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Choosing the Right Atypical Antipsychotic in Bipolar I and II Patients

Thomas L. Schwartz, MD

Professor and Chair of Psychiatry and Behavioral Sciences
SUNY Upstate Medical University
Syracuse, New York

Thomas L. Schwartz, MD, has no relevant conflicts of interest to report.

View ClinicalThoughts from this Author

Released: October 15, 2021

A Patient Walks Through Your Door With Bipolar Disorder. What Should You Do?
From an office-based practice point of view, the first dilemma is that most patients come in reporting depressive symptoms. Major depressive disorder (MDD) presents identically to bipolar disorder (BP) in patients who are in the midst of a major depressive episode (MDE). The first step is to make an accurate diagnosis using the DSM-5. It is pivotal to determine if there were any prior (hypo)manic episodes of a sustained enough nature to meet the DSM-5 criteria for bipolar I or II disorder. Using the Rapid Mood Screener or similar diagnostic aid may be warranted. It also makes sense, while a patient is in a MDE, to determine if any mixed features are present. This would mean 3 or more of the following criteria are met: elevated mood, grandiosity, talkativeness, flight of ideas, hyperactivity (goal directed or risky), or hyposomnia. Clinically, some feel that agitation, distractibility, and irritability should also weigh into the spectrum of mixed features, but this is not sanctioned by the DSM-5. Once a solid bipolar I or II disorder diagnosis is established by confirming a previous history of (hypo)mania, and that the patient is in a current MDE with or without mixed features, it sets the healthcare professional on course to make some pivotal treatment decisions regarding psychopharmacologic approaches. The following thoughts focus on treating the predominant depressive states with which patients with BP present.

Generally, What Medication Options Exist for Patients With BP?
Clearly, the healthcare professional wants to prevent mania and future cycling. In the United States, lithium, divalproex, olanzapine, risperidone, ziprasidone, aripiprazole, carbamazepine, asenapine, and cariprazine are indicated to alleviate acute mania. The second-generation antipsychotics (SGAs) usually require moderate to higher dosing strategies to stop mania. Lithium and the anticonvulsants require dosing to a therapeutic blood level. 

There is a different set of approved medications for BP depressive states, which includes olanzapine/fluoxetine combination, quetiapine, lurasidone, cariprazine, and interventional vagus nerve stimulation (VNS) therapy. Electroconvulsive therapy (ECT) can be used for mania or depression. Significant off-label data exist for other agents such as lumateperone (significant data in both bipolar I and II depression), lamotrigine (significant maintenance data), lithium (significant depression data), modafinil (significant depression data), and others. Finally, sometimes if mania is well controlled and stabilized with a primary mood stabilizing psychotropic, then unipolar antidepressants (typically selective serotonin reuptake inhibitors or norepinephrine–dopamine reuptake inhibitors) can be added off-label; however, this is controversial when looking at their effectiveness and their risks for inducing mania, mixed features, or rapid cycling and should not be used in patients with BP who exhibit any level of mixed features while depressed.

The SGAs seem to be well positioned in that they may be able to treat acute mania and help prevent future manic episodes by antagonizing dopamine-2 receptors. Some of the SGAs possess greater antidepressant properties (serotonin-2a, 2c, or 7 receptor antagonism, serotonin-1a receptor partial agonism, norepinephrine transporter and/or serotonin transporter antagonism) than others that vary widely across the different SGA agents. In short, certain SGAs seem able to treat both poles of BP.

The Art of Being a Psychopharmacologist When Managing BP
Typically, it makes sense to choose an approved agent that has generally been well researched and passed usual regulatory requirements showing both efficacy and safety in BP. There is a growing trend that psychopharmacologists should try aggressive monotherapies rather than layer on multiple drugs in polypharmacy attempts. This approach lowers adverse effect burden, lowers cost, and likely increases compliance. Given that certain SGAs possess properties that can treat BP in total, they seem to be excellent frontline treatments. The greatest risks might be the development of metabolic or movement disorder. Informed consent and consistent monitoring are imperative. Low doses of SGAs may offer less stability as usually the D2 receptor affinity is lower than that of the serotonin receptor–binding affinities. In short, lower doses are fairly good at treating depression but not preventing mania. In patients with BP, dosing should be escalated to moderate or high doses in accordance with the prescribing information to provide the best overall mood stability.

Patients who present with preexisting conditions such as diabetes, hypertension, obesity, and/or hyperlipidemia likely should be offered an SGA with less risk of exacerbating these conditions. Patients without these diseases currently, but who have an extensive family history of these diseases, might also want to avoid taking an SGA with greater weight gain and metabolic risks. The newer SGAs, such as lurasidone, cariprazine, and off-label lumateperone, seem to be more metabolically friendly and are the SGAs with antidepressant BP approvals. Olanzapine/fluoxetine combination or quetiapine are indicated to treat both poles of BP but carry much greater metabolic risks. Cariprazine carries the approval for treating both sides of BP, where lurasidone is indicated only for MDEs. Other SGAs that not only appear to have varying antidepressant properties but also may be safer regarding metabolic syndrome include lumateperone, ziprasidone, and aripiprazole; however, these have varying FDA indications that do not include bipolar depression at this time.

Patients with a history of movement disorder likely should receive an SGA with lower risks of creating more movement disorder, such as quetiapine. Patients who are already fatigued from depression should receive a less-sedating SGA, whereas those with insomnia would perhaps benefit from one that carries sedating properties. The point to consider is that following FDA approvals makes sense, but with some patients, the healthcare professional must weigh the risk–benefit ratio of possibly moving to an off-label approach with a bit less evidence but with greater safety and less adverse effect burden in mind. The approach of considering FDA approval status or the evidence base available and modifying SGA choice as either an adverse event or treatment resistance mounts should allow the healthcare professional to maximize the effectiveness and tolerability down to the individual patient level.


Fountoulakis KN, Grunze H, Vieta E, et al. The International College of Neuro-Psychopharmacology (CINP) Treatment Guidelines for Bipolar Disorder in Adults (CINP-BD-2017), Part 3: The Clinical Guidelines. Int J Neuropsychopharmacol. 2017;20:180-195.

Gijsman HJ, Geddes JR, Rendell JM, et al. Antidepressants for bipolar depression: a systematic review of randomized, controlled trials. Am J Psychiatry. 2004;161:1537-1547.

McIntyre RS, Patel MD, Masand PS, et al. The Rapid Mood Screener (RMS): a novel and pragmatic screener for bipolar I disorder. Curr Med Res Opin. 2021;37:135-144.

McIntyre RS, Berk M, Brietzke E, et al. Bipolar disorders. Lancet. 2020;396:1841-1856.

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;20:97-170.

Your Thoughts?
Tell us about your thought process when you see a patient with suspected bipolar I or II disorder. What techniques have you used to differentiate between bipolar I or bipolar II? Which BP clinical cases have been most challenging to recognize and diagnose? Please share your experiences and thoughts in the comments box.

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