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7 Ways to Improve Lithium’s Tolerability

7 Ways to Improve Lithium’s Tolerability


  • Most of the adverse effects of lithium are manageable—and a little knowledge goes a long way here. View the slides in PDF format.


  • I have an unhealthy fear of certain medications, specifically tricyclics, MAOIs, and lithium. It’s not their efficacy that scares me, but their reputation for side effects. In spite of this, I’m constantly surprised by how well-tolerated they are in practice. In the case of lithium, that surprise has been confirmed in both medical research and patient surveys. When it comes to the side effects that matter most to patients—sedation,[1] weight gain,[1] and cognition[2,3]—lithium’s tolerability ranks right behind lamotrigine. That tolerability may partly explain why these 2 medications were also the top-rated mood stabilizers in an online survey where patients rated the interventions they found most helpful for bipolar disorder (n = 3330 and counting).


  • Most of the side effects that occur with lithium are manageable, and a little knowledge goes a long way here. To begin with, titrate slowly (eg, raise the dose by 300 mg every 5-7 days) and use slow-release versions (these cut the rate of most side effects in half).[4] Dose reduction improves most adverse reactions, and though serum levels of 0.8 to 1.2 mEq/L may be necessary for acute mania, the optimal level for acute depression and long-term prevention in bipolar disorder is lower (0.4-0.8; optimal is 0.6 mEq/L).[5] In the elderly, even lower levels are often necessary for tolerability, and—due to their unique blood-brain distribution—the level can usually be reduced in this population without losing its effectiveness.[6]


  • As a first step, reduce caffeine and other tremor-promoting drugs. Beta-blockers tend to be effective, and though propranolol (average dose, 120 mg/d) is the most commonly used, there are papers that support other options (atenolol, metoprolol, nadolol).[7] Beta-blockers have a minor interaction with lithium, raising its levels by up to 20%. The calcium-channel blocker nimodipine (120 mg/d) has good research for essential tremor and potential benefits in mania and rapid cycling.[7] High-dose vitamin B6 (900-1200 mg/d) has 2 studies for lithium-induced tremor and may improve akathisia and tardive dyskinesia from antipsychotics as well.[7]


  • Mild gastrointestinal symptoms tend to start early and disappear after the first week on lithium. Nausea is the most common, and this improves by taking it with food or switching to an extended-release form. Diarrhea, on the other hand, tends to improve with the immediate-release version of lithium.[8] Common remedies for nausea (eg, ondansetron, promethazine, ginger capsules) or diarrhea (eg, loperamide, milk of magnesia) can be used.


  • Weight gain is relatively mild with lithium. About 30% of patients gain 4 to 10 lb on lithium, and most of that weight gain occurs in the first few years of treatment.[9] Strategies include avoiding caloric beverages, optimizing thyroid function, and any reasonable approaches for weight loss (eg, diet, topiramate).


  • Sexual side effects are understudied in lithium, but aspirin improved erectile dysfunction in a randomized, double-blind trial of men on lithium (dosage, 240 mg/d).[10] PDE5 inhibitors (sildenafil, tadalafil, vardenafil) can also be used.[10]


  • Lithium’s most serious risk is renal insufficiency, and there are at least 3 ways to protect against this adverse effect. Single-day dosing (usually at night) improves renal function and polyuria.[4,8] Lower serum levels are less nephrotoxic, so reduce the dose if renal function starts to slow and consult a nephrologist if creatinine rises to 1.5 mg/dL.[8] Nephrogenic diabetes insipidus is both a side effect of lithium and a risk factor for renal insufficiency. Treating this syndrome with amiloride appears to reduce fibrotic changes in the kidneys.[11]


  • Thyroid problems on lithium are usually treatable, and even subclinical hypothyroidism may warrant intervention. A controlled study found that patients were less likely to relapse into depression on lithium if their thyroid-stimulating hormone level was close to 2.4 microIU/mL.[12]


  • Any standard treatment for acne can be used with lithium,[10] but attention should be given to minocycline as this neuroprotective agent has positive studies for bipolar and unipolar depression (the dose for depression is 200 mg/d[13]; lower doses are used for acne, eg, 1 mg/kg/d).[14] Probiotics should be taken along with oral antibiotics. Psoriasis is a relative contraindication with lithium, but studies suggest it may be manageable with 2 therapies that also treat bipolar depression: inositol (6 g/d)[8] and high-dose omega-3 fatty acids (4-6 g/d).[15]


  • Lithium is among the top-ranked, but least utilized, therapies for bipolar disorder,[16] treatment-resistant depression,[17] and suicidality.[18] Patients with those problems deserve a trial of it, and it’s our job to make those trials as tolerable as possible. I hope these strategies help, and that you’ll post some of your own below.


  • About the author

    Dr. Aiken is the Director of the Mood Treatment Center and an Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine. He does not accept honoraria from pharmaceutical companies but receives honoraria from W.W. Norton & Co. for Bipolar, Not So Much, which he coauthored with James Phelps, MD.

View the slides in PDF format.

REFERENCES

1. Srivastava S, Ketter TA. Clinical relevance of treatments for acute bipolar disorder: balancing therapeutic and adverse effects. Clin Ther. 2011;33:B40-B48.

2. Gualtieri CT, Johnson LG. Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium. MedGenMed. 2006;8:46.

3. Wingo AP, Wingo TS, Harvey PD. Effects of lithium on cognitive performance: a meta-analysis. J Clin Psychiatry. 2009;70:1588-1597.

4. Girardi P, Brugnoli R, Manfredi G, et al. Lithium in bipolar disorder: optimizing therapy using prolonged-release formulations. Drugs R D. 2016;16:293-302.

5. Severus WE, Kleindienst N, Seemüller F. What is the optimal serum lithium level in the long-term treatment of bipolar disorder—a review? Bipolar Disord. 2008;10:231-237.

6. De Fazio P, Gaetano R, Caroleo M. Lithium in late-life mania: a systematic review. Neuropsychiatr Dis Treat. 2017;13:755-766.

7. Baek JH, Kinrys G, Nierenberg AA. Lithium tremor revisited: pathophysiology and treatment. Acta Psychiatr Scand. 2014;129:17-23.

8. Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. Int J Bipolar Disord. 2016;4:27.

9. Aprahamian I, Teixeira de Sousa R, da Costa Lane Valiengo L, et al. Lithium safety and tolerability in mood disorders: a critical review. Rev Psiq Clín. 2014;41:9-14.

10. Murru A, Popovic D, Pacchiarotti I, et al. Management of adverse effects of mood stabilizers. Curr Psychiatry Rep. 2015;17:603.

11. Kalita-DE Croft P, Bedford JJ, Leader JP, et al. Amiloride modifies the progression of lithium-induced renal interstitial fibrosis. Nephrology (Carlton). 2016 Sep 28. doi: 10.1111/nep.12929.

12. Frye MA, Yatham L, Ketter TA, et al. Depressive relapse during lithium treatment associated with increased serum thyroid-stimulating hormone: results from two placebo-controlled bipolar I maintenance studies. Acta Psychiatr Scand. 2009;120:10-13.

13. Rosenblat JD, Kakar R, Berk M, et al. Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis. Bipolar Disord. 2016;18:89-101.

14. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74:945-973.

15. Akkerhuis GW, Nolen WA. Lithium-associated psoriasis and omega-3 fatty acids. Am J Psychiatry. 2003;160:1355.

16. Sani G, Perugi G, Tondo L. Treatment of bipolar disorder in a lifetime perspective: is lithium still the best choice? Clin Drug Investig. 2017;37:713-727.

17. Shelton RC, Osuntokun O, Heinloth AN. Therapeutic options for treatment-resistant depression. CNS Drugs. 2010;24:131-161.

18. Tondo L, Baldessarini RJ. Suicidal behavior in mood disorders: response to pharmacological treatment. Curr Psychiatry Rep. 2016;18:88.

Comments

Yes, I would agree that lithium is one of the most effective medications for bipolar disorder, BUT, when patients are allowed to stay on it for 20 years, it will take its toll on kidney function and then they must come off. After taking it for that time period, it is not easy to wean off and decompensation is common. I have had quite a few patients require hospitalization because of the difficulty of weaning off lithium after they were already in stage 3 kidney disease.

Length of administration needs to be closely monitored.

Carol @

You've touched on the most difficult area in managing lithium. This paper from the Mayo Clinic has good insights:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477477/

Keep in mind all mood stabilizers have medical risks that may warrant their eventual discontinuation (except perhaps lamotrigine)

Chris @

(lamotrigine has short term medical risks - Stevens Johnson Syndrome - but few significant long term risks - an important quality in a chronic disorder like bipolar)

-Chris Aiken, MD

Chris @

Great information. I will be utilizing this info for all our clients on Lithium therapy. I have witnessed positive life altering effects with Lithium.....clients have reclaimed their lives! Thank you!

Charlene Mulder RN
Belleville, Ontario, Canada

charlene @

Good work!
To what extent is applicable in all practices the Australian remarks about incidence of Lithium Related Acute Kidney Failure events, requiring transplant?
Lithium, same as diuretics for hypertension, seems connected to a slow, bu steady decline in renal function, its opportunities for adverse drug-dug interactions are high, so interfering episodes, as diarrhea, dehydration, fever,..and patients requiring a mood stabilizer are not among those having a most trustable therapy compliance.
I'd say Li is a forbidden drug in women with pregnancy possibility, as Valproic, so, I'd be a bit less optimistic regarding Lithium.
The discovery that places with a higher Lithium content in tap water have less suicides and less dementias is valuable.
I went astonished when one of my patients told me her employer practitioner measured Lithium levels to all; as expected, all had zero Li, this is the normal level in the absence of Lithium containing drugs, and prescribed them Li in order that 'they don't become depressed', in the end, that company practitioner was a visionary, but in the right direction

Jose @

Very interesting story. One under appreciated drug interaction is lithium toxicity due to hyponatremia on other drugs (e.g. carbamazepine and oxcarbamazepine). Otherwise lithium and carbamazepine have studies supporting synergistic benefits both in their tolerability and efficacy when used together.

Pregnancy is now considered a relative - not absolute- contraindation for lithium, and there are dosing strategies to minimize its risks to the fetus, e.g.:

https://www.ncbi.nlm.nih.gov/m/pubmed/28673946/

Thanks for your comments! -Chris Aiken, MD

Chris @

is there a pdf version of this?

Leslie @

Excellent article. short and to the point. Yes lithium is the most succesfull intervention for Bipolar Disorder.

Olga I. @

Yes, lithium was the "manic-depressive" drug of choice at one time, however lab testing and blood level volatility interfered with prescription use and new pipeline drugs w/pharma backing took the lead...."salt, it's what's for "bio-chemistry" dinner"

David @

Yes there is an interesting history there that needs to be told. Funding sources go a long way to reduce the stigma and fears associated with psychiatric medicine, and lithium has never benefited from that good PR.
-Chris Aiken, MD

Chris @

Dear Dr Akien
I viewed your presentation and itt is quite accurate .
I am a disabled family medicine practitioner. I was diagnosed with Bipolar 1 disorder and placed on Lithium 4 years ago . I initially the 900 mg dose was a bit too much my cognition was awful . Since then we have reduced the dose to 600 mg and that works . The side effects that I have are weight gain 10-20 lbs and tremor. My renal function is comprised CKD 2-3 . My nephrologist and psychiatrist work together and i have lab work done every month to monitor my lithium level and renal function . So far my labs have been fine . I would encourage other doctors to not shay away from Lithium . It has helped me to some extent we are currently looking for additional medication to compliment the Lithium . my psychiatrist is part of the Penn medicine group at University of Penna. If you ever what a patients perspective through the eyes of a doctor let me know . If I can help one person I would be grateful
Sincerely
Barbara Saracino DO, BSRN

Barbara @

Thank you I appreciate your story and persistence it shows. As you've seen, ithium acts very differently depending on the level, and those levels need to be personalized while guided by the long-term outcome studies.

-Chris Aiken, MD

Chris @

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