Clozapine atypical antipsychotic medications

Tuunainen A, Wahlbeck A, Gilbody SM. Newer atypical antipsychotic medication versus clozapine for schizophrenia. Cochrane Database of Systematic Reviews 2000. Issue 2. 

Thunainen A, Wahlbeck K, and Gilbody S. Newer atypical antipsychotic medication in comparison to clozapine A systematic review of randomized trials. Schizophr Res 2002 56 1-10. 

Eigure 41.1 shows a decision tree for treatment with antipsychotics in EOS. Treatment is usually initiated with an atypical antipsychotic medication. Depending on the individual reaction (efficacy and side effects), the current medication can be switched or maintained. Only after two different compounds are not effective or not tolerated should treatment with clozapine be initiated. 

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. 

Other, chemically distinct dopamine blockers were then developed, such as thiothixene, haloperidol, loxapine, molindone, and pimozide. All of these antipsychotics are potent dopamine blockers and collectively were called neuroleptics because they inadvertently cause certain neurological side effects (discussed below). More recently, atypical antipsychotic medications have been developed (clozapine and risperidone), which are effective antipsychotics yet are weak dopamine blockers and cause minimal neurological side effects. This group is discussed separately below. 

At present there are several medications that have been approved that involve the neurochemical serotonin. The first two medications are clozapine and risperidone and the two newer medications are Seroquel and Zyprexa. To date, these medications have been termed the atypical antipsychotic medications, because they are effective in reducing symptoms of schizophrenia and are less likely to cause extrapyramidal side effects than the other antipsychotic medications (Karper Krystal, 1996). 

Although we include clozapine as a newer atypical antipsychotic medication, it does have a long history and in some texts may be listed as a traditional antipsychotic. Known by the brand name Clozaril, clozapine was originally synthesized in 1957 and in 1960 was one of the first antipsychotics released on the European market (Hippius, 1989). It was believed to be more successful than the typical antipsychotics because it did not seem to have the same negative side-effect profiles. Years later, eight documented cases of death were attributed to infections secondary to clozapine-induced agranulocytosis, and the product was withdrawn from unrestricted use (Davis Casper, 1977). Based on later studies that supported the success of clozapine with strict monitoring for treatment-resistant schizophrenia, the FDA approved it in 1990 (Barnes McEv-edy, 1996). 

Nevertheless, some atypical antipsychotic drugs, such as clozapine and olanzapine, have been linked to substantial weight gain, hyperlipidemia and type II diabetes, a new range of medically serious side-effects. 

Quetiapine (Seroquel). Another atypical antipsychotic, quetiapine has also been approved by the FDA for the treatment of acute mania. It is usually administered twice daily at doses of 150-750mg/day. Like its counterparts, quetiapine is a well-tolerated medication. Its common side effects are drowsiness, dizziness, and headache. It causes less weight gain than olanzapine or clozapine but more than ziprasidone or aripiprazole. Quetiapine also does not cause agranulocytosis nor does it increase the risk of seizures. It can occasionally cause mild changes in liver function tests, but these usually return to normal even if the patient continues taking quetiapine. 

Loxapine (Loxitane). Loxapine is a medium potency antipsychotic, and it has several interesting features. First, it is chemically very similar to clozapine, the first of the atypical antipsychotics. In the test tube, loxapine actually behaves more like an atypical antipsychotic (more on that later), but when patients are treated with it, loxapine acts more like a traditional typical antipsychotic. A second point of interest is that loxapine is actually the major active metabolite of the antidepressant amoxa-pine (Ascendin). As a result, one can use a single medication (amoxapine) to treat both depression and psychosis. In practice, however, the use of what is essentially a fixed dose combination medication should be avoided. Using amoxapine does not allow separate adjustment of the antipsychotic and antidepressant, and most importantly, amoxapine is the only antidepressant associated with the risk of TD. 

Therefore, we believe that this alone is not a sufficient definition for atypicality. We prefer to define atypical antipsychotics as those that are less prone to causing EPS because they work differently than the typical antipsychotics. This, of course, raises the question of just how these medications work. Using clozapine as the starting point to answer this question has proved difficult. Why The problem is that clozapine interacts with so many different types of nerve cell receptors that it becomes hard to tell which of these actions makes the difference. 

A host of medications have been nsed to treat TD including medications that block norepinephrine activity (clonidine and propranolol), dopamine-activating medications (bromocriptine), benzodiazepines, acetylcholine-activating medications, calcium channel blockers, and monoamine oxidase inhibitors. In addition, vitamin E supplementation and atypical antipsychotics including clozapine have been used to treat TD. 

Antipsychotic medications (atypical [eg, olanzapine, clozapine]) Isoniazid... 

In the Expert Consensus survey (Rush and Frances, 2000) the expert clinicians rated newer atypical antipsychotics highest for treatment of schizophrenic patients who are compliant with medication. Risperidone was rated highest of the atypicals, followed by olanzapine. In the case of patients with numerous failed trials with other antipsychotics, the experts voted for clozapine. For patients noncompliant with oral medication, respondents endorsed long-acting depot antipsychotics. Once again, these were impressions based on personal clinical experiences rather than hard empirical data. 

The choice of antipsychotic medication is often determined, in large part, by anticipated side effects. In most circumstances, atypical antipsychotics (except for clozapine) are best tolerated and are preferred as first-line agents. Clozapine is generally reserved for patients with refractory iUness because of the risk of agranulocytosis. 

Several newer antipsychotic medications have been developed that seem different or atypical, compared with their predecessors. These agents include clozapine (Clozaril), risperidone (Risperdal), and several others listed in Tables 8-1 and 8-2. Although there is some debate about what exactly defines these drugs as atypical, the most distinguishing feature is that they have a much better side-effect profile, including a decreased risk of producing extrapyramidal (motor) side effects.17,45,57... 

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