At this point, you could have a patient who has met the minimal Package Insert (FDA-Approved) criteria to be considered for clozapine: "...failure to respond adequately to [at least two] appropriate courses of standard antipsychotic drugs, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects [such as akathisia]...". Note that these criteria were developed before the availability of the newer generation of (what may now be considered) standard antipsychotics.
You could also have arrived here with a patient who is well-established as treatment resistant, having failed (or not tolerated) a trial of clozapine in the past. The patient is not on clozapine now, and you are exploring what other options might be reasonable to consider.
The next question will pose 5 options. One of those is clozapine, which is probably inappropriate if your patient is in the second category, unless a reconsideration is possible because not all parameters that could have led to a successful outcome with clozapine have been tried. The Help section will define those parameters. The other 4 options could be reasonable for many patients at this point in the algorithm, although the option of using two (non-clozapine) atypical antipsychotics at once is perhaps the least evidence-based and certainly the most expensive pathway.
One set of options is trying the rest of the non-clozapine atypical antipsychotics one-by-one. Significant evidence has been presented that these medications are somewhat superior to many of the older generation of "neuroleptic" antipsychotics, in the effect on positive symptoms and, even more, on negative symptoms. (1-4) And, clinical experience suggests that failure to respond to one, or intolerance of one, does not necessarily predict failure on the others. In some populations, good studies have even found one to be superior to another. (5) However, these findings do not enable a priori prediction of who will respond best to one versus another. Side effect differences are more likely to influence the selection preferences.
We usually recommend trying at least two of the new generation antipsychotics, plus a trial of one from the standard, typical neuroleptic group, before turning to clozapine. Some prominent clinicians have even advocated that there is no longer a role for the older neuroleptics, other than in acutely agitated, uncooperative patients who require parenteral treatment. However, we have observed patients who, after initial treatment with adequate trials of new generation antipsychotics and failure to respond to those antipsychotics, have responded robustly to a typical neuroleptic.
Also, one may consider trying at least one or two adjunctive medication trials (added-on to the antipsychotic). The choices depend on the particulars of the clinical presentation of the patient in question: e.g. - are there concomitant mood, obsessive-compulsive, impulsive, epileptic, organic, or other problems?
Most evidence and opinion still consider clozapine to be the most powerful antipsychotic available. (6)
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