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Lithium (LITHOBID) is a mood-stabilizing drug that has been available for many decades.[1] It is approved by the Food and Drug Administration (FDA) for treatment of bipolar disorder, also known as manic depression, a chronic mental illness that causes unusual shifts in mood, energy and activity levels.[2]
Lithium remains the best and most well-established medication for bipolar disorder, so it is prescribed for life in many patients.[3] It is the drug of choice both for controlling...
Lithium (LITHOBID) is a mood-stabilizing drug that has been available for many decades.[1] It is approved by the Food and Drug Administration (FDA) for treatment of bipolar disorder, also known as manic depression, a chronic mental illness that causes unusual shifts in mood, energy and activity levels.[2]
Lithium remains the best and most well-established medication for bipolar disorder, so it is prescribed for life in many patients.[3] It is the drug of choice both for controlling symptoms during acute manic episodes and in preventing or decreasing the intensity of future manic episodes.[4],[5]
Lithium can interact with many commonly used drugs. Many of these interactions can result in either dangerous lithium toxicity or other potentially life-threatening adverse effects, depending on the other drug being used concomitantly.
Lithium toxicity
The product labeling for lithium includes a black-box warning, the strongest type of warning that the FDA can require, indicating that lithium toxicity is closely related to blood lithium levels and can occur at levels only slightly above the level needed to achieve the desired therapeutic effect.[6] For this reason, patients using lithium need to have frequent blood tests to monitor levels of the drug when starting the drug or undergoing dose adjustments and periodically thereafter once stable blood lithium levels are achieved.
The Table below lists some of the many drugs that, when taken concomitantly with lithium, may increase blood lithium to toxic levels. The list includes angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) and diuretics (often called water pills), all of which are commonly used to treat hypertension, heart failure and kidney disease. Nonsteroidal anti-inflammatory drugs (NSAIDs), which are used to treat pain, fever and inflammation, are another group of commonly used drugs that can lead to lithium toxicity (see Table at the bottom). ACE inhibitors, ARBs, diuretics and NSAIDS can increase lithium levels by interfering with the elimination of lithium from the body by the kidneys.[7]
Examples of Drugs That Can Cause Lithium Toxicity When Taken Concomitantly With Lithium (Combination Products Excluded)
| Generic Name | Brand Name(s) |
|---|---|
| Angiotensin-Converting Enzyme Inhibitors | |
| benazepril* | LOTENSIN |
| captopril* | generic only |
| enalapril* | EPANED, VASOTEC |
| fosinopril* | generic only |
| lisinopril* | PRINIVIL, QBRELIS, ZESTRIL |
| moexipril* | generic only |
| perindopril* | generic only |
| quinapril* | ACCUPRIL |
| ramipril* | ALTACE |
| trandolapril* | generic only |
| Angiotensin II Receptor Blockers | |
| azilsartan* | EDARBI |
| candesartan* | ATACAND |
| eprosartan* | generic only |
| irbesartan* | AVAPRO |
| losartan* | COZAAR |
| olmesartan** | BENICAR |
| telmisartan* | MICARDIS |
| valsartan* | DIOVAN |
| Diuretics | |
| bumetanide* | BUMEX |
| chlorothiazide | DIURIL |
| chlorthalidone | generic only |
| furosemide* | LASIX |
| hydrochlorothiazide | MICROZIDE |
| indapamide** | generic only |
| methyclothiazide | generic only |
| metolazone | ZAROXOLYN |
| spironolactone* | ALDACTONE |
| triamterene** | DYRENIUM |
*Designated as Limited Use
**Designated as Do Not Use
Nausea, diarrhea, vomiting, loss of appetite, drowsiness, muscle weakness and decreased coordination are early signs of lithium toxicity. With increasing blood lithium levels, patients can experience giddiness, ataxia (severe lack of muscle control or coordination of voluntary movements), slurred speech, blurred vision, tinnitus (perception of noise or ringing in the ears) and markedly increased urine output. Severe lithium toxicity can lead to seizures, coma, dangerous abnormal heart rhythms and even death.
For patients taking ACE inhibitors, ARBs, diuretics or NSAIDS, lithium therapy generally should be initiated at a lower dose, and the dose should be increased slowly. Patients also should undergo frequent blood tests to check lithium levels until they achieve a stable blood level of the drug.
Patients who have been on a stable dose of lithium and subsequently begin taking an ACE inhibitor, ARB, diuretic or NSAID should undergo more frequent blood tests for lithium levels and be monitored closely for symptoms of lithium toxicity until the blood lithium level is shown to be stable in the desired therapeutic range. Importantly, it sometimes takes up to two to three weeks after starting the interacting drug before lithium toxicity becomes evident.
Serotonin syndrome
Lithium used alone can precipitate serotonin syndrome, a potentially life-threatening condition. The risk of this syndrome is increased when lithium is taken concomitantly with other medications that increase serotonin levels in the body — so-called serotonergic drugs.
The Table below lists many commonly used serotonergic drugs that can have this dangerous interaction with lithium, including the selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors, which are approved by the FDA for treatment of depression and various other psychiatric disorders. The dietary supplement St. John’s wort also can cause this same interaction.
Drugs that Increase the Risk of Serotonin Syndrome When Taken Concomitantly With Lithium
| Generic Name | Brand Name(s) and FDA-Approved Uses |
|---|---|
| Selective Serotonin Reuptake Inhibitors | |
| citalopram* | CELEXA: depression |
| escitalopram* | LEXAPRO: major depression, generalized anxiety disorder |
| fluoxetine* |
PROZAC: major depression, obsessive-compulsive disorder, bulimia nervosa, panic disorder, bipolar disorder, treatment-resistant depression SARAFEM, SELFEMRA: premenstrual dysphoric disorder SYMBYAX**: bipolar disorder, treatment-resistant depression |
| fluvoxamine* | LUVOX: obsessive-compulsive disorder |
| paroxetine |
BRISDELLE***: hot flashes associated with menopause PAXIL*: major depression, obsessive-compulsive disorder, panic disorder, social anxiety disorder, generalized anxiety disorder, posttraumatic stress disorder PEXEVA*: major depression, obsessive-compulsive disorder, generalized anxiety disorder |
| sertraline* | ZOLOFT: major depression, obsessive-compulsive disorder, panic disorder, social anxiety disorder, posttraumatic stress disorder, premenstrual dysphoric disorder |
| vilazodone* | VIIBRYD: major depression |
| Serotonin and Norepinephrine Reuptake Inhibitors | |
| desvenlafaxine* | KHEDEZLA, PRISTIQ: major depression |
| duloxetine*** | CYMBALTA: major depression, generalized anxiety disorder, diabetic peripheral neuropathy, fibromyalgia, chronic musculoskeletal pain |
| levomilnacipran† | FETZIMA: major depression |
| milnacipran*** | SAVELLA: fibromyalgia |
| venlafaxine* | EFFEXOR XR: major depression, generalized anxiety disorder, social anxiety disorder, panic disorder |
| Tricyclic Antidepressants | |
| amitriptyline*** | generic only: depression |
| amoxapine*** | generic only: depression |
| desipramine* | NORPRAMIN: depression |
| doxepin*** |
SILENOR: insomnia generic only: depression, anxiety |
| imipramine*** | SURMONTIL, TOFRANIL: depression |
| nortriptyline* | PAMELOR: depression |
| Triptans | |
| almotriptan | AXERT: migraine headaches |
| eletriptan | RELPAX: migraine headaches |
| frovatriptan | FROVA: migraine headaches |
| naratriptan | AMERGE: migraine headaches |
| rizatriptan | MAXALT: migraine headaches |
| sumatriptan | IMITREX, ONZETRA XSAIL, TREXIMET**: migraine headaches |
| zolmitriptan | ZOMIG: migraine headaches |
| Other Drugs | |
| fentanyl* | ABSTRAL, ACTIQ, DURAGESIC, FENTORA, LAZANDA, SUBSYS: pain |
| tramadol*** | CONZIP, ULTRACET**, ULTRAM: pain |
*Designated as Limited Use
**Combination drug that contains another active ingredient not listed
***Designated as Do Not Use
†Designated as Do Not Use for Seven Years (until August 2020)
Symptoms of serotonin syndrome overlap with those of lithium toxicity and include agitation, hallucinations, delirium, dizziness, sweating, flushing, tremor, rigid muscles, loss of coordination, seizures, nausea, vomiting and diarrhea. The condition can progress to coma and death. All patients taking lithium should be alert for symptoms of serotonin syndrome, and concomitant treatment with lithium and any serotonergic drugs should be discontinued immediately in any patient experiencing such symptoms.
What You Can Do
These types of potentially dangerous drug interactions reinforce the importance of bringing all of the prescription and nonprescription drugs that you take each time you visit any doctor. Because many drugs, including others not listed in this article, may have dangerous interactions with lithium, find out from your doctor whether any other drugs that you take will interact with your lithium treatment.
References
[1] Geddes JR, Miklowitz DJ. Treatment of bipolar disorder. Lancet. 2013;381(9878):1672-1682.
[2] National Institutes of Health. Bipolar disorder. April 2016. https://www.nimh.nih.gov/health/topics/bipolar-disorder/index.shtml. Accessed December 16, 2016.
[3] Malhi GS, Outhred T. Therapeutic mechanisms of lithium in bipolar disorder: recent advances and current understanding. CNS Drugs. 2016;30(10):931-949.
[4] ANI Pharmaceuticals, Inc. Label: lithium (LITHOBID). April 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/018027s064lbl.pdf. Accessed December 5, 2018.
[5] Oruch R, Elderbi MA, Khattab HA, et al. Lithium: A review of pharmacology, clinical uses, and toxicity. Eur J Pharmacol. 2014 Oct 5;740:464-473.
[6] ANI Pharmaceuticals, Inc. Label: lithium (LITHOBID). April 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/018027s064lbl.pdf. Accessed December 5, 2018.
[7] Ibid.
