This lecture will focus on the clinical use of clozapine.
It remains underutilized because of realistic concerns
about its side effects, because of the extra time it takes to
initiate and manage a patient on clozapine, but also
because some clinicians lack experience with it: this
lecture will be particularly supportive to them. First, there
will be a review of appropriate evidence-based indications
for clozapine, and an examination of the place of
clozapine in the sequence of trials recommended in
different psychopharmacology algorithms for
schizophrenia that have been developed. All algorithms
suggest use of clozapine after unsatisfactory response to
two or at the most three adequate monotherapy trials of
antipsychotic drugs. Before clozapine, patients should
have the opportunity to try one or more of the possibly
more effective antipsychotics: olanzapine, risperidone,
and first-generation neuroleptics such as perphenazine.
Olanzapine is not first line due to its metabolic toxicity.
Clozapine can be particularly effective for people with
suicidal behavior (treatment-resistance not required in this
case), assaultive behavior, substance abuse, polydipsia/
hyponatremia, and nonadherence histories.
The pre-treatment workup will be presented followed
by a discussion of issues in the informed consent process
for clozapine with both competent and incompetent
patients. Getting consent to clozapine is facilitated by
having the ability to present an appropriately positive and
convincing description of the potential benefits of this
medication and its ability to improve quality of life.
Next, dosing strategies will be reviewed for different
age groups, including the role of plasma levels; optimal
results occur at levels over 350-450 ng/ml of the parent
compound. Contingencies such as dose interruptions and
drug interactions will be discussed. For example, heavy
cigarette smokers can have very low clozapine levels, and
patients on fluvoxamine will get extremely high levels if
the dose is not lowered.
Side effects will then be discussed. Neutropenia is
sometimes benign (as in the cases of benign ethnic
neutropenia and morning pseudoneutropenia) and might
not require discontinuation of clozapine and may be
managed successfully. Agranulocytosis must not be
rechallenged, however, and treatment with granulocyte
colony stimulating factor may be necessary. Seizures are a
common problem but usually do not require stopping
clozapine. Valproate is perhaps the best anticonvulsant to
employ. Myocarditis and cardiomyopathy are lifethreatening
complications that need to be detected early: be
suspicious if the patient develops tachycardia accompanied
by fever, fatigue, dyspnea, chest pain, and flu-like
symptoms. Weight gain, metabolic syndrome, and insulin
resistance are well-known problems that often pose
difficulties. A few medication treatments for this have had
modest success (metformin, topiramate) but proper
nutrition and exercise are the mainstays which patients may
be more willing to pursue when they improve clinically.
Constipation is a major side effect in up to 15% of patients,
can be life-threatening, but often can be avoided with a high
fiber diet, adequate hydration, exercise, and stool softeners.
Other clozapine side effects are relatively minor but can be
very annoying for patients and become a threat to their
compliance: sedation (caffeine may help), hypersalivation (many possible remedies, few proven), tachycardia (betablocker
may be necessary), hypotension/dizziness
(hydration, support-hose), and obsessive-compulsive
symptoms (sertraline may be the preferred medication
treatment) are in this category. Rebound psychosis after
abrupt discontinuation of clozapine can be severe but it
may help to use an anticholinergic to minimize cholinergic
hypersensitivity associated with clozapine withdrawal.