Marco Mula, MD, PhD

For a long time, the correlation between epilepsy, seizures, and emotions has been a matter of debate, fascinating generations of clinicians and neuroscientists. In his famous quotation, Hippocrates reported that “melancholics ordinarily become epileptics, and epileptics, melancholics: what determines the preference is the direction the malady takes; if it bears upon the body, epilepsy, if upon the intelligence, melancholy.”

 This ancient observation has been recently revitalized by modern epidemiological data that suggest a bidirectional relationship between epilepsy and mood disorders and between epilepsy and suicide.

 However, psychiatric comorbidity in epilepsy represents not only a matter of intellectual interest but also an important variable that affects prognosis in terms of morbidity and mortality.

Mood and anxiety disorders are the most frequently reported psychiatric comorbidities with epilepsy, with a prevalence of 20% to 22%; however, in select populations, the prevalence can reach 50%.

 Reasons for the association are both biological and psychosocial. Epilepsy is a chronic disorder that brings about a number of social limitations and discriminations that lead to demoralization and poor self-esteem. Moreover, epilepsy and mood disorders seem to share a common neurobiology, with involvement of the limbic structures and the modulation of major neurotransmitter pathways by anticonvulsant medications.

Compared with mood disorders, psychoses seem to be relatively rare in patients with epilepsy but represent serious complications that affect morbidity and mortality. Epidemiological data indicate that the incidence of non-organic, non-affective psychoses, including schizophrenia and related disorders, is generally overrepresented in patients with epilepsy compared with the general population or those with other chronic medical conditions. Higher prevalence has been seen in hospitalized patients.

 The relationship between epilepsy and psychoses has strong neurobiological underpinnings related to the involvement of specific brain areas.

The issue of phenomenology and diagnosis of mood disorders

Mood disorders in epilepsy frequently go unrecognized and untreated because of lack of time, lack of training, and clinicians’ reluctance to refer patients because of psychiatric symptoms. In addition, up to 50% of patients with epilepsy and depression present psychiatric symptoms that are not captured by standardized classificatory systems, such as DSM and ICD-5.

 This is particularly evident in the case of interictal dysphoric disorder (IDD).

The concept of IDD is derived from Kraepelin and Diefendorf

 who observed that in patients with untreated epilepsy, a pleomorphic pattern of depressive symptoms intermixed with euphoric moods, irritability, fear, and anxiety as well as with anergia, pain, and insomnia could develop. This concept has been subsequently rejuvenated by Blumer,

 who coined the term “IDD” and described 8 key symptoms, grouped into 3 categories: labile depressive symptoms (depressive mood, anergia, pain, insomnia); labile affective symptoms (fear, anxiety); and “specific” symptoms (paroxysmal irritability, euphoric moods).

The specific symptoms are a peculiar symptom cluster characterized by periodic mood changes and outbursts of irritability and aggressive behavior. These episodes occur without external triggers and without clouding of consciousness; they begin and end quickly and recur fairly regularly (every few days to every few months and last from a few hours to 2 days). The symptom cluster described in patients with IDD and epilepsy is quite peculiar and is rarely reported in psychiatric practice, even in patients with rapid cycling bipolar disorder or cyclothymia. It is interesting to note that in about 50% of patients, dysphoric symptoms present a clear-cut relationship with epileptic seizures occurring either preictally or postictally.

Epileptic seizures are characterized not only by the ictal phase but also by a number of behavioral manifestations that may precede or follow the seizure. Such peri-ictal symptoms may fail to meet temporal DSM criteria when too short-lasting. However, it appears that they are highly responsible for the atypical presentations of psychiatric disorders in epilepsy.

Alternatively, peri-ictal symptoms may be misleadingly interpreted as psychiatric manifestations when they are long-lasting. In fact, a cross-sectional study of patients shows that a diagnosis of bipolar disorder can be overestimated in epilepsy if peri-ictal mood changes are not correctly identified.

 In fact, of the 11.8% of DSM-based diagnoses of bipolar disorder, only 1.4% can be considered as a “pure” psychiatric diagnosis because in all other cases, manic/hypomanic symptoms are temporally related to seizures that occur either postictally or preictally. Thus a careful assessment of seizure-based behavioral manifestations should always be part of a routine assessment, with treatment strategies based on peri-ictal symptoms.

The Interictal Dysphoric Disorder Inventory (IDDI) is used for the evaluation of IDD and the identification of seizure-associated symptoms.

 This 38-item, self-report questionnaire looks at a time interval of 12 months and provides a total score in addition to 3 subscale scores that mirror the major symptom categories of IDD. The questionnaire is also used to measure the degree of interference or distress caused by mood symptoms. The IDDI has demonstrated good internal consistency, acceptable sensitivity, and excellent specificity. The Appendix to the questionnaire includes 6 questions that pinpoint the time course and duration of mood symptoms and their associations with seizures or antiepileptic drug therapy.

Psychoses of epilepsy have fascinated neuropsychiatrists for decades. Although an important topic of research, psychoses of epilepsy are definitely less prevalent than seizure-based psychotic symptoms. Mood symptoms are conveniently classified according to their temporal relationship with seizures as preictal, ictal, or postictal.

Ictal psychoses usually represent a nonconvulsive epileptic status of temporal lobe origin. Postictal psychoses are probably the most relevant in epidemiological terms, representing approximately 25% of all psychoses of epilepsy. They are usually precipitated by a series of secondary generalized tonic-clonic seizures followed by a period of normal mental state of 24 to 48 hours. Almost all patients have this lucid interval, and failure to recognize it can lead to misdiagnoses. The pathophysiology of postictal psychoses is unknown, but it is a highly stereotyped phenomenon that occurs mainly in patients with mild intellectual disabilities, temporal lobe epilepsy, and extratemporal structural lesions. Findings indicate a correlation between postictal psychoses and dÃ©jÃ  vu auras or ictal fear.

The phenomenology of postictal psychoses is polymorphic, but most patients present with abnormal mood and paranoid delusions with mystic and religious content. Consciousness can be variably impaired (eg, from overwhelming confusion to totally clear sensorium). High levels of anxiety with a fear of impending death represent another typical symptom that may precipitate in episodes of violence, self-injury, or suicide if command hallucinations are present.

Postictal psychoses are characterized by spontaneous remission within days or weeks; antipsychotic drug treatment is only required to reduce mortality and morbidity. Finally, it has to be kept in mind that in a minority of cases, postictal psychoses may evolve into chronic interictal psychosis.

Nowadays, interictal psychoses represent a rare complication, and the general impression is that this is probably because of effective treatment of epileptic syndromes. In fact, interictal psychoses usually develop subtly after 25 years of active lesional temporal lobe epilepsy. Neuropathology studies of patients with interictal psychoses show cerebral malformations, such as hamartomas and gangliogliomas, and gross abnormalities, such as enlarged ventricles and periventricular gliosis.

The link between interictal psychoses and mesiotemporal lobe structures is well established and demonstrated by clinical and neuroimaging findings.

 However, the timing of the lesions and the functional changes in the brain of patients with interictal psychoses are largely different from those described in schizophrenia, which suggests that the pathophysiology of interictal psychoses is largely integrated with that of epilepsy.

The phenomenology of interictal psychoses seems to be slightly different from that of schizophrenia. Slater and Beard

 emphasized the preservation of affect in the context of first-rank symptoms of Schneider, with religious mystical content. The paucity of negative symptoms and the absence of formal thought disorders and catatonic states have also been proposed.19 The longterm prognosis of interictal psychoses seems to be better than that of schizophrenia, with less reported long-term cognitive deterioration and institutionalization. This is probably because of the preservation of personality and the tendency for psychotic symptoms to attenuate over time.

Landolt phenomenon, also known as “forced normalization” or “paradoxical normalization,” can occasionally be seen.

 In the 1950s, Landolt published a series of papers on patients in whom a psychotic state emerged when their epilepsy was controlled.

 described the clinical counterpart of this phenomenon: patients who became psychotic on sudden remission of seizure symptoms. Landolt originally associated the forced normalization phenomenon with focal epilepsies, but subsequent studies suggest an association with generalized epilepsies.

 In any case, what seems to be striking is the association with neurobiological mechanisms underlying seizure control. In fact, Landolt’s phenomenon has been reported not only with antiepileptic drugs but also with vagus nerve stimulation, and it is likely implicated in psychoses following surgery.

It terms of phenomenology, the classic presentation is that of psychosis, but other symptoms may be present, such as manic episodes, depressive episodes, and dissociative states. Generally, forced normalization is a self-limited phenomenon that lasts days or weeks, and drug treatment is only required to reduce mortality and morbidity.

Data on treatment of psychiatric disorders in epilepsy are still limited and based mainly on clinical observations. However, in recent years, international societies (eg, the International League Against Epilepsy and the American Epilepsy Society) have paid increasing attention to the problem.

Treatment follows the internationally accepted guidelines for treating psychiatric disorders while keeping in mind pharmacodynamic and pharmacokinetic idiosyncra-sies, such as drug interactions and the effects of psychotropic medications on seizure threshold.

 New generations of antidepressants and antipsychotics can be considered reasonably safe in patients with epilepsy, if they are appropriately prescribed in terms of titration and dosages. The “start low/go slow” recommendation represents a starting point, but bear in mind that low starting doses do not necessarily correspond to low target doses. The primary goal is full symptom remission.

Dr Mula is Consultant in Neurology and Epileptology with the Epilepsy Group in the department of neurology at St George’s Hospital in London. At the time of the writing of this article, Dr Mula was in the division of neurology at Trinity Hospital in Borgomanero, Italy. He reports no conflicts of interest concerning the subject matter of this article.

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 Krishnamoorthy ES, Trimble MR, Blumer D. The classification of neuropsychiatric disorders in epilepsy: a proposal by the ILAE Commission on Psychobiology of Epilepsy. 

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 Blumer D. Dysphoric disorders and paroxysmal affects: recognition and treatment of epilepsy-related psychiatric disorders. 

 Mula M, Jauch R, Cavanna A, et al. Interictal dysphoric disorder and periictal dysphoric symptoms in patients with epilepsy. 

 Mula M. The interictal dysphoric disorder of epilepsy: a still open debate. 

 Mula M, Schmitz B, Jauch R, et al. On the prevalence of bipolar disorder in epilepsy. 

 Savard G, Andermann F, Olivier A, RÃ©millard GM. Postictal psychosis after partial complex seizures: a multiple case study. 

 Tebartz Van Elst L, Baeumer D, Lemieux L, et al. Amygdala pathology in psychosis of epilepsy: a magnetic resonance imaging study in patients with temporal lobe epilepsy. 

 Mula M, Cavanna A, Collimedaglia L, et al. Clinical correlates of schizotypy in patients with epilepsy. 

 Slater E, Beard AW. The schizophrenia-like psychoses of epilepsy, V: discussion and conclusions. 

 Getz K, Hermann B, Seidenberg M, et al. Negative symptoms in temporal lobe epilepsy [published correction appears in 

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Forced Normalization and Alternative Psychoses of Epilepsy

. Petersfield, UK: Wrightson Biomedical Pub Ltd; 1998.

 Gatzonis SD, Stamboulis E, Siafakas, et al. Acute psychosis and EEG normalisation after vagus nerve stimulation. 

 Mula M, Kanner AM. Introduction-Treatment of psychiatric disorders in adults with epilepsy: what every epileptologist should know. 

 Mula M, Monaco F, Trimble MR. Use of psychotropic drugs in patients with epilepsy: interactions and seizure risk. 

Articles

Psychiatric comorbidity in epilepsy represents not only a matter of intellectual interest but also an important variable that affects prognosis in terms of morbidity and mortality.

Epilepsy and Seizures: Neuropsychiatric Implications

The Intricacies of Diagnosis and Treatment, by Thomas L. Schwartz, MD

Strategies for Assessing and Treating Comorbid Panic and Generalized Anxiety Disorder, by Kristalyn Salters-Pedneault, PhD

Can Anticonvulsants Help Patients With Anxiety Disorders? by Marco Mula, MD, PhD

SSRIs as Antihypertensives in Patients With Autonomic Panic Disorder, by Sean Hood, MBBS, MSc

Achieving Remission in Generalized Anxiety Disorder, by Laura A. Mandos, PharmD, Jennifer A. Reinhold, PharmD, and Karl Rickels, MD

Anxiety disorders are chronic conditions that follow a relapsing/remitting course.

 The evidence to support this view comes primarily from cross-sectional and retrospective assessments of duration of illness and, in part, from prospective studies. The waxing and waning nature of panic disorder and generalized anxiety disorder (GAD), for example, has been clearly demonstrated. Much less information is available about the course of illness of social phobia. However, both community studies and patient samples suggest an age of onset of social phobia in mid to late teens with a chronicity that is equal to or greater than that of panic disorder.

 Nevertheless, this recognition has not reshaped our basic treatment approach, which focuses almost entirely on the acute control of symptoms and only secondarily acknowledges relapse prevention.

In addition, the natural history of anxiety disorders is frequently complicated by Axis I and Axis II comorbidity that seems to be significantly higher among patients who seek treatment than in persons in the community who are not in treatment.

 In fact, it has been estimated that 73% of patients with panic disorder had other comorbid conditions that ranged from major depression to substance abuse until the onset of the Axis II disorders, mostly cluster C type 1 to 2. It is, therefore, evident that any long-term anxiolytic treatment strategy must take account of these high rates of comorbidity that appear to develop during the longitudinal phase of the anxiety disorder.

A variety of drug classes have been shown to be effective in treating anxiety disorders. SSRIs are the current gold standard for anxiety disorders. Effective in about 50% to 60% of patients, serotonin noradrenalin reuptake inhibitors are now considered the gold standard specifically for panic disorder and GAD. Benzodiazepines have a rapid onset of action, but their long-term use may lead to complications, such as abuse liability, dependence, and withdrawal risk if the dosage is not tapered properly. Moreover, in some patients, benzodiazepines may cause sedative effects and cognitive deficits that significantly affect quality of life and social functioning.

The basis for the use of anticonvulsant drugs in treating anxiety disorders can be found in the main cerebral structures involved in fear circuits. Although numerous brain regions are likely to be involved, the amygdala and the hippocampus play a key role.

 The amygdala is im­portant in experiencing fear and its autonomic and endocrine response through the output to the hypothalamus, while the output to periaqueductal gray matter is mainly implicated in avoidance behavior, which is also typical of fear response.

 In addition, the hippocampus is important in the re-experiencing of fear and the cognitive aspects of fear and anxiety.

The reduction of an excessive output from these neurons may theoretically diminish anxiety symptoms. In fact, anticonvulsant drugs exert their antiseizure activity by decreasing the excessive outbursts from epileptic neurons. Therefore, these drugs could reduce symptoms of anxiety by decreasing neuronal activation within fear circuits. Unlike other drug classes, anticonvulsants are not usually categorized according to their mechanisms of action or chemical structure. This is because their actions are not completely understood at the molecular level, and current knowledge indicates that almost all antiepileptic drugs have more than one mechanism of action (

). Among all known mechanisms, the potentiation of g-aminobutyric acid (GABA)-ergic inhibition and the modulation of voltage-activated calcium channels may be most responsible for the pathophysiology of anxiety.


GABA is the principal inhibitory neurotransmitter and, along with serotonin and noradrenalin, is one of several neurotransmitters that appear to be involved in the pathogenesis of anxiety.

 receptors, such as benzodiazepines, have both anxiolytic and antiseizure effects via GABA

 mediated reduction of neuronal excitability. The GABA

 receptor subtype regulates excitability and rapid changes in fear arousal, such as anxiety, panic, and acute stress response.

However, the sedative hypnotic effect of benzodiazepines is the result of an allosteric-positive modulation of GABA

 receptors that contain the alpha-1 subunit. The anxiolytic effect seems to be related to an allosteric modulation of receptors that contain the alpha-2 subunit.

 It is evident that GABA modulation is a determinant for both anxiety and seizures: in fact, GABA

 antagonists produce convulsions in animals. A study using pos­itron emission tomography showed that patients with panic disorder have a decrease in GABA

Not all classic GABA-ergic anticonvulsants exert helpful psycho­active properties. Although their pharmacological profile suggests anxio­lytic properties, barbiturates, vigabatrin, and topiramate may have treatment-emergent psychiatric adverse effects. Agitation and hyperactivity have been described with barbiturates, especially in children, and it is well documented in the neurological literature that both vigabatrin and topiramate are associated with depression and psychoses.

 This may be a consequence of GABA-ergic neurotransmission. The emerging understanding of different roles for phasic or synaptic inhibition and tonic inhibition mediated by different subpopulations of GABA

 receptors may lead to targeted compounds for anxiety disorders.


Calcium channel blockers represent another class of molecules that can be of relevance in anxiety. They have been shown to be of value in ameliorating symptoms in animal models of anxiety.

 In general terms, calcium channels can be categorized according to their biophysical and pharmacological properties in 2 main subfamilies: high-voltage–activated and low-voltage–activated channels. The former are differentiated into different subtypes: l-type (generating a long-lasting current); and N-, P/Q-, and R-types (expressed in nerve terminals and responsible for the cal­cium entry that triggers neurotransmitter release). On the other hand, low-voltage–activated calcium channels (T-type) generate transient currents, have a somatodendritic localization, and are critical to pacemaker activity and some patterns of burst firing.

Among the different subtypes, it seems that high-voltage calcium chan­nels, in particular the N- and P/Q-types, may represent interesting molecular targets for antianxiety compounds because they regulate neu­­ro­transmitter release during syn­aptic neurotransmission, especially excit­atory neurotransmission. The alpha-2-delta is a particular subunit of these channels, and it has been hypothesized that its modulation can be of value in controlling anxiety symptoms.

In the case of gabapentin and pregabalin, N- and P/Q-type channels represent the main molecular target-in particular the alpha-2-delta subunit, type 1 and type 2. It has been suggested that the binding to this calcium channel subunit causes a channel conformational change, which lowers calcium influx and neuron depolarization and, therefore, firing. It also has been suggested that the expression of the alpha-2-delta subunit differs in different cell types in response to different conditions. For example, in chronic neuropathic pain, alpha-2-delta subunits may be up-regulated, which explains, at least in part, the efficacy of gabapentin and pregabalin in such a condition.

 It remains to be determined whether such plastic changes are also present in anxiety disorders.

Despite numerous open studies and reports, most publications have sever­al methodological limitations, includ­ing inadequate sample size; lack of pla­ce­­bo control; use of outcome measures, such as the clinical global impression scales; and lack of controlling for patient variables, such as comorbidity, diagnostic subtype, and concom­i­tant medications.

 These factors may help explain why anti­­con­vul­sants have yielded inconsistent results in the treatment of anxiety disorders.


The strongest evidence is for pregabalin in patients with GAD with and without comorbidity (

). Pregabalin has been shown to be effective at high dosages (300 to 600 mg/d) in a number of controlled studies compared with benzodiazepines and venlafaxine.

 Recent data support the efficacy of pregabalin in the long-term treatment and in the amelioration of comorbid depressive symptoms.

Regarding other anticonvulsant drugs, tiagabine is the only other compound being investigated for GAD. This agent has shown promise in an open study. However, controlled data from 260 patients showed no significant difference from placebo in responder rates measured with the Hamilton Anxiety Scale.


Controlled studies show interesting results for pregabalin (600 mg/d) and gabapentin (900 to 3600 mg/d).

 Both drugs share the same mechanisms of action, namely the modulation of N- and P/Q-type voltage-dependent calcium channels.

Among other anticonvulsant drugs, valproate and topiramate have been shown to ameliorate phobic symptoms in small open studies involving 17 and 23 patients, respectively.

 Further controlled studies are warranted to reach definitive conclusions.

Data on levetiracetam are not conclusive either. An open-label, flexible-dose study in 20 patients showed a clinically significant reduction in anxiety and phobic symptoms.

 However, results of a controlled study comprising 16 subjects were clearly negative, although some methodological limitations such as the small sample size make it impossible to get definitive evidence about this anticonvulsant for social phobia.


Although a number of anticonvul­sant drugs have been used for panic disorder, conclusive data are not avail­able. The majority of studies have been uncontrolled and have had small sample sizes. The results for gabapentin have been somewhat mixed, although post hoc analyses of a controlled study suggest that gabapentin (600 to 3600 mg/d) may be useful in patients with moderate to severe panic disorder.

There are no more than anecdotal reports for vigabatrin, tiagabine, and oxcarbazepine. The literature is inconclusive for carbamazepine. Although an open study suggested a possible antipanic effect, the only controlled study conducted in a limited sample of 14 patients showed no effect.

 Theoretically, data on valproate may be more interesting and promising, although currently they are still limited to open studies.


At present, controlled studies of anticonvulsants involve lamotrigine and valproate.

 In one study, lamotri­gine was associated with a significant diminution in the re-experiencing and avoidance/numbing symp­toms relative to placebo.

 Unfortunately, only 10 patients in that study were followed and the dosage range was quite large (25 to 500 mg).

 These factors make any useful measure of effect size impossible.

Open studies of valproate for the treatment of posttraumatic stress disorder (PTSD) were initially promising, but a randomized, double-blind, placebo-controlled trial showed that the response to valproate monotherapy in 85 older male combat veterans was no different from that with placebo.

 Further studies are needed to determine the efficacy of monotherapy in women and the possible effectiveness of valproate as augmentation therapy.

Among other anticonvulsants, data are limited to open studies, which suggest some improvement in hyperarousal symptoms with carbamazepine, phenytoin, topiramate, and levetiracetam.

 Nonetheless, these are uncontrolled data that may deserve further investigations without any clear indication at the moment.


Among all anticonvulsant drugs, data on topiramate, from open studies, are the most compelling.

 Lamo­trigine has been shown to be ineffective, while information on carbamazepine is limited to case reports.

We are still far from straightforward guidelines on the use of anticonvulsants in patients with anxiety disorders. Apart from the direct com­parison between pregabalin and ven­lafaxine for GAD, there are no head-to-head comparisons with first-line agents (ie, antidepressant drugs) for the long-term treatment of anxiety symptoms.

 Furthermore, there are no data about which clinical subgroups may preferentially respond to these drugs. Recent data on pregabalin suggest some utility in GAD with comorbid depression.

We can speculate that patients with comorbid bipolar disorders may benefit from a mood stabilizer with anxiolytic properties. In this setting, lamotrigine and valproate may represent valuable options, although evidence on these 2 compounds in treating anxiety disorders per se is weak. Gabapentin has not been shown to have strong mood-stabilizing properties and there are no data for pregabalin.

 Their use in patients with bipolar disorders and comorbid anxiety disorders seems premature.

Patients with anxiety disorders, obesity, and comorbid eating disorders (eg, binge-eating disorder, bulimia) may benefit from treatment with topiramate, although promising results are still confined to obsessive- compulsive disorder and PTSD.


The rationale for the use of anticonvulsants in anxiety disorders is supported by neurobiological underpinnings that make these compounds a likely alternative for short-term treatment in patients who do not respond to benzodiazepines or who have a contraindication (an addiction disorder, respiratory problems, or who are at risk for falls). However, data are limited, and current criteria for levels of evidence and lines of treatment recommendations suggest strong evidence only for pregabalin in patients with GAD with or without comorbidity (

Pregabalin and gabapentin have been shown to be promising in social phobia. Data about gabapentin in panic disorder are somewhat mixed; they suggest a possible role only in patients who are moderately to severely affected. In any case, these compounds must still be considered second- or even third-line treatment.

Further studies are needed on the neu­robiology of anxiety disorders and neuropharmacology of anticonvulsant drugs to develop pharmacological treatment strategies that target symptom patterns and patients’ needs.


Carbamazepine (Carbatrol, Tegretol, others)
Ethosuximide (Zarontin)
Felbamate (Felbatol)
Gabapentin (Neurontin)
Lamotrigine (Lamictal)
Levetiracetam (Keppra)
Oxcarbazepine (Trileptal)
Phenytoin (Dilantin)
Pregabalin (Lyrica)
Tiagabine (Gabitril)
Topiramate (Topamax)
Valproate/valproic acid (Depakote, others)
Venlafaxine (Effexor)
Vigabatrin (Vigabatrine)
Zonisamide (Zonegran)

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The rationale for the use of anticonvulsants in anxiety disorders is supported by neurobiological underpinnings that make these compounds a likely alternative for short-term treatment.