Mini-CAT expanded from RT3-WK2 PICO

Clinical Question: 29 y/o F, with a history of bipolar I disorder, who presents for depression for several days. Patient states she has been sleeping for over ten hours a day and has no interest in her daily activities for over a month. Patient is currently on Lithium for her bipolar disorder and the team caring for her is assessing additional treatments for her bipolar depression.

PICO Question:

Does Lurasidone, in addition to standard therapy, decrease depressive symptoms in bipolar I disorder compared to no additional treatment?

P	I	C	O
Bipolar disorder	Lurasidone	No additional medication	Decrease in symptoms
Bipolar I disorder	Latuda	Monotherapy with Lithium	Decrease in depression
Bipolar depression		Placebo	Symptom resolution
		Control group	Decrease in mania
			Efficacy

Search Strategy:

Google Scholar:

• Lurasidone bipolar depression – 4,150 results
  • Five years – 2,240 results
• Lurasidone as adjunct treatment for bipolar depression – 2,170 results
  • Five years – 1,120 results
• Lurasidone efficacy with lithium for bipolar disorder – 2,130 results
  • Five years – 1,170 results

PubMed:

• Lurasidone with lithium for bipolar depression – 51 results
  • Five years – 22 results
• Lurasidone as adjunctive treatment for bipolar – 43 results
  • Five years – 15 results 

ScienceDirect:

• Lurasidone with lithium for bipolar disorder – 338 results
  • Five years – 204 results
• Lurasidone efficacy for bipolar depression – 395 results
  • Five years – 238 results

Cochrane:

• Lurasidone with lithium for bipolar – 93 results
  • Five years – 35 results
• Lurasidone for bipolar disorder – 203 results
  • Five years – 105 results

I narrowed my articles for this mini-CAT by first reviewing the articles previously chosen for my PICO. I concluded that all three previous articles that I analyzed remained high level of evidence articles that addressed the question. However, I still researched with the search terms and strategies above to identify if there were better articles available. I looked at articles from within the last five years and continued to search for meta-analyses and systematic reviews. However, my fourth article was from seven years ago. While this is not within the five-year criteria I was hoping to search from, I chose the last article because it was a randomized, double-blind, placebo-controlled trial that assessed the efficacy of lurasidone as adjunctive treatment with lithium or valproate for bipolar depression. Since this article directly related to the search question and still maintained a high level of evidence as a double-blind RCT, I found it appropriate to include it in this analysis. Additionally, I wanted to evaluate lurasidone as an adjunct to base therapy, so I did not include articles evaluating lurasidone as monotherapy for bipolar depression, and I did not include studies that only focused on pediatric populations.

Articles Chosen:

Article 1:

Link: https://www.sciencedirect.com/science/article/abs/pii/S0165032719316507 PDF:

Abstract: Background: Few evidence-based treatments and guidelines reflect greater uncertainty regarding consensus treatment algorithms than those for unipolar disorder. This meta-analysis aimed to evaluate the efficacy and side effects of lurasidone by comparing with placebo in bipolar I depression. Methods: Electronic databases, such as PubMed, the Cochrane Library, Web of Science, and Embase, were searched until May 30, 2018, for randomized controlled trials on comparison lurasidone therapy with placebo. The primary efficacy assessment included MADRS total score and CGI-BP-S total score, the secondary efficacy assessment included the response and the remission rates and the safety and tolerability were also evaluated applying the Simpson-Angus Scale. Results: The meta-analysis compromised 7 studies. Efficacy analysis suggested that lurasidone was more effective than placebo: MADRS total score (MD:−4.31, 95%CI: (−6.93,−1.7), P = 0.001) and the CGI-BP-S total score (MD:−0.37, 95%CI: (−0.59,−0.15), P = 0.0008) were obtained for both lurasidone-treated and placebo groups. Response rates (RR: 1.73, 95%CI: (1.46, 2.05), P < 0.00001) and Remission rates (RR: 1.57, 95%CI: (1.38, 1.79), P < 0.00001). The safety analysis between lurasidone and placebo showed no difference: at least one event (RR: 1.12, 95% CI :(1.00, 1.26), p = 0.05 and the influence on glucose (MD: 0.35, 95% CI :(−1.09, 1.79), p = 0.63. Limitation: The present conclusion is limited by the limited included studies. The different dose of lurasidone should be considered in the future. Conclusion: Compared with placebo, adjunctive lurasidone significantly improved depressive symptoms and is very well tolerated with minimal side effects on the endocrine and cardiovascular systems in clinical patients with bipolar I depression.

Article 2:

Link: https://pubmed.ncbi.nlm.nih.gov/28689688/ PDF:

Abstract: Lurasidone (DS-RAn) has demonstrated efficacy in the acute treatment of bipolar depression, both as monotherapy, and as combination therapy with lithium or valproate. To evaluate the recurrence prevention efficacy of lurasidone for the maintenance treatment of bipolar I disorder, patients received up to 20 weeks of open-label lurasidone (20–80 mg/d) combined with lithium or valproate during an initial stabilization phase. A total of 496 patients met stabilization criteria and were randomized to 28 weeks of double-blind treatment with lurasidone (20–80 mg/d) or placebo, in combination with lithium or valproate. Based on a Cox proportional hazard model, treatment with lurasidone reduced the probability of recurrence of any mood episode by 29% (primary endpoint), however, the reduction did not achieve statistical significance. Probability of recurrence on lurasidone was significantly lower in patients with an index episode of depression (HR, 0.57; P=0.039), in patients with any index episode who were not rapid-cycling (HR, 0.69; P=0.046), and when recurrence was based on MADRS, YMRS, or CGI-BP-S severity criteria (HR, 0.53; P=0.025; sensitivity analysis). Long-term treatment with lurasidone combined with lithium or valproate was found to be safe and well-tolerated, with minimal effects on weight or metabolic parameters.

Article 3:

Link: https://pubmed.ncbi.nlm.nih.gov/27089521/ PDF:

Abstract: In this study, designed to evaluate the efficacy of lurasidone as adjunctive therapy with lithium or valproate, patients with bipolar I depression were randomized to 6 weeks of double-blind treatment with lurasidone (N = 180) or placebo (N = 176), added to background treatment with lithium or valproate. All patients were treated with lithium or valproate for a minimum of 4 weeks prior to screening. This was confirmed either by prospective treatment after study enrolment (run-in cohort), or retrospectively, with blood levels of lithium and valproate at screening (non-run-in cohort). Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP-S), respectively. Treatment with lurasidone was associated with non-significant improvement at week 6 vs. placebo for the MADRS total score (−11.8 vs −10.4; P = 0.176), and the CGI-BP-S score (−1.36 vs −1.13; P = 0.095). Significant separation from placebo was observed from weeks 2–5 for the MADRS and weeks 3–5 for the CGI-BP-S. Improvement in the placebo-subtracted MADRS total score was notably larger at week 6 for the non-run-in cohort compared to the run-in cohort (LS mean difference in endpoint change scores, −4.6; P = 0.009). Adverse events most frequently reported for lurasidone were akathisia, somnolence, and extrapyramidal side effects. In conclusion, lurasidone adjunctive with lithium or valproate demonstrated significant improvement in depressive symptoms based on the MADRS from weeks 2–5 but not at the primary week 6 endpoint.

Article 4:

Link: https://pubmed.ncbi.nlm.nih.gov/24170221/ PDF:

Abstract: Objective: Few studies have been reported that support the efficacy of adjunctive therapy for patients with bipolar I depression who have had an insufficient response to monotherapy with mood-stabilizing agents. The authors investigated the efficacy of lurasidone, a novel antipsychotic agent, as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression. Method: Patients were randomly assigned to receive 6 weeks of double-blind adjunctive treatment with lurasidone (N=183) or placebo (N=165), added to therapeutic levels of either lithium or valproate. Primary and key secondary endpoints were change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) and depression severity score on the Clinical Global Impressions scale for use in bipolar illness (CGI-BP), respectively. Results: Lurasidone treatment significantly reduced mean MADRS total score at week 6 compared with the placebo group (−17.1 versus −13.5; effect size=0.34). Similarly, lurasidone treatment resulted in significantly greater endpoint reduction in CGI-BP depression severity scores compared with placebo (−1.96 versus −1.51; effect size=0.36) as well as significantly greater improvement in anxiety symptoms and in patient-reported measures of quality of life and functional impairment. Discontinuation rates due to adverse events were 6.0% and 7.9% in the lurasidone and placebo groups, respectively. Adverse events most frequently reported for lurasidone were nausea, somnolence, tremor, akathisia, and insomnia. Minimal changes in weight, lipids, and measures of glycemic control were observed during treatment with lurasidone. Conclusions: In patients with bipolar I depression, treatment with lurasidone adjunctive to lithium or valproate significantly improved depressive symptoms and was generally well tolerated.

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition)	Outcome(s) studied	Key Findings	Limitations and Biases
Wang, H., Xiao, L., Wang, HL., Wang, GH. (2020)	Meta-analysis	– Authors searched PubMed, Cochrane Central Register of Controlled Trials, Web of Science and Embase. – They searched for RCTs from database inception to 5/31/2018. – RCTs comparing lurasidone with placebo in treatment of bipolar depression in children, adolescents and adults were assessed. – Inclusion criteria: RCTs comparing lurasidone efficacy in patients with bipolar depression versus placebo. Studies in which patients were diagnosed with bipolar depression or bipolar I depression. – Exclusion criteria: observational studies, review articles and meta-analysis. Trials not including lurasidone or trials that did not report adverse events and efficacy. Trials not published in English were also excluded. – Outcomes: Montgomery Asberg Depression Rating Scale (MADRS) and Clinical Global Impressions scale for bipolar illness (CGI-BP-S) – Out of 1,524 studies identified, seven trials were included.	– Primary outcome of improvement in symptoms was assessed with MADRS and CGI-BP-S. – Secondary outcomes: response/remission rates, safety and tolerability of lurasidone using the Simpson-Angus Scale	– Significant improvement in MADRS was found with lurasidone. – CGI-BP-S, for the five studies that were included, found a decrease in the score in the lurasidone group, meaning it improved symptoms, in comparison to the placebo groups. – Response and remission rates were also increased in the lurasidone group in comparison to placebo, meaning that patients had a better response and longer remission with lurasidone. – Both adverse events and increase in glucose level were not significantly different for the lurasidone groups in comparison to the placebo groups. – Lurasidone, with a base therapy of lithium or valproate, was found to improve depressive symptoms, with limited side effects, in bipolar depression patients.	– Only seven studies included – Analysis of MADRS, CGI-BP-S and response rate could not fully be evaluated between studies because of a lack of data – Variation in the design of the studies that were included. – Only two or three of the seven included studies analyzed adverse events – The included studies did not report the effect of the base therapy (lithium or valproate) on outcomes specifically – Except for one trial, the doses of lurasidone were not evaluated
Calabrese, J., Pikalov, A., Streicher, C., Cucchiaro, J., Mao, Y., Loebel, A. (2017)	Randomized controlled trial	– Double-blind, placebo controlled RCT – Inclusion criteria: Patients had to meet the DSM-IV criteria for bipolar 1 disorder with one or more manic, mixed or depressed episode in the past 2 years and a Young Mania Rating Scale or Montgomery-Asberg Rating scale of > 14 if on base therapy or >18 if not on a current therapy – Exclusion criteria: substance abuse/dependence, acute or unstable medical condition, use of potent cytochrome P450 3A4 inhibitor or inducer, history of multiple non-response to medication – 965 entered the stabilization phase and ultimately 496 met stabilization criteria and were randomized to combination therapy with lurasidone (246 patients) or placebo (250 patients) – Patients received 12-20 weeks of lurasidone with lithium or valproate, and if clinically stable, were then randomized to an additional 28 weeks of double-blind treatment with either lurasidone or placebo in combination with lithium or valproate.	– Primary outcomes: time to recurrence of any mood episode as defined by the DSM-IV criteria, need for treatment, need for hospitalization, rating scores – Secondary outcomes: time to recurrence of mood episode, changes in rating scales from baseline to the end	– There was a non-significant association of lurasidone with time to recurrence of mood disorder. – Recurrence at week 28 was 20.9% for lurasidone and 51.5% for the placebo, meaning that there was lower risk of mood disorder recurrence in patients receiving the lurasidone. Lurasidone reduced the probability of mood recurrence by 29%. – Lurasidone also increased the time to recurrence of depressive episode, mania, hypomania or mixed in comparison to placebo, although all of these were non-significant. – 62.2% of patients in the lurasidone group and 60.4% in the placebo group experienced at least one adverse event.	– Short duration of maintenance treatment of only six months. – The above could have been too short of a period to allow for a mood episode to recur in patients who were stabilized during the open-label treatment. – Sample size was likely too small resulting in insufficient power to assess the significance of mania recurrence – Dosages of lurasidone could have played a role in the results. – Generalizing this to a greater population, such as those with other psychiatric comorbidities, may be difficult as patients had to meet specific criteria to enter this trial.
Suppes, T., Kroger, H., Pikalov, A., Loebel, A. (2016)	Randomized Controlled Trial	– Double-blind placebo controlled RCT – Inclusion criteria: 18–75-year-old patients with bipolar I disorder with a major depressive episode and a history of at least one manic or mixed episode with or without rapid cycling and without psychotic features. – Exclusion criteria: reduction > 25% in MADRS score, scored > 4% on MADRS suicidal thoughts item, imminent risk of suicide or injury to self/others, hospitalized for manic or mixed episode within 60 days, received certain medications, history of substance abuse, history of non-response to medications – Cohorts were treated for at least 28 days with lithium or valproate prior to screening and blood levels of the medications had to be within therapeutic range – Total of 365 patients, ages ranging from 18 to 75, in multiple countries (North America, Asia, South American and Europe) were in this study. – Patients were randomized to either adjunctive lurasidone 20-120 mg/day or a placebo. Neither the investigators, study staff nor patients knew what treatment they were receiving. – Lurasidone (or placebo) was started at 20 mg/day then increased to 40 mg/day on day 4 then 60 mg/day on day 7 and after the first week could be adjusted to up to 120 mg/day as the investigator saw was needed.	– Primary outcome: Mean change from baseline to week 6 in MADRS total score. – Secondary outcome: mean change from baseline to week 6 in the CGI-BP-S assessment. – Other secondary efficacy assessments used included the Quick Inventory of Depressive Symptomatology, self-rated Hamilton Anxiety Rating Scale and Quality of Life Enjoyment and Satisfaction Questionnaire	– No significant difference in mean change from baseline to after week six in the MADRS total score for either Lurasidone or placebo group. However, there was a statistical difference, superior for lurasidone, in weeks 2-5 for change from baseline in the MADRS and change in weeks 3-5 in the CGI-BP-S. – Adverse events were more frequent in the lurasidone group and included akathisia (14.4% in comparison to 5.3% in placebo), somnolence (11.9% versus 4.7%), EPS (12.4% vs. 7.6%). – There were no significant differences in vital signs, EKG or laboratory measures between the treatment groups.	– Population enrolled in this study only included bipolar I depression patients, which limits the population in which this study can be generalized to. – Short-term study, which may have limited the effect of the medications on symptoms in these patients
Loebel, A., Cucciharo, J., Silva, R., Kroger, H., Kaushik, S., Xu, J., and Calabrese, J. (2014)	Randomized Controlled Trial	– Double-blind placebo controlled randomized trial – Inclusion criteria: 18–75-year-old patients with bipolar I disorder with major depressive episode with or without rapid cycling and without psychotic features. Patients had to be confirmed to be not responding to 28-day trial of lithium or valproate. Serum levels for the two drugs above had to be within normal limits. – Exclusion criteria: Decrease in MADRS score > 25% between screening and baseline, score of > 4 on MADRS suicidal thoughts, imminent risk to self or others, history of nonresponse to medications – 348 patients were randomized to either adjunctive treatment with 20-120 mg/day of lurasidone or a placebo (in addition to the base therapy of either lithium or valproate) – Dose of the base therapy was adjusted to be within normal serum levels throughout the study	– Primary outcomes: mean change from baseline to week 6 in MADRS score – Secondary outcomes: average change from baseline to week 5 in CGI-BP, Quick Inventory of Depressive Symptomatology, Hamilton Anxiety Rating Scale and Quality of Life Enjoyment and Satisfaction Questionnaire	– Statistically significant decrease from baseline to week 6 on MADRS when comparing lurasidone to placebo group. – Lurasidone group had a greater improvement on each of the MADRS items in comparison to the placebo. The significant differences were seen in apparent sadness, reported sadness, reduced sleep, lassitude (which is a lack of energy), inability to feel and pessimistic thoughts –  Time to response was significantly reduced in the lurasidone group compared to placebo. – Proportion of participants achieving remission at the end of six weeks was significantly greater in the lurasidone group compared to placebo (50% versus 35%) – Serious adverse events were low in both lurasidone group (1.1%) and placebo (1.2%). EPS related adverse events was 15.3% in the lurasidone group and 9.8% in the placebo group	– Patients with bipolar I disorder were enrolled only, therefore this study cannot extend to other psychiatric conditions such as bipolar II disorder. Additionally, those with serious psychiatric comorbidities were excluded. – This was a short study of six weeks, therefore lurasidone treatment cannot be generalized to longer-term safety or maintenance efficacy.

Conclusions:

Article 1: Wang et al., concluded that lurasidone in conjunction with base therapy of lithium or valproate improved the depressive symptoms in patients with bipolar depression. Additionally, the authors found that lurasidone was well tolerated with minimal side effects.

Article 2: Calabrese et al., concluded that patients with bipolar I disorder who were stabilized on a base therapy of lithium or valproate for up to 20 weeks in combination with lurasidone, had a decrease, while non-significant, in the probability of a mood episode in comparison to the placebo groups. 

Article 3: Suppes et al., did not find significant improvement in MADRS or other efficacy assessments when comparing lurasidone with adjunctive lithium or valproate to placebo treatment at the end of six weeks. However, a significant improvement in depressive symptoms on the MADRS was found in the lurasidone group in comparison to the placebo group from week two through five.

Article 4: Loebel et al., found that lurasidone as adjunctive treatment in combination with stable doses of lithium or valproate had a significant effect on improving the depressive symptoms for patients with bipolar I disorder and was well-tolerated with minimal adverse events.

The overall conclusion based on these four studies is that lurasidone in addition to lithium or valproate base therapy for bipolar I depression decreases depressive symptoms. While the second and third article did not find statistically significant differences, improvements in symptoms with lurasidone were seen throughout all four articles. 

Clinical Bottom Line:

Weight of evidence:

I weighed the first article by Wang et al., the most because it was a meta-analysis whereas the other three articles were all randomized controlled trials. Additionally, it was the most recent article as it was from 2020. It was a meta-analysis of seven studies all evaluating lurasidone versus placebo in bipolar disorder patients, which found lurasidone to be more effective than placebo in decreasing symptoms. The authors appropriately discussed the need to assess the safety of lurasidone and that such must be taken into account when prescribing lurasidone as long-term treatment.

The second article was weighed next because it had a larger population size in comparison to the other two randomized controlled trials. Additionally, it was also a longer trial of 28 weeks with either lurasidone or placebo in addition to the base therapy, which allowed for a greater length of time for therapy and changes in rating scores.

The last two articles were similar; however, I weighed the third article next because it had slightly more participants than the fourth article despite not finding a statistically significant difference between the two treatment groups. The third article discussed the efficacy and safety of lurasidone as adjunctive treatment separately and at length, as it is important weigh the benefits and risks of any treatment. Lastly, the fourth article was the weakest as it was the oldest article, had the smallest population and was also shorter in treatment, six weeks, which was also seen in the third article. Additionally, because the lurasidone group had dose flexibility, it was difficult to determine a relationship between dose and response to treatment.

It was beneficial that all four articles used the same rating scales, MADRS +/- CGI-BP. This aided in my ability to compare the studies to each other. Weaknesses of all the studies included the difficultly in generalizing to larger populations, as the articles only focused on bipolar I disorder patients, mostly without significant psychiatric comorbidities, thus making it more difficult to extend these findings to other populations. While this does not impact my clinical bottom line significantly, because the patient population I focused on was bipolar I disorder, it is significant to consider for many other populations.

Magnitude of effects:

Article 1. The meta-analysis found significant effect of lurasidone on MADRS (MD: -4.31, 95% CI: (-6.93, -1.7), P = 0.001). The CGI-BP-S score decreased significantly in the lurasidone group in comparison to the placebo (MD: -0.37, 95% CI: (-0.59, -0.15, P = 0.0008). An increase in response rate was found in the lurasidone group in comparison to placebo (RR: 1.73, 95% CI (1.46, 2.05), P < 0.00001). An increase in remission rate was found for the lurasidone group (RR: 1.57, 95% CI (1.38, 1.79), P <0.00001).

Article 2. After 28 weeks of treatment, the probability of mood episode recurrence for lurasidone in comparison to placebo was 20.9% versus 51.5%, with a risk reduction of 29%. Lurasidone also increased time to recurrence of a mood episode, with a risk reduction of 43%. Improvement was found from baseline to endpoint in mean MADRS total score (18.2 to 4.0) and CGI-BP-S score (4.0 to 1.7) for the lurasidone group.

Article 3: No significant difference was found from baseline to week 6 in MADRS scores for lurasidone versus placebo (-11.8 vs. -10.4, P = 0.176; effect size 0.16). No significant difference was found from baseline to week 6 for CGI-BP-S scores comparing lurasidone to placebo (-1.36 vs. -1.13, P = – 0.095, effect size 0.20).

Article 4: From baseline to week six, total MADRS score was significantly greater in the lurasidone group in comparison to the placebo (-17.1 vs. -13.5; P = 0.005). CGI-BP scores changed significantly more in the lurasidone group versus placebo (-1.96 vs. -1.51, p = 0.003). Additionally, median time to remission was significantly shorter in the lurasidone group (35 versus 43 days, p = 0.001).

Clinical Significance:

The results found above are clinically significant as each of the studies did find improvement in depressive symptoms when lurasidone was used as an adjunctive treatment with lithium or valproate for bipolar depression, regardless of if these results were statistically significant. In addition to this, most of the articles found a shorter time to remission with lurasidone treatment and increase in response rate with this additional treatment. Also, all the studies found minimal adverse events when lurasidone was added in comparison to placebo. However, the adverse effects such as extrapyramidal symptoms, somnolence etc. must be taken into account prior to prescribing this medication. These minimal risks have to be weighed with the benefit of improved symptoms, which can possibly positively impact the patient’s social and occupational functioning as well. While many of these studies are of small population sizes, it is reasonable to add lurasidone for a patient with depressive recurrences in bipolar depression on lithium or valproate base therapy.

Other Considerations:

Future research should utilize larger population sizes, longer treatment times and continue to assess the efficacy of lurasidone as an additional antipsychotic in patients on lithium or valproate. Compliance and whether the patient is currently stabilized on base therapy are other considerations that must be taken into account. Many of these studies did not evaluate patients under the age of 18 with bipolar disorder. Lastly, future studies assessing the use of lurasidone in patients with bipolar I with other significant psychiatric comorbidities or patients with recent or current substance abuse should also be assessed, as the articles summarized above had these populations in their exclusion criteria.