(1/174) Regulation of ionotropic glutamate receptors in the rat brain in response to the atypical antipsychotic seroquel (quetiapine fumarate).
The interplay between dopamine and glutamate appears to be relevant in the etiopathology of schizophrenia. Although currently used antipsychotics do not interact with glutamatergic receptors, previous results have demonstrated that the expression profile of ionotropic glutamate receptors can be regulated by drugs such as haloperidol or clozapine. In the present investigation, the mRNA levels for NMDA and AMPA receptor subunits were measured after chronic treatment with the novel antipsychotic agent Seroquel (quetiapine fumarate, quetiapine) as compared to haloperidol and clozapine. Similarly to the prototype atypical clozapine, quetiapine reduced the mRNA expression for NR-1 and NR-2C, two NMDA forming subunits, in the nucleus accumbens. Furthermore, quetiapine, but not haloperidol or clozapine, increased the hippocampal expression for the AMPA subunits GluR-B and GluR-C. The differences between classical and atypical antipsychotics, as well as among the novel agents, might be relevant for specific aspects of their therapeutic activity and could provide valuable information for the role of glutamate in specific symptoms of schizophrenia. (+info)
(2/174) Atypical antipsychotics and dopamine D(1) receptor agonism: an in vivo experimental study using core temperature measurements in the rat.
The study objectives were to examine the effects of the atypical antipsychotic drugs olanzapine, risperidone, and quetiapine on core temperature in the rat in relation to such effects produced by clozapine and to compare possible in vivo intrinsic efficacy of olanzapine, risperidone, and quetiapine at dopamine (DA) D(1) receptors with such effects previously shown for clozapine. Core temperature measurements were made in adult male Wistar rats maintained under standard laboratory conditions using a reversed 12-h daylight cycle. Clozapine (0-32 micromol/kg s.c.), olanzapine (0-32 micromol/kg s.c.), and risperidone (0-4 micromol/kg s.c.) all produced a dose-dependent hypothermia. Except for slight nondose-dependent hyperthermia, there were no effects of quetiapine (0-16 micromol/kg s.c. or i.p.) on the core temperature. The hypothermia produced by clozapine, but not that produced by equipotent doses of olanzapine or risperidone, was fully antagonized by pretreatment with the DA D(1) receptor antagonist SCH-23,390 (0.1 micromol/kg s.c.). On the other hand, quinpirole-induced hypothermia (4 micromol/kg s.c.) was partially antagonized by olanzapine (2 micromol/kg s.c.), risperidone (4 micromol/kg s.c.), and quetiapine (16 micromol/kg s.c.) but not by clozapine (1 micromol/kg s.c.). Clozapine preferentially stimulates DA D(1) receptors in comparison with olanzapine and risperidone, whereas olanzapine, risperidone, and quetiapine preferentially block DA D(2) receptors compared with clozapine. It is suggested that stimulation of DA D(1) receptors, presumably in the prefrontal cortex, is a distinguishing feature of clozapine responsible for its favorable profile on cognitive functioning in schizophrenia. (+info)
(3/174) Quetiapine (Seroquel) concentrations in seven postmortem cases.
Quetiapine is a new antipsychotic drug that has been available in the United States since September 1997. It belongs to a new chemical class of drugs called the dibenzothiazepine derivatives and is easily detected with a basic drug screen. The Los Angeles County Department of Coroner Toxicology Laboratory has encountered quetiapine in seven postmortem cases. Tissue distributions were determined in each of the seven cases. The analysis of quetiapine from postmortem specimens consisted of an n-butylchloride basic extraction with presumptive identification and quantitation on a gas chromatograph-nitrogen-phosphorus detector. Linearity was achieved from 0.10 to 3.0 mg/L with a limit of quantitation of 0.10 mg/L. Confirmation of quetiapine was performed on a gas chromatograph-mass spectrometer by comparison with a pure analytical standard. The tissue distribution of quetiapine was as follows: heart blood present, but less than (+<) 0.10-49 mg/L (seven cases); femoral blood +< 0.10-1.4 mg/L (five cases); liver +< 0.10-112 mg/kg (five cases); spleen 4.0 mg/kg (one case); urine 0-3.0 mg/L (two cases); bile 0.60-7.5 mg/L (three cases); and gastric contents +< 0.01-18 mg total (five cases). To our knowledge, this is the first report of the presence of quetiapine in postmortem specimens. (+info)
(4/174) Striatal and extra-striatal D(2)/D(3) dopamine receptor occupancy by quetiapine in vivo. [(123)I]-epidepride single photon emission tomography(SPET) study.
BACKGROUND: Selective action at limbic cortical dopamine D(2)-like receptors could mediate atypical antipsychotic efficacy with few extrapyramidal side-effects. AIMS: To test the hypothesis that quetiapine has 'limbic selective' D(2)/D(3) receptor occupancy in vivo. METHOD: The high-affinity D(2)/D(3) ligand [(123)I]-epidepride and single photon emission tomography were used to estimate D(2)/D(3) specific binding and an index of relative percentage D(2)/D(3) occupancy in striatal and temporal cortical regions for quetiapine-treated patients (n=6). Quetiapine-, and previously studied typical-antipsychotic- and clozapine-treated patients were compared. RESULTS: Mean (s.d.) relative percentage D(2)/D(3) receptor occupancy by quetiapine was 32.0% (14.6) in striatum and 60.1% (17.2) in temporal cortex (mean daily dose 450 mg: range 300-700 mg/day). Quetiapine treatment resulted in limbic selective D(2)/D(3) blockade similar to clozapine and significantly higher than typical antipsychotics. CONCLUSIONS: Preliminary data suggest that limbic selective D(2)/D(3) receptor blockade is important for atypical drug action. (+info)
(5/174) Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis.
OBJECTIVE: To develop an evidence base for recommendations on the use of atypical antipsychotics for patients with schizophrenia. DESIGN: Systematic overview and meta-regression analyses of randomised controlled trials, as a basis for formal development of guidelines. SUBJECTS: 12 649 patients in 52 randomised trials comparing atypical antipsychotics (amisulpride, clozapine, olanzapine, quetiapine, risperidone, and sertindole) with conventional antipsychotics (usually haloperidol or chlorpromazine) or alternative atypical antipsychotics. MAIN OUTCOME MEASURES: Overall symptom scores. Rate of drop out (as a proxy for tolerability) and of side effects, notably extrapyramidal side effects. RESULTS: For both symptom reduction and drop out, there was substantial heterogeneity between the results of trials, including those evaluating the same atypical antipsychotic and comparator drugs. Meta-regression suggested that dose of conventional antipsychotic explained the heterogeneity. When the dose was =12 mg/day of haloperidol (or equivalent), atypical antipsychotics had no benefits in terms of efficacy or overall tolerability, but they still caused fewer extrapyramidal side effects. CONCLUSIONS: There is no clear evidence that atypical antipsychotics are more effective or are better tolerated than conventional antipsychotics. Conventional antipsychotics should usually be used in the initial treatment of an episode of schizophrenia unless the patient has previously not responded to these drugs or has unacceptable extrapyramidal side effects. (+info)
(6/174) Enhanced neurotensin neurotransmission is involved in the clinically relevant behavioral effects of antipsychotic drugs: evidence from animal models of sensorimotor gating.
To date, none of the available antipsychotic drugs are curative, all have significant side-effect potential, and a receptor-binding profile predictive of superior therapeutic ability has not been determined. It has become increasingly clear that schizophrenia does not result from the dysfunction of a single neurotransmitter system, but rather from an imbalance between several interacting systems. Targeting neuropeptide neuromodulator systems that concertedly regulate all affected neurotransmitter systems could be a promising novel therapeutic approach for schizophrenia. A considerable database is concordant with the hypothesis that antipsychotic drugs act, at least in part, by increasing the synthesis and release of the neuropeptide neurotensin (NT). In this report, we demonstrate that NT neurotransmission is critically involved in the behavioral effects of antipsychotic drugs in two models of antipsychotic drug activity: disrupted prepulse inhibition of the acoustic startle response (PPI) and the latent inhibition (LI) paradigm. Blockade of NT neurotransmission using the NT receptor antagonist 2-[[5-(2,6-dimethoxyphenyl)-1-(4-(N-(3-dimethylaminopropyl)-N-methylcarbamoyl)-2- isopropylphenyl)-1H- pyrazole-3-carbonyl]-amino]-adamantane-2-carboxylic acid, hydrochloride (SR 142948A) prevented the normal acquisition of LI and haloperidol-induced enhancement of LI. In addition, SR 142948A blocked the PPI-restoring effects of haloperidol and the atypical antipsychotic drug quetiapine in isolation-reared animals deficient in PPI. We also provide evidence of deficient NT neurotransmission as well as a left-shifted antipsychotic drug dose-response curve in isolation-reared rats. These novel findings, together with previous observations, suggest that neurotensin receptor agonists may represent a novel class of antipsychotic drugs. (+info)
(7/174) Quetiapine and obsessive-compulsive symptoms (OCS): case report and review of atypical antipsychotic-induced OCS.
The atypical antipsychotics have advanced the treatment of schizophrenia and have proved to be effective agents in treating other disorders with or without psychotic features. We review the literature concerning an increasingly reported and interesting adverse effect, atypical antipsychotic-induced obsessive-compulsive symptoms (OCS). The first known report of quetiapine exacerbating OCS in a 43-year-old man with obsessive-compulsive disorder (OCD), trichotillomania, delusional disorder and bipolar II disorder is presented. Mechanisms, including 5-HT2A and 5-HT2C antagonism, serotonergic regulation of dopamine systems and putative dopaminergic subtypes of OCS and OCD, are discussed. Given the paradoxical efficacy of the atypical antipsychotics in pure OCD, the neurobiology and comorbidity of OCD and schizophrenia, as well as the increasing use of atypical antipsychotics, a cautious and rational pharmacotherapeutic treatment approach is recommended. (+info)
(8/174) Neuropsychological change in patients with schizophrenia after treatment with quetiapine or haloperidol.
OBJECTIVE: To assess the efficacy of quetiapine, a recently introduced second generation antipsychotic medication, in reducing cognitive impairment in patients with schizophrenia. DESIGN: Prospective, randomized, double-blind clinical trial. PATIENTS: 25 patients who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, (DSM-IV) criteria for schizophrenia were recruited from 3 Canadian hospitals. INTERVENTION AND OUTCOME MEASURES: After a 48-hour washout period, 25 patients with schizophrenia were randomly assigned to double-blind treatment with quetiapine or haloperidol for 6 months and evaluated with rating scales for psychotic symptoms, mood and extrapyramidal side effects, as well as standardized neuropsychological measures sensitive to 6 cognitive domains: fine motor skill, attention span, verbal reasoning and fluency, visuospatial construction and fluency, executive skills and visuomotor tracking, and immediate recall of verbal and nonverbal materials. The measures were repeated 8 weeks and 6 months after treatment was initiated. RESULTS: Quetiapine improved psychosis and mood without inducing extrapyramidal symptoms. Quetiapine also had beneficial effects on cognitive skills, particularly verbal reasoning and fluency skills and immediate recall, with additional improvements on executive skills and visuomotor tracking and on the average of the 6 cognitive domains with sustained treatment. Patients taking haloperidol showed improvements in general clinical status, but no specific improvements on the positive syndrome, the negative syndrome, depression ratings or cognitive skills. CONCLUSIONS: These preliminary results support the potential value of quetiapine for improving cognitive impairment in patients with schizophrenia and emphasize the importance of further research with this promising atypical antipsychotic. (+info)