Weight gain Patients being treated with TCAs often gain weight, most likely because of carbohydrate craving associated with H2 blockade. Patient education, monitoring of weight, and dietary counseling may be necessary during TCA use. Regular exercise is recommended, although depressed patients often lack the motivation and energy to exercise.
Cardiovascular toxicity All TCAs have potential cardiovascular effects (Table 3), which are seen on an ECG as increased PR, QRS, or QTc intervals, especially at higher dosages or in patients with pre-existing cardiac disease.19 Orthostatic hypotension is among the most common cardiovascular side effects, particularly in the elderly, and may result in falls or other injuries.
A baseline ECG is recommended before starting TCA therapy, especially in depressed patients with cardiac conduction delays (primary or secondary to concomitant medications). Routine ECGs should be used to monitor patients:
- with pre-existing cardiac disease;
- taking higher-than-recommended dosages of a TCA;
- taking other medications that may affect cardiac conduction.
When in doubt, obtaining a cardiology consultation is recommended.
CNS effects Signs of CNS toxicity include confusion, memory impairment, delirium, seizures, coma, and eventual respiratory depression.20 Risk factors include toxic TCA plasma levels, elderly patient age, and concomitant use of other medications, such as psychotropics (neuroleptics), anticholinergics, and antihistamines. CNS toxicity may be difficult to diagnose, as it may initially resemble worsening of depressed mood. Confusion or worsening of memory or cognitive function are predictors of CNS toxicity.
A patient with anticholinergic-related delirium should be monitored on a medical unit. A trial of physostigmine may be warranted to confirm the diagnosis.
Neurologic symptoms Maprotiline and clomipramine have been associated with an increased risk of seizures. Use reduced dosages in patients with a history of seizures or concomitant use of medications that may increase maprotiline or clomipramine levels or decrease the seizure threshold (e.g., other antidepressants, withdrawal from benzodiazepines). Amoxapine has been associated with extrapyramidal symptoms secondary to a neuroleptic metabolite.
Overdose The severity of adverse side effects often depends upon drug concentration. An overdose of as little as a 2-week supply of a TCA can cause potentially fatal arrhythmias.
Priapism Trazodone has been associated with priapism, which has an incidence rate of 1/6,000 in patients taking this drug. Priapism is a medical emergency that requires prompt treatment.
Administration
TCAs are well-absorbed following oral administration and reach peak plasma levels in 2 to 6 hours. The average half-life of approximately 24 hours often allows therapeutic levels to be achieved with once-daily dosing at bedtime (Table 3).
TCAs are metabolized primarily by the cytochrome P-450 2D6 (CYP2D6) isoenzyme. Patients differ by a factor of 30- to 40-fold in their rate of metabolism of some TCAs, depending on individual genotypes.
The 7 to 9% of Caucasians classified as poor metabolizers at CYP2D6 require much lower-than-usual dosages of secondary amine TCAs.21 he 50% of Asians who are intermediate metabolizers require one-half the usual dosage. Tailor therapy to the individual patient, starting low, checking plasma levels, and monitoring for side effects.
For patients who would benefit from TCAs’ H1 anxiolytic effects, start with bid or tid dosing and later switch to once daily after achieving efficacy.
When using TCAs, start low and go slow to maximize efficacy and minimize side effects, especially in the elderly patient. The goal is to treat the patient, not to achieve target serum levels. The most favorable results have been demonstrated when patients are maintained at the dosages to which they respond when their disorder is in the acute stage.17
Symptoms usually improve after 2 weeks of TCA therapy, and up to 6 weeks may be required for a clinically significant effect. For many depressed patients, symptoms of insomnia, anxiety, and poor appetite improve within the first few days.
Monitoring serum levels
Serum levels are useful for monitoring treatment, compliance, and toxicity.22 Because the most accurate TCA serum levels are found at steady state, check the level after the patient has been on TCA therapy for at least 5 days and 8 to 12 hours after the last dose. Serum levels may also guide dosage increases in patients who exhibit a partial response to therapy.
Table 4
DRUGS THAT INTERACT WITH TCAs
| Anticholinergic agents |
| Barbiturates |
| Cimetidine |
| Disulfiram |
| ETOH |
| Flecainide |
| Guanethidine |
| Haloperidol |
| MAOIs |
| Methylphenidate |
| Phenothiazines |
| Phenytoin |
| Propafenone |
| Quinidine |
| SSRIs (e.g., fluoxetine, sertraline, paroxetine) |
| Sympathomimetic drugs (e.g., norepinephrine, epinephrine) |
| Warfarin |
Nortriptyline has a therapeutic window between 50 and 150 ng/mL. Patients who do not respond to serum levels higher than 150 ng/mL may respond when the dosage is reduced and the serum level falls to within that range. If response is adequate and without side effects, however, there is no need to reduce the dose. Other, less clear therapeutic windows have been described for other TCAs (Table 3).