Dosing Tips for Lithium: How to Improve Tolerability

Chris Aiken, MD

,
Kellie Newsome, PMH-NP

Although lithium is a first-line treatment that ranks high on the list of patient’s favorites, it has fallen out of general use, particularly in the United States. When lithium works well, its benefits tend to last. It is among the top medications that prevent hospitalization. More in this podcast.

PSYCHPEARLS PODCAST

Transcript edited for clarity. -Ed

CHRIS AIKEN: I have an unhealthy fear of certain medications. Tricyclics, MAOIs, and lithium. All of these have a reputation for adverse effects that is – perhaps – unearned. In practice, I’m constantly surprised by how well-tolerated they turn out to be. In the case of lithium, that surprise has been confirmed both in medical research and patient surveys. When it comes to the side effects that matter most to patients – sedation,1 weight gain,1 and cognition2,3 ­­– lithium’s tolerability ranks right behind lamotrigine if we look at the clinical research. For example, the risk of sedation is only 1 in 16 to 1 in 27 on lithium, compared to 1 in 5 for many other mood stabilizers.

But let’s look beyond the clinical research. A few years ago a Google company called CureTogether posted an online survey asking people with bipolar disorder what they found most helpful in their recovery. Over 3000 responded, and only 2 medications made their top 10 list: Lamotrigine and lithium. The rest of the top 10 were behavioral tools.

KELLIE NEWSOME: Let’s read all 10 of them:

1. Regimented sleep

2. Reducing alcohol

3. Exercise

4. Lamotrigine

5. Sunlight

6. Mindfulness

7. Psychotherapy

8. Self-tracking & journaling

9. Reducing caffeine

10. Lithium

Most of the lithium’s adverse effects are manageable, and in this podcast we’ll show you how to do it. To start with, titrate lithium slowly. Lithium’s main benefits are in long-term prevention, so there’s usually no reason to rush it (unless you are trying to help a manic patient stay out of the hospital). Start with 300 mg at night and raise it by 300 mg every 5-7 days. Cut those numbers in half if the patient is frail, elderly, or is taking a medication like a thiazide diuretic that can raise lithium.

The main reason people stop lithium in the early phase is nausea. A slow release version will reduce that risk, as will taking the lithium after a meal or with a glass of milk. Most other adverse effects improve with slow release as well – it cuts their overall rate by about 50% - except one: diarrhea. 4 Patients with diarrhea on lithium due better with instant release lithium that gets in and out of their system faster.8

Common remedies for nausea (eg, ondansetron, promethazine, ginger capsules) or diarrhea (eg, loperamide, milk of magnesia) are safe to take with lithium.

CHRIS AIKEN: Another way to improve side effects is to lower the dose. For most patients, the optimal blood level for long-term prevention is 0.6, or somewhere in the range of 0.4-0.8. The same blood level is ideal for treating depression – whether bipolar depression or unipolar. The only place where you’ll need a high dose is in acute mania, where serum levels of 0.8-1.2 are usually necessary.

Children need the same blood levels as adults, but the elderly are different. Aim for a serum level that’s 30% below the usual in patients over age 60, and then further personalize that dose based on their response.6 The blood-brain barrier becomes more permeable as we age, so more lithium gets into the older brain at lower serum levels. Conservative dosing in the elderly has another benefit: These patients are much more sensitive to lithium’s side effects, particularly imbalance and tremor.

KELLIE NEWSOME: Tremor is one of the most common side effects with lithium, and it is very sensitive to the dose. The first step is to lower caffeine and – if possible – other tremor-promoting medications like bupropion (Wellbutrin) or atypical antipsychotics. Beta-blockers help lithium tremor, and although propranolol is the most commonly used, there is research supporting other beta blockers like atenolol, metoprolol, and nadolol for lithium tremor.7 The average dose of propranolol is around 120 mg/day. Usually we start with instant release propranolol and then change to the extended release after figuring out how much they need.

You may read that beta-blockers interact with lithium, and this is true, but the interaction is minor. They usually raise its levels by about 20%.

CHRIS AIKEN: Another option with dual-benefits for lithium tremor is nimodipine. This calcium-channel blocker has good research for essential tremor, and is used third-line for mania and mania and rapid cycling.7 It’s well tolerated, and a typical target dose is 120mg a day. If your patient doesn’t want to add another medication in and prefers natural remedies, there’s high-dose vitamin B6. In doses from 900-1200 mg/day vitamin B6 improved lithium-related tremor, and it may reduce adverse effects on antipsychotics as well. B6 has open-label data for akathisia and tardive dyskinesia.7 Although natural, high-dose B6 is not risk free and can rarely cause neuropathy which usually resolves with discontinuation of the vitamin. It is hard to find B6 in a dose that high, so I keep a list of products on my website (moodtreatmentcenter.com/products).

KELLIE NEWSOME: Weight gain is a side effect on most patient’s minds when considering lithium, but the risk of significant weight gain is much lower than most patients expect. I start with some reassuring data: In a large meta-analysis, patients actually lost weight on lithium during the acute phase of treatment.20 Over the long-term, however, weight gain is possible. About 1 in 3 patients will gain 4-10 lbs on lithium, and most of that weight gain occurs in the first few years of treatment.9

But the most important part of this education is to let your patient know that there is something they can do about it. Lithium will make them thirsty, so if they stick with water and avoid caloric beverages they can lower that risk – and that includes avoiding diet soft drinks which actually cause weight gain through indirect metabolic effects even though they have no calories of their own.

Another way to reduce weight gain is to optimize thyroid function on lithium. Beyond that, any reasonable approaches for weight loss can be used, such as diet, exercise, or medications like topiramate 50-100 mg/day.

Like most psychiatric medications, lithium can cause sexual dysfunction. We know of one evidence-based remedy for this: Aspirin, at least for men. In a randomized, double-blind trial of men with sexual dysfunction on lithium aspirin 240 mg/day improved the problem.10

Phosphodiesterase inhibitors (sildenafil, tadalafil, vardenafil) can also be used.

CHRIS AIKEN: Now we get to the most serious risk with lithium: Renal insufficiency. Here is what I tell patients. As you age, the kidneys tend to slow down, and lithium can make them slow down even more in some patients who take it long term. We will monitor the kidneys and may need to lower or stop it if we see this happening, because if we don’t catch it it could – very rarely – go on to kidney failure.

There are at least 3 ways to protect against renal problems on lithium.

First, give the entire dose at night. This strategy improved renal function in a few long term comparison studies.4,8

Next, avoid toxic levels. High levels of lithium can kill kidney cells, and that may be why one large study found a direct correlation between number of toxic episodes on lithium and renal problems. It also looked like the kidneys were spared in that study if the lithium levels were kept at or below 0.8.

Watch out for extreme polyuria and polydipsia. These are signs of nephrogenic diabetes insipidus, which is both an adverse effect on lithium and a risk factor for renal insufficiency. A laboratory test will reveal elevated sodium in the blood and very dilute urine; check for urine osmolality, urine sodium, basic metabolic panel. Nephrogenic diabetes insipidus is a risk factor for future renal insufficiency, and there is some evidence that treating the syndrome can reduce that risk by preventing fibrotic changes in the kidneys, such as with amiloride.11

If the serum creatinine starts to rise, lower the lithium to the lowest effective dose and check it more often. Consult a nephrologist if the serum creatinine rises to 1.5 mg/dl.8

Another medical risk with lithium is hypothyroidism. This is usually treatable with a thyroid supplement, and you don’t need to stop lithium because the thyroid function goes down. If you do come off lithium, the hypothyroidism usually resolves – but not always – so you can gingerly try to come off the thyroid medication while checking levels.

Hypothyroidism may be worth addressing on lithium even when it is subclinical. A controlled study from the Mayo Clinic found that patients prescribed lithium were less likely to relapse into depression if their TSH was close to 2.4 microIU/ml.12

KELLIE NEWSOME: Lithium has several dermatologic risks. It can cause acne and psoriasis, and some patients report thinner, brittle hair on it although overt hair loss is rare.

Any standard treatments for acne can be used with lithium,10 but one to consider is minocycline. This antibiotic has neuroprotective and antiinflammatory effects, and it may treat depression, according to a handful of small-to-medium size controlled trials in bipolar and unipolar depression (the dose of minocycline for depression is 200 mg/day;13 lower doses are used for acne, eg, 1 mg/kg/day).14

I advise patients to take a probiotics along with their antibiotic to avoid problems in the gut microbiome. Probiotics also have a growing evidence base in depression, anxiety, and bipolar, and there’s some evidence that probiotics help acne. Psoriasis – those scaly, dry patches of skin that worsen in the winter and tend to show up on the elbows, knees, palms, face, or back - is a relative contraindication with lithium. For this I will refer to a dermatologist, but I may suggest 2 CAM treatments that can help bipolar and psoriasis. In a few small trials, psoriasis improved with inositol (6 g/day)8 and high dose omega-3 fatty acids (4-6 g/day)15 – both of which are fairly risk free and have small studies in bipolar depression.

Although lithium is a first-line treatment that ranks high on the list of patient’s favorites, it has fallen out of general use, particularly in the United States.16,17 When drugs meet that fate, they are often reserved for the most refractory patients, such as patients with severe mania who require high doses, which doesn’t help lithium’s reputation. Adverse effects should not stand in the way of its usage – when they are managed carefully and I have found that surprisingly tolerable.

But still, about 1 in 10 patients don’t tolerate it and have to stop the medication.

About 1 in 3 patients with bipolar disorder respond very well to lithium – and these tend to be the patients with classic, “textbook case” bipolar – with euphoric manias that are cleanly separated from depressions, and low rates of rapid cycling, mixed states, and major psychiatric comorbidities. These need not be patients with bipolar I though – patients with bipolar II can have classic hypomanias, and in one study lithium worked better for bipolar II than bipolar I.

When lithium works well, its benefits tend to last. It is among the top medications that prevent hospitalization.19 Its preventative effects have outshined other mood stabilizers, like valproate, in head-to-head trials, and it has added benefits that are relevant to bipolar disorder. Lithium prevents suicide, dementia, and some new evidence suggests it may lower the stroke risk and aid cardiac remodeling after a heart attack – that’s good news if it holds up, because stroke is the #1 cause of death in bipolar disorder, and cardiovascular disease tends to start 20 years earlier in patients with bipolar disorder than it does in the general population.17-18

KELLIE NEWSOME: I hope you will join us again for more practical updates on PsychPearls, and you can also catch us every Monday on the Carlat Psychiatry Podcast.

Chris Aiken, MD, is the Mood Disorders Section Editor for Psychiatric TimesTM, the Editor in Chief of The Carlat Psychiatry Report,and the Director of the Mood Treatment Center. He has written several books on mood disorders, most recently The Depression and Bipolar Workbook. He can be heard in the weekly Carlat Psychiatry Podcast with his cohost Kellie Newsome, PMH-NP. The author does not accept honoraria from pharmaceutical companies but receives royalties from PESI for The Depression and Bipolar Workbookand from W.W. Norton & Co. for Bipolar, Not So Much.

Kellie L. Newsome, PMH-NP, is the cohost of the Carlat Psychiatry Podcast and is also a practicing Psychiatric Mental Health Nurse Practitioner in Winston Salem, NC, at the Mood Treatment Center. Raised in Tasmania, Australia, Kellie moved to the United States in 1998.

References

1. Srivastava S, Ketter TA. Clinical relevance of treatments for acute bipolar disorder: balancing therapeutic and adverse effects. Clin Ther. 2011;33(12):B40-8.

2. Gualtieri CT, Johnson LG. Comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium. MedGenMed. 2006;8(3):46.

3. Wingo AP, Wingo TS, Harvey PD. Effects of lithium on cognitive performance: a meta-analysis.J Clin Psychiatry. 2009;70(11):1588-97.

4. Girardi P, Brugnoli R, Manfredi G, et al. Lithium in bipolar disorder: optimizing therapy using prolonged-release formulations. Drugs R D. 2016;16(4):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(2):231-7.

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(1):17-23.

8. Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. Int J Bipolar Disord. 2016;4(1):27.

9. AprahamIan I, TeIxeIra de SouSa R, da CoSTa L et al. Lithium safety and tolerability in mood disorders: a critical review.Rev Psiq Clín. 2014;41(1):9-14.

10. Murru A, Popovic D, Pacchiarotti I, et al. Management of adverse effects of mood stabilizers. Curr Psychiatry Rep. 2015;17(8):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.

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(1):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(2):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(5):945-73.

15. Akkerhuis GW, Nolen WA. Lithium-associated psoriasis and omega-3 fatty acids. Am J Psychiatry. 2003;160(7):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(8):713-727.

17. Post RM. The new news about lithium: An underutilized treatment in the United States. Neuropsychopharmacology. 2018;43(5):1174-1179.

18. Tondo L, Baldessarini RJ. Suicidal behavior in mood disorders: response to pharmacological treatment. Curr Psychiatry Rep. 2016;18(9):88.

19. Joas E, Karanti A, Song J, et al. Pharmacological treatment and risk of psychiatric hospital admission in bipolar disorder. Br J Psychiatry, 2017;210:197-202.

20. Srivastava S, Ketter TA. Clinical relevance of treatments for acute bipolar disorder: balancing therapeutic and adverse effects. Clin Ther. 2011;33(12):B40-B48.