Antipsychotic for bipolar depression

An Overview of Atypical Antipsychotics for Bipolar Depression

January 3, 2020

Chris Aiken, MD

For most patients, bipolar is a disorder of depression. It’s here that they spend the majority of their days...

For most patients, bipolar is a disorder of depression. It’s here that they spend the majority of their days, so an atypical antipsychotic that has benefits in depression is usually the best choice.¹

The atypical antipsychotics are complex drugs. No two have the same profile, and the line between their receptor profile and clinical effects is a hard one to follow. Only four are FDA-approved in bipolar depression: cariprazine (Vraylar^®), lurasidone (Latuda^®), olanzapine-fluoxetine combination (Symbyax^®), and quetiapine (Seroquel^®). The Tableprovides dosage ranges for the four atypical antipsychotics that are FDA-approved for bipolar depression. Most of the other atypical antipsychotics have been tried but failed to show efficacy in bipolar depression, including a few that work in unipolar depression: aripiprazole, ziprasidone, and risperidone.² Asenapine (Saphris^®), brexpiprazole (Rexulti^®), and paliperidone (Invega^®) are untested.

Cariprazine (Vraylar^®)

Cariprazine (no equivalent generic version equivalent in the US) is FDA-approved for both manic and depressive episodes in bipolar disorder. It has favorable rates of weight gain and fatigue, especially in the lower dose range. Adverse effects that get in the way for patients include akathisia and extrapuramidal symptoms. The number needed to treat is higher than for other atypical antipsychotics for bipolar depression (10 versus 2 to 6 for remission and response).³

To minimize akathisia, start with 1.5 mg every other day. Cariprazine’s long half-life (2-5 days) allows this kind of dosing.

Lurasidone (Latuda^®)

Lurasidone (no equivalent generic version available in the US) is FDA-approved for bipolar depression in patients as young as 12 years. It has favorable rates of weight gain and fatigue and is the only atypical antipsychotic with evidence to improve cognition in bipolar disorder, based on a small controlled trial in euthymic bipolar I patients.⁴

No studies have been undertaken in patients with mania, although it does work in unipolar depression with mixed features. It must be taken with a meal of more than 350 kcal. Nausea and akathisia are common causes of discontinuation.

We don’t know the ideal dose of lurasidone because it was dosed flexibly in the bipolar depression trials. An analysis of that data suggests it that higher doses are more effective, with a linear dose-response relationship between 20 and 120 mg.⁵

Olanzapine-fluoxetine combo (OFC) (Symbyax)

Statistically speaking, OFC may be the most effective therapy for acute bipolar depression, with a number needed to treat (NNT) of 2 compared with 5 to 11 for other FDA-approved atypical antipsychotics. ³

Olanzapine does not treat depression on its own so it requires the fluoxetine component to work. This is a potential draw-back because fluoxetine may worsen manic or mixed symptoms. The prescription can be written as a single combo pill, which helps some patients save on their copays, or as the two medications, which is cheaper for patients who pay full price for the medicine.

Weight gain and metabolic adverse effects are also significant risks with this medicine, but they can be ameliorated somewhat with metformin. This anti-diabetic agent has the best preventative effects for weight gain on atypical antipsychotics, and it works better when started earlier (500-1000 mg/d with food).⁶

Although ost meta-analyses rank OFC at the top of the efficacy list in bipolar depression, the story is different in unipolar depression, where its efficacy usually ranks near the bottom among atypical antipsychotic anugmentation agents.⁷

Quetiapine (Seroquel)

Quetiapine is FDA-approved for both manic and depressed episodes in bipolar disorder. Moreover, it may improve sleep quality and comorbid anxiety.^8,9 Quetiapine has favorable rates of akathisia and extrapyramidal effects.

However, quetiapine’s adverse effects, particularly sedation and hypotension, are a common cause of discontinuation and emergency department visits.¹⁰ Weight gain and metabolic effects are significant long-term problems. Furthermore, despite early hopes, patients on quetiapine are at risk for tardive dyskinesia.¹¹

Both the extended release (XR) and instant release (IR) versions of quetiapine are FDA-approved for bipolar depression. For reasons that have more to do with its patent than its pharmacology, only the XR is approved in unipolar depression.

Quetiapine IR can be dosed all-at-night, and this strategy usually results in less daytime fatigue than the XR version. Hypotension, however, is lessened with the smoother peaks of quetiapine XR, particularly in doses higher that 300 mg.¹²

Conclusion

None of the atypical antipsychotics stands out as the best choice for bipolar depression. Both of the generic options are low on tolerability, but OFC is the most likely to work and quetiapine has additional benefits in sleep and anxiety. Cariprazine and lurasidone are better tolerated overall, unless the problem is akathisia or out-of-pocket expense.

Disclosures:

Dr Aiken is the Director of the Mood Treatment Center and an Instructor in Clinical Psychiatry at the Wake Forest University School of Medicine. As the Editor in Chief of The Carlat Psychiatry Report, he hosts a weekly podcast with Kellie Newsome on psychiatric practice. He is the coauthor with Jim Phelps, MD, of Bipolar, Not So Much. He does not accept honoraria from pharmaceutical companies.

References:

1. Taylor DM, Cornelius V, Smith L, et al. Comparative efficacy and acceptability of drug treatments for bipolar depression: a multiple-treatments meta-analysis. Acta Psychiatr Scand. 2014;130:452-469.

2. Judd LL, Schettler PJ, Akiskal HS, et al. Long-term symptomatic status of bipolar I vs bipolar II disorders. Int J Neuropsychopharmacol. 2003;6:127-137.

3. Pinto JV, Saraf G, Vigo D, et al. Cariprazine in the treatment of bipolar disorder: a systematic review and meta-analysis. Bipolar Disord. Oct 16, 2019 [Epub ahead of print].

4. Yatham LN, Mackala S, Basivireddy J, et al. Lurasidone versus treatment as usual for cognitive impairment in euthymic patients with bipolar I disorder: a randomised, open-label, pilot study. Lancet Psychiatry. 2017;4:208-217.

5. Chapel S, Chiu YY, Hsu J, et al. Lurasidone dose response in bipolar depression: a population dose-response analysis. Clin Ther. 2016;38:4-15.

6. Hendrick V, Dasher R, Gitlin M, et al. Minimizing weight gain for patients taking antipsychotic medications: the potential role for early use of metformin. Ann Clin Psychiatry. 2017;29:120-124.

7. Spielmans G, Berman MI, Linardatos E, et al. Adjunctive atypical antipsychotic treatment for major depressive disorder: a meta-analysis of depression, quality of life, and safety outcomes. PLoS Med. 2013;10:e1001403.

8. Gedge L, Lazowski L, Murray D, et al. Effects of quetiapine on sleep architecture in patients with unipolar or bipolar depression. Neuropsychiatr Dis Treat. 2010;6:501-508.

9. Lydiard RB, Culpepper L, SchiÃ¶ler H, et al. Quetiapine monotherapy as treatment for anxiety symptoms in patients with bipolar depression: a pooled analysis of results from 2 double-blind, randomized, placebo-controlled studies. Prim Care Comp J Clin Psychiatry. 2009;11:215-225.

10. Hampton LM, Daubresse M, Chang HY, et al. Emergency department visits by adults for psychiatric medication adverse events. JAMA Psychiatry. 2014;71:1006-10014.

11. Carbon M, Kane JM, Leucht S, et al. Tardive dyskinesia risk with first- and second-generation antipsychotics in comparative randomized controlled trials: a meta-analysis. World Psychiatry. 2018;17:330-340.

12. Kishi T, Ikuta T, Sakuma K, et al. 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;115:121-128.

Atypical antipsychotics for bipolar disorder

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Review

. 2005 Jun;28(2):325-47.

doi: 10.1016/j.psc.2005.01.001.

Lakshmi N Yatham¹

Affiliations

Affiliation

¹ Mood Disorders Clinical Research Unit, University of British Columbia, Room 2C7-2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada. [email protected]

PMID: 15826735
DOI: 10.1016/j.psc.2005.01.001

Review

Lakshmi N Yatham. Psychiatr Clin North Am. 2005 Jun.

. 2005 Jun;28(2):325-47.

doi: 10.1016/j.psc.2005.01.001.

Author

Lakshmi N Yatham¹

Affiliation

¹ Mood Disorders Clinical Research Unit, University of British Columbia, Room 2C7-2255 Wesbrook Mall, Vancouver, BC V6T 2A1, Canada. [email protected]

PMID: 15826735
DOI: 10.1016/j.psc.2005.01.001

Abstract

Atypical antipsychotic agents have been widely investigated for their efficacy in acute mania. The data to date suggest that olanzapine,risperidone, quetiapine, aripiprazole, and ziprasidone are effective, with no significant differences in antimanic efficacy among these agents. These agents are effective as an alternative to lithium or divalproex as monotherapy or in combination with these mood stabilizers. The data concerning their utility in acute bipolar depression and maintenance treatment of bipolar disorder are limited. The studies to date suggest that olanzapine has modest acute antidepressant properties but probably has efficacy comparable to lithium and divalproex in preventing manic and depressive episodes. Quetiapine seems to have robust antidepressant properties, but these data need to be replicated in further trials before quetiapine can be recommended as a first-line agent for acute bipolar depression. Aripiprazole has shown promise in preventing manic episodes in one 6-month study, but further studies with at least 1-year duration and larger sample sizes are needed before this agent can be recommended as a monotherapy for prophylaxis of bipolar disorder. It is currently unknown if risperidone, aripiprazole, and ziprasidone have any efficacy in treating acute bipolar depression. Similarly, long-term studies are needed to ascertain the role of risperidone, quetiapine, and ziprasidone in the maintenance treatment of bipolar disorder. Overall, the atypical antipsychotic agents as a group represent an effective and relatively safe addition to the armamentarium for the treatment of bipolar disorder.

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Use of atypical antipsychotics in the treatment of depressive episodes in bipolar disorder | Streltsov

Introduction

Bipolar disorder is an endogenous affective disorder that manifests itself with episodes of mania (hypomania) and depression [1]. There are currently two types of bipolar disorder: bipolar I disorder and bipolar II disorder [2]. Bipolar I disorder is manifested by mania and mixed states [3]. Type II bipolar disorder is manifested by depressive and hypomanic episodes. Manic episodes do not occur in this type of disorder.

Depressive episodes are more pronounced in type II bipolar disorder than in type I [4]. Depressive episodes are the leading manifestation of the disease in patients with bipolar disorder [5]. In a systematic literature review of long-term treated patients with bipolar I disorder, researchers concluded that depression accounts for approximately 70% of affective episodes [6].

The prevalence of bipolar disorder ranges from 1% to 2.4% [7]. The percentage of suicides in patients with bipolar disorder is 4 - 19% [eight].

Problems in the treatment of depressive episodes in bipolar disorder

Adequate treatment of recurrent depressive episodes in bipolar disorder has long been a clinical problem, as antidepressants have failed to demonstrate sufficient efficacy in bipolar depression in short- and long-term studies [9].

Long-term treatment for bipolar type 2 disorder is primarily "prophylactic" in that it aims to prevent and/or reduce the frequency and severity of relapses of affective symptoms through a combination of pharmacological and complementary psychological interventions [10]. Compared with bipolar I disorder, there are limited studies demonstrating sufficient efficacy of one treatment option over others in bipolar II disorder [11].

Use of atypical antipsychotics in bipolar depression

Lurasidone

Lurasidone is an atypical antipsychotic drug with high affinity for dopamine D2 receptors, serotonin 5-HT7 and 5-HT2A receptors, moderate affinity for seroton-HT5 receptor the absence of a noticeable affinity for h2-histamine and M1-muscarinic receptors [12].

Ishigooka J., Kato T., Miyajima M. et al. conducted a 28-week study of the safety and efficacy of lurasidone. For this, patients were selected from a 6-week, double-blind, randomized study, in which patients were divided into three groups: taking the drug at dosages from 20 to 60 mg, taking 80-120 mg and taking placebo. Efficacy was assessed using the Montgomery Asberg Depression Rating Scale (MADRS). By the end of week 28, the overall mean MADRS score decreased as in the group previously treated with lurasidone for 6 weeks (by 8.9points) and in the group previously treated with placebo (by 11.3 points). Side effects included akathisia, headache, and drowsiness [13].

Raison C.L., Siu C., Pikalov A. et al. performed a double-blind, 6-week, placebo-controlled study to investigate the association between pre-treatment levels of highly sensitive C-reactive protein (CRP) and changes in depressive symptoms and cognitive functioning in 10 patients – 17 years old with bipolar disorder. Patients were divided into groups taking flexible doses of lurasidone (20-80 mg) and groups taking placebo. The study found that patients with high baseline CRP levels responded better to lurasidone treatment than those with low baseline CRP levels, but only in patients with normal or low body mass index (BMI) levels. Lurasidone was more effective than placebo regardless of baseline CRP [14].

Cariprazine

Cariprazine is a partial agonist of dopamine receptors D ₂ and D ₃, and serotonin receptor 5-HT _1A [15]. The unique affinity for the D ₃ receptor may mediate the anti-anhedonic, procognitive, and antidepressant effects of cariprazine [16][17].

Durgam S., Earley W., Lipschitz A. et al. conducted an 8-week, randomized, double-blind, placebo-controlled trial to investigate the efficacy and safety of cariprazine in patients with major depressive episodes in bipolar disorder. Patients were randomly assigned to either placebo or cariprazine at doses of 0.75, 1.5, and 3.0 mg/day. Efficacy was assessed using the MADRS and the severity subscale of the Global Clinical Impression Scale (GCI-S). Cariprazine at 1.5 mg/day showed a significant reduction in MADRS scores from baseline by week 6 compared with placebo (least squares mean difference was -4.0). When taking cariprazine at a dosage of 3 mg/day, the difference in the mean least squares was -2. 5. The 0.75 mg daily dose was similar to the placebo dose.

The most commonly reported adverse events in patients treated with cariprazine were akathisia and insomnia. Weight gain was slightly higher in patients treated with cariprazine than with placebo [18].

Another double-blind, placebo-controlled study of the safety and efficacy of cariprazine by Earley W., Burgess M.V., Rekeda L. et al. reported similar results. Patients aged 18 to 65 years who met the DSM-5 criteria for bipolar I disorder with a current depressive episode were selected for the study. Patients were divided into three groups: taking 3 mg cariprazine per day, taking 1.5 mg cariprazine per day and taking placebo. Efficacy was assessed using MADRS and GCI-S. After 6 weeks, data were obtained that both doses of cariprazine were significantly more effective than placebo. Both doses of cariprazine were associated with lower CGI-S scores compared with placebo, but the differences did not reach statistical significance. Side effects in the groups taking cariprazine were recorded twice as often as in the placebo group. The most common side effects were nausea, akathisia and dizziness [19].

Olanzapin

Olanzapin-a drug that has an affinity to serotonin 5-nt _2a, 5-nt _2C, 5-nt ₃, 5-nt ₆, D ₁, D _{3333 2} , D ₃ , D ₄ and D ₅ , muscarinic, adrenergic α ₁ and histamine H ₁ receptors [20].

Katagiri H., Tohen M., McDonnell D.P. et al. conducted a 6-week, double-blind, randomized trial of the efficacy and safety of olanzapine in bipolar depression. Compared with placebo, patients in the olanzapine group showed a decrease in MADRS scores. But in this group, side effects were more common, such as weight gain, increased levels of cholesterol, triglycerides, low-density lipoproteins, and a decrease in high-density lipoproteins [21].

Pan P. Y., Lee M.S., Lo M.C. found that olanzapine
was more effective than lamotrigine in preventing
depressive episodes in patients with bipolar disorder [22].

Quetiapine

Quetiapine is an atypical antipsychotic that blocks dopamine D2 and serotonin 5-HT2 receptors [23].

Kishi T., Ikuta T., Matsuda Y. et al. studied the efficacy and safety of extended-release quetiapine 300 mg/day and olanzapine 5-20 mg/day in patients with bipolar depression using a Bayesian analysis. As a result, it was found that there is no significant difference in effectiveness between the drugs. In patients treated with quetiapine, drowsiness was a common side effect, and in the olanzapine group, frequent side effects were: weight gain, increased blood prolactin levels, and decreased high-density lipoprotein levels [24].

Simon J., Geddes J.R., Gardiner A. conducted a multicentre, double-blind, placebo-controlled study comparing quetiapine alone versus quetiapine plus lamotrigine. It was found that the combination of quetiapine with lamotrigine was more effective than quetiapine alone [25].

Risperidone

Lindström L., Lindström E., Nilsson M. et al. conducted a meta-analysis of 15 RCTs to investigate the efficacy of atypical antipsychotics from 6 months to 4 years in bipolar disorder in 6142 patients. As monotherapy, olanzapine, quetiapine, and risperidone were found to be superior to placebo in reducing the overall risk of relapse [26].

A retrospective study of the effectiveness of taking risperidone to reduce the risk of affective episodes in patients with bipolar disorder showed that additional administration of the drug reduced the risk of developing manic episodes, but did not reduce the risk of developing depressive episodes [27].

In the course of comparing the safety of quetiapine and risperidone in patients with bipolar disorder, it was found that side effects such as weight gain, increased prolactin levels were detected when taking risperidone [28].

Aripiprazole and ziprasidone

Bahji A., Ermacora D., Stephenson C. et al. conducted a systematic review and meta-analysis of RCTs on the efficacy and safety of pharmacological therapy for bipolar depression. During which 50 studies with 11448 patients were analyzed. aripiprazole and ziprasidone were ineffective compared with placebo in the treatment of bipolar depression. Aripiprazole had more side effects than placebo.

Olanzapine, quetiapine and cariprazine were more effective than placebo in the treatment of bipolar depression [29].

In another systematic review and meta-analysis conducted to investigate the efficacy and safety of aripiprazole in bipolar disorder, it was found that the drug was effective in the treatment of mania, psychosis, but did not show efficacy in the treatment of bipolar depression [30].

Conclusion

Lurasidone, cariprazine, olanzapine, and quetiapine were significantly more effective than placebo.

Risperidone, aripiprazole and ziprasidone have been shown to be ineffective in the treatment of bipolar depression.

Olanzapine causes more serious side effects (weight gain, increased cholesterol, triglycerides, low-density lipoprotein and decreased high-density lipoprotein) than lurasidone, cariprazine, and quetiapine.

Combination of quetiapine with lamotrigine is more effective than antipsychotic alone.

In normal weight children and adolescents with higher pre-treatment CRP levels, lurasidone was associated with a better response to antidepressant therapy than placebo. CRP and BMI may be useful diagnostic and prognostic biomarkers in the treatment of children and adolescents with bipolar depression with lurasidone.

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Is the prescription of antidepressants for bipolar depression justified in terms of evidence-based medicine? | Potanin

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An Overview of Atypical Antipsychotics for Bipolar Depression

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