Clozapine other atypicals

Impaired glucose tolerance/ Clozapine, other atypicals (MB increased basehne risk in... 

Whether the amelioration of negative symptoms results from an action in the cortex and, in particular, the prefrontal cortex requires further study. The fact that clozapine, the atypical drug that is currently most effective in this respect, has actions there which are not shown by other compounds is encouraging even though the precise mechanism by which it works remains to be elucidated. 

Table 11.4 shows that clozapine has approximately 10 times higher affinity for the D4 and 5-HT2A-receptors than the D2-receptor and shows a greater occupancy of the 5-HT2 than the D2-like receptors. The other atypical neuroleptic risperidone has a similar affinity for the two D2-like receptors but an affinity for the 5-HT2a-receptor that is just over 3 times lower than for the D2-receptor. Receptor occupancy in vivo shows a similar profile to clozapine. In contrast, haloperidol s affinity for the D4-receptor is just under 3 times lower and over 100 times lower for the 5-HT2a-receptor, with no binding to the latter in vivo. The fractional occupancy of striatal... 

The seeds of this transformation were sown some years ago. The first so-called atypical antipsychotic, clozapine (Clozaril), was devised in the 1960s. Clozapine was used widely in Europe until a series of deaths from a toxic hematological (blood) side effect called agranulocytosis occurred in the mid-1970s. Clozapine resurfaced in the 1980s and was approved for use (under strict guidelines) in the United States in 1990. Since that time, several other atypical antipsychotics have been approved, and others loom on the horizon. 

The success of clozapine makes it reasonable to try it or one of the other atypical antipsychotics. Althongh we know that the atypical agents are far less likely to cause TD, other than clozapine, we do not currently know enough about how well they treat preexisting TD. 

Clozapine is an atypical antipsychotic that is usually used in patients who are inadequately controlled with other antipsychotics. The reason is that clozapine is associated with a risk of potentially fatal agranulocytosis. As with other atypicals, side-effects of clozapine include occurrence of hyperglycaemia and diabetes. 

The first atypical antipsychotic is clozapine. Several other atypical antipsychotics have been developed since clozapine was introduced. The first was risperidone, followed by olanzapine, quetiapine, and ziprasidone. 

Clozapine was the first atypical antipsychotic released in the United States. However, clozapine is associated with the risk of leukopenia and, potentially, lethal agranulocytosis. Because of these concerns, hematological monitoring during clozapine pharmacotherapy is required (Alphs and Anand, 1999). Due to these hematological risks, clozapine is indicated only for patients with treatment-resistant schizophrenia. The other atypical antipsychotics, risperidone, olanzapine, quetiapine, and ziprasidone, that are marketed in the United States can be used as first-line treatments for adults with schizophrenia. 

Risperidone, a novel benzisoxazole derivative, is an atypical antipsychotic medication that combines dopamine D2 receptor antagonism with potent 5-HT2 receptor antagonism. Risperidone has a higher affinity for dopamine D2 receptors than does clozapine. Risperidone also antagonizes dopamine Dj and D4 receptors, aj- and a2-adrenergic receptors, and histamine Hj receptors. Although the optimal dose of risperidone in North American trials was 6 mg/day, subsequent clinical experience has indicated that most patients do well at lower doses of 3-6 mg/day, and elderly patients may require doses as low as 0.5 mg/day. Unlike other atypical antipsychotics. 

In spite of its limitations, clozapine brought renewed impetus in the quest for improved antipsychotic medications. For the first time, negative symptoms, so disabling to patients in the interpersonal, social, and occupational spheres, were seen as amenable to treatment. Other atypicals followed, all with important contributions to the treatment of positive, negative, and cognitive symptoms. These properties, as in the case of clozapine, are thought to result from a balanced effect on dopamine and serotonin receptors. These compounds also have a broader spectrum of action, leading to their proven use in the treatment of manic... 

Clozapine and olanzapine are the most likely of the atypical agents to cause anticholinergic (anti-muscarinic) effects. They are more likely than other atypicals to cause weight gain (glucose tolerance may be impaired and should be monitored in susceptible individuals) and are second only to quetiapine in their sedative effects. Sexual dysfunction and skin problems are rare with atypical antipsychotics. Risperidone and amisulpride are as likely as classical antipsychotics to raise prolactin concentrations and cause galactorrhoea. 

Since the release of clozapine, researchers have sought to develop an atypical antipsychotic without the side effects of clozapine (especially aplastic anemia). As of this writing, two other atypical agents have been released risperidone and olanzapine, and several others may soon be released, including sertindole and quetiapine. These agents vary somewhat in their pharmacological profile and, as a group, may... 

Other atypical antipsychotics commonly prescribed for treatment of autism include olanzapine, quetiapine, ziprasidone, and clozapine (Oswald and Sonenklar, 2007). Placebo-controlled trials of these agents in ASD populations have not been reported, with the exception of a small pilot study of olanzapine in which three of six children treated with olanzepine were rated as responders, compared to one of five in the placebo group (Hollander et al., 2006b). Open-label studies (reviewed by... 

Systematic reviews In a meta-analysis of randomized comparisons of clozapine with other atypical antipsychotic drugs, the... 

Systematic reviews Ziprasidone has been compared with other atypical antipsychotic drugs in a systematic review [151 ]. The rate of premature study discontinuation was very high (59% n=3361). Ziprasidone was less efficacious than amisulpride, olanzapine, and risperidone, but based on limited data there were no significant differences in tolerability between ziprasidone and amisulpride or clozapine. Ziprasidone produced less weight gain than olanzapine (median difference, -3.8 95% Cl = -4.7, -3.0 ... 

Asenjo Lobos C, Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Leucht S. Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2010 (11) CD006633. 

Reference has been made already to the shortcomings of the term neuroleptic . We now have a situation in which the drugs that are most useful in schizophrenia are regarded as atypical. While the term was introduced to cover those neuroleptics that do not cause EPSs, it has become synonymous with clozapine which has additional advantages over other neuroleptics (e.g. reduces negative symptoms, see text). Thus it is not always clear what is meant or covered by atypical. Hopefully this distinction between the neuroleptics will become unnecessary as better compounds are developed and the older ones become obsolete. 

Pharmacotherapy is the cornerstone of acute and maintenance treatment of bipolar disorder. Mood-stabilizing drugs are the usual first-choice treatments and include lithium, divalproex, carbamazepine, and lamotrigine. Atypical antipsychotics other than clozapine are also approved for treatment of acute mania. Lithium, lamotrigine, olanzapine, and aripiprazole are approved for maintenance therapy. Drugs used with less research support and without Food and Drug Administration (FDA) approval include topiramate and oxcarbazepine. Benzodiazepines are used adjunctively for mania. 

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