Would it be appropiate to initiate treatment with citalopram in a patient who is already taking ami

Fråga: Would it be appropiate to initiate treatment with citalopram in a patient who is already taking amitriptyline, and who previously developed an adverse drug reaction when amitriptyline was combined with fluoxetine? Please include a comparison between citalopram, fluoxetine and amitriptyline at the level of drug metabolism. Background: A female patient was treated with amitriptyline, 100 mg every evening, for chronic pain. When fluoxetine (Fontex) was introduced, 20 mg twice daily, she experienced a flush-reaction together with a short episode of hypomania. The questioner suspected a drug interaction and is considering replacing fluoxetine by citalopram. Amitriptyline treatment will continue.

Sammanfattning: In the present case, the symptoms described might be an adverse reaction to fluoxetine only. Nevertheless, it is also important to consider whether the reaction can be explained by serotonin hyperstimulation due to the combined treatment with fluoxetine and amitriptyline. Finally, if a combination of amitriptyline and an SSRI-agent will be tried, rather than monotherapy with amitriptyline, citalopram appears to be an appropriate choice from a pharmacokinetic perspective. Caution with dosage is highly recommended, as well as monitoring of plasma concentrations.

Svar: The question about drug interactions between tricyclic antidepressants and SSRI-agents has previously been discussed in Drugline (eg 1, 2).

Of all SSRI-agents on the Swedish market, fluoxetine and paroxetine are the most potent inhibitors of CYP2D6, ie the major cytochrome P450 enzyme responsible for the metabolism of amitriptyline and other tricyclic antidepressants (3, 4). When either of these two SSRIs is used in combination with tricyclics, the risk of significant drug interactions is high. For example, it has been described that the total plasma level of desipramine increased 300-400 per cent during combined treatment with fluoxetine, 20 mg daily. The effect was even more pronounced at higher doses of fluoxetine (4, and references therein). In vitro-studies have confirmed that the various SSRI-agents show different potency of CYP2D6 inhibition, where a >10-fold higher concentration of citalopram is required to achieve a significant CYP2D6 inhibition (5-20 uM), compared to fluoxetine or paroxetine (0.1-0.9 uM) (3, 5). Assuming that the average plasma concentration range of citalopram (0.05-0.2 uM) (6) is similar to that in the liver, no significant CYP2D6 inhibition should occur at normal doses of citalopram. Therefore, the plasma concentration of most tricyclics (except for imipramine which is also metabolised by CYP2C19) should be essentially unaffected by citalopram. Support for this is given by a limited number of cases (n=5) described in the literature, where citalopram at doses of 20-60 mg was not found to influence the plasma concentration of amitriptyline (7).

However, it is also important to consider that CYP2D6, as well as the P450 responsible for citalopram metabolism (CYP2C19), are both genetically polymorphic enzymes where a significant part of the population (approximately 7 and 3 per cent, respectively) has an impaired metabolism of many psychoactive drugs, usually requiring dose adjustments.

In this context, it should be underscored that monitoring of drug plasma concentrations, is indeed a very useful means to exclude major abnormalities in pharmacokinetics that are related to genetic factors or drug interactions. It is recommended that a morning sample (before drug intake) from the patient in question is sent for analysis to the Division of Clinical Pharmacology at the University Hospital in Lund or Linköping.

Furthermore, it is important to consider the possibility that the symptoms described briefly above, ie flush and reversible hypomania, are related to the Serotonin Syndrome. This is a rare adverse reaction caused by serotonin hyperstimulation, which is characterised by mood disturbances, eg agitation, and/or myoclonia, hyperreflexia, ataxia, fever (8). A prompt recovery is usually observed after cessation of serotonergic drugs. The Serotonin Syndrome is more common in patients on the combination of SSRI-agents and monoaminoxidase inhibitors (8), than with SSRI/tricyclic-combinations (9). If the patient in question experienced serotonin hyperstimulation by fluoxetine and amitriptyline, the risk of developing similar symptoms by citalopram should be smaller, but still significant.

Finally, an alternative treatment strategy to consider, in order to avoid drug interactions, would be monotherapy with amitriptyline, for instance on a twice-daily basis, instead of the suggested combination of amitriptyline and citalopram.