Question. I am a pharmacist who practices in a mental health hospital. We are seeing some levels of both clozapine and norclozapine that are beyond the generally accepted blood levels. My own research on the subject has indicated that 1) Clozaril level is generally equated with efficacy, norclozaril level with adverse effects, 2) the optimal ratio of Clozaril to norclozaril is 2:1, 3) if the levels are high, but the patient is doing well and is suffering from no adverse effects, then leave the dose alone, and 4) some SSRI’s and Tagamet can be used in rapid cyclers to even out the Clozaril/norclozaril ratios. What is your opinion on correct Clozaril levels?
Answer.Understanding the relationship of clozapine levels to clinical response is very much a work in progress. I will tell you my general sense of where things are, then try to answer some of the specific questions you raise.
First, I think there is fairly good evidence linking clozapine (Clozaril) blood levels to therapeutic response, and to some extent to side effects. Second, there seems to be much less conclusive data on the ratios you mention, though there are some data implicating norclozapine with hematologic problems. An excellent study on clozapine blood levels and therapeutic response by VanderZwaag et al appeared in the December 1996 American Journal of Psychiatry. That group found that clozapine levels above 200 ng/ml led to better outcome than levels in the 50-150 ng/ml range; and that there was no real advantage for levels in the 350-450 ng/ml range over the 200-300 ng/ml range. Indeed, at week 6, sleepiness was correlated with increasing serum level and was most frequent in the group with clozapine (Clozaril) blood levels in the 350-450 ng/ml range. (Tachycardia and orthostasis, however, were not correlated with blood levels.) This study did not look at norclozapine levels.
An earlier study by Perry et al in the February 1991 American Journal of Psychiatry also found a correlation between total clozapine (Clozaril) plus norclozapine plasma levels and clinical response, but did not analyze the clozapine:norclozapine ratios. I did not find any studies showing the optimal ratio of clozapine (Clozaril) to norclozapine to be 2:1, but did find one study showing that norclozapine levels tend to be higher in adolescents (Piscitelli et al, Journal of Clinical Psychiatry, Sept. 1994:55, supplement B 94-7). I also found a study linking norclozapine/clozapine ratio to reduced neutrophil count (Mauri et al, Psychopharmacology [Berlin] June 1998; 137(4):341-4). By the way, in Parkinson’s disease patients with L-dopa induced psychosis, the plasma levels of clozapine (Clozaril) and norclozapine needed for therapeutic response may be much lower than in schizophrenic patients (clozapine between 4.5 and 16 ng/ml, norclozapine between 2.6 and 6 ng/ml), according to Meltzer et al in Neuropsychopharmacology, Feb. 1995, 12(1):39-45.
I generally agree that doses should be left alone if the patient is doing well, even if the clozapine (Clozaril) level is high – we are treating people, not laboratory values. However, since there is a correlation between clozapine (Clozaril) dose and seizure risk, and between dose and plasma levels, I might try to see if the patient could do as well on somewhat lower clozapine (Clozaril) doses/levels. For example, I might try a very gradual reduction in clozapine (Clozaril) dose over many months, measuring levels and clinical response as I reduced the dose. If the patient showed any signs of relapse, I would re-start the previous dose. (Some patients may require adjunctive valproate to “cover” break-through seizures.)
I’ve seen no studies on the use of SSRIs or Tagamet (cimetidine) for purposes of “evening out” the clozapine (Clozaril) to norclozapine ratio, but would have very serious reservations about using any antidepressant in a rapid cycler, with or without clozapine, since antidepressants often worsen the cycling rate. Until I see some controlled studies, I am not yet prepared to consider the clozapine/norclozapine ratio as a critical factor in response.