Is there a risk for interaction between serotonin uptake inhibitors (ie paroxetine, citalopram) and

Fråga: Is there a risk for interaction between serotonin uptake inhibitors (ie paroxetine, citalopram) and lithium?

Sammanfattning: It is likely, albeit not proven, that combined usage of 5HT uptake inhibitors and lithium may lead to pharmacodynamic interactions and/or synergistic effects. Most speculation concerns the influence on serotonin levels. Only one study mentioned the possible interaction in the excretion of citalopram metabolites in the kidney. All side-effects refer to elevated 5HT levels or lithium levels although the causal relationship is often unclear. Given the general opinion in the handbooks and articles and taking into consideration the reported cases and the risk for neurotoxicity and serotonine-related symptoms, such as the serotonin syndrome, it is not advisable to combine 5HT uptake inhibitors and, lithium and if done, the described adverse effects should always be considered.

Svar: Besides citalopram and paroxetine, fluvoxamine and fluoxetine will also be discussed, because of their similarities in serotonin uptake inhibition, which causes increased synaptic levels of 5HT. Lithium increases the presynaptic formation, storage and release of serotonin (1). Therefore, it might be expected that these drugs together produce an increased incidence and severity of 5HT-related side-effects (2). In the most severe cases, a life-threatening serotonin syndrome comprising hyperthermia, tremor and convulsions may develop (3).

Lithium is commonly used in combination with 5HT reuptake inhibitors. While this combination therapy has shown to be successful in treatment-resistant depression, it is still far from clear what predictors of beneficial response might exist, what the necessary lithium blood levels should be or whether and which interactions or synergistic mechanisms are involved. Since lithium is used in a small therapeutic index, serum levels are measured to regulate the therapy.

It is unclear how lithium and 5HT reuptake inhibitors can influence each other´s blood levels. Several studies have shown that lithium has no effect on blood antidepressant levels (4). Several cases of neurotoxicity have been reported in patients receiving fluoxetine and lithium. The neurotoxicity generally occurred within a few days of starting concurrent therapy and consisted of confusion, ataxia, dizziness, stiffness of arms and legs, dysarthria, tremor and absence seizures. The order of administration of the drugs did not appear to be a factor in these cases. The authors could not however define a mechanism (5). On the other hand, one patient receiving a combination of lithium and fluoxetine showed increased lithium levels. She suffered within a few days after the addition of fluoxetine to her therapy from stiffness in her legs and arms, dizziness and unsteadiness in walking, ataxia and dysarthria (6). Another case described a patient treated with lithium and fluoxetine, who developed neurotoxicity (seizures) while his serum levels were within the therapeutic range (5,7). However, it has been suggested that CNS tissue lithium concentrations would be better reflected by erythrocytes than by serum levels, because any factor raising the erythrocyte/plasma ratio could result in the development of CNS toxicity, even within therapeutic plasma levels (7).

The CSM (Committee on Safety in Medicines) has received some tens of reports of adverse reactions, where patients were concomitantly treated with fluvoxamine and lithium: eg hyperarousal, nausea, somnolence, cramp, tremor, five cases of convulsions and one case of hyperpyrexia (8,2). One case of severe somnolence was reported; however, various studies have given equivocal or contradictory results as to whether somnolence can be directly caused by increased 5HT concentrations in the brain (2,5).

Concomitant therapy of citalopram and lithium was tested in a study in eight healthy young volunteers, all extensive metabolisers of sparteine and mephenytoin, but no statistically significant interactions were found. Concurrent citalopram treatment did not influence the lithium kinetics. However, while lithium appears not to influence drug oxidation, interaction with the citalopram metabolites that appear to be actively excreted via the kidney cannot be excluded (9).

No specific information was found on paroxetine concerning its interaction or synergistic effects with lithium. 1 Reus VI: Rational polypharmacy in the treatment of mood disorders. Ann Clin Psychiatry 1993; 5: 91-100 2 Evans M, Marwick P: Fluvoxamine and lithium: an unusual interaction. Br J Psychiatry 1990; 156: 286 3 Committe on safety of medicines. Fluvoxamine and fluoxetine - interaction with monoamine oxidase inhibitors, lithium and tryptophan. Current problems 1989; 26: 4 Nelson JC: Combined treatment strategies in psychiatry. J Clin Psychiatry 1993; 54(suppl): 42-49 5 Hansten, Horn, Drug interactions and updates. 1993; page 491-492 6 Salam AA, et al: A case of severe lithium toxicity induced by combined fluoxetine and lithium carbonate. Am J Psychiatry 1989; 146: 278 (letter) 7 Sacristan JA, Iglesias C, Arellano F, Lequerica J: Absence seizures induced by lithium: possible interaction with fluoxetine. Am J Psychiatry 1991; 148: 146-147 8 FASS 1994; page 94, 1089 9 Gram LF, Hansen MGJ, Sindrup SH, Brosen K, Poulsen JH, Aaes-Jörgensen T, Overo KF: Citalopram: interaction studies with levomepromazine, imipramine, and lithium. Ther Drug Monit 1993; 15: 18-24 10 Drugline nr 08556 (year 1992)