Epilepsy, depression and antidepressant drugs

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Journal of Clinical Neuroscience (2001) 8(3), 209–215 © 2001 Harcourt Publishers Ltd DOI: 10.1054/jocn.2000.0896, available online at http://www.idealibrary.com on

Review

Epilepsy, depression and antidepressant drugs M. R. Salzberg1 MD FRANZCP, F. J. E. Vajda2 MD FRCP FRACP 1

St. Vincent’s Mental Health Service, 2Australian Centre for Clinical Neuropharmacology, St Vincent’s Hospital, Melbourne, Australia

Summary Apart from constituting an important management problem, depression coexisting with epilepsy is also an interesting psychiatric phenomenon, with multiple interacting biological, psychological and social factors involved in its causation. New research approaches to the study of epilepsy and depression, including neuroimaging, neurochemical and neuroendocrine techniques, and the arrival of new classes of antidepressants in recent years, suggest it is timely to reconsider this topic. We review current knowledge of the prevalence and causes of interictal depression in epilepsy, focussing mainly on neurobiological factors, and give an overview of recent concepts concerning the management of depression. We also discuss pharmacological treatment of depression in epilepsy, focussing on the association between antidepressants and seizures, and drug interactions. © 2001 Harcourt Publishers Ltd Keywords: epilepsy, seizures, depression, antidepressive agents, drug interactions

INTRODUCTION Epilepsy and depression commonly occur together, presenting problems of management. The interesting question of whether the rate of depression is elevated in epilepsy (compared to the rate in other diseases and in the general community) remains unresolved. Of the pre-ictal, ictal, post-ictal and interictal depressive syndromes, it is interictal depression that is the focus here. This paper reviews the prevalence and causes of depression in epilepsy, describes the management of depression generally and the relevant pharmacology of available antidepressants, and considers the important issues of seizure threshold and pharmacokinetic interactions. Guidelines are offered for the use of antidepressants in patients with epilepsy.

A new dimension emerged with the advent of temporal lobe epilepsy surgery: the observation, yet to be confirmed, of high rates of post-operative mood disorder, especially depression;6,7 rates probably exceeding those for other neurosurgery. Risk factors and correlates for interictal depression

DEPRESSION IN EPILEPSY

Although we may not know whether the rate of depression is elevated, it is worthwhile to examine its correlates. Again, the evidence is inconclusive but there are promising findings. In considering (or conducting) this research, it is more useful to think about the full spectrum of affective symptoms (including anxiety, irritability, anger and mania) than to focus on depressive symptoms alone.3 Wiegartz et al.8 conveniently grouped the factors under three headings:

Is the rate of depression elevated?




Given the strong clinical impression of an association between epilepsy and interictal depression and the great neurobiological interest of the issue, we wish to know whether the rate of depressive disorder is higher in persons with epilepsy than in the general population and in persons with other disorders. In spite of many studies, the findings are disappointingly inconclusive.1–3 Given the prevalence of depression in the general community (lifetime prevalence 17% for major depression alone4 and in the medically ill5), it is uncertain whether rates in epileptic populations are elevated. Most studies have inadequate statistical power or inappropriate study design. The published evidence is rendered even more inconclusive by the diversity of psychiatric measures, epilepsy diagnoses and sampling strategies. Patients in community surveys and patients recruited in tertiary referral centres may have different associations between epilepsy and psychopathology, as is the case for other disorders.

Received 26 July 2000 Accepted 11 October 2000 Correspondence to: Dr M Salzberg, St Vincent’s Mental Health Service, 41 Victoria Pde, Fitzroy VIC 3065, Australia. Tel.:;61-3-92884124; Fax:;61-3-92884147







Neurobiological. Temporo-limbic as opposed to other foci have been implicated repeatedly.9,10 The evidence regarding laterality of seizure focus is complex, but Wiegartz et al. concluded from recent functional imaging studies11–13 that a left-sided focus is associated with depression, especially in patients with neuropsychological or imaging evidence of frontal dysfunction. This is consistent with findings in neuroimaging studies of depression in nonepileptic subjects and those with other neurological disorders.14 However, in patients with longstanding lesions, such as mesial temporal sclerosis (MTS), transfer of function may occur to other parts of the brain, including the contralateral hemisphere, creating difficulties when comparing epileptic with nonepileptic populations. Psychosocial factors. Examples are the stresses and difficulties of living with epilepsy, including disability, stigma, isolation and the risk of physical injury and death. Iatrogenic factors. Namely, antiepileptic drugs (AEDs) and epilepsy surgery. Amongst AEDs, relatively convincing evidence exists for barbiturates, phenytoin, valproate, ACTH, acetazolamide, vigabatrin, tiagabine, felbamate and topiramate as causes of depression. Despite their beneficial effects on mood and use as mood stabilisers, valproate and carbamazepine (CBZ) have been implicated in cases of depression. Temporal lobe surgery may be complicated by postoperative mood disorder.6,7 209

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Although the evidence is meagre, general risk factors for depression presumably are relevant, including genetic predisposition; aspects of personality and cognitive style, such as locus of control; and life events. Is the interictal depression of epilepsy qualitatively different from other depression? In general, there is little good evidence bearing on this point. Blumer and colleagues delineate a syndrome they term interictal dysphoric disorder,15–17 recurrent brief dysphoric episodes (hours to days) characterised by combinations of depressed mood, anergia, irritability, euphoria, atypical pain, insomnia, fear and anxiety. In their view this is attributable to ‘paroxysmal excessive neuronal activity’16 largely occurring in mesial temporal lobe epilepsy patients, but also in nonepileptic patients with limbic pathology. Proposed mechanisms and models of associations between epilepsy and depression If indeed there is an elevated rate of depression in epilepsy, particularly temporolimbic epilepsy, then there are several logical causal possibilities: 1. Depression may cause or aggravate epilepsy; 2. Epilepsy may cause depression; 3. Underlying processes, such as mesial temporal sclerosis, may cause both the epilepsy and the depression; 4. Combinations of these processes may be involved, e.g., epilepsy may cause depression, which in turn aggravates epilepsy, by, say, cortisol-mediated hippocampal damage.18,19 A role for AEDs, which have potential psychotropic effects, is also an important possibility. The available theories can be divided into: (i) neurochemical (ii) neuroendocrine (iii) kindling, secondary epileptogenesis and secondary inhibition,20,21 and (iv) ‘forced normalisation’.22








Neurochemical. Some neurotransmitter systems implicated in epilepsy are the same as those implicated in depression. Systems under investigation in epileptogenesis include: the excitatory amino acids (glutamate, aspartate); amines (noradrenaline, serotonin, acetylcholine); various neuropeptides; purines (adenosine); and nitric oxide.23 Noradrenaline and serotonin are central to much contemporary theorising about depression, with some evidence suggesting roles for dopamine, acetylcholine and gamma-amino butyric acid (GABA).24,25 Neuroendocrine. A neglected possibility is neuroendocrine disturbance associated with epilepsy, due either to underlying epileptogenic pathology, the seizures themselves or both.26,27 It is not widely appreciated that medial temporal lobe structures, particularly hippocampus and amygdala, have neuroendocrine functions, exerting powerful control on the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis dysfunction has been implicated in the pathogenesis of depression.28 Antidepressants may act in part through the HPA axis.29 HPA dysfunction has been reported in epilepsy, particularly TLE,30 but deserves further study. Anterior temporal lobectomy is likely to cause temporary disinhibition of the HPA axis, leading to abnormal cortisol hypersecretion, perhaps explaining the postoperative depression.26 Gonadal steroids have been implicated increasingly in the biology of depression,31 affect seizure threshold and may be dysregulated in temporal lobe epilepsy.32–35 AEDs can affect folate and tryptophan metabolism, thus potentially contributing to depression, as may endogenous opioid dysregulation.36 Kindling, secondary epileptogenesis and secondary inhibition20,21 may underlie the psychopathology of epilepsy. A kindling model may explain the many correspondences between the natural histories of epilepsy, bipolar disorder and migraine.20

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‘Forced normalisation’ is the observation that EEG abnormalities may resolve (and seizures cease or diminish) before the onset of psychopathology.22,37,38 It may occur spontaneously, as the illness fluctuates, or following seizure control by AEDs39 or surgery. The mechanisms are unknown, but plausible hypotheses are emerging.

OVERVIEW OF MANAGEMENT OF DEPRESSION Pharmacological treatment of depression should be placed within a general management framework. The key issues are: (1) recognition of depression, (2) assessment and (3) formulation of a comprehensive, individualised management plan. Recognition of depression Both primary care and specialist physicians, including neurologists,40 miss the diagnosis.41 Reasons include factors in the patient, such as somatization and alexithymia, and factors in the physician, such as lack of interest in psychological health or hurried interview technique. It is important to discriminate grief and shortterm reactions from depressive illness, but it is equally important not to miss the diagnosis of true depressive illness, given its treatability and serious potential consequences. Clinicians can screen for depression utilising questionnaires such as the Prime-MD42 or SPHERE,43 or by including relevant probe questions in routine interviews. Once diagnosed, the severity of depression can be assessed using rating scales.44,45 Loss of interest or pleasure, sleep and appetite disturbance, depressive thinking (guilt, worthlessness, hopelessness) and suicidal thinking are key symptoms for which to probe. Formal diagnosis of major depression using DSM-IV criteria requires duration of at least 2 weeks, the presence of at least five of nine core symptoms and significant functional impairment or distress.46 Differential diagnoses of the depression syndrome In general hospital inpatients, conditions to differentiate from depression include delirium, particularly of the apathetic or hypoactive type, and dementia or frontal lobe syndrome, which too can present with apathy and lack of spontaneity. Inertia and slowed thinking may be misattributed to side effects of AEDs. It is important to probe for past hypomanic or manic episodes to make the diagnosis of bipolar disorder. Differential diagnoses of the depression syndrome Alcohol or drug abuse and other medical (including neurological) conditions (including disorders that give rise to epilepsy, such as stroke or traumatic brain injury)47,48 may cause depression. In older patients, there is an association between the occurrence of depressive illness and subsequent onset of Alzheimer’s or vascular dementia. In Huntington’s disease, major depression often precedes onset of neurological signs. Many medications in common use are implicated in depression,47 including AEDs. Comorbid psychiatric conditions (including personality disorder, anxiety disorders or eating disorders) may be present. Assessing severity and suicide risk Severe depression may be complicated by psychotic symptoms (e.g. delusions of guilt or poverty); and in extreme cases may result in physical debility due to malnutrition or dehydration. Severity can be rated on clinical impression or by using rating scales, e.g., Hamilton (HDRS, an observer rated scale),45 © 2001 Harcourt Publishers Ltd

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Montgomery-Asberg Depression Rating Scale (MADRS, observer rated)44 or the Beck Depression Inventory (a self-completed scale).49 The clinician should routinely probe for suicidal thinking, plans, intent and past suicidal behaviour. Depression accounts for much of the elevated suicide rate in epilepsy patients.50,51

Selection and use of antidepressants


Comprehensive management of depression Milder depression may respond to psychotherapy alone, such as cognitive behavioural therapy (CBT)52 or Interpersonal Therapy (IPT).53 For moderate episodes, a combination of psychotherapy and antidepressant medication is indicated. Severe depression may require hospitalisation (sometimes involuntarily, under mental health legislation), electroconvulsive therapy, and treatment of physical complications (such as dehydration) as well as antidepressants. Education of the patient and carers about the illness and practical interventions to reduce stress in family, work or other sectors of the patient’s life are important. Patients with moderate or severe depression should be referred to a psychiatrist. This should be done urgently where there is suicidal thinking, psychotic symptoms, psychomotor retardation or agitation, or physical debility. Two important findings from the last decade of depression research are that depression is frequently under-treated, and recurrence rates, even with treatment, are very high54,55 35–50% will have a recurrence within 2 years and 60–80% will have at least once recurrence within 10–12 years. The likely causes of recurrence are complex but include inadequate doses of antidepressants for inadequate duration and failure to provide proven psychological therapies, such as CBT or IPT. There is good evidence for benefit from longterm maintenance treatment, both psychotherapeutic and pharmacological.56







PHARMACOLOGICAL TREATMENT OF DEPRESSION Classes of antidepressant medication Currently available antidepressant drugs are usually classified in terms of actions on monoamine neurotransmitter receptors, especially serotonin, noradrenaline and dopamine.57,58 Tricyclic antidepressants (TCA) act primarily through blockade of reuptake of both noradrenaline and serotonin. The recent serotonin specific reuptake inhibitors (SSRIs) act selectively on serotonin reuptake. More recently, drugs were designed to target more than one system, e.g. venlafaxine (which inhibits both serotonin and noradrenaline reuptake), nefazodone (a 5-HT2 antagonist and SSRI) and mirtazapine (a 5-HT2, 5-HT3 and alpha-2-adrenergic antagonist). The connection between action at such receptors and actual mechanism of action is unclear. Historically, antidepressants provided a potent tool to study mood disorders and led to the development of the monoamine theories both of mood disorder and of antidepressant action.24,59 But there are competing theories,60 including that antidepressants act by modifying neurendocrine (specifically HPA) modulation of serotonergic and/or noradrenergic systems,29 and theories implicating the sigma and NMDA receptors, interleukins (IL-2 and -6), Substance P and prostaglandin E2 and the neuronal cytoskeleton.60 Despite the different profiles and types of monoaminergic action, and despite the considerable structural heterogeneity within classes, there is little difference in the efficacy of the various antidepressants, except in certain subtypes of depression. The receptor-based classification is more useful clinically in understanding side effects and toxicity than understanding antidepressant action. © 2001 Harcourt Publishers Ltd




Selection. For unipolar major depression, the choice depends on comorbid medical conditions; drug-induced side effects and toxicity, including toxicity in overdose; previous response to antidepressants; and family history of drug treatment response. SSRIs and other recent drugs are considerably more expensive than TCAs and MAOIs. At present, SSRIs or an SNRI (venlafaxine) are recommended as first-line treatment, the choice determined by potential side effects. For the depressive phase of bipolar disorder, lithium has an antidepressant effect without the risk of inducing mania associated with all antidepressants. Lithium is not effective as sole agent in unipolar depression, although useful in augmenting antidepressants. For delusional depression, combined antidepressant and antipsychotic treatment is usually needed and ECT should be considered. For depression with comorbid psychiatric disorders, e.g. OCD or eating disorders, SSRIs are probably the drug of choice. In the elderly, anticholinergic and cardiovascular side effects are potentially more serious, thus desipramine, nortriptyline and most SSRIs are acceptable but should be used at lower doses. For so-called atypical depression (depression with, amongst other features, so-called ‘reverse vegetative symptoms’, such as over-sleeping and over-eating), MAOIs are claimed to be differentially more effective than TCAs and possibly SSRIs.61 Duration of antidepressant therapy. For first episode unipolar major depression, treatment is continued for at least 6 months after resolution of symptoms. For recurrent major depression, maintenance therapy should be continued for at least 3 years. A small subset of patients experiencing multiple, frequent or severe episodes may require lifelong maintenance. Causes and management of non-response. About 30% of patients respond inadequately to the first drug and some have intolerable side effects. For inadequate response at 4–6 weeks, review the diagnosis, check compliance and assess for aggravating factors such as stressors or personality disorder. The dose should then be increased. If there is still an inadequate response at 8 or 12 weeks, the main options include lithium augmentation, change of antidepressant or ECT. Changeover between antidepressants is potentially hazardous, most requiring washout times ranging from days to weeks. Novel antidepressant strategies under investigation include antiglucocorticoids, such as metyrapone;62 transcranial magnetic stimulation (TMS)63 and vagal nerve stimulation (VNS).64 Withdrawal or discontinuation. Many antidepressants produce withdrawal syndromes,65–67 with unpleasant symptoms which may be mistaken for recurrence of depression. Thus medication should be tapered and withdrawn gradually.

ANTIDEPRESSANT THERAPY IN EPILEPSY The two key issues are risk of seizures with antidepressant therapy68 and interactions between antidepressants and antiepileptic drugs. Data on the effects of psychotropic drugs on epilepsy are derived from various sources, including adverse drug reaction committees (ADRCs) of several countries; pharmaceutical company reports; reports from the peer-reviewed medical literature, including epidemiological studies, studies of drug effects on the EEG, in vitro preparations and animal studies. The human literature, although extensive, is problematic as discussed below. Animal models are difficult to extrapolate to humans. The same antidepressant may have different physiological effects in different animals and neural tissue. Some antidepressants cause EEG abnormalities but not necessarily seizures. Journal of Clinical Neuroscience (2001) 8(3), 209–215

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Experimental models using implanted electrodes suggest a risk with certain drugs that does not tally with seizure experience in humans. All this is consistent with current appreciation of the complexity of epileptogenesis.69–71 There is no simple ‘gold standard’ or index by which to rank the seizure potential of antidepressants. Associations between antidepressants and seizures in humans Problems with human studies include failure to differentiate patients with well-documented epilepsy from patients, never previously subject to epilepsy, who have a single seizure when exposed to an antidepressant; and lack of definition of seizures. ADRC data represent only a small percentage of the total number of events. They do not accurately estimate incidence of adverse reactions, but rather bring to attention those unnoticed in clinical trials. Cumulative risk with long term antidepressant therapy has not been adequately examined. Rosenstein72 noted that many antidepressant-related seizures occur in people with additional seizure risk factors. The high seizure rate associated with overdose suggests a dose dependent phenomenon, noted particularly with amoxapine and maprotiline. Rapid dose escalation increases risk of seizures. Data from the United Kingdom Committee for Safety of Medicines73 suggests that there is a potential under-reporting of seizures with TCAs because, since the advent of SSRIs, tricyclics have been less frequently prescribed in high-risk populations partly because of their presumed epileptogenic potential. The data confirms the clinical impression that some TCAs (maprotiline, clomipramine and the tetracyclic mianserin) have a relatively high epileptogenic potential.74 Imipramine has been the most extensively studied TCA.75 Peck et al.76 performed a meta-analysis of 98 papers published over an 11-year period (1955 to 1966). The incidence of seizures at less than 200 mg per day was about 0.1%. At higher dose, the incidence was 0.6%, suggesting a dose-related phenomenon. Amitriptyline was associated with a much lower incidence (0.055%) based on a meta-analysis of 50 papers. The Boston Collaborative Drug Surveillance Program77 monitored all patients aged 20–70 years receiving TCAs, excluding patients with conditions predisposing to seizures. The risk of seizures was less than 1 in 1 000. These data may represent an underestimate. Buckley et al.78 found that of 302 patients treated for TCA poisoning, 15 developed seizures. Dothiepin was responsible for nine of these. Overdose of dothiepin was associated with 13% of patients experiencing seizures. This compared with an incidence of 2% of all other TCA overdoses. Patients with brain injury are at particular risk.79 Overdose reports must be interpreted with caution as they are usually anecdotal and uncontrolled. Jick et al.80 carried out an extensive retrospective study of computer records of 42 000 recipients of antidepressant drugs, restricted to persons with no known condition predisposing to convulsions. Only 16 subjects developed a convulsive disorder judged as possibly caused by an antidepressant, a frequency substantially less than 1 in 1 000 recipients. For TCAs specifically, a total of 32 000 patients received over 200 000 prescriptions. In only 10 could antidepressant related seizure not be ruled out. Less than 30% had conditions predisposing to seizures (i.e. at least 21 000 users had no predisposition to seizures). The final incidence was estimated at 0.4% for 1 000 patients at risk. SSRIs now account for an increasing percentage of the market of antidepressants each year. Marketing claims for SSRIs as drugs of choice and safest in the treatment of depression make it more likely that seizures occurring with SSRIs would be reported. Journal of Clinical Neuroscience (2001) 8(3), 209–215

Fluvoxamine and paroxetine have been associated with a disproportionate number of reports given their market share. Of the atypical SSRIs, trazodone appears to have a low seizure potential, but apparently a higher number of seizures have been reported with venlafaxine to date. Small-scale studies to assess predisposing factors have been reported. Edwards and Wheal74 concluded that a convulsive seizure is an uncommon but important unwanted effect of antidepressant medication. Routine EEG may be helpful in diagnosis but is less likely to be effective than ambulatory monitoring. The true risk of rare events such as antidepressant-related seizures can only be established confidently by large-scale epidemiological studies, presently lacking. The nature and quality of data vary greatly for the different antidepressants. The widespread perception that some drugs specifically induce or exacerbate seizures in subjects with epilepsy may prevent afflicted persons from receiving appropriate therapy.81 The scientific literature shows that TCAs cause seizures in overdose but in lower dose may even have anticonvulsant activity. This almost certainly stems from their capacity to block noradrenaline and/or serotonin reuptake but may be due also to local anaesthetic, antihistaminic or antimuscarinic activity. The SSRIs have very low convulsant liability and may be used safely in epileptic patients with depression.

MECHANISMS BY WHICH ANTIDEPRESSANTS MAY AFFECT SEIZURE ACTIVITY Mechanisms proposed to date have focussed on monoamines, known to play an important role in seizure genesis. Although antidepressant drugs modify noradrenergic, dopaminergic and serotonergic transmission, they are not free of effects on other neurotransmitters that may also have a role in epileptogenesis.








Dopamine. Levels of dopamine may be raised by antidepressants and seizures may be associated with raised dopamine levels.82 However, dopamine agonists, e.g. levodopa, may raise the seizure threshold, whereas dopamine antagonists are known to lower it.82 Apomorphine has been reported to block photosensitivity in myoclonic epilepsy. However, bupropion has been implicated in causing seizures.83 In practice, most drugs that act on the dopamine system have only a modest effect on seizures.84 Serotonin. Serotonin has been implicated in the genesis of seizures in most mammalian seizure models. SSRIs have been shown to lower as well as raise seizure threshold.85,86 In audiogenic epilepsy in mice, there is evidence of reduced brain serotonin levels. Increased serotonin in the Papio papio model shows protective effects.87 In genetically epilepsy prone (GEPR) rats, sertraline, an SSRI drug, produces a dose-dependent reduction in audiogenic seizures.88 Acetylcholine. Cholinergic activity has been increasingly implicated in the genesis of epileptic seizures and cholinergic agonists may precipitate seizures. In contrast, pilocarpine reduces seizures in rodents.87 Many neuroleptics and antidepressants have anticholinergic properties, but in humans evidence is lacking as to whether the proconvulsant or anticonvulsant effects predominate. Basal forebrain cholinergic neurones have been implicated in the mechanism of kindling. Atropine and mecamylamine both retard development of amygdaloid kindling, whilst local injection of cholinergic agonists into the brain results in seizures.23 Some species of rat, genetic absence epilepsy rats (GAERS), exhibit spike and wave discharges during quiet wakefulness. Fronto-parietal cortex and relay nuclei in the ventrolateral part of the thalamus are critical for generation of absence seizures.89 These structures are under control of ascending cholinergic neurons. Autosomal dominant frontal © 2001 Harcourt Publishers Ltd

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lobe epilepsy is associated with a missense mutation in the neuronal nicotinic acetylcholine receptor.90 Impaired transmission in patients with this mutation could lead to an exacerbation of their epileptogenesis.23 The active cholinergic transmission during sleep may explain nocturnal seizures. Noradrenaline. Noradrenaline attenuates seizures in virtually every animal species with the exception of the tottering mouse model. Noradrenergic mechanisms modulate epileptic discharges induced by both chemical and electrical kindling.23,87 In amygdaloid kindling of rats, reserpine depletion of forebrain noradrenaline facilitates the rate of kindling development, but noradrenaline depletion after kindling does not exacerbate kindled seizures.91 Pharmacological studies with selective adrenoreceptor drugs have shown that the alpha-2 agonist, clonidine, dose-dependently suppressed kindling development in rats, whilst alpha-2 adrenoreceptor antagonists facilitated it. Neither drug modified seizures in previously kindled animals.92 The beta-adrenoreceptor antagonist propranolol significantly retarded development of the fully kindled state in rats. It is thought that noradrenaline rather than dopamine modulates seizure activity, and attenuation of noradrenaline transmission contributes to the kindling phenomenon.93 Seizures occurring with antidepressant drug overdose are also possibly due to inhibition of noradrenaline reuptake.94 Excitatory amino acids. Edwards and Wheal74 ascribed a prominent role to excitatory amino acid receptors, especially Nmethyl-D-aspartate (NMDA) subtypes. They concluded that any mechanism that leads to depolarisation of neurones is likely to result in a facilitation of NMDA-receptor involvement in excitatory neurotransmission. This is particularly true of cortex and hippocampus where these receptors exist in highest density. Gamma-amino butyric acid (GABA). Preclinical experimental approaches include modulation of GABAA and GABAB receptormediated synaptic inhibition, modulation of potassium conductance normally associated with the GABAB receptor and modulation of the slow calcium- activated potassium conductance which is lost in the kainic acid (KA) epilepsy model. The actions of 5-HT on potassium conductance in hippocampal neurones are important because 5-HT has been found to block both the slow GABA-receptor mediated, as well as the calciumactivated, potassium conductance that follows bursts of action potentials in these cells.95,96 The effects of 5-HT on calciumactivated events are thought to be direct, but failure of slow potassium-mediated inhibitory post-synaptic potential (IPSP) is thought to be mediated through some pre-synaptic mechanism that reduces the feed forward inhibition from interneurones.96 An injection of KA into the lateral ventricles may have a direct effect on cells in the raphe nuclei, resulting in increased release of 5-HT in hippocampus. Sloviter and Damiano97 reported a failure of inhibition of the dentate gyrus following systemic application of KA and attributed it to the loss of inhibitory interneurones, a finding confirmed by others.98–100 Epileptiform bursts are mediated at least in part by NMDA receptors. However at supra-threshold levels of stimulation, not all epileptiform bursting activity was blocked by NMDA receptor- antagonists. The data suggest there are several excitatory amino acid receptor subtypes involved in epileptiform bursting activity and they may be recruited independently. Antidepressants and ECT both downregulate beta-adrenergic binding and upregulate GABA binding, but several AEDs (including barbiturates, benzodiazepines, vigabatrin and tiagabine) act by virtue of their GABAergic effects. It is thus difficult to implicate the GABA system in any epileptogenic effects of antidepressants.

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Glutamate and excitatory amino acids are clearly important in epilepsy causation. Schwartzkroin69 discussed mechanisms involving voltage-dependent membrane conductances, ion channels and ion distribution in epileptogenesis. These mechanisms are currently the subject of intense investigation, and may be the final common pathway for the expressions of both genetic and environmental influences that bear on epileptogenesis.





Neuropeptides. Endogenous opioids appear to be epileptogenic in rodents but not in primates.101 Both ECT and tricyclic antidepressants act synergistically with morphine.102 Somatostatin. Somatostatin appears to be epileptogenic in various animal models and has been postulated to have a role in the mechanism of action of some AEDs. There have been consistently low neuropeptide levels in the cerebrospinal fluid of patients with depression, but relevance to seizures is uncertain.99

Drug interactions Concomitant administration of AEDs and psychoactive drugs has become increasingly common for the treatment of mood disorders in epilepsy. Pharmacokinetic interactions can occur during various phases of handling of a drug, i.e. absorption, distribution, biotransformation and excretion. Of these, biotransformation is the most affected, usually by competition for the same metabolic pathway, and inhibition or induction of activity of the microsomal cytochrome P450 oxidase system (CYPS).103,104 The CYP system is classified into three major groups and five sub-families. Significant genetic variation has been documented for some of the enzymes by which psychotropic drugs are metabolised. The elderly generally show more prolonged elimination half-lives and more adverse effects. CYP substrates competitively inhibit metabolism of other co-substrates, and some drugs induce or inhibit their own metabolism as well as those of other drugs.105 EFFECTS OF AEDS ON ANTIDEPRESSANTS Phenobarbital, primidone, phenytoin and carbamazepine are microsomal inducers and stimulate the degradation of TCAs, including nortriptyline, protriptyline, imipramine, clomipramine and desmethylclomipramine. Reduction of mianserin and nomifensine levels may occur as a result of an accelerated process of desmethylation.106 Valproate (VPA) can inhibit the metabolism of TCAs. Data on the effects of AEDs on plasma levels of SSRIs are lacking, but the serotonergic syndrome was observed in a patient receiving fluoxetine with CBZ.

EFFECTS OF ANTIDEPRESSANTS ON ANTIEPILEPTIC DRUGS (AEDS) TCAs may have an inhibitory effect on the elimination of AEDs with the risk of toxic phenomena.105,107,108 Phenytoin (PHT) levels may be increased in patients treated with nortriptyline, imipramine, nomifensine, trazodone or viloxazine. Amitriptyline affects distribution of valproate in volunteers. Viloxazine and carbamazepine interact because of interference by the antidepressant on CBZ at various metabolic levels. Many case reports and a few controlled studies have demonstrated that SSRIs may raise serum levels of concurrent TCAs, with adverse effects.109 Fluoxetine has been shown either to increase CBZ levels or leave them unaffected. A Parkinson-like syndrome has been described in association with these drugs. CBZ-10,11-epoxide levels were either increased or unaffected by concomitant fluoxetine administration in patients with epilepsy and depression. Single cases of fluoxetine affecting plasma phenytoin Journal of Clinical Neuroscience (2001) 8(3), 209–215

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levels and VPA levels up to toxic values have been reported. Sertraline has a lesser effect on increasing AED levels and citalopram also has a minimal effect. Thus in patients on chronic AED therapy, these drugs have advantages. Fluvoxamine is reported to have caused a substantial rise in CBZ levels accompanied by symptoms of intoxication.110 The data suggest that some of the new antidepressants interfere with AED metabolism by inhibition of P450 cytochrome isoenzymes. Citalopram and sertraline have the most favourable profile in relation to drug interactions.108 Interactions between these antidepressants and antiepileptics are complex, with interindividual genetically controlled variation in liver activity of P450 isoenzymes. Therapeutic monitoring of AEDs may be a useful adjunct to therapy.

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CONCLUSION

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Depression and seizures represent a complex area of diagnosis and therapeutics. A significant part of the burden of depressive illness is unrecognised by clinicians. The occurrence of a single seizure in a patient on antidepressants represents a different aspect of the problem from the use of antidepressants in chronic epilepsy. The risk associated with use of antidepressants causing seizures is low. Different agents may have different propensities for lowering seizure threshold and SSRIs have a more favourable profile in this respect than TCAs. Data relevant to seizure causation are of indifferent quality and come from a variety of sources. Interaction between antidepressants and antiepileptic drugs may compromise the optimum management of these two common and distressing disorders.

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18. 19. 20. 21.

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