Psychiatric Issues in Patients with Epilepsy and Mental Retardation

Raj D. Sheth

Arthur Rifkin

Psychotropic Properties of Antiepileptic Drugs in Patients with Mental Retardation

People with intellectual disability (ID) have subaverage intellectual functioning, usually defined as an intelligence quotient (IQ) of 70 or less. Such people show impairments in adaptation compared with expected functioning for their age and cultural group, such as impairment in communication, self-care, home living, social skills, use of community resources, self-direction, academic skills, work, leisure, health, and safety. These symptoms must start before the age of 18 years. Subcategories by IQ are: mild 50 to 70, moderate 35 to 50, severe 20 to 35, and profound less than 20 (1).

Approximately 1% of the population have ID, half of them to a mild degree. Neurological comorbidity is frequent: epilepsy 15% to 30%, cerebral palsy (CP) 20% to 30%, and sensory impairment 10% to 20% (2). This varies according to the severity of the ID. In one series of school-aged children with severe ID, 36% had seizure, 19% had CP, 10% had visual impairment, and 6% had hearing disorder (3). In a series of school-aged children with mild ID, 12% had seizures, 9% had CP, none had visual impairment, whereas 7% had hearing disorder (4).

The etiology of ID involves physical, social, and psychological factors, which often interact. The most common cause is genetic disorders—32%, such as chromosomal aberrations (e.g., Down’s syndrome from trisomy 21), malformations due to microdeletions (e.g., Angelman’s syndrome, Prader-Willi syndrome, Williams syndrome), monogenic mutations (e.g., tuberous sclerosis, fragile X syndrome), and multifactorial ID (e.g., “familial” ID).

Prenatal disorders due to external causes account for 12% of cases, such as maternal infections (e.g., rubella, human immunodeficiency virus [HIV], cytomegalovirus, and Toxoplasma infections), toxins (e.g., fetal alcohol syndrome), and other insults such as radiation and trauma. Perinatal causes account for 11%, such as infections (e.g., meningitis,
herpes), delivery problems (e.g., asphyxia and trauma), and other causes such as hypoglycemia and hyperbilirubinemia. Postnatal causes account for 8%, such as infections (e.g., meningitis and encephalitis), toxins (e.g., lead poisoning), other central nervous system (CNS) disorders, such as cerebrovascular accidents, tumors, and trauma, and psychosocial problems. Malformations of unknown cause occur in 8% of cases (e.g., neural tube defects and the Cornellia de Lange’s syndrome). In 25% of cases, the cause is unknown (5).

Mental Disorders in Persons with Intellectual Disability

Several factors make it difficult to diagnose mental disorders in the presence of ID. Cognitive impairment, poor ability to communicate, and sensory and motor disabilities interfere with the usual assessment of symptoms. Recognizing abnormalities of mood, language, and reality testing largely depends on the patient reporting subjective states. Many patients with ID cannot do this well, or cannot do it at all. Diagnosis of these problems relies more on observed behavior. Instead of describing hallucinations, the observer may see the patient gesticulating to a nonexistent person or voice. Depression may appear as a sad facial expression and as an observed lack of interest and enjoyment. Similarly, behavior indicating fear may be the only manifestation of anxiety.

To further complicate the matter, developmental thoughts and behavior may be confused with psychopathology. A normal 6-year-old child may have imaginary friends. So may an adult with a mental age of 6 years without it constituting psychopathology. Illogical speech and neologisms commonly occur in normal children and do not necessarily indicate psychopathology in a person with ID in the same mental age as the normal child.

Finally, diagnosis is difficult in persons with ID because of the frequent occurrence of aggression, especially in adults. Mental disorders of adults rarely depend on the presence of aggression. Aggression may be found in persons without ID, having disorders such as schizophrenia, mania, and dementia, but does not represent an essential, diagnostic symptom. In persons with ID, aggression constitutes the most common symptom, usually without clear symptoms indicating a common mental disorder. How to deal with this remains controversial. Some clinicians consider aggressive symptoms as variants of the usual symptoms characteristic of common disorders, such as schizophrenia, mood disorders, and anxiety disorders, claiming that the usual diagnostic criteria become altered in persons with ID.

Other clinicians reject the “medical model” of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) and consider aggressive behavior acquired as the result, usually, of poor care and stressful conditions. Such clinicians aver that unsupportive conditions, in which many people with ID find themselves, cause anger and frustration, which they express with aggressive behavior. This aggression may follow the frustration of observing how people with normal intelligence have more autonomy and access to pleasurable activities than they do, or from the mistreatment many such persons receive from inhumane caregivers and/or from inhumane conditions.

Still other clinicians consider aggressive behavior a manifestation of the lack of frontal lobe inhibition, because many people with ID have CNS impairment that is more widespread than that affecting intelligence alone (6).

These conceptual models to account for aggressive behavior in persons with ID need not be viewed as necessarily separate. Diagnosis should provide the clinician with a shorthand way to summarize useful data. The diagnostic schema of DSM-IV has validity as descriptions that predict, to some extent, the likelihood that such symptoms occur together, course, familial predilection, and response to treatment. If a disorder has a well-delineated etiology and pathophysiology, they become the basis of diagnosis. Unfortunately, such information is lacking for persons with ID who show aggression, and is missing, usually, for those with all mental disorders.

The diagnosis of intermittent explosive disorder (IED) in DSM-IV serves as a useful category for persons with excessive
aggression not due to any other mental disorders, such as psychosis, mood disorders, or anxiety disorder. IED does not discount possible etiologies of learned behavior or CNS impairment. An agreed-upon category creates a means to examine groups of such patients and to observe associations to etiological and treatment variables. Yet, the uncomfortable situation of the lack of clear, valid diagnoses of mental disorders in persons with ID, exists.

The uncertainty about the diagnosis of mental disorder in persons with ID has led to epidemiological confusion. Corbett (7) found, in a cohort of 402 adults with severe or profound mental retardation, that 51% received an International Classification of Disease (ICD) diagnosis, of whom 25% had a diagnosis of behavior/personality disorder. In Denmark, using ICD criteria, Lund (8) sampled 324 adults from the national register of 22,500 adults with ID. He found that the most common diagnosis was behavioral disorders (19% of men, 7% of women). He found schizophrenia, affective disorder, dementia, and neurosis in only 1% to 3%. Ballinger et al. (9) reported ICD-9 diagnoses in 100 randomly selected adults with ID living in an institution, and found that 17% had personality disorder, 15% had conduct disturbance, and 12% were psychotic. Eaton and Menolascino (10) described DSM-III diagnoses of 168 consecutive referrals for psychiatric evaluation and reported that 27% had schizophrenia, 25% had personality disorder, 19% had an adjustment disorder, 27% had organic brain syndrome, and 0.8% had anxiety disorder. Russell and Tanguay (11) using DSM-II criteria in 93 consecutive admissions to an adolescent unit reported that 33% had behavioral disorders, 21% had transient situational disturbance, 14% had special symptoms, 13% had neuroses, 12% had personality disorder, and 12% had schizophrenia or autism. In a recent study, King et al. (12) described their diagnoses of 251 patients, using DSM-III-R criteria, institutionalized for severe to profound mental retardation, who were referred for psychiatric evaluation. They found that 12% had impulse control disorder, 10% had stereotypy/habit disorder, 1% was psychotic, 2% had major depression, 3% had mania, 5% had an anxiety disorder, and 3% had attention-deficit hyperactivity disorder (ADHD). These studies did not use structured diagnostic interview schedules.

Drug Treatment of Mental Disorders in Persons with Intellectual Disability

Many patients with ID receive psychotropic drugs: 57% in institutions, 41% in community-based programs, and 22% in school-based programs. Antipsychotic drug (APs) and antiepileptic drugs (AEDs) are the most commonly used drugs (13). By far, APs remain the most used drugs even in patients with ID and aggressive symptoms without psychosis. Some surveys have shown that schizophrenia has a higher lifetime prevalence in patients with ID than in the general population, for example, 3.4% to as high as 12.4% (14).

Antipsychotic Drugs

One excellent review of 24 studies of antipsychotic medications in mentally retarded schizophrenic patients (15) excluded studies that lacked a placebo control group, studies with treatment period of less than 1 month, or studies that did not report outcome measures in a manner permitting statistical analysis. Only one study met these criteria that had only four subjects (the other subjects in the trial had other diagnoses or were not mentally retarded) (16). Therefore, there is no support from randomized controlled trials to use antipsychotic medications for this indication.

Another question concerns using antipsychotic medications in nonpsychotic mentally retarded patients who have an impulse control disorder, the main use of antipsychotic medications in adults with ID. A search of the literature for studies with a placebo control and random assignment yields only four studies. Van Hemert (17) compared pipamperone (an antipsychotic not marketed in the United States) with placebo in 20
female inpatients in a crossover design. The data analysis of unvalidated rating scales precludes any conclusion.

Albert et al. (18) studied an experimental antipsychotic medication (SCH-12679) in 18 female inpatients, but did not present analyzable data. Buitelaar et al. (19) compared risperidone with placebo in 38 inpatients aged 12 to 18 years with chronic aggressive behavior, who had not responded to outpatient treatment. This really constitutes a study of treatment nonresponders and does not address the question of the value of the drug for patients who are more typical. On a global measure, the severity score of the CGI (Clinical Global Impressions) scale (20), they found risperidone significantly superior to placebo at endpoint and at the second, fourth, and sixth (and final) weeks. They measured efficacy as well on two rating scales, the OAS-M, a modified version of the Overt Aggression Scale (21) and the ABC (Aberrant Behavior Checklist) (22) completed by ward personnel and teachers. Of 22 comparisons with these instruments, only 2 showed a significant drug–placebo difference—the teachers’ ratings on the ABC overall score, and hyperactivity. This seems a rather weak support for the superiority of risperidone.

One recent study also tested risperidone (23). The study of 13 subjects aged 6 to 18 years, with “persistent behavioral disturbance” was for 4 weeks of treatment. They reported that five of six subjects given risperidone improved considerably, versus none of the seven subjects treated with placebo, a significant difference (chi square = 6.285, p = 0.012). On the dimensional measures of change, risperidone was significantly superior to placebo in 6 of 21 comparisons: irritation and hyperactivity on the ABC, the mean score of the CGI, on a visual analog scale of the severity of the most important symptoms, and social relationships and occupational attitudes on the Personal Assessment Checklist, an unvalidated measure.

It is surprising and shocking that the frequent use of APs in patients with ID has such a weak database. It signifies the less importance given to ID by psychopharmacologists. Given the common practice of using APs for this indication and the substantial anecdotal evidence, it seems reasonable to use them, especially since no other drugs have more proof of efficacy.

APs are categorized as first generation APs (FGAs) or second generation APs (SGAs). SGAs consist of olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole, often called atypical APs. The FGAs (“typical” APs) consist of all other APs (clozapine is considered separately). SGAs have the advantage of causing fewer extrapyramidal side effects and less tardive dyskinesia compared with usual doses of FGAs, but some SGAs are more likely to cause the metabolic syndrome (weight gain, hyperlipidemia, increased insulin tolerance, and hypertension), such as olanzapine, risperidone, and quetiapine. In recent years, the use of SGA has enormously surpassed that of FGAs.

A recent study (24) compared SGAs (except for aripiprazole) with a low dose of a FGA—perphenazine. Olanzapine proved slightly more effective, but was much more likely to cause weight gain. Perphenazine was not associated with more extrapyramidal side effects or tardive dyskinesia during the period of observation (maximum 18 months, usually less). Previous comparisons of SGAs with FGAs used higher dosages of FGAs (25). SGAs are considerably more expensive than FGAs. Further research should provide a firmer basis for choosing SGAS or FGAs. All comparisons of FGAs and SGAs used subjects with schizophrenia or schizoaffective disorder. It remains to be seen which agents are more useful in patients with ID. At present, it seems best to use a low-dose FGA, ziprasidone, or aripiprazole. The FGA has the decided advantage of costing less. Most persons with ID receive government assistance for medical and other care. If such programs must spend much of their funds for SGAs, they will have less money for other important services.

Drugs for Attention-Deficit Hyperactivity Disorder

The differential diagnosis of ADHD and IED may be confusing. The presence of ID itself leads to impaired attention and impulsivity. Clinicians should use the diagnosis of ADHD to indicate inattention, hyperactivity, and impulsivity only when these symptoms far surpass the norm in persons with ID. Aman et al. (26) compared methylphenidate (MPD) to thioridazine to placebo in a crossover design, each treatment given for 3 weeks. They showed MPD as significantly better than placebo on the Connors’ Teachers Questionnaire on scales of conduct, problem behavior, inattention, and hyperactivity, and on the global rating. Thioridazine was significantly superior to placebo on some of these scales. Response was limited to those with IQs above 45. No studies have appeared for the treatment of adults with mental retardation and ADHD. It seems reasonable to try MPD in such patients; the drug is relatively safe, and whether the patient responds will be seen within a few weeks.

Lithium

One double-blind placebo-controlled study by Tyrer et al. (27), using a 1-month crossover design in 25 hospitalized patients with aggressive behavior, found only one significant difference (a factor rating stereotypy and antisocial behavior) of 6 factor scores on a behavior rating scale.

Craft et al. (28) studied 42 aggressive, mentally retarded, hospitalized subjects from five institutions, administering lithium or placebo for 4 months. On a global measure, they found lithium significantly superior to placebo.

The possibility of a concomitant diagnosis of mania in mentally retarded persons is present. Rivinus and Harmatz (29) point out that a change in usual behavior resulting in increased speech, motor activity, aggressiveness, sleeplessness, and decreased appetite should suggest mania. They report lithium treatment in five such subjects to whom they administered lithium openly for 1 year, then replaced it with placebo for 3 months, and resumed lithium for 1.5 years when “manic symptoms reappeared.” Their anecdotal data show reduced symptomatology during lithium treatment. One might question the diagnosis of mania for symptoms that lasted so long.

Worrall et al. (30) administered lithium to eight aggressive nonmanic adults with ID. Three became less aggressive, one worsened, two did not change, and two developed too many side effects to continue the trial.

Opioid Antagonists

Naloxone and naltrexone have been studied for self-injurious behavior (SIB). A number of anecdotal reports and crossover, placebo-controlled studies have shown generally positive results (31). One explanation is that these patients have high levels of endogenous opioids and, therefore, a high pain threshold, which leads to SIB to attract attention or to increase arousal. Conversely, some think that patients injure themselves to induce increases in endogenous opioids, which causes euphoria. In animals, opioid agonists induce self-mutilation. Studies have found increased opioid concentrations in the cerebrospinal fluid (CSF) of children with SIB (32) and increased levels of β-endorphin (33).

Unfortunately, none of the clinical studies has used double-blind, placebo-controlled designs that permit statistical analyses to determine significance. The significance levels reported in some studies seem spurious because the “N” used for computations comes from the number of observations of a few patients rather than the number of subjects. All that seems justified at this time is to try naltrexone in such patients because it has relatively few side effects and its effect should be seen without the need for a long trial.

Anticonvulsants

There is one anecdotal report of carbamazepine (CBZ) reducing the aggression in a person with ID who did not have epilepsy (34).
A placebo-controlled study of divalproex in 20 children and adolescents without ID, who showed aggressive behavior and no other Axis I disorder, demonstrated superiority for the anticonvulsant (35). Barratt (36) found phenytoin (PHT) superior to placebo in prisoners, without ID, with impulsive aggression, and not effective in those with premeditated violence.

Allopurinol

Lara (37,38) reported anecdotes of allopurinol reducing aggression in patients with known CNS impairment, one of whom had ID.

β-Blockers

The studies of β-blockers for aggression have used, mainly, subjects other than mentally retarded persons. It is not clear how they work, although animal studies indicate that the antiaggressive dose is much smaller than the dose that inhibits other activities. Perhaps it is merely a nonspecific sedative effect. These drugs also block serotonergic receptors. Fourteen studies have tested propranolol in aggressive patients, but only two studies have involved mentally retarded patients (39). Only 1 of the 14 studies used a placebo control and that study had only nine demented subjects; therefore, no study has tested efficacy definitively. In the two studies on mentally retarded subjects, 19 of 22 (86%) responded. Most studies used propranolol as adjunctive to other drugs. Propranolol elevates blood levels of patients using APs, which possibly, but not likely, accounts for its efficacy.

Nadolol has been tested in aggressive schizophrenic patients by a double-blind, placebo-controlled, and parallel design study. It significantly reduced aggressive behavior (40); however, the groups differed significantly at baseline and the statistical analysis of the endpoint data did not take this into account.

Propranolol and nadolol appear worthy of a trial in aggressive mentally retarded patients although the evidence for efficacy is hardly conclusive.

Serotonergic Drugs

Because of the findings that low CSF 5-HIAA correlates with aggressive behavior (41), some studies have appeared using drugs that enhance serotonergic activity to treat aggressive behavior. No definitive studies in mentally retarded subjects or those with any other diagnosis have appeared. Anecdotal reports have been published; for example, (42) using trazodone and tryptophan (a serotonin precursor) in one mentally retarded patient with success, and a retarded adult with Down’s syndrome did well on trazodone and a “serotonin-enhancing” diet (43). Ratey et al. (44) found buspirone effective in mentally retarded aggressive subjects, in an anecdotal report.

Benzodiazepines

Short-term use of benzodiazepines (BZs) is a standard treatment of serious aggressive behavior, regardless of diagnosis. Despite its ubiquitous use, there are few systematic studies. BZs are among the safest of drugs and seem more appropriate for short-term use than an antipsychotic, the other drug most commonly used for this indication. The fear of paradoxical reactions with increased aggression to BZs has caused concern in some. Apart from paper and pencil tests of normal volunteers showing elevations of scores on measures of hostility, there exists no clear evidence that BZs increase aggression in patients to any clinically important extent (45). Most patients described in the literature to exemplify this reaction had similar rages while not receiving a BZ.

For long-term treatment of aggression, no studies have appeared using BZs, but despite this, they deserve a place in the ranking of drugs to be tried, but not a very high one.

Epilepsy Consideration in Treatment

The occurrence of epilepsy and psychiatric disorders in the same patient is relatively frequent because in 50% of patients with epilepsy, seizures are symptomatic of an underlying neurological deficit (46,47).
Accordingly, it is not surprising that the two disorders frequently coexist and often respond to similar therapeutic agents.

Recently, efforts to systematically understand the relationship between epilepsy and psychiatric disorders were undertaken by Hermann et al. (48). They examined the nature and extent of differences in self-reported psychiatric symptoms between patients with temporal lobe epilepsy and matched healthy controls, and attempted to correlate the duration of temporal lobe epilepsy with comorbid interictal psychiatric symptoms in 54 patients compared with 38 healthy controls. The Symptom Checklist-90-Revised90-Revised (SCL-90-R) was used to assess the nature and severity of psychiatric symptomatology and epilepsy; patients completed the Quality of Life in Epilepsy-8989 (QOLIE-89) to define health-related quality of life. Compared with healthy controls, patients with epilepsy exhibited significantly worse scores across all but one of the 12 SCL-90-R scales. Among patients with epilepsy, increasing chronicity was associated with significantly worse scores across all SCL-90-R scales and increased emotional–behavioral distress was associated with worse scores across all 17 QOLIE-89 scales. They concluded that comorbid interictal psychiatric symptoms are elevated among patients with temporal lobe epilepsy compared with healthy controls and appear to be modestly associated with increasing duration of epilepsy.

Not uncommonly, however, medication used to treat one disorder may result in improvement or exacerbation of the other disorder. In the 1960s, there was an appreciation for the adverse psychiatric consequences of treating seizures in patients with ID. Often, the psychiatric manifestations were subclinical and not overtly manifest, while at other times there was an exacerbation of psychiatric comorbidity (49). The emergence of new psychiatric symptoms in patients otherwise totally healthy raised concern of the potential for negative psychotropic effects of AEDs. The most direct evidence was uncovered with the sudden emergence of severe aggressive behavioral attention problems when phenobarbital (PHB) was used to treat febrile seizures (50). Furthermore, AEDs may impact sleep architecture and result in behavioral changes, particularly attention deficit disorder (51). Hence, it is important to understand the potential for favorable and unfavorable adverse psychotropic effects of AEDs. Although the selection of AEDs for use primarily in epilepsy is well defined, there remains considerable therapeutic uncertainty in choosing an appropriate AED to treat seizures and comorbid psychiatric disorders.

Early attempts to understand similar relationships with other AEDs relied on personal experience and opinion (52,53). Coulter systematized AED choices for treating both epilepsy and comorbid psychiatric conditions based on relative efficacy of the drug against specific seizure type (54). In this formulation, PHT and CBZ were most commonly used to treat partial seizures; valproic acid (VPA), gabapentin (GPN), lamotrigine (LTG), tiagabine (TGB), and topiramate (TPM) were also thought to be effective. Ethosuximide (ESM) is indicated in the treatment of absence seizures; VPA and LTG may also be considered. The dominant features of Lennox-Gastaut syndrome, generalized myoclonic, tonic, and atonic seizures can be treated with VPA, LTG, felbamate (FBM), or TPM. Generalized tonic-clonic seizures can be treated with PHT, CBZ, FBM, LTG, or TPM.

Currently, there is a lack of studies that focus on the management of psychiatric disorders occurring in patients with ID and epilepsy. Insights gained from AED usage in other populations can be applied in the management of patients with ID and epilepsy. However, caution is required in the direct application of this literature since many reports are anecdotal and most fail to examine premorbid psychiatric status. Furthermore, many reports are based on cases with very high anticonvulsant levels (55). Other methodological pitfalls in the literature include associating mood change with the introduction of a new AED and ignoring
potential effects of discontinuing the current agent, disregarding the positive effects on mood achieved by reducing seizures, failure to address the complex relationship of drug-induced cognitive impairment with mood, poor recognition of important inequities in drug trial comparison groups (e.g., groups with noncomparable drug levels), analysis of limited samples, selection bias, the negative effect of polytherapy irrespective of the specific agent, and failure to apply correction methods in statistical analysis of large numbers of variables. Other confounding variables include reliance on retrospective data, focusing on transient acute drug effects, and inappropriate extrapolation of the data on drug effects in healthy volunteers to patients with epilepsy (56). There may also be significantly lower rates of psychotropic effects on mood and behavior noted in general drug trial reports compared with studies that specifically target these factors, although reasons underlying this observation are not clear.

For most AEDs, numerous conflicting reports abound concerning both positive and negative psychotropic effects, and the reader of the medical literature needs to remember that mean tendencies may differ from individual patient experience. Another challenge in analyzing psychotropic effects of AEDs relates to our inability to assess these effects as completely independent variables. Patients who experience a reduction in or resolution of seizures as a result of AED therapy may experience associated elevations in mood and improvements in quality of life. Conversely, the stigma of taking AEDs or reactions to experiencing side effects (e.g., cosmetic effects, fatigue, cognitive impairments) may adversely affect mood and behavior (57).

This section focuses on the psychotropic effects of individual AEDs, although clinicians are very likely to encounter developmentally disabled epileptic patients receiving more than one medication, including antiepileptic and psychotropic drugs. This confounds the clinician’s attempt to determine which agent is specifically responsible for the positive or negative effects on behavior. Recent consensus among epileptologists on the value of striving for AED monotherapy in the treatment of the non-ID epileptic patient should also apply to the population with ID. Numerous studies have demonstrated that reduction in AED polypharmacy does not necessarily lead to seizure exacerbation, and patients may enjoy improvements in cognition and behavior when they receive smaller number of medications (58,59).

Effects of AED on behavior may relate to their variable effects on different groups of cortical neurons. AEDs may alter neurotransmitter levels (e.g., norepinephrine and γ-aminobutyric acid [GABA]) or ion channel function, which in turn may impact on both seizures and mood (55). For example, the mood instability of bipolar disorder has been theorized to occur on the basis of decreased GABAergic neurotransmission or by altered sodium channel function. Some AEDs may improve mood instability by increasing GABA and by modifying sodium channel function.

In children with ID and epilepsy multiple factors—including efficacy, pediatric-friendly formulations, ease of dosing and titration, and tolerability issues (such as possible drug interactions and adverse events)—affect the selection of the best AED. Behavioral problems are common in children with epilepsy and can be aggravated or initiated by AED therapy (60).

Individual Antiepileptic Drugs

Ketter et al. (61) proposed classifying AEDs into two global categories based on their psychotropic properties and mechanisms of action. One group is considered to have “sedating” effects in association with fatigue, cognitive slowing, and possible anxiolytic and antimanic effects. These actions are speculated to be related to a predominance of GABA inhibitory neurotransmission potential and occur with barbiturate, BZ, valproate, GPN, TGB, and vigabatrin (VGB). A second group is thought to have “activating” effects with possible anxiogenic and antidepressant effects. The second group
is associated with attenuation of glutamate excitatory neurotransmission and includes FBM and LTG. TPM, which possesses both GABAergic and antiglutamatergic actions, is said to have a mixed profile. Animal models and evidence from clinical experience are used to support this classification.

Only gold members can continue reading. Log In or Register to continue