Epilepsy & Behavior

Epilepsy & Behavior 3 (2002) S13S18 www.academicpress.com

Treatment of psychosis, aggression, and irritability in patients with epilepsy

Kenneth R. Alper,a,* John J. Barry,b and Antoaneta J. Balabanovc
a

Departments of Psychiatry and Neurology, Mt. Sinai School of Medicine, New York University, Comprehensive Epilepsy Center, 560 First Avenue, Rivergate 4th oor, New York, NY 10016, USA b Department of Psychiatry, Stanford University School of Medicine, Stanford, CA, USA c Department of Neurological Sciences, Rush Medical College, Chicago, IL, USA Accepted 9 August 2002

Abstract Psychosis, irritability, and aggression in persons with epilepsy are frequently the focus of clinical intervention. These neuropsychiatric symptoms may occur due to the bidirectional relationship between psychosis and epilepsy, in which the potential etiopathogenic mechanisms are believed to be closely related to the seizure disorder itself and also may result from underlying brain injury or behavioral intolerance of antiepileptic or other medication. Epileptic patients are at heightened risk for mood disorders, psychotic disorders, and delerium. The possible lowering of seizure threshold by psychotropic drugs should not contraindicate appropriate use of psychotropic agents, and risk may be minimized by the selection of agents not associated with a relatively high likelihood of altering seizure threshold. Behavioral toxicity of antiepileptic drugs (AEDs) is addressed by selection of alternative agents, and some AEDs appear to possess positive psychotropic eects. The use of antipsychotic, antidepressant, and other psychotropic agents in psychosis, irritability, and aggression in epilepsy is discussed, including dosage ranges, major side eects, and potential interactions between antieplieptic and psychotropic medication. 2002 Elsevier Science (USA). All rights reserved.
Keywords: Psychosis of epilepsy; Depression; Antipsychotic drugs; Antidepressant drugs; Antiepileptic drugs; Intractable epilepsy

1. Introduction The approach to the treatment of psychosis, irritability, and aggression in patients with epilepsy (PWE) is often dependent on their temporal relations to seizure occurrence. A classication scheme based on the development of psychopathological features observed during the prodromal, ictal, peri-ictal, and interictal periods provides a framework to discuss treatment alternatives. 2. Historical perspectives and prevalence 2.1. Psychosis Psychosis of epilepsy (POE) is a term applied to a group of psychotic disorders with a distinct phenome*

Corresponding author. E-mail address: kral@nyu.edu (K.R. Alper).

nology in which the potential etiopathogenic mechanisms are believed to be closely related to the seizure disorder itself. As early as the 19th century, scholars identied a bidirectional relationship between psychosis and epilepsy [1,2]. In the 1950s, several investigators reported that patients with epilepsy, in particular those with temporal lobe epilepsy (TLE), suered from an interictal psychotic disorder that diered in many ways from schizophrenia. Hill [3] and Pond [4] noted that these patients did not display the lack of aect and asocial or withdrawn attitude that was typical of the schizophrenic patient. In their classic paper, Slater et al. [5] highlighted again the dierences described by Hill and Pond. Still, these patients psychotic episodes included paranoid delusions with visual and auditory hallucinations; accordingly, Slater et al. coined the term schizophrenia-like psychosis in recognition of the similarities between these two disorders. Further systematic analyses of these psychiatric phenomena by

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others continued depicting a psychotic disorder that, while sharing pivotal symptoms, diered in important ways from the psychotic disorders aecting the nonepileptic patient. The reported incidence of psychosis in TLE is 14%, compared with an incidence of 3.3% in idiopathic generalized epilepsy. The prevalence of POE may range between 0.6 and 7% in community samples and may be as high as 1927% in hospital-derived patient populations [6]. Ictal psychosis is relatively uncommon and its prevalence and incidence rates remain unknown, while postictal psychosis (PIP) comprises about 25% of all POE [7]. PIP is reviewed in detail in the article by Smith and Spitz in this issue and will not be considered here. 2.2. Irritability and aggression Irritability is a relatively common phenomenon in PWE, but its actual prevalence is yet to be established. Irritability is a symptom that is frequently seen as part of a depressive disorder in PWE. In a prospective review designed to determine the safety of sertraline in PWE in depressive or obsessivecompulsive disorders, Kanner et al. [8] evaluated 100 patients using DSM-IV criteria. Of the 97 patients with depressive complaints, 69 presented with a pleomorphic picture, with irritability a predominant complaint in 36% of the group. Blumer [9] has developed the term interictal dysphoric disorder, which he views as a subictal variation whose essential clinical attribute is paroxysmal affects ranging from irritability to anger to rage. The dysphoric disorder may also occur in the absence of epilepsy in patients with brain lesions or as premenstrual dysphoric disorder. However, this concept is controversial [10]. The incidence and prevalence of aggression in PWE are not known. Ictal aggression and violence are rare. These acts are frequently nondirected and stereotyped [11]. Aggression more commonly takes place in the postictal state where psychosis, depression, and delirium are present, associated with impaired consciousness [11]. Interictal aggression in PWE is most frequently encountered in patients with associated CNS pathology, e.g., from trauma or encephalitis [11]. In addition, one review of 44 PWE who had histories of violence concluded that interictal aggressive acts were more often associated with mental retardation and psychopathology than with epileptiform activity [12]. Aggression and impulse control can be particular problems in patients with developmental disabilities (DD), where self-injurious behavior is more frequent. The rates of epilepsy in patients with DD are directly related to the level of cognitive compromise, with a prevalence of up to 50% in the severely disabled [13].

2.3. Diagnostic considerations Ictal psychosis is an expression of seizure activity and often a manifestation of nonconvulsive status epilepticus (absence status or simple and complex partial status epilepticus originating in limbic structures) and may frequently present as a delirium [14]. The relatively frequent absence of an electrographic ictal pattern of simple partial seizures on scalp EEG may lead to its misdiagnosis as a primary psychiatric disorder. Interictal psychosis (IIP) is signicantly more common than ictal psychosis and often resembles the psychosis seen in schizophrenia, with potential dierences debated in the literature [10]. For example, when compared with psychosis in nonepileptic patients, those with IIP have been reported to display some distinctive features such as absence of negative symptoms, better premorbid state, less deterioration of personality, and better response to pharmacotherapy. Interictal psychotic symptoms may result from toxicity from antiepileptic drugs (AEDs), including ethosuximide, phenytoin, phenobarbital, primidone, vigabatrin, lamotrigine, topiramate, levetiracetam, and zonisamide [7,15]. Symptoms may remit with a decrease in dose or change to another AED. In addition, AED withdrawal can be associated with psychosis [16], and IIP can be seen after temporal lobectomy, with a reported range of 328% [14]. 2.3.1. Aggression Ictal aggression and violence are frequently nondirected and stereotyped. Aggression more commonly takes place in the postictal state. During this period, resistive violence can occur. Well-directed aggression is more frequent in the presence of delusions and hallucinations that occur during an episode of postictal and IIP and, as stated above, among patients with mental retardation.

3. General considerations regarding the treatment of psychosis, aggression, and irritability in patients with epilepsy 3.1. Use of restraints If possible, avoid the use of restraints in postictal aggression or irritability. In centers experienced in the care of PWE, patients who are confused and who wish to leave the bed are often allowed to do so escorted by sta. Often a delirious or confused postictal epileptic patient will ambulate briey and eventually accept guidance back to the bed. This is strongly preferable to the situation all too commonly seen in emergency and other settings with less experience with epileptic patients. A confused or delirious postictal patient may be

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unnecessarily restrained, resulting in an avoidable vicious cycle involving restraint, a signicant escalation of agitation, and further restraint and further agitation [17]. In the setting of invasive monitoring for epilepsy surgery, prophylactic use of antipsychotic medication in patients with known prior histories of postictal psychosis or confusion can help avoid the use of restraints in a situation where allowing ambulation may not be a practical option. 3.2. Family history Evaluate the family psychiatric history. There is evidence to suggest that a family history of response to a specic psychotropic agent is predictive of a positive response [18]. Also, epilepsy and the conditions that pose a risk for epilepsy, such as stroke or head trauma, can signicantly alter the phenomenological expression of neuropsychiatric disorders. In this setting, a family history of a favorable response to a specic psychotropic agent may provide a basis for expectation of response that may be less obvious from the patients behavioral presentation. Family psychiatric history may also aect the expression of psychopathology in epilepsy as suggested by the observation of an apparent association of PIP with a family history of mood disorder [19]. 3.3. Pharmacologic treatment The risk/benet ratio generally favors the use of psychotropic medications when indicated in epilepsy. Most antidepressant and antipsychotic medications are associated with an incidence of seizures in patients without preexisting epilepsy in phase III trials on the order of 0.10.5%. However, several psychotropics are relatively contraindicated in PWE because of associated seizure-induction potential (see below). Relatively infrequently, some epileptic patients have increased seizure frequency on psychotropic medications not usually associated with lowering the seizure threshold [8]. Studies in which seizure frequency has been measured prior to and after starting psychotropic medication did not nd a statistically signicant group eect of psychotropic medication on seizure frequency [2023], although it appears that exacerbation of seizure frequency may occur in individual patients [8]. A commonly accepted approach to treating PWE is to use antipsychotics and antidepressants, but to avoid agents that appear to be associated with a relatively greater risk of lowering the seizure threshold, namely the antipsychotics clozapine (Clozaril), chlorpromazine (Thorazine), and loxapine (Loxitane) and the antidepressants clomipramine (Anafranil), amoxapine (Ascendin), maprotiline (Ludiomil), and bupropion (Wellbutrin). In addition to avoiding specic agents, it

should be kept in mind that the potential seizurethreshold-lowering properties of psychotropic drugs tend to be dose-related, and it is therefore preferable to be conservative with respect to dosage and the rate at which dosages are increased. It has been the experience of the authors that epilepsy patients often seem to respond to relatively low dosages of psychotropic drugs.

4. Overview of psychopharmacologic agents used in the treatment of psychosis, aggression, and irritability in patients with epilepsy 4.1. Antipsychotics The S2-D2 or atypical neuroleptics are current rstline treatment for psychosis and are used in aggression and irritability. The term S2-D2 refers to the action of antagonism of atypical antipsychotics at the dopamine type 2 receptor, which is also an attribute of typical antipsychotics, and in addition, antagonism of the serotonin type 2A receptor, which is a distinguishing attribute of atypical antipsychotics. The serotonin type 2A receptor is thought to mediate the eects of classical indolealkylamine and phenethylamine hallucinogens such as D -lysergic acid diethylamide (LSD) and mescaline, and antagonism of this receptor has been thought to exert an antipsychotic eect. It is also theorized that antagonism of the 5HT2A receptor confers selectivity for the greater antagonism of dopamine (DA) in the mesocortical and mesolimbic than in the nigrostriatal DA pathways [24]. The relatively lesser blockade of atypical antipsychotics in the nigrostriatal DA pathway is associated with less tendency toward producing dystonia, akathisia, and tardive dyskinesia than typical antipsychotics. Among the S2-D2 antipsychotics, we use olanzapine (Zyprexa) most frequently, with doses ranging from 5 to 25 mg/day. The smallest available unit dose is 2.5 mg, which may be sucient for the long-term treatment of some patients with interictal psychosis. The major side eects associated with olanzapine are somnolence, weight gain, and glucose intolerance. Risperidone (Risperdal) is another frequently used atypical antipsychotic agent, with a dosage range in acute psychosis of 0.56 mg/day; the smallest available unit dose is 0.25 mg. Risperidone is associated with weight gain and an apparently somewhat greater incidence of extrapyramidal side eects than other atypical antipsychotics [25,26]. However, one of the authors (Dr. Barry) has found the use of low-dose risperidone to be very useful in PWE and aggressive behaviors. Many such patients have DD, and starting with a dose of 0.5 mg and increasing as necessary is often useful. It is often possible to use dosages below 2 mg, at which extrapyramidal reactions are less frequent.

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Quetiapine (Seroquel) is an additional S2-D2 agent that is relatively less associated with weight gain. Its dosage range for acute psychosis is 50600 mg/day; the smallest available unit dose is 25 mg. Ziprasidone (Geodon) is currently the most recently introduced S2-D2 agent; dosages for acute psychosis range from 40 to 160 mg/day. Concern regarding possible prolongation of the QT interval was raised during clinical trials and some clinicians obtain pre- and post-EKGs to measure the QT interval in patients treated with ziprasidone, although few actual problems have been evident in postmarketing surveillance. Clozapine (Clozaril) is an atypical antipsychotic with relatively high epileptogenicity, whose use in epilepsy is not generally recommended. Molindone (Moban) is a typical antipsychotic with a limited market in general psychiatry but very low apparent epileptogenicity and thus specic usefulness in epilepsy. One of the authors (Dr. Alper) has used molindone extensively with generally good success in patients with poor seizure control. Like the atypical antipsychotics that were introduced relatively later, molindone appears to have a greater eect on mesolimbic and mesocortical dopamine neurons than on those in the nigrostriatal dopamine system [27]. The dosage range of molindone in acute psychosis is 50 200 mg/day, and the smallest unit dose is 5 mg. None of the antipsychotics discussed above is available in a form allowing intravenous (IV) or intramuscular (IM) administration. Given the advantages of atypical antipsychotics, we have generally relied on them as rst-line agents when the oral route is appropriate and used typical antipsychotics when rapid IV or IM administration has been necessary. One of us (Dr. Alper) has relied mainly on IM perphenazine, which is rapidly absorbed, at a dosage of 5 mg repeated as needed up to a total dose of 20 mg/day. On the other hand, another author (Dr. Barry) has primarily used IV haloperidol. Dosages of 25 mg for moderately severe agitation and delirium can be used, often with a benzodiazepine, with reevaluation every 30 min [28]. IV haloperidol has a very low incidence of extrapyramidal reactions compared with the oral preparation [29], although, rarely, torsades de pointes may occur. 4.2. Benzodiazepines The use of benzodiazepines as psychotropic drugs in epilepsy is limited by problems with tolerance, sedation, and occasional behavioral toxicity [30]. We have used benzodiazepines such as lorazepam (Ativan) in the treatment of acute psychosis, at a dose of 0.52.0 mg, concurrent with the use of antipsychotic medication and generally given at night to help reinforce a normal sleep schedule.

4.3. Antidepressants The serotonin reuptake inhibitors (SRIs) are currently the class of antidepressants most commonly recommended for use in PWE. Among the SRIs, one factor guiding the choice of agents is minimizing interactions with liver microsomes. Sertraline (Zoloft) and citalopram (Celexa) appear to be relatively advantageous in this regard. Citalopram has minimal interactions with CYP-450 and is often the rst choice in the treatment of epilepsy patients with depression and irritability. Citalopram can be started at a low dose of 10 mg/day with dosage escalation of 10 mg every two to three weeks as needed up to a maximum of 60 mg/day, though dosages above 40 mg appear to be rarely needed in this population. Hovorka et al. [23] studied the eectiveness of citalopram in a group of depressed PWE, and noted a response rate of 65.1% with a dose range of 1040 mg with no exacerbation of seizures. Antidepressants may also lower the seizure threshold, and the rapidity of dosage escalation appears to be a factor. Thus a gradual increase in dose is suggested. An additional advantage of gradual dose escalation is that it provides a time window for response to relatively lower dosages, which is advisable given that the risk of seizure induction with psychotropic drugs tends to be dose-related. Side eects associated with SRIs include sexual dysfunction, weight gain, and gastrointestinal upset. In patients who do not respond well to SRIs, a possible alternative is venlafaxine (Eexor), which is a reuptake inhibitor of both serotonin and norepinephrine. The dose range of venlafaxine we use in patients with epilepsy is usually 75225 mg/day. Blumer [9] has recommended the tricyclic antidepressants (TCAs) for depression in PWE, and these drugs are sometimes coadministered with SRI antidepressants as an augmenting strategy. The TCAs include amitriptyline (Elavil), imipramine (Tofranil), nortriptyline (Pamelor), desipramine (Norpramin), and doxepin (Sinequan). As with most psychotropic agents, the tendency to lower seizure threshold is dose-related [31,32], and seizures are frequently seen in tricyclic overdoses. Serum levels should be followed closely since other drugs may increase and/or decrease the hepatic metabolism of TCAs and seizure induction seems to be directly related to serum levels [33]. Buspirone (BuSpar) is a serotonin 1A partial agonist originally marketed as an anxiolytic that has been reported to be eective for the treatment of aggression in a variety of neuropsychiatric conditions including head trauma, dementia, and developmental disorders [34,35]. In the experience of one author (Dr. Alper), buspirone appears to be particularly eective in patients with brain injury with a family history of anxiety disorder. Buspi-

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rone is typically given in two or three divided dosages in the range of 1060 mg/day. b-Adrenergic receptor blockers such as propranolol, nadolol, and pindolol have been used for the treatment of aggression, mainly in patients with schizophrenia, mental retardation, and traumatic brain injury [36,37]. Dosages of propranolol greater than 800 mg are usually not needed [37]. However, the use of dosages in this range is often limited by bradycardia and hypotension and may not be well tolerated by patients on anticonvulsants. Positive results have been reported in demented elderly patients treated with lower dosages ranging from 10 to 80 mg/day [38]. Metabolism of propranolol occurs via cytochromes 1A2, 2D6, and 2C19; thus drugdrug interactions can take place. SRIs may increase and carbamazepine decrease the levels of bblockers [13]. 4.4. Psychostimulants Amphetamines have unique activity in the treatment of impulsivity, aggression, distractibility, and motor hyperactivity in those patients with attention-decit/ hyperactivity disorders (ADHD). Methylphenidate (0.3 mg/kg) was used in one study and no increase in seizure activity was witnessed in those children who were seizure-free [39]. Of the ve patients with continued seizure activity, three sustained an increase in seizure rate. Overall, there was a 70% improvement according to parent reports. Methylphenidate was found to be safe and associated with seizure reduction even in high-risk patients [40]. Lithium has also been used in the treatment of aggression and agitation in patients with mental retardation and traumatic brain injury, but patients with brain injury are particularly sensitive to its neurotoxic eects [37]. It is proconvulsant but apparently used safely in epileptics with bipolar disorder [41]. Encephalopathy has been seen with the use of lithium in combination with carbamazepine [42]. 4.5. Antiepileptic drugs One of the most frequently successful pharmacological interventions in the setting of an epilepsy center is to adjust AEDs on the basis of the occurrence of behavioral toxicity. Although improved behavior generally parallels improved seizure control, behavioral toxicity of AEDs is still a common problem. Phenobarbital, possibly the most frequent oender, is often a cause of behavioral dyscontrol, irritability, and depression [43], and should be suspected in behavioral problems in patients taking this drug. Cognitive problems, depression, and psychosis have been observed with topiramate and are apparently dose-related and may be minimized somewhat if lower starting dosages and slower escalation

rates are used [44]. Psychosis and depression have also been observed with another carbonic anhydrase inhibiting drug, zonisamide [45]. Levetiracetam has been associated with anxiety and psychosis, which are apparently dose-related [46]. Valproate and carbamazepine are the AEDs usually used to treat aggressive or irritable behavior. These drugs, together with lamotrigine, and to a lesser extent, gabapentin and topiramate, have been used in the treatment of bipolar mood disorders [47,48]. The mood stabilizing AEDs can also be associated with behavioral toxicity, although this is relatively infrequent. Irritability and depression may occasionally be seen with valproate. Lamotrigine has been reported to provoke aggressive behavior and violence in some mentally retarded patients with epilepsy [49,50], and rarely can precipitate agitation and excitement, apparently mainly in children. Gabapentin has been reported to cause oppositional and aggressive behavior in learning-disabled children [51].

5. Conclusion Psychosis, irritability, and aggression in PWE may occur due to the bidirectional relationship between psychosis and epilepsy, in which the potential etiopathogenic mechanisms are believed to be closely related to the seizure disorder itself, and also may be a behavioral manifestation of comorbid neurological pathology. The use of appropriate psychotropic agents should minimize the possible lowering of seizure threshold and interactions with AEDs. The possibility of behavioral toxicity of AEDs should also be appreciated and may frequently improve with medication adjustment, while in addition, some AEDs appear to possess positive psychotropic eects.

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