This work may not be copied, distributed, displayed, published, reproduced, transmitted, modified, posted, sold, licensed, or used for commercial purposes. By downloading this file, you are agreeing to the publisher’s Terms & Conditions.

Educational Activity

Evidence-Based Treatment Targets, Selection, and Strategies for Acute Manic and Mixed Episodes of Bipolar I Disorder

Trisha Suppes, MD, PhD

Published: December 31, 2019


Too many patients receive incorrect treatment for bipolar disorder; prescribing seems to differ more by clinician than by patient characteristics. New treatment guidelines are available for the management of acute manic episodes and can help clinicians make treatment decisions tailored to their patients’ individual symptom clusters and illness characteristics, leading to greater chances of lasting remission. However, many clinicians lack familiarity with these symptom targeting best practices. Therefore, clinicians need education on how to manage bipolar I disorder symptoms with evidence-based treatment options. In addition, as new treatment targets are identified, clinicians need education on psychopharmacologic and pharmacokinetic advances.

From the Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, and the US Department of Veterans Affairs Palo Alto Health Care System, California.
From the Series: Strategies for Acute and Maintenance Treatment of Bipolar I Disorder
To cite: Suppes T. Evidence-based treatment targets, selection, and strategies for acute manic and mixed episodes of bipolar I disorder. J Clin Psychiatry. 020;81(1):OT18053BR1C.
To share:
© Copyright 2019 Physicians Postgraduate Press, Inc.

Support Statement

Supported by an educational grant from Otsuka America Pharmaceutical, Inc., and Lundbeck.

Learning Objective

After completing this educational activity, you should be able to:

  • Select evidence-based treatment for acute manic or mixed episodes of bipolar I disorder by considering patient characteristics and treatment mechanism of action

Release, Review, and Expiration Dates

This brief report activity was published in December 2019 and is eligible for AMA PRA Category 1 Credit™ through December 31, 2021. The latest review of this material was November 2019.

Statement of Need and Purpose

Too many patients receive incorrect treatment for bipolar disorder; prescribing seems to differ more by clinician than by patient characteristics. Third-generation antipsychotics target the symptoms of bipolar disorder in a novel way and may help patients avoid side effects associated with other antipsychotics. However, many clinicians lack familiarity with these medications’ pharmacologic attributes. Therefore, clinicians need education on how to manage bipolar I disorder symptoms with evidence-based treatment options. In addition, as new treatment targets are identified, clinicians need education on psychopharmacologic and pharmacokinetic advances.

The treatment of bipolar disorder requires that both manic and depressive symptoms be controlled, and the therapeutic effect must be maintained after an acute mood episode has resolved. Although numerous treatments are available, many patients are unable to maintain recovery. Consequently, clinicians need updated information on best practices for addressing not only acute treatment of bipolar disorder but also maintenance treatment, including weighing the evidence about the utility of oral versus long-acting injectable agents, measurement-based care, and strategies for promoting adherence and functional improvement.

This activity was designed to meet the needs of participants in CME activities provided by the CME Institute of Physicians Postgraduate Press, Inc., who have requested information on bipolar I disorder.

Disclosure of Off-Label Usage

Dr Suppes has determined that, to the best of her knowledge, chlorpromazine, clonazepam, clozapine, haloperidol, lorazepam, loxapine, midazolam, oxcarbazepine, promethazine, rTMS, and tamoxifen are not approved by the US Food and Drug Administration for the treatment of bipolar disorder mania.

Review Process

The faculty member(s) agreed to provide a balanced and evidence-based presentation and discussed the topic(s) and CME objective(s) during the planning sessions. The faculty’s submitted content was validated by CME Institute staff, and the activity was evaluated for accuracy, use of evidence, and fair balance by a peer reviewer who is without conflict of interest.


This activity is derived from the planning teleconference series “Strategies for Acute and Maintenance Treatment of Bipolar I Disorder,” which was held in July and August 2019 and supported by an educational grant from Otsuka America Pharmaceutical, Inc., and Lundbeck. The opinions expressed herein are those of the faculty and do not necessarily reflect the opinions of the CME provider and publisher or the commercial supporter.

Faculty Affiliation

Trisha Suppes, MD, PhD
Stanford University School of Medicine and the US Department of Veterans Affairs Palo Alto Health Care System, California

Financial Disclosure

The faculty for this CME activity and the CME Institute staff were asked to complete a statement regarding all relevant personal and financial relationships between themselves or their spouse/partner and any commercial interest. The Accreditation Council for Continuing Medical Education (ACCME) defines a commercial interest as any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. The ACCME defines relevant financial relationships as financial relationships in any amount occurring within the past 12 months that create a conflict of interest. The CME Institute has resolved any conflicts of interest that were identified. No member of the CME Institute staff reported any relevant personal financial relationships. Faculty financial disclosure is as follows:

Dr Suppes is a consultant for Allergan, Impel NeuroPharma, and Sunovion; has received grant/research support from Merck, National Institutes of Health, National Institute on Drug Abuse, Palo Alto Health Sciences, Stanley Medical Research Institute, the US Department of Veterans Affairs (VA) Cooperative Studies Program, and the VA Office of Research & Development PRIME Care Study; and has received other financial or material support from Jones and Bartlett, Wolters Kluwer Health (UpToDate), and Hogrefe Publishing.

Accreditation Statement

The CME Institute of Physicians Postgraduate Press, Inc., is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Credit Designation

The CME Institute of Physicians Postgraduate Press, Inc., designates this enduring material for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Note: The American Nurses Credentialing Center (ANCC) and the American Academy of Physician Assistants (AAPA) accept certificates of participation for educational activities certified for AMA PRA Category 1 Credit™ from organizations accredited by the ACCME.

To obtain credit for this activity, study the material and complete the CME Posttest and Evaluation.


Through the American Board of Medical Specialties (“ABMS”) ongoing commitment to increase access to practice relevant Continuing Certification Activities through the ABMS Continuing Certification DirectoryEvidence-Based Treatment Targets, Selection, and Strategies for Acute Manic and Mixed Episodes of Bipolar I Disorder has met the requirements as a MOC Part II CME Activity (apply toward general CME requirement) for the following ABMS Member Boards:


Psychiatry and Neurology

Available Credit

  • 0.50 AMA PRA Category 1 Credit™
  • 0.50 Participation

This CME activity is expired. For more CME activities, visit
Find more articles on this and other psychiatry and CNS topics:
The Journal of Clinical Psychiatry
The Primary Care Companion for CNS Disorders

Bipolar disorder is a highly disabling condition affecting approximately 4.4% of adults in the US.1 The past-year prevalence of bipolar I disorder in the US is 0.6%.2 Untreated bipolar disorder increases the risk of suicide, dysfunction in social and professional life, legal issues, and long-term functional impairment.3–6 More than 80% of adults with bipolar disorder report serious impairment within a year of experiencing a bipolar episode.1 Additionally, evidence suggests that recurrent manic episodes are associated with physical changes in the brain that are not seen in patients who achieve sustained remission.7

When clinicians intervene in a timely, appropriate manner, high rates of recovery and remission8,9 and preserved quality of life10,11 are possible for patients who have recently experienced an episode of mania. (See a PDF iconpatient case illustrating current treatment strategies.) Successful early intervention may interrupt the potential for neuroprogression of bipolar disorder negatively impacting the brain7 and help prevent recurrence.

  Patient Perspectives
One man described the disabling course of unresolved bipolar disorder that he experienced before finally receiving effective treatment:
“I consulted psychiatrists and counselors over the years as abrupt, disruptive mood shifts cost me two marriages and numerous jobs. It wasn’t until 2006, while living in a homeless shelter, that I was accurately diagnosed and prescribed effective medication. Now, at 66, I’m a peer specialist in Calgary.”12

CANMAT-ISBD Guidelines for Acute Mania

The 2018 Canadian Network for Mood and Anxiety Treatments (CANMAT) and the International Society for Bipolar Disorders (ISBD) guidelines13 are the most current and comprehensive evidence-based guidelines available for the treatment of bipolar disorder. The guidelines provide a measurement-based hierarchy of first-line through third-line pharmacologic interventions for acute mania in bipolar disorder (AV 1).13 New to the 2018 guidelines is the inclusion of cariprazine as a first-line monotherapy. Earley et al14 found that cariprazine demonstrated a significant reduction in manic symptoms compared with placebo and did not induce depression. Also new in the 2018 guidelines, olanzapine, ziprasidone, and haloperidol have been downgraded to second-line options due to safety and tolerability concerns.13

AV 1. Recommendations for Pharmacologic Management of Acute Mania in Bipolar Disordera (0:00)

aBased on Yatham et al.13

Assessment. Before initiating treatment, patients should be assessed for13:

  • Risk of aggression, violence, and threat of safety to others
  • Suicide risk, particularly when mixed features are present
  • Degree of insight
  • Ability to adhere to treatment
  • Comorbidity
  • Psychosocial support network availability
  • Physical status and laboratory parameters
  • Current and prior therapies

Assessment results can be used to determine if a patient should be treated in the ambulatory or inpatient setting.13 Clinicians must take care to exclude illicit or prescribed drugs as causative factors of mania, and any existing antidepressant therapy should be discontinued. A previous diagnosis of bipolar disorder is sufficient for immediate antimanic therapy, but the patient should be monitored and the diagnosis confirmed after antidepressant cessation when dealing with a first episode of mania. To meet DSM-5 critieria2 for a bipolar disorder manic episode potentially triggered by the use of antidepressants, after cessation of the antidepressant and a clearance duration of at least 5 half-lives, if the patient continues to then meet full syndromal time and severity criteria, the diagnosis would be bipolar disorder. A history of the patient’s responses to prior therapies, if any, should be obtained when possible as it can inform therapeutic strategies moving forward. Psychoeducation should be provided to the patient and the patient’s family to help address deficits in insight.

Treatment selection and progression. The CANMAT treatment algorithm generally recommends that patients start with one of the first-line treatments and progress through each of the appropriate first-line options (AV 2),13 and then each second-line and third-line option depending on response, with adherence assessed and medication optimized at each step. Polytherapy is often needed versus monotherapy, but combination therapy is associated with increased safety and tolerability issues compared with monotherapy.13

AV 2. Recommendations for Short-Term Pharmacologic Management of Agitationa (0:00)

aBased on Yatham et al.13

Clinicians must consider the episode’s full diagnostic profile and account for individual patient characteristics when selecting treatment, rather than simply starting at the top of the first-line recommendations and working down. For instance, divalproex is a first-line treatment both as monotherapy and in combination with several of the atypical antipsychotics. However, because of its potential for teratogenic activity, other options might be considered for women of child-bearing age. The following clinical features should guide first- and second-line treatment selections:

Agitation. Agitation during a manic episode is common, particularly when mixed features are present, and severity ranges from fidgeting and pacing to aggressive behavior that may be dangerous to the patient and others.15 Severe agitation should be addressed quickly to reduce the patient’s distress and allow clinicians to safely assess and evaluate the underlying episode. Clinicians should remember that akathisia can be mistaken for agitation and should be considered as treatment begins.

  Patient Perspectives
A woman living with bipolar disorder described her experiences with manic episodes and agitation:
“I get like 24 hours of euphoria and then a feeling like ants in my pants—like I’m crawling out of my skin. I get very agitated and I pick on people. I scratch my neck until it’s red. I feel so yecch.”12

Agitation in bipolar mania is assumed to be a manifestation of the manic episode; therefore, effective treatments for mania should also be effective in resolving agitation.13 Time to therapeutic onset is the recommended guideline for treatment selection. If the chosen antimanic intervention does not reduce agitation, a variety of pharmacotherapeutic options exist (AV 3),13,16 although availability of certain treatments varies by country. Oral preparations are preferable, but intramuscular injections can be administered when oral medications are ineffective. If a patient agrees to an oral medication but there is reason to believe that the patient might hide the medication in the cheek, an orally dispersing tablet can be used.

AV 3. Acute Mania Treatment Algorithma

aBased on Yatham et al (2019)13 and Yatham et al (2006).16

Anxiety. The presence of anxiety during a manic episode is associated with an increased manic severity,17 higher rate of medication-related adverse events, and longer time to remission18 compared to mania without anxious symptoms. Evidence suggests an anxiolytic benefit for divalproex, quetiapine, olanzapine, and carbamazepine, but this area has overall not been well studied.13 Acute manic agents on the whole often impact anxiety as the acute manic symptoms improve.13,19

Mixed features. Approximately one-fourth of manic episodes occur with depressive symptoms.20 Mixed features are associated with increased disability and higher rates of suicidality compared to manic episodes without depressive symptoms.20,21 Of the treatments recommended for bipolar mania with mixed features, the atypical antipsychotics and divalproex are effective monotherapies, although polytherapy with one of the first-line combination treatments may be best for many patients.13

  Patient Perspectives
One individual described her mixed features and the accompanying suicidality:
“If I can hang on, the mixed mood will pass, which will make the suicidal images less intense (they never go away completely). My psychiatrist increased my antipsychotic med drastically a few days ago. And my therapist is checking in on me daily. There’s a bed waiting for me at the hospital if I need it. … I really, really want to hurt myself. I don’t have a good plan, and my access to any means has been extremely limited.”22

Follow-up: “I checked myself in [to the hospital], as the mixed mood didn’t get better and I got closer and closer to hurting myself as the thoughts bore down on me. … Just needed a restful place to feel safe and wait for the suicidal thoughts to wane.”

Psychotic features. Psychotic features frequently co-occur with manic episodes. Coryell et al23 found that more than half of study participants experiencing a manic episode had psychotic features. While successful intervention for mania also reduces psychotic symptoms, current evidence does not indicate superiority among first-line treatment options (monotherapy or combination),13 unless the psychotic symptoms are mood incongruent (other than grandiose delusions). For mood-incongruent psychosis, the combination of lithium or divalproex plus an atypical antipsychotic is recommended. One might view mood-incongruent psychotic thinking as a form of mixed mania, which generally may require combination medications during acute-phase treatment. Additionally, when schizoaffective disorder with manic symptoms is a diagnostic possibility, either an atypical antipsychotic monotherapy or the combination of an atypical antipsychotic and a mood stabilizer is recommended.13

Rapid cycling. Approximately one-third of patients with bipolar disorder experience rapid cycling at some point during their lifetime course of illness.13 Rapid cycling is associated with greater clinical severity of manic episodes25 and depressive symptoms,26 a longer and more disabling course of illness,26,27 higher rates of alcohol and substance abuse,27 and increased suicidality28 compared to subjects without rapid cycling. Patients should be assessed for thyroid illness and other medical causes, antidepressant use, and substance use, which may contribute to rapid cycling.13 Gradual discontinuation of some substances may be desirable for withdrawal prevention, but clinicians should prioritize rapid mood stabilization when possible.

No first-line treatment for acute mania has demonstrated superior efficacy in treating rapid cycling.13 Thus, CANMAT guidelines13 recommend selecting treatment most likely to be effective for the patient in the maintenance phase.13 Polytherapy may be more helpful for rapid cycling than monotherapy, but no evidence supports greater efficacy of triple mood stabilizer therapy compared to double mood stabilizer therapy.


For acute manic episodes, clinicians generally should select the safest and most effective first-line treatment option that might also be continued into the maintenance phase. However, a manic episode’s specific characteristics might require fast-acting treatment with pharmacologic interventions that, while necessary and beneficial in the short term, have too many safety and tolerability issues to be used beyond the acute phase of treatment. For example, a patient might present with agitation and psychotic features severe enough to warrant a clinician prescribing a more sedating second-line agent like olanzapine as a temporary rescue medicine for immediate symptom reduction. Clinicians must consider the severity and features of the manic episode, along with individual patient characteristics, and use their judgement to select treatments that best balance side effect profiles with time to onset of efficacy.

Clinical Points

  • Follow up-to-date, evidence-based treatment guidelines for acute manic episodes.
  • Assess patients for illness features that guide treatment choices.
  • Prioritize immediate symptom reduction within safe limits to preserve brain health.
  • Select pharmacotherapeutic treatments that can be used in the acute and maintenance phases of treatment when possible.

© Copyright 2019 Physicians Postgraduate Press, Inc.


  1. Bipolar disorder. National Institute of Mental Health website. Published November 2017. Accessed November 5, 2019.
  2. American Psychiatric Association. Diagnostic and Statistical Manual for Mental Disorders. Fifth Edition. Washington, DC: American Psychiatric Association; 2013.
  3. Keck PE Jr, Kessler RC, Ross R. Clinical and economic effects of unrecognized or inadequately treated bipolar disorder. J Psychiatr Pract. 2008;14(suppl 2):31–38. PubMed CrossRef
  4. Goldberg JF, Ernst CL. Features associated with the delayed initiation of mood stabilizers at illness onset in bipolar disorder. J Clin Psychiatry. 2002;63(11):985–991. PubMed CrossRef
  5. Berk M, Malhi GS, Hallam K, et al. Early intervention in bipolar disorders: clinical, biochemical and neuroimaging imperatives. J Affect Disord. 2009;114(1–3):1–13. PubMed CrossRef
  6. McCabe PJ, Christopher PP, Pinals DA, et al. Predictors of criminal justice involvement in severe mania. J Affect Disord. 2013;149(1–3):367–374. PubMed CrossRef
  7. Kozicky J-M, McGirr A, Bond DJ, et al. Neuroprogression and episode recurrence in bipolar I disorder: a study of gray matter volume changes in first-episode mania and association with clinical outcome. Bipolar Disord. 2016;18(6):511–519. PubMed CrossRef
  8. Gignac A, McGirr A, Lam RW, et al. Course and outcome following a first episode of mania: four-year prospective data from the Systematic Treatment Optimization Program (STOP-EM). J Affect Disord. 2015;175:411–417. PubMed CrossRef
  9. Gignac A, McGirr A, Lam RW, et al. Recovery and recurrence following a first episode of mania: a systematic review and meta-analysis of prospectively characterized cohorts. J Clin Psychiatry. 2015;76(9):1241–1248. PubMed CrossRef
  10. Michalak EE, Torres IJ, Bond DJ, et al. The relationship between clinical outcomes and quality of life in first-episode mania: a longitudinal analysis. Bipolar Disord. 2013;15(2):188–198. PubMed CrossRef
  11. Oldis M, Murray G, Macneil CA, et al. Trajectory and predictors of quality of life in first episode psychotic mania. J Affect Disord. 2016;195:148–155. PubMed CrossRef
  12. Jackel D. Bipolar & Getting a Grip on Mania. Bphope website. Published 2017. Accessed October 2, 2019.
  13. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97–170. PubMed CrossRef
  14. Earley W, Durgam S, Lu K, et al. Clinically relevant response and remission outcomes in cariprazine-treated patients with bipolar I disorder. J Affect Disord. 2018;226:239–244. PubMed CrossRef
  15. Dundar Y, Greenhalgh J, Richardson M, et al. Pharmacological treatment of acute agitation associated with psychotic and bipolar disorder: a systematic review and meta-analysis. Hum Psychopharmacol. 2016;31(4):268–285. PubMed CrossRef
  16. Yatham LN, Kennedy SH, O’Donovan C, et al; Guidelines Group, CANMAT. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: update 2007. Bipolar Disord. 2006;8(6):721–739. PubMed CrossRef
  17. González-Pinto A, Galán J, Martín-Carrasco M, et al. Anxiety as a marker of severity in acute mania. Acta Psychiatr Scand. 2012;126(5):351–355. PubMed CrossRef
  18. Feske U, Frank E, Mallinger AG, et al. Anxiety as a correlate of response to the acute treatment of bipolar I disorder. Am J Psychiatry. 2000;157(6):956–962. PubMed CrossRef
  19. Rakofsky JJ, Dunlop BW. Treating nonspecific anxiety and anxiety disorders in patients with bipolar disorder: a review. J Clin Psychiatry. 2011;72(1):81–90. PubMed CrossRef
  20. Reinares M, Bonnín C del M, Hidalgo-Mazzei D, et al. Making sense of DSM-5 mania with depressive features. Aust N Z J Psychiatry. 2015;49(6):540–549. PubMed CrossRef
  21. Castle DJ. Bipolar mixed states: still mixed up? Curr Opin Psychiatry. 2014;27(1):38–42. PubMed CrossRef
  22. Deborah. Mixed Mood Blues. Suddenly Bipolar: Trying to Find Stability and a New Normal. Published September 22, 2019. Accessed October 17, 2019.
  23. Coryell W, Leon AC, Turvey C, et al. The significance of psychotic features in manic episodes: a report from the NIMH collaborative study. J Affect Disord. 2001;67(1–3):79–88. PubMed CrossRef
  24. Suppes T, Baldessarini RJ, Faedda GL, et al. Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry. 1991;48(12):1082–1088. PubMed CrossRef
  25. Nierenberg AA, Akiskal HS, Angst J, et al. Bipolar disorder with frequent mood episodes in the national comorbidity survey replication (NCS-R). Mol Psychiatry. 2010;15(11):1075–1087. PubMed CrossRef
  26. Lee S, Tsang A, Kessler RC, et al. Rapid-cycling bipolar disorder: cross-national community study. Br J Psychiatry. 2010;196(3):217–225. PubMed CrossRef
  27. Carvalho AF, Dimellis D, Gonda X, et al. Rapid cycling in bipolar disorder: a systematic review. J Clin Psychiatry. 2014;75(6):e578–e586. PubMed CrossRef
  28. Valentí M, Pacchiarotti I, Undurraga J, et al. Risk factors for rapid cycling in bipolar disorder. Bipolar Disord. 2015;17(5):549–559. PubMed CrossRef
  29. Frey BN, Zunta-Soares GB, Caetano SC, et al. Illness duration and total brain gray matter in bipolar disorder: evidence for neurodegeneration? Eur Neuropsychopharmacol. 2008;18(10):717–722. PubMed CrossRef
  30. Abé C, Ekman C-J, Sellgren C, et al. Manic episodes are related to changes in frontal cortex: a longitudinal neuroimaging study of bipolar disorder 1. Brain. 2015;138(pt 11):3440–3448. PubMed CrossRef

Volume: 81

Quick Links: