Neuroleptics have two common uses in patients with developmental disabilities and epilepsy:

  1. They are the primary pharmacologic intervention for patients with a psychotic disorder resulting from a primary psychiatric or an organic etiology.
  2. They are used frequently to ameliorate both acute and chronic aggression and self-injurious behaviors.

Types of antipsychotics

The antipsychotic drugs can be divided into typical and atypical categories, depending on their affinity for blocking the dopamine D2 receptor site. The typical neuroleptics function almost exclusively at this site. In contrast, the atypical antipsychotics additionally block other dopamine subtypes and serotonin receptors. The significantly decreased rate of extrapyramidal side effects and tardive dyskinesia associated with the atypical agents probably stems from these unique factors.85

The typical neuroleptics were discovered in the 1950s and revolutionized the treatment of schizophrenia. They include:

  • phenothiazines (chlorpromazine, fluphenazine, trifluoperazine, perphenazine, thioridazine)
  • butyrophenones (haloperidol)
  • thioxanthenes (thiothixene)
  • dihydroindolones (molindone)
  • dibenzoxazepines (loxapine)

The typical neuroleptics were found to be especially useful for the positive symptoms of schizophrenia (e.g., hallucinations, delusions) but had less effect on the negative symptoms (e.g., withdrawal, flattened affect).

Side effects

Side effects of the typical antipsychotics have limited their utility.32 Extrapyramidal side effects (EPRs) are the most common type. The most frequent EPR is akathisia, described as a feeling of anxiety that can result in pacing, aggression, and suicide. It is seen in 25% to 75% of patients treated with these drugs.85 Dystonia is seen in up to 21%, especially young males. Drug-induced parkinsonism can occur in approximately 30% of patients treated chronically with these drugs. EPRs are treated with anticholinergic drugs, propranolol, or amantadine.

Other side effects include prolactin elevation, weight gain, and cardiovascular effects.86

The most disturbing complications of traditional antipsychotics are tardive dyskinesia (TD) and neuroleptic malignant syndrome (NMS). The 1-year incidence of TD is 5% but it steadily increases in ensuing years, with nearly 70% of patients becoming symptomatic by 25 years. Most susceptible are those who have manifested EPRs, patients with an affective disorder, and the elderly.

NMS has a frequency of 0.01–2.4%. It manifests as muscle rigidity, autonomic instability, hyperthermia, and changing level of consciousness. The mortality rate is 20–30% in patients with florid symptoms.86

The incidence of EPR side effects, TD, and NMS is substantially lower with the atypical neuroleptics. These agents do have idiosyncratic side effects, however:86

  • clozapine—agranulocytosis, with an incidence of 1% in the first year and a maximal risk in the initial 4 to 18 weeks of treatment
  • risperidone—QT interval prolongation
  • olanzapine—hepatic transaminase enzyme elevations (especially in the first few weeks), which eventually may normalize
  • quetiapine—lens changes, requiring intermittent ocular examinations

Do antipsychotics induce seizures?

All antipsychotic medications decrease the seizure threshold to varying degrees. Table: Antipsychotics and Seizure Incidence lists available data.88–99

The possible mechanisms by which antipsychotics lower the seizure threshold include disruption of the dopaminergic-cholinergic balance and depletion of g-aminobutyric acid (GABA). Seizure potential is dose-related, so high-dose therapy and rapid upward dose titration should be avoided. Prophylactic use of an anticonvulsant may be necessary. The incidence of seizures with clozapine has been associated in studies with increases in dosage and drug level.

The rate of potential seizure induction is prohibitive for:

  • clozapine
  • loxapine
  • chlorpromazine

An intermediate range of less than 1.0–1.2% seizure induction applies to:

  • fluphenazine
  • thioridazine
  • perphenazine
  • trifluoperazine

The typical agents with the least seizure-induction activity are:

  • haloperidol
  • molindone
  • pimozide

The antipsychotics of choice on the basis both of epileptogenesis and of the side effect profiles are atypical agents:

  • risperidone
  • olanzapine
  • quetiapine

Drug interactions

Most antipsychotics are metabolized by the 2D6 and CYP3A subfamilies of the cytochrome P450 system. Drug-drug interactions thus are a significant possibility. Fluoxetine can increase serum levels of antipsychotics, whereas such drugs as the barbiturates and carbamazepine can lower them.85,87 For example, carbamazepine can decrease haloperidol levels by as much as 50–60% and similarly can decrease risperidone and olanzapine levels.59 Therefore, the addition of carbamazepine to a stable antipsychotic regimen may aggravate psychosis, and the discontinuation of carbamazepine after prolonged use may result in NMS.59

Choosing an antipsychotic

As noted above, the atypical antipsychotic agents have largely supplanted their older relatives, except in more acute circumstances (e.g., postictal psychosis) in which parenteral forms are required.

Clozapine was the first to be approved, in 1990. It has a unique mechanism of action, with greater D1 than D2 and increased D3 and D4 antagonism. Its effects on serotonin receptors, however, have heralded other atypical agents. Clozapine's dose-dependent lowering effect on the seizure threshold87 has greatly limited its utility in treating epilepsy patients.

Risperidone, olanzapine, and the newest atypical agent, quetiapine, on the other hand, may offer significant advantages in patients with comorbid epilepsy. Like clozapine, these drugs have potent serotoninergic activity and sparing effects on the nigrostriatal dopaminergic neurons, with much lower incidence of EPR side effects, TD, and NMS than with traditional antipsychotics.87 They are not free of side effects, however, as noted above.

Aggression and self-injurious behavior may be a significant problem in patients with developmental disorders. Several studies have confirmed the unique safety and effectiveness of the atypical antipsychotics for these target symptoms. Risperidone has been evaluated in a double-blind, placebo-controlled fashion in patients with pervasive developmental disorders and in adults with autism and was found to reduce repetitive behaviors, anxiety, irritability, and aggression significantly. The response rate was 60% with a mean dosage of 2.9 ± 1.4 mg per day with no evidence of EPR side effects or seizures.100 Risperidone was found to be useful also in controlling explosive aggression in autistic patients101 (at 0.5 mg twice daily) and in patients with behavioral disturbances associated with mental retardation102 (at 1–8 mg per day).

Likewise, olanzapine has been evaluated in a pilot study involving children, adolescents, and adults with pervasive developmental disorders. Significant decreases in aggression, irritability, self-injurious behavior, and depression were found, with a comparable increase in social relatedness.103 Weight gain and sedation were the most significant side effects.

Quetiapine also might be useful for the same target symptoms. The high 5-hydroxytryptamine-2:D2 ratio has been postulated to underlie the low frequency of EPR side effects for the atypical agents.87

Adapted from: Barry JJ and Huynh N. Psychotropic drug use in patients with epilepsy and developmental disabilities. In: Devinsky O and Westbrook LE, eds. Epilepsy and Developmental Disabilities. Boston: Butterworth-Heinemann; 2001;205–217. With permission from Elsevier (www.elsevier.com).

Authored By: 
John J. Barry MD
Nga Huynh PharmD
I<
Reviewed By: 
Steven C. Schachter MD
on: 
Monday, May 31, 2004