Lithium with Fluoxetine Interaction Details

Brand Names Associated with Lithium

Brand Names Associated with Fluoxetine

Medical Content Editor Dr. Brian Staiger, PharmD
Last updated Nov 21, 2023

Interaction Effect

An increased risk of serotonin syndrome

Interaction Summary

The concomitant use of lithium with serotonergic drugs, such as SSRIs, may result in serotonin syndrome, which can be life-threatening. Signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms. Monitor all patients on lithium therapy for serotonin syndrome, especially during initiation. If concomitant use is required, notify patients of the increased risk and monitor for symptoms. Immediately discontinue treatment with lithium and any concomitant serotonergic agent if symptoms occur and initiate supportive treatment. Plasma lithium levels should be monitored with appropriate adjustment to the lithium dose . Concomitant use of lithium and various SSRIs has been associated with enhanced side effects of either or both drugs, and with or without elevated lithium levels .

Severity

Major

Onset

Unspecified

Evidence

Established

How To Manage Interaction

The concomitant use of lithium with other serotonergic drugs, such as SSRIs, may result in serotonin syndrome, which can be life-threatening. Signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms. Monitor all patients on lithium therapy for serotonin syndrome, especially during initiation. If concomitant use is required, notify patients of the increased risk and monitor for symptoms. Immediately discontinue treatment with lithium and any concomitant serotonergic agent if symptoms occur and initiate supportive treatment. Plasma lithium levels should be monitored with appropriate adjustment to the lithium dose .

Mechanism Of Interaction

Additive serotonergic effects

Literature Reports

A) Concomitant administration of oral lithium carbonate and oral FLUoxetine resulted in increased lithium serum levels with lithium toxicity in a 44-year old woman with a bipolar affective disorder. FLUoxetine 20 mg daily was added to a regimen of lithium 1200 mg daily following patient complaints of weakness, tiredness, decreased concentration, and early morning awakening. Lithium serum levels increased to 1.7 mEq/L from a range of 0.75 to 1.15 mEq/L prior to FLUoxetine. FLUoxetine was discontinued and the dose of lithium decreased; this resulted in a decrease in the lithium serum level within 48 hours to 1.2 mEq/L. The neurologic symptoms subsided within seven days as the lithium serum level decreased to 0.9 mEq/L. The contribution of FLUoxetine to lithium toxicity in this patient was obscured by the fact that the lithium was reduced at the time of FLUoxetine withdrawal .

B) A 53-year old woman who had been taking FLUoxetine 20 mg daily and LORazepam 0.5 mg four times daily for a major depressive disorder had lithium 900 mg per day added to her regimen in order to augment her response to FLUoxetine. Within 48 hours, the patient became confused, ataxic, and developed a coarse tremor in her right arm. Vital signs showed a rectal temperature of 101 degrees F, and laboratory values were normal except for an elevated leukocyte count and slightly elevated bilirubin level. After discontinuation of lithium and FLUoxetine, the patient's symptoms resolved over the next four days. At no point did the lithium levels reach a toxic level, suggesting that the patient's symptoms were due to a toxic reaction between FLUoxetine and lithium .

C) Serotonin syndrome was precipitated when lithium 300 mg twice daily was added to a three-month regimen of FLUoxetine 40 mg per day. Five days later, the patient's lithium level was measured at 0.65 mEq/L and the dose was increased to 300 mg three times daily. Two days after this dosage change, the patient experienced akathisia, myoclonus, hyperreflexia, shivering, tremor, diarrhea, and incoordination. After discontinuation of lithium and initiation of cyproheptadine therapy, the patient's symptoms began to improve. The patient was discharged on a regimen of FLUoxetine 40 mg per day without further symptoms of serotonin syndrome .

D) Serotonin syndrome was described in a 53-year-old patient who was stabilized on lithium 1400 mg daily (serum level 0.71 mmol/L) and was given fluvoxaMINE 50 mg daily. Over a 10-day period the fluvoxaMINE dose was increased to 200 mg daily; tremor and difficulty with fine hand movements developed. After two weeks, tremor, impaired motor function coordination, marked bilateral hyperreflexia of biceps and knee jerks, and clonus in both ankles were seen. After 12 weeks of continued therapy, during which time no further deterioration occurred, nortriptyline 100 mg daily replaced fluvoxaMINE, and the neuromuscular symptoms abated over a 2-week period. After four weeks the patient's neurological exam was normal .

E) Three cases of mania were reported in patients who were treated with lithium and fluvoxaMINE. The mania appeared 10 days, four weeks, and five weeks, respectively, after cotherapy was begun. FluvoxaMINE was discontinued and, in two of the three patients, the mania resolved, and successful treatment of depression occurred with lithium alone. The third patient improved, but depression reappeared within a month of fluvoxaMINE discontinuation .

F) In an open-labeled, placebo-controlled study, lithium 600 mg was administered to 16 subjects orally twice daily on days one through eight and once in the morning on day nine. In addition, oral sertraline 100 mg or placebo was given twice, ten hours and two hours prior to lithium dosing on day nine. The steady-state lithium level was only decreased by 1.4% (0.01 mEq/L) and the lithium renal clearance increased by 6.9% (0.11 L/hour) when sertraline was coadministered. Seven subjects experienced side effects, mainly tremors, after receiving lithium and sertraline, whereas no subjects who ingested placebo and lithium experienced side effects .

G) Coadministration of racemic citalopram (40 mg/day for 10 days) and lithium (30 mmol/day for 5 days) had no significant effect on the pharmacokinetics of citalopram or lithium .

Lithium Overview

• Lithium is used to treat and prevent episodes of mania (frenzied, abnormally excited mood) in people with bipolar disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Lithium is in a class of medications called antimanic agents. It works by decreasing abnormal activity in the brain.

Fluoxetine Overview

• Fluoxetine is used to treat depression, obsessive-compulsive disorder (bothersome thoughts that won't go away and the need to perform certain actions over and over), some eating disorders, and panic attacks (sudden, unexpected attacks of extreme fear and worry about these attacks). Fluoxetine is also used to relieve the symptoms of premenstrual dysphoric disorder, including mood swings, irritability, bloating, and breast tenderness. It is also used along with olanzapine (Zyprexa) to treat depression that did not respond to other medications and episodes of depression in people with bipolar I disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). Fluoxetine is in a class of medications called selective serotonin reuptake inhibitors (SSRIs). It works by increasing the amount of serotonin, a natural substance in the brain that helps maintain mental balance.

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Definitions

Severity Categories

Contraindicated

These drugs, generally, should not be used together simultaneously due to the high risk of severe adverse effects. Combining these medications can lead to dangerous health outcomes and should be strictly avoided unless otherwise instructed by your provider.

Major

This interaction could result in very serious and potentially life-threatening consequences. If you are taking this drug combination, it is very important to be under close medical supervision to minimize severe side effects and ensure your safety. It may be necessary to change a medication or dosage to prevent harm.

Moderate

This interaction has the potential to worsen your medical condition or alter the effectiveness of your treatment. It's important that you are monitored closely and you potentially may need to make adjustments in your treatment plan or drug dosage to maintain optimal health.

Minor

While this interaction is unlikely to cause significant problems, it could intensify side effects or reduce the effectiveness of one or both medications. Monitoring for changes in symptoms and your condition is recommended, and adjustments may be made if needed to manage any increased or more pronounced side effects.

Onset

Rapid: Onset of drug interaction typically occurs within 24 hours of co-administration.

Delayed: Onset of drug interaction typically occurs more than 24 hours after co-administration.

Evidence

Level of documentation of the interaction.

Established: The interaction is documented and substantiated in peer-reviewed medical literature.

Theoretical: This interaction is not fully supported by current medical evidence or well-documented sources, but it is based on known drug mechanisms, drug effects, and other relevant information.

How To Manage The Interaction

Provides a detailed discussion on how patients and clinicians can approach the identified drug interaction as well as offers guidance on what to expect and strategies to potentially mitigate the effects of the interaction. This may include recommendations on adjusting medication dosages, altering the timing of drug administration, or closely monitoring for specific symptoms.

It's important to note that all medical situations are unique, and management approaches should be tailored to individual circumstances. Patients should always consult their healthcare provider for personalized advice and guidance on managing drug interactions effectively.

Mechanism Of Interaction

The theorized or clinically determined reason (i.e., mechanism) why the drug-drug interaction occurs.

Disclaimer: The information provided on this page is for informational purposes only and should not be considered medical advice. Always consult with a qualified healthcare professional regarding your specific circumstances and medical conditions.

Where Does Our Information Come From?

Information for our drug interactions is compiled from several drug compendia, including:

• Gold Standard Drug Database
• Micromedex
• Lexicomp
• DrugBank

The prescribing information for each drug, as published on DailyMED, is also used. 

Individual drug-drug interaction detail pages contain references specific to that interaction. You can click on the reference number within brackets '[]' to see what reference was utilized.

The information posted is fact-checked by HelloPharmacist clinicians and reviewed quarterly.