Clinical Challenges in Bipolar Disorder

Sep 16, 2017

Here: a Q&A about diagnostic challenges in the real world; pharmacologic and non-medication options; and management of common adverse events in patients with DSM-5 bipolar and related disorders.


Dr Ketter is Professor Emeritus of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA.

Editor’s Note: We are pleased to present this Q&A with Dr Ketter, based on his presentation at the 2017 Psychiatric Congress, “Solving Clinical Challenges in Bipolar Disorder.” Dr Ketter’s presentation takes place on Sunday, September 17 at 9:15 am.

The presentation “Bipolar Disorder-Solving Clinical Challenges,” strives to address complex conundrums commonly faced by psychiatrists when managing their patients with bipolar disorder. Highlights are summarized here.

Q: What are some of the issues that psychiatrists who treat patients with bipolar disorder face?

A: Crucial diagnostic challenges include distinguishing bipolar disorder from unipolar major depressive disorder. Crucial therapeutic challenges include prioritizing efficacy (therapeutic effects) versus tolerability (adverse effects) and managing adverse effects (especially weight gain/sedation versus akathisia). Although adjunctive (added to pharmacotherapy) psychotherapies have proven useful, there remains limited access to evidence-based treatments.1

Q: What do you mean by diagnostic nosology?

A: Diagnostic nosology is our system of diagnosing psychiatric disorders, which currently in the US is based upon DSM-5, which was published in 2013. Even with the advances in DSM-5 nosology, accurate diagnosis of bipolar disorder remains challenging because of its: (1) complex, variable symptoms (with different bipolar subtypes, mood states, courses, and age-dependent presentations); and (2) confounding comorbidities (eg, substance abuse, anxiety, disruptive behavioral [ADHD, oppositional defiant, and conduct], and Cluster B disorders).

DSM-5 has some clear limitations, including failing to integrate well-established bipolar outcome risk factors for depressive presentations such as: depression onset prior to age 25 years; depression with lifetime history of psychosis; and depression with at least one first-degree relative with mania.2

Q: Are the criteria new for assessing and diagnosing bipolar disorders?

A: Yes. DSM-5 has added the mixed features specifier for manic, hypomanic, and depressive episodes. DSM-5 has also permitted full hypo/manic episodes emerging during antidepressant treatment and persisting beyond the expected duration of physiological antidepressant treatment effect to be sufficient for hypo/manic episodes (ie, considered bipolar disorder rather than mere antidepressant-induced hypo/manic episodes).

Q: Are there any new screening tools for bipolar disorders?

A: Screening tools have yet to integrate DSM-5 advances, and are thus still based on DSM-IV (ie, the Mood Disorder Questionnaire for Hypo/Manic episodes (4), and the Patient Health Questionnaire for Depressive episodes3,4).

Nevertheless, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study Clinical Monitoring Form (CMF) to establish clinical status at each visit proved very useful.5 CMF assessments entailed diagnosing 4 DSM-IV syndromal episodes (depressed, hypomanic, manic, mixed), 2 subsyndromal states (continued symptoms, roughening), and 2 euthymic states (recovered, and recovering). Clinical statuses indicated if new mood interventions were: (1) practically mandated (for syndromal episodes); (2) elective (for subsyndromal states); or (3) commonly avoided, unless there are adverse effects (for euthymic states).

Q: What are the latest treatment guidelines for bipolar disorders?

A: Treatment guidelines have integrated efficacy/tolerability in assessing treatment options. The British Association for Psychopharmacology published bipolar disorder treatment guidelines in 2016 (which were not based on DSM-5).6 Unfortunately the last complete American Psychiatric Association Bipolar Disorder Guideline was a decade and a half ago (in 2002), with only a partial update in 2005-2007.7,8

The most recent North American guideline was published by the Canadian Network for Mood and Anxiety Treatments (CANMAT) and the International Society for Bipolar Disorders (ISBD) as a collaborative update of the CANMAT guidelines for the management of patients with bipolar disorder in 2013.9

Q: What is the gold standard of treatment? Would most patients benefit from both psychopharmacology and behavioral interventions?

A: Treatment of bipolar disorder is complex, and commonly administered according to current bipolar illness phase (ie, acute bipolar depression, acute mania, or bipolar maintenance) and clinical urgency (ie, presence/absence of marked clinical/functional risks), as well as prior efficacy/tolerability. Urgent acute presentations commonly necessitate administering combination therapies and prioritizing efficacy more than tolerability. In contrast, non-urgent sub-acute to acute presentations and bipolar maintenance presentations commonly result in administering monotherapies and prioritizing tolerability more than efficacy.

Although acute bipolar depression is more common than acute mania, its treatment is more variable. In less urgent depressive presentations, antidepressants (that aside from fluoxetine combined with olanzapine, are not FDA-approved for acute bipolar depression) are commonly used in spite of their documented efficacy limitations, possibly because of their somatic tolerability strengths. However, antidepressants are commonly administered along with an antimanic agent to attenuate the risk of antidepressant treatment-emergent mania or mood cycling.

Even with the advances in DSM-5 nosology, accurate diagnosis of bipolar disorder remain a challenge.

In more urgent depressive presentations, antipsychotics, which are FDA-approved for acute bipolar depression are commonly used (lurasidone monotherapy or added to lithium or valproate, quetiapine monotherapy, and olanzapine combined with fluoxetine), because of their documented efficacy strengths, and in spite of their, at times, challenging somatic tolerability limitations. Acute bipolar depression commonly involves sufficient efficacy/tolerability challenges to merit consideration of novel (non-antidepressant/antipsychotic) non-FDA-approved interventions.

For acute mania the most common treatments in the US are lithium more than antimanic antipsychotics (especially in less urgent manic presentations), whereas in Europe, antimanic antipsychotics more than lithium (especially in more urgent manic presentations). In both the US and Europe, monotherapy with an antimanic mood stabilizer or antimanic antipsychotic is more common in less urgent manic presentations, whereas combination therapy (antimanic mood stabilizer plus antimanic antipsychotic) monotherapy is more common in more urgent manic presentations.

Lithium is the gold standard for bipolar maintenance treatment in both the US and Europe. However, several antipsychotics have been FDA-approved for bipolar maintenance treatment as both monotherapy and added to lithium or valproate.

Adjunctive (added to pharmacotherapy) psychotherapies (cognitive behavioral, family-focused, interpersonal and social rhythm, and psychoeducation) have demonstrated efficacy in bipolar maintenance more than acute bipolar depression treatment. Psychologically minded patients commonly find such interventions helpful.


1. Ketter TA. Handbook of Diagnosis and Treatment of Bipolar Disorder. Washington, DC: American Psychiatric Publishing, Inc.; 2010.

2. Ketter TA. Advances in the Treatment of Bipolar Disorder. Washington, DC: American Psychiatric Publishing, Inc.; 2015.

3. Hirschfeld RM, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry. 2000;157:1873-5.

4. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med. 2001;16:606-613.

5. Sachs GS, Guille C, McMurrich SL. A clinical monitoring form for mood disorders. Bipolar Disord. 2002;4:323-327.

6. Goodwin GM, Haddad PM, Ferrier IN, et al. Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2016;30:495-553.

7. American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4 Suppl):1-50.

8. Hirschfeld RMA. Guideline watch (November 2005): practice guideline for the treatment of patients with bipolar disorder, 2nd ed. Focus. 2007;5:34-39.

9. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord. 2013;15:1-44.