Revisiting Tricyclic Antidepressants: Understanding the Differences and Advantages for Effective Depression Treatment

HISTORY OF TCAs

Monoamine oxidase inhibitors and tricyclics were first discovered in 1952. After World War Two, large amounts of rocket fuel hydrazine were given to the pharmaceutical industry. The compound isoniazid was derived from hydrazine, and it was found to have antitubercular and mood-elevating properties. [Yanez et al., 2012]

Irving J. Selikoff and Edward Robitzek studied the clinical effects of iproniazid.

They observed that this drug greatly stimulated the central nervous system, which was initially interpreted as a side effect. [Yanez et al., 2012]

Many studies on the antidepressant effects of antitubercular hydrazide agents were performed.

Imipramine was initially trialled in psychosis, but both drugs were found to be effective at treating endogenous depression as well as motor retardation.

Other tricyclics, such as amitriptyline, were later synthesised by modifying the structure of imipramine and the desmethyl derivative of imipramine. Desipramine was introduced in 1964 as the active metabolite of imipramine.

In 1963, nortriptyline was approved in Great Britain, followed by trimipramine, protriptyline (1966), iprindole (1967), dothiepin and doxepin (1969). [Fangmann et al., 2008]

• Imipramine was the first tricyclic antidepressant and is an imino-dibenzyl compound that was first marketed in 1959
• Several other TCAs were synthesised over the next two decades, including the prototypical amitriptyline and trimipramine.
• Today, several FDA-approved TCAs are used to treat MDD, including amitriptyline, amoxapine, desipramine, doxepin, nortriptyline, protriptyline, and trimipramine (clomipramine is also approved for OCD).

MECHANISM OF ACTION OF TCAs

VARIATIONS IN THE POTENCY AND AFFINITY OF TRICYCLIC ANTIDEPRESSANTS (TCAs) FOR DIFFERENT RECEPTORS AND TRANSPORTERS.

The potency of TCAs as NRIs and SRIs can vary by approximately 1000-fold. [Gillman, 2007]

Different TCAs have different affinities for NAT and SERT:

• Clomipramine has a NA/5HT ratio of approximately 1:2 (NAT Ki = 54 nmol/l; SERT Ki = 0.14 nmol/l).
• Amitriptyline has a NA/5HT ratio of approximately 1:1.5 (NAT Ki = 50 nmol/l; SERT Ki = 20 nmol/l).
• Nortriptyline has a NA/5HT ratio of approximately 10:1.
• Desipramine has variable affinities for NAT and SERT (NAT Ki = 0.3-8.6 nmol/l; SERT Ki = 22-180 nmol/l).

The potency of TCAs at muscarinic receptors can vary:

• Nortriptyline has one-half the potency of amitriptyline at muscarinic receptors.
• At an NRI-equivalent dose to amitriptyline, nortriptyline has one-tenth of the anti-muscarinic effect and 1/15 of the sedative effect.
• Amitriptyline does not have clinically significant serotonergic effects.

Clomipramine more closely conforms to the criteria for SNRI status than SNRI drugs duloxetine and venlafaxine, with a NA/5HT ratio of approximately 1:2. [Gillman, 2007]

• Clomipramine is still the “gold standard” SNRI drug and may be more effective than other antidepressants in severe depression.
• The antihistamine chlorpheniramine is a more potent SRI than most TCAs currently used.
• Doxepin is the most potent and selective H1 antagonist and is a sedative at doses of 5-25 mg.
• Desipramine has significantly less affinity for muscarinic receptors than any other member of the class.
• The antagonism of 5-HT2A or 5-HT2C receptors may improve sleep in depression.
• The affinity as α1 adrenoceptor antagonists is very similar for all drugs except dothiepin, and hence postural hypotension constitutes a useful clinical marker of the magnitude of these drugs’ effect.

Clinical Implications: 

• Nortriptyline is considered to be the most effective psychotropic TCA, with a wide margin between desired effects, side effects, and toxicity, making it safe to combine with either MAOIs or selected SSRIs (such as sertraline and possibly citalopram) for the treatment of refractory patients who may require combination antidepressant therapy. [Gillman, 2007]
• Nortriptyline and desipramine have the most pharmacologically desirable characteristics as noradrenaline reuptake inhibitors (NRIs) and as drugs with few interactions that are also safe when coadministered with either MAOIs or SSRIs.
• NRIs, for example, nortriptyline, can weaken the hypertensive response known as the ‘cheese reaction’ caused by tyramine found in certain foods, which can sometimes pose a problem for patients taking MAOIs. Combining these two medications will likely offer some degree of safeguard against a tyramine-triggered episode of hypertension, which may be either partial or complete depending on the dosage. [Gillman, 2007]
• A review of individual studies has demonstrated that clomipramine may be more effective than non-TCAs in severe and psychotic depression. [Wijkstra et al., 2006]
• There is an increased acknowledgement that SNRI strategies are more effective in treating severe depression. Therefore, using two drugs to adjust the SRI/NRI ratio may be desirable, especially when considering the variations in response between individuals and illnesses.

PHARMACOKINETICS OF TCAs

Following oral administration, TCAs are primarily absorbed in the small intestine and reach peak plasma concentrations within 2 to 6 hours. However, it has been reported that there are dietary effects of TCA metabolism with high-fibre diets resulting in reduced TCA absorption and lowered TCA plasma levels.

TCAs are often considered a homogeneous class of drugs; however, there are essential differences [Rudorfer and Potter 1999]:

• TCAs undergo extensive first-pass metabolism, but this is highly variable, ranging from 87% for doxepin to 10-25% for protriptyline
• Secondary amine TCA compounds are active metabolites of tertiary amine TCAs: nortriptyline and desipramine are demethylation products of amitriptyline and imipramine, respectively.
• Tertiary amine TCAs are demethylated into secondary amine compounds.
• Desipramine and nortriptyline have much higher distribution volumes than their parent compounds (imipramine and amitriptyline, respectively) [Amitai and Frischer, 2004], [Amitai and Frischer, 2006]

Hepatic metabolism is the principal clearance method for TCAs and the primary source of interindividual variability in TCA steady-state plasma concentrations. Unfortunately, detailed pharmacokinetic and pharmacodynamic data are scarce as most metabolic studies were performed in the 1980s and 90s.

• One study on amitriptyline in 2016 showed 28 metabolites were detected in urine. [Zhou et al., 2016]
• Of note, five bioactive conjugated metabolites were suggested to be toxicity biomarkers.

Clinical response and levels:

• Because of the wide variation in the absorption and distribution of tricyclic antidepressants in body fluids, it is difficult to correlate plasma levels and therapeutic effects directly. Dosage adjustments should be made according to the patient’s clinical response and not based on plasma levels. [PI]
• Patients with plasma TCA concentrations over 450 ng/ml tend to develop cognitive or behavioural toxicity (agitation, confusion, memory impairment, pacing). Significant toxicity and death are associated with concentrations above 1000 ng/ ml. [Gillman, 2007]

CLINICAL INDICATIONS AND DOSING

Clomipramine: [PI]

MDD, OCD and phobias

• A standard dose is between 25 and 250 mg/day (maximum recommended).
• Start treatment with one tablet of 25 mg 2 or 3 times daily. Then, raise the daily dosage stepwise, e.g. 25 mg every few days (depending on how the medication is tolerated) to 4 to 6 tablets of 25 mg. Once a distinct improvement has occurred, adjust the daily dosage to a maintenance level averaging 2 to 4 tablets of 25 mg.

Cataplexy associated with narcolepsy

• Orally in a daily dose of 25 to 75 mg.
• Administer nocte only in cases where Clompiramine does not appear to exacerbate insomnia.
• Caution in older people: Start treatment with one tablet of 25 mg daily. Gradually raise the dosage to an optimum level of 50 to 75 mg daily.
• The side effects of clomipramine are similar to those from amitriptyline due to its H1, Alpha1 and VSSC antagonism. Therefore, it is a second-line treatment after SSRIs when treating OCD.

Amitriptyline: [PI]

MDD:

• 75 mg a day in divided doses
• If necessary, this may be increased to 150 mg a day.

For greater severity of depression (e.g. hospitalised patients):

100 mg a day may be required initially. This can be increased gradually to 200 mg a day if necessary. A small number of hospitalised patients may need as much as 300 mg daily. [TGA]

Elderly patients:

• 50 mg daily in older patients who may not tolerate higher doses.
• Maintenance dosage from 50 to 100 mg per day.

Enuresis

• 10 mg at bedtime for children under 6 years of age. 
• The dosage should be increased in older children according to weight and age. 
• Children 6 to 10 years: 10 to 20 mg per day. 
• 11 to 16: 25 to 50 mg at bedtime 

Neuropathic pain

• 10-75 mg

Nortriptyline: [PI]

MDD:

• Adult Dose: 25 mg 3 or 4 times daily
• According to the TGA, doses above 100 mg are not recommended.
• Doses of 150 mg per day are reported in the literature. This variation may be linked to the range of plasma levels for a response. 
• Optimal responses to nortriptyline have been associated with plasma concentrations of 50 to 150 ng/mL (190 to 570 nmol/L).
• However, other studies have reported the minimum therapeutic level of plasma nortriptyline to be 70 ng/ml, corresponding to 47% NAT occupancy as measured by PET imaging. [Takano et al., 2014]
• More than 50% of central NAT occupancy is identified as appropriate for the nortriptyline maintenance treatment of patients with MDD. [Takano et al., 2014]
• The doses for 50-70% NAT occupancies in the brain are between 75-200 mg/d of nortriptyline. [Takano et al., 2014]
• Older patients have been reported to have more significant plasma concentrations of the active nortriptyline metabolite 10-hydroxy-nortriptyline

Imipramine [PI]

MDD:

• Initiate treatment with 25 mg up to three times daily. 
• Raise the daily dosage stepwise to 150 to 200 mg.
• In severe cases, maximum doses are 300 mg /day.

Nocturnal enuresis:

From the age of 5 years onwards: 

Initial daily dose:

• 5 to 8 years of age: 20-30mg/day
• 9 to 12 years of age: 25-50mg /day
• A daily dosage of 2.5 mg/kg should not be exceeded in children

Doxepin: [PI]

MDD:

• 30 mg to 300 mg daily
• Usually administered in a three-times daily regimen. 
• When the optimum dose has been reached, it may be given as a single daily dose up to a maximum of 150 mg
  

Insomnia [Katwala et al., 2013]

• Doxepin 1, 3, and 6 mg. 
• The recommended dose of doxepin for adults is 6 mg once daily.
• The starting dose for older patients >65 years old is 3 mg once daily.
• The daily dose can be increased to 6 mg if clinically required.(Katwala et al, 2013)
• To minimise the potential for next-day effects, doxepin should not be taken within 3h of a meal.

Dothiepin: [PI]

Adults:

• Start with 25 mg three times daily for one to two weeks.
• The daily dosage should be increased by 25 to 50 mg at intervals of one to two weeks if the response is inadequate.
• The daily dose should not exceed 200 mg.
• Up to 150 mg of the daily dose may be given as a single night-time dose once an effective dose has been established.

SAFETY PROFILE

Safety profile

The most commonly reported adverse events are related to cardiovascular, cognitive function, and psychomotor manifestations.

• Adrenergic (alpha1) receptor inhibition increases the risk of imbalance-related issues, orthostatic hypotension, and tachycardia.
• Histamine (H1) receptor inhibition is associated with side effects such as hypotension, sedation, and weight gain.
• Muscarinic (M1) cholinergic receptor inhibition is linked to blurred vision, constipation, dry mouth, sinus tachycardia, and urinary retention. In addition, in the elderly, muscarinic antagonism can result in delirium even from ‘therapeutic’ doses.
• Voltage-sensitive sodium channel (VSSC) blockade is also associated with arrhythmias, coma, and seizures in overdose.

Serious toxic cardiovascular effects (orthostatic hypotension, conduction abnormalities, and tachycardia) have been attributed to TCAs. As such, patients with a family history of either QTc interval prolongation or sudden cardiac death should, for the most part, not be treated with TCAs.

QTc Prolongation and Psychotropics- Management of Prolonged QTc Interval in Psychiatry

All patients starting a TCA need screening for pre-existing cardiac conditions, including prolonged QTc intervals, heart disease, and a family history of arrhythmias. Patients who test positive for pre-existing heart conditions may need additional evaluation by a cardiologist before initiating treatment.

TCAs in Pregnancy:

• The use of TCAs during pregnancy has correlated with congenital eye, ear, face, and neck defects. [Bérard et al., 2017]
• Specifically, clomipramine has associations with more severe neonatal symptoms such as cardiac defects. [Gentile, 2014]
• Therefore, TCAs are not generally considered safe to use during pregnancy.

TCAs in breastfeeding: 

• Regarding breastfeeding, all TCAs, except for doxepin, have not been associated with adverse effects from breastfeeding and therefore are regarded as safe.
• Nortriptyline appears to be the safest for use during breastfeeding due to its non-sedating profile. [Lanza and Wisner, 2009]

Drug interactions: 

CYP2D6 primarily metabolises TCAs.

Interactions with the CYP450 system vary across the TCA class, with clinically significant interactions with CYP1A2 (amitriptyline and imipramine) and CYP2C19 (amitriptyline, imipramine, doxepin, clomipramine) reported in the literature. [Gillman, 2007]

Research also shows that TCAs should not be administered concomitantly with an SSRI or a MAO inhibitor due to the risk of inducing serotonin syndrome.

Amitriptyline does not produce Serotonin toxicity (ST) when added to an MAOI. It may thus be inferred that amitriptyline does not significantly raise serotonin levels in humans. In contrast, clomipramine frequently precipitates severe ST with MAOIs and causes fatalities. [Gillman, 2007]

• Desipramine and nortriptyline are weak CYP450 2D6 inhibitors with fewer drug interaction issues than other TCAs.
• Amitriptyline, imipramine, clomipramine, dothiepin and doxepin are more potent CYP450 inhibitors and significantly inhibit CYP 2C19 and 1A2.
• Doxepin, used in low doses as a sedative, is less likely to cause clinically significant interactions, but higher doses may interact with drugs dependent on CYP2C19, such as phenytoin.

TCAs are less troublesome than SSRIs in relation to CYP450 interactions.

Although TCAs are suggested to be the most effective antidepressants available, their broad spectrum of adverse effects often leads to a lack of patient acceptability. Thus, when prescribing TCAs, clinicians must weigh the potential benefits against the risks and consider the patient’s medical history and preferences.

Pharmacogenomics and Drug Prescribing (Genetically Guided Prescribing) in Psychiatry – The Current State of Evidence

OTHER INDICATIONS

Clinical evidence

Over the last decade, several in vitro and in vivo studies have shown the antitumoral activity of TCAs beyond their utility to treat cancer-related neuropathic pain [Dharmshaktu et al. 2012]; [Finnerup et al. 2015]

Of note, Bielecka-Wajdman et al. showed that imipramine and amitriptyline could reverse the malignant phenotype of some glioblastomas. [Bielecka-Wajdman et al, 2017]. 

• More recently, imipramine has shown further potential as an anti-glioblastoma therapeutic [Hsu et al. 2020]
• It has also been proposed that novel imipramine-blue nanoparticles could be used as a therapy for medulloblastoma cancers (the most common malignant brain tumour in children) [Macdonald et al. 2021]
• [Yueh et al., 2021] showed that imipramine triggers apoptosis in NSCLC cells, suppressing their migration and invasion potential.
• Finally, imipramine also inhibits the growth of oestrogen-receptor-positive breast cancers by disrupting oestrogen receptor signalling and various DNA repair mechanisms. [Timilsina et al 2022]
• Migraine prophylaxis: Tricyclic antidepressants, such as amitriptyline and doxepin, effectively reduce the frequency and severity of migraines and are commonly used for prophylaxis. [Pringsheim, et al, 2012]. 
• Neuropsychiatry of Chronic Migraine – Pathophysiology and Treatment
• Fibromyalgia: Tricyclic antidepressants, including amitriptyline, are recommended as second-line treatment options for fibromyalgia when preferred treatments, such as pregabalin, duloxetine, and milnacipran, fail. [Calandre et al, 2015]. 
• The Neuropsychiatry of Fibromyalgia – Etiology and Management
• Nocturnal enuresis of children: Tricyclic antidepressants, such as imipramine, effectively reduce the frequency of nocturnal enuresis in children and are recommended as second-line treatment options after desmopressin. [Gepertz  & Nevéus, 2004].

SUMMARY

Clinicians must recognise that not all TCAs are the same and that their disadvantages and risks may have been overemphasised compared to newer medications.

Nortriptyline is considered to have superior pharmacological properties compared to other TCAs. In addition, combining with MAOIs or selected SSRIs is safe with expert psychopharmacologist oversight, making it advantageous for treating refractory patients requiring combination antidepressant treatment.

Clomipramine is still regarded as the “gold standard” SNRI drug, and its high affinity for SERT and NAT transporters makes it the most potent and effective single SNRI drug available.

Amitriptyline has evidence for efficacy, but nortriptyline may be preferred in certain situations due to its pharmacological advantages.

Dothiepin is more toxic than all other TCAs, and doxepin has found a use in dermatology due to its potent antihistamine sedative properties. A direct comparison of nortriptyline vs clomipramine would be helpful in the future.

Overall, tricyclic antidepressants remain a valuable option in treating depression, especially for refractory cases that require combination therapy.