Best Management of Antipsychotics in Epilepsy: Affected by Government Shutdown?

It’s uncommon to get a question from a neurologist about which antipsychotics lower the seizure threshold the least in patients with seizure disorders. In fact, I usually have to run a PubMed literature search. But I got this initial message from PubMed that I’m sure others have noticed:

“PubMed is open, however it is being maintained with minimal staffing due to the lapse in government funding. Information will be updated to the extent possible, and the agency will attempt to respond to urgent operational inquiries. For updates regarding government operating status see”

More specifics on how the government shutdown affects us can be found at Government Shutdown |

Admittedly, the PubMed issue related to minimal staffing hardly slows me down, but it brought home to me the realization that politics, especially politics for its own sake without regard to the consequences for the people, can be a very bad thing.

I finally got the answer to consultee’s question from a sharp clinical pharmacist who was able to find a fairly recent review on the topic [1].

The bottom line on the question is a moving target because it depends on factors including but not limited to the context of the diagnosis of a psychotic disorder, formulary restrictions in a particular location which may influence clinical treatment decision-making regarding a specific patient population, whether the patient in question is compliant with taking oral medication, and whether the patient has a comorbid medical condition that bears on the question, e.g., long QT syndrome.

The literature is also limited by a dearth of studies on the effects of antipsychotics on seizure thresholds in those who suffer from seizure disorders.

It’s interesting to note that epilepsy itself can lead to interictal psychoses which can persist, and which often leads to the necessity to treat with an antipsychotic drug, despite the risk for lowering the seizure threshold.

Some antipsychotics carry a higher risk for lowering seizure threshold and these include clozapine, loxapine, possibly olanzapine, and chlorpromazine. In fact, when patients receive above 600 mg a day of clozapine (some would argue the decision point should be keyed to the clozapine plasma level), we usually recommend adding an anticonvulsant in an effort to prevent seizures. And the choice of anticonvulsant in this setting can be critical. For example, carbamazepine, which is also used as a mood stabilizer in some patients who have affective psychoses, can lead to hyponatremia (low sodium) which can itself lower the seizure threshold. Carbamazepine can lower the blood level of antipsychotics by the anticonvulsant’s tendency to induce metabolic enzymes that increase the clearance of the antipsychotic.

The other important issue about carbamazepine is its synergistic interaction with clozapine, which can increase the risk for leukopenia. It’s best to avoid the combination whenever possible.

Often valproate is recommended in the  scenario above, but as Kanner points out, this drug can inhibit the metabolism of drugs like clozapine. Valproate can also rarely cause delirium through a complex metabolic pathway influenced by genetic abnormalities–valproate–associated hyperammonemic encephalopathy.

This is anything but an exhaustive review of the subject and the issue is not something that is always on the radar of psychiatric consultants. I can see how the government shutdown can get in the way of even routine patient care, when the goal is to provide the most up-to-date treatment guided by the medical literature.


1. Kanner, A. M. (2008). “The use of psychotropic drugs in epilepsy: what every neurologist should know.” Semin Neurol 28(3): 379-388.

Psychiatric disorders, such as mood, anxiety, attention deficit, and psychotic disorders, are among the most frequent comorbidities experienced by patients with epilepsy. While these psychiatric disorders have typically been considered as one of its complications, there is increasing evidence of a bidirectional relationship between the seizure disorder and mood and ADHD. Indeed, not only are patients with epilepsy at greater risk of developing these two disorders, but patients with mood and attention deficit disorders are at greater risk of developing epilepsy. Comorbid psychiatric disorders have a negative impact on the quality of life of patients with epilepsy. For patients with pharmacoresistant epilepsy, mood disorders are a stronger predictor of a worse perception of their quality of life than is their seizure frequency and severity. Thus, the use of psychotropic drugs is often necessary in patients with epilepsy, be they children or adults. Unfortunately, there are many misconceptions regarding the safety of psychotropic drugs, particularly of antidepressants and central nervous system stimulants, which are often erroneously thought of as being “proconvulsant.” Such misconceptions have resulted in the undertreatment of psychiatric comorbidities in patients with epilepsy. This article provides a practical review of the use of antidepressants, central nervous system stimulants, and antipsychotic drugs in patients with epilepsy.



  1. Hi Jim,

    I have a link to some references (this service is still working during that shutdown):

    Reference #2 is interesting and looks like it expands Khan’s work on FDA data bases. From a clinical standpoint, I think it also confirms the usual suspects but reading the entire reference is required. I think that the proconvulsive effects of psychiatric medications are investigated in the pre-clinical phases. I can’t help but think that this is another failure on the part of the FDA. If that information is investigated – it should be out there and easily accessible and it is not.


    • Thanks, George. Belatedly I realized I might have given the impression that PubMed was not available–it is and I could access it. What’s interesting about the Alper paper, just as you indicate, is the authors’ observation that the FDA didn’t include information on the incidence of seizures in the placebo group in clinical trials. They go on to say, “Future clinical trials of psychotropic medications provide an excellent opportunity to independently confirm the results reported here, and to extend on these findings if the FDA would provide access to information regarding the occurrence of seizures in clinical trials (italics mine).”


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