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Amitriptyline

Classification: A

Drug products: ADT, Amitriptylin "DAK", Amitriptylin Abcur, Amitriptylin Orifarm, Amitriptyline Hydrochloride, Amitriptyline Strides, Laroxyl, Saroten®, Triptyl, Tryptizol, Tryptizol®

ATC code: N06AA09

Substances: amitriptyline, amitriptyline chloride

Summary

The efficacy of amitriptyline in treatment of depression is similar in men and women. Evidence of sex differences in the effect in migraine is unclear. Clinical studies on sex differences regarding the effects of amitriptyline in treatment of bipolar disorder or neuropathic pain are lacking.

Amitriptyline is associated with QT-prolongation on ECG and thus a risk of potentially fatal arrhythmia of the type Torsade de Pointes ventricular tachycardia. No difference in risk between men and women has been shown but female sex is a known risk factor for Torsade de Pointes ventricular tachycardia.

Additional information

Depression is almost twice as common in women as in men [1]. Women have an earlier age of onset and increased duration of depressive episodes. The mechanisms behind these sex differences may be due to several factors such as differences in neurobiology [2, 3], inflammatory markers, diagnostic tools, or health seeking behavior [4, 5]. Although depression is more prevalent in women, most basic research studies on depression have been focusing on males [2]. However, there are reports of sex differences in response to antidepressant treatment, although no clear consensus exist [3].

Women are two to three times more likely to suffer from an anxiety disorder [1]. Sex differences in symptomology and comorbidity have been reported. These sex differences may be due to several factors such as genetic, neurodevelopmental, environmental, and neurobiological [6].Amitriptyline is also used in treatment of neuropathic pain, which is more common in women than in men [7].

Pharmacokinetics and dosing

Several studies have shown similar plasma levels of amitriptyline in depressed men and women receiving standard routine doses [8-13]. However, women >50 years old had higher total tricyclic antidepressants (TCA) plasma levels (amitriptyline + its active metabolite nortriptyline) per milligram of drug administrated than age-matched men [10].

The mean ratio of nortriptyline/amitriptyline was similar in depressed men and women (26 men, 39 women) receiving 50-200 mg/day for >3 weeks [14]. Another even smaller study in chronic pain patients (8 men, 11 women) found a higher mean nortriptyline/amitriptyline ratio in women after receiving amitriptyline 75 mg /day for 6 weeks [11]. The authors speculate that this indicates a sex difference in amitriptyline metabolism [11]. Amitriptyline is metabolized by CYP2D6 [15]. No sex difference in general has been reported for this enzyme although the activity increases during pregnancy [16, 17].

Effects

A meta-analysis consisting of three RCTs of amitriptyline and 27 RCTs of imipramine (in total 1555 men, 2331 women) showed no sex differences in TCA efficacy in major depression [18].

The effect of TCAs and MAO inhibitors in patients with major depression, generalized anxiety, or panic disorder were evaluated with pooled data from five double-blind studies (in total 40 men, 111 women, on amitriptyline 21 men, 25 women). The studies lasted between 4-6 weeks. Men with panic attacks responded better to TCAs such as amitriptyline than to MAOIs, while women with panic attacks responded better to MAOIs than to TCAs [19].

The efficacy of amitriptyline as migraine prophylaxis in adults has been evaluated in a double-blind, randomized, 3-armed crossover study (8 men, 22 women). Patients initially received placebo followed by a 4-week period with amitriptyline 40 mg, propranolol 25 mg or placebo. Amitriptyline reduced the severity, frequency, and duration of headache attacks. Amitriptyline response was associated with female sex [20, 21]. Since the study included a low number of men, there is insufficient evidence to draw any conclusions about the effect in men.

No studies with a clinically relevant sex-analysis regarding the effects of amitriptyline in neuropathic pain have been found.

Adverse effects

Amitriptyline has been associated with prolonged QT-interval and a risk of Torsade de Pointes ventricular tachycardia [22].  Risk factors of drug-induced ventricular arrhythmias are female sex, hypokalemia, bradycardia, and base line QT-prolongation [23].

A systematic review reports that men have a six-fold higher risk of amitriptyline-associated sexual dysfunction than women. Amitriptyline was associated with a detoriation of sexual function in men, while a trend of improvement was observed in women [24].

The risk of venous thromboembolism (VTE) in antidepressant users was evaluated in a nested case-control study based on UK register data (in total 1346 men, 2521 women). Users of amitriptyline had almost a 2-fold increased risk (OR 1.7) for VTE compared with non-users but no sex difference was noted. An increased risk of VTE was found among women currently using oral contraceptives (OR 2.2) or hormone replacement therapy (OR 2.2) [25].

The fracture risk in patients taking antidepressants has been evaluated in a Danish case-control study (cases: 60 107 men, 64548 women; controls: 180 321 men, 193 641 women). For TCAs, an increase in fracture risk was only seen with amitriptyline, and the risk was higher with increased use (DDD/day), however no sex-stratified data was shown [26].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Other information

Drug utilization of ten commonly prescribed antidepressants during the period 2009-2014 in Sweden, Denmark, Germany, and Spain were analyzed in a large register study (in total 4 833 774 initiators included). Women comprised the majority of initiators for all antidepressants studied. In Sweden, 69% of the initiators on amitriptyline were women [27].

Adherence to amitriptyline, nortriptyline or imipramine in patients with pain was evaluated retrospectively by analyzing urine specimens and comparing with medication lists reported by the health care provider in a U.S. study (30 910 men, 24 386 women). Women were more adherent than men (68% vs. 61%) suggesting higher compliance in women [28].

TCA intoxications have been reported to be more frequent among women, but patterns differ between populations [29,30]. Also, toxic TCA plasma concentrations (>450 mcg/dl) have been found to a higher extent in women [31].

Updated: 2022-02-21

Date of litterature search: 2021-06-18

References

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Authors: Linnéa Karlsson Lind

Reviewed by: Diana Rydberg

Approved by: Karin Schenck-Gustafsson