The preclinical discovery and development of quetiapine for the treatment of mania and depression.

INTRODUCTION: Bipolar disorder is a chronic disabling condition characterized by alternating manic and depressive episodes. Bipolar disorder has been associated with functional impairment, poor quality of life, morbidity and mortality. Despite its significant clinical, social and economic burden, treatment options for bipolar disorder are still limited. Several clinical trials have shown efficacy of the atypical antipsychotic quetiapine (QTP) in the treatment of this condition. However, the mechanisms underlying the antidepressant and anti-manic effects of QTP remain poorly understood. Areas covered: The article provides the emerging evidence from pre-clinical studies regarding the antidepressant and anti-manic mechanisms of action of QTP. In combination with its primary active metabolite norquetiapine, QTP modulates several neurotransmitter systems, including serotonin, dopamine, noradrenaline and histamine. QTP also seems to influence mediators of the immune system. Expert opinion: Pre-clinical studies have provided valuable information on the potential antidepressant mechanisms of action of QTP, but pre-clinical studies on QTP's anti-manic effects are still scarce. A major problem refers to the lack of valid experimental models for bipolar disorder. Additionally, immune and genetic based studies are largely descriptive. The role of the QTP metabolite norquetiapine in modulating non-neurotransmitter systems also needs to be further addressed.

P50 suppression and its neural generators in antipsychotic-naive first-episode schizophrenia before and after 6 months of quetiapine treatment.

BACKGROUND: Numerous studies have demonstrated sensory gating deficits in schizophrenia. However, only a few longitudinal studies report on the effects of antipsychotic treatment on sensory gating deficits and their results are inconsistent. In the present study, P50 suppression and its neural generators were investigated in antipsychotic-naïve first-episode patients with schizophrenia before and after 6 months of treatment with quetiapine. METHODS: Thirty-four antipsychotic-naïve first-episode schizophrenia patients and age and gender matched healthy controls were tested in an auditory sensory gating paradigm at baseline and after 6 months. During this period, the patients were treated with quetiapine, while controls received no treatment. Sixteen patients completed the study. RESULTS: Patients showed significant reduced P50 suppression compared with controls at baseline but not at follow-up. Furthermore, a significant positive correlation between baseline P50 suppression and dose of quetiapine at follow-up was found. P50 suppression in patients receiving above median dosages of quetiapine increased significantly from baseline to follow-up. At baseline, a frontocentral source was significantly more active in patients than in controls at the time of the testing stimulus. CONCLUSIONS: The present findings suggest that P50 suppression deficits are already present at an early stage of schizophrenia. Furthermore, particularly those patients with more severe gating deficits appeared to need higher dosages of quetiapine, although their clinical symptoms did not seem to indicate this. Quetiapine treatment significantly improved these gating deficits. Furthermore, a frontocentral source in the brain appeared to be involved in the deficient P50 gating of the patients.

A human laboratory study investigating the effects of quetiapine on marijuana withdrawal and relapse in daily marijuana smokers.

Marijuana withdrawal contributes to the high relapse rates in individuals seeking treatment for marijuana-use disorders. Quetiapine, an atypical antipsychotic, reduces characteristic symptoms of marijuana withdrawal in a variety of psychiatric conditions, including mood lability, sleep disruption and anorexia. This human laboratory study investigated the effectiveness of quetiapine to decrease marijuana withdrawal and relapse to marijuana use in non-treatment-seeking marijuana smokers. Volunteers were maintained on placebo or quetiapine (200 mg/day) in this double-blind, counter-balanced, within-subject study consisting of two 15-day medication phases, the last 8 days of which were in-patient. On the first in-patient day, active marijuana [6.2% delta (9)-tetrahydrocannabinol (THC)] was repeatedly smoked under controlled conditions. For the next 3 days, inactive marijuana (0.0% THC) was available for self-administration (withdrawal). On the subsequent 4 days, active marijuana (6.2% THC) was available for self-administration (relapse). Volunteers (n = 14) who smoked an average of 10 marijuana cigarettes/day, 7 days/week, completed the study. Under placebo, withdrawal was marked by increased subjective ratings of negative mood, decreased sleep quality, and decreased caloric intake and weight loss. Compared with placebo, quetiapine improved sleep quality, increased caloric intake and decreased weight loss. However, quetiapine increased marijuana craving and marijuana self-administration during the relapse phase. These data do not suggest that quetiapine shows promise as a potential treatment for marijuana dependence.

Upregulation of adenosine A2A receptors induced by atypical antipsychotics and its correlation with sensory gating in schizophrenia patients.

Sensory gating deficits have been found in patients with schizophrenia and their unaffected relatives. However, the underlying neurobiological mechanism of this deficit remains unclear. Pre-clinical studies have implicated adenosine in sensory gating deficits in schizophrenia. Therefore, the current study investigated a possible relationship between peripheral adenosine A2A receptor (ADORA2A) and sensory gating indices (P50 measures) in medication-free schizophrenia (n=31) and healthy (n=21) groups. The effects of six-week antipsychotic treatment were examined. At baseline, schizophrenia patients showed impaired sensory gating compared to healthy controls. However, there was no significant difference in ADORA2A gene expression among groups. In addition, ADORA2A expression was not correlated with sensory gating at any time point. Following treatment, we found a significant upregulation of ADORA2A expression. Intriguingly, we observed a significant positive association between ADORA2A upregulation and baseline P50 amplitudes in the schizophrenia group. A main finding of the current pilot study is the upregulation of ADORA2A expression following treatment with antipsychotics. In addition, this upregulation was predicted by baseline P50 amplitude, an observation that awaits replication in an expanded sample.

Inhibition of D-amino acid oxidase activity by antipsychotic drugs evaluated by a fluorometric assay using D-kynurenine as substrate.

A facile fluorometric assay using D-kynurenine as a substrate was utilized for evaluating the inhibition of D-amino acid oxidase (DAAO), which is one of the products of a susceptibility gene for schizophrenia, by commercial antipsychotic drugs, namely, chlorpromazine (CPZ), carbamazepine, sulpiride, quetiapine, and imipramine. CPZ inhibited DAAO (65.8 ± 13.2 µM, n = 3) as reported previously, and other drugs also inhibited DAAO activity. Among these, quetiapine had the smallest IC(50) value (19.5 ± 2.60 µM, n = 3). The proposed assay can be useful for the evaluation or screening of DAAO-inhibitory drugs.

Soluble interleukin-2 receptor levels correlated with positive symptoms during quetiapine treatment in schizophrenia-spectrum disorders.

BACKGROUND: Some but not all antipsychotics have been shown to modulate plasma cytokine levels in schizophrenia patients. Thus far, the most consistent finding has been the increase in plasma levels of soluble interleukin (IL)-2 receptor (sIL-2R) associated with clozapine treatment. Quetiapine is a second-generation antipsychotic with a pharmacological profile similar to that of clozapine, but its immunomodulatory effects have not been investigated in schizophrenia yet. The purpose of this exploratory study was to examine the changes in plasma levels of sIL-2R in schizophrenia during quetiapine treatment and association with psychopathology. METHODS: Participants were 29 schizophrenia-spectrum disorder patients (DSM-IV criteria), and 28 healthy controls. Patients had a comorbid substance use disorder (cannabis>alcohol>cocaine), since quetiapine is increasingly used in this population of dual diagnosis. No participant suffered from infection or overt inflammatory diseases. On baseline, patients taking mostly second-generation antipsychotics were switched to quetiapine for a 12-week open-label trial. Five patients were drop-outs. Mean dose of quetiapine for trial completers (n=24) was 466.6mg±227.3. Psychiatric variables were evaluated with the Positive and Negative Syndrome Scale and the Calgary Depression Scale for Schizophrenia. Plasma sIL-2R levels were assessed at baseline, weeks 6 and 12 in patients, and in healthy controls, using sandwich immunoassay. Plasma IL-6 and IL-1 receptor antagonist (IL-1RA) were measured for comparison purposes. RESULTS: On baseline, plasma sIL-2R, IL-6 and IL-1RA levels were higher in dual-diagnosis patients, compared to controls. Plasma sIL-2R further increased after quetiapine treatment (p=0.037), while plasma IL-6 and IL-1RA did not change. Clinical improvements were observed in positive, negative and depressive symptoms, and substance abuse severity (all p<0.01). Interestingly, changes in sIL-2R levels during treatment were inversely correlated with changes in positive symptoms (r=-0.524; p=0.009). That is, increases in sIL-2R levels were associated with reductions in positive symptoms. CONCLUSION: These data show that quetiapine elevates, like clozapine, sIL-2R levels in schizophrenia. Furthermore, the results suggest that sIL-2R alterations in schizophrenia rely on complex interplays between antipsychotics and the positive symptoms of the disorder. Future randomized controlled trials involving larger samples of schizophrenia patients are warranted to determine whether changes in plasma sIL-2R are quetiapine-related.

Prepulse inhibition of the startle reflex in schizophrenia remains stable with short-term quetiapine.

PURPOSE: To study the short-term effect of treatment with quetiapine on prepulse inhibition (PPI) deficits of the startle reflex in schizophrenia patients. SUBJECTS AND METHODS: Using PPI, we studied a group of 21 schizophrenia patients and 16 controls. Seventeen of the patients were re-tested with PPI after 21 days of treatment with quetiapine. RESULTS: At baseline, an almost significant decrease in PPI was found in the patients as compared to the controls. PPI measurements did not change in the patients after 21 days of treatment with quetiapine, despite their clinical improvement. CONCLUSION: Our results suggest that short-term quetiapine treatment may not modify PPI measures in schizophrenia patients.

Agmatine disrupts prepulse inhibition of acoustic startle reflex in rats.

Agmatine is a guanidine-amine formed by the enzymatic decarboxylation of arginine. Agmatine has been proposed to be a neuromodulator and its downstream derivatives, the polyamines, have been suggested to be responsible for sensory gating deficits seen in schizophrenia. In this study, male Wistar rats underwent treatments with agmatine, vehicle or other agents known to alter sensory gating in an experimental paradigm of prepulse inhibition (PPI) of the acoustic startle response. Apomorphine (1 mg/kg s.c.), a nonselective dopamine agonist known to disrupt PPI responses, was injected as the positive reference. Neither apomorphine nor agmatine (40-160 mg/kg i.p.) induced effects on the intensity of startle reflex without a prepulse. However, apomorphine or agmatine (160 mg/kg i.p.) disrupted the PPI of acoustic startle reflex. Furthermore, when given 30 min prior, agmatine acted additively with apomorphine's effect on PPI. In an attempt to gain more insight, haloperidol (1 and 2 mg/kg i.p.), clozapine (2.5-7.5 mg/kg i.p.) or quetiapine (2.5 and 7.5 mg/kg i.p.) was also injected prior to agmatine (160 mg/kg i.p.). Haloperidol (1 mg/kg) and clozapine (2.5 and 5 mg/kg) were able to prevent the PPI-disrupting effects of apomorphine. However, none of these antipsychotics prevent the PPI-disrupting effects of agmatine. These results suggest that agmatine disrupts the PPI of acoustic startle reflex of rats in a fundamentally different manner than apomorphine does. It may also have a critical role in the pathogenesis of sensorimotor gating-related dysfunctions.

Effects of olanzapine and quetiapine on corticotropin-releasing hormone release in the rat brain.

An altered regulation of the corticotropin-releasing hormone (CRH) system in the CNS is consistently associated with anxiety and depression; several drugs used to treat CNS disorders modulate--usually in a negative manner--CRH turnover in the brain, and it can be postulated that their effectiveness may be at least in part related to their effects on CRH. This study was aimed to investigate the effects of two atypical antipsychotics also employed in the treatment of bipolar disorders, i.e. quetiapine (QTP) and olanzapine (OLZ), on CRH release from isolated rat brain regions. Acute rat hypothalamic and hippocampal explants were exposed for 1 h to plain medium or medium containing the test drugs, either under baseline conditions or after stimulation of CRH release by veratridine or 56 mM KCl. CRH immunoreactivity present in the incubation medium and in the tissues was assessed by radioimmunoassay. QTP 10 microM but not OLZ inhibited baseline CRH secretion from the hypothalamus; neither drug affected basal CRH release from the hippocampus. Both QTP and OLZ, 1 and 10 microM, inhibited veratridine- or K(+)-stimulated CRH release from the hypothalamus, whereas OLZ only, when given at 10 microM, was able to inhibit stimulated CRH release from the hippocampus. In conclusion, two widely used atypical antipsychotics, QTP and OLZ are able to acutely reduce the release of CRH from isolated rat hypothalami and hippocampi.

N-desalkylquetiapine, a potent norepinephrine reuptake inhibitor and partial 5-HT1A agonist, as a putative mediator of quetiapine's antidepressant activity.

Quetiapine is an atypical antipsychotic drug that is also US FDA approved for treating bipolar depression, albeit by an unknown mechanism. To discover the potential mechanism for this apparently unique action, we screened quetiapine, its metabolite N-Desalkylquetiapine, and dibenzo[b,f][1,4]thiazepine-11(10-H)-one (DBTO) against a large panel of G-protein-coupled receptors, ion channels, and neurotransmitter transporters. DBTO was inactive at all tested molecular targets. N-Desalkylquetiapine had a high affinity (3.4 nM) for the histamine H(1) receptor and moderate affinities (10-100 nM) for the norepinephrine reuptake transporter (NET), the serotonin 5-HT(1A), 5-HT(1E), 5-HT(2A), 5-HT(2B), 5-HT(7) receptors, the alpha(1B)-adrenergic receptor, and the M(1), M(3), and M(5) muscarinic receptors. The compound had low affinities (100-1000 nM) for the 5-HT(1D), 5-HT(2C), 5-HT(3), 5-HT(5), 5-HT(6), alpha(1A), alpha(2A), alpha(2B), alpha(2C), H(2), M(2), M(4), and dopamine D(1), D(2), D(3), and D(4) receptors. N-Desalkylquetiapine potently inhibited human NE transporter with a K(i) of 12 nM, about 100-fold more potent than quetiapine itself. N-Desalkylquetiapine was also 10-fold more potent and more efficacious than quetiapine at the 5-HT(1A) receptor. N-Desalkylquetiapine was an antagonist at 5-HT(2A), 5-HT(2B), 5-HT(2C), alpha(1A), alpha(1D), alpha(2A), alpha(2C), H(1), M(1), M(3), and M(5) receptors. In the mouse tail suspension test, N-Desalkylquetiapine displayed potent antidepressant-like activity in VMAT2 heterozygous mice at doses as low as 0.1 mg/kg. These data strongly suggest that the antidepressant activity of quetiapine is mediated, at least in part, by its metabolite N-Desalkylquetiapine through NET inhibition and partial 5-HT(1A) agonism. Possible contributions of this metabolite to the side effects of quetiapine are discussed.

Weight gain and psychiatric treatment: Is there a role for green tea and conjugated linoleic acid?

Dietary supplement use is widespread in developed nations. In particular, patients who utilize mental health services also report frequent consumption of dietary supplements, often in relation to management of adverse events and specifically weight gain. Weight gain induced by psychotropic medications can further compound psychological distress and negatively influence compliance. Here we report on four cases of social anxiety disorder treated with the atypical antipsychotic quetiapine. Self-administration of conjugated linoleic acid and green tea extract may have influenced objective anthropomorphic measurements; each patient had an unexpected decrease in total body fat mass, a decrease in body fat percentage and an increase in lean body mass. Since weight gain is a common and undesirable side-effect with psychiatric medications, our observation strongly suggests the need for controlled clinical trials using these agents.

Quetiapine regulates the stress-induced increase in corticotropin-releasing factor mRNA expression in the rat hypothalamus.

Corticotropin-releasing factor (CRF) is a key regulator of the stress response. We investigated the effects of the atypical antipsychotic drug quetiapine on CRF mRNA expression in the rat hypothalamus following immobilization stress. Pretreatment with 10 mg/kg quetiapine significantly reduced the immobilization stress-induced increase in CRF mRNA expression in the paraventricular nucleus of the hypothalamus. These results suggest that quetiapine may modulate the stress response via regulation of CRF mRNA expression.

Evaluation of antipsychotic drugs as inhibitors of multidrug resistance transporter P-glycoprotein.

RATIONALE: The multidrug resistance transporter, P-glycoprotein (P-gp), is involved in efflux transport of several antipsychotics in the blood-brain barrier (BBB). OBJECTIVES: In the present study, we evaluated the inhibitory effect of the antipsychotics, i.e., risperidone, olanzapine, quetiapine, clozapine, haloperidol, chlorpromazine, a major metabolite of risperidone, 9-OH-risperidone, and a positive control inhibitor, PSC833, on the cellular uptake of a prototypic substrate of P-gp, rhodamine (Rhd) 123, in LLC-PK1 and L-MDR1 cells. MATERIALS AND METHODS: After incubation of the antipsychotics (1-100 microM) and the positive (10 microM PSC833) or negative (1% dimethyl sulfoxide) controls with 5 microM Rhd 123 for 1 h, the effects of the antipsychotics on the intracellular accumulation of Rhd 123 were examined using a flow cytometric method. RESULTS: All the antipsychotics showed various degrees of inhibitory effects on P-gp activity. The rank order of the concentration of inhibitor to cause 50% of the maximal increment of intracellular Rhd 123 fluorescence (EC(50)) was: PSC833 (0.5 microM) < olanzapine (3.9 microM) < chlorpromazine (5.8 microM) < risperidone (6.6 microM) < haloperidol (9.1 microM) < quetiapine (9.8 microM) < 9-OH-risperidone (12.5 microM) < clozapine (30 microM). Considering that the antipsychotics' plasma concentrations are generally lower than 1 microM, the present results suggest that olanzapine and risperidone are the only agents that may inhibit P-gp activity in the BBB. However, most of the antipsychotics are extensively accumulated in tissues. In addition, when given orally, the drug concentrations in the gastrointestinal tract are likely to be high. CONCLUSIONS: Pharmacokinetic interactions due to inhibition of P-gp activity by the antipsychotics appear possible and warrant further investigation.

Antipsychotic effects on prepulse inhibition in normal 'low gating' humans and rats.

Development of new antipsychotics and their novel applications may be facilitated through the use of physiological markers in clinically normal individuals. Both genetic and neurochemical evidence suggests that reduced prepulse inhibition of startle (PPI) may be a physiological marker for individuals at-risk for schizophrenia, and the ability of antipsychotics to normalize PPI may reflect properties linked to their clinical efficacy. We assessed the effects of the atypical antipsychotic quetiapine (12.5 mg p.o.) on PPI in 20 normal men with a 'low PPI' trait, based on PPI levels in the lowest 25% of a normal PPI distribution. The effects of quetiapine (7.5 mg/kg s.c.) on PPI were then assessed in rats with phenotypes of high PPI (Sprague Dawley (SD)) and low PPI (Brown Norway (BN)); effects of clozapine (7.5 mg/kg i.p.) and haloperidol (0.1 mg/kg s.c.) on PPI were also tested in SD rats. At a time of maximal psychoactivity, quetiapine significantly enhanced PPI to short prepulse intervals (20-30 ms) in 'low gating' human subjects. Quetiapine increased PPI in low gating BN rats for prepulse intervals <120 ms; this effect of quetiapine was limited to 20 ms prepulse intervals in SD rats, who also exhibited this pattern in response to clozapine but not haloperidol. In both humans and rats, normal 'low gating' appears to be an atypical antipsychotic-sensitive phenotype. PPI at short intervals may be most sensitive to pro-gating effects of these drugs.

Effects of haloperidol, clozapine, and quetiapine on sensorimotor gating in a genetic model of reduced NMDA receptor function.

RATIONALE: Reduced N-methyl D-aspartate (NMDA) receptor function is hypothesized to contribute to the pathophysiology of schizophrenia. In order to model chronic and developmental NMDA receptor hypofunction, a mouse line was developed that expresses low levels of the NMDA R1 (NR1) subunit of the NMDA receptor. These mice show increased acoustic startle reactivity and deficits in prepulse inhibition (PPI) of acoustic startle. OBJECTIVES: The present study tested the hypothesis that these altered acoustic startle responses in the NR1 hypomorphic (NR1-/-) mice would be affected by antipsychotic drug treatment. METHODS: Mice were injected with drugs 30 min before assessment of acoustic startle responses with and without prepulse stimuli. RESULTS: Haloperidol (0.5 or 1.0 mg/kg) did not reduce the increased startle reactivity in the NR1-/- mice, but did increase PPI in both the mutant and wild type mice. Clozapine (3 mg/kg) and quetiapine (20 mg/kg) reduced startle magnitude and increased PPI in both the wild type and mutant mice. The antidepressant drug imipramine (10 and 20 mg/kg) had minimal effects on startle amplitude in NR1-/- or wild type mice. However, for the 20-mg/kg dose of imipramine, a significant increase in PPI was observed in the wild type animals, but not in the mutant mice. CONCLUSIONS: The results demonstrate that PPI can be increased in a mouse model of chronic NMDA receptor hypofunction by typical and atypical antipsychotic drugs. The similar effects of typical and atypical antipsychotic drugs to increase PPI in the wild type and mutant mice indicates that the assessment of behavior of the NR1 hypomorphic mice in the PPI paradigm offers no advantage over the wild type controls for identifying new clozapine-like drugs.

Varied effects of atypical neuroleptics on P50 auditory gating in schizophrenia patients.

OBJECTIVE: Sensory gating deficits found in schizophrenia can be assessed by using a paired auditory stimulus paradigm to measure auditory evoked response. The ratio of the P50 response amplitude of the second or test stimulus to that of the first or conditioning stimulus is expressed as a percentage. Normal subjects generally suppress the second response and typically have ratios of less than 40%. Subjects with schizophrenia and half their first-degree relatives have deficits in sensory gating, with P50 ratios that are generally greater than 50%. Treatment with typical neuroleptics does not reverse this deficit. However, previous studies have shown that treatment with clozapine, an atypical neuroleptic, ameliorates this deficit in clinically responsive patients. This study sought to determine whether other atypical neuroleptics improve P50 ratios. METHOD: P50 evoked potential recordings were obtained from 132 patients with schizophrenia and 177 healthy comparison subjects. Eighty-eight patients were being treated with atypical neuroleptics (clozapine [N=26], olanzapine [N=31], risperidone [N=22], and quetiapine [N=9]). Thirty-four patients were taking typical neuroleptics, and 10 were unmedicated. RESULTS: Healthy subjects exhibited P50 suppression that was significantly better than the schizophrenia patients receiving typical neuroleptics (mean=19.8% [SD=21.0%] versus 110.1% [SD=87.9%]). Patients receiving atypical neuroleptics had a mean P50 ratio that fell between these two means (mean=70.4%, SD=53.7%). When patients treated with different atypical neuroleptics were compared, only the clozapine group had mean P50 ratios that were in the normal range. All other groups exhibited auditory P50 response inhibition that was significantly poorer than that of the healthy subjects. CONCLUSIONS: Improvement in P50 gating appears to be greatest in patients treated with clozapine.

Sleep-promoting properties of quetiapine in healthy subjects.

The aim of this study was to investigate the effects of quetiapine, an atypical antipsychotic, on polysomnographic sleep structure and subjective sleep quality. This double-blind, placebo-controlled, randomized cross-over study investigated the polysomnographic sleep structure and subjective sleep quality of 14 healthy male subjects given placebo, quetiapine 25 mg or quetiapine 100 mg. Volunteers were studied 3 times for 3 consecutive nights (N0, adaptation; N1, standard sleep conditions; N2, acoustic stress) 4 days apart. Treatment was administered orally 1 h before bedtime on nights 1 and 2. Quetiapine 25 mg and 100 mg significantly improved sleep induction and continuity under standard and acoustic stress conditions. Increases in total sleep time, sleep efficiency, percentage sleep stage 2 and subjective sleep quality were seen. A significant increase in periodic leg movements during sleep was observed with quetiapine 100 mg. The sleep-improving properties of quetiapine may be important in counteracting different aspects of psychopathology in schizophrenia and other disorders. These sleep-inducing and sleep-modifying properties are probably related to quetiapine's receptor-binding profile, including its antihistaminergic, antidopaminergic and antiadrenergic properties. Other mechanisms might be relevant as well and further investigation is required.

Quetiapine reduces nocturnal urinary cortisol excretion in healthy subjects.

RATIONALE: Hypothalamic-pituitary-adrenal (HPA) axis dysfunction is a frequent finding in psychiatric disorders, including psychotic depression and schizophrenia. Conflicting results exist concerning the influence of antipsychotics on the HPA-axis. OBJECTIVE: Therefore, this double-blind, placebo-controlled, randomized cross-over study investigated the effect of quetiapine on nocturnal urinary cortisol and melatonin excretion in 13 healthy male subjects under conditions of undisturbed and experimentally disturbed sleep. METHODS: Volunteers were studied 3 times for 3 consecutive nights (N0, adaptation; N1, standard sleep conditions; N2, acoustic stress) 4 days apart. Placebo, quetiapine 25 mg or quetiapine 100 mg was administered orally 1 h before bedtime on nights 1 and 2. Urine produced during the 8-h bedtime period was collected for later determination of cortisol and melatonin concentrations by standard radioimmunoassays. RESULTS: MANOVA showed a significant effect for N1 vs. N2 with elevated total amount of cortisol ( p<0.005) and melatonin ( p<0.05) excretion after acoustic stress. Both quetiapine 25 mg and 100 mg significantly ( p<0.0005) reduced the total amount of cortisol excretion in comparison to placebo. No interaction effect of stress condition was observed. There was no effect of quetiapine on melatonin levels. CONCLUSION: The significant reduction of nocturnal cortisol excretion following quetiapine reflects a decreased activity of the HPA-axis in healthy subjects. This finding may be an important aspect in quetiapine's mode of action in different patient populations.

Quetiapine attenuates levodopa-induced motor complications in rodent and primate parkinsonian models.

The contribution of serotoninergic mechanisms to motor dysfunction in Parkinson's disease (PD) has yet to be fully elucidated. Recent clinical observations increasingly suggest that drugs able to block serotonin 5HT2A/C receptors can benefit patients with certain extrapyramidal movement disorders. To further explore the roles of these and other neurotransmitter receptors in the pathogenesis of parkinsonian signs and levodopa-induced dyskinesias; we evaluated the effects of quetiapine, an atypical antipsychotic with 5HT2A/C and D2/3 antagonistic activity, on motor behavior in 6-hydroxydopamine-lesioned rats and MPTP-lesioned nonhuman primates. In hemiparkinsonian rats, quetiapine (5 mg/kg, po) reversed the shortened motor response to levodopa challenge produced by 3 weeks of twice-daily levodopa treatment (P < 0.01). Quetiapine (5 mg/kg po) also normalized the shortened response to the acute injection of either a dopamine D1 receptor agonist (SKF 38392) or a D2 agonist (quinpirole) in rats that had received chronic levodopa treatment. Quetiapine had no effect on parkinsonian dysfunction when given alone or with levodopa to parkinsonian rats and monkeys. Quetiapine (4 mg/kg, po) did, however, substantially reduce levodopa-induced dyskinesias when coadministered with levodopa (P < 0.05). These results suggest that quetiapine could confer therapeutic benefits to patients with levodopa-induced motor complications. Moreover, our findings may indicate that 5HT2A/C receptor-mediated mechanisms, alone or in combination with other mechanisms, contribute to the pathogenesis of the altered motor responses associated with the treatment of PD.

In vivo 5-HT2A receptor blockade by quetiapine: an R91150 single photon emission tomography study.

BACKGROUND: Atypical antipsychotic drugs are thought to show a high degree of 5-HT2A receptor blockade, which may prevent the emergence of extrapyramidal symptoms. METHOD: 5-HT2A binding was estimated using 123I-5-I-R91150 and single photon emission tomography (SPET) in six schizophrenic subjects treated with quetiapine at a mean (+/-SD) daily dose of 350+/-123 mg for at least 5 weeks and a matched sample of six healthy volunteers. Clinical and side-effect ratings were performed at baseline and at the time of SPET scanning. The reference region approach was used to define a 5-HT2A binding index in the frontal and temporal cortex. RESULTS: Quetiapine treatment resulted in a significant decline in 5-HT2A receptor availability in the frontal cortex (mean 0.98+/-0.09) relative to healthy volunteers (mean 1.33+/-0.16). All patients showed improvements in clinical symptom or side-effect ratings. The mean frontal cortex:cerebellum ratio after quetiapine treatment was significantly negatively correlated with reduction in the Abnormal Involuntary Rating scale and Simpson-Angus scores (P<0.05 Bonferroni corrected), but not with the reduction in the scores from the scale for the assessment of positive symptoms, the scale for the assessment of negative symptoms, the Montgomery-Asberg depression rating scale or patient age. CONCLUSION: Quetiapine treatment results in significant in vivo blockade of cortical 5-HT2A, similar to other atypical antipsychotic drugs. This effect may contribute to its placebo level extrapyramidal side-effect profile.