Additional hurdles include the required washout period from serotonergic medications and interactions with sympathomimetics. MAOIs pose the highest risk of serotonin syndrome; however, this usually occurs if given concomitantly with other serotonergic agents. The standard recommendation is a 14-day washout period from SSRIs (5 weeks for fluoxetine and 3 weeks for vortioxetine), SNRIs, mirtazapine, and other antidepressants. It can be distressing for patients to be without medication during that period. Because some antidepressants have much shorter half-lives, waiting 5 half-lives (typically 5 to 7 days) for the discontinued medication to be excreted is feasible if patients are closely monitored.5,12,13,25,27,30 There are rare instances where a TCA may be combined with an MAOI (typically initiated within 1 to 2 days of each other), but never clomipramine or imipramine due to their potent serotonin reuptake inhibition.31 If switching to an alternative MAOI, waiting 7 to 14 days is recommended to allow adequate time for the inhibited enzyme to regenerate.14-17,32 Taking medications that increase dopamine and norepinephrine (eg, stimulants or oral over-the-counter decongestants) with an MAOI is typically not recommended due to the risk of hypertensive crisis.25,27 In severe TRD or comorbid ADHD, successful simultaneous use of methylphenidate or amphetamine—typically at low doses—with close blood pressure monitoring has been reported.33 There have also been positive cases of the use of modafinil in combination with an MAOI; however, this should be done with caution.34,35 Clinicians must use clinical judgment when considering a combination of medications that pose a higher risk.
Tricyclic antidepressants
TCAs work differently than MAOIs to increase monoamines. They inhibit presynaptic serotonin and norepinephrine transporters in the CNS to increase levels of these chemicals in the synaptic cleft. While all TCAs inhibit these transporters, they do so at varying levels (Table 336-51). Based on their chemical structure, TCAs can be categorized into secondary and tertiary amines. Tertiary amines are metabolized via demethylation into their derivatives (Table 336-51). Patients who have recently suffered a myocardial infarction (MI) should avoid tertiary amines. TCAs can reduce heart rate variability, which is already decreased after an MI, thus presenting the potential for cardiac arrhythmias. TCAs should also be avoided in patients with cardiac conduction abnormalities.38-46,52 Patients with a prior baseline cardiac conduction defect, such as a bundle branch block, are at higher risk for further cardiac abnormalities. In those with a preexisting first-degree heart block, TCAs can still be used, but electrocardiogram monitoring is recommended.52,53 TCAs have also been reported to decrease the seizure threshold.38-46 They can be used with caution in patients who have a history of epilepsy or head trauma, or with concomitant medications that lower the seizure threshold.38-46
Overdose risk is a concern with TCAs because ingestion of 10 to 20 mg/kg can lead to significant toxicity.54 This is due to their blockage of voltage-gated sodium channels found in the CNS and heart, which contributes to overdose symptoms such as a widened QRS complex and seizures. Symptoms usually develop within 2 hours but may be delayed up to 6 hours.55 Patients with a history of overdose must be carefully assessed before initiating a TCA. Prescribing a limited supply of these medications may be valuable. The use of TCAs has often been limited due to their adverse effects, most of which are associated with their respective affinities for alpha 1, muscarinic 1, and histamine 1 receptors. Inhibition of the alpha 1 receptor is associated with hypotension, muscarinic 1 with anticholinergic adverse effects, and histamine 1 with sedation and weight gain. Tertiary amines have a higher affinity for these receptors compared to secondary amines, leading to a more significant adverse effect profile.36,50 Among TCAs, amitriptyline is the most likely to cause hypotension, whereas desipramine and nortriptyline are least likely. Amitriptyline and clomipramine are most likely to cause anticholinergic adverse effects, whereas desipramine and nortriptyline are the least likely. Amitriptyline, doxepin, and imipramine have the highest propensity for QTc prolongation.36
Beyond treating MDD, TCAs have shown benefits for treating other disease states (Table 438-46,49,56-61). These differing indications may help psychiatrists determine the best TCA to prescribe for a given patient. Amitriptyline is the most studied TCA for MDD; however, nortriptyline is typically preferred due to its favorable tolerability profile.4,62 Nortriptyline also has data supporting its use in ECT to prevent relapse.63 Amitriptyline and nortriptyline have shown benefits in patients with neuropathic pain and for migraine prophylaxis.56-60 Although frequently used for MDD, clomipramine is not FDA-approved for this indication, but is for obsessive-compulsive disorder.39 Doxepin is FDA-approved for insomnia at lower doses and for MDD at higher doses.40 Therefore, it may benefit patients with sleep difficulties secondary to depression. Desipramine has been used off-label to treat ADHD in children and has shown some benefits in adults.64-66 Protriptyline, trimipramine, and amoxapine are infrequently used in clinical practice.
A unique feature of TCAs is the ability to monitor serum concentrations (Table 336-51).Guidelines recommend therapeutic drug monitoring (TDM) with amitriptyline, clomipramine, imipramine, and nortriptyline for routine use. TDM is still recommended for doxepin, desipramine, and trimipramine, but its utility is largely for treatment failure or resistance.37 These plasma levels can be altered based on coadministered medications (Table 538-46) and should be closely monitored. Physicians should obtain a trough level after at least 5 half-lives and before the next dose is due, and use TDM as indicated to optimize dosing.
Continue to: CASE CONTINUED