Continuing Education Activity

Tricyclic antidepressants (TCAs) constitute a class of medications used to manage and treat major depressive disorder (MDD). These medications function by inhibiting the reuptake of neurotransmitters, such as serotonin and norepinephrine, which can modulate mood, attention, and pain in individuals. The U.S. Food and Drug Administration (FDA) has approved different TCAs for specific indications based on clinical trials and proven evidence of their effectiveness and safety for specific medical conditions. Evidence-based guidelines recommend TCAs as a second-line treatment for MDD following selective serotonin reuptake inhibitors (SSRIs). Although TCAs demonstrate equivocal efficacy with SSRIs when treating MDD, these medications cause more significant adverse effects due to their anticholinergic activity and lower threshold for overdose. Due to these factors, TCAs are typically not considered the first-line treatment for MDD, even though they have been proven highly effective in managing severe or treatment-refractory depression. This activity highlights the mechanism of action, indications, contraindications, adverse event profile, monitoring protocols, relevant interactions, off-label uses, and other pivotal facets of TCA therapy to enhance the competence of interprofessional healthcare team members when caring for patients with MDD and related conditions.

Objectives:

• Identify appropriate candidates for TCA therapy based on the severity of MDD and potential treatment resistance.
• Differentiate TCAs from other classes of antidepressant medications, understanding their unique mechanisms of action, adverse effect profiles, and indications for use.
• Implement evidence-based guidelines when prescribing TCAs, considering the established efficacy and safety parameters for specific indications.
• Communicate about the benefits, risks, and potential side effects of TCA therapy with patients, enabling informed decision-making and treatment adherence.

Indications

Tricyclic antidepressants (TCAs) constitute a class of medications that were initially introduced to the market in 1959 as a pharmacotherapy for major depressive disorder (MDD).[1] TCAs are now regarded as second-line treatment options alongside selective serotonin reuptake inhibitors (SSRIs). They acquire the name "tricyclic" due to the presence of 3 rings in their chemical structure. These medications function by inhibiting the reuptake of neurotransmitters such as serotonin and norepinephrine, which can modulate mood, attention, and pain in individuals. 

The first TCA, imipramine, was initially created as an antipsychotic but was later discovered to have potent antidepressant properties. Imipramine's success prompted additional research, leading to the formulation of subsequent TCAs such as amitriptyline, nortriptyline, desipramine, and doxepin. 

Table 1. FDA Approval Dates for TCAs

FDA-Approved Indications

The U.S. Food and Drug Administration (FDA) has approved different TCAs for specific indications based on clinical trials and proven evidence of their effectiveness and safety for specific medical conditions. The approval of TCAs varies depending on the formulation, encompassing treatment for various conditions.[2] TCAs that have received FDA approval for the treatment of MDD comprise amitriptyline, amoxapine, doxepin, desipramine, nortriptyline, protriptyline, imipramine, and trimipramine.[3][4] Clomipramine holds FDA approval for treating obsessive-compulsive disorder (OCD) in individuals aged 10 and older.[5] 

Although TCAs demonstrate equivocal efficacy with SSRIs when treating MDD, these medications cause more significant adverse effects due to their anticholinergic activity and lower threshold for overdose.[6][7] Due to these factors, TCAs are typically not considered the first-line treatment for MDD, even though they have been proven highly effective in treating severe or treatment-refractory depression.[8] 

Off-Label Uses

The off-label indications of TCAs include migraine prophylaxis, OCD, insomnia, anxiety, and the management of chronic pain, particularly neuropathic pain conditions such as myofascial pain, diabetic neuropathy, and postherpetic neuralgia.[9][10][11][12][13][14][15] Doxepin and amitriptyline are the most frequently utilized TCAs used for migraine prophylaxis.[16][17] 

Following the lack of success with preferred treatments, including pregabalin, duloxetine, and milnacipran, TCAs are currently utilized as second-line treatment options for fibromyalgia.[18][19] TCAs can also be used to treat nocturnal enuresis in children when the first-line therapy with desmopressin proves ineffective.[20]

Table 2. Off-Label Uses of TCAs

Mechanism of Action

TCAs exert their effects by modulating around 5 distinct neurotransmitter pathways. These medications function by inhibiting serotonin and norepinephrine reuptake within the presynaptic terminals, resulting in elevated concentrations of these neurotransmitters within the synaptic cleft. The increased levels of norepinephrine and serotonin in the synapse can contribute to the antidepressant effect. In addition, the neurotransmitters act as competitive antagonists on postsynaptic cholinergic (alpha-1 and alpha-2), muscarinic, and histamine receptors (H1).[21][22] The molecular structure of each receptor significantly impacts TCA's affinity for each of these receptors.

The chemical structure of a TCA comprises a 3-ringed arrangement with an attached secondary or tertiary amine. Desipramine, nortriptyline, and protriptyline are categorized as secondary amines, whereas amitriptyline, clomipramine, doxepin, imipramine, and trimipramine belong to the group of tertiary amines. Tertiary amines typically exhibit significant serotonin reuptake inhibition, whereas secondary amines display heightened inhibition of norepinephrine uptake.[23] 

The varied amine structures and chemical compositions observed in TCA usage contribute to the diverse adverse effects observed. These factors impact the affinity and binding of TCA receptors.[24] The inhibition of norepinephrine and serotonin reuptake is believed to underlie the mechanism of TCA utilization in treating neuropathic pain and headache.

Pharmacokinetics

Understanding the pharmacokinetic properties of TCAs is essential for determining appropriate dosing strategies, predicting drug interactions, and enhancing therapeutic outcomes.

The vital components of TCA pharmacokinetics are outlined below.

Absorption: TCAs are readily absorbed in the body following oral administration and usually achieve peak plasma concentrations within 2 to 8 hours. Bioavailability ranges from 40% to 50%, depending on the specific TCA. Food consumption can impact the absorption of TCAs, particularly those with greater lipophilicity, such as amitriptyline. Eating food can slow down the absorption rate and cause a delay in the onset of action.

Distribution: TCAs exhibit moderate-to-high protein binding, primarily to plasma albumin and extravascular tissues, resulting in a substantial apparent volume of distribution of 5 to 30 L/kg. The degree of protein binding varies among different TCAs. Due to their lipophilic characteristics, TCAs distribute widely throughout the body, including the central nervous system. This attribute of TCA contributes to their capacity to influence diverse neurotransmitter systems.

Metabolism: The majority of TCAs undergo comprehensive hepatic metabolism through cytochrome P450 (CYP) enzymes, primarily CYP2D6 and CYP2C19. The metabolic pathways include demethylation, hydroxylation, and glucuronidation, forming active and inactive metabolites. Genetic polymorphisms within CYP enzymes can significantly impact the metabolism of TCAs, resulting in divergent drug responses and potential interactions.

Elimination: TCAs and their metabolites are primarily eliminated via the renal route, with only about 5% excreted unchanged. The elimination half-life of TCAs differs across various compounds, typically ranging from 10 to 50 hours.

Administration

Available Dosage Forms

TCAs are available in the form of oral tablets, capsules, and solutions. Although intravenous (IV) administration of certain TCAs, including clomipramine, has been used in clinical trials, IV is not a customary route for TCA administration.[25] Topical creams and transdermal patches have been studied for specific TCAs, such as imipramine and doxepin. However, oral administration (PO) remains the standard method of administration for TCAs.[26] 

Strength

The dosages for each TCA drug may differ, but due to their high risk of adverse effects, the initial dose of the medication is kept low and gradually increased depending on the response levels of the patients.[27] Patients unresponsive to low doses of TCA may respond to higher doses, mainly because TCAs have demonstrated increased efficacy at higher dosages compared to high doses of SSRIs.[27] 

Although blood monitoring of TCA concentrations is feasible, there exists mixed evidence regarding the impact of this monitoring on treatment outcomes.[7] In general, patients are typically administered an oral dose of a TCA once daily due to the extended half-life and sedative effects characteristic of this drug class.[24]

Table 3. Adult Dosages of TCAs

Specific Patient Population

Patients with hepatic impairment: Impaired hepatic function can diminish the clearance and lead to increased accumulation of TCAs, which undergo substantial metabolism in the liver. Patients with compromised hepatic function might necessitate reduced doses and more frequent monitoring of plasma levels and adverse effects associated with TCAs. Nortriptyline and desipramine may be preferred over other TCAs in patients with hepatic impairment due to their lower potential for causing hepatotoxicity.

Patients with renal impairment: As TCAs and their metabolites are predominantly eliminated through the renal route, renal impairment in patients can significantly affect their pharmacokinetics. Nortriptyline may be preferred over other TCAs in patients with renal impairment due to its less-active metabolites and reduced anticholinergic effects.

Pregnancy considerations: Certain studies have indicated that TCAs might elevate the risk of congenital malformations, potentially associated with defects in their eyes, ears, face, and neck. In addition, TCAs have been linked to preterm delivery, low birth weight, neonatal withdrawal syndrome, and persistent pulmonary hypertension in newborns.[28] Specifically, clomipramine is associated with more severe neonatal symptoms, including cardiac defects.[29] However, other studies have not identified substantial connections between TCAs and adverse pregnancy outcomes. Overall, TCAs are not typically considered safe medication during pregnancy. 

If there is a clinical necessity, the decision to use TCAs during pregnancy should be based on carefully evaluating the benefits and risks unique to each case. This should encompass the severity of maternal depression, the response to previous treatments, the potential for drug interactions, and a patient's preferences. Certain TCAs, notably nortriptyline and desipramine, are preferred during pregnancy due to their reduced fetal exposure and more favorable safety profile.

Breastfeeding considerations: TCAs are excreted into breast milk in varying quantities, depending on their lipophilicity, protein binding, and metabolism. Generally, infants are exposed to low levels of TCAs through breast milk, and there are usually no significant adverse effects. However, a few cases of sedation, irritability, poor feeding, and colic have been reported. TCAs, except doxepin, have not been linked to detrimental effects on breastfeeding, and therefore, they are considered safe for use.[30] Nortriptyline is considered the safest medication to use during breastfeeding due to its non-sedating profile.[29]

Pediatric patients: TCAs are generally not approved for use in pediatric patients due to safety concerns and the availability of other better and safer treatment options for this population. The majority of TCAs have not demonstrated superior efficacy compared to placebo for treating depression within pediatric populations. However, clomipramine is an exceptional drug with FDA approval for treating OCD in individuals aged 10 and older.

Geriatric patients: Caution is advised for older patients using TCA medications due to age-related changes in pharmacokinetics, increased sensitivity to anticholinergic effects, and potential drug interactions. Lower initial doses and a more gradual titration might be necessary for older patients to mitigate the drug's potential risks or adverse effects. Consistent monitoring for cognitive impairment falls and other possible side effects is pivotal within this patient demographic. Nortriptyline and desipramine may be preferred medications over other TCAs among older adults due to their reduced anticholinergic effects, diminished cardiac toxicity, and more linear pharmacokinetics.

Adverse Effects

TCAs exhibit diverse receptor affinities that contribute to various adverse effects, including constipation, dizziness, and xerostomia.[31] As these drugs inhibit cholinergic receptors, their utilization can result in blurred vision, constipation, xerostomia, confusion, urinary retention, and tachycardia in individuals taking the drug.[32] The alpha-1 adrenergic receptor blockade can induce orthostatic hypotension and dizziness.[31][32] TCA-induced histamine blockade (H1) may lead to sedation, increased appetite, weight gain, and confusion in patients.[33][31]

TCAs may also induce cardiovascular complications, including arrhythmias such as QTc prolongation, ventricular fibrillation, and sudden cardiac death, particularly in individuals with preexisting ischemic heart disease.[34] Therefore, assessing a patient's cardiac health is important before prescribing TCAs. Evidence suggests that TCAs elevate the risk of seizures in individuals with epilepsy, and their usage necessitates caution within this population.[35] TCAs may cause a minor elevation of liver enzymes; however, acute hepatitis is seldom associated with using TCAs.[33][36]

TCA use has been demonstrated to heighten the risk of suicidal ideation and behavior, particularly in individuals aged 24 or younger. Individuals who start taking TCAs at age 24 or younger should be closely monitored for any suicidal thoughts and behaviors.[36]

Drug-Drug Interactions

TCAs have the potential to interact with various medications, thereby leading to clinically significant drug-drug interactions. These interactions can affect TCA plasma levels and therapeutic response, increasing the risk of adverse effects. Healthcare professionals must remain vigilant about potential interactions when prescribing TCAs concurrently with other medications. 

Table 4. TCA Drug-Drug Interactions and Adverse Effects

Contraindications

TCAs are contraindicated within certain populations and when used concurrently with specific medications. TCAs should not be prescribed to individuals with a family history of QTc interval prolongation or sudden cardiac death. Hypersensitivity reactions to a TCA drug are considered an absolute contraindication. Patients who have a hypersensitivity reaction to a TCA drug can be prescribed a different medication within the same class with caution. TCAs should not be administered concurrently with monoamine oxidase inhibitors (MAOIs), such as phenelzine, due to the risk of developing serotonin syndrome.[37] 

Furthermore, patients should abstain from MAOI usage for at least 14 days before initiating TCA therapy. The combination of TCAs and SSRIs is not recommended, as this combination has been demonstrated to escalate plasma concentrations of TCAs and heighten the risk of serotonin syndrome.[38][39]

The utilization of TCAs necessitates caution in individuals with angle-closure glaucoma, as the drug's anticholinergic effects could potentially heighten the risk of an acute ocular crisis.[40] TCAs should be used cautiously in patients with a history of seizures, as they might lower the seizure threshold. In addition, caution is warranted in patients with urinary retention, as TCAs' anticholinergic properties could exacerbate this symptom.[32][35] Although coronary artery disease (CAD) is not an absolute contraindication for TCAs, clinicians should typically exercise caution when considering this medication for patients with CAD.[41] 

Due to the metabolism of TCAs by cytochrome P450 enzymes in the liver, caution is necessary when prescribing these medications to patients with hepatic impairment. Clomipramine has demonstrated the highest incidence of drug-induced liver injury, particularly within the TCA class of drugs. As a result, this drug is not the preferred choice for patients with suboptimal liver function.[42]

Box Warning

The FDA mandates that all TCAs include a boxed warning on the label, cautioning users about the potential risks and elevation of suicidal thoughts or behaviors when using these drugs. This risk is particularly pronounced in children, adolescents, and young adults between the ages of 18 and 24.

Precautions

TCAs are associated with a higher risk of drug overdose compared to many other classes of antidepressants. In addition, meticulous monitoring of cardiac function, electrocardiogram (ECG), and blood pressure is vital when prescribing TCAs, especially for patients with known cardiac abnormalities.

Monitoring

TCAs generally exhibit a narrow therapeutic index, and the specific therapeutic range for each TCA depends on the prescribed drug. Due to the narrow therapeutic index of TCAs, patients should undergo vigilant monitoring for signs of toxicity, such as QRS-widening on ECG, tremors, confusion, muscle rigidity, and coma.[23]

All patients commencing a TCA therapy should undergo screening for preexisting cardiac conditions, including prolonged QTc intervals, heart disease, and a family history of arrhythmias. Patients who test positive for preexisting heart conditions might necessitate further evaluation by a cardiologist before initiating TCA treatment. Furthermore, these patients should undergo consistent monitoring for the emergence of new cardiac symptoms. Patients with low potassium blood concentrations should undergo periodic monitoring to mitigate the risk of developing arrhythmias.[34] Obtaining an ECG for further evaluation is recommended in patients aged 50 and older.

All patients initiating TCA treatment or currently using TCAs as medications should be monitored for the aggravation of depressive symptoms or the emergence of new-onset suicidal thoughts or behaviors. Monitoring the blood TCA levels could benefit non-adherent patients with reduced tolerability or minimal drug response. However, mixed evidence exists on the effectiveness of blood concentration monitoring on clinical outcomes.[7]

Toxicity

Due to their narrow therapeutic index, TCAs are prone to induce toxicity in the event of accidental or intentional overdose. These drugs have exhibited higher rates of death per 1 million prescriptions than other antidepressants, primarily attributed to elevated rates of suicide resulting from deliberate overdose.[43] Newer TCAs, such as amitriptyline, have a higher safety margin than older TCAs, such as desipramine, nortriptyline, and trimipramine, which induce toxicity even at lower doses.

Signs and Symptoms of TCA Overdose

Signs and symptoms of TCA overdose include ECG abnormalities such as QTc prolongation and widened QRS complex, hypotension, seizures, tremors, coma, xerostomia, urinary retention, and respiratory depression.[44] TCAs' most frequent causes of death are generally attributed to hypotension or arrhythmias.[45] 

Management of TCA Overdose

Management of TCA overdose necessitates stabilizing the patient and promptly addressing their acute complications, as listed below.

• Activated charcoal may be administered to patients for TCA overdose to prevent drug absorption; however, its use must occur within 2 hours of TCA ingestion.[46] 
• Patients with a prolonged QRS interval should be administered sodium bicarbonate to elevate their serum pH levels and diminish the concentration of active free TCA medication.[47] 
• Lidocaine could be considered a potential reversal agent in TCA-induced cardiotoxicity resistant to sodium bicarbonate.[45] 
• Patients experiencing TCA-induced seizures should be provided with benzodiazepines for treatment.[48] 
• Patients who manifest hypotension should receive IV crystalloids, whereas those demonstrating signs of respiratory compromise should be administered respiratory support.
• Patients with hypotension unresponsive to crystalloids should be considered for a trial of norepinephrine.[49]

Given the risk of serotonin syndrome, the concurrent use of TCAs and MAOIs should be avoided.[37] Patients with serotonin syndrome present with dilated pupils, hyperreflexia, myoclonus, diarrhea, tremors, and confusion. The treatment approaches for serotonin syndrome encompass cooling, discontinuation of serotonergic drugs, and the use of cyproheptadine.

Enhancing Healthcare Team Outcomes

Nowadays, TCAs are frequently prescribed for off-label uses. Although physicians may prescribe TCAs to treat MDD, they are rarely recommended as a first-line treatment due to their adverse effect profile, encompassing anticholinergic, antihistamine, and antiadrenergic effects. Moreover, numerous safer alternatives, such as SSRIs, are accessible. Nevertheless, physicians might still prescribe TCAs in cases of MDD where conventional antidepressant pharmacotherapy has proven ineffective. Regardless of the indications for TCAs, patients who require treatment with TCAs need the involvement of an interprofessional team to help maintain patient safety.

If cardiac function abnormalities are present, collaboration among a patient's primary care physician or advanced practice practitioner, psychiatrist, and cardiologist is crucial for maintaining the patient's stability and averting adverse outcomes. Patient monitoring for signs of suicidal intent is necessary to prevent instances of toxicity and overdose.[50] Maintaining communication between the patient's cardiologist and prescriber is vital to preempt cardiotoxic outcomes in patients with predisposing risk factors for cardiac dysfunction.[34]

Pharmacists are critical in taking care of patients who are prescribed TCAs. Pharmacists can verify the correct dosage and identify significant drug-drug interactions. Furthermore, as TCAs predominantly undergo liver metabolism, pharmacists can mitigate the risk of interactions with other drugs by identifying concomitant medications that impact hepatic metabolism.[51] Nursing staff can contribute to the process by evaluating patient adherence and overseeing the monitoring of adverse effects. Frequent and open communication among all interprofessional healthcare team members is crucial to provide optimal patient care while minimizing adverse events associated with TCAs.