Antipsychotics and seizures: What are the risks? Some agents may lower the seizure threshold, but higher-quality evidence is needed ntipsychotics, especially second-generation antipsy- chotics (SGAs), have been proven effective for treat- Aing psychosis as well as mood disorders.1,2 Because antipsychotics can lower the epileptogenic threshold, sei- zures are a serious potential adverse effect. Antipsychotics can cause isolated EEG abnormalities in 7% of patients with no history of epilepsy, and clinical seizures in .5% to 1.2% of such patients.3 Additionally, the neuropathophysiology underlying epilepsy can predispose patients to psychiatric disorders4; the estimated prevalence of psychosis in patients with epilepsy is approximately 7%.5 This review will shed light on the risk of clinical seizures related to antipsychotics. Comparing seizure risk among antipsychotics KEVIN SOMERVILLE In a review of the World Health Organization’s adverse drug Rita Khoury, MD reactions database, Kumlien and Lundberg6 calculated the Geriatric Psychiatry Fellow ratio of the number of reports of seizures to the total num- Elias Ghossoub, MD ber of reports for each drug. They found that approximately Clinical Fellow, Forensic Psychiatry 9% of all adverse drug reaction reports involving clozapine • • • • were due to seizures. Equivalent ratios were 5.90% for que- Department of Psychiatry and Behavioral Neuroscience tiapine, 4.91% for olanzapine, 3.68% for risperidone, 3.27% Saint Louis University School of Medicine for haloperidol, and 2.59% for aripiprazole. Using the data- St. Louis, Missouri base of the Pharmacovigilance Unit of the Basque Country, Lertxundi et al7 reported a 3.2-fold increased risk of seizure with SGAs in comparison with first-generation antipsychot- ics (FGAs) (95% confidence interval [CI], 2.21 to 4.63), which went down to 2.08 (CI, 1.39 to 3.12) once clozapine was excluded. However, as the authors of both studies noted, Disclosures The authors report no financial relationships with any companies whose products are mentioned Current Psychiatry in this article, or with manufacturers of competing products. Vol. 18, No. 3 21 the quality and relevance of this data are thioridazine, and haloperidol were 2 to 3 limited because it relies on spontaneous times more likely to develop seizures than reporting. those treated with risperidone; risks associ- Overall, the evidence regarding the sei- ated with the rest of the FGAs were similar zure risk associated with antipsychotics is to that of risperidone. scarce. To the best of our knowledge, only 2 The results of these 2 large cohort studies large observational studies have compared are somewhat concurrent in indicating that, Antipsychotics the seizure risks associated with different other than clozapine, SGAs incur similar and seizures antipsychotics. risks of seizures; furthermore, they specify Using data from the UK-based Clinical that, contrary to earlier studies,10 haloperi- Practice Research Datalink between 1998 dol is associated with significantly higher and 2013, Bloechlinger et al8 examined odds of seizures. While both of these cohort the incidence rates of seizures among studies controlled for several sociodemo- patients newly diagnosed with schizo- graphic and clinical confounders, they have phrenia, affective disorders, or dementia several limitations. First, diagnoses of sei- who were prescribed antipsychotics. They zures were based on information available Clinical Point excluded patients with a history of seizures in databases, which might be subject to Most of the evidence or antiepi leptic use. In the cohort of 60,121 inaccuracies. Second, neither study evalu- patients, the incidence rates of seizures per ated the effect of drug dosage and duration on antipsychotics 10,000 person-years were 11.7 (CI, 10.0 to of exposure on new-onset seizures. and seizure risk is 13.4) for those who did not use antipsychot- low quality and relies ics, 12.4 (CI, 10.9 to 13.8) for past users, 115.4 on case reports or (CI, 50.1 to 180.7) for current users of halo- Most evidence is from case reports peridol, 48.8 (CI, 30.7 to 66.9) for current Other than these 2 large studies, most of expert opinions users of quetiapine, 25.9 (CI, 11.8 to 40.0) for the evidence addressing the relationship current users of risperidone, and 19.0 (CI, between the use of antipsychotics and inci- 8.7 to 29.3) for current users of olanzapine. dence of seizures is low quality and relies No data were available about clozapine use. on case reports or expert opinions. Older In subsequent analyses, the authors studies found that, among FGAs, seizure found that among patients with affective risk is highest with chlorpromazine and disorders, only current use of medium- to promazine, and lowest with thioridazine high-potency FGAs (haloperidol, prochlor- and haloperidol.10 As for SGAs, case reports perazine, and trifluoperazine) was associ- have described seizures associated with the ated with a significantly increased risk of use of quetiapine, aripiprazole, risperidone, seizures (adjusted odds ratio: 2.51, CI, 1.51 paliperidone, and olanzapine. to 4.18) compared with non-users.8 Among patients with dementia, current use of olan- Quetiapine. Three case reports published zapine or quetiapine and current use of any between 2002 and 2010 describe general- FGAs were associated with significantly ized tonic-clonic seizures secondary to increased odds of seizures. This study sug- quetiapine use.11-13 In placebo-controlled tri- gests that the underlying mental illness als, seizures were reported to have occurred might modulate the seizure risk associated in 1 of 951 patients receiving quetiapine with antipsychotics.8 compared with 3 of 319 patients receiving Wu et al9 conducted a study based on placebo.14 the National Health Insurance Research Discuss this article at Database in Taiwan. They examined the Aripiprazole. Five case reports described star- www.facebook.com/ 1-year incidence of new-onset seizures ing spells and tonic-clonic seizures in patients MDedgePsychiatry among patients diagnosed with schizo- receiving 10 to 15 mg of aripiprazole.15-19 In the phrenia or mood disorders who were new New Drug Application (NDA) for aripipra- to antipsychotic treatment, and calculated zole, the incidence of seizures was estimated the risk of seizure associated with each to be .11% (1 of 926 patients) in placebo- antipsychotic in reference to risperidone. controlled trials and .46% (3 of 859 patients) in Current Psychiatry 22 March 2019 They found that those receiving clozapine, haloperidol-controlled trials.20 continued Table 1 Case reports of seizures attributed to aripiprazole Dose of Case antipsychotic/ report Summary serum levels EEG result Notes Thabet Child, age 3, with 30 mg/d Mild, History of a single et al19 (2013) accidental ingestion generalized unprovoked Antipsychotics Two staring spells slowing generalized tonic- clonic seizure at the and seizures (absence seizures), one of which was followed by age of 18 months a generalized seizure with normal EEG. Was not maintained on antiepileptic medications Yueh et al18 Man, age 54 15 mg/d Normal Seizures concomitant (2009) Two tonic-clonic seizures with abrupt discontinuation of benzodiazepines Clinical Point Arora and Boy, age 13 10 mg/d Generalized 17 Arndorfer Four weeks of treatment epilepsy (2007) Use caution Staring spells and hand when prescribing twitching. No full-blown tonic-clonic seizures or risperidone or loss of consciousness paliperidone to Tsai16 (2006) Patient with 10 mg/d Normal Maintained on schizophrenia flunitrazepam 2 mg/d a patient with a Six weeks of treatment history of seizures Generalized tonic-clonic seizures Resolution of seizures after switch to olanzapine Malik and Man, age 31, with 15 mg /d Ravasia15 delusional disorder (2005) Two seizures (1 complex partial) 3 weeks after treatment initiation Risperidone’s product labeling suggests drugs. Komossa et al25 found that risperi- the drug should be used with caution in done is less epileptogenic than clozapine, patients with a history of seizures or con- with a relative risk of .22. ditions that could result in a lower seizure threshold. In Phase III placebo-controlled Paliperidone is the active metabolite of trials, seizures occurred in .3% of patients risperidone and does not have pharmaco- treated with risperidone, although in some kinetic interactions with drugs metabolized cases, the seizures were induced by electro- by the cytochrome P450 (CYP) enzymes. Its lyte disturbances such as hyponatremia.21 labeling indicates that the drug should be Gonzalez-Heydrich et al22 and Holzhausen used with caution in patients with a history et al23 found no increase in seizure activity of seizures.26 In Phase III placebo-controlled among patients with epilepsy who were trials of paliperidone, the rate of seizures receiving risperidone. Lane et al24 pub- was .22%.27 Two case reports suggest close lished a case report of a geriatric woman monitoring of seizure risk in patients who presented with a generalized tonic- receiving paliperidone.28,29 Liang et al29 clonic seizure related to rapid titration of reported that co-administration of valproic risperidone; however, with slower titra- acid could mask an underlying decrease of tion and lower doses, she stopped having the seizure threshold caused by antipsy- Current Psychiatry 24 March 2019 seizures without adding any antiepileptic chotics such as paliperidone. continued on page 26 continued from page 24 Table 2 Case reports of seizures attributed to olanzapine Dose of antipsychotic/ Case report Summary serum levels EEG result Notes Anzellotti et al32 Man, age 47 10 to 15 mg/d Left fronto-temporal focus with History of epilepsy treated with phenobarbital (2016) Lingual dystonia, repetitive recruiting polyspikes, followed 150 mg/d, and topiramate, 300 mg/d Antipsychotics episodes of right mouth deviation by generalized spikewave and seizures and eyelid myoclonia complexes at 4 to 5 Hz Rosen et al37 Woman, age 67 2.5 mg/d (no Initially: generalized slowing + History of Alzheimer’s disease, hypertension, (2011) Seven years of treatment recent dose spikes and sharp waves dyslipidemia, hypothyroidism.