Severe Diurnal Somnolence Induced by Fluvoxamine-Lithium Combination

Clinical studies [4] suggest that lithium in combination with antidepressants (AD) can be effective in treatment of bipolar depression, refractory major depression (MD) and relapse of recurrent MD. The efficacy of the combination of lithium and AD has been attributed to a lithium-induced increase of serotonin neurotransmission [1]. The combination of lithium with serotonin selective reuptake inhibitors (SSRI) must be monitored because drug interactions may induce the serotonin syndrome [9] and increase plasma lithium levels (as observed after fluoxetine, but not with other SSRIs) [5] [7].

Therefore, patients treated with lithium-fluvoxamine combination may complain of side effects such as anxiety, agitation, insomnia and tremor [6] [8]. Nevertheless, we report a case of severe diurnal somnolence in a patient treated with lithium-fluvoxamine combination.

A 40-year-old man sought treatment for an episode of major depression, which had been refractory to paroxetine (60 mg/day), mirtazapine (60 mg/day) and venlafaxine (225 mg/day). Clorimipramine was started and progressively titrated to 300 mg/day without a significant clinical improvement. Then lithium was added, leading to a slight reduction in depressive symptom severity, even though plasma levels ranged between 0.58 mEq/L and 0.74 mEq/L.

Two months later, clorimipramine was discontinued and fluvoxamine was administered and titrated to 300 mg/day. During the next two months a complete remission of depressive symptoms was observed, but a severe diurnal somnolence occurred: the patient repeatedly fell asleep at work and had to pull over while driving his car because of sleepiness. Somnolence was not due to increased plasma lithium levels (0.61-0.68 mEq/L), insomnia, neurological disorders, or administration of other drugs. Moreover, blood count, renal and liver function tests, and electrolytes were in the normal range. Lithium was decreased (plasma level 0.20 mEq/L), but somnolence persisted even after fluvoxamine reduction to 200 mg/day. Therefore, lithium was discontinued, leading to recovery from somnolence after a few days. Fluvoxamine was well tolerated during the six months of continuation treatment.

This case report confirms that somnolence may represent a side effect of the fluvoxamine-lithium combination, as first described by Evans and Marwick [3].

It is difficult to establish the mechanism by which this uncommon side effect occurred in our patient when we take into account the following:

pharmacokinetic interactions were not involved: (1) plasma lithium concentrations were not increased by fluvoxamine and (2) even though plasma fluvoxamine levels were not measured, lithium is known 6 to be unable to increase fluvoxamine concentrations. An idiosyncratic effect is unlikely because somnolence occurred after two months of therapy and not during the first days of treatment, as observed by Evans and Marwick 3. Even though the involvement of a serotonergic mechanism may be supposed (probably through a GABAergic pathway), somnolence was not observed during the two months of combination of lithium with clorimipramine, which is a well-known serotonergic antidepressant 2.

This case report suggests that sleepiness may also occur in patients treated with lithium-fluvoxamine combination, even though anxiety agitation and insomnia are more frequently observed. Description of further cases is needed to confirm this observation and to establish the mechanism underlining this uncommon adverse reaction, because in our patient somnolence could not be explained by pharmacokinetic interactions or by idiosyncratic reactions.

References

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