superior efficacy and to cause fewer movement disorders. However, clozapine carries a significant risk of serious blood disorders. Newer atypical antipsychotics are safer alternatives that might share the benefits of clozapine. It is thus of interest to compare the effectiveness of newer atypical antipsychotics with the effectiveness of clozapine.
To evaluate the clinical effects of newer atypical antipsychotic drugs in comparison to clozapine for schizophrenia.
Publications in all languages were searched from the following databases: Biological Abstracts/BIOSIS (1980-1999), The Cochrane Schizophrenia Group's Register of Trials (1998), The Cochrane Library CENTRAL Register (Issue 4, 1999), EMBASE (1980-1998), MEDLINE (1966-1999), LILACS/CD-ROM (1998), and PsycLIT/PsycINFO (1974-1999). Trials were also sought from recent conference proceedings and reference lists of included papers. Authors of recent trials and the manufacturers of clozapine, iloperidone, olanzapine, quetiapine, remoxipride, risperidone, sertindole, ziprasidone and zotepine were contacted.
All randomised controlled trials comparing clozapine with newer atypical antipsychotic drugs were included by independent assessment by two reviewers.
Data were extracted independently by two reviewers. Relative risks (RR) and 95% confidence intervals (CI) of homogenous dichotomous data were calculated. A random effects model was used for heterogeneous dichotomous data. Where possible the number needed to treat (NNT) statistic with 95%CI were also calculated. Weighted or standardised means were calculated for continuous data. Due to the small number of included studies, sensitivity analyses or funnel plot statistics were not undertaken for this version of the review.
The current review includes eight studies (22 papers), of which three studies are 4-6 weeks in duration and only one study is of more than 12 weeks' duration. Newer atypical drugs seemed to be broadly similar to clozapine using a clinical global index or trialists' definitions of improvement, but this result was obtained from a relatively small number of studies. Due to the small number of studies and patients, wide confidence intervals were seen when their effectiveness as measured by symptom rating scales was compared. Social functioning was better in patients on newer atypical medication (risperidone) than in those on clozapine, but this finding is based on a single underpowered trial and has to be interpreted with caution. Clozapine and newer atypical drugs showed their adverse effect profile to be dissimilar: while clozapine produced more fatigue, hypersalivation, nausea, and orthostatic dizziness, new atypical drugs, with the exception of olanzapine, produced more extrapyramidal symptoms. The impact of these drugs and their effects on patients' day-to-day quality of life, service use, hospital admission, and pharmacoeconomics was not measured.
The equal effectiveness and tolerability of new atypical drugs in comparison with clozapine is not yet demonstrated. Lack of statistical power to determine the comparative efficacy and effectiveness of newer atypical drugs makes it difficult to judge whether newer drugs are more effective, less effective or equivalent. Trials of sufficient power, with longer duration, measuring clinically important outcomes, are needed to assess the true comparative clinical effectiveness, tolerability and cost effectiveness of newer drugs in relation to clozapine.
Compared to conventional antipsychotic medications, atypical antipsychotic medications demonstrate greater central serotonin (5HT2) receptor antagonism than dopamine type 2 (D2) receptor antagonism. Nefazodone, an antidepressant medication, exhibits 5HT2 receptor antagonism; we therefore wondered if its addition to stable regimens of antipsychotic medication would increase antipsychotic efficacy, independently of a primary effect on mood, through the mechanism of augmented 5HT2 receptor antagonism. In a pilot investigation, we administered nefazodone (400 mg/d) for 6 weeks as an open-label adjunct to antipsychotic medication in 10 patients with chronic schizophrenia. The patients were moderately depressed at baseline but did not meet criteria for major depressive episode. The Brief Psychiatric Rating Scale (BPRS) and Montgomery-Asberg Depression Rating Scale scores showed statistically significant and clinically robust improvements with nefazodone treatment, which were maintained at follow-up evaluation 2 weeks after the end of nefazodone treatment. There were no adverse events. These results suggest that nefazodone may be a safe and effective adjunct to antipsychotic medications in schizophrenia and that augmentation of 5HT2 antagonism may prove to be a viable strategy for "boosting" antipsychotic efficacy and for treating depressive symptoms in schizophrenia.
The aim of this study was to compare in vivo striatal D2 dopamine receptor occupancy induced by olanzapine and haloperidol in schizophrenic patients using a baseline-endpoint [(123)I]IBZM single photon computed emission tomography (SPECT) design. The relationships of striatal D2 receptor occupancy with clinical efficacy and extrapyramidal symptoms (EPS) were also assessed. Twenty-seven inpatients with schizophrenia or schizophreniform disorder were included in a 4-week prospective, randomized, double-blind, parallel and comparative clinical trial. Thirteen patients were treated with haloperidol (10 mg/day) and 14 with olanzapine (10 mg/day). Ratings of clinical status and EPS were obtained weekly. The percentage of D2 receptor occupancy was estimated by using basal ganglia (striatum)/frontal cortex IBZM uptake ratios obtained from each patient before and after 4 weeks of maintained antipsychotic treatment. Olanzapine led to a mean striatal D2 receptor occupancy of 49% (range 28-69%), which was significantly lower than that induced by haloperidol (mean 64%, range 46-90%). The baseline-endpoint SPECT design used in this study revealed lower antipsychotic D2 occupancy percentage values than those reported in the literature, using other approaches. The degree of striatal D2 receptor occupancy correlated to the EPS, which predominantly appeared in patients on haloperidol. No relationship was found between the striatal D2 receptor occupancy and clinical improvement. Olanzapine induced a lower striatal D2 occupancy than haloperidol. This low striatal D2 occupancy, together with the lower incidence of EPS in olanzapine-treated patients, contributed to confirm the atypical behavior of this new antipsychotic drug. Nevertheless, conclusions based on SPECT-estimated percentages of antipsychotic D2 occupancy should be cautious, since the SPECT design could influence the results. In this regard, SPECT studies including baseline and endpoint examinations should be encouraged.
Single photon emission computed tomography (SPECT) using (123)I iodobenzamide (IBZM) as tracer substance has been shown to be a useful tool to visualize dopamine 2 (D2) receptor occupancy.
We investigated the striatal D2 receptor occupancy of zotepine which is referred to the class of atypical antipsychotic drugs.
(123)I IBZM and SPECT were used to visualize striatal dopamine 2 (D2) receptor occupancy in zotepine-treated schizophrenic patients. Two groups of schizophrenic patients receiving either 150 mg/day zotepine (n=6) or 300 mg/day (n=6) underwent examination. For the quantification of striatal D2 receptor occupancy, striatal IBZM binding in patients treated with antipsychotics was compared to untreated healthy controls (n=8) reported earlier.
Zotepine led to a mean overall striatal D2 receptor occupancy of 73%. Patients with 150 mg daily showed a significantly lower occupancy (65.8%, SD=6.2) than patients with 300 mg/day (77.8%, SD=10.7; P<0.05). No clinically relevant extrapyramidal side effects occurred during treatment with zotepine.
There was no correlation between the degree of striatal D2 receptor occupancy and clinical improvement.
Although the principal brain target that all antipsychotic drugs attach to is the dopamine D2 receptor, traditional or typical antipsychotics, by attaching to it, induce extrapyramidal signs and symptoms (EPS). They also, by binding to the D2 receptor, elevate serum prolactin. Atypical antipsychotics given in dosages within the clinically effective range do not bring about these adverse clinical effects. To understand how these drugs work, it is important to examine the atypical antipsychotics' mechanism of action and how it differs from that of the more typical drugs.
This review analyzes the affinities, the occupancies, and the dissociation time-course of various antipsychotics at dopamine D2 receptors and at serotonin (5-HT) receptors, both in the test tube and in live patients.
Of the 31 antipsychotics examined, the older traditional antipsychotics such as trifluperazine, pimozide, chlorpromazine, fluphenazine, haloperidol, and flupenthixol bind more tightly than dopamine itself to the dopamine D2 receptor, with dissociation constants that are lower than that for dopamine. The newer, atypical antipsychotics such as quetiapine, remoxipride, clozapine, olanzapine, sertindole, ziprasidone, and amisulpride all bind more loosely than dopamine to the dopamine D2 receptor and have dissociation constants higher than that for dopamine. These tight and loose binding data agree with the rates of antipsychotic dissociation from the human-cloned D2 receptor. For instance, radioactive haloperidol, chlorpromazine, and raclopride all dissociate very slowly over a 30-minute time span, while radioactive quetiapine, clozapine, remoxipride, and amisulpride dissociate rapidly, in less than 60 seconds. These data also match clinical brain-imaging findings that show haloperidol remaining constantly bound to D2 in humans undergoing 2 positron emission tomography (PET) scans 24 hours apart. Conversely, the occupation of D2 by clozapine or quetiapine has mostly disappeared after 24 hours.
Atypicals clinically help patients by transiently occupying D2 receptors and then rapidly dissociating to allow normal dopamine neurotransmission. This keeps prolactin levels normal, spares cognition, and obviates EPS. One theory of atypicality is that the newer drugs block 5-HT2A receptors at the same time as they block dopamine receptors and that, somehow, this serotonin-dopamine balance confers atypicality. This, however, is not borne out by the results. While 5-HT2A receptors are readily blocked at low dosages of most atypical antipsychotic drugs (with the important exceptions of remoxipride and amisulpride, neither of which is available for use in Canada) the dosages at which this happens are below those needed to alleviate psychosis. In fact, the antipsychotic threshold occupancy of D2 for antipsychotic action remains at about 65% for both typical and atypical antipsychotic drugs, regardless of whether 5-HT2A receptors are blocked or not. At the same time, the antipsychotic threshold occupancy of D2 for eliciting EPS remains at about 80% for both typical and atypical antipsychotics, regardless of the occupancy of 5-HT2A receptors.
The "fast-off-D2" theory, on the other hand, predicts which antipsychotic compounds will or will not produce EPS and hyperprolactinemia and which compounds present a relatively low risk for tardive dyskinesia. This theory also explains why L-dopa psychosis responds to low atypical antipsychotic dosages, and it suggests various individualized treatment strategies.
Several techniques can be used to measure indirectly the effect of drugs (e.g., EEG, fMRI) in healthy volunteers and in patients. Although each technique has its merits, a direct link between drug efficacy and site of action in vivo usually cannot be established. In addition, when the specific mode of action of a drug has been determined from preclinical studies, it is often not known whether the administered dose is optimal for humans. Both industry and academia are becoming more and more interested in determining the dose-related occupancy of specific targets caused by administration of drugs under test. Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are noninvasive imaging techniques that can give insight into the relationship between target occupancy and drug efficacy, provided a suitable radioligand is available. Although SPECT has certain advantages (e.g., a long half-life of the radionuclides), the spatial and temporal resolution as well as the labeling possibilities of this technique are limited. This review focuses on PET methodology for conducting drug occupancy studies in humans.
ANTIPSYCHOTIC drugs, or neuroleptics, are thought to act by blocking dopamine receptors in the nervous system1-4. Recent direct evidence, based on stereospecific binding assays, supports this hypothesis of antipsychotic drug action5-9. As only a few antipsychotic drugs had been tested for their effects on the binding of haloperidol5-8, the question remained whether all antipsychotic drugs, regardless of chemical structure, would block the stereospecific binding of haloperidol. We report here that all clinically effective antipsychotic drugs (tested so far) block the stereo-specific binding of 3H-haloperidol at concentrations which correlate directly with the clinical potencies.
The purpose of the present study is to visualize and quantify dopamine D2 receptors in the living human brain using an 123I-labeled ligand and the single photon emission computerized tomography (SPECT) technique. S-(-)-Iodobenzamide [S-(-)-IBZM] has been shown to be a highly selective ligand with high affinity for D2 receptors in experimental studies. Five millicuries (185 MBq) of 123I-labeled S-(-)-IBZM was administered intravenously to 12 control subjects, 22 parkinsonian patients under L-Dopa therapy, 12 parkinsonian patients without L-Dopa, 10 unmedicated patients with Huntington's disease, and 12 patients under different neuroleptics. Data collection with a rotating double-head scintillation camera started 1 h after injection and lasted for 50 min. In a semiquantitative approach, a ratio was calculated between mean counts per pixel in the striatum and a region in the lateral frontal cortex, which was 1.74 +/- 0.10 in the control group. A marked reduction of this ratio was found in patients with Huntington's disease (1.38 +/- 0.12; p = 0.0001), no significant changes in untreated parkinsonian patients (1.67 +/- 0.14), but a reduction in L-Dopa-treated cases (1.59 +/- 0.13; p = 0.0014). A curvilinear relationship was found between total daily dose of neuroleptics and the reduction of this ratio. Estimated receptor blockade under full neuroleptic treatment was 75-80%. S-(-)-IBZM binding was reduced with increasing age (p less than 0.01). Specific binding was reduced markedly when the racemic mixture of IBZM was used, and no specific binding was seen with the R-(+)-isomer, demonstrating the stereoselectivity of IBZM binding.(ABSTRACT TRUNCATED AT 250 WORDS)
Dopamine receptors belong to a superfamily of receptors that exert their biological effects through guanine nucleotide-binding (G) proteins. Two main dopamine receptor subtypes have been identified, D1 and D2, which differ in their pharmacological and biochemical characteristics. D1 stimulates adenylyl cyclase activity, whereas D2 inhibits it. Both receptors are primary targets for drugs used to treat many psychomotor diseases, including Parkinson's disease and schizophrenia. Whereas the dopamine D1 receptor has been cloned, biochemical and behavioural data indicate that dopamine D1-like receptors exist which either are not linked to adenylyl cyclase or display different pharmacological activities. We report here the cloning of a gene encoding a 477-amino-acid protein with strong homology to the cloned D1 receptor. The receptor, called D5, binds drugs with a pharmacological profile similar to that of the cloned D1 receptor, but displays a 10-fold higher affinity for the endogenous agonist, dopamine. As with D1, the dopamine D5 receptor stimulates adenylyl cyclase activity. Northern blot and in situ hybridization analyses reveal that the receptor is neuron-specific, localized primarily within limbic regions of the brain; no messenger RNA was detected in kidney, liver, heart or parathyroid gland. The existence of a dopamine D1-like receptor with these characteristics had not been predicted and may represent an alternative pathway for dopamine-mediated events and regulation of D2 receptor activity.
Dopamine receptors belong to the family of G protein-coupled receptors. On the basis of the homology between these receptors, three different dopamine receptors (D1, D2, D3) have been cloned. Dopamine receptors are primary targets for drugs used in the treatment of psychomotor disorders such as Parkinson's disease and schizophrenia. In the management of socially withdrawn and treatment-resistant schizophrenics, clozapine is one of the most favoured antipsychotics because it does not cause tardive dyskinesia. Clozapine, however, has dissociation constants for binding to D2 and D3 that are 4 to 30 times the therapeutic free concentration of clozapine in plasma water. This observation suggests the existence of other types of dopamine receptors which are more sensitive to clozapine. Here we report the cloning of a gene that encodes such a receptor (D4). The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes. The pharmacological characteristics of this receptor resembles that of the D2 and D3 receptors, but its affinity for clozapine is one order of magnitude higher. Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs.
A dopamine receptor has been characterized which differs in its pharmacology and signalling system from the D1 or D2 receptor and represents both an autoreceptor and a postsynaptic receptor. The D3 receptor is localized to limbic areas of the brain, which are associated with cognitive, emotional and endocrine functions. It seems to mediate some of the effects of antipsychotic drugs and drugs used against Parkinson's disease, that were previously thought to interact only with D2 receptors.
Using PET, we investigated the potency in six patients of therapeutic doses of neuroleptic drugs for preventing specific binding of trace doses of intravenously administered 76Br-labelled bromospiperone to corpus striatum in vivo. Measured receptor occupancy showed a clear-cut dose-dependent saturation curve with increasing daily oral dose of neuroleptics, indicating the validity and reliability of the method when used as an in vivo radioreceptor assay. Following drug withdrawal in eight patients, recovery to normal or supranormal receptor availability occurred in a matter of days. The results demonstrate an approach that may help resolve controversies about, and design better strategies for, neuroleptic treatment schedules.
The authors examined the potencies of 22 neuroleptic drugs competing for binding sites associated with dopamine, serotonin, alpha-adrenergic, and histamine receptors in brain membranes. They found that although many neuroleptics are quite potent in competing at several of these receptor sites, the average antipsychotic clinical potency correlates closely only with the drug affinity for dopamine receptors labeled by 3H-spiroperidol At clinically effective doses, however, substantial occupancy of serotonin, alpha-adrenergic, and histamine receptors often occurs and may account for some of the auxiliary actions of neuroleptics.
Neurotransmitter receptors may be involved in a number of neuropsychiatric disease states. The ligand 3-N-[11C]methylspiperone,
which preferentially binds to dopamine receptors in vivo, was used to image the receptors by positron emission tomography
scanning in baboons and in humans. This technique holds promise for noninvasive clinical studies of dopamine receptors in
humans.
Zusammenfassung
Die striatale Dopamin-D2-Rezeptoranreicherung von 123J-IBZM wurde bei 32 Patienten (18 ohne und 14 mit neuroleptischer Therapie) semiquantitativ unter Anwendung verschiedener ROI-Techniken ausgewertet. Ziel der Studie war es, die von verschiedenen Untersuchern gefundenen unterschiedlichen Quotienten (Striatum/Kortex) unter dem Aspekt der angewandten ROI-Technik zu untersuchen. Es konnte gezeigt werden, daß bei Verwendung des gleichen SPECT-Systems keine größeren Unterschiede zwischen Rechteck-ROI und manuell erstellten ROI gleicher Größe auftreten. Eine hochsignifikante Trennung zwischen behandelten und unbehandelten Patienten ergab sich für alle untersuchten Auswerteverfahren. Der ermittelte Quotient wird wesentlich durch das Auflösungsvermögen der Kamera und nur relativ geringfügig durch die verwendete ROI-Technik bestimmt. Die Quotienten verschiedener Arbeitsgruppen sind quantitativ nicht miteinander vergleichbar.
• Several groups have reported increased densities of D2 dopamine receptors in the basal ganglia of schizophrenic brains postmortem. The significance of this finding has been questioned, since an upregulation of receptor number may be a neuronal response to neuroleptic drug treatment. We have used positron emission tomography and [11 C]raclopride to examine central D2 dopamine receptor binding in 20 healthy subjects and 18 newly admitted, young, neuroleptic-naive patients with schizophrenia. An in vivo saturation procedure was applied for quantitative determination of D2 dopamine receptor density (Bmax) and affinity (Kd). When the two groups were compared, no significant difference in Bmax or Kd values was found in the putamen or the caudate nucleus. The hypothesis of generally elevated central D2 dopamine receptor densities in schizophrenia was thus not supported by the present findings. In the patients but not in the healthy controls, significantly higher densities were found in the left than in the right putamen but not in the caudate nucleus.
• The treatment of schizophrenic patients who fail to respond to adequate trials of neuroleptics is a major challenge. Clozapine, an atypical antipsychotic drug, has long been of scientific interest, but its clinical development has been delayed because of an associated risk of agranulocytosis. This report describes a multicenter clinical trial to assess clozapine's efficacy in the treatment of patients who are refractory to neuroleptics. DSM-III schizophrenics who had failed to respond to at least three different neuroleptics underwent a prospective, single-blind trial of haloperidol (mean dosage, 61 ±14 mg/d) for six weeks. Patients whose condition remained unimproved were then randomly assigned, in a double-blind manner, to clozapine (up to 900 mg/d) or chlorpromazine (up to 1800 mg/d) for six weeks. Two hundred sixty-eight patients were entered in the doubleblind comparison. When a priori criteria were used, 30% of the clozapine-treated patients were categorized as responders compared with 4% of chlorpromazine-treated patients. Clozapine produced significantly greater improvement on the Brief Psychiatric Rating Scale, Clinical Global Impression Scale, and Nurses' Observation Scale for Inpatient Evaluation; this improvement included "negative" as well as positive symptom areas. Although no cases of agranulocytosis occurred during this relatively brief study, in our view, the apparently increased comparative risk requires that the use of clozapine be limited to selected treatment-resistant patients.
• Using positron emission tomography and the carbon 11—labeled ligand raclopride, central D2-dopamine receptor occupancy in the putamen was determined in psychiatric patients treated with clinical doses of psychoactive drugs. Receptor occupancy in drug-treated patients was defined as the percent reduction of specific carbon 11—raclopride binding in relation to the expected binding in the absence of drug treatment. Clinical treatment of schizophrenic patients with 11 chemically distinct antipsychotic drugs (including both classic and atypical neuroleptics such as clozapine) resulted in a 65% to 85% occupancy of D2-dopamine receptors. In a depressed patient treated with the tricyclic antidepressant nortriptyline, no occupancy was found. The time course for receptor occupancy and drug levels was followed after withdrawal of sulpiride or haloperidol. D2-dopamine receptor occupancy remained above 65% for many hours despite a substantial reduction of serum drug concentrations. In a sulpiride-treated patient, the dosage was reduced in four steps over a nine-week period and a curvilinear relationship was demonstrated between central D2-dopamine receptor occupancy and serum drug concentrations. The results demonstrate that clinical doses of all the currently used classes of antipsychotic drugs cause a substantial blockade of central D2-dopamine receptors in humans. This effect appears to be selective for the antipsychotics, since it was not induced by the antidepressant nortriptyline.
• Positron emission tomography and selective radioligands were used to determine D, and D2 dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2 occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2 occupancy than those without side effects. This finding indicates that neurolepticinduced extrapyramidal syndromes are related to the degree of central D2 occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2 occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2 occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2 occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D, occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1 occupancy was 38% to 52%. The D, occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.
To the Editor.—
The kinetics of receptor-ligand interaction predict a curvilinear relationship between free brain ckade (inset). 6 5 4 in 3 2 e d c e a m x o p p A i 0 10 20 30 40 50 60 Plasma Haloperidol Level, ng/mL 20 40 60 80 100 Plasma Haloperidol Level, ng/mL ligand concentration or neuroleptic plasma level and dopamine receptor occupancy. Based on positron emission tomography (PET) studies using 11C-raclopride in several subjects, Farde et al1 recently presented a theoretical binding curve for this relationship. Cambon et al2 derived a similar curvilinear relationship from 76Br-labeled bromospiperone PET scans of six subjects who had varying diagnoses and were receiving either haloperidol or thioproperazine.We conducted similar studies using the D2 radioligand 18F-j!V methylspiperone (NMS) to estimate dopamine receptor availability in patients with schizophrenia. Subjects included patients who were not receiving neuroleptic therapy and others who were treated
1. Als pharmakologische Charakteristika der Medikamente, die bei Schizophrenien therapeutisch wirksam sind, galten bisher der kataleptische Effekt, die Hemmung pharmakogener Stereotypien und bedingter Reflexe. Substanzen mit diesem pharmakologischen Wirkungsbild werden als Neuroleptika bezeichnet.
2. Der Begriff “Neuroleptikum” ist ursprünglich von Klinikern als Kurzformel für ein bestimmtes klinisches Wirkungsbild geprägt worden, wobei therapeutische Wirkungsqualitäten (“antipsychotischer Effekt”) und bestimmte Nebenwirkungen (extrapyramidalmotorischer Effekt) berücksichtigt wurden.
3. Der Nachweis einer antipsychotischen Wirkung beim Clozapin, dem die unter 1 aufgeführten pharmakologischen Wirkungen und die unter 2 erwähnten extrapyramidalmotorischen Nebenwirkungen fehlen, macht es zweifelhaft, ob überhaupt schon dem antipsychotischen Effekt äquivalente Wirkungen beim Tier und entsprechende charakteristische Nebenwirkungen beim Menschen erfaßt worden sind.
4. Kataleptogener Effekt im Tierversuch und extrapyramidalmotorische Nebenwirkungen bei therapeutischer Anwendung haben einen Wert als Indikatorphänomene nur dann, wenn es sich um klassische Neuroleptika handelt.
5. Begriffe wie der der “Neuroleptika” dürfen nicht zu schnell mit einer klinischen Wirkung identifiziert werden. Das Ziel pharmakopsychiatrischer und psychopharmakologischer Forschung muß es sein, neue Stoffe mit antipsychotischer Wirkung zu entwickeln. Dieses Ziel ist nicht gleichbedeutend mit der Suche nach immer neuen klassischen “Neuroleptika”, bei denen eine einzelne Nebenwirkung (extrapyramidalmotorische Störungen) bereits in die Definition des Begriffes eingegangen ist.
Summary
1. The cataleptic effect, the inhibition of pharmacogenic stereotypies and conditioned avoidance have been, up to the present time, the pharmacological characteristics of drugs which are therapeutically active against schizophrenia. Substances with this pharmacological activity pattern are designated as neuroleptics.
2. The term “neuroleptic” was originally coined by clinicians as an abbreviation for a certain clinical activity pattern whereby therapeutic actions (“antipsychotic effect”) and certain side-effects (extrapyramidal motoric effect) were taken into account.
3. The demonstration of an antipsychotic effect with Clozapine, for which the pharmacological effects mentioned in 1. and the extrapyramidal motoric side-effects mentioned in 2. are absent, makes it doubtful whether effects in the animal equivalent to the antipsychotic effect and the corresponding characteristic side-effects in man have been detected at all.
4. Only when classical neuroleptics are being dealt with, do the cataleptic effect in animal experiments and the extrapyramidal motoric side-effects during therapeutic use have some value as indicator phenomena.
5. Concepts like that of the “neuroleptics” must not be identified too hastily with a clinical effect. The goal of pharmaco-psychiatric and psychopharmacological research must be to develop new substances with therapeutic efficacy against the symptomatology of schizophrenia. This goal is not synonymous with the continual search for new classical “neuroleptics” by which a single side effect (extrapyramidal motoric disturbances) has already been incorporated into the definition of the concept.
The ascending monoamine pathways in the rat brain are demonstrated by the pile up of fluorescent material occurring in the axons after various types of lesions. The anatomy of the pathways is outlined in drawings of frontal sections of the brain and the origin and termination of several pathways is determined by studying the anterograde and retrograde degeneration occurring after well localised lesions. It is possible to separate the ascending NA pathways into a dorsal and a ventral bundle of axons. The dorsal bundle innervates the cortex and the hippocampus and the ventral bundle supplies NA nerve terminals to the medulla, the pons, the mesencephalon and the diencephalon. The dorsal bundle is found to originate in the locus coeruleus. Lesions of this nucleus abolish the nerve terminals in all cortical areas and in several other areas of the brain indicating a unique role for the locus coeruleus in influencing the activity of the entire brain. The 5-HT pathways have a distribution similar to the ventral NA pathyway. The course of the nigro-striatal and the meso-limbic DA pathways is presented in detail.
Several benzodiazepines (chlordiazepoxide, clonazepam, diazepam and flunitrazepam) markedly counteracted the elevation of the homovanillic acid (HVA) content of the rat brain induced by neuroleptics (haloperidol, pimozide, chlorpromazine, and clozapine). A similar effect was obtained with the inhibitor of GABA transaminase, aminooxyacetic acid (AOAA). The interaction of benzodiazepines with the neuroleptic-induced HVA increase was similar in the striatum and in the limbic forebrain and was antagonized by the GABA receptor-blocking agent, picrotoxin. Both the benzodiazepines used and AOAA potentiated the cataleptic effect of the four neuroleptics. It is concluded that benzodiazepines, by intensifying GABA-ergic transmission, enhance the ongoing inhibition of mesencephalic dopamine neurons exerted by the striatonigral GABA system. As a consequence, the feedback activation of dopamine neurons induced by the neuroleptic blockade of dopamine receptors in the striatum and the limbic system is attenuated. This results in a reduction of the neuroleptic-induced increase of HVA and in the potentiation of the cataleptic effect of neuroleptics.
According to the dopamine hypothesis of schizophrenia, D2 receptor blockade is essential for a drug to have antipsychotic potency, and antipsychotic potency and D2 blockade are linearly related in vitro. To test this assumption in vivo, we have compared clinical response with central D2 dopamine receptor availability measured by 123I-iodobenzamide single photon emission tomography in two groups of schizophrenic patients. 6 patients were on typical antipsychotic drugs and 10 were on the atypical antipsychotic clozapine, including 2 patients from the first group. The patients on typical antipsychotics showed poor therapeutic response despite D2 receptor blockade. Significant clinical improvement occurred in all patients on clozapine, but at a lower level of D2 blockade by the drug. These findings suggest a more complex relation between D2 blockade and clinical efficacy than was previously thought.
A double-blind multicentre study comparing the efficacy and safety of remoxipride in controlled-release formulation (REM-CR), given once a day, and immediate-release formulation (REM-IR) and haloperidol, given twice daily, was conducted in patients with schizophrenic illness. In total, 150 inpatients were randomized: 49, 51 and 50 in the REM-CR, REM-IR, and haloperidol groups, respectively. The mean daily dose of REM-CR during the last week of treatment was 361 mg, that of REM-IR 332 mg. In the haloperidol group the corresponding dose was 12.5mg per day. The study treatment period was four weeks. The median BPRS total score was 37.5 in the REM-CR group at start of treatment, and 14.5 at last rating (n = 38). For the REM-IR group and the haloperidol group the corresponding figures were 36.0 and 38.0 at start of treatment and 18.0 (n = 43) and 16.5 (n = 40) at last rating. No statistically significant differences were found between the treatments. Therapy-emergent extrapyramidal symptoms (Simpson & Angus rating scale) were significantly (p less than 0.05) more frequent and more severe during haloperidol than during REM-CR and REM-IR treatment, despite significantly higher concurrent use of anticholinergic drugs in the haloperidol group.--REM-CR was comparable in efficacy and tolerability to REM-IR. The tolerability profile favoured both remoxipride formulations over haloperidol. Evaluation of the clinical chemistry, haematology, and cardiovascular data showed no clinically significant deleterious effects on any organ system for either drug.
[123I]IBZM is a new radioactive labelled ligand which has a high affinity and specificity to D2-dopamine receptors. The in vivo kinetics of [123I]IBZM were studied in patients with unilateral and bilateral accentuated idiopathic Parkinson's disease. The uptake in the basal ganglias and the imaging properties of this D2 receptor antagonist as a radiopharmaceutical for SPECT examinations had to be investigated. 5 patients, aged 42-66 years, (2 m/3 f) were examined. Each patient received 185 MBq [123I]IBZM intravenously. Blood samples were taken 0-120 min post injection (p.i.) and time activity curves were plotted. Three SPECT examinations were performed (I: 30-50 min; II: 50-70 min; and III: 70-90 min p.i.). The count rates (counts/pixel) in the basal ganglias and the cerebellum were measured for each SPECT series on transverse slices using the region-of-interest technique. The time-activity curve of [123I]IBZM shows a rapid decline in plasma during the first 10 min followed by a plateau until 120 min after injection. The SPECT examinations demonstrate the highest count rate in the basal ganglia during SPECT series III (i.e., 70-90 min p.i.). The side-to-side difference of the count rates were in the range of 3% in four patients, and 10% in one patient. The biokinetic data of [123I]IBZM make this substance capable as a radiopharmaceutical for SPECT examinations. The basal ganglia are best visualized 70-90 min p.i., thus [123I]IBZM seems to be a promising imaging agent for diseases of the D2-dopaminergic receptor system.
Nine double-blind studies comparing remoxipride to haloperidol in the treatment of acute schizophrenia formed the basis of this analysis. All studies followed a basic protocol with the main assessments performed regularly during the 4-6 week trial period according to the same methodology, thus allowing the data to be pooled. The results showed that remoxipride in a daily dose of 150-600 mg had a therapeutic effect comparable to that of haloperidol (5-45 mg/day), both on positive and negative symptoms. There was a clear advantage for remoxipride over haloperidol with regard to adverse events/symptoms, particularly extrapyramidal symptoms, but also drowsiness/somnolence and tiredness/fatigue. Anticholinergic drugs were used consistently less frequently as concomitant medication to alleviate extrapyramidal symptoms in the remoxipride group: the use of sedatives/hypnotics was approximately the same in both groups. Based on these and supportive clinical data, remoxipride seems to have a clinical profile characterized by antipsychotic efficacy in acute schizophrenia, apparently equal to that of haloperidol, and good tolerability in being non-sedative (in terms of drowsiness/somnolence) and with low incidences of extrapyramidal, autonomic, and endocrine symptoms.
Remoxipride is a new antipsychotic drug that binds selectively to the D2-dopamine receptor subtype as demonstrated in animal studies in vitro and in vivo. It is generally assumed that the antipsychotic effect of neuroleptic drugs is mediated by blockade of dopamine receptors. The aim of the present study was to use positron emission tomography (PET) and the ligand [11C] raclopride to examine the central D2-dopamine receptor occupancy in man during oral administration of remoxipride. After oral administration of remoxipride 100 mg three times daily to a healthy male subject there was a 73% central D2-dopamine receptor occupancy. In a schizophrenic patient treated with remoxipride 200 mg twice daily there was a 71% occupancy. These occupancy values are similar to the values of 65-85% previously found in a series of patients treated with neuroleptics representative of all currently used chemical classes. In a separate experiment, remoxipride was labelled with 11C and injected intravenously and the distribution of radioactivity to the brain examined. Radioactivity appeared in the brain during the first minutes after injection and 4.5 min after injection it accounted for 0.8% of the total radioactivity injected, thus indicating that [11C]remoxipride had rapidly passed through the blood-brain barrier.
In vitro receptor ligand binding studies in the rat showed that remoxipride displaced different radioligands at the dopamine D 2 , but not the D 1 receptor. Remoxipride did not block dopamine‐stimulated adenylate cyclase activity in vitro suggesting that it did not directly interact with the dopamine D 1 receptor. Like other antipsychotic compounds, it increased dopamine turnover in the dopamine‐rich areas of the brain. It showed no affinity for a wide range of neurotransmitter receptors, with the exception of the opiate sigma receptor. The affinity of remoxipride for the D 2 receptor was low in vitro, while in vivo, the affinity was relatively high. Remoxipride was far more potent in preventing [ ³ H]raclopride‐binding than [ ³ H]spiperone‐binding to the D 2 receptor in vivo. When the D 2 receptor was labelled with [ ³ H]spiperone, remoxipride was shown to exert a preferential blockade of this binding in extrastriatal areas of the brain (for example, olfactory tubercle, septum, substantia nigra) in vivo. After the injection of high doses of remoxipride most if not all drug in the brain was identified as authentic remoxipride.
After injection of [ ³ H]remoxipride in smaller and larger doses, radioactivity was detected in all areas of brain examined, including cerebellum and neocortex. Most of the remoxipride‐derived radioactivity was found in the choroid plexus and circumventricular organs, while smaller amounts were recovered in the striatum, olfactory tubercle, and substantia nigra. Taken together, these findings suggest that remoxipride acts at both the central D 2 and sigma receptors and that its affinity for the D 2 receptor is relatively low in vitro. A regional preference for D 2 receptors can be observed in vivo depending upon the radioligand used.
Remoxipride blocks dopamine agonist-induced effects in the rat, mediated by dopamine D2 receptors with an in-vivo potency less than that of haloperidol but greater than that of chlorpromazine, thioridazine, and sulpiride. Unlike haloperidol and sulpiride, remoxipride has weaker antagonistic effects towards presynaptic dopamine activity compared to its effects on postsynaptically mediated activity. Remoxipride causes a preferential inhibition of dopamine agonist-induced locomotion as compared to stereotyped behaviour, suggesting that it may exert a preferential blockade of mesolimbic dopamine neurotransmission. The low tendency of remoxipride to cause catalepsy in the rat is indicative of a weak effect on striatal dopamine neurotransmission and predicts a low liability to induce extrapyramidal side effects in man. Remoxipride causes a smaller elevation of prolactin than sulpiride at doses producing central dopamine receptor blockade. The results suggest that remoxipride, unlike haloperidol, can discriminate between different types of dopamine mediated functions probably by having a preferential action on subpopulations of functionally coupled dopamine D2 receptors.
Striatal D2 dopaminergic receptors of 12 drug-free schizophrenic patients and 12 normal subjects were investigated with positron emission tomography and [76Br]bromospiperone. Patients were classified according to DSM-III criteria, and their clinical symptoms were rated according to Andreasen's negative and positive symptom scales. The ratio of striatal to cerebellar radioactivity was taken as an index of striatal D2 dopamine receptor density. There was no significant difference between the control subjects and the overall schizophrenic group and no significant relationship between this index and the symptom ratings. However, state-dependent variables could partly account for the striatal D2 receptor density variability.
The selection and early development of clozapine was based upon its gross behavioural, arousal-inhibiting, sleep-promoting, and caudate spindle-prolonging properties. Compared to classical neuroleptics, clozapine causes only a short-lasting elevation of plasma prolactin levels, elevates both striatal homovanillic acid and dopamine content, is devoid of marked apomorphine-inhibitory or cataleptogenic activity and fails to induce supersensitivity of striatal dopaminergic systems after chronic administration. Clozapine's intrinsic anticholinergic activity, while stronger than that of other neuroleptic agents, does not appear to underlie either its failure to induce tardive dyskinesias or its superior antipsychotic activity. Furthermore, the overlap between clozapine and several classical neuroleptics with regard to alpha-adrenergic-, serotonin- and histamine-blocking activity makes it unlikely that one or more of these properties is the key to its atypical characteristics. More recent findings show that clozapine and classical neuroleptics differ with regard to their indirect effects on nigral GABA-ergic mechanisms implicated in the induction of tardive dyskinesias and, possibly in keeping with this, that clozapine and similar agents exhibit preferential blockade of D-1 dopamine receptors in the whole animal. Such an action of clozapine in man could well explain both its low EPS liability and, in some subjects, its superior antipsychotic activity.
The percentage occupation of striatal dopamine D2 receptors has been evaluated in 25 patients using 76Br-bromospiperone positron emission tomography (PET) and prolactin plasma levels (PRL) during oral neuroleptic treatment (11 studies), 1-90 days following discontinuation of such treatment (16 studies), and 1-120 days after last intramuscular administration of depot neuroleptics (nine studies). The PET-estimated occupation was highly significantly correlated in a sigmoid-like fashion to the logarithm of the chlorpromazine-equivalent dose of oral neuroleptics (suggesting a strict dose-occupation relationship during oral neuroleptic treatment and supporting the D2-mediated hypothesis of neuroleptic action), while PRL was weakly related to daily dosage. Following withdrawal, return to normal receptor availability, as estimated by PET, occurred within 5-15 days (suggesting that protracted effects of neuroleptics after withdrawal are not due to sustained D2 receptor occupation), but PRL values fell even more rapidly. Efficient treatment with depot neuroleptics resulted in marked PET-estimated D2 receptor occupation, stable over the whole 4-week drug-administration interval, suggesting that longer intervals could be appropriate; PRL values bore no relationship to PET-estimated occupation, indicating variable intersubject tolerance to neuro-endocrine dopamine blockade. Overall, PET was much more sensitive than PRL to estimate striatal D2 receptor occupation in vivo.
D2 dopamine receptors in the putamen of living human subjects were characterized by using the selective, high-affinity D2
dopamine receptor antagonist carbon-11-labeled raclopride and positron emission tomography. Experiments in four healthy men
demonstrated saturability of [11C]raclopride binding to an apparently homogeneous population of sites with Hill coefficients
close to unity. In the normal putamen, maximum binding ranged from 12 to 17 picomoles per cubic centimeter and dissociation
constants from 3.4 to 4.7 nanomolar. Maximum binding for human putamen at autopsy was 15 picomoles per cubic centimeter. Studies
of [11C]raclopride binding indicate that clinically effective doses of chemically distinct neuroleptic drugs result in 85
to 90 percent occupancy of D2 dopamine receptors in the putamen of schizophrenic patients.
3-N-(2-[18F]-fluoroethyl)-spiperone [( 18F]-FESP) was synthesized at high specific activity by condensation with 2-[18F]-fluoroethyltosylate (35 TBq/mmol). In vivo binding studies in baboons by positron emission tomography exhibited regio-selective uptake in the striatum which was saturable with the cold ligand and prevented by pretreatment with (+)-butaclamol. The pharmacokinetic behaviour, i.e. the absolute uptake in tissue and the striatum-to-cerebellum ratio, was very similar to that of methylspiperone. Analysis of the radioactivity in mouse brain after administration of [18F]-FESP indicated a high in-vivo stability (greater than 90% after 210 min in the striatum). Comparative distribution studies of other N-fluoroalkylspiperones in mice suggest that FESP and the N-fluoropropyl analogue are the most potent D2 receptor ligands.
In developing central nervous system (CNS) dopamine D-2 receptor imaging agents, enantiomers, R-(+) and S-(-) isomers, of 3-[125I]iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2- pyrrolidinyl)methyl]benzamide, [125I]IBZM, were synthesized, and their in vitro binding characteristics were evaluated in rat striatum tissue preparation. The (S)-(-)-[125I]IBZM showed high specific dopamine D-2 receptor binding (Kd = 0.43 nM, Bmax = 0.48 pmol/mg of protein). Competition data of various ligands for IBZM binding displayed the following rank order of potency: spiperone greater than (S)-(-)-IBZM greater than (+)-butaclamol much greater than (R)-(+)-IBZM greater than (S)-(-)-BZM greater than dopamine greater than ketanserin greater than SCH23390 much greater than propanolol. The results indicate that [125I]IBZM binds specifically to the dopamine D-2-receptor with stereospecificity. The [123I]IBZM is potentially useful as an imaging agent for the investigation of dopamine D-2 receptors in humans.
An indirect approach to the relationship among drug dose, plasma level, and the competition between a labeled neuroleptic drug [18F]N-methylspiroperidol (18F-NMS) for binding sites in striatal tissue in normal and schizophrenic subjects is described. The slope of the line plotting the ratio of activity in the striatum (As) to activity in the cerebellum (Ac) versus time up to 5 hr postinjection of 18F-NMS is taken as a marker of site occupancy. An inverse relation between labeled competitor uptake and drug plasma level has been demonstrated for the classes of antipsychotic drug studied. Striatal uptake studies showed a progressive increase in all subjects following drug withdrawal up to 156 hr postwithdrawal. Uptake and clearance of 18F-NMS in cerebellar tissue was not appreciably affected by antipsychotic medication or drug withdrawal.
The in vitro binding properties of the [125I] labeled benzamide (S(-)-N-[(1-ethyl-2-pyrrolidinyl)-methyl]-2-hydroxy-3-iodo-6-methoxy- benzamide, IBZM) were determined in bovine and mouse caudate membrane homogenates and by autoradiography of mouse brain slices. [125I]-IBZM binding is saturable and reversible with a Bmax of 373 +/- 51 fmol/mg protein and a Kd of 3.1 +/- 0.62 nM (mean +/- SD, Scatchard analyses) and 0.56 nM as calculated by association and dissociation time constants. In competition experiments, Ki values for the D-2 antagonists YM-09151-2 and spiperone are 4 orders of magnitude lower than the Ki value for the D-1 antagonist SCH-23390 and S(-)-IBZM is ten-fold more potent than R(+)-IBZM. [125I]-IBZM has a low affinity for serotonin S-2 and for alpha receptors. Therefore, it is a highly selective ligand for dopamine D-2 receptors. Autoradiographic images of brain sections incubated with [125I]-IBZM show the dopamine D-2 receptors of the striatum, nucleus accumbens and olfactory tubercle with a high ratio of specific to nonspecific binding. Thus, S(-)-IBZM, when labeled with [123I], may be useful for in vivo imaging of dopamine D-2 receptors by single photon emission computerized tomography (SPECT).
This chapter discusses the dose equivalence of the antipsychotic drugs. The pharmacologic effects of drugs provide a major tool for investigation of biochemical theories of mental illness such as the dopamine theory of schizophrenia. The dose necessary to produce a given pharmacologic effect is determined from biochemical pharmacologic investigation that is based on empirically determined data. The dose of the drug, which is marketed, often is taken as the dose that produces the human antipsychotic effect. A great many factors other than empirical evidence enter into the determination of a dose at which a drug is marketed. This involves commercial decisions by the drug company, medical legal decisions by their legal department, pressures from the food and drug administration, and historical accident in the early drug trials of a given drug. In double blind studies using flexible doses, physicians adjust the dose given to patients by their clinical response not knowing as to which medication was actually administered by adjusting the number of tablets. The physician generally knows that they are administering numbers of tablets that could be one of several medications or one of several medications and/or placebo. They adjust the number of tablets to obtain the maximum clinical response.
This is an account of further work on a rating scale for depressive states, including a detailed discussion on the general problems of comparing successive samples from a ‘population’, the meaning of factor scores, and the other results obtained. The intercorrelation matrix of the items of the scale has been factor-analysed by the method of principal components, which were then given a Varimax rotation. Weights are given for calculating factor scores, both for rotated as well as unrotated factors. The data for 152 men and 120 women having been kept separate, it is possible to compare the two sets of results. The method of using the rating scale is described in detail in relation to the individual items.
The striatal dopamine-D2-receptor uptake of 123I-IBZM in 32 patients (18 without and 14 under therapy with typical neuroleptics) was measured semiquantitatively using different ROI techniques. The aim of the study was to evaluate the influence of these techniques on the different ratios (striatum/cortex) found by various examiners. Using the same SPECT system no major differences were found between rectangular and manually drawn ROIs of the same size. All ROI techniques could differentiate between patients with and without therapy on a highly significant level. Therefore, the resulting ratio is mainly dependent on the spatial resolution of the camera system and only to a relatively minor extent on the ROI technique. Ratios obtained by different observers are not comparable quantitatively.
Tritiated haloperidol and tritiated dopamine label postsynaptic dopamine receptors in mammalian brain. Clinical potencies of butyrophenones, phenothiazines, and related drugs correlate closely with their ability to inhibit tritiated haloperidol binding. These binding methods provide a simple in vitro means for evaluating new drugs as potential antischizophrenic agents.