Clozapine Augmentation for Treatment-Resistant Schizophrenia: What Does the Evidence Say?

David N. Osser, MD

Associate Professor of Psychiatry
Harvard Medical School
Brockton Division of the VA Boston Healthcare System

Last updated: June 15, 2018

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.

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.


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.


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.


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.


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.


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



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  8. Melzer-Ribeiro, Debora Luciana, et al. “Efficacy of electroconvulsive therapy augmentation for partial response to clozapine: a pilot randomized ECT–sham controlled trial.” Archives of Clinical Psychiatry (São Paulo) 44.2 (2017): 45-50.
  9. Hahn, Margaret K., et al. Topiramate in schizophrenia: a review of effects on psychopathology and metabolic parameters. Clinical schizophrenia & related psychoses 6.4 (2013): 186-196.

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