Although the mood-stabilizing drugs lithium and valproate are considered gold standards when it comes to managing bipolar disorder, relying on just one of those may not be ideal.
That's why adjunctive therapies — sometimes called "add-ons" — are often needed to reduce the incidence of breakthrough symptoms like agitation, fatigue, social withdrawal, impulsivity, and others, explains says Jonathan Terry, DO, a psychiatrist and the assistant dean at California Health Sciences University College of Osteopathic Medicine in Clovis, California.
"While lithium and valproate remain the cornerstone of treatment, clinical experience aligns with the data: A significant majority of patients require a multimodal approach to achieve true functional recovery," he says.
When symptoms occur more often, and with greater intensity, it's often an indication that monotherapy is not working as well as it should, says Khendra Peay, MD, a psychiatrist and the founder of Capital Area Child and Adolescent Psychiatry in Washington, DC. Breakthrough signs are similar to those seen with a relapse, which can include:
Sleep disturbances, such as insomnia, trouble staying asleep, and difficulty adhering to a sleep schedule
Significant changes in mood, including irritability, elevated mood, and sadness
Pacing or fidgeting
Changes in appetite, including both increased and decreased appetite
Racing thoughts or obsessive interest in new projects
Loss of interest in usual activities or social connections
Often, an add-on medication can reduce the frequency and duration of breakthrough episodes, and the choice of adjunctive therapy depends on what type of symptoms you're experiencing most, says Dr. Terry. Here are seven medications to consider.
1. Lamotrigine (Lamictal) for Depression-Heavy Cycles
Lamotrigine (Lamictal) is actually an anticonvulsant medication, but over time has been found to be potentially helpful for stabilizing mood and reducing depression by calming overactive nerves in the body.
"This would not be a first-line medication like lithium or valproate, but can be very helpful for many with bipolar," explains Douglas Misquitta, MD, a psychiatrist and an assistant clinical professor of psychiatry and behavioral health at the Ohio State University Wexner Medical Center in Columbus, Ohio. "The key is slow increase in the dose, no faster than every two weeks, to reduce the risk of a potentially serious side effect called Stevens-Johnson syndrome, which can affect various organs of the body,” Dr. Misquitta says. “However, this is a rare development."
2. Cariprazine (Vraylar) for Balanced Control
Cariprazine is a partial dopamine agonist that acts like a thermostat, dialing levels of the neurotransmitter dopamine up or down depending on the brain's needs.
It came to market in 2023 and is one of the few medications that are approved by the U.S. Food and Drug Administration (FDA) for both manic/mixed episodes and bipolar depression. It may be best for people living with bipolar who need a "top-down" approach for mania and also struggle with depressive dips.
3. Lumateperone (Caplyta) for Bipolar Depression
Lumateperone targets the brain chemicals serotonin, dopamine, and glutamate simultaneously. It may help by targeting the "lows" of bipolar 1 or 2 with a focus on tolerability.
It’s also known for a lower risk of weight gain and movement disorders (extrapyramidal symptoms) compared with older antipsychotics.
4. Aripiprazole (Abilify) for Energy Regulation
Aripiprazole (Abilify) is in the atypical or second-generation antipsychotic class of medications. It’s initially used to treat symptoms including hallucinations in psychotic disorders such as schizophrenia, says Misquitta. But, over time, it can also be helpful as an add-on to treat depression, and to stabilize mood in bipolar disorder. That can lead to better energy regulation rather than experiencing highs and lows.
Side effects can include weight gain, negative effects on cholesterol and blood sugar (increasing diabetes risk over time), and can in some people cause a very uncomfortable restlessness called akathisia, Misquitta adds.
5. Quetiapine (Seroquel) for Comprehensive Coverage
Quetiapine (Seroquel) is another atypical antipsychotic. At lower doses, it’s highly sedating and aids with the insomnia often seen in bipolar disorder, says Terry. At higher doses, it provides powerful anti-manic and anti-depressive effects.
"The primary benefit is its efficacy across the entire mood spectrum," he says. "However, considerations must include the risk of metabolic syndrome, requiring regular monitoring of weight, blood glucose, and lipid profiles."
6. Lurasidone (Latuda) for Stubborn Bipolar Depression
Lurasidone (Latuda) is an atypical antipsychotic used in schizophrenia and bipolar depression. It affects how your brain uses both dopamine and serotonin to provide better mood regulation.
"It is a potent option for bipolar depression," says Hussain Abdullah, MD, a psychiatrist and an assistant professor of psychiatry at Hackensack Meridian School of Medicine in New Jersey. "A critical practical consideration is that it must be taken with a meal of at least 350 calories to ensure proper absorption; without this, the clinical efficacy is significantly diminished."
7. Emerging NMDA Modulators (Ketamine) for Rapid Response
Ketamine is not FDA-approved to treat bipolar disorder. But researchers are looking into whether it is safe and effective for this purpose, and some doctors prescribe it off-label. NMDA modulators target the neurotransmitter glutamate rather than serotonin or dopamine.
"Ketamine and other NMDA modulators represent a significant shift toward rapid-acting antidepressant effects by targeting the glutamate system," Dr. Abdullah says. "This intervention may be appropriate for treatment-resistant bipolar depression where traditional agents have failed, or in acute situations where suicidal ideation requires immediate mitigation."
These modulators can serve as a "bridge" to provide quick, temporary relief while long-term stabilizers are adjusted and optimized, he adds.
Dr. Peay emphasizes, "The use of agents like ketamine for psychiatric and other medical indications is still investigational. The safety and efficacy have not been fully reviewed by the FDA for bipolar specifically."
When someone reports that they are stable but not well, or when the side effects of increasing a primary medication become intolerable, it's a clear sign that an add-on is required to bridge the gap, says Terry.
If you’re experiencing breakthrough symptoms, it’s time to have a conversation with your healthcare provider.
Questions to Ask Your Doctor
Given my specific breakthrough symptoms, which add-on might be the best choice for managing those issues?
What's the expected timeline for improvement? When can I know that it's working?
What are the most common side effects for this particular adjunctive therapy? Are there any serious enough that I would need to stop taking the medication?
How will this interact with my current mood stabilizer?
What will need to be monitored while I'm on this? For example, weight gain, blood sugar changes, or other possible effects?
The Takeaway
A mood stabilizer is an important part of bipolar disorder management, but many people require more than one medication to achieve symptom control.
Adjunctive treatments can address specific breakthrough symptoms that are starting to occur with more frequency and intensity.
A discussion with your doctor about the right adjunctive therapy should include the timeframe for improvement and possible side effects.
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Resources
Fountoulakis K et al. Challenges in the Development of Treatment Guidelines for Bipolar Disorder. Frontiers in Psychiatry. June 9, 2025.
Cariprazine in the Treatment of Bipolar Disorder: Within and Beyond Clinical Trials. Frontiers in Psychiatry. December 14, 2021.
McIntyre RS et al. The Efficacy of Lumateperone in Patients With Bipolar Depression With Mixed Features. The Journal of Clinical Psychiatry. April 24, 2023.
Aripiprazole (oral route). Mayo Clinic. January 1, 2026.
Angela D. Harper, MD, is in private practice at Columbia Psychiatric Associates in South Carolina, where she provides evaluations, medication management, and psychotherapy for adults.
A distinguished fellow of the American Psychiatric Association, Dr. Harper has worked as a psychiatrist throughout her career, serving a large number of patients in various settings, including a psychiatric hospital on the inpatient psychiatric and addiction units, a community mental health center, and a 350-bed nursing home and rehab facility. She has provided legal case consultation for a number of attorneys.
Harper graduated magna cum laude from Furman University with a bachelor's degree and cum laude from the University of South Carolina School of Medicine, where she also completed her residency in adult psychiatry. During residency, she won numerous awards, including the Laughlin Fellowship from the American College of Psychiatrists, the Ginsberg Fellowship from the American Association of Directors of Psychiatric Residency Training, and resident of the year and resident medical student teacher of the year. She was also the member-in-training trustee to the American Psychiatric Association board of trustees during her last two years of residency training.
Harper volunteered for a five-year term on her medical school's admission committee, has given numerous presentations, and has taught medical students and residents. She currently supervises a nurse practitioner. She is passionate about volunteering for the state medical board's medical disciplinary commission, on which she has served since 2015.
She and her husband are avid travelers and have been to over 55 countries and territories.
Elizabeth Millard is a Minnesota-based freelance health writer. Her work has appeared in national outlets and medical institutions including Time, Women‘s Health, Self, Runner‘s World, Prevention, and more. She is an ACE Certified Personal Trainer and a Yoga Alliance Registered Yoga Teacher, and is trained in obesity management.
