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Up to 30% of patients with treatment-resistant schizophrenia treated with clozapine have residual
positive symptoms. Clozapine augmentation is a common approach, but the evidence supporting
this practice is limited.

According to the latest evidence, risperidone, lamotrigine, topiramate, or ECT are potential
augmenting options.

David N. Osser, MD

Associate Professor of Psychiatry

Harvard Medical School
Brockton Division of the VA Boston Healthcare System
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We are now at the tail end of the algorithm. What do you do if even clozapine has not produced a
satisfactory response? Node 4, clozapine augmentation.
Up to 30% of people with refractory schizophrenia treated with clozapine exhibit residual positive
symptoms. So what to do? Clozapine augmentation is a common approach. Unfortunately, positive
evidence supporting augmentation is very limited.

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Before considering clozapine augmentation, you should do a number of things. First, reevaluate your
diagnosis. Be sure you still think you have treatment-resistant schizophrenia. It’s possible that you
have a severe case of schizoaffective disorder or bipolar disorder with psychotic features. Potential
comorbid substance abuse could certainly be undermining all your meds from working and vigorous
attempts to treat that problem should occur. Medication adherence certainly could be getting in the
way of completing your adequate trials and determining if anything can really work for this patient.

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What augmentations do we have? Risperidone and lamotrigine are the best studied options. Each
has five placebo-controlled randomized trials. In the citations I offer you, those are both meta-
analyses of the five trials respectively of those two options. The result of those meta-analyses was
that neither had impressive efficacy. They were reasonably well tolerated, so not unreasonable to
try. At least some of the studies in each cluster of studies were positive. Others were negative. The
studies that had risperidone dose over 4 mg, it seemed to do better than the idea of low dose
risperidone. Just add a little bit of a strong D2 blocking antipsychotic to the clozapine. That did not
work. In fact, maybe the placebo was better. But full dose risperidone did seem to work at least in
one of the studies. So if you are going to risperidone, I would do that. Lamotrigine also had a mixed
bag in terms of the studies. There was one very positive study and the others were all unimpressive.
In fact, one of the literature reviewers said that the study that was positive was such an unbelievable
outlier that they felt it should be removed from the meta-analysis, in which case they concluded very
solidly that lamotrigine did nothing. But I would prefer to have some hope and believe that maybe
there’s something about the patients in that positive study that might apply to some of your
patients. So it’s one of the things that you could try.

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What else do we have beside those two best studied options? We have ECT. ECT added to ongoing
clozapine. We have one study where they had clozapine alone as a control and many case reports of
positive results with ECT and clozapine. Those are moderately impressive, except that there was a
study published where they did a sham-controlled trial of ECT in clozapine-treated patients. There
was another, one group where they did everything in a group of patients, putting them under
anesthesia, putting them to sleep, bringing them back to the recovery room, back to the ward. Just
no ECT. And in that study, the ECT had no efficacy. So that was a head scratcher. Anyway, ECT is on
our list of things you could consider as an augmentation with a 2017 hiccup as far as how
enthusiastic we can be about it.

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And a final option would be topiramate. There have been a number of meta-analyses because
there’s been a lot of interest in topiramate for weight loss in patients on clozapine and also on other
antipsychotics like olanzapine with weight gain where it has efficacy for weight loss. They also
measured psychopathology in a lot of these studies. When you meta-analyze those aspects of the
studies, there seemed to be some reduction in schizophrenia primary positive symptoms while they
were on topiramate. So I think that deserves inclusion among the augmentations that you could
consider for clozapine when the response is unsatisfactory.

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So in summary on clozapine augmentation, you can try it but the evidence is weak and the options
are risperidone, lamotrigine, topiramate or ECT.