01. Lurasidone for Bipolar Depression: What Is the Optimal Dose?

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Optimal Lurasidone Dosing for Bipolar Depression

Imagine if a simple adjustment in medication dose could not only improve your bipolar patient outcomes but also reduce side effects. This recent BMJ Mental Health meta-analysis by Lin and colleagues challenges conventional dosing wisdom for lurasidone in bipolar depression, offering actionable insights that can strengthen your clinical approach to treating patients with this disorder.

Regarding the methodology, the investigators conducted a rigorous systematic review and dose-response meta-analysis of five high-quality randomized controlled trials involving over 2000 patients treated for six weeks. They used advanced statistical techniques to explore non-linear relationships between dose and clinical outcomes.

40-60mg: Optimal Efficacy, Reduced Side Effects

The meta-analysis found that a daily dose between 40 and 60 mg of lurasidone generally yields optimal efficacy for improving:

• Depressive symptoms
• Anxiety
• Reducing disability.

I loved that they measured disability and anxiety as well as depression, and it’s really helpful to know this 40-60 mg range helped with all three aspects.

Low Dose Range Outperforms Higher Doses

The second interesting pearl here is that the most effective dose range was this low dose of 40-60 mg, especially given that the FDA-recommended dose range for lurasidone goes up to 120 mg in bipolar disorder.

This data suggests that instead of pushing dosage up, we should give patients a good trial of lurasidone at this lower dose for bipolar depression. This makes treatment easier as the starting dose is 20 mg. We can let a patient land at 40-60 mg fairly quickly, then give them a good trial of around a month at this dose and look for change.

NNT Improves at Lower Dose Range

A previous study ranked the number needed to treat (NNT) to decrease depressive symptoms in bipolar disorder with various medications (as a refresher, the NNT is the statistical calculation of the number of patients you would need to treat with a medication for one of them to improve):

• Olanzapine plus fluoxetine: NNT of 4
• Lurasidone: NNT of 5
• Quetiapine: NNT of 6
• Lamotrigine: NNT of 6

However, when lurasidone was set within the specific dose range of 40-60 mg, the present study showed a pooled NNT of 3. This really stands out and puts lurasidone at this lower dose range higher on my personal ranked list of medications to trial for bipolar depression.

Receptor Binding May Explain Efficacy Pattern

The authors postulate this finding relates to the different receptors that lurasidone hits. Think of the 40-60 mg range like a key that might hit the right pins or receptors in the most optimal way.

Lurasidone has 5-HT7 antagonism as well as histamine and alpha-receptor antagonism, the latter contributing to cognitive impairments and side effects. At lower doses than 40 mg, the mood regulating receptors might not be hit enough. At 40-60 mg, the 5-HT7 antagonism which improves mood might be best balanced against the histamine and alpha-receptor antagonism.

When to Consider Dose Increases

Clinicians should consider increasing the dose above 40-60 mg if:

• Depressive or anxiety symptoms persist despite a good trial at this dose
• There’s insufficient improvement in functional outcomes

Look for clear, quantifiable improvements in mood and daily functioning before considering a careful uptitration.

Risk-Benefit Profile at 40-60mg

The study found no association between dosage and risk of hypomania/mania or study dropout. Interestingly, there was a trend towards mild protection against hypomania or mania at 50-60 mg.

However, increasing lurasidone dosage was associated with an increased incidence of side effects such as akathisia and parkinsonism. This highlights the need for continued vigilance in monitoring these potential motor side effects, especially when increasing the dose above 60 mg.

This lower dose range of 40-60 mg may be more effective for mood and safer with regard to akathisia and parkinsonism risk than higher doses.

Metabolic Monitoring

The meta-analysis revealed important information about metabolic effects of lurasidone

• Weight gain tends to occur at doses below 60 mg, without further gain at higher doses.
• Fasting blood glucose levels begin to rise at doses above 70 mg
• Prolactin levels increase with dosage
• Lipid risk increased but was not dose-related

Baseline screening (weight, fasting glucose, hemoglobin A1c, lipids, abdominal circumference) is essential before initiating lurasidone. Ongoing monitoring should be regularly conducted, especially around times of dose escalation.

Improving Medication Adherence

Medication adherence is always a challenge in managing bipolar disorder. Lurasidone has a specific challenge: it should be taken with food, at least 350 calories. Without this, its absorption is significantly hindered. To improve adherence:

• Educate patients on the importance of timing doses with meals
• Discuss ideal timing (e.g., with dinner or a planned after-dinner snack for those who find it sedating)
• Check in regularly about how the timing is working

Open discussion about this need when initiating lurasidone and during follow-ups is critical. It’s not uncommon to wonder if lurasidone is ineffective, only to later discover the patient wasn’t taking it with enough food.

Summary and Clinical Implications

This meta-analysis reinforces that a daily dose of 40-60 mg of lurasidone is optimal for treating bipolar depression, associated anxiety, and disability. This range is also least associated with akathisia and parkinsonism, compared to higher doses.

Clinicians should:

• Consider individual patient factors and progressive improvement
• Closely monitor for side effects
• Ensure comprehensive metabolic screening regardless of dosage
• Trial dose increases only if full remission isn’t achieved after at least a month at 40-60 mg

By integrating these dosing recommendations with thoughtful communication and personalized care strategies, we can optimize treatment outcomes for our patients with bipolar depression.

Abstract

Efficacy and acceptability of lurasidone for bipolar depression: a systematic review and dose–response meta-analysis

Yu-Wei Lin, M.D.; Yang-Chieh Brian Chen, M.D.; Kuo-Chuan Hung, M.D.;  Chih-Sung Liang, M.D.; Ping-Tao Tseng, M.D.; Andre F Carvalho, M.D.; Eduard Vieta, M.D.; Marco Solmi, M.D.; Edward Chia-Cheng Lai, M.D.; Pao-Yen Lin, M.D.; Chih-Wei Hsu, M.D. & Yu-Kang Tu, M.D.

Question The optimal dose of lurasidone for bipolar depression is unclear. This study examined its dose–response relationship for efficacy, acceptability, and metabolic/endocrine profiles.

Study selection and analysis Five databases and grey literature published until 1 August 2024, were systematically reviewed. The outcomes included efficacy (changes in depression, anxiety, clinical global impression, disability and quality of life), acceptability (dropout, manic switch, suicidality and side effects) and metabolic/endocrine profiles (changes in body weight, glucose, lipid and prolactin levels). Effect sizes were calculated using a one-step dose–response meta-analysis, expressed as standardised mean differences (SMDs), risk ratios (RRs) and mean differences (MDs) with 95% CIs.

Findings Five randomised clinical trials (2032 patients, mean treatment duration 6 weeks) indicated that the optimal therapeutic dose of lurasidone (40–60 mg) improved depression (50 mg: SMD −0.60 (95% CI −0.30, –0.89)), anxiety (50 mg: −0.32 (95% CI −0.21, –0.42)), clinical global impression (50 mg: −0.67 (95% CI −0.30, –1.03)) and disability (50 mg: −0.38 (95% CI −0.08, –0.69)). Side effects increased with higher doses (50 mg: RR 1.15 (95% CI 1.05, 1.25); 100 mg: 1.18 (95% CI 1.02, 1.36)), but dropout, manic switch and suicidality did not show a dose–effect relationship. Weight increased at doses<60 mg (40 mg: MD 0.38 (95% CI 0.16, 0.60) kg), while blood glucose levels rose at doses>70 mg (100 mg: 3.16 (95% CI 0.76, 5.57) mg/dL). Prolactin levels increased in both males (50 mg: 3.21 (95% CI 1.59, 4.84) ng/mL; 100 mg: 5.61 (95% CI 2.42, 8.81)) and females (50 mg: 6.64 (95% CI 3.50, 9.78); 100 mg: 5.33 (95% CI 0.67, 10.00)).

Conclusions A daily dose of 40–60 mg of lurasidone is a reasonable choice for bipolar depression treatment.

Trial registration number INPLASY202430069.

Reference

Lin, Y. M.D.; Brian Chen, Y. M.D.; Hung, K. M.D.; Liang, C. M.D.; Tseng, P. M.D.; Carvalho, A. M.D.; Vieta, E. M.D.; Solmi, M. M.D.; Lai, E. M.D.; Lin, P. M.D.; Hsu, C. M.D. & Tu, Y. M.D. (2024). 

Efficacy and acceptability of lurasidone for bipolar depression: a systematic review and dose–response meta-analysis

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BMJ Mental Health 27

:e301165.