These mood stabilizers cover a lot of ground, but it is important to know how to use them.
In an earlier article titled Top Mood Stabilizers for Bipolar Disorder, I highlighted 4 mood stabilizers that are essential in the treatment of bipolar disorder: Lithium, lamotrigine, quetiapine, and lurasidone.1 That article explained why and when to use them, and in this one I’ll cover how.
Lithium is often dosed twice a day, but there’s little need to do this with its 24 hour half life. Instead, give the entire dose at night. This improves tolerability and lowers the risk of renal toxicity.2 Divided dosing may be necessary, however, if the patient requires a serum level above 0.8 mmol/L. Tolerability improves further with extended release forms and slow titration (e.g. start 300 mg qhs, raise by 300 mg per week; dose lower if there are drug interactions).2,3 Constipation, however, is one adverse effect that fares better with immediate release.
There is no target dose for lithium, but there are target blood levels: 0.6-0.8 for depression and maintenance and 0.8-1.2 for active mania. Children require the same levels, but patients over 65 may need levels that are 20-30% lower because older brains absorb lithium more readily.4 Learn more about how to improve lithium’s tolerability and reduce its renal risks.
Quetiapine (Seroquel). With benefits in depression, mania, anxiety, and insomnia, quetiapine is one of the most useful mood stabilizers on the block. Unfortunately it’s also one of the most difficult to tolerate. Several of its adverse effects improve by changing the formulation. Morning grogginess improves by using the immediate release (IR) form and giving the entire dose at night. The XR form, however, is better for orthostasis, agitation, and nausea because it smoothes over the serum peaks that trigger those symptoms. Orthostasis is usually not a problem at doses ≤ 300 mg/day, which is where its antidepressant effects tend to max out.5 Higher doses (400-800 mg/day) are better for mania, mixed states, and schizophrenia. The XR may be necessary at those doses or in the elderly.
One problem with the XR form is that the capsules are prone to dose-dumping, where they inadvertently release the entire dose at once. This tends to happen when quetiapine XR is taken with alcohol or a large, fatty meal, so it should be taken 30 minutes away from food. The XR form peaks in 4-5 hours, while the IR peaks in 1-2 hours, and when quetiapine peaks, the patient is likely to collapse in bed. That leaves a very narrow window to time the dose with the XR form: 30 minutes away from dinner and 4-5 hours before bed.
Lamotrigine (Lamictal). The most important step in dosing lamotrigine is to follow the manufacturer’s titration guidelines to prevent life-threatening allergic reactions. Although benign rashes are still common (10%) with this strategy, it does reduce the risk of serious rashes from 1% to 0.1–0.01%.7 Lamotrigine should be stopped at the appearance of any rash within the first two months, and patients need to retitrate the medication if they’ve been off it for more than a week. After titration, the target dose for bipolar disorder is 50-200 mg/day, but this range needs to be adjusted in a few groups (see Table).8,9 Higher doses work in epilepsy, but in bipolar disorder they tend to worsen cognition without improving mood.
Tolerability is one of lamotrigine’s strong suits, and a few of its adverse effects improve by changing the formulation.
XR: Improves nausea, dizziness, and imbalance.10 However, lamotrigine’s half-life is 25-33 hours so the XR form is usually not necessary in bipolar disorder.
ODT: improves the bitter taste and swallowing problems.11
Immediate release: improves insomnia (as does morning dosing)
Both the ODT and XR forms are generic. Learn more about how to reduce lamotrigine’s adverse effects and maximize its efficacy.
Lurasidone (Latuda). The most important dosing tip with lurasidone is to take it within 30 minutes of a large (> 350 kcal) meal. Otherwise, only about half of the medication gets absorbed. Nausea is one of the main reasons patients stop lurasidone, and this improves by taking it just after a meal. The other problematic side effect is akathisia, which improves with gradual titration (e.g. starting at 20 mg daily and increasing by 20mg per week).
For bipolar depression, lurasidone’s therapeutic range is 20-120 mg/day for adults and 20-80 mg/day for adolescents (where it is approved down to age 10). Most patients take 40 mg/day, and there is evidence of a linear dose-response relationship between 20 and 120 mg/day.12 The dose should be lowered by about 50% with CYP3A4 inhibitors (including grapefruit).
The Bottom Line. Lithium, quetiapine, lamotrigine, and lurasidone are ranked first line in recent practice guidelines for bipolar disorder. They are good places to start, and each needs to be personalized along the way.
1. Aiken, C. Top mood stabilizers in bipolar disorder. Psychiatric Times, May 2019.
2. Gitlin M. Lithium side effects and toxicity: prevalence and management strategies. Int J Bipolar Disord. 2016;4(1):27.
3. 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.
4. Nolen WA, Licht RW, Young AH, et al. What is the optimal serum level for lithium in the maintenance treatment of bipolar disorder? A systematic review and recommendations from the ISBD/IGSLI Task Force on treatment with lithium. Bipolar Disord. 2019;21(5):394â409.
5. Kishi T, Ikuta T, Sakuma K, Matsuda Y, Iwata N. Comparison of quetiapine immediate- and extended-release formulations for bipolar depression: A systematic review and network meta-analysis of double-blind, randomized placebo-controlled trials. J Psychiatr Res. 2019;115:121â128.
6. Wittmann M, Hausner H, KÃ¶stlbacher A, Hajak G, Haen E. Individual clearance and therapeutic drug monitoring of quetiapine in clinical practice. Neuro Endocrinol Lett. 2010;31(2):203â207.
7. Aiken CB, Orr C. Rechallenge with lamotrigine after a rash: a prospective case series and review of the literature. Psychiatry (Edgmont). 2010;7(5):27â32.
8. van Dijkman SC, de Jager NCB, RauwÃ© WM, Danhof M, Della Pasqua O. Effect of age-related factors on the pharmacokinetics of lamotrigine and potential implications for maintenance dose optimisation in future clinical trials. Clin Pharmacokinet. 2018;57(8):1039â1053.
9. Tomson T, Landmark CJ, Battino D. Antiepileptic drug treatment in pregnancy: changes in drug disposition and their clinical implications. Epilepsia. 2013;54(3):405â414.
10. Ramey P, Osborn M, Abou-Khalil B. Conversion from immediate-release to extended-release lamotrigine improves seizure control. Epilepsy Res. 2014;108(9):1637â1641.
11. Sajatovic M, Thompson TR, Nanry K, Edwards S, Manjunath R. Prospective, open-label trial measuring satisfaction and convenience of two formulations of lamotrigine in subjects with mood disorders. Patient Prefer Adherence. 2013;7:411â417.
12. Chapel S, Chiu YY, Hsu J, et al. Lurasidone dose response in bipolar depression: A population dose-response analysis. Clin Ther, 2016;38(1):4-15.
Dr Aiken is the Director of the Mood Treatment Center, Editor in Chief of The Carlat Psychiatry Report, and Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine. He is the author of The Depression and Bipolar Workbook and coauthor, with Jim Phelps, MD, of Bipolar, Not So Much. He can be heard in the weekly Carlat Psychiatry Podcast with his co-host Kellie Newsome, PMH-NP. Dr Aiken is Section Chief of Psychiatric Times. 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.