Treating bipolar depression starts with being as sure as possible that your patient has bipolar disorder. Many patients claim to have “bipolar.” On further investigation, their “mood swings” are transitory, lasting minutes or hours and triggered by situations. Try to interview patients with DSM 5 standards in mind, watch for substance abuse and personality disorders, and be aware of conditions like ADHD or OCD that may complicate bipolar disorder. Grandiosity or a feeling of invincibility often accompany the high energy of bipolar, but are not usually seen in ADHD. Many depressed patients have decreased ability to sleep, not the decreased need for sleep found in bipolar.

Lamotrigine is a good bipolar foundation medication. It has low side effects if titrated slowly to minimize the risk of rash. Most people tolerate it well, it is relatively safe in pregnancy, and has few long-term side effects. Lithium is more complicated to use but is a standard for typical bipolar patients. Valproic acid, carbamazepine, and oxcarbazepine are other foundation drugs. Oxcarbazepine is not FDA indicated but seems to work almost as well as carbamazepine with far fewer monitoring and side effect concerns. There are significant pregnancy concerns with valproic acid, carbamazepine, and lithium, though lithium is not as risky as it was once thought to be. These medications are not likely, by themselves, to bring a patient out of an acute bipolar depression, but sometimes patients will remit and these medications may help keep them in the middle. Make sure thyroid tests are normal, monitor needed blood tests, let patients know drugs may affect vitamin levels, and look for medical triggers of depression.

The standard, FDA approved, medications for bipolar depression are quetiapine, fluoxetine/olanzapine combination, lurasidone, cariprazine, and lumateperone. All the atypical antipsychotics have some degree of 5HT2a antagonism. Quetiapine or fluoxetine/olanzapine are more likely to increase weight and appetite, and are more likely to lead to glucose intolerance and lipid elevations. Lurasidone must be taken after food, but has low metabolic and weight concerns. Cariprazine and its active metabolite have about a one month half-life. Titrate slowly as cariprazine accumulates, may be activating and cause akathisia, and once in, takes a long time to leave. Cariprazine has D3 greater than D2 tight binding as a partial agonist. Lumateperone is a potent 5HT2a receptors antagonist and has much less activity at dopamine receptors. It may be quite sedating for some patients. Clozapine, like for schizophrenia, may help in some treatment resistant patients.

The clever clinician will use the side effect and receptor binding profiles to help determine how to choose medications. It makes sense to use sedating drugs for patients unable to sleep and activating drugs for those who sleep too much. It makes sense to use drugs that cause weight gain for thin, undernourished patients. This is not a perfect system, but is a way to start. Record what works and what does not. We do not have a way to predict what will work for whom, but we should be able to learn from each drug a patient tries. Listen to your patients and adjust based on their feedback.

There is great controversy over whether unipolar antidepressants have a place in bipolar treatment. I have patients who respond to bupropion, SSRI’s or even SNRI’s for what clearly is bipolar. I would advise to use these drugs as a last resort, but SSRI’s, if a patient is on adequate coverage to prevent mania, may help with anxiety disorders, OCD, or PTSD. Pramipexole was never FDA approved for bipolar, but has good research support. Like cariprazine, pramipexole is a D3/D2 partial agonist, but leans more towards the agonist side so is not an antipsychotic. Ropinirole, a D2 agonist, also has shown efficacy for bipolar depression. Finally, topiramate needs mention. It does not have antidepressant efficacy, but may help with managing weight gain caused by other drugs and has mild bipolar maintenance benefits for some patients. OCD in bipolar patients may be different from OCD in patients without bipolar. Topiramate is a good choice for OCD when SSRI’s do not work or are contraindicated.