Add-on Cariprazine in Patients with Long-term Clozapine Treatment and Treatment Resistant Schizophrenia: Two Cases of Psychotic Deterioration and Pisa Syndrome

Background: 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. Method: 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. Results: 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. Conclusion: 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. Relevance: 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.

Evidence for antagonist activity of the dopamine D3 receptor partial agonist, BP 897, at human dopamine D3 receptor

The focal distribution of the dopamine (DA) D(3) receptor in brain regions implicated in emotional and cognitive functions has made this target a main focus of drug discovery efforts. This paper will review the most recent lines of research in support of the use of selective DA D(3) receptor antagonists for the pharmacotherapeutic management of drug addiction: (1) expression of the DA D(3) receptor in the rodent and human brain; (2) changes in expression of the DA D(3) receptor following exposure to drugs of abuse, and (3) efficacy of selective DA D(3) receptor antagonists in preclinical paradigms assessing the behavioral effects of drugs such as cocaine, nicotine, alcohol, methamphetamine, and heroin. This manuscript, however, will not review the effects of nonselective DA D(2)/D(3) receptor antagonists or partial D(3) receptor agonists. Growing evidence suggests that selective DA D(3) receptor antagonists do not affect the primary reinforcing effects of drugs of abuse, but rather seem to regulate the motivation to self-administer drugs under schedules of reinforcement that require an increase in work demand. In addition, selective antagonism at DA D(3) receptors appears to disrupt significantly the responsiveness to drug-associated stimuli that play a key role in reinstatement of drug-seeking behavior. These preclinical findings will be discussed in the context of translational research relevant to the design of early clinical trials and hypothesis testing in humans.

RationaleSecond-generation antipsychotics occupy dopamine D2 receptors and act as antagonists or partial agonists at these receptors. While these drugs alleviate positive symptoms in patients with schizophrenia, they are less effective for treating cognitive deficits and negative symptoms. Dopamine D3 receptors are highly expressed in areas of the brain thought to play a role in the regulation of motivation and reward-related behavior. Consequently, the dopamine D3 receptor has become a target for treating negative symptoms in combination with D2 antagonism to treat positive symptoms in patients with schizophrenia.ObjectiveThe purpose of this study was to determine the cariprazine receptor occupancies in brain for D2 and D3 receptors in patients with schizophrenia.MethodsUsing [11C]-(+)-PHNO as a radioligand, positron emission tomography (PET) scans were performed in eight patients at baseline and postdose on days 1, 4, and 15. Plasma and cerebrospinal fluid (CSF) samples were analyzed for cariprazine concentrations.ResultsA monotonic dose-occupancy relationship was observed for both receptor types. After 2 weeks of treatment, near complete (∼100 %) occupancies were observed for both receptors at a dose of 12 mg/day. At the lowest cariprazine dose (1 mg/day), mean D3 and D2 receptor occupancies were 76 and 45 %, respectively, suggesting selectivity for D3 over D2 receptors at low doses. An exposure-response analysis found a ∼3-fold difference in EC50 (D3 = 3.84 nM and D2 = 13.03 nM) in plasma after 2 weeks of dosing.ConclusionThis PET imaging study in patients with schizophrenia demonstrated that cariprazine is a D3-preferring dual D3/D2 receptor partial agonist.Electronic supplementary materialThe online version of this article (doi:10.1007/s00213-016-4382-y) contains supplementary material, which is available to authorized users.

Dopamine signaling through D1 receptors in the prefrontal cortex (PFC) plays a critical role in the maintenance of higher cognitive functions, such as working memory. At the cellular level, these functions are predicated to involve alterations in neuronal calcium levels. The dendrites of PFC neurons express D1 receptors and N-type calcium channels, yet little information exists regarding their coupling. Here, we show that D1 receptors potently inhibit N-type channels in dendrites of rat PFC neurons. Using coimmunoprecipitation, we demonstrate the existence of a D1 receptor-N-type channel signaling complex in this region, and we provide evidence for a direct receptor-channel interaction. Finally, we demonstrate the importance of this complex to receptor-channel colocalization in heterologous systems and in PFC neurons. Our data indicate that the N-type calcium channel is an important physiological target of D1 receptors and reveal a mechanism for D1 receptor-mediated regulation of cognitive function in the PFC.

Back to table of contents Previous article Next article LETTERFull AccessImprovement in Pisa Syndrome and Tardive Dyskinesia Following Aripiprazole TreatmentJia-Chi Shan M.D.,Mei-Chih Meg Tseng M.D., M.Sc.,Jia-Chi Shan M.D.Search for more papers by this author,Mei-Chih Meg Tseng M.D., M.Sc.Search for more papers by this author,Published Online:1 Jul 2009AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail To the Editor: Tardive dystonia and tardive dyskinesia, parts of a group of delayed-onset neuroleptic-induced movement disorders, may coexist but are postulated to be different in prevalence, demographic profiles, clinical presentations, and to have different neurochemical mechanisms. 1 Drug-induced Pisa syndrome, manifesting as a tonic lateral flexion of trunk after exposure to neuroleptics, consists of both acute and persistent types. Thus, Pisa syndrome can also be viewed as an atypical subtype of tardive dystonia. 1 , 2 Aripiprazole exerts a therapeutic effect by partial D2 agonism rather than D2 receptor blockage, 3 implying its possibly beneficial effect to delayed-onset extrapyramidal symptoms. Previous reports often focused on the issue relevant to either one of the tardive syndromes. We report on a patient whose Pisa syndrome and tardive dyskinesia were improved following aripiprazole treatment. Case Report Ms. Y, a 31-year-old schizophrenia patient (DSM-IV criteria), had psychotic symptoms onset at the age of 20. Her symptoms were rapidly alleviated after 6 months of sulpiride therapy with trihexyphenidyl. She had received treatment with trifluoperazine, haloperidol, clotiapine, and zotepine in the following years for intermittent relapsing symptoms. Oral-buccal-lingual dyskinesia was first noticed after she had been treated with risperidone for 2 years. Her antipsychotic was then switched to olanzapine. Moreover, she developed left-tilting of her trunk and right-sided rotation of her neck with subjective stiffness in her chin and shoulders during olanzapine treatment. A diagnosis of tardive dystonia was made according to Burke and colleagues’ criteria. 4 Her dystonic reaction showed no improvement after high-dose anticholinergic medication (biperiden, 8 mg) was added on and olanzapine was withdrawn. Lingual dyskinesia was partially ameliorated after replacement of olanzapine by amisulpride for 2 months, but Pisa syndrome did not improve. Eventually, aripiprazole and amantadine were substituted for amisulpride and biperiden, respectively. Tardive dyskinesia disappeared in one month, and Pisa syndrome was improved significantly after 2 months’ administration of aripiprazole, 30 mg/day, and amantadine, 200 mg/day. Discussion Despite the sharing dopamine blockade in the pathogenesis of Pisa syndrome and tardive dyskinesia, cholinergic-dopaminergic imbalance may better account for the former whereas dopamine receptor hypersensitivity may account for the latter. 2 Our patient developed persistent motor symptoms insidiously after long-term conventional and atypical antipsychotics, which excluded an acute tonic reaction. 2 This patient’s tardive syndromes were neither resolved by withdrawal of olanzapine (a multi-acting receptor-targeted antipsychotic with high 5HT2/D2 ratio), nor treatment of amisulpride (a D2/D3 receptor antagonist with high D3/D2 ratio). 3 Unlike other atypical antipsychotics, aripiprazole shows higher affinity at D2 receptors than at 5-HT2 receptors, and its weak partial 5HT 1A agonism is demonstrated in a recent study. 5 Thus, aripiprazole successfully improved both tardive dyskinesia and Pisa syndromes, possibly because it can reverse D2 receptor hypersensitivity and restore cholinergic-dopaminergic balance via D2 partial agonism. As for amantadine, there has been no substantial evidence regarding its effect on treating tardive dystonia. The role played by amantadine in this patient was unclear. In summary, we suggest that aripiprazole is a potential drug for the management of Pisa syndrome coexistent with tardive dyskinesia. Aripiprazole is also a drug candidate to study the differential neurochemical mechanism of various subtypes of tardive syndromes.Department of Psychiatry, National Taiwan University Hospital, Taipei, TaiwanDepartment of Psychiatry, National Taiwan University Hospital, Yun-Lin Branch, Douliou; Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan

Estimation of Baseline Dopamine D2 Receptor Occupancy in Striatum and Extrastriatal Regions in Humans with Positron Emission Tomography with [18F] Fallypride

Opposite effects of dopamine D2 and D3 receptors on learning and memory in the rat

As for all proteins, G protein-coupled receptors (GPCRs) undergo synthesis and maturation within the endoplasmic reticulum (ER). The mechanisms involved in the biogenesis and trafficking of GPCRs from the ER to the cell surface are poorly understood, but they may involve interactions with other proteins. We have now identified the ER chaperone protein calnexin as an interacting protein for both D(1) and D(2) dopamine receptors. These protein-protein interactions were confirmed using Western blot analysis and co-immunoprecipitation experiments. To determine the influence of calnexin on receptor expression, we conducted assays in HEK293T cells using a variety of calnexin-modifying conditions. Inhibition of glycosylation either through receptor mutations or treatments with glycosylation inhibitors partially blocks the interactions with calnexin with a resulting decrease in cell surface receptor expression. Confocal fluorescence microscopy reveals the accumulation of D(1)-green fluorescent protein and D(2)-yellow fluorescent protein receptors within internal stores following treatment with calnexin inhibitors. Overexpression of calnexin also results in a marked decrease in both D(1) and D(2) receptor expression. This is likely because of an increase in ER retention because confocal microscopy revealed intracellular clustering of dopamine receptors that were co-localized with an ER marker protein. Additionally, we show that calnexin interacts with the receptors via two distinct mechanisms, glycan-dependent and glycan-independent, which may underlie the multiple effects (ER retention and surface trafficking) of calnexin on receptor expression. Our data suggest that optimal receptor-calnexin interactions critically regulate D(1) and D(2) receptor trafficking and expression at the cell surface, a mechanism likely to be of importance for many GPCRs.

A series of secondary and tertiary N-alkyl derivatives of (R)-2-amino-5-fluorotetralin have been prepared. The affinities of the compounds for [3H]raclopride-labeled cloned human dopamine (DA) D2 and D3 receptors as well as [3H]-8-OH-DPAT-labeled rat hippocampal 5-HT1A receptors were determined. In order to selectively determine affinities for the high-affinity agonist binding site at DA D2 receptors, the agonist [3H]quinpirole was used. The intrinsic activities of the compounds at DA D2 and D3 receptors were evaluated in a [35S]GTP gamma S binding assay. The novel compounds were characterized as dopaminergic antagonists or inverse agonists. The antagonist (R)-2-(butylpropylamino)-5-fluorotetralin (16) bound with high affinity (Ki = 4.4 nM) to the DA D3 receptor and was the most D3-selective compound (10-fold). (R)-2-[[4-(8-Aza-7, 9-dioxospiro[4.5]decan-8-yl)butyl]propylamino]-5-fluorote tralin (18) bound with very high affinity to both DA D3 and 5-HT1A receptors (Ki = 0.2 nM) and was also characterized as a dopaminergic antagonist. (R)-2-(Benzylpropylamino)-5-fluorotetralin (10) behaved as an inverse agonist at both DA D2 and D3 receptors. It decreased the basal [35S]GTP gamma S binding and potently inhibited the DA-stimulated [35S]GTP gamma S binding. It is apparent that the intrinsic activity of a 2-aminotetralin derivative may be modified by varying the N-alkyl substituents.

Many effects resulting from D2 dopamine (DA) receptor stimulation are manifest only when D1 DA receptors are stimulated by endogenous DA. When D1 receptor stimulation is enhanced by administration of selective D1 receptor agonists, the functional effects of selective D2 agonists are markedly increased. These qualitative and quantitative forms of D1/D2 DA receptor synergism are abolished by chronic DA depletion when both D1 and D2 DA receptors are supersensitive. Using both electrophysiological and behavioral methods, the present study examined the effects of selective D1 and D2 receptor supersensitivity, induced by repeated administration of selective D1 or D2 receptor antagonists, on the synergistic relationships between D1 and D2 receptors. Daily administration of the selective D2 antagonist eticlopride (0.5 mg/kg, s.c.) for 3 weeks produced a selective supersensitivity of both dorsal (caudate-putamen) and ventral (nucleus accumbens) striatal neurons to the inhibitory effects of the D2 agonist quinpirole (applied by microiontophoresis). This treatment also abolished the normal ability of the D1 agonist SKF 38393 to potentiate quinpirole-induced inhibition, and relieved D2 receptors from the necessity of D1 receptor stimulation by endogenous DA (enabling), as indicated by significant electrophysiological and behavioral (stereotypy) effects of quinpirole in eticlopride-pretreated, but not saline-pretreated, rats that were also acutely depleted of DA. Daily administration of the selective D1 receptor antagonist SCH 23390 (0.5 mg/kg, s.c.) caused supersensitivity of striatal neurons to the inhibitory effects of SKF 38393 and also abolished both the ability of SKF 38393 to potentiate quinpirole-induced inhibition and the necessity of D1 receptor stimulation for such inhibition. However, both quinpirole-induced inhibition of striatal cells and stereotyped responses were also somewhat enhanced in SCH 23390-pretreated rats. When such D1-sensitized rats were acutely depleted of DA, the behavioral effects of quinpirole were intermediate between saline-pretreated rats with acute DA depletion and SCH 23390-pretreated rats without acute DA depletion. Based upon these and related results, it is argued that the enhanced effects of quinpirole in D1-sensitized rats are due to a heterologous sensitization of D2 receptors rather than to enhanced enabling resulting from supersensitive D1 receptors. It is suggested that supersensitivity of either D1 or D2 receptors can lead to an uncoupling of normal qualitative and quantitative D1/D2 synergisms and that the heterologous regulation of D2 receptor sensitivity by D1 receptors may be related to uncoupling of functional D1/D2 synergisms.

Roles of NMDA and dopamine D1 and D2 receptors in the acquisition and expression of flavor preferences conditioned by oral glucose in rats

A large number of ligand binding studies have shown that clozapine has a number of receptor affinities, including those of the dopamine (DA) D1 and D2 receptor families. The study of intrinsic efficacy at these receptors is less straight-forward. In the experiments summarised here, evidence is presented that clozapine behaves as an agonist at DA D1 receptors. Thus, the hypothermia produced by clozapine (2.5 mg kg(-1)) in the rat is fully antagonised by either of the selective DA D1 receptor antagonists SCH-23390 (0.1 mg kg(-1)) or NNC-687 (4 mg kg(-1)). These results provide an intriguing explanation for the clinical profile of clozapine as an atypical antipsychotic drug. Thus, there are supporting clinical and laboratory observations implicating DA D1 receptors in the prefrontal cortex in cognitive functions. Finally, clozapine displays features with regard to extrapyramidal motor mechanisms, and seizure thresholds, that could be explained by its properties as a DA D1 receptor agonist.

Because long-term antipsychotics elicit behavioral dopamine supersensitivity, the present study examined whether 7-9 days administration of partial dopamine D2 agonists with antipsychotic activity, bifeprunox and aripiprazole, could induce biochemical changes that suggest dopamine supersensitivity. In rats, behavioral dopamine supersensitivity is associated with increased dopamine D2(High) receptors in homogenized striata. In control rat striata, bifeprunox and aripiprazole had similar K(i) values at D2 receptors. In human cloned D2Long receptors, however, aripiprazole had a K(i) of 9.6 nM and recognized 41% of the D2 receptors to be in the D2(High) state, while the values for bifeprunox were 1.3 nM and 69%, indicating that bifeprunox had higher potency and efficacy at D2. Nine days of subcutaneously injected bifeprunox (0.25 mg/kg/day) and 7 days of aripiprazole (1.5 mg/kg) increased D2(High) receptors by 102-129% and 108-188%, respectively, although the total population of D2 receptors revealed no significant changes. The increase in D2(high) receptors induced by dopamine D2 partial agonists appear to be of smaller magnitude than those seen previously with D2 antagonist antipsychotics. Future research needs to test directly whether long-term treatment with dopamine partial agonists leads to any behavioral dopamine supersensitivity.

Cannabinoid CB1 receptors are densely expressed on striatal projection neurons expressing dopamine D1 or D2 receptors. However, the specific neuronal distribution of CB1 receptors within the striatum is not known. Previous research has established that the endocannabinoid system controls facilitation of behavior by dopamine D2 receptors, but it is not clear if endocannabinoids also modulate D1 receptor-mediated motor behavior. In the present study, we show that cannabinoid CB1 receptor mRNA is present in striatonigral neurons expressing substance P and dopamine D1 receptors, as well as in striatopallidal neurons expressing enkephalin and dopamine D2 receptors. We explored the functional relevance of the interaction between dopamine D1 and D2 receptors and cannabinoid CB1 receptors with behavioral pharmacology experiments. Potentiation of endogenous cannabinoid signaling by the uptake blocker AM404 blocked dopamine D1 receptor-mediated grooming and D2 receptor-mediated oral stereotypies. In addition, contralateral turning induced by unilateral intrastriatal infusion of D1 receptor agonists is counteracted by AM404 and potentiated by the cannabinoid antagonist SR141716A. These results indicate that the endocannabinoid system negatively modulates D1 receptor-mediated behaviors in addition to its previously described effect on dopamine D2 receptor-mediated behaviors. The effect of AM404 on grooming behavior was absent in dopamine D1 receptor knockout mice, demonstrating its dependence on D1 receptors. This study indicates that the endocannabinoid system is a relevant negative modulator of both dopamine D1 and D2 receptor-mediated behaviors, a finding that may contribute to our understanding of basal ganglia motor disorders.