Olanzapine: an atypical antipsychotic for schizophrenia

Olanzapine is a serotonin-dopamine receptor antagonist primarily used in the treatment of psychotic illnesses. It has been shown in numerous large trials to be as equally effective as haloperidol in the acute treatment and maintenance treatment of schizophrenia. However, olanzapine was shown to be more effective than haloperidol in the treatment of negative symptoms and to cause significantly fewer extrapyramidal symptoms. Furthermore, early reports suggest that olanzapine produces less tardive dyskinesia than haloperidol, though longer follow-up data are needed. Current studies have failed to demonstrate the efficacy of olanzapine in the treatment of refractory schizophrenia. One comparison trial of olanzapine versus risperidone has indicated similar efficacy. Clinical trials in acute mania have found olanzapine to be more effective than placebo. However, there is no role for olanzapine monotherapy in bipolar disorder given current studies. Although olanzapine has shown a low rate of extrapyramidal symptoms, it is not without adverse effects. Clinically significant weight gain has been noted with olanzapine in each of the large clinical trials. The degree of weight gain is similar to clozapine and probably greater than that observed with risperidone. The long-term medical consequence of atypical antipsychotic-induced weight gain is not known at this time. While generally considered first-line drugs from an efficacy and adverse effect standpoint, pharmacoeconomic studies are needed to justify the large acquisition cost of olanzapine compared to typical agents.     

Which atypical antipsychotic for schizophrenia?

Until the early 1990s, first-line drug therapy for patients with acute schizophrenia was usually a traditional antipsychotic, such as haloperidol. As recently as 1997, we recommended that newer, so-called 'atypical' antipsychotic drugs, such as olanzapine and risperidone, should be reserved for patients unable to tolerate traditional drugs. Now, atypical antipsychotics are widely regarded as better than traditional drugs, being generally less likely to cause troublesome extrapyramidal effects or hyperprolactinaemia. Current atypical antipsychotics differ from one another in important respects. Here we consider how important differences in their unwanted-effect profiles may influence the choice between these drugs for patients with schizophrenia.     

Olanzapine,an atypical antipsychotic,increases rates of punished responding in pigeons

The effects of olanzapine [LY 170053; 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2, 3b][1,5]benzodiazepine), a potential atypical antipsychotic, were determined in pigeons whose keypeck responding was punished. These effects were compared to the anxiolytic agents chlordiazepoxide and pentobarbital, and to other antipsychotic agents. Keypeck behavior was maintained under a multiple FR30 FR30 schedule, signalled by white and red stimulus lights, respectively. Each component of the schedule alternated every 3 min with a 30-s timeout. During the white keylight component, responding was maintained by food presentation. During the red keylight component, responding was maintained by food and simultaneously suppressed by electric shock presentation, with response rates being only about 5% of those during the white stimulus light. Olanzapine (0.01–1.0 mg/kg) increased punished responding at doses below those which had an effect on unpunished responding. Clozapine (0.01–1.0 mg/kg), ritanserin (0.1–3.0 mg/kg), and, to a lesser extent, risperidone (0.1–1.0 mg/kg) were also effective at increasing punished responding. Generally, the maximum effect seen with olanzapine was equal to that seen with ritanserin, and it exceeded that seen with clozapine. However, these effects were generally less than those seen with chlordiazepoxide and pentobarbital. Haloperidol (0.01–0.1 mg/kg) was completely without effect on punished responding, while it caused decreases in unpunished behavior. These results provide further evidence that olanzapine has a profile in behavioral tests unlike the typical antipsychotic haloperidol. Moreover, this profile is similar to clozapine, a clinically effective antipsychotic with an atypical profile.     

Olanzapine for schizophrenia refractory to typical and atypical antipsychotics: an open-label, prospective trial

The role of olanzapine in treatment-resistant schizophrenia is still unresolved. This article presents an open-label, prospective, 14-week trial with olanzapine in patients with schizophrenia and schizoaffective disorder selected for unambiguous resistance to either clozapine or risperidone and to typical antipsychotics. Forty-three inpatients (mean age, 41.6 years; mean duration of illness, 21.7 years) were enrolled and treated after cross-titration from their previous antipsychotic treatment with olanzapine 10 to 40 mg daily without any concomitant antipsychotic medication. Patients were evaluated with the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions Scale, and the Extrapyramidal Symptom Rating Scale. The change with olanzapine treatment was associated with a PANSS total score improvement of 3.7 (SD = 15.6; not significant). There was a significant improvement for the PANSS cognitive and depression/anxiety factors, whereas the PANSS excitement factor worsened. The improvement rate was superior in patients receiving olanzapine doses higher than 20 mg. A total of 16.7% of patients reached response criteria set forth by a previous study. There was a significant decrease in extrapyramidal side effects (t = 2.04; p < 0.05) and statistically significant, yet modest, weight gain. These results indicate that olanzapine is only modestly effective in these severely treatment-resistant patients with schizophrenia. However, a trial with olanzapine can be recommended in these patients before moving to augmentation strategies, given the lack of proven alternatives and the observation that 16.7% of patients reached the response criteria.     

Clozapine: an atypical antipsychotic agent

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosage, and cost of the atypical antipsychotic drug clozapine are reviewed. Clozapine is a dibenzazepine compound chemically similar to loxapine but with a distinct pharmacologic profile. Unlike currently available medications, clozapine has a low potential for causing extrapyramidal symptoms and does not induce dopamine type 2 receptor hypersensitivity. It shows affinity in vitro not only for dopamine type 1 and 2 receptors but also for histamine type 1, alpha-adrenergic type 1 and 2, serotonin type 2, and muscarinic receptors. Clozapine given orally is nearly completely absorbed and readily metabolized. Urinary excretion is the major route of metabolite elimination. Clozapine has been used to treat schizophrenia, nonschizophrenic psychotic states, depression, neuroses, and behavioral disorders. Double-blind comparative studies have shown clozapine to be superior to haloperidol, chlorpromazine, and placebo in treating the symptoms of schizophrenia, as measured with validated psychiatric rating scales. Adverse effects include orthostatic hypotension, tachycardia, benign hyperthermia, hypertension, seizures, and sedation. Many of these effects are transient. Because of the risk of agranulocytosis, a comprehensive case-management system has been developed. In treating acute psychosis, the optimum dosage of clozapine is 300-450 mg/day given orally in divided doses. The high cost of clozapine may be offset by improved patient response and reduced hospital costs. Clozapine may be superior to other agents in the treatment of refractory schizophrenia and is associated with a negligible incidence of extrapyramidal symptoms.     

Choosing an atypical antipsychotic

The atypical antipsychotics vary in terms of their pharmacological profiles, particularly in relation to their tolerability, effects on safety parameters and patient acceptability. Olanzapine, risperidone and ziprasidone are associated with extrapyramidal symptoms (EPS) in a dose-dependent manner, whereas quetiapine has been shown to produce a significantly lower incidence of substantial EPS effects than haloperidol, and less EPS requiring treatment than risperidone. Similarly, unlike risperidone and haloperidol, quetiapine treatment has been associated with a significant reduction in serum prolactin levels, and has normalized raised prolactin levels after discontinuation of previous treatment. Weight gain is also one of the major unwanted adverse effects of treatment with many antipsychotic drugs but, in contrast, quetiapine has demonstrated a neutral or 'normalizing' effect on body weight. In comparison with other antipsychotics, quetiapine has been shown to possess a favourable safety profile, with no requirement for routine blood, thyroid, or liver monitoring during treatment. Overall, quetiapine therapy has produced high levels of patient satisfaction and compliance and this, coupled with its efficacy in reducing psychoses of various origins, has made it an attractive treatment option in both patients at increased risk of EPS, and the general population.     

Olanzapine,a novel atypical antipsychotic,reversesd-amphetamine-induced inhibition of midbrain dopamine cells

This study compared the ability of the novel atypical antipsychotic olanzapine with that of clozapine to reverse thed-amphetamine-induced inhibition of substantia nigra (A9) and ventral tegmental area (A10) dopamine (DA) cells. Extracellular single-unit recordings were made from A9 and A10 DA cells in anesthetized rats. When administered alone, neither olanzapine nor clozapine altered the firing rate of A9 or A10 DA cells. Administration ofd-amphetamine (0.5, 1.0 and 2.0 mg/kg, IV, decreased the firing rate of A9 and A10 DA cells. Olanzapine completely reversed the inhibitory effects ofd-amphetamine on A10 DA cells (ED₁₀₀=0.18 mg/kg, IV) and on A9 DA cells (ED₁₀₀=1.0 mg/mg, IV). Clozapine completely reversed the inhibitory effects ofd-amphetamine on A10 DA cells (ED₁₀₀=3.8 mg/kg, IV), but only partially reversed the effects ofd-amphetamine on A9 DA cells at the highest dose tested (8.0 mg/kg, IV). Thus, olanzapine, like clozapine, was more potent in reversing the effects ofd-amphetamine on A10 than A9 DA cells. In addition, olanzapine was more potent than clozapine in the reversal ofd-amphetamine effects on A9 and A10 DA cells. These results indicate that olanzapine and clozapine have similar effects on DA unit activity and predict that olanzapine should have an atypical antipsychotic profile in man.     

Clinical pharmacokinetics of quetiapine: an atypical antipsychotic

Quetiapine is a dibenzothiazepine derivative that has been evaluated for management of patients with the manifestations of psychotic disorders. In pharmacokinetic studies in humans, quetiapine was rapidly absorbed after oral administration, with median time to reach maximum observed plasma concentration ranging from 1 to 2 hours. The absolute bioavailability is unknown, but the relative bioavailability from orally administered tablets compared with a solution was nearly complete. Food has minimal effects on quetiapine absorption. The drug is approximately 83% bound to serum proteins. Single and multiple dose studies have demonstrated linear pharmacokinetics in the clinical dose range (up to 375mg twice daily). The drug is eliminated with a mean terminal half-life of approximately 7 hours. The primary route of elimination is through hepatic metabolism. In vitro studies show that quetiapine is predominantly metabolised by cytochrome P450 (CYP) 3A4. After administration of [14C]quetiapine, approximately 73% of the radioactivity was excreted in the urine and 21% in faeces. Quetiapine accounted for less than 1% of the excreted radioactivity. 11 metabolites formed through hepatic oxidation have been identified. Two were found to be pharmacologically active, but they circulate in plasma at 2 to 12% of the concentration of quetiapine and are unlikely to contribute substantially to the pharmacological effects of the drug. The pharmacokinetics of quetiapine do not appear to be altered by cigarette smoking. Oral clearance declines with age, and was reduced in 2 of 8 patients with hepatic dysfunction but not in patients with renal impairment. Quetiapine has no effect on the in vitro activity of CYP1A2, 2C9, 2C19, 2D6 and 3A4 at clinically relevant concentrations. The lack of effect of quetiapine on hepatic oxidation was confirmed in vivo by the lack of effect of quetiapine on antipyrine disposition. Quetiapine had no effect on serum lithium concentration. Phenytoin and thioridazine increase the clearance of quetiapine, and ketoconazole decreases clearance. No clinically significant effects of cimetidine, haloperidol, risperidone or imipramine on the pharmacokinetics of quetiapine were noted. Quetiapine dosage adjustment, therefore, may be necessary when coadministered with phenytoin, thioridazine or other potent CYP3A4 inducers or inhibitors. The relationship between the therapeutic effects and the plasma concentrations of quetiapine has been investigated in a multicentre clinical trial. There was no statistically significant association between trough plasma quetiapine concentration and clinical response as measured by traditional assessments of psychotic symptom severity. Subsequent clinical studies of the plasma concentration versus effect relationships for quetiapine may help to further define guidelines for dosage regimen design.     

非典型抗精神病药利培酮的药代动力学研究进展

利培酮(risperidone)是已在中国上市的非典型抗精神病药,由于其疗效肯定,且锥体外系反应及运动功能抑制等药物不良反应少,因而倍受关注。因此本文就利培酮在人体内吸收、分布、代谢、排泄的药代动力学特征,年龄、肝。肾功能损伤等因素对这些过程造成的影响及其他药物的相互作用做一综述。     

非典型抗精神病药氯氮平的临床再评价

氯氮平属于非典型抗精神病药物，临床疗效好且不良反应少。本文对氯氮平血药浓度与临床疗效的关系及影响氯氮平血药浓度的因素进行综述，并报告我室对氯氮平进行临床再评价的工作。     

Recent advances in novel atypical antipsychotic agents: potential therapeutic agents for the treatment of schizophrenia

There are now numerous drugs in advanced stages of clinical testing as potential antipsychotics. The major focus of development of antipsychotics is serotonin (5-HT)_2A antagonism, based on the hypothesis that this property is a critical facet of the pharmacology of clozapine and risperidone. These drugs have been found to exhibit relatively potent 5-HT_2A antagonism compared to their dopamine D₂ antagonistic effects. A large number of other antipsychotics with a similar 5-HT_2A/D₂ profile have been identified. In general, these compounds have minimal cataleptic effects at doses that block dopamine receptor agonist-induced behaviour, and have highly selective effects on mesolimbic dopamine neurones. Because they differ in relative potency as antagonists of a variety of other key receptors (e.g., D₁, D₂, D₃, D₄, D₅, 5-HT_2A, 5-HT_2C, 5-HT₆, 5-HT₇, M₁ and α₁-adrenoceptors), it is likely that these compounds will have significantly different side effects and efficacy profiles (multi-acting receptor targeted agents [MARTA]). Some may be effective in treating negative symptoms and improving cognitive dysfunction. The potential usefulness of N-methyl-D-aspartate (NMDA) receptor agonists for schizophrenia is limited by possible epileptogenic or neurotoxic side effects. In this respect, ligands at strychnine-insensitive glycine binding sites of the NMDA receptor ion channel complex and metabotropic glutamate receptors (mGluR) are expected to have relatively few side effects. A novel sigma₁ receptor antagonist appears to be of particular interest based upon its ability to block the behavioural effects of phencyclidine (PCP). The close relationship between some neuropeptides, such as cholecystokinin and neurotensin, and dopaminergic systems in the brain is sufficient to sustain interest in these apart from the tantalising possibility of mediation by a neuropeptide system of some of the psychopharmacology of schizophrenia.     

A review of atypical antipsychotic drugs versus conventional medication in schizophrenia

Atypical antipsychotics are replacing conventional antipsychotics for the treatment of schizophrenia. They are considered to be at least as effective as conventional agents, with most producing fewer extrapyramidal symptoms. This review presents the evidence from published meta-analyses and describes differences in clinical effectiveness and tolerability between conventional and atypical antipsychotic agents. In addition, it discusses some of the more significant adverse effects including tardive dyskinesia, weight gain, diabetes and sudden death. Results from meta-analyses are conflicting, with some finding no significant advantages on measures of efficacy or tolerability for atypical antipsychotics over moderate daily doses of conventional drugs. Other results have shown that some atypical drugs have at least minor efficacy advantages over conventional comparators. Atypical antipsychotics exhibit a much reduced risk for tardive dyskinesia compared with conventional drugs. However, weight gain is more common with some atypical drugs (especially clozapine and olanzapine). Both conventional and atypical antipsychotics have been associated with diabetes, with most reports implicating both clozapine and olanzapine. Finally, atypical antipsychotics (unlike conventional drugs) have little or no effect on QT and are not associated with sudden death.     

A review of atypical antipsychotic drugs versus conventional medication in schizophrenia

Atypical antipsychotics are replacing conventional antipsychotics for the treatment of schizophrenia. They are considered to be at least as effective as conventional agents, with most producing fewer extrapyramidal symptoms. This review presents the evidence from published meta-analyses and describes differences in clinical effectiveness and tolerability between conventional and atypical antipsychotic agents. In addition, it discusses some of the more significant adverse effects including tardive dyskinesia, weight gain, diabetes and sudden death. Results from meta-analyses are conflicting, with some finding no significant advantages on measures of efficacy or tolerability for atypical antipsychotics over moderate daily doses of conventional drugs. Other results have shown that some atypical drugs have at least minor efficacy advantages over conventional comparators. Atypical antipsychotics exhibit a much reduced risk for tardive dyskinesia compared with conventional drugs. However, weight gain is more common with some atypical drugs (especially clozapine and olanzapine). Both conventional and atypical antipsychotics have been associated with diabetes, with most reports implicating both clozapine and olanzapine. Finally, atypical antipsychotics (unlike conventional drugs) have little or no effect on QT and are not associated with sudden death.     

JL 13, an atypical antipsychotic: a preclinical review

The extensive pharmacological evaluation of JL 13 as an atypical antipsychotic drug has revealed a close similarity to clozapine, however with some major advantages. JL 13 was characterized as a weak D(2) antagonist, both in vitro and in vivo, with a strong affinity for the D(4) and the 5-HT(2A) receptors. It has no affinity for the 5-HT(2C) receptor. In vivo microdialysis experiments in rat showed that JL 13, like clozapine, preferentially increased extracellular dopamine concentrations in the prefrontal cortex compared to nucleus accumbens or striatum. Behavioral studies showed that JL 13, like clozapine, has the profile of an atypical antipsychotic. Thus, JL 13 did not antagonize apomorphine-induced stereotypy nor did it produce catalepsy, but it antagonized apomorphine-induced climbing in rodents. It was inactive against d-amphetamine-induced stereotypy but antagonized d-amphetamine-induced hyperactivity in the mouse. Likewise, in the paw test, it was more effective in prolonging hindlimb retraction time than prolonging forelimb retraction time. Like other antipsychotic drugs, JL 13 reversed the apomorphine- and amphetamine-induced disruption of prepulse inhibition. In a complex temporal regulation schedule in the dog, JL 13 showed a high resemblance with clozapine without inducing sialorrhea, palpebral ptosis or any significant motor side effects. In rats and squirrel monkeys JL 13 induced a high degree of generalization (70%) to clozapine. Regarding behavioral toxicology, JL 13 did not produce dystonia or Parkinsonian symptoms in haloperidol-sensitized monkeys. After acute administration, again like clozapine, JL 13 induced only a transient increase in circulating prolactin. Last but not the least, regarding a possible hematological toxicity, unlike clozapine, JL 13 did not present sensitivity to peroxidase-induced oxidation. Moreover, its electrooxidation potential was close to that of loxapine and far from that of clozapine. Taking all these preclinical data into account, it appears that JL 13 is a promising atypical antipsychotic drug.     

Mechanism of action of atypical antipsychotic drugs and the neurobiology of schizophrenia

Atypical antipsychotics have greatly enhanced the treatment of schizophrenia. The mechanisms underlying the effectiveness and adverse effects of these drugs are, to date, not sufficiently explained. This article summarises the hypothetical mechanisms of action of atypical antipsychotics with respect to the neurobiology of schizophrenia.When considering treatment models for schizophrenia, the role of dopamine receptor blockade and modulation remains dominant. The optimal occupancy of dopamine D(2) receptors seems to be crucial to balancing efficacy and adverse effects - transient D(2) receptor antagonism (such as that attained with, for example, quetiapine and clozapine) is sufficient to obtain an antipsychotic effect, while permanent D(2) receptor antagonism (as is caused by conventional antipsychotics) increases the risk of adverse effects such as extrapyramidal symptoms. Partial D(2) receptor agonism (induced by aripiprazole) offers the possibility of maintaining optimal blockade and function of D(2) receptors. Balancing presynaptic and postsynaptic D(2) receptor antagonism (e.g. induced by amisulpride) is another mechanism that can, through increased release of endogenous dopamine in the striatum, protect against excessive blockade of D(2) receptors.Serotonergic modulation is associated with a beneficial increase in striatal dopamine release. Effects on the negative and cognitive symptoms of schizophrenia relate to dopamine release in the prefrontal cortex; this can be modulated by combined D(2) and serotonin 5-HT(2A) receptor antagonism (e.g. by olanzapine and risperidone), partial D(2) receptor antagonism or the preferential blockade of inhibitory dopamine autoreceptors.In the context of the neurodevelopmental disconnection hypothesis of schizophrenia, atypical antipsychotics (in contrast to conventional antipsychotics) induce neuronal plasticity and synaptic remodelling, not only in the striatum but also in other brain areas such as the prefrontal cortex and hippocampus. This mechanism may normalise glutamatergic dysfunction and structural abnormalities and affect the core pathophysiological substrates for schizophrenia.     

Ziprasidone: a new atypical antipsychotic

This paper reviews the clinical pharmacology, efficacy and safety of the new atypical antipsychotic, ziprasidone. All published citations regarding ziprasidone were retrieved and reviewed using a MEDLINE search (completed for citations to early 2001). In addition, abstracts from recent scientific meetings presenting data not yet published were reviewed. Like other new antipsychotic medications, ziprasidone fits the profile of an atypical agent, exerting efficacy in positive and negative symptoms of psychosis, as well as affective symptoms, with a low risk of neurological and neuroendocrinological side effects. Unlike newer agents, it does not appear to be associated with weight gain in most patients.     

Ziprasidone: a new atypical antipsychotic

This paper reviews the clinical pharmacology, efficacy and safety of the new atypical antipsychotic, ziprasidone. All published citations regarding ziprasidone were retrieved and reviewed using a Medline^® search (completed for citations to early 2001). In addition, abstracts from recent scientific meetings presenting data not yet published were reviewed. Like other new antipsychotic medications, ziprasidone fits the profile of an atypical agent, exerting efficacy in positive and negative symptoms of psychosis, as well as affective symptoms, with a low risk of neurological and neuroendocrinological side effects. Unlike newer agents, it does not appear to be associated with weight gain in most patients.