Antipsychotics atypical clozapine-like

A role for the 5-HT7 receptor in the regulation of circadian rhythms has been implicated. As discussed above, 5-HT has been known for some time to induce phase shifts in behavioral circadian rhythms and modulate neuronal activity in the suprachiasmatic nucleus, the likely site of the mammalian circadian clock. The pharmacological characteristics of the effect of 5-HT on circadian rhythms are consistent with 5-HT7 receptor. Moreover, mRNA for the 5-HT7 receptor is found in the suprachiasmatic nucleus. There is also increasing evidence that the 5-HT7 receptor may play a role in psychiatric disorders. The regional distribution of 5-HT7 receptors in brain includes limbic areas and cortex. Atypical antipsychotics, such as clozapine and risperidone, and some antidepressants display high affinity for this receptor. In the periphery, 5-HT7 receptors havebeenshown to mediate relaxation of vascular smooth muscle. 

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. 

Risperidone (Risperdal). Risperidone was the second atypical antipsychotic released in the United States. It is actually quite different from clozapine, and, in general, members of the class of atypical antipsychotics are often not all that similar among themselves. Risperidone blocks D2 receptors as do haloperidol and fluphenazine, but it probably blocks a lower percentage of D2 receptors, more like clozapine than haloperidol. In addition to blocking dopamine D2 receptors, risperidone also blocks serotonin type 2 receptors. 

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. 

Tardive dyskinesia refers to uncontrollable facial movements. It is more likely to occur in the elderly. Tardive dyskinesia is commonly associated with the use of antipsychotic drugs, such as haloperidol. The atypical antipsychotics, such as clozapine, olanzapine, risperidone and quetiapine are less likely to cause tardive dyskinesia. 

The conventional antipsychotics have little effect on the negative psychotic symptoms such as autism, stupor and emotional withdrawal. The so-called atypical antipsychotics, or second-generation antipsychotics, like the heterocyclic compound risperidone, the benzamide sulpiride and several diben-zepines of which clozapine is the best known, have a broader spectrum which means that they also have an effect on the negative psychotic symptoms. Most share a common attribute of working on serotonin receptors as well as dopamine receptors. They have a low risk of extrapyramidal side effects. 

In the late 1980s, clozapine a chlorpromazine like compound with a multiplicity of effects was rediscovered and termed an atypical neuroleptic. It appears to be the only genuinely atypical agent - that is an agent with significant beneficial treatment effects in the absence of EPS (see Wahlbeck et ah, 1999). A second generation of antipsychotics have succeeded clozapine been marketed as being atypical. 

Atypical antipsychotics cause fewer EPS than do conventional antipsychotics. Clozapine and quetiapine are the least likely to cause EPS and are therefore recommended for treatment of psychosis in patients with Parkinson s disease. With the notable exception of risperidone, atypical antipsychotics cause substantially less hyperprolactinemia than do conventional antipsychotics. Weight gain is a side effect of all atypical antipsychotics except ziprasidone and aripiprazole. Concerns about cardiac conduction delay with ziprasidone therapy exist and warrant consideration in patients who have... 

The effectiveness of the second generation antipsychotics (now called atypicals, because they have weak D2 blocking properties) show that this concept is not valid. Drugs like clozapine do not cause the Parkinsonian side effects even though they are very successful in terminating psychosis. 

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. 

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