Amitriptyline

Additional information

Pharmacokinetics and dosing

Several studies have shown similar plasma levels of amitriptyline in depressed men and women receiving standard routine doses [2-5]. However, women >50 years old had higher total TCA plasma levels (amitriptyline + its active metabolite nortriptyline) per milligram of drug administrated than age-matched men [4].

The mean ratio of nortriptyline/amitriptyline was in one study (26 men, 39 women) showed to be similar in depressed men and women receiving 50-200 mg/day for >3 weeks [6] while a small study in chronic pain patients (8 men, 11 women) found a higher mean nortriptyline/amitriptyline ratio in women than men after receiving amitriptyline 75 mg /day for 6 weeks [5]. The authors speculate that this indicates a sex difference in amitriptyline metabolism [5]. Amitriptyline is metabolized by CYP2D6 [7]. No sex difference in general has been reported for this enzyme although the activity increases during pregnancy [8,9].

Effects

The effect of tricyclic antidepressants (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 [10].

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

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 [11, 12].

Adverse effects

Amitriptyline has been associated with prolonged QT-interval and a risk of Torsade de pointes ventricular tachycardia [13]. Among the known risk factors of drug-induced ventricular arrhythmias are female sex, hypokalemia, bradycardia, and base line QT-prolongation [14].

The risk of venous thromboembolism (VTE) in antidepressant users was evaluated in a nested case-control study based on data from the UK General Practice Research Database GPRD (in total 1346 men, 2521 women). Current users of amitriptyline had almost a 2-fold increased risk (OR 1.7) for VTE compared with nonusers of any antidepressant, no sex difference in risk was noted. When analyzed women only, an increased risk of VTE was found among women currently using oral contraceptives (odds ratio 2.2) and among women using hormone replacement therapy (odds ratio 2.2) [15].

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 increased with increased use (DDD/day). No sex differences in the risk of fracture were seen for antidepressants in general but the authors caution that the number of men participating in the studies was limited among younger subjects [16].

Amitriptyline has been associated with weight-gain, but without any correlation to sex (in total 22 men, 51 women; on amitriptyline 6 men, 12 women) [17]. A cross-sectional study of American veterans (in total 1364 men, 329 women; on fluoxetine 15 men, 5 women) examined the association between use of antidepressant and Restless Legs Syndrome (RLS). Current use of amitriptyline, citalopram or paroxetine was associated with RLS in men (amitriptyline RR 2.40), while only fluoxetine was associated with RLS in women (RR 2.47) [1].

Reproductive health issues

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

Other information

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. Women were more adherent than men (68% vs. 61%) [18].

TCA intoxications have been reported to be more frequent among women, but patterns differ between populations [19, 20]. Also, toxic TCA plasma concentrations have been found to a higher extent in women [21].