Seizures from tricyclic antidepressants

In clinical practice, a number of patients with SRI-resistant OCD receive simultaneous treatment with two potent SRls. Apart from encouraging case reports of coadministering fluoxetine and clomipramine in adolescents [Simeon et al. 1990] and adults [Browne et al. 1993] with OCD, the efficacy and safety of this approach have not been subjected to rigorous examination. Because of the risks associated with fluoxetine-induced elevations in plasma levels of tricyclic antidepressants, caution should be exercised when these drugs are used concurrently [Rosenstein et al. 1991]. Clomipramine s potential for lowering seizure threshold is of particular concern, making it advisable to measure clomipramine plasma levels before and after addition of another SRI. 

For many drugs, at least part of the toxic effect may be different from the therapeutic action. For example, intoxication with drugs that have atropine-like effects (eg, tricyclic antidepressants) reduces sweating, making it more difficult to dissipate heat. In tricyclic antidepressant intoxication, there may also be increased muscular activity or seizures the body s production of heat is thus enhanced, and lethal hyperpyrexia may result. Overdoses of drugs that depress the cardiovascular system, eg, 13 blockers or calcium channel blockers, can profoundly alter not only cardiac function but all functions that are dependent on blood flow. These include renal and hepatic elimination of the toxin and any other drugs that may be given. 

Correct answer = D. MAO inhibitors and aspirin can be taken concurrently. Hypertensive crisis may result from use (concurrently or within 2 weeks) of MAO inhibitors and indirect sympathomimetic amines, such as ephedrine. Concomitant use of MAO inhibitors and tricyclic antidepressants may result in mutual enhancement of effects with the possibility of hyperpyrexia, hypertension, seizures and death. Tyramine-containing foods, such as aged cheeses and beer, may precipitate a hypertensive crisis because of the accumulation and release of stored catecholamines from nerve endings. MAO inhibitors may lead to an exaggerated response to dopamine. 

Overall, amoxapine appears to have some advantage over other tricyclic antidepressants possible earlier onset of action and relative freedom from serious cardiotoxic effects. Its major drawbacks are the potential for neuroleptic adverse effects, a high incidence of seizures, deaths in overdose (2), and the possibility of long-term neurological damage. 

Early signs of tricyclic antidepressant toxicity are due to anticholinergic effects and include tachycardia, mydriasis, dry mouth, low-grade fever, diminished bowel sounds, CNS excitation, and delirium. More serious toxicity is manifested by coma, respiratory depression, seizures, and cardiovascular toxicity including conduction disturbances, hypotension, ventricular arrhythmias, and asystole. Seizures cause hyperthermia, rhabdomyolysis, and metabolic acidosis. Clinical deterioration can be rapid and catastrophic in patients with tricyclic antidepressant overdose. Death most often occurs due to dysrhythmia and circulatory collapse. The typical therapeutic dose of a tricyclic antidepressant is 2-4 mg kg day Doses of 15-20 mg kg are potentially lethal. Therapeutic drug levels for most tricyclic antidepressants range from 100 to... 

The CNS manifestations of tricyclic antidepressant overdose may vary from mild agitation or drowsiness to delirium, coma, respiratory depression, or seizures. These manifestations are thought to result in part from central anticholinergic and antfliistaminic actions of these drugs. 

Patients may deteriorate rapidly and progress from no symptoms to life-threatening cardiotoxicity or seizures within 1 hour. Major symptoms of tricyclic antidepressant overdose typically are manifest within 6 hours of ingestion. The principal effects of tricyclic antidepressant poisoning involve the cardiovascular system and the central nervous system and can result in arrhythmias, hypotension, coma, and seizures (see below). 

Tricyclics modify peripheral sympathetic effects in two ways through blockade of norepinephrine reuptake at neuroeffector junctions and through alpha adrenoceptor blockade. Sedation and atropine-like side effects are common with tricyclics, especially amitriptyline. In contrast to sedative-hypnotics, tricyclics lower the threshold to seizures. The answer is (B). Selective serotonin reuptake inhibitors cause sexual dysfunction in some patients, with changes in libido, erectile dysfunction, and anorgasmia. Tricyclic antidepressants may also decrease libido or prevent ejaculation. Of the heterocyclic antidepressants bupropion is the least likely to affect sexual performance. The drug is also used in withdrawal from nicotine dependence. The answer is (B). 

Limited effectiveness and toxicity are the major reasons for switching a patient from one antidepressant drug to another. SSRIs are sometimes superior to tiicychcs in their clinical efficacy, and in this case amitriptyline had not proved effective after a reasonable trial (8 weeks). At that time, the depressive symptoms in this patient included feelings of worthlessness and possibly suicidal ideation. Tricyclic overdose is especially dangerous in depressed patients, who often use medications close at hand in attempting suicide. Ingestion of just a 2-week supply of amitriptyline can cause severe hypotension, cardiac arrhythmias, seizures, coma, and death ( one-prescription lethal ). 

C. Seizures are common with tricyclic antidepressant toxicity and may be recurrent or persistent. The muscular hyperactivity from seizures and myoclonic jerking, combined with diminished sweating, can lead to severe hyperthermia (see p 21), resulting in rhabdomyolysis, brain damage, multisystem failure, and death. 

Carbamazepine is an anticonvulsant that is structurally related to tricyclic antidepressants such as amitriptyline and imipramine. Carbamazepine is effective in the treatment of psychomotor and grand mal seizures and pain from trigeminal neuralgia and, in combination with other drugs, for psychiatric disorders such as mania and extreme aggression. Carbamazepine is also occasionally used to control pain in persons with cancer. Carbamazepine was first mar-... 

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