Atypical Antipsychotics and Serotoninergic Antidepressants in Patients with Epilepsy: Pharmacodynamic Considerations *Riccardo Torta and †Francesco Monaco *Department of Neurosciences, University of Turin, Turin; and †Department of Neurology, University A. Avogadro, Novara, Italy Summary: Purpose: To discuss the pharmacodynamic aspects of the administration of atypical antipsychotics (APs) and se- rotoninergic antidepressants (SSRIs) to patients with epilepsy. Methods: This article represents an overview of all studies concerning the administration of APs and SSRIs to people with epilepsy. In particular, it deals with the relationship between neuroleptics (NLTs), APs, SSRIs, serotonin, and dopamine, with special focus on the possible epileptogenic role of psy- choactive drugs. Results: NLTs may induce seizures by blocking D 2 ,H 1 , and .1 receptors, or by sexual hormone activation or a pharmaco- logic kindling mechanism. The difference among APs in their ability to induce seizures is related mainly to the percentage of D 2 -receptor occupancy and possibly also to their action on neurosteroids. Seizures occur at SSRIs therapeutic doses, with a 0.1–4% incidence. Coversely, in animal studies fluoxetine was claimed to exert an anticonvulsant action. Conclusions: The study of the pharmacodynamic aspects of the administration of APs and SSRIs to patients with epilepsy can help to evaluate the importance of some mechanisms of action of several psychoactive drugs in relation to their pro- or anticonvulsant activity. Key Words: Antipsychotics— Antidepressants—Epilepsy. One of the most important issues in treating people with epilepsy with psychotic or mood disorders is the safety of psychotropic drugs, as far as their epileptogenic potential is concerned (1,2). Historically, the proconvul- sant action of neuroleptics (NLTs) was related to their D 2 -receptor blocking activity, and, partially, to their ac- tivity on histaminergic receptors (3). With regard to the potential proconvulsant action of antidepressants (ADs), many speculations were made, particularly regarding their antagonism of histaminergic receptors and on their ability of inducing a kindling phenomenon (4). With the introduction of both pro- and antiserotonin- ergic compounds, such as the selective serotonin reup- take inhibitors (SSRIs) and the atypical antipsychotics (APs), the simplistic antidopaminergic hypothesis of the NLT proconvulsant activity was not acceptable. The hy- pothesis that the increase of serotonin (5-HT) could rep- resent the main protective activity of SSRIs against convulsions, as initially hypothesized for fluoxetine (5– 8), was refuted by the fact that among APs, the sero- toninergic blockade did not represent per se a risk factor for epileptogenicity. This was further demonstrated by the great difference in AP convulsant action noted with clozapine and zotepine but not risperidone and olanzap- ine, although all these drugs are powerful serotoninergic blockers (3). We discuss some data supporting or refuting old and new hypotheses on the pro- or anticonvulsant activity of serotoninergic agents, a rather complex issue that cannot be explained on the basis of a single neurotransmitter action. NEUROLEPTICS, ATYPICAL ANTIPSYCHOTICS, SEROTONIN, AND DOPAMINE The clinical benefits of dopamine (DA) in the man- agement of epilepsy have been known for a century, and the introduction of NLTs 40 years ago led to the occur- rence of seizures as side effects of DA-receptor block- ade. The discovery of multiple DA-receptor families (mainly D 1 and D 2 , but also D 3 ,D 4 , and D 5 ), sometimes mediating opposing influences on neuronal excitability, heralded a new era of DA epilepsy research (11). NLTs can induce seizures by the blockade of several receptors, by a hormonal mechanism, or by a kindling activity. The traditional anticonvulsant action of dopamine was attributed to D 2 -receptor stimulation in forebrain. How- ever, the advent of selective D 1 agonists, with procon- Address correspondence and reprint requests to Dr. R. Torta at De- partment of Neurosciences, Via Cherasco, 15, Turin, 10126, Italy. Epilepsia, 43(Suppl. 2):8–13, 2002 Blackwell Publishing, Inc. © International League Against Epilepsy 8