Your patient is on clozapine, our most powerful pharmacotherapy for schizophrenia, and the level of recovery is still unsatisfactory. We will offer a series of steps to optimize the results with clozapine. We are assuming that the patient is appropriately on clozapine. That is, the patient has had at least two adequate trials of other antipsychotics with unsatisfactory results, as is required in the package insert. However, it is possible that some patients may have been started on clozapine without having met these requirements. For these patients, the physician could still proceed to try these clozapine optimization steps. But, the alternative of completing two adequate trials of other antipsychotics first, should be considered. This might be effective, and pose less risk to the patient. If you want to pursue this option, click here.
Here is our sequential strategy for trying to address resistance to clozapine. For a full review of the evidence behind the various options, consult the review by Buckley et al,¹ though these authors do not propose a sequence of steps to follow.
1. Adjust clozapine plasma level (NOT clozapine plus norclozapine) to above 350 ng/ml if side effects allow, going up to the Package Insert maximum dose of 900 mg per day if necessary.² [Note that the studies establishing this plasma level measured the parent compound (clozapine) only, and did not obtain metabolite (norclozapine) levels. Some labs give you both levels and suggest they should be added to determine therapeutic level, but this will not give you information to enable you to compare your patient's levels with the levels found in the best studies. Studies in the early 90s, cited in the papers in reference (2) established that there is no difference in the predictability of response with parent compound versus combined levels]
If you need to go over 600 mg per day the manufacturer currently recommends obtaining an EEG and if abnormal, using an anticonvulsant such as valproate for prophylaxis of seizures. Clozapine levels over 350 ng/ml are associated with an increased risk of seizures, drowsiness, and slowing on the EEG.³ About 6% of patients in one study (ref 3) did not achieve clozapine levels over 350 despite 900 mg of clozapine. Smoking may be a factor in this, due to nicotine's stimulation of cytochrome P450 1A2 metabolism of clozapine.
Some studies have indicated that certain SSRIs, especially fluvoxamine because of it's P450 1A2 inhibitory activity, can be added to clozapine to boost the blood level and reduce the dose of clozapine needed to produce levels over 350 ng/ml.(4) For example, a dose of 100 mg of clozapine plus 50 mg of fluvoxamine puts 2/3 of patients above 350 ng/ml. Heavy smokers were again found in the group that did not achieve therapeutic levels on this combination.(4) The impact of this combination on therapeutic outcome is not clear. Some studies showed improved efficacy and some showed apparently reduced effect of the clozapine.(4) Two patients were reported to develop extrapyramidal symptoms on the combination. Medication costs were reduced by using the combination, however.(4) With close monitoring of benefits and side effects, this approach seems worth further assessment.
2. Obsessive-compulsive symptoms may be induced or exacerbated during clozapine treatment and contribute to the unsatisfactory response. If an SSRI is used for treatment of this, or other anxiety or depressive symptoms, take into account that the clozapine blood level may be raised by 1,000% or more, depending on the SSRI used. (See Centorrino F et al. Am J Psychiatry 1996;153:820-822) Fluvoxamine causes the greatest increases as noted above. Clomipramine has also been reported to be useful for obsessive-compulsive symptoms but watch for synergism of side effects e.g. those related to alpha blockade, anticholinergic effects, cardiac toxicity, and weight gain.
3. There have been some encouraging reports that risperidone may be added to clozapine to provide enhanced efficacy with reasonable safety.(5) (Cost, of course, will be very high!) In theory, it seems like a good idea because risperidone will add the one important receptor activity that seems weak with clozapine (D2 blockade) without altering the apparently desirable high 5HT2/D2 ratio that is present with clozapine. Unfortunately, risperidone had very little effect in a recent report in which the patients were first optimized to a blood level of 350 ng/ml before adding risperidone.(6) It may be useful to add risperidone when patients are intolerant of having their clozapine dose raised to 350 ng/ml. Note a case report of cardiac palpitationson this combination which turned out to be atrial ectopic beats.(7) Reports of use of other atypical antipsychotics to augment clozapine are appearing, including a case series of 11 patients involving ziprasidone. (7a) However these patients started with an average dose of 855 mg of clozapine, and it was tapered to 459 mg during the trials. There was improvement (quantity unspecified) in negative and cognitive symptoms but there could be a number of explanations.
4. Occasionally it seems helpful to have patients on clozapine plus a low dose of a typical neuroleptic. Many clinicians have found that, when switching patients from a typical neuroleptic to clozapine, it proved difficult (in a minority of patients) to remove the typical without losing some of the apparent benefits from starting the clozapine. This suggests that adding back a neuroleptic may be helpful. Loxitane was one neuroleptic reported to be helpful in this circumstance. (8)
5. Augmentation with lamotrigine was recently reported in 6 patients, and the results were very impressive at doses from 125 mg to 250 mg per day. The mechanism is proposed to be inhibition of release of glutamate.(9) However, there has been no replication of these impressive findings. It may also seem plausible to try topiramate as an augmentation for residual positive symptoms, given this lamotrigine report and because of the possible advantages to reduce weight gain. However, a case series of 5 patients (4 on clozapine) demonstrated significant deterioration of PANSS positive and negative symptom scores.(10) This suggests caution when considering this adjunctive treatment, and raises doubts about the lamotrigine.
6. Be careful when changing people from clozapine to other treatments: rebound, rapid-onset psychosis, that is sometimes even more refractory to treatment than the previous period of psychosis, is a risk.(11) This might be a "supersensitivity" psychosis that could be managed by adding an anticonvulsant like valproate or clonazepam as we have advocated elsewhere for supersensitivity phenomena from standard antipsychotics.(12)
7. ECT is a consideration for antipsychotic-refractory patients. ECT experts used to stress that it deserved more consideration than it was usually accorded, particularly for first-break and other young patients with excitement, catatonia, prominent positive symptoms, and schizoaffective disorder.(13) The new generation of antipsychotics seems to have produced a reduction of interest in ECT. However, there are 20 cases published where ECT was combined with clozapine with fairly reasonable safety and effectiveness.(14) Some patients did develop spontaneous seizures, tachycardia, and elevated blood pressure. Maintenance ECT in schizophrenia has been described as well tolerated and successful in a published case series of 9 patients as recently as 1995.(15)
Recommendation #101
