Amitriptyline

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. Differences in neurobiology [2, 3], hormones, inflammatory markers, diagnostic tools, or health seeking behavior [4, 5] may be of importance.  Although depression is more prevalent in women, most preclinical studies on depression have used  male animals [2].

Women are two to three times more likely to suffer from an anxiety disorder [1]. Sex differences in symptomatology and comorbidity  may be due to genetic, hormonal, neurodevelopmental, environmental, and neurobiological factors [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].