02. Is Lurasidone Effective for Bipolar Depression with Comorbid Anxiety?

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Lurasidone for Bipolar Depression with Anxiety

I’d wager a guess that every single one of you has helped manage a patient with bipolar depression who also has significant anxiety. Anxiety in bipolar is so often a challenge given the mainstay medications are SSRIs and don’t usually play so well with bipolar. Today, we’re diving into this crucial area—managing bipolar depression when anxiety is also a major player.

Our focus today is on a recent post-hoc analysis published in the Journal of Affective Disorders titled “Lurasidone for bipolar I depression with comorbid anxiety symptoms: Post-hoc-analysis of randomized, placebo-controlled studies.” This paper offers some really valuable insights into using Lurasidone in these challenging cases.

Anxiety Comorbidity Impacts Bipolar Outcomes

So why is this topic important? Well, anxiety comorbidity is incredibly common in bipolar disorder with one study in this paper noting that about 37.5% of patients with bipolar I depression also have severe anxiety symptoms. And when anxiety is present, it’s not just an added symptom.

It’s associated with a whole host of adverse outcomes:

• Greater illness severity
• Reduced treatment response
• Increased functional impairment
• Higher risk of suicide attempts

The DSM-5 even includes anxious distress as a specifier for bipolar depression highlighting its clinical significance.

Limited Evidence-Based Options Currently Available

Current guidelines like those from CANMAT and ISBD emphasize prioritizing mood stabilization before tackling specific anxiety symptoms. While we have some options like Quetiapine and Olanzapine-Fluoxetine combination that have shown preliminary efficacy for anxiety in bipolar depression, evidence-based options remain limited. This is where this paper sheds new light.

Lurasidone is already approved worldwide for schizophrenia and bipolar depression and previous studies hinted that it has both antidepressant and anxiety-reducing effects. The big question was, does it work for bipolar depression specifically when anxiety is a major player too?

Study Design and Key Questions

This post-hoc analysis pooled data from two previously conducted six-week randomized, double-blind, placebo-controlled studies on Lurasidone monotherapy for bipolar I depression.

Patients were divided into two groups based on their baseline Hamilton Anxiety Rating Scale (HAM-A) score:

• Severe anxiety group: HAM-A score of 18 or higher
• Non-severe group: HAM-A score below 18

About a third of patients had severe anxiety at baseline. The original studies tested two dose ranges of lurasidone:

• Lower dose range: 20 to 60 mg per day
• Higher dose range: 80 to 120 mg per day

The key questions were:

1. How effective and safe is Lurasidone in patients with bipolar depression, regardless of anxiety severity?
2. Does the lower dose range (20 to 60 mg per day) show significant antidepressant and anxiolytic efficacy in those with severe anxiety?

Efficacy in Severe Anxiety Group

The lower dose (20-60 mg/day) showed significant improvements in depression (MADRS scores), response rates (≥50% improvement, NNT=5), and remission rates (NNT=7). The higher dose (80-120 mg/day) did not demonstrate the same significant benefit.

Efficacy in Non-Severe Anxiety Group

For the non-severe anxiety group, both the lower dose range and the higher dose range of Lurasidone significantly improved depression scores.

Both doses led to better response and remission rates compared to placebo. The NNT for response was 5 for the lower dose and 6 for the higher, while the NNT for remission was 8 for the lower dose and 7 for the higher.

Efficacy for Anxiety Symptoms

Anxiety symptoms were measured using the HAM-A.

For the severe anxiety group:

• Lower dose (20 to 60 mg) significantly reduced anxiety scores
• Higher dose didn’t reach statistical significance

For the non-severe anxiety group:

• Both doses showed significant improvement in anxiety symptoms

Clinical Takeaway: Optimal Dose

So the big takeaway for effectiveness? The sources really emphasized that Lurasidone at 20 to 60 mg per day appears to be effective for both depressive and anxiety symptoms in bipolar I depression no matter if your anxiety is severe or not. This is especially helpful given how tough it can be to treat bipolar depression when anxiety is prominent.

Plus, it seems to keep those symptoms at bay in the long run during the open-label extension phases.

Safety and Tolerability Profile

Lurasidone demonstrated a generally good safety profile:

• Most common adverse events: akathisia and nausea
• Minimal changes in metabolic laboratory parameters or body weight
• Low rate of treatment-emergent mania

When comparing Lurasidone to other common treatments like Olanzapine-Fluoxetine combination or Quetiapine, this paper highlights that while the antidepressant effect might be comparable, Lurasidone stands out regarding metabolic safety. Olanzapine and Fluoxetine and Quetiapine are associated with notably higher weight gain and risk of metabolic adverse events compared to lurasidone.

Dose-Dependent Effects in Severe Anxiety

The higher dose (80-120 mg) was less effective than the lower dose for both depression and anxiety in the severe anxiety group. Possible explanations include:

• Type 2 error due to small sample size
• Excessive D2 receptor blockade at higher doses, linked to dysphoria
• Higher akathisia rates with the higher dose, potentially mimicking anxiety symptoms

This aligns with research indicating optimal effects for bipolar depression may occur at doses of 40 to 60 mg, although higher doses might be beneficial for schizophrenia.

Dosing Strategy: More Isn’t Always Better

So a clinical pearl takeaway. For our patients with bipolar depression and significant anxiety, starting at the lower end of the lurasidone dose range, 20 to 60 mg per day, appears to be more effective and better tolerated than higher doses.

More isn’t always better especially when we’re dealing with the nuanced neurobiology of anxiety.

Study Limitations

Now, as with any research, it’s important to look at the limitations.

• This was a post hoc analysis which means these results need to be confirmed by dedicated prospective trials.
• Long-term open-label phase lacked a placebo control group
• Definition of severe anxiety based on HAM-A score, not formal DSM-5 diagnosis
• Study population may limit generalizability to all community patients

Bottom Line for Clinicians

This post hoc analysis strongly suggests that lurasidone in the 20 to 60 mg per day range is an effective treatment option for patients with bipolar I depression even those with severe comorbid anxiety symptoms. It effectively addresses both depressive and anxiety symptoms and it does so with a generally good safety profile particularly regarding metabolic parameters.

For your patients struggling with anxiety alongside their bipolar depression, remember that the lower dose range appears to be the sweet spot potentially offering better efficacy and fewer side effects like akathisia especially in those with higher baseline anxiety.

Abstract

Lurasidone for bipolar I depression with comorbid anxiety symptoms: Post-hoc-analysis of randomized, placebo-controlled studies

Takeshi Inoue, Takahiro Masuda, Fumiya Sano & Hidenori Maruyama

Background

Anxiety comorbidity is common in patients with bipolar disorder and is associated with higher severity and reduced treatment response. The aim of this study was to assess the efficacy and safety of lurasidone in patients with bipolar depression who present with or without severe anxiety symptoms.

Methods

Data were pooled from 2 bipolar I depression studies of very similar design that randomized patients, double-blind, to 6 weeks of treatment with lurasidone (20–60 mg/day or 80–120 mg/day) versus placebo. Patients were categorized into 2 groups based on their Hamilton Anxiety Rating Scale (HAM-A) score at baseline: a “severe” anxiety group (HAM-A ≥ 18) and a “non-severe” anxiety group (HAM-A < 18). The primary efficacy measure was the Montgomery-Åsberg Depression Rating Scale (MADRS).

Results

In the severe anxiety group, significant improvement in the MADRS total score was observed with a moderate effect size (0.40) on lurasidone 20–60 mg, but lurasidone 80–120 mg was not significant (effect size, 0.21); however, in the non-severe anxiety group significant improvement was observed in both lurasidone treatment groups (effect size, 0.51 and 0.54, respectively). Common adverse events were akathisia and nausea, and the change in laboratory parameters and body weight were small and not clinically meaningful.

Limitations

This was a post-hoc analysis of a short-term study.

Conclusions

This analysis suggests that lurasidone 20–60 mg is effective in patients with bipolar I depression regardless of their anxiety severity, with a generally good safety profile.

Reference

Inoue, T.; Masuda, T.; Sano, F. & Maruyama, H. (2025). Lurasidone for bipolar I depression with comorbid anxiety symptoms: Post-hoc-analysis of randomized, placebo-controlled studies. Journal of Affective Disorders Volume 385, 119348