Lack Of Extrapyramidal Side Effects Research Articles

Discriminative stimulus properties of 1.25 mg/kg clozapine in rats: Mediation by serotonin 5-HT2 and dopamine D4 receptors

The atypical antipsychotic drug clozapine remains one of most effective treatments for schizophrenia, given a lack of extrapyramidal side effects, improvements in negative symptoms, cognitive impairment, and in symptoms in treatment-resistant schizophrenia. The adverse effects of clozapine, including agranulocytosis, make finding a safe clozapine-like a drug a goal for drug developers. The drug discrimination paradigm is a model of interoceptive stimulus that has been used in an effort to screen experimental drugs for clozapine-like atypical antipsychotic effects. The present study was conducted to elucidate the receptor-mediated stimulus properties that form this clozapine discriminative cue by testing selective receptor ligands in rats trained to discriminate a 1.25mg/kg dose of clozapine from vehicle in a two choice drug discrimination task. Full substitution occurred with the 5-HT2A inverse agonist M100907 and the two preferential D4/5-HT2/α1 receptor antagonists Lu 37-114 ((S)-1-(3-(2-(4-(1H-indol-5-yl)piperazin-1-yl)ethyl)indolin-1-yl)ethan-1-one) and Lu 37-254 (1-(3-(4-(1H-indol-5-yl)piperazin-1-yl)propyl)-3,4-dihydroquinolin-2(1H)-one). Partial substitution occurred with the D4 receptor antagonist Lu 38-012 and the α1 adrenoceptor antagonist prazosin. Drugs selective for 5-HT2C, 5-HT6 muscarinic, histamine H1, and benzodiazepine receptors did not substitute for clozapine. The present findings suggest that 5-HT2A inverse agonism and D4 receptor antagonism mediate the discriminative stimulus properties of 1.25mg/kg clozapine in rats, and further confirm that clozapine produces a complex compound discriminative stimulus.

The treatment of autism with pipamperone: A case report

IntroductionAdults with autism spectrum disorders (ASD) often have behavioral disorders, like aggression, agitation and self-injury. These problems are frequently severe enough to limit educational and developmental progress. Only risperidone and aripiprazole have so far been approved by the FDA for the treatment of behavioral disturbance associated with autism. These drugs are not very effective in the long term, with little benefits to the social functioning and they are associated with side effects. This case report describes the use of pipamperone, in treating behavioral disorders of a patient with autism spectrum disorder and severe mental retardation.Case presentationHere is presented the case of a 32-year-old man with autism spectrum disorder, severe mental retardation (caused by undiagnosed phenylketonuria for the first 3 years of life) treated with antipsychotics since childhood. He showed numerous episodes of psychomotor agitation, hetero-direct physical aggression and self-injury, and movement disorders induced by drugs. Treatment with pipamperone reduced drastically crises of psychomotor agitation, and behavioral disorders, without extrapyramidal side effects, and led to an improvement in social functioning. The control of behavioral symptoms associated with adherence to treatment was maintained for 6-month follow up. These clinical observations are supported by ratings using: ABC, CGI-S and CGI-I, VABS, SAS, AIMS.ConclusionThis case report provides the first potential evidence that pipamperone may be effective in treating behavioral problems associated with autism spectrum disorders. Moreover, the improvement of social functioning and the lack of extrapyramidal side effects make this drug notable for its effectiveness and tolerability.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity results in favourable antipsychotic-like activity in rodent models: II. behavioural characterisation of RG-15

RG-15 (trans-N-[4-[2-[4-(3-cyano-5-trifluoromethyl -phenyl) -piperazine -1 -yl] -ethyl] -cyclohexyl] -3 -pyridinesulfonic amide dihydro-chloride), is a highly selective dopamine D3/D2 receptor antagonist with subnanomolar affinity for the D3 receptor and nanomolar affinity for the D2 receptor. We found that RG-15 showed a good oral bioavailability (54%) and high brain levels (approx. 900 ng/g) in rats and demonstrated antipsychotic efficacy in amphetamine-induced hyperactivity and conditioned avoidance response tests in rats, yielding ED50 (median effective dose) values of 8.6 and 12 mg/kg orally, respectively. At six- to eightfold higher doses, RG-15 blocked spontaneous motor activity, while a 30 mg/kg dose of the compound caused an increase in the home-cage motility of rats. The drug did not produce catalepsy up to 160 mg/kg oral dose; moreover, it inhibited haloperidol-induced catalepsy in the range 15-60 mg/kg. RG-15 (10 mg/kg orally) restored the impaired learning performance of scopolamine- or diazepam-treated rats in a water-labyrinth paradigm. It is assumed that the motor activating, anticataleptic and cognitive-enhancing properties of RG-15 result from its potent D3 antagonism. In this regard, RG 15 clearly differs from other antipsychotics. Olanzapine, clozapine and amisulpride all showed efficacy against amphetamine-induced hyperactivity and on conditioned avoidance, but compared to RG-15, they proved to be more cataleptogenic and depressed or did not change the home-cage activity of animals. Olanzapine was also inactive in the learning paradigm. Our results suggest that subnanomolar dopamine D3 receptor antagonism coupled to moderate D2 affinity may result in an antipsychotic profile characterised by a lack of extrapyramidal side effects and secondary negative symptoms with simultaneous efficacy on positive and cognitive symptoms of schizophrenia.

Amoxapine as an Antipsychotic

It has been proposed that the lack of extrapyramidal side effects of atypical antipsychotic drugs is caused by their fast dissociation or low affinity for the D2 receptor or their concomitant high affinity for other receptors, for example, 5HT2 and D4. We noted that amoxapine, an established antidepressant, has affinity for 5HT2 and D2 receptors, and its effects in preclinical model are very similar to atypical antipsychotics. The objective of this study was to examine the antipsychotic effect and side effect profile of amoxapine versus haloperidol in a double-blind study for 6 weeks in patients with schizophrenia. A total of 54 patients with schizophrenia were titrated to the starting dose of 150 mg/d of amoxapine or 5 mg/d of haloperidol within 3 days. Clinical efficacy and side effects were monitored at baseline, and Weeks 2, 4, and 6.Forty-one patients completed 5 weeks, and 36 patients completed the 6 weeks of follow-up. Both treatment groups showed significant improvement in Positive and Negative Syndrome Scale positive (30%) and total scores (20%), without significant differences between the groups. In addition, in the amoxapine group, significant improvement was seen in the negative symptoms and the Clinical Global Impression. No significant changes were seen on Calgary Depression Scale for Schizophrenia, side effect checklists, and prolactin levels in both groups. The results suggest that amoxapine may be as effective an antipsychotic as haloperidol as predicted by its affinity for D2 and 5HT2 receptors, supporting earlier studies. However, it did not prove to have fewer extrapyramidal side effects than haloperidol, possibly because the baseline scores were very low.

Lack of extrapyramidal side effects predicts quality of life in outpatients treated with clozapine or with typical antipsychotics

We compared symptom severity and quality of life (QOL) in schizophrenic patients adequately treated with typical antipsychotics (TAP) or clozapine (CZP). Groups did not differ in symptom severity or QOL. Clozapine caused fewer extrapyramidal symptoms. Negative and extrapyramidal symptoms predicted QOL. Similar outcome in both groups suggests a common ceiling to antipsychotic efficacy.

Risperidone-associated hyperprolactinemia: evaluation in twenty psychiatric outpatients

Despite the lack of extrapyramidal side effects, some atypical antipsychotics can induce an increase in prolactinemia, as the conventional neuroleptics do. We decided to evaluate the effects of risperidone on serum prolactin levels and prolactin-related adverse effects in 20 outpatients of an Italian community psychiatric service. Patients enrolled in this study were on risperidone (2–8 mg per day; mean dose=4.15±0.4 mg per day) treatment in the period May–November 2002. The 20 patients, 13 women and 7 men (mean age=36.38±3.2 years for women and 29.7±2.2 for men) who accomplished inclusion criteria, participated in the study after giving informed written consent. Raised prolactin levels were observed in 13 (9 women and 4 men) out of 20 patients, but only 8 patients presented prolactin-related adverse effects, libido reduction being the most frequent. In this observational study, risperidone enhanced serum prolactin in 65% of patients. A good correlation was found between age and prolactin levels in pre-menopausal women, although no clear correlation among duration of treatment, dose used, prolactin levels and prolactin-related adverse effects could be established.

Central Muscarinic Acetylcholine Receptor Availability in Patients Treated with Clozapine

Clozapine is the prototypical atypical antipsychotic. In vitro, clozapine antagonizes a broad range of receptors, including dopamine, serotonin and muscarinic acetylcholine receptors. In vivo, receptor occupancy studies have shown moderate dopamine D(2) receptor blockade as well as high serotonin 5HT(2) receptor blockade for clozapine. Using [I-123]IQNB SPECT, we explored the influence of clozapine on muscarinic receptors in vivo. Eight schizophrenia patients underwent a total of 12 [I-123]IQNB SPECT scans after treatment with low to moderate doses of clozapine (mean 210 mg/day, range 50-450 mg/day). Muscarinic receptor availability was determined for basal ganglia, cortex, thalamus, and pons. A group of 12 age- and sex-matched unmedicated schizophrenia patients was used for comparison. Compared to unmedicated patients, [I-123]IQNB binding was lower in all regions in subjects treated with clozapine and decreased with increasing dose. In patients treated with a daily clozapine dose of at least 200 mg (mean 275+/-88 mg/day), these differences were highly significant (p <0.003) with mean reductions of muscarinic receptor availability of 45% for basal ganglia, 58% for cortex, 66% for pons, and 79% for thalamus. These preliminary data indicate that reduction of muscarinic receptor availability by clozapine can be measured in vivo and that moderate daily doses are associated with moderate to high reductions of muscarinic receptor availability. These results may explain, at least in part, the lack of extrapyramidal side effects as well as some side effects seen with clozapine.

The adenosine A2A receptor agonist CGS 21680 exhibits antipsychotic-like activity in Cebus apella monkeys

The adenosine A2A receptor agonist CGS 21680 has shown effects similar to dopamine antagonists in behavioural assays in rats predictive for antipsychotic activity, without induction of extrapyramidal side-effects (EPS). In the present study, we examined whether this functional dopamine antagonism and lack of EPS in rodents could also be observed in non-human primates. We investigated the effects of CGS 21680 on behaviours induced by D-amphetamine and (−)-apomorphine in EPS-sensitized Cebus apella monkeys. CGS 21680 was administered s.c. in doses of 0.01, 0.025 and 0.05 mg/kg, alone and in combination with D-amphetamine and (−)-apomorphine. The monkeys were videotaped after drug administration and the tapes were rated for EPS and psychosis-like symptoms. CGS 21680 decreased apomorphine-induced behavioural unrest, arousal (0.01–0.05 mg/kg) and stereotypies (0.05 mg/kg) while amphetamine-induced behaviours (unrest, stereotypies, arousal) were unaffected. EPS were not observed at any dose. At 0.05 mg/kg CGS 21680 produced vomiting. The two lower doses did not produce observable side-effects. Though the differential effect on amphetamine- and apomorphine-induced behaviours is intriguing, CGS 21680 showed a functional anti-dopaminergic effect in Cebus apella monkeys without production of EPS. This further substantiates that adenosine A2A receptor agonists may have potential as antipsychotics with atypical profiles.

Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [ 123 I]epidepride single photon emission tomography (SPET) study

Previous work suggests clozapine preferentially targets limbic cortical dopamine systems, which could help account for its lack of extrapyramidal side effects (EPS) and superior therapeutic efficacy. To test the hypothesis that olanzapine, a novel atypical antipsychotic drug, occupies temporal cortical D2/D3 receptors to a greater extent than striatal D2/D3 receptors in vivo. Nine schizophrenic patients taking either olanzapine [(n=5; mean (SD) age: 32.5 (6.5) years; daily dose: 18.3 (2.6) mg] or sertindole [(n=4; mean (SD) age: 30.3 (7.4) years; daily dose: 16 (5.6) mg] were studied with [123I]epidepride ((S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxybenz amide) and single photon emission tomography (SPET). An estimate of [123I]epidepride 'specific binding' to D2/D3 receptors was obtained in patients and age-matched healthy volunteers. A summary measure was generated representing striatal and temporal cortical relative %D2/D3 receptor occupancy by antipsychotic drugs. Occupancy data were compared with previously studied groups of patients receiving typical antipsychotic drugs (n=12) and clozapine (n=10). Mean striatal and temporal cortical %D2/D3 receptor occupancy in olanzapine-treated patients was 41.3% (SD 17.9) and 82.8% (SD 4.2), respectively. Unexpectedly low levels of striatal relative %D2/D3 receptor occupancy were seen in two patients with typical antipsychotic-drug-induced movement disorder prior to switching to olanzapine. In the temporal cortex, mean D2/D3 dopamine receptor occupancy levels above 80% were seen for all antipsychotic drugs studied. The atypical antipsychotic drugs olanzapine and sertindole, in common with clozapine, demonstrate higher occupancy of temporal cortical than striatal D2/D3 dopamine receptors in vivo at clinically useful doses. This could help mediate their atypical clinical profile of therapeutic efficacy with few extrapyramidal side effects. Limbic selective blockade of D2/D3 dopamine receptors could be a common action of atypical antipsychotic drugs.

The role of alpha2-adrenoceptor antagonism in the anti-cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat.

1. The mechanism underlying the anticataleptic properties of the atypical neuroleptic agent, clozapine, has been investigated in the rat. 2.The close structural analogues of clozapine, loxapine (0.1 mg kg(-1) s.c.) and iso-clozapine (1 and 3 mg kg(-1) s.c.) induced catalepsy in rats. In contrast, clozapine and the regio-isomer of loxapine, iso-loxapine (up to 10 mg kg(-1) s.c.) did not produce catalepsy, but at a dose of 1 mg kg(-1) significantly inhibited catalepsy induced by loxapine (0.3 mg kg(-1) s.c.). 3. Radioligand binding assays showed that cataleptogenic potential was most clearly predicted by the D2/5-HT1A, D2/5-HT1B/1D and D2/alpha2-receptor affinity (KD) ratios: i.e. 30-100-fold higher ratios were calculated for loxapine and iso-clozapine, whereas the ratios were less than 1 for clozapine and iso-loxapine. The ratios of affinities for D2 to 5-HT2A, 5-HT2C or D1 did not reflect the grouping of cataleptic and non-cataleptic compounds. 4. Co-treatment with the alpha2-adrenoceptor antagonists, yohimbine (1-10 mg kg(-1) s.c.), RX 821002 (1-10 mg kg(-1) s.c.) and MK-912 (0.3 and 1 mg kg(-1) s.c.) dose-dependently inhibited the cataleptic response to loxapine (0.3 mg kg(-1)). Yohimbine (1-10 mg kg(-1) s.c.) also dose-dependently inhibited the cateleptic response to haloperidol (0.3 mg kg(-1) s.c.). The alpha2-adrenoceptor antagonists had no effect per se. 5. Neither yohimbine (10 mg kg(-1)) nor RX821002 (3 mg kg(-1)) altered the cataleptic response to the D1 receptor antagonist, SCH 23390 (1 mg kg(-1) s.c.), while, like clozapine, both compounds abolished the response to the 5-HT2A receptor antagonist, MDL 100,151 (3 mg kg(-1) s.c.). 6. The present data strongly implicate alpha2-adrenoceptor blockade in the anticataleptic properties of clozapine and suggest that its lack of extrapyramidal side effects in the clinic may also be a consequence of this property.

Long-term effect on outcome of clozapine in chronic therapy-resistant schizophrenic patients

Controlled clinical trials have shown that the atypical neuroleptic clozapine is highly effective in schizophrenic patients who are unresponsive to conventional neuroleptic agents. The long-term outcome of clozapine treatment was studied in 122 patients who were treated between 1974 and 1991. The mean duration of treatment was 5.2 years. At follow-up, 74 patients (61%) were still receiving clozapine. Only 11 patients discontinued treatment because of adverse events and eight because of poor compliance. Clinical improvement was seen in 87% of patients; 40% had resumed employment after 2 years' treatment. About one-third of patients who received clozapine for 5-10 years continued to improve during this time; this was probably because of a continuing process of socialisation. Thus, clozapine offers important advantages in schizophrenic patients resistant to conventional neuroleptics in terms of long-term efficacy and lack of extrapyramidal side-effects.

Antipsychotic effects of bretazenil, a partial benzodiazepine agonist in acute schizophrenia—A study group report

The results of an open tolerability and exploratory efficacy study of bretazenil, a partial benzodiazepine-receptor agonist in hospitalized schizophrenic patients with an acute psychotic episode (DSM-III-R criteria), are presented. The duration of the study was 6 weeks, with a mandatory titration (ascending doses of 3–18 mg/day) period of 14 days. The assessment criteria for tolerability were the frequency of adverse events (including EPS), vital signs and laboratory tests. The efficacy criteria, which were only descriptively analysed, were: (a) Clinical Global Impression (CGI, percentage of “very much” and “much” improvement); and (b) change in BPRS total score (e.g. percentage of patients showing ≥40% decrease of BPRS score at the end of the treatment). Sixty-six patients (aged 21–62 years) with acute episodes of schizophrenia of moderate to marked severity (mean BPRS score = 46.3, range 26–76) were included in the study. Of these 66 patients (68%) were reportedly non-responders ( n = 10) or partial responders ( n = 35) to previous neuroleptic therapy. Twenty patients (30%) terminated the trial prematurely due to therapeutic failure (no improvement or worsening after 2 weeks of treatment), 17% of patients dropped out due to other reasons (transfer to other hospitals, withdrawal of consent, intercurrent diseases) and 4.5% of patients stopped the treatment due to adverse reactions. Four patients (6%) showed early complete remission and refused to be further treated. The analysis of efficacy (intention-to-treat) revealed a sustained decrease of BPRS scores with 49% of patients showing ≥40% BPRS score change by the end of the treatment. Forty-four per cent of patients improved “very much” or “much”. Eleven patients (17%) were full responders (BPRS score decrease 75–100%) and 21 patients (32%) showed at least 40% reduction of BPRS score. The reduction of BPRS scores in completers only was 60%. All BPRS factor scores decreased in parallel and, particularly, no preferential decrease of anxiety/depression subscores was found. The analysis of tolerability showed that 59% of patients presented no complaints at all. The most frequent treatment-related adverse reactions in the remaining patients were: sedation ( n = 14), dizziness ( n = 4) and headache ( n = 3). The results of this study suggest moderate antipsychotic efficacy of bretazenil in schizophrenic patients. They encourage further investigations of partial benzodiazepine-receptor agonists in this indication, particularly because of the excellent tolerability and lack of extrapyramidal side-effects.

D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients.

Central D1, D2, and 5-HT2 receptor occupancy in schizophrenic patients treated with clozapine was determined and related to clozapine serum concentrations. Seventeen patients treated with clozapine (125-600 mg/day) were examined with positron emission tomography (PET) and one to three of the following selective radioligands: [11C]SCH23390 (N = 11), [11C]raclopride (N = 16), and [11C]N-methylspiperone (N = 5). Clozapine concentration in serum was determined by gas chromatography/mass spectrometry. D2 receptor occupancy (20%-67%) was lower than that previously determined in patients treated with classical neuroleptics (70%-90%). D1 receptor occupancy (36%-59%) was higher than that induced by classical neuroleptics (0%-44%). 5-HT2 receptor occupancy was very high (84%-94%), even at low clozapine doses. Despite a 20-fold range in clozapine serum concentration (105-2121 ng/ml) at the time of PET examination, D2 receptor occupancy was low in all patients and was not described by the curvilinear relationship between serum drug concentration and receptor occupancy that has been demonstrated for classical antipsychotics. The results confirm in an extended series of patients that clozapine is atypical with regard to degree of D2 receptor occupancy, a finding that may explain the lack of extrapyramidal side effects. The combination of relatively high D1, low D2, and very high 5-HT2 receptor occupancy values is unique to clozapine. Clozapine serum concentrations have not been unequivocally shown to predict clinical effects. In this study, concentration did not predict degree of occupancy in brain. Thus, careful clinical titration cannot be replaced by monitoring of drug concentrations for optimization of clozapine treatment in individual patients.

Clozapine Reduces Treatment-Related Parkinson's Psychosis

Psychotic symptoms and other cognitive changes may accompany the treatment of Parkinson's disease with dopaminergic drugs, particularly in demented patients. Clozapine, with its relative lack of extrapyramidal side effects, would seem to be an …

Peripheral and central adrenoceptor modulation of the behavioural effects of clozapine in the paw test.

1. In rats, the atypical neuroleptic, clozapine, has been found to increase the hindlimb retraction time but not the forelimb retraction time, in the paw test. These parameters have predictive validity for the antipsychotic efficacy and extrapyramidal side-effects of drugs, respectively. The present study analysed to what extent drugs acting on adrenoceptors affect the behavioural effect of clozapine in the paw test. 2. The alpha 1-adrenoceptor agonist, ST 587 but not the peripherally working alpha 1-agonist, methoxamine, decreased the effect of clozapine on the hindlimb retraction time. The alpha 1-antagonist phenoxybenzamine increased this effect of clozapine, and blocked the effect of ST 587 on clozapine at low doses. Only the combination of phenoxybenzamine with clozapine produced an increase in forelimb retraction time. 3. The alpha 2-adrenoceptor agonist, clonidine, decreased the effect of clozapine on the hindlimb retraction time. This effect was neither antagonized by the alpha 2-antagonist rauwolscine nor by the alpha 1-antagonist phenoxybenzamine. Rauwolscine or the peripherally working alpha 2-antagonist L-659,066 did not influence the effect of clozapine on the hindlimb retraction time. The forelimb retraction time was not affected by any of the drug combinations. 4. In contrast to the beta 2-adrenoceptor agonist, clenbuterol, which was ineffective, the peripherally acting beta-agonist, (-)-isoprenaline, increased the effects of clozapine on the hindlimb retraction time. The beta-antagonist, (-)-propranolol as well as the peripherally acting beta-antagonist, nadolol decreased this effect of clozapine. Low doses of the peripherally acting beta 1-antagonist, atenolol, as well as low doses of the beta2-antagonist, ICI-118,551, decreased the effect of clozapine. A low dose of nadolol blocked the effect of (-)-isoprenaline on clozapine. Only the combination of clenbuterol with clozapine produced an increase in forelimb retraction time.5. It is concluded that blockade of central alpha l-adrenoceptors plays an important role in the effect of clozapine on the hindlimb retraction time. Furthermore, the effect of clozapine on the hindlimb retraction time is strongly modulated by peripheral beta 1- and/or beta 2-adrenoceptors. Given the predictive validity of the paw test, the presented data suggest that the alpha 1-adrenoceptor antagonist properties of clozapine are important for its therapeutic effects, but not for its lack of extrapyramidal side-effects.

Atypical Neuroleptic Malignant Syndrome (NMS) with an Atypical Neuroleptic Clozapine-induced NMS without Rigidity

AbstractClozapine has been recently FDA approved and is expected to become very popular because of its efficacy and lack of extrapyramidal side effects. The neuroleptic malignant syndrome (NMS) has already been reported in two cases associated with clozapine use. In this article, we present a case in which a patient receiving clozapine monotherapy developed a complex of symptoms that appeared to be NMS without rigidity. The case meets specific criteria for NMS and the absence of rigidity may be attributable to the anatomic selectivity of clozapine's dopamine blockade.

Antiemetic action of 5-HT 3 receptor antagonists: review of preclinical and clinical results with ICS 205–930

These results thus indicate, that ICS 205-930 is a very effective antiemetic for cancer chemotherapy-induced emesis in man. Given as a single dose prior to the chemotherapeutic agent, ICS 205-930 inhibits emesis and nausea for at least 24 hr. Together with the lack of extrapyramidal side-effects, these properties of ICS 205-930 indicate a clear superiority to the current therapeutic standard metoclopramide.

Increased release of dopamine [formula omitted] by BMY-14802: Contrasting pattern to clozapine

In preclinical studies, BMY-14802 [α-(fluorophenyl)-4-(5-fluoro-2-pyramidinyl)-1-piperazine-butanol], a potent sigma ligand, exhibited a profile similar to clozapine, an atyplcal antipsychotic agent. Several atyplcal antipsychotics have previously been demonstrated to increase dopamine (DA) metabolism without altering DA release in vivo , suggesting a potential mechanism for their lack of extrapyramidal side effects. BMY-14802 increased DA metabolism and release while clozapine increased DA metabolism but decreased DA release in the mouse. This is the first demonstration of a sigma ligand mediated DA release in vivo . The lack of extrapyramidal side effects, despite the enhanced DA release in vivo after BMY-14802 suggests that the atyplcal profile of clozapine can not be explained by its depressant actions on DA release alone.

Long-term experience with clozapine in Denmark: research and clinical practice.

In Denmark, the use of clozapine has increased markedly (15-25% per year) since 1983, when the drug was relaunched--after its withdrawal in 1975. Several factors have contributed to this development: 1) the interesting pharmacology of clozapine, especially the atypical influence on dopamine transmission, including a relatively high D-1/D-2 receptor affinity ratio, 2) the potent anti-anxiety and anti-psychotic effect in severe and otherwise therapy-resistant psychotic patients, and 3) the lack of extrapyramidal side effects. A special monitoring form (for registration of total and differential leucocyte counts, ECG, body weight, drugs, doses and reason for possible withdrawal of the clozapine) is used in most Danish psychiatric institutions. This form secures the regular control of vital parameters and serves as an instrument for surveys of the use of clozapine in Denmark. Also, more selective studies are being carried out, e.g., on the effect of clozapine monotherapy versus combined therapy, and on the influence of clozapine on cardiovascular functions, including left ventricular output (echocardiography).

Typical and atypical antipsychotic occupancy of D 2 and S 2 receptors: An autoradiographic analysis in rat brain

In thin sections of rat brain, [ 3H]spiperone binds to D 2 sites in the basal ganglia (caudate-putamen, nucleus accumbens, olfactory tubercle) and S 2 sites in the claustrum and motor cortex. The in vitro displacement of [ 3H]spiperone from these regions was quantified autoradiographically with the “atypical” neuroleptics clozapine and thioridazine, which ameliorate psychosis, a “typical” neuroleptic, haloperidol, which also induces extrapyramidal side effects, or with metoclopramide, which induces extrapyramidal side effects but is an ineffective antipsychotic. Whereas metoclopramide was equipotent at D 2 sites, haloperidol was less potent and clozapine and thioridazine more potent by 2- to 3-fold at competing for D 2 sites in the nucleus accumbens or olfactory tubercle than in the caudate-putamen. As measured autoradiographically or with tissue homogenates, clozapine, thioridazine, and five other atypical neuroleptics were 4- to 800-times more potent at competing for S 2 sites in the frontal cortex than for D 2 sites in the basal ganglia. A preference of atypical antipsychotics for D 2 receptors in the nucleus accumbens and olfactory tubercle and for the S 2 receptor may explain the relative lack of extrapyramidal side effects produced by these compounds.