Clozapine second-generation effects

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. 

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. 

A mutual increase in serum levels of both thioridazine and paroxetine is evident when these agents are combined. Paroxetine has also been shown to increase haloperidol and perphenazine serum levels, with associated extrapyramidal side-effects. The mechanism is presumably via inhibition of hepatic enzymes. With respect to the second-generation antipsychotic drugs (SCAs), paroxetine at a dose of 20 mg/daily produces a 3-9-fold elevation in plasma risperidone. If paroxetine is administered with clozapine, mean plasma concentrations of clozapine and norclozapine may increase significantly (by about 30%). 

---