Seizures with neuroleptics and antidepressants

Seizures remain among the most serious side effects of psychotropic drugs. The authors review the literature associating neuroleptic and antidepressant medications with seizures, discussing the relative "seizurogenicity" of different medications, risk factors for seizures, and drugs of choice for high-risk patients. Case histories are presented. Available evidence suggests that molindone, fluphenazine, and haloperidol are among the least seizurogenic neuroleptics and that doxepin, monoamine oxidase inhibitors, or electroconvulsive therapy may be safest in treating the depressed patient at risk for seizures.     

Convulsive attacks due to antidepressant drug overdoses: Case reports and discussion

Antidepressant drug overdoses have been reported to induce seizures, but the etiology of this phenomenon is still unclear. Recently we treated three patients who suffered from epileptic seizures after acute overdoses of three antidepressant drugs: (a) Dibenzepin HCl (Noveril), (b) Maprotiline HCl (Ludiomil), and (c) Clorimipramine (Anafranil). After a review of the pertinent literature, the possible role of antidepressant drugs in the genesis of epileptic seizures is discussed.     

Can long-term treatment with antidepressant drugs worsen the course of depression?

BACKGROUND: The possibility that antidepressant drugs, while effectively treating depression, may worsen its course has received inadequate attention. METHOD: A review of the literature suggesting potential depressogenic effects of long-term treatment with antidepressant drugs was performed. A MEDLINE search was conducted using the keywords tolerance, sensitization, antidepressive agents, and switching. This was supplemented by a manual search of Index Medicus under the heading "antidepressant agents" and a manual search of the literature for articles pointing to paradoxical effects of antidepressants. RESULTS: A number of reported clinical findings point to the following possibilities: very unfavorable long-term outcome of major depression treated by pharmacologic means, paradoxical (depression-inducing) effects of antidepressant drugs in some patients with mood and anxiety disturbances, antidepressant-induced switching and cycle acceleration in bipolar disorder, occurrence of tolerance to the effects of antidepressants during long-term treatment, onset of resistance upon rechallenge with the same antidepressant drug in a few patients, and withdrawal syndromes following discontinuation of mood-elevating drugs. These phenomena in susceptible individuals may be explained on the basis of the oppositional model of tolerance. Continued drug treatment may recruit processes that oppose the initial acute effects of a drug and may result in loss of clinical effect. When drug treatment ends, these processes may operate unopposed, at least for some time, and increase vulnerability to relapse. CONCLUSION: The possibility that antidepressant drugs may worsen the course of depression needs to be tested, even though its scientific exploration is likely to encounter considerable methodological and ideological difficulties. The clinical implications of this hypothesis in depression are considerable. Antidepressant drugs are crucial in the treatment of major depressive episodes. However, appraisal of paradoxical effects that may occur in susceptible patients during long-term treatment may lead to more effective use of the drugs.     

Topiramate efficacy in an infant with partial seizures refractory to conventional antiepileptic drugs.

Many studies showed that Topiramate (TPM) may be a useful drug in a wide spectrum of childhood epilepsies. We report a 3-month-old female with stormy onset of secondarily generalized partial seizures. She showed a high seizure frequency and a progressive worsening electroencephalogram (EEG), despite standard antiepileptic drugs administration. TPM succeeded in controlling seizures, even after the other drugs were discontinued. This case suggests that TPM may represent a good choice for the treatment of partial seizures refractory to conventional drugs in infants.     

Antidepressant therapeutic effect of mianserin-induced generalized tonic-clonic seizure in an elderly patient

Generalized tonic-clinic seizures may appear as a side-effect of all antidepressant drugs, including mianserin. We present here a case of an 83-year-old woman whose major depressive episode (superimposed on mild dementia) completely resolved following a generalized tonic-clonic seizure. The improvement, which was maintained for 3 months, may be attributable to the drug-induced single convulsion. It would be of interest to know whether other psychiatrists have had similar experiences concerning an immediate antidepressant effect to a single tonic-clonic seizure (drug-induced or provoked by electroconvulsive therapy). If a subgroup of patients responsive to single generalized tonic-clonic seizure were to exist (especially among elderly patients), it would allow them to receive a minimal number of electroconvulsive therapy (ECT) sessions, decreasing the probability of the appearance of ECT side-effects.     

Acute effects of antidepressants on hippocampal seizures

Electrically kindled hippocampal seizures in rats were used to evaluate the acute effects of the antidepressants amitriptyline, imipramine, desipramine, bupropion, maprotiline, and trazodone on behavioral and electrical convulsions. All of the drugs reduced afterdischarge duration significantly. Behavioral seizures were not significantly reduced by bupropion or trazodone, whereas the other drugs did reduce seizure severity. Afterdischarge threshold was not modified by these drugs. In contrast, phenobarbital significantly elevated threshold and reduced seizure severity and afterdischarge duration. Amitriptyline was the most effective antidepressant, attenuating both seizure severity and afterdischarge duration.     

Does viloxazine have epileptogenic properties?

Six cases of convulsive seizures occurring during treatment with viloxazine notified to the Committee on Safety of Medicines (CSM) and two other cases from Japan were reviewed. A critical study of the patient's histories suggests a possible causal connection between drug and seizures in only two of these cases. The occurrence of convulsions is not in keeping with the results of animal experiments and of clinical trials in which epileptic patients were included, both of which suggest that viloxazine does not have epileptogenic properties and may have anticonvulsant actions. A worldwide review of clinical trials in which unwanted effects have been recorded suggests that viloxazine, even if possessing convulsive properties like other anti-depressants, is probably less epileptogenic than conventional tricyclics and is not contraindicated in epileptic patients requiring antidepressant medication.     

Bupropion-induced convulsions: preclinical evaluation of antiepileptic drugs

Bupropion, a unique, non-nicotine smoking cessation aid and an effective antidepressant, is well known to produce seizures following overdosing in humans. However, the experimental background for the usefulness of antiepileptic drugs in the protection against bupropion-induced convulsions has not been established yet. Therefore, we tested if the antiepileptic drugs were able to protect mice against clonic convulsions induced by intraperitoneally (i.p.) administered bupropion in the CD97 dose (139.5 mg/kg). Among 13 tested drugs, clonazepam showed the greatest potency (dose-dependent full protection; ED50 = 0.06 mg/kg, i.p.). No signs of locomotor impairment were observed in the rotarod test after anticonvulsive doses of clonazepam, resulting in a broad therapeutic window and favorable protective index (PI) (33.3). Gabapentin produced dose-dependent protection against convulsions at nontoxic doses (up to 1000 mg/kg), having PI>29. Diazepam in a very high dose showed full protection but its PI (1.7) was much less favorable than that of clonazepam. The PI values for ethosuximide, phenobarbital and valproate were slightly higher than unity and lower than 2, and for topiramate and felbamate were lower than unity. Phenytoin, carbamazepine, and lamotrigine as well as tiagabine failed to block the convulsant effects of bupropion even at doses that caused severe motor impairment. Our results encourage clinical testing of clonazepam against seizures developing after bupropion overdose.     

Antidepressants in epilepsy

People with epilepsy (PWE) frequently suffer from comorbid mood and anxiety disorders. Depression is one of the major psychiatric comorbidities having a negative impact on the quality of life in people with epilepsy. A review of the literature indicates that the majority of antidepressant-related seizures have been associated with either ultra-high doses or overdosing and, generally, the risk of antidepressant-associated seizures is low. Correspondingly, there is some evidence indicating that antidepressants of most widely used groups may additionally lower the risk of triggering seizures. Four antidepressants are not recommended for patients with epilepsy, i.e.: amoxapine, bupropion, clomipramine and maprotiline. Clinicians applying first line of depression treatment in patients with epilepsy should consider use of SSRIs or SNRIs, particularly sertraline, citalopram, mirtazapine, reboxetine, paroxetine, fluoxetine, escitalopram, fluvoxamine, venlafaxine, duloxetine. Implementation of anticonvulsive drugs in depressed patients should include valproate, carbamazepine, lamotrigine, gabapentin, pregabalin. The paper reviews the evidence for the clinical use of antidepressants in PWE.     

Seizure-inducing effects of antiepileptic drugs: a review

Seizure-inducing effects can be observed in the treatment of epileptic patients with antiepileptic drugs (AED). This may be a paradoxical reaction (for example the increase of complex focal seizures due to carbamazepine, vigabatrin or phenytoin treatment) or a result of AED-induced encephalopathy (commonly induced by valproate in patients with complex focal seizures). A seizure increase during intoxication with AEDs is a rare phenomenon, thus, it is not directly related to this condition. An incorrect choice of drugs in the treatment of an epileptic syndrome or seizure type may provoke seizures (as for example the provocation of absences due to carbamazepine or phenytoin). The possible seizure-inducing effect of AEDs has to be differentiated from seizure occurrence due to the natural course of epilepsy. This may be especially difficult in patients suffering from West syndrome or Lennox-Gastaut syndrome, in whom seizure frequency may vary even without medication. However, especially in these patients, drug-induced worsening of seizure manifestation is often observed. In general, a seizure-inducing effect of antiepileptic drugs has to be considered when a seizure increase is observed soon after the initiation of therapy, when a stepwise increase of the dosage is followed by a further increase of seizures, a decrease of seizures is seen with tapering of the dosage and a renewed increase of seizures can be observed after this therapy has been reestablished. Finally, one knows that the clinical condition of encephalopathy due to valproate or carbamazepine is accompanied by seizure increase. In spite of these clinical aspects, the underlying mechanisms of seizure increase mostly remain unclear. From animal experiments it is obvious that especially carbamazepine and phenytoin may provoke generalized seizures as absences or myoclonic seizures. A seizure increase during vigabatrin therapy has been attributed to the increase of the cerebral amount of gamma-amino-butyric acid, which is known to possibly exhibit inhibitory or excitatory neuronal effects. The occurrence of tonic seizures in patients with Lennox-Gastaut syndrome has been attributed to the sedative effect of the drugs; however, this conclusion is controversial. From a clinical point of view, one should consider young age of the patient, mental retardation, antiepileptic polytherapy, high frequency of seizures or prominent epileptic activity in the electroencephalogram previous to medication as risk factors for a possible seizure-inducing effect of antiepileptic drugs.