Adjunctive Medications for Bipolar Disorder
Mental Health ConditionsBipolar Disorder

Beyond Lithium: Medications That Can Help Bipolar Disorder When Mood Stabilizers Aren’t Enough

Beyond Lithium: Medications That Can Help Bipolar Disorder When Mood Stabilizers Aren’t Enough
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Published on January 23, 2026
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Lithium or forms of lithium extended-release (Lithobid), a mood-stabilizing medication used for bipolar disorder, can improve symptoms during manic and mixed episodes, and is one of the primary choices for mood maintenance with this condition.

But when you have residual bipolar symptoms while taking lithium, your provider may recommend adjunctive therapy, which means adding a second or third medication. This added medication may be one that’s approved by the U.S. Food and Drug Administration (FDA), or one that’s used off-label — meaning it’s not FDA-approved for that specific condition, but there is research backing up its use.

“I think of adding adjuncts anytime there are symptoms present that are not clear-cut,” says Aparna Kumar, a psychiatric mental health nurse practitioner and an associate professor at Emory University's Nell Hodgson Woodruff School of Nursing in Atlanta. “Unfortunately, in the case of bipolar disorder, this is the rule rather than the exception.”

When Are Adjunctive Medications Used?

Adjunctive medications are used for bipolar disorder when you have continued symptoms even while taking your primary medication.

 These residual symptoms can include anxiety, depression, and panic, says Kumar.

“When first-line agents for bipolar disorder lead to an improvement in symptoms but not to complete remission, or if someone cannot tolerate first-line agents, other classes of psychotropic medications can be utilized, typically as adjuvant to the mainstream treatment,” says Paula Zimbrean, MD, a psychiatrist and a professor of psychiatry at Yale School of Medicine in New Haven, Connecticut.

Lithium and valproic acid (Depakote) are the two main first-line agents for bipolar disorder.

 But during depressive, manic, or mixed episodes, you may need adjuvant treatment, says Dr. Zimbrean. Mood stabilizers work faster than antidepressants, so providers may be quicker to suggest a second medication for manic and mixed episodes, says Zimbrean.

But symptoms of depression are more persistent, says Zimbrean. “So patients with lots of depression may have a second medication recommended, but that may occur later in treatment.”

Depression in bipolar disorder is very difficult to treat, says Kumar. “Because traditional antidepressants can cause mania, they can worsen symptoms and even destabilize mood.” But your provider can help you discover the best combination of medications to treat your bipolar symptoms.

Atypical Antipsychotics

Atypical antipsychotics are a common group of medications used as adjuncts for bipolar disorder.

 “Some of these agents have not been approved by the FDA for treatment of bipolar disorder, but there is research showing that they have a benefit,” says Zimbrean.

Deciding which medication to add depends on the severity and type of symptoms, your history of response to medications, and your preference, says Zimbrean. “For instance, a patient who is improving on lithium, but continues to be anxious and have trouble sleeping, may benefit from adding a low dose of [a second generation atypical antipsychotic].”

Atypical antipsychotics treat bipolar symptoms by blocking signals from brain messengers like dopamine and serotonin. Depending on which messenger the drug targets most, some work better for manic and mixed episodes, while others treat depressive episodes best.

If you need adjunctive therapy, your provider may recommend adding one of these atypical antipsychotics.

  • Aripiprazole (Abilify) treats acute manic and mixed episodes.

  • Asenapine (Saphris) treats acute manic and mixed episodes. It’s placed under the tongue, which allows it to reach the bloodstream more effectively than if swallowed.
  • Cariprazine (Vraylar) treats acute manic, mixed, and depressive episodes.

  • Lurasidone (Latuda) treats bipolar depression.

  • Olanzapine (Zyprexa) treats acute manic and mixed episodes, and when added to lithium, can work faster than other adjuncts.
  • Quetiapine (Seroquel) treats acute manic, mixed, and depressive episodes.
  • Risperidone (Risperdal) treats acute manic and mixed episodes.

  • Ziprasidone (Geodon) treats bipolar mania and is also used as maintenance therapy.

Many atypical antipsychotics have similar side effects, which may include:

  • Drowsiness
  • Dizziness
  • Nausea, vomiting, or diarrhea
  • Weight gain
  • High cholesterol
  • Changes in heart rhythm
  • Insulin resistance and an increased risk of developing diabetes
  • Abnormal blood test results (for example, changes in blood counts or liver enzymes)
  • Involuntary movements, restlessness, tremors, or jerking motions
Some have more specific side effects. For example, asenapine can cause mouth numbness, and ziprasidone can cause a skin rash.

Atypical antipsychotics may be discouraged for some people with liver disease, glaucoma, or a weak immune system. These medications also increase the risk of stroke and death in older adults with dementia. If these medications are being used for depression, there is a risk of suicidal and hostile ideation in young adults and children.

Anticonvulsants

The FDA has approved anticonvulsant drugs to treat seizure activity, but many providers also prescribe them off-label as mood stabilizers.

Some common anticonvulsants used for bipolar disorder include the following options.

  • Carbamazepine (Tegretol) treats acute manic and mixed episodes by calming brain activity and protecting brain cells.

     Its most common side effects include dizziness, drowsiness, poor muscle coordination, urinary retention, increased pressure inside the eye, constipation, nausea, vomiting, and skin reactions. You shouldn’t take carbamazepine while pregnant, or if you have bone marrow depression (such as during cancer treatment). This drug can also increase the risk of delirium in older adults.

  • Lamotrigine (Lamictal) may improve bipolar symptoms by calming overactive brain signals.

     Lamotrigine can cause side effects like nausea, vomiting, chest pain, back pain, headache, irritability, and weight changes, and occasionally causes a serious rash. The severity of the rash varies, but there is a risk of Stevens Johnson syndrome, a rare but serious disorder of the skin and mucous membranes that requires hospitalization.

     It may also hold some risk for a developing fetus, so your provider may recommend a different option if you are pregnant.

  • Valproic acid (Depakote) is used as a first-line mood stabilizer for bipolar disorder, but it can also be added to lithium as an adjunctive therapy.

     This medication works by increasing GABA (a neurotransmitter in the brain) and protecting brain cells, among other actions. Valproic acid can cause a wide range of side effects, including headaches, abdominal pain, drowsiness, dizziness, tremors, diarrhea, nausea, vomiting, tremor, nervousness, emotional instability, depression, and appetite and weight changes. You shouldn’t take this medication if you are pregnant or if you have certain disorders, including liver disease.

Adjunctive Medications for Acute Mania and Mixed Episodes

Bipolar disorder causes mood episodes, which can be manic, depressive, or a mix of the two. Acute mania can last weeks, and providers typically offer short-term adjunctive therapy with the medications listed above for these episodes, although some atypical antipsychotics may provide long-term benefits.

Atypical antipsychotics are used for acute mood stabilization, and they work fast to manage psychosis, agitation, and sleep disruption associated with mania.

 But other medication types can improve specific symptoms that may come with acute mania and mixed episodes.

Benzodiazepines for Anxiety and Insomnia

Benzodiazepines like lorazepam (Ativan) and clonazepam (Klonopin, Rivotril) activate GABA in the brain, which relaxes your muscles and calms your nervous system.

 “In general, medications like benzodiazepines can be very effective for helping to maintain sleep and ultimately make sure that the person's mood stays stable by lowering anxiety and focusing on sleep,” says Kumar.
These medications can help you manage severe anxiety, agitation, and insomnia during an acute episode, but they can only be taken short-term because of side effects and a high risk of dependence.

Side effects of benzodiazepines include slow breathing, drowsiness, confusion, headaches, irregular heartbeats, nausea, vomiting, diarrhea, tremors, and misuse or dependence.

 While taking these medications, your provider will monitor your symptoms and decrease your dose when it’s time to stop taking them.

Antidepressants as Adjuncts for Depressive Episodes

About 50 to 60 percent of people with bipolar disorder take antidepressants in addition to their primary treatment, but experts disagree about how well they work for depressive episodes.

In fact, antidepressants may even increase the risk of mania, rapid cycling (switching) between manic and depressive stages, and worsened symptoms overall.

 When used, antidepressants should be given with a mood stabilizer to lessen your switch risk.

Research suggests that selective serotonin reuptake inhibitors (SSRIs) are safer than other types of antidepressants like tricyclic antidepressants (TCAs). But more research is needed to understand how these medications and others, like serotonin-norepinephrine reuptake inhibitors (SNRIs), affect bipolar disorder.

The Takeaway

  • During an acute bipolar manic, depressive, or mixed episode, you may need an additional (adjunctive) medication added to your primary mood stabilizer.
  • For manic and mixed episodes, your provider may recommend an atypical antipsychotic, anticonvulsant, or other medications to help you sleep and manage symptoms.
  • If you notice a change in your bipolar symptoms, your provider can help you determine which treatment adjuncts may work best.

Resources We Trust

EDITORIAL SOURCES
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Lee S. Cohen, MD

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Castle Connolly Top Doctor, From NewYork-Presbyterian

Lee S. Cohen, MD, is an associate professor of clinical psychiatry at Columbia University Irving Medical Center, maintains a clinical practice focused on expert and complex diagnostics, and is considered an international expert in clinical psychopharmacology. He is also the director of the Clinical Neuroscience Center, involved in innovative development and discovery of new compounds for neuropsychiatric conditions and directly consults with multiple pharmaceutical companies worldwide.

Dr. Cohen graduated from the Sophie Davis Biomedical Education Program at the CUNY School of Medicine at The City College of New York, an accelerated six-year BS/MD program. He then completed his MD at SUNY Stony Brook School of Medicine.

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