Subjective experience and dopamine D2 receptor occupancy in patients treated with antipsychotics: clinical implications.

OBJECTIVES: This paper gives an overview of studies on the association between dopaminergic neurotransmission and the subjective experience of patients with schizophrenia. METHODS: We undertook a review of the literature. RESULTS: Dopaminergic neurotransmission may be relevant for subjective experience. Higher striatal D2 receptor occupancy by typical and atypical antipsychotics is related to worse subjective experience, more severe negative symptoms, and depression. Individuals with lower baseline dopamine function are at an increased risk for dysphoric responses during antipsychotic therapy with dopaminergic-blocking drugs. There is preliminary evidence that a window of striatal D2 receptor occupancy between 60% and 70% is optimal for the subjective experience of patients. These occupancies are often reached even with low dosages of antipsychotic drugs. CONCLUSIONS: Reaching an optimal dopamine D2 receptor occupancy is clinically relevant, since subjective experience associated with antipsychotic medication is related to medication compliance. Antipsychotic drug dosages often need to be lower than levels in common use.     

Time course of dopamine D2 receptor occupancy by clozapine with medium and high plasma concentrations

Most antipsychotics were thought to induce antipsychotic action at an excess of 70% striatal dopamine D2 receptor occupancy, while the clinical dose of clozapine was reported to show less than 60% occupancy. High-dose clozapine could occupy as high as 80% of striatal dopamine D2 receptor in monkey PET studies. Although the time course of dopamine D2 receptor occupancy is an important property of antipsychotics, that by clozapine has not been investigated in a clinical setting. We measured the time course of extrastriatal dopamine D2 receptor occupancy with different doses of clozapine and evaluated whether the measured occupancies fitted the binding theory. Three consecutive PET scans with [11C]FLB 457 were performed for two patients with schizophrenia, chronically taking 600 mg/day and 200 mg/day of clozapine, respectively. Series of occupancies were also measured in combination with fluvoxamine or paroxetine in one patient. Dopamine D2 receptor occupancies were also simulated using individual clozapine plasma data and previously determined in vivo ED50 value. The occupancy of one patient with high plasma concentration (1207 ng/ml at peak time) was around 75% at peak and around 60% after 26 h. Another patient with medium plasma concentration (649 ng/ml at peak time) showed less than 50% occupancy at peak, decreasing to 15% after 25 h. The measured occupancy values fitted well with the simulated occupancy values. At high plasma concentration, clozapine can induce high extrastriatal dopamine D2 receptor occupancy in the human brain, and this finding fitted well with the theoretical estimation.     

Hit-and-run actions at dopamine receptors, part 1: Mechanism of action of atypical antipsychotics.

Either 5-HT2A antagonism or fast dissociation from D2 receptors may define an atypical antipsychotic. To have little or no motor symptoms from an antipsychotic, it is clear that D2 receptor binding in the striatum must be less than that caused by conventional antipsychotics. Pure 5-HT2A antagonism by itself does not result in robust antipsychotic actions. However, 5-HT2A antagonism can reduce D2 antagonism and thereby reduce motor symptoms without reversing antipsychotic actions. If, however, this 5-HT2A antagonism is overwhelmed by too much D2 antagonism, it cannot result in such atypical antipsychotic actions. Another route to reducing D2 receptor binding appears to be to shorten binding time, also known as rapidly dissociating from the D2 receptor. Many of the agents with atypical antipsychotic clinical properties hit the D2 receptor hard enough to cause antipsychotic effects and then run before they cause extrapyramidal side effects.     

Rapid release of antipsychotic drugs from dopamine D2 receptors: an explanation for low receptor occupancy and early clinical relapse upon withdrawal of clozapine or quetiapine.

OBJECTIVE: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.     

Half a century of antipsychotics and still a central role for dopamine D2 receptors

A review of the history of antipsychotics reveals that while the therapeutic effects of chlorpromazine and reserpine were discovered and actively researched almost concurrently, subsequent drug development has been restricted to drugs acting on postsynaptic receptors rather than modulation of dopamine release. The fundamental property of atypical antipsychotics is their ability to produce an antipsychotic effect in the absence of extrapyramidal side effects (EPS) or prolactin elevation. Modulation of the dopamine D2 receptor remains both necessary and sufficient for antipsychotic drug action, with affinity to the D2-receptor being the single most important discriminator between a typical and atypical drug profile. Most antipsychotics, including atypical antipsychotics, show a dose-dependent threshold of D2 receptor occupancy for their therapeutic effects, although the precise threshold is different for different drugs. Some atypical antipsychotics do not appear to reach the threshold for EPS and prolactin elevation, possibly accounting for their atypical nature. To link the biological theories of antipsychotics to their psychological effects, a hypothesis is proposed wherein psychosis is a state of aberrant salience of stimuli and ideas, and antipsychotics, via modulation of the mesolimbic dopamine system, dampen the salience of these symptoms. Thus, antipsychotics do not excise psychosis: they provide the neurochemical platform for the resolution of symptoms. Future generations of antipsychotics may need to move away from a "one-size-fits-all polypharmacy-in-a-pill" approach to treat all the different aspects of schizophrenia. At least in theory a preferred approach would be the development of specific treatments for the different dimensions of schizophrenia (e.g., positive, negative, cognitive, and affective) that can be flexibly used and titrated in the service of patients' presenting psychopathology.     

Differential effects of clozapine versus other antipsychotics on clinical outcome and dopamine release in the brain

The first atypical antipsychotic, clozapine (Clozaril), dramatically improved the outcome of treatment of patients with schizophrenia in two ways. First, it reduced psychotic symptoms without eliciting significant neurological side effects. Second, it was effective in approximately 30% of individuals who were previously refractory to treatment. Efforts to develop similar drugs have been partially successful in that newer antipsychotics are also less likely to produce neurological side effects. However, it has not yet been established that the newest antipsychotics are more effective than conventional agents in individuals who are refractory to treatment. In the first part of this review, the results of studies that evaluated the new antipsychotics and provided an outcome measure of response rate (regardless of how this index was defined) are summarized. Even with this broad criterion, the evidence suggests that the newer antipsychotics do not share the clinical advantages of clozapine. To explore the possible mechanisms for the clinical advantage of clozapine, evidence of antipsychotic-induced dopamine release in the brain is discussed in the second half of this article. This analysis indicates that acute clozapine administration induces the release of more dopamine in the cortex than in the striatum or limbic system. With conventional antipsychotics, this relationship is reversed. The newest antipsychotics do not show a preference among these sites. Moreover, after long-term treatment, tolerance develops to haloperidol, but not to clozapine, with regard to the amount of dopamine released in the brain. No data are available on the newest antipsychotics. Although more studies need to be done-especially studies of the effects of long-term administration of various conventional and atypical antipsychotics-this distinction might be relevant to the unique clinical advantage of clozapine.     

Chronic treatment with dopamine receptor antagonists: behavioral and pharmacologic effects on D1 and D2 dopamine receptors

Rats were treated for 21 d with the selective D1 dopamine receptor antagonist SCH23390, the selective D2 dopamine receptor antagonist spiperone, the nonselective dopamine receptor antagonist cis-flupentixol, or a combination of SCH23390 and spiperone. In addition, a group of rats received L-prolyl-L-leucyl-glycinamide (PLG) for 5 d after the 21 d chronic spiperone treatment. Chronic treatment with SCH23390 resulted in a significant increase in D1 dopamine receptor density with no change in the D2 dopamine receptor density. Conversely, spiperone treatment resulted in a significant increase in D2 dopamine receptors and no change in D1 dopamine receptor density. PLG treatment had no effect. SCH23390 plus spiperone treatment resulted in a significant increase in both D1 and D2 dopamine receptor densities. However, although in vitro cis-flupentixol has an equal affinity for D1 and D2 dopamine receptors, only the D2 dopamine receptor density increased after chronic treatment with cis-flupentixol. In vivo treatment with the protein-modifying reagent N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), which irreversibly inactivates D1 and D2 dopamine receptors, was used to investigate the paradoxical, selective D2 dopamine receptor up-regulation induced by cis-flupentixol treatment. In vivo treatment with cis-flupentixol before EEDQ administration prevented the D1 and D2 dopamine receptor reductions induced by EEDQ. However, cis-flupentixol protected, in a dose-dependent manner, a greater percentage of D2 dopamine receptors than of D1 dopamine receptors from EEDQ-induced modification. These data indicate that, in vivo, cis-flupentixol preferentially interacts with D2 dopamine receptors and could explain why only D2 dopamine receptors were up-regulated following chronic treatment with cis-flupentixol. Rats were tested for their cataleptic response to the administered drug over the course of the chronic drug treatment. Catalepsy scores of rats receiving spiperone decreased over the course of treatment, with a significant reduction in catalepsy occurring by treatment day 5. The profound catalepsy observed in rats receiving SCH23390 did not change over the 21 d of treatment. Rats receiving cis-flupentixol demonstrated tolerance to its cataleptogenic effects, with a significant reduction in catalepsy observed by treatment day 7. During the 3 week treatment, the time between drug injection and a full cataleptic response to cis-flupentixol increased from 20 to 60 min, suggesting a tolerance to the D2, but not D1, dopamine receptor antagonism by cis-flupentixol.(ABSTRACT TRUNCATED AT 400 WORDS)     

Anesthetics inhibit high-affinity states of dopamine D2 and other G-linked receptors

The high-affinity states of dopamine D2 and D3 receptors, serotonin 5HT-2A receptors, beta-2-adrenoceptors, alpha-1 and alpha-2 adrenoceptors, opiate receptors, and muscarinic receptors were inhibited by clinical concentrations of anesthetics, including isoflurane, halothane, chloral hydrate, ketamine, and ethanol. The inhibition occurred not only in vitro, but also in vivo in rats anesthetized with isoflurane, with the high-affinity states recovering at different rates. Because the high-affinity states of G-protein-linked receptors are physiologically functional, their general inhibition by clinical concentrations of anesthetics may underlie general anesthesia and may explain some of the side effects of anesthetics. Subanesthetic concentrations of the anesthetics, including ketamine, stimulated the incorporation of GTP into the cloned dopamine D2 receptors. It is possible that the classical stage 2 excitement phase which occurs with subanesthetic concentrations of general anesthetics and ketamine may be associated with this general stimulation of a variety of G-protein-linked receptors, as found in the present study, while the stage 3 level of surgical anesthesia may be associated with the inhibition of the high-affinity states of several receptors.     

Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity

Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex.     

Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects.

Positron emission tomography and selective radioligands were used to determine D1 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 neuroleptic-induced 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 D1 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 D1 occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.     

Cocaine occupancy of sigma1 receptors and dopamine transporters in mice

Activation of sigma₁ (σ₁) receptors contributes to the behavioral and toxic effects of (?)‐cocaine. We studied a key step, the ability of (?)‐cocaine to occupy σ₁ receptors in vivo, using CD‐1^® mice and the novel radioligand [¹²⁵I]E‐N?1‐(3′‐iodoallyl)‐N′‐4‐(3″,4″‐dimethoxyphenethyl)‐piperazine ([¹²⁵I]E‐IA‐DM‐PE‐PIPZE). (?)‐Cocaine displayed an ED₅₀ of 68 μmol/kg for inhibition of specific radioligand binding in whole brain, with values between 73 and 80 μmol/kg for heart, lung, and spleen. For comparison, an ED₅₀ of 26 μmol/kg for (?)‐cocaine occupancy of striatal dopamine transporters (DAT) was determined by inhibition of [¹²⁵I]3β‐(4‐iodophenyl)tropan‐2β‐carboxylic acid isopropyl ester ([¹²⁵I]RTI‐121) binding. A chief finding is the relatively small potency difference between (?)‐cocaine occupancy of σ₁ receptors and the DAT, although the DAT occupancy is likely underestimated. Interactions of (?)‐cocaine with σ₁ receptors were assessed further using [¹²⁵I]E‐IA‐DM‐PE‐PIPZE for regional cerebral biodistribution studies and quantitative ex vivo autoradiography of brain sections. (?)‐Cocaine binding to cerebral σ₁ receptors proved directly proportional to the relative site densities known for the brain regions. Nonradioactive E‐IA‐DM‐PE‐PIPZE gave an ED₅₀ of 0.23 μmol/kg for occupancy of cerebral σ₁ receptors, and a 3.16 μmol/kg (i.p.) dose attenuated (?)‐cocaine‐induced locomotor hyperactivity by 30%. This effect did not reach statistical significance, but suggests that E‐IA‐DM‐PE‐PIPZE is a probable σ₁ receptor antagonist. As groundwork for the in vivo studies, we used standard techniques in vitro to determine ligand affinities, site densities, and pharmacological profiles for the σ₁ and σ₂ receptors expressed in CD‐1^® mouse brain. Synapse 70:98–111, 2016. © 2016 Wiley Periodicals, Inc.     

Cardiac safety parameters of olanzapine: comparison with other atypical and typical antipsychotics

Alterations of electrocardiogram results and cases of sudden cardiac death have been reported since the beginning of neuroleptic treatment. In particular, a temporal association exists between some antipsychotics and prolongation of the heart rate-corrected QT interval (QTc), an event that may increase the risk for developing a potentially fatal ventricular tachycardia arrhythmia known as torsades de pointes if it significantly exceeds normal intraindividual and interindividual variation. Although the incidence of serious adverse cardiac events in response to antipsychotic medications is relatively low, any possibility for the occurrence of cardiotoxicity warrants continued study. The present article reviews important differences among antipsychotic drugs in the potential for, and occurrence of, serious adverse cardiac outcomes and suggests that olanzapine, as therapeutically administered to patients with schizophrenia and related psychoses, does not contribute significantly to a QTc prolongation that could result in potentially fatal ventricular arrhythmias.     

Extrastriatal dopamine D2 receptor occupancy in olanzapine-treated patients with schizophrenia

Olanzapine is described as a multi-acting receptor-targeted antipsychotic agent. Although regional differences of dopamine D₂ receptor occupancy, i.e., limbic selectivity, were reported for olanzapine, contradictory results were also reported. We measured dopamine D₂ receptor occupancy of olanzapine in extrastriatal regions in patients with schizophrenia using positron-emission tomography with [¹¹C]FLB457 and the plasma concentrations of olanzapine. Ten patients with schizophrenia taking 5–20 mg/day of olanzapine participated. Dopamine D₂ receptor occupancy in the temporal cortex ranged from 61.1 to 85.8%, and plasma concentration was from 12.7 to 115.4 ng/ml. The ED₅₀ value was 3.4 mg/day for dose and 10.5 ng/ml for plasma concentration. The ED₅₀ values obtained in this study were quite similar to those previously reported in the striatum. In conclusion, although the subjects and methods were different from previous striatal occupancy studies, these results suggest that limbic occupancy by olanzapine may not be so different from that in the striatum.