Pharmacotherapy of Bipolar Treatment

 Hey team! Today I’ll be breaking down the pharmacotherapy of bipolar disorder—including the pharmacology behind the medications we use and why certain ones are preferred over others. My goal is to help you no understand the why, the how, and the watch-outs behind the drug choices.
I was listening to a podcast recently on bipolar treatment and came across a simple mnemonic to organize the different classes of drugs we pull from: “The 4 Ls” — lithium, lamictal, lumateperone, and lexapro. It's not perfect, but it gives us a helpful framework. Lithium stands alone in its class, while Lamictal represents the antiepileptic mood stabilizers, Lumateperone stands in for the atypical antipsychotics, and Lexapro reminds us of the antidepressants—though we'll get to why those are controversial in bipolar treatment.

Let’s start with lithium, which I like to think of as the grandpa who refuses to retire. He’s old, he’s scary but incredibly good at his job—and has more evidence behind him than almost any other psych med. Lithium’s mechanism isn’t perfectly understood, it doesn't have an easy to track receptor binding profile like most drugs. Instead, it modulates multiple intracellular pathways that regulate how neurons communicate. It mimics sodium on the outside of cells, but once inside, it inhibits secondary messengers like inositol monophosphatase (IMP) and glycogen synthase kinase-3 (GSK-3), affecting everything from circadian rhythm to neuronal resilience. Over time, this reduces manic overactivation while boosting underactive circuits in depression. It’s also one of the few medications shown to actually reduce suicidality—not just in bipolar patients, but across the board.

Lithium is typically dosed between 600 and 1500 mg per day, preferably given once at night to minimize the load on the kidneys. It follows linear pharmacokinetics—so if 1000 mg yields a serum level of 0.9, 500 mg will get you 0.45. Also it has a half life of 5 hours so you can expect steady state levels after about 5 days. For maintenance, we generally aim for levels between 0.4 and 1.0 mEq/L, but for acute mania, higher levels around 1.2 may be needed. Toxicity can occur around 2.0, so lab monitoring is key—especially early in treatment. As I said, above lithium competes with sodium, so there is indeed an important balance between sodium intake and sodium elimination (high sodium = low lithium AND low sodium = high lithium, big no no). Therefore, we should be very cautious with individuals who either consume lots of sodium or are on drugs that decrease sodium (looking at you diuretics, cough cough HCTZ). You’ll want to monitor lithium levels twice within the first six months, along with electrolytes, kidney function (BUN/SCr), thyroid, and calcium. A quick note that because they are processed through the kidneys, drugs, that interfere with that should be used with great cation. This includes ACEs, and NSAIDs which can increase levels of lithium. Side effects include tremor (action tremor at therapeutic levels, resting tremor with toxic levels), nausea, fatigue, cognitive dulling, weight gain, and, in the long term, possible hypothyroidism and renal impairment. Oh—and it’s a hard no during pregnancy. But don't let that scare you, this drug works very well, it reduces both psychiatric and non-psychiatric hospitalizations, something most psych medications for bipolar cant say. 

Next up are the antiepileptics—or mood stabilizers (but not lithium)—which I like to think of as your extended family: some lift you up, some bring you down, and while they’re all related, each one brings its own vibe. I’ll be focusing on the main four: lamotrigine, valproate, carbamazepine, and oxcarbazepine. Originally designed to treat epilepsy, these meds work by calming over excited neurons—mostly by affecting voltage sensitive sodium channels and dampening hyperactivity. By decreasing activity, these agents seem to calm down networks who's over activity is associated with the symptoms of bipolar whether that's mania or depression. But their psychiatric utility goes deeper and isn't exactly the same for each agent. They also influence intracellular pathways much like lithium.
Lamotrigine is the go-to for bipolar depression. It’s not FDA-approved for that indication, but that hasn’t stopped anyone. The key with lamotrigine is the slow titration: if you go too fast, you risk Stevens-Johnson Syndrome (SJS)—a rare but terrifying rash where your skin basically says, “I quit.” Dosing starts at 12.5 mg/day or 25 mg every-other-day if the patient is on valproate (because valproate increases lamotrigine levels), or 25 mg if not. And it’s titrated up to a target of 200 mg per day going slowly by 25mg.

Carbamazepine is the classic anti-manic agent. It has a long track record, but comes with baggage: it induces CYP3A4 (amongst other CYPs), including its own metabolism, so the more you take, the more your liver chews it up. This means levels can drop over time unless you adjust the dose. It also requires blood count monitoring, especially with initiation, due to rare risks of aplastic anemia and agranulocytosis. Another thing to note is that, like many psych drugs for some reason, it can increase ADH (anti-diuretic hormone) levels leading to hyponatremia, so watch those electrolytes! 

Now oxcarbazepine on the other hand is  the cleaner cousin. It doesn’t induce CYPs, it has a far lower risk of hematologic toxicity and it carries a lower SJS risk. It sounds like an upgrade, but it’s less effective, making it feel like that student that looks good on paper but never quite delivers in the real world.

Valproate is a heavy hitter for acute mania, agitation, and aggression. But there’s no such thing as a free lunch here—it’s a teratogen, full stop. Side effects include resting tremor, weight gain, hair loss, thrombocytopenia and is associated with polycystic ovary syndrome in women. Let's not forget that this is not a potent drug either, it's given up to 4 times a day with a max daily dose of 3800mg. It’s effective, but not a first choice in women of reproductive potential.

Now let’s talk about the atypical antipsychotics, which are used across all phases of bipolar—mania, depression, and maintenance. These aren’t just for psychosis anymore. In fact, antipsychotics are now often used more for mood disorders than for schizophrenia. Some people have pushed for renaming them based on mechanism (like “serotonin-dopamine antagonists”), but that hasn’t caught on, so I’ll stick with the term “atypical antipsychotic,” even if it’s a little outdated.

Not all antipsychotics are created equal. Some are better for mania, others for depression, and a few work well across the board. Among the newer and more tolerable options, we’ve got lumateperone, lurasidone, cariprazine, and aripiprazole. These tend to have lower rates of sedation and metabolic complications compared to the more classic players like quetiapine, olanzapine, and risperidone.
Lumateperone is one of the newest antipsychotics on the market, with a clean receptor profile. It acts as a D2 antagonist postsynaptically, a partial agonist presynaptically (a smart combo), blocks 5HT2A, and also affects serotonin transporters. It’s only approved for bipolar depression and only comes in one dose—42 mg. Clean, simple, done.

Lurasidone is also approved for bipolar depression and maintenance. It antagonizes D2, 5HT2A, 5HT7 (which may help cognition and depression), and has partial 5HT1A agonism. It needs to be taken with at least 350 calories or its absorption drops significantly—so it’s not ideal for patients with disordered eating. Akathisia is a common side effect early on but tends to resolve.

Cariprazine is unique in that it’s a high-affinity partial agonist at D3 receptors, which gives it a pro-cognitive, energizing profile. It’s studied in both mania and depression, but its long half-life and slow steady-state make it suboptimal for acute episodes. Still, it’s very effective in bipolar depression, and targets D2, 5HT1A, and 5HT2A receptors as well.

Aripiprazole, while useful for mania and as adjunct therapy in unipolar depression, often underperforms in bipolar depression. It acts as a partial agonist at D2 and 5HT1A, and as an antagonist at 5HT2A. One important side effect to monitor is the rare but real increase in impulsive behaviors like gambling or compulsive shopping. It's rare, but not rare enough to ignore.

Risperidone is mechanistically straightforward—a D2 and 5HT2A antagonist—but at higher doses, it can feel like expensive Haldol. It carries a high risk of EPS, especially at doses above 6 mg, and can cause hyperprolactinemia leading to symptoms like galactorrhea, amenorrhea, and sexual dysfunction. It’s approved for mania and maintenance, and comes in VERY long-acting injectable forms (along with its metabolite, paliperidone), which can be helpful for patients with poor adherence.

Finally, quetiapine and olanzapine are effective across all phases of bipolar disorder—mania, depression, and maintenance—but come with a metabolic price tag. Both are associated with substantial weight gain and increased risk of diabetes. Quetiapine, due to its histamine blockade, is often used off-label for sleep, especially at low doses. Olanzapine is sometimes combined with fluoxetine in a formulation approved for bipolar depression (Symbyax), and is also used as an augmentation strategy in treatment-resistant unipolar depression. Both of these drugs share structural similarities with clozapine, and while they’re nowhere near as effective for treatment-resistant schizophrenia, they carry some of the same risks—minus the agranulocytosis. On the plus side, they have lower risk for drug-induced parkinsonism.

As far as practical pearls go: olanzapine is metabolized by CYP1A2, so smoking can significantly reduce its levels. Lurasidone must be taken with food, and aripiprazole can occasionally lead to impulse-control issues that should be screened for. With all atypical antipsychotics, regular metabolic monitoring is essential. This includes fasting glucose, lipids, weight, and blood pressure. If a patient shows signs of hormonal imbalance, consider checking prolactin levels as well (especially if on a strong D2 blocker like risperidone).

Before we wrap up, let’s talk about the final “L” in the mnemonic: Lexapro, standing in for the antidepressants. And let me be clear right off the bat—they are not first-line treatment for bipolar depression. In fact, monotherapy with antidepressants in bipolar disorder is actively risky.
Why? Because antidepressants—especially SSRIs like Lexapro—can destabilize mood in people with bipolar disorder. This isn’t just about switching into mania (though yes, that happens). It’s also about what’s often called "roughening" of the illness—where patients develop rapid cycling, irritability, agitation, or emotional volatility that didn’t exist before. And once that pattern sets in, it can be extremely difficult to undo.

That said, antidepressants are still widely prescribed—sometimes too casually—for bipolar patients. If you’re going to use them, it should only be as adjunctive therapy, in conjunction with a mood stabilizer or an antipsychotic that protects against mania. Even then, it should be reserved for cases where first-line options like lamotrigine or atypical antipsychotics (like lurasidone, cariprazine, or quetiapine) have already been tried—or when the patient has a long, well-documented history of bipolar II depression without manic switching. But again: never as monotherapy. Never first-line. 

Did I miss anything? Absolutely. I didn't include any first generation antipsychotics (none on label but when hasn't that stopped anyone. looking at you lamotrigene). I also didn't talk about ziprasidone, it's just another me-too anyways. Most importantly, I didn't talk about anything non-pharmacologic related, which is arguably more important then pharmacotherapy in terms of long-term stability and wellness. This is through healthy living, including diet, sleep, exercise, substance use and more in addition to psychotherapy and interpersonal relationships. But that's not what I sought out to do, hence the title of the post.

 I hope you enjoyed, and I look forward to reading and writing more about psychiatry and pharmacotherapy.