The Corpus Callosum

It is refreshing to see something like this.  Both drugs are
available as generics, so the financial motivation for a study like
this is not great.  But the clinical benefit could e substantial,
albeit for a small subset of patients.

Clozapine is considered to be the most efficacious antipsychotic
medication, in that it is the drug to which the highest percentage of
persons with psychosis have a positive response.  It is, however,
considered a third-line drug.  The reason is that about 1% of
patients will develop severe granulocytopenia.  So, in general, a
patient will be tried on at least two different antipsychotic
medications before undergoing a trial of clozapine.  It generally
is used for treatment of schizophrenia, but may be used also for
bipolar disorder, or variants of those two conditions.

Even though clozapine is the most efficacious antipsychotic, many
patients are left with significant residual symptoms.  What then?

In such a situation, you can 1) do nothing, 2) increase the dose ,
3)decrease the dose, (including decrease to zero) 4) switch to a
different medication, or 5) add another medication.  Option #1 may
be feasible, but often is not a practical option.  Option #2 makes
sense, up to a point, but there there is a limit.  Once you reach
the limit, you have to chose one of the other options.  Option #3
rarely makes any sense, assuming that a proper titration schedule was
followed.  Option #4 may make sense, but remember, by the time a
patient is on clozapine, it is unlikely that a different antipsychotic
medication would be helpful.  So, usually Option #5 is the right

People have tried augmentation (adding a second medication to add to
the effect of the first) with a variety of substances.  Depakote
often is a good one.  The thing is, clozapine tends to carry with
it a heavy burden of adverse effects.  Depakote may add to that
burden.  Same with lithium.  Some will add a first- or
second-generation antipsychotic, but I’ve never been a fan of that
approach.  Occasionally, I’ve gotten lucky with oxcarbazepine or
an antidepressant.  Once, I got lucky with

Now, there is a meta-analysis that shows reasonably well-proven
efficacy of augmentation with lamotrigine.  This is attractive,
because most persons won’t get a big increase in the adverse effect

The meta-analysis was done by the Cochrane group.  There is an
open-access synopsis published in Current Psychiatry online.  (You
may have to register, which is free, and I think is open to anyone, but
I am not 100% sure of that.)

Clozapine is not enough: Augment with lamotrigine?

Current antipsychotics are reasonably effective in treating positive
symptoms, but they do less to improve the negative and cognitive
symptoms that contribute to patients’ long-term poor functional
capacity and quality of life. So what do psychiatrists do in clinical
practice to mitigate antipsychotics’ limitations? We augment.

Schizophrenia patients routinely are treated with polypharmacy–often
with antidepressants or anticonvulsants–in attempts to improve negative
symptoms, aggression, and impulsivity. Most adjuncts, however–including
divalproex, antidepressants, and lithium–have shown very small,
inconsistent, or no effects. The only agent with a recent meta-analysis
supporting its use as augmentation in treatment-resistant schizophrenia
is lamotrigine, an anticonvulsant approved for use in epilepsy…

The authors add a few points.  High doses may be required, greater
than 200mg.  This augmentation strategy may help with residual
negative symptoms, even if positive symptoms are adequately
controlled.  There was some evidence for improvement in cognitive
symptoms as well.

The article goes into some detail about a hypothesis regarding the
effects on glutamate transmission.  While interesting, it is not
yet established very well.

Probably, most general psychiatrists would have only a few patients for
whom this augmentation strategy might be appropriate.  Also, both
medications carry serious risks, so it is important that the
practitioner be well-versed in psychopharmacology prior to undertaking
this strategy.  Even so, it is a welcome development.


  1. #1 Will
    August 24, 2009

    “Some will add a first- or second-generation antipsychotic, but I’ve never been a fan of that approach.”

    Just curious what your arguments were against augmenting with 1st and 2nd gens? I work in a 212 bed psychiatric facility in Minneapolis. I know of plenty of residents who are on Clozaril paired with many 1st and/or 2nd gen antipsychotics. Granted, many of our residents are some of the most severe cases of Sz/Schizoaffective out there.

    On a related note, I would be interested in your thoughts on the CATIE study.

  2. #2 SHF M.D.
    August 25, 2009

    My son is prodromal schizophrenic or schizoaffective. I am an md (not psychiatrist) and have gotten lots of input about best approach and have done lots of research. My inclination at this point is to try clozaril now with hopes of avoiding full blown illness – I understand that there is no proof that this will happen – but if I wait for proof of anything it will be too late for him. My understanding is that although 1% on clozaril develop agranulocytosis, usually it will resolve if blood work is followed carefully and clozaril is stopped. Your thoughts on this would be appreciated – Thanks