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Home , Paliperidone, Risperidone, Seizure threshold

and : What are the risks?

Some agents may lower the threshold, but higher-quality evidence is needed

ntipsychotics, especially second-generation antipsy- chotics (SGAs), have been proven effective for treat- Aing 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 • • • • were due to seizures. Equivalent ratios were 5.90% for que- Department of Psychiatry and Behavioral Neuroscience tiapine, 4.91% for , 3.68% for , 3.27% Saint Louis University School of Medicine for , and 2.59% for . 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 , 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 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 antiepileptic­ 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 , 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 and disorders, only current use of medium- to , and lowest with thioridazine high- FGAs (haloperidol, prochlor- and haloperidol.10 As for SGAs, case reports , and ) 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 , 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 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 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 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 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 (2016) Lingual , 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. Maintained on a stable changes) dose of gabapentin Generalized myoclonus Normalization 2 days after discontinuation Behere et al35 Man, age 25 Gradual increase Generalized spikes + sharp Maintained on , 150 mg/d, procyclidine, (2009) Three months of treatment with to 20 mg/d and slow wave discharges 5 mg/d, and , 20 mg/d adjunctive sertraline Normalization 1 month after Two tonic-clonic seizures discontinuation Clinical Point Resolution of seizures after Clearance of switch to haloperidol Spyridi et al39 Woman, age 48 Rapid titration to Status epilepticus Hospitalized for management of anorexia nervosa. olanzapine is lower (2009) Treatment for 2 days status 30 mg/d Switch from quetiapine to olanzapine. was in women, and epilepticus increased from 30 to 60 mg/d concomitantly with switch most case reports of Camacho et al36 Woman, age 54 5 mg/d High-amplitude generalized History of Alzheimer’s disease. Maintained on olanzapine-related 2005) Treatment for 2 days spikes, and spike/wave and , 20 mg/d, and donepezil, 5 mg/d polyspike/wave complexes Myoclonic status seizures occurred in Normalization 36 hours after women discontinuation Wooley and Smith34 Man, age 30, with schizophrenia 10 mg/d Multifocal and generalized History of seizure disorder, maintained on valproic acid (2001) Three months of treatment epileptiform discharges Generalized tonic-clonic seizures Resolved with discontinuation Lee et al33 Woman, age 31 10 mg/d Resolution of seizures with History of organic brain disease, anemia, and (1999) Thirteen days of treatment discontinuation of olanzapine generalized seizure disorder. Maintained on and initiation of phenytoin multiple medications, including , valproic Three generalized tonic-clonic acid, bethanechol, nitrofurantoin, benztropine. seizures Seizures concomitant with abrupt discontinuation of haloperidol, 80 mg/d Wyderski et al38 Woman, age 41, with Unknown (1999) use disorder Five months of treatment Status epilepticus

Olanzapine is a thienobenzodiazepine A literature review for olanzapine derivative and is chemically related to yielded 1 case report of repetitive focal sei- clozapine.30 The olanzapine NDA31 shows zures and lingual dystonia,32 5 case reports that 23 of 3,139 patients developed sei- of generalized tonic-clonic seizures and zures, mainly tonic-clonic, with evidence myoclonus,33-37 and 2 case reports of status suggesting that the seizures may have epilepticus.38,39 Olanzapine’s clearance is been due to confounding factors such as 25% to 30% lower in women, and most of a history of seizures or metabolic abnor- these case reports occurred women.40 malities. There were no statistically sig- Details of the above case reports are nificant differences in the rate of seizures summarized in Table 1 (page 24) (aripip- associated with olanzapine compared with razole15-19), Table 2 (olanzapine32-39), and placebo or haloperidol (P = .252 and .168, Table 3, (page 28) (paliperidone,28,29 que- Current Psychiatry 26 March 2019 respectively). tiapine,11-13 and risperidone22-24). Table 2 cumulative risk of 10% after 3.8 years of treat- Case reports of seizures attributed to olanzapine ment. The literature has described clozapine- induced generalized tonic-clonic, myoclonic, Dose of simple and complex partial, and absence MDedge.com/psychiatry antipsychotic/ 44 45 Case report Summary serum levels EEG result Notes seizures. Table 4 (page 29) lists the esti- Anzellotti et al32 Man, age 47 10 to 15 mg/d Left fronto-temporal focus with History of epilepsy treated with phenobarbital mated frequency of each seizure type based (2016) Lingual dystonia, repetitive recruiting polyspikes, followed 150 mg/d, and topiramate, 300 mg/d on 101 cases of clozapine-induced seizures. episodes of right mouth deviation by generalized spikewave Myoclonic seizures and drop attacks could complexes at 4 to 5 Hz and eyelid myoclonia be precursors/warning signs of grand mal Rosen et al37 Woman, age 67 2.5 mg/d (no Initially: generalized slowing + History of Alzheimer’s disease, hypertension, tonic-clonic seizures.46,47 Seizures have been (2011) recent dose spikes and sharp waves dyslipidemia, hypothyroidism. Maintained on a stable Seven years of treatment observed at all stages of treatment, but were changes) dose of gabapentin Generalized myoclonus Normalization 2 days after discontinuation more common during initiation of cloza­ pine, which emphasizes the importance of a Behere et al35 Man, age 25 Gradual increase Generalized spikes + sharp Maintained on sertraline, 150 mg/d, procyclidine, progressive and slow titration.43,48 The inci- (2009) Three months of treatment with to 20 mg/d and slow wave discharges 5 mg/d, and propranolol, 20 mg/d adjunctive sertraline Normalization 1 month after dence of seizures was estimated to be 6% in Two tonic-clonic seizures discontinuation a sample of 216 patients with schizophrenia Resolution of seizures after with no history of epilepsy who were pre- Clinical Point 49 switch to haloperidol scribed clozapine. With clozapine, Spyridi et al39 Woman, age 48 Rapid titration to Status epilepticus Hospitalized for management of anorexia nervosa. Regarding a possible association between (2009) Treatment for 2 days status 30 mg/d Switch from quetiapine to olanzapine. Mirtazapine was clozapine dose or clozapine plasma levels seizures have been epilepticus increased from 30 to 60 mg/d concomitantly observed at all stages with switch and seizure risk, there is a positive linear relationship between the dose of clozapine Camacho et al36 Woman, age 54 5 mg/d High-amplitude generalized History of Alzheimer’s disease. Maintained on of treatment but are and its serum concentration over a dosing 2005) Treatment for 2 days spikes, and spike/wave and citalopram, 20 mg/d, and donepezil, 5 mg/d more common during polyspike/wave complexes range of 25 to 800 mg/d.50 However, the Myoclonic status initiation of therapy Normalization 36 hours after plasma concentration is also significantly discontinuation affected by factors such as smoking, gen- 34 Wooley and Smith Man, age 30, with schizophrenia 10 mg/d Multifocal and generalized History of seizure disorder, maintained on valproic acid der, age, drug interactions, and CYP geno- (2001) epileptiform discharges Three months of treatment types. Therefore, the same clozapine dose Resolved with discontinuation Generalized tonic-clonic seizures will yield a lower serum concentration in Lee et al33 Woman, age 31 10 mg/d Resolution of seizures with History of organic brain disease, anemia, and an older male who smokes compared with (1999) Thirteen days of treatment discontinuation of olanzapine generalized seizure disorder. Maintained on 51 and initiation of phenytoin multiple medications, including lithium, valproic a younger, non-smoking female. Perry et Three generalized tonic-clonic 52 acid, bethanechol, nitrofurantoin, benztropine. al suggested a dosing nomogram to cal- seizures Seizures concomitant with abrupt discontinuation of culate the influence of gender and smok- haloperidol, 80 mg/d ing. Seizure risk, especially for tonic-clonic 38 Wyderski et al Woman, age 41, with alcohol Unknown seizures, has been reported to increase with (1999) use disorder clozapine doses >600 mg/d,53 and with Five months of treatment plasma concentrations exceeding 1,000 to Status epilepticus 1,300 mg/L.54 However, in a 2011 regression analysis, Varma et al55 found no statistically significant relationship between seizure . According to the NDA safety risk and clozapine oral dose; there was not database, the seizure rate attributed to enough data to test a correlation between ziprasidone was 1.8 per 100 subject-years clozapine plasma levels and the incidence or 0.54% of participants (12 of 2,588).41 No of seizures. additional studies have been published regarding its seizure risk. How antipsychotics might lower the seizure threshold Clozapine has a black-box warning Researchers have suggested several pos- To the best of our knowledge, clozapine is the sible mechanisms to explain how antipsy- only antipsychotic that carries an FDA “black- chotics might lower the seizure threshold. box” warning regarding its risk of inducing Antagonism of D4, Current Psychiatry seizures.42 Devinsky and Pacia43 reported a H1, and -muscarinic receptors Vol. 18, No. 3 27 Table 3 Case reports of seizures attributed to paliperidone, quetiapine, and risperidone Dose of Case antipsychotic/ report Summary serum levels EEG result Notes Paliperidone

Antipsychotics 29 and seizures Liang et al Man, age 41 9 mg/d for 1 Maintained on valproic (2011) Three months of month acid for management of treatment and aggression; discontinued prior to seizure Schneider Man, age 46 3 mg/d on History of diabetes 28 and Lizer Four days of treatment Day 1 mellitus, hypertension, and (2008) 6 mg/d on dyslipidemia. Maintained Days 2, 3, on metformin, , and 4 simvastatin, enalapril, , , Clinical Point and . First episode of atrial fibrillation Many antipsychotics simultaneous with seizure and antiepileptics Quetiapine are metabolized by Young et Woman, age 27 Overdose with No epileptiform 13 al (2009) 24 hours after 30 g. Blood activity CYP enzymes, and intoxication levels 8.67 mg/L on Day 1 interactions may Late onset of (normal range: impair seizure control 2 seizures 0.1 to 1 mg/L) Dogu et al12 Woman, age 75, with 500 mg/d Non-specific History of Alzheimer’s (2003) visual hallucinations generalized disease. Maintained and delusions slowing at 6 to on for Eighteen months of 7 Hz aggression; serum level treatment 6.7 mEq/L Two generalized tonic- clonic seizures Hedges Woman, age 27 100 mg/d Maintained on olanzapine, and One day after initiation 15 mg/d, and sertraline, 11 Jeppson of treatment 100 mg/d. Concomitant (2002) slow taper of clonazepam Generalized tonic- clonic seizure Risperidone Holzhausen 54 children, age 2 to .01 to History of comorbid et al23 18 (mean age: 10) .14 mg/kg/d epilepsy (2007) No exacerbation of seizures in 94.5% of cases Gonzalez- 21 youths, age 4 to 19 2.4 to 3.5 mg/d History of comorbid Heydrich No exacerbation of epilepsy 22 et al seizure in all cases (2004) Lane et al24 Woman, age 64 2 mg/d on Normal before Was being treated with (1998) Two days of treatment Day 1 and after sulfamethoxazole- 4 mg/d on treatment trimethoprim and Generalized tonic- clonic seizure Day 2 There were no seizures after risperidone was stopped, then re- initiated 15 days later at a lower dose and with a slower titration Current Psychiatry schedule 28 March 2019 seems to induce EEG alterations and Table 4 56 increase the risk of seizures. Additionally, Frequency of clozapine-induced N modulation of the -methyl-d-aspartate seizures, by type and the gamma-aminobutyric acid path- MDedge.com/psychiatry a ways might also be implicated.57,58 Certain Seizure type Frequency brain regions upon which antipsychotics Generalized act (eg, the hippocampus and the amyg- Tonic-clonic 54% dala) might be associated with a higher Myoclonic and/or atonic 28% susceptibility to convulsions compared Tonic-clonic with other 12% with cortical regions.59,60 Another mecha- seizure types nism described in epilepsy is “kindling,” Partial which consists of a progressive increase Simple 3% in brain excitability after repeated admin- Complex 3% istration of a fixed subconvulsive dose of aAmong 101 cases of clozapine-induced seizure an excitatory agent; clozapine is believed Source: Adapted from reference 45 to have a higher “kindling” activity compared with other antipsychotics.59,60 Clinical Point Overall, these proposed mechanisms Determining seizure remain speculative.57 of clozapine while it decreases plasma con- centrations of norclozapine; norclozapine is risk depends on the the main clozapine metabolite responsible seizurogenic potential Watch for pharmacokinetic for inducing seizures.66,67 of the antipsychotic interactions and on the patient’s The CYP enzymes involved in drug metab- individualized olism include CYP1A2, CYP2C9, CYP2C19, Steps for minimizing seizure risk CYP2D6, and CYP3A4. Most commonly Determining the seizure risk for a patient predisposing factors used antiepileptics and antipsychotics are taking an antipsychotic is challenging metabolized by CYP enzymes, and may because doing so depends not only on the also act as inhibitors or inducers of these seizurogenic potential of each drug but enzymes.61 Drug interactions may impair also on individualized predisposing fac- seizure control, which is why monotherapy tors.11,57,68 Choosing the “best” antipsychotic is preferable to combination treatment in therefore largely depends on each patient’s patients with epilepsy.62 Carbamazepine profile. The predisposing factors consist and phenytoin are inducers of both mainly of the individually inherited seizure CYP1A2 (which metabolizes olanzapine threshold (personal history of febrile con- and clozapine), and CYP3A4 (which metab- vulsions or a family history of seizures) and olizes haloperidol, risperidone, quetiapine, other comorbid seizurogenic conditions, ziprasidone and clozapine). Paliperidone such as a history of head trauma, brain is not metabolized by CYP enzymes.62 injury, intellectual disability, cerebral arte- Discontinuing an enzyme-inducing agent riosclerosis, neurodegenerative diseases, may result in increased antipsychotic encephalopathy, chronic renal insufficiency, plasma concentrations, which might lead to and hyponatremia. Furthermore, seizure an increased risk of seizures. risk depends on the antipsychotic dose Valproic acid, which is often used to pre- administered and the rate of titration.11 vent or treat clozapine-induced seizures, There is not enough evidence to recom- has an unclear effect on clozapine plasma mend performing an EEG in all patients concentrations.63 Although valproic acid taking antipsychotics. Such testing is rec- is known to inhibit clozapine metabolism, ommended only for patients who have 2 reports have suggested that the plasma predisposing factors for seizures. If an EEG concentrations of clozapine and its metab- shows any abnormality in a patient taking olites may decrease after adding valproic clozapine, consider decreasing the clozap- acid.64,65 Other studies have found that val- ine dose69,70 or adding an antiepileptic drug Current Psychiatry proic acid increases plasma concentrations such as valproic acid or lamotrigine.44,70 Vol. 18, No. 3 29 continued Table 5 Prevention of clozapine-induced seizures Primary prevention42,51,57 • Screen for risk factors predisposing to seizures • Titrate clozapine dose slowly and gradually • Avoid concomitant use of drugs that lower the seizure threshold • Avoid concomitant use of drug inhibitors of CYP enzymes that metabolize clozapine (1A2, 2D6 Antipsychotics and 3A4), including , caffeine, ciprofloxacin, erythromycin, citalopram, and and seizures • Educate the patient about the risk of smoking cessation abruptly increasing clozapine blood levels and reducing seizure threshold • Screen for drop attacks, myoclonic jerks, or partial seizures that may precede generalized tonic- clonic seizures. If present, measure clozapine plasma levels and decrease the dose of clozapine Secondary prevention, first seizure45,51,74 • If a seizure occurs independent of a dose increase, investigate possible causes that might have increased clozapine plasma levels (eg, co-administration of drugs that lower seizure threshold or inhibit CYP enzymes 1A2, 2D6, or 3A4, or smoking cessation) Clinical Point • Measuring clozapine plasma levels can be helpful in monitoring drug exposure • Post-seizure, hold clozapine for 24 hours and then resume at a lower dose; last dose prior to the There is no consensus seizure-inducing dose or half of the seizure-inducing dose are suggested options Secondary prevention, second seizure: Consider adding valproic acid or another in on co-prescribing an selected patients (eg, if valproic acid is contraindicated44) antiepileptic agent First choice: Valproic acid45,51,55,74 for patients receiving • Due to the risks associated with valproic acid treatment (eg, neutropenia, thrombocytopenia, weight gain, and hyperammonemia), and the low incidence of clozapine-related seizures even at clozapine higher plasma clozapine levels, routine prophylactic therapy is not recommended • If a second seizure occurs, or if high clozapine doses (above that which induced the seizure) are required, valproic acid is the anticonvulsant of choice for clozapine-related tonic-clonic, myoclonic, or atonic seizures • Particularly recommended in Other : • Lamotrigine. Slow titration of lamotrigine is necessary in order to the anticonvulsant dose of 200 mg/d; this might conflict with the immediate need to control seizures69 Avoid: • Phenytoin. Drug–drug interactions lead to a potential decrease in clozapine plasma levels and an increased risk of phenytoin toxicity75 • Carbamazepine. Drug–drug interactions lead to a potential decrease clozapine plasma levels. Carbamazepine increases the risk of agranulocytosis and of myoclonic seizures51 CYP: cytochrome P450

Although clozapine carries a black-box difficulties, or if seizures occur. Liukkonen et warning of increased risk of causing sei- al72 advised initiating an antiepileptic at the zures, there is no consensus regarding the start of clozapine treatment in patients who of co-prescribing an antiepileptic. are taking other epileptogenic medications, Some studies have suggested prescrib- patients with pre-existing seizure disorder, ing valproic acid prophylactically,71 after and patients with neurologic abnormalities. the occurrence of 1 seizure,59 or after 2 On the other hand, Caetano51 argued against seizures.54,72 Others have recommended primary prevention of seizures for patients prescribing prophylactic valproic acid for receiving >600 mg/d of clozapine, suggest- patients taking ≥600 mg/d of clozapine or ing that “the risk of seizures would be better whose clozapine plasma levels are >500 managed by close clinical monitoring and mg/L.73 Varma et al55 recommended start- measures of clozapine serum concentration ing an antiepileptic medication if there are rather than adding an anticonvulsant drug.” clear epileptiform discharges on EEG, if Current recommendations for primary and Current Psychiatry 30 March 2019 the patient develops stuttering or speech secondary prevention of clozapine-induced seizures are detailed in Table 542,44,45,51,55,57,69,74,75 (page 30). Related Resources Studies addressing the seizurogenic poten- • Druschky K, Bleich S, Grohmann R, et al. Seizure rates under treatment with antipsychotic drugs: Data from the AMSP MDedge.com/psychiatry tial of SGAs other than clozapine have a low project. World J Biol Psychiatry. 2018;15:1-10. level of evidence and include patients who • Epilepsy Foundation. For professionals: Antipsychotics. had comorbid conditions and were taking https://www.epilepsy.com/learn/professionals/diagnosis- treatment/psychotropic-drugs-developmental-disabilities/ other medications that could cause seizures. comorbid-5. Additionally, clinical trials of SGAs rarely Drug Brand Names include patients with seizure disorders; this Aripiprazole • Abilify Mirtazapine • Remeron might underestimate the risk of seizures.4 Benztropine • Cogentin Nitrofurantoin • Furadantin The effect of the mental illness itself Bethanechol • Duvoid Olanzapine • Zyprexa Carbamazepine • Carbatrol, Paliperidone • Invega on the seizure threshold needs to be con- Tegretol Phenobarbital • Luminal sidered.43 Bloechlinger et al8 found that Chlorpromazine • Thorazine Phenytoin • Dilantin Cimetidine • Tagamet • dementia might be inherently associated Ciprofloxacin • Cipro Compazine with a higher risk of antipsychotic-related Citalopram • Celexa Procyclidine • Kemadrin Clonazepam • Klonopin Propranolol • Inderal seizures. Moreover, numerous qualitative Clozapine • Clozaril Quetiapine • Seroquel EEG studies have found abnormalities in Donepezil • Aricept Risperidone • Risperdal Clinical Point 20% to 60% of patients with schizophrenia.56 Enalapril • Vasotec Sertraline • Zoloft Erythromycin • Erythrocin Simvastatin • Zocor The effect of the Other quantitative studies have reported Escitalopram • Lexapro Sulfamethoxazole/ mild and nonspecific EEG abnormali- Flunitrazepam • Rohypnol trimethoprim • Bactrim, mental illness itself Fluvoxamine • Luvox Sulfatrim ties, such as increased delta and/or theta Gabapentin • Neurontin Topiramate • Topamax on seizure activity, in many non-medicated patients Haloperidol • Haldol Trifluoperazine • Stelazine threshold needs Lamotrigine • Lamictal Valproic acid • Depakene, 10,76 with schizophrenia. Additionally, brain Lithium • Eskalith, Lithobid Depakote to be considered tissue analysis of deceased patients who Metformin • Fortamet, Ziprasidone • Geodon Glucophage had schizophrenia has shown a significant increase in dopamine concentrations in the left amygdala compared with controls, and this might be responsible for enhanced elec- trical activity in this region.10 Some studies Although evidence suggests antipsy- have described EEG slowing in the frontal chotics can induce different types of epi- brain regions of patients with schizophre- leptic seizures, the quality of this evidence nia,77 and was selectively normalized in is low. Randomized controlled trials are these areas with antipsychotics.78 needed to determine which antipsychotics increase seizure risk and whether there is a dose-effect relationship. As always, start low, go slow Mounting evidence suggests that antipsy- References 1. Bruijnzeel D, Suryadevara U, Tandon R. Antipsychotic chotic medications decrease the seizure treatment of schizophrenia: an update. Asian J Psychiatr. threshold. Practitioners should thus be 2014;11:3-7. 2. Hrdlicka M, Dudova I. Atypical antipsychotics in the cautious in prescribing antipsychotics and treatment of early-onset schizophrenia. Neuropsychiatr Dis should target reaching the minimal effective Treat. 2015;11:907-913. 3. Koch-Stoecker S. Antipsychotic drugs and epilepsy: dose with slow titration, especially in patients indications and treatment guidelines. Epilepsia. 2002; with predisposing factors for epilepsy. 43(suppl 2):19-24. continued

Bottom Line Among second-generation antipsychotics, clozapine appears to increase the risk of clinical seizure the most. Correlations with dosage and/or plasma levels have not been proven. Psychiatrists should be vigilant for pharmacokinetic interactions Current Psychiatry between antipsychotics and antiepileptics, notably via CYP1A2 and CYP3A4. Vol. 18, No. 3 31 4. Alper K, Schwartz KA, Kolts RL, et al. Seizure incidence in drugsatfda_docs/nda/2006/021999s000_MedR_Part4.pdf. psychopharmacological clinical trials: an analysis of Food Accessed January 28, 2019. and Drug Administration (FDA) summary basis of approval 28. Schneider RA, Lizer MH. Apparent seizure and atrial reports. Biol Psychiatry. 2007;62(4):345-354. fibrillation associated with paliperidone. Am J Health 5. Torta R, Keller R. Behavioral, psychotic, and System Pharm. 2008;65(22):2122-2125. disorders in epilepsy: etiology, clinical features, and 29. Liang CS, Yang FW, Chiang KT. 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