Olanzapine and quetiapine

Risperidone was launched in China in 1997. Following that, other atypical medication including olanzapine and quetiapine were introduced in the market in 1999 and 2000, respectively. These were followed by the development of generic arip-iprazole and ziprasadone in 2005 and 2006, respectively. Brand-name aripiprazole and ziprasadone will also be launched in 2007 in China. 

An, B. F., Zhang, M. L. Qi, S. G. (2006). Comparative study between the effect of olanzapine and quetiapine in first-episode schizophrenia. Chinese Journal of Clinical Psychiatry, 16(2), 84-5. 

In the Expert Consensus survey, the respondents endorsed risperidone, olanzapine, and quetiapine, in that order, followed by high-potency traditional antipsychotics, for managing self-injury. A placebo-controlled study comparing risperidone with a classical antipsychotic, such as haloperidol, could provide valuable data for this field. 

D2 receptor, albeit with different specificity. Older examples of dopamine antagonists are chlorpromazine, haloperidol and many derivatives of these prototype compounds. Newer antipsychotic drugs such as risperidone, olanzapine and quetiapine have retained this mechanism of action, although no longer exclusively. 

Reported least in clinical trials with olanzapine and quetiapine... 

Antipsychotic drugs are also indicated for schizoaffective disorders, which share characteristics of both schizophrenia and affective disorders. No fundamental difference between these two diagnoses has been reliably demonstrated. They are part of a continuum with bipolar psychotic disorder. The psychotic aspects of the illness require treatment with antipsychotic drugs, which may be used with other drugs such as antidepressants, lithium, or valproic acid. The manic phase in bipolar affective disorder often requires treatment with antipsychotic agents, although lithium or valproic acid supplemented with high-potency benzodiazepines (eg, lorazepam or clonazepam) may suffice in milder cases. Recent controlled trials support the efficacy of monotherapy with atypical antipsychotics in the acute phase (up to 4 weeks) of mania, and olanzapine and quetiapine has been approved for this indication. 

FIGURE 11—36. Structural formulas for clozapine and four other antipsychotics, namely, olanzapine, quetiapine, loxapine, and zotepine. Interestingly, all five of these are also SDAs, but not all of them appear to be atypical antipsychotics (e.g., loxapine is conventional, and zotepine is still being characterized). Abo, clinical properties and pharmacological characteristics vary considerably among those that are clearly atypical (i.e., clozapine, olanzapine, and quetiapine). 

The atypical antipsychotics are still relatively new, particularly some members. Information about new drugs is first available from clinical trials and then modified by observations from clinical practice, and the atypical antipsychotics are no exception to this pattern. Some findings from clinical practice have already confirmed those from clinical trials for the three marketed atypical antipsychotics (i.e., risperidone, olanzapine, and quetiapine) and are generally applicable to choosing an atypical antipsychotic for patients with a wide variety of psychotic disorders, although least is known about ziprasidone, the newest member of this group. 

The new atypical antipsychotics including risperidone, olanzapine and quetiapine act by ... 

The atypical antipsychotics are divided into two major pharamacological groups, namely the multiple receptor antagonists, such as clozapine, olanzapine and quetiapine, and the more selective 5-HT2/D2 antagonists as exemplified by risperidone, sertindole, ziprasidone and zotepine. The benzamide antipsychotic amisulpride is the most selective antagonist for the D2/D3 receptors which presumably gives it the mesocortical selectivity of action with a minimal effect on the dopamine receptors in the basal ganglia. 

Recreational drug users note the same effects. Several comment on similarities between olanzapine and quetiapine and the benzodiazepine drugs, such as diazepam (Valium), because of the intense sedation. However none report the euphoria that characterises benzodiazepine effects. One correspondent reported protracted insomnia after stopping olanzapine, comparing it to benzodiazepine withdrawal (Sixseal.com 2007). 

Because of the apparent structural similarities of these clozapine-analogues, the question arises of how different are these compounds in their receptorial, pharmacological, and clinical actions Some of the major features of the clozapine analogues, olanzapine and quetiapine, are compared with clozapine in the following section. 

Atypical antipsychotics including clozapine, olanzapine, and quetiapine (as well as those which do not belong to this chemical class, e.g., risperidone, ziprasidone, sertindole, etc.) show affinities to various degrees to an array of receptors in the... 

Tab 13.2 Rank order of in-vitro affinity of dozapine, olanzapine and quetiapine to various receptors. 

Tab 13.4 Comparison of ED50 (mg kg-1, s.c.) values for clozapine, olanzapine and quetiapine from one laboratory.3 ... 

The availability of a great number of data obtained with different radioligands, membrane preparations, different tissue sources and differences in the assay conditions makes the comparison of receptor profile of clozapine, olanzapine and quetiapine (as well as other antipsychotics) extremely difficult This issue has become even more complicated since the availability of recombinant receptors from various species expressed in various expression systems that resulted in a continuously growing number of K, data and further additions to the receptor profile. (For example, in May 2005, when the latest search in the database http // kidb.cwru.edu/pdsp.php was made, 464, 272, and 156 K, values for various receptors and transporters were recorded for clozapine, olanzapine, and quetiapine, respectively, representing an average K, growth rate of 11 to 16 per month over the past five months.) Different data from the same authors obtained at different times further complicate the comparisons. The receptor K, data in Tab. 13.1 illustrate the situation to some extent. 

In the in-vitro kinetic experiments, the rates of association (Kon) and dissociation (Kan) of various (labeled) antipsychotic compounds to dopamine D2 receptors were determined. Kapur and Seeman found that antipsychotics substantially differ (almost 1000-fold) in their Koff rate (whereas only 10-fold differences were found in the Kon rate), and that this value is highly correlated with their affinity to D2 receptors. These authors also demonstrated that Koff for clozapine, olanzapine and quetiapine was 1.386 min"1, 0.039 min"1, and 3.013 min"1, respectively, and assumed that the rate of how rapidly they left the receptor was an important mechanism in their atypical antipsychotic action. Indeed, this fully explained the lack of extrapyramidal symptoms (EPS) and hyperprolactinemia and the low risk for tardive dyskinesia [34—36]. In this regard, quetiapine (which has the lowest affinity to D2 receptors) seems to be the most atypical among all tested antipsychotics, followed by clozapine and olanzapine (nevertheless, olanzapine s Koff value is close to those of raclopride and chlorpromazine). 

Clozapine, olanzapine, and quetiapine display significant affinity to histamine Hj receptors, and it is widely accepted that some side effects of these agents (e.g., weight gain liability, sedation) are attributed to their histamine antagonism... 

Clozapine has been found effective in patients who did not improve during treatment with first-generation antipsychotics, and since the hematological side effects permit only its restricted use, this dmg has a unique indication for treatment- resistanf schizophrenia. Another unique indication for clozapine is the reduction in the risk of recurrent suicidal behavior in schizophrenia or schizoaffective disorders. The indications of clozapine and its two analogues, olanzapine and quetiapine, are summarized in Tab. 13.5. The US labels of these drugs served as the data source [62-64]. Clozapine and olanzapine, but not quetiapine, are available in intramuscular form, which is helpful in the treatment of acutely agitated patients with diagnoses as defined in Tab. 13.5. 

Clozapine has well-documented efficacy in the treatment of mania, including treatment-resistant mania [74], although it has not been approved for this indication. Olanzapine and quetiapine both have been approved for the treatment of mania, though not for the treatment of bipolar depression. Olanzapine also has approval for maintenance treatment of bipolar disorder. 

The discovery of the atypical antipsychotic clozapine opened a new era and set new standards in the drug treatment of schizophrenia. Modifications of the diben-zoazepine structure in clozapine resulted in olanzapine and quetiapine, which are among the most frequently used antipsychotic drugs. From a chemical viewpoint, clozapine, olanzapine and quetiapine can be considered as structural analogues. Although they share some common features in their molecular mechanism of action, the three compounds show significant differences in their clinical efficacy and adverse event profile. 

Clozaril causes potentially fatal agranulocytosis of white blood cells due to bone marrow suppression. The mechanism is probably a direct toxic effect on bone marrow cells. When tested, the neuroleptics chlor-promazine, olanzapine, and quetiapine were also toxic to bone marrow cells (Pereira et al., 2006). 

Boot E, de Haan L. Massive increase in serum creatine kinase during olanzapine and quetiapine treatment, not during treatment with clozapine. Psychopharmacology (Berl) 2000 150(3) 347-8. 

No recognised classification system exists for atypical antipsychotics.Tentative terms based on receptor binding profiles have been applied to certain drug groupings.for example broad spectrum atypicals for clozapine, olanzapine and quetiapine. whilst risperidone and ziprasidone have been described as high affinity serotonin-dopamine antagonists . 

The newer atypical psychotropics vary widely in their receptor binding profiles. Olanzapine and quetiapine bear resemblance to the profile of clozapine in that their therapeutic effects appear to derive from action on different receptors and transmitter systems. All atypicals (except amisulpride) exhibit greater antagonism of SHT -receptors than Baroceptors compared with the classical agents. Atypical drugs that do antagonise dopamine D -receptors appear to have affinity for those in the... 

Olanzapine and Quetiapine. Olanzapine (Zyprexai and quetiapine (Seroquel) po.s.sess tricyclic systems uiih greater electron density than chlorpromazinc. They thus re-semhie clozapine. The drugs are atypical antipsychotics. 

Rats reared in isolation after weaning also experience deficits in PPI (159) and decreased social interaction. This effect has been attributed to enhanced dopaminergic activity (160). Isolation rearing deficits are maximal at puberty (161,162) and thus parallel the ontog-eny of schizophrenia in humans. The disruption of PPI in young rats reared in isolation is reversed by a broad spectrum of antipsychotic drugs including haloperidol, risperidone, clozapine, olanzapine, and quetiapine (153,163). 

Drug discrimination has also been used to compare antipsychotic drugs that act through different receptor mechanisms. The close structural analogs olanzapine and quetiapine... 

I Sedation and Cognition. Sedation must be recognized as an antipsychotic side effect and not as an indication of therapeutic effect. It occurs more frequently with antipsychotics with antihistaminic properties. Chlorpromazine, thioridazine, mesoridazine, clozapine, olanzapine, and quetiapine are most frequently implicated. Administration of most or all of the daily dosage at bedtime (depending on the drug half-life) can decrease daytime sedation and in some patients eliminate the need for hypnotic agents. Sedation occurs early in treatment... 

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