Nl5-art and antidepresssants

Interactions between the ART and antidepressants
Tricyclic antidepressants (TCA) possess a small therapeutic range, thus, drug concentration
can quickly reach toxic levels. Among others, cardiac arrhythmia, anticholinergic effects,
sedation and confusion may occur if the drug concentration is reaching toxic levels. As the HI-
virus affects the basal ganglia and cause anticholinergic effects, antidepressants that show a
lower tendency for anticholinergic effects should be preferred.
Interactions: while the combination of TCA’s and protease inhibitors (PI’s) can result in
increased or even toxic TCA levels, the combination with NNRTI’s can lead to decreased TCA
levels. Thus, a reduced efficacy of the TCA’s will be expected. TCA’s are mainly metabolized by
the CYP-2D6 which is not much affected by the ART. Some TCA’s such as amitriptyline
(Saroten), clomipramine (Anafranil), imipramine (Tofranil) and trimipramine (Stangyl) are
also metabolized by the isoenzyme CYP-3A4. Since the ART can affect the isoenzyme CYP-
3A4, interactions as described above are possible. Desipramine (Petylyl), nortriptyline
(Nortilen), maprotiline (Ludiomil) and doxepin (Aponal) are presumably not metabolized by
the CYP-3A4.
Selective serotonin re-uptake inhibitors (SSRI’s) possess a large therapeutic range, thus,
fluctuations of drug levels are not strong associated with toxic effects. Their cardiotoxic effect is
relatively low and anticholinergic side-effects are not substantial as with tricyclic antidepressants
(TCA’s). The SSRI’s do not differ significantly in their efficacy, but primarily in the type of side-
effects and drug-drug interactions. Within the drug class, the most important side-effects are
sexual dysfunction with an incidence of 30 % (Citalopram: 3 %) and gastrointestinal problems
(20 %), in particular at the beginning of therapy. Furthermore, agitation, insomnia, xerostomia,
headache, hypoglycaemia and mania can also occur.
Interactions: the combination of SSRI’s and protease inhibitors can lead to increased SSRI
levels; the combination with NNRTI’s can result in decreased SSRI levels. Since the SSRI’s
themselves can also cause an inhibiting effect, the levels of protease inhibitors and NNRTI’s
may additionally increase. The different substances of SSRI’s are metabolized by many different
isoenzymes. Thus, the prediction of drug-drug interaction cannot be made in general.
MAO-inhibitors are primarily characterized by drug-drug interactions with food rather than with
the ART. Thus, tyramine-containing food such as cheese, soybean products and wine may
cause the so-called tyramine-reaction. Tyramine is also metabolized by the MAO-enzyme. For
some patients, the inhibition of the tyramine metabolism can already result in increased blood
pressure. For this reason, official diet guidelines have to be maintained if irreversible MAO-
inhibitors are taken.
Other antidepressants are usually CYP-3A4 substrates whose drug concentrations increase
under PI-containing regimes and decrease under NNRTI-containing regimes. During the ART,
the dose of a selected antidepressant has to be potentially adapted.
St. John’s wort has a strong effect on the ART. It causes clinically relevant interactions with
other drugs. This herbal extract is a strong inducer of the isoenzyme CYP-3A4 and P-
glycoprotein. PI’s and NNRTI’s concentrations can reach sub-therapeutic plasma levels and can
reduce the effectiveness of the ART. St. John’s wort is also found in herbal drugs combinations
such as Remifemin plus. These combinations should also be avoided.

Table: Overview of interactions between ART and SSRI’s, and other antidepressants
Interactions with
Interactions
Further remarks and
protease inhibitors (PI’s)
with NNRTI’s
comments
SSRI’s
BID) and fluoxetine. Symptoms: psychic changes, myoclonus, fever, diarrhoea and vormiting. Symptoms disappear after discontinuing of RTV and fluoxetine as well as dose reduction of fluoxetine up to 50 %, RTV 100 BID [2,3] possibly increase the dose of paroxetine. Contraindication in
toxicity; if necessary, reduce dose of mirtazapine. Trazodone: Cmax 34 % ↑, T ½: 122 % ↑, CL 52 % ↓ Reports about fatigue ,sickness, vertigo, hypertension and unconsciousness [8,9] Theoretically: venlafaxine ↑, PI’s ↑ 36 % ↓, level of venlafaxine unchanged [10] References:
1. Gutierrez MM, Rosenberg J, Abramowitz W. An evaluation of the potential for pharmacokinetic interaction between escitalopram and cytochrome P450 3A4 inhibitor ritonavir. Clin Ther 2003;25:1200-10.
2. Bellibas SE. Ritonavir-fluoxetine interaction. Antimicrob Agents Chemother 2000;43:1815.
3. DeSilva KE, LeFlore DB, Marston BJ et al. Serotonin syndrome in HIV-infected individuals receiving antiretroviral therapy and fluoxetine.AIDS 2001;15:1281-5.
4. Blenke A, Van der Lee MJ, Verweij-Van Wissen C et al. Combined use of paroxetine and fosamprenavir/ritonavir: a pharmacokinetic interaction study in healthy volunteers [abstract 13]. 6th Int Workshop on Clin Pharmacol of HIV
Ther, Quebec, 2005.
5. Eugen-Olsen J, Benfield T,et al.Effect of the serotonin receptor agonist, buspirone, on immune function in HIV-infected individuals:6-month randomized, double-blind, placebo-controlled trial.HIV Clin Trials 2000;1:20-6.
6. Piscitelli SC, Burstein AH, Chaitt D et al. Indinavir concentrations and St. John's wort. Lancet 2000;355:547-8.
7. de Maat MMR, Hoetelmans RMW, Mathot RAA et al. Drug interaction between St John's wort and nevirapine. AIDS 2001;15:420-1.
8. Zalma A, von Moltke LL, Granda BW. In vitro metabolism of trazodone by CYP3A: inhibition by ketoconazole and human immunodeficiency viral protease inhibitors. Biol Psychiatry 2000;47:655-61.
9. Greenblatt DJ, von Moltke LL, Harmatz JS et al. Short-term exposure to low-dose ritonavir impairs clearance and enhances adverse effects of trazodone. J Clin Pharmacol 2003;43:414-22.
10. Levin GM, Nelson LA, DeVane CL, Preston SL. A pharmacokinetic drug-drug interaction study of venlafaxine and indinavir. Psychopharmacol Bull 2001;35:62-71.
11. Tseng A. Interaktionstabelle des General Hospitals von Toronto www.tthhivclinc.com
12. Spina E, Scordo MG, D'Arrigo C. Metabolic drug interactions with new psychotropic agents. Fundam Clin Pharmacol. 2003 Oct;17(5):517-38.
13. Fachinformationen
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Source: http://www.ifi-interaction-hotline.com/BaseCMP/documents/5000/NL5-ART_and_antidepresssants.pdf