Antidepressants and Bipolar Disorder: The Real Risk of Mood Destabilization

When someone with bipolar disorder feels deep, crushing depression, it’s tempting to reach for an antidepressant. After all, they work for unipolar depression. But in bipolar disorder, that simple solution can backfire-sometimes dramatically. What looks like improvement can quickly turn into mania, rapid cycling, or a mixed state where sadness and agitation crash together. This isn’t rare. It’s well-documented. And yet, antidepressants are still prescribed far too often.

Why Antidepressants Are Risky in Bipolar Disorder

Antidepressants were never designed for bipolar disorder. They were made for unipolar depression-where there’s only one mood pole: low. Bipolar disorder has two: low and high. Introducing a drug that lifts mood in someone whose brain already swings between extremes can tip the balance. Instead of easing depression, it can trigger a switch into mania or hypomania.

Studies show that about 12% of people with bipolar disorder who take antidepressants experience a polarity switch-meaning their depression flips into mania. That number jumps to 31% in real-world, retrospective data. For comparison, the natural switch rate with mood stabilizers alone is around 10.7%. So antidepressants don’t just add benefit-they add risk.

The risk isn’t the same for everyone. People with Bipolar I, a history of prior antidepressant-induced mania, rapid cycling, or mixed features during depression are at highest risk. In fact, if you’ve had one episode triggered by an antidepressant before, your chance of it happening again is more than three times higher.

Not All Antidepressants Are Equal

Some antidepressants are riskier than others. Tricyclics like amitriptyline carry the highest switch risk-up to 25%. SNRIs like venlafaxine aren’t much better. But SSRIs like sertraline or escitalopram? They’re lower, around 8-10%. Bupropion (Wellbutrin) is often preferred because it doesn’t strongly affect serotonin, which may reduce the chance of triggering mania.

Still, even SSRIs can cause problems. One patient in Leeds told me their doctor prescribed sertraline for a depressive episode. Within two weeks, they were sleeping only two hours a night, spending money recklessly, and convinced they were on a special mission. Hospitalized. That’s not an outlier. It’s a known pattern.

The bottom line: no antidepressant is safe in bipolar disorder without a mood stabilizer or atypical antipsychotic in place. Even then, the benefit is small.

The Numbers Don’t Add Up

Let’s look at the math. For unipolar depression, antidepressants work well. You need to treat about 6-8 people to see one respond. In bipolar depression? You need to treat nearly 30 people to get one meaningful response. That’s a huge difference.

Meanwhile, the number needed to harm-how many people you have to treat before one has a switch-is about 200. Sounds low risk? Not when you consider how many people are on these drugs. With an estimated 50-80% of bipolar patients in the U.S. being prescribed antidepressants, that’s tens of thousands of people at risk every year.

And here’s the kicker: antidepressants don’t even help prevent relapse. In fact, long-term use (over 24 weeks) increases the chance of future depressive episodes by 37%. They may help in the short term, but over time, they can make the illness worse.

What Works Better

The FDA has approved four medications specifically for bipolar depression-and none are traditional antidepressants:

• Quetiapine (Seroquel): 50-60% response rate, less than 5% switch risk
• Lurasidone (Latuda): 50% response rate, only 2.5% switch risk
• Cariprazine (Vraylar): 48% response rate, 4.5% switch risk
• Olanzapine-fluoxetine (Symbyax): 50% response rate, 5-7% switch risk

These drugs don’t just treat depression-they stabilize mood. They’re not perfect. Weight gain, sedation, and metabolic side effects are real concerns. But they don’t flip your mood. That’s the difference.

And now, newer options are emerging. Esketamine nasal spray (Spravato), approved for treatment-resistant depression, showed a 52% response rate in bipolar depression with just 3.1% switch risk in a 2023 trial. It’s not widely used yet, but it points to where the field is headed: treatments that lift mood without destabilizing it.

Who Should Even Consider Antidepressants?

The International Society for Bipolar Disorders (ISBD) 2022 guidelines are clear: antidepressants should be avoided as monotherapy. They should only be used as a short-term add-on in severe, treatment-resistant cases-after at least two FDA-approved treatments have failed.

Even then, they’re not for everyone. Avoid them if you have:

• Bipolar I disorder
• A history of antidepressant-induced mania
• Four or more mood episodes per year (rapid cycling)
• Mixed features (depression with agitation, irritability, racing thoughts)

The only group where antidepressants might be cautiously considered: people with Bipolar II, no prior switches, pure depression (no mixed symptoms), and no rapid cycling. Even then, use the lowest effective dose for the shortest time possible-no longer than 8-12 weeks.

Monitoring and What to Watch For

If an antidepressant is used, weekly check-ins for the first month are non-negotiable. Look for early signs of mania:

• Needing less sleep but feeling energized
• Racing thoughts or pressured speech
• Impulsive spending, risky sex, or reckless decisions
• Unusual irritability or anger
• Grandiose ideas (“I can start a company,” “I’m destined for greatness”)

These aren’t subtle. They’re sudden. And they happen fast-often within days. If any of these appear, stop the antidepressant immediately. Don’t wait. Don’t adjust the dose. Stop it.

And never keep an antidepressant going if someone is already in a mixed state. That’s like pouring gasoline on a fire.

Why Do Doctors Still Prescribe Them?

If the risks are so clear, why are antidepressants still used in 80% of community clinics?

Three reasons:

1. Diagnosis errors: Nearly 40% of bipolar disorder cases are misdiagnosed as unipolar depression at first. If you think someone has regular depression, antidepressants seem logical.
2. Pressure from patients: People in deep depression beg for something that works fast. Mood stabilizers take weeks. Antidepressants can show results in 2-4 weeks.
3. Clinical inertia: It’s easier to keep prescribing what’s familiar than to switch to a complex regimen with multiple meds and close monitoring.

But here’s the truth: the longer you wait to get the right treatment, the more episodes you have. And each episode makes the next one easier to trigger. Antidepressants might feel like a quick fix-but they’re a long-term trap.

What Patients Need to Know

If you have bipolar disorder and are on an antidepressant:

• Ask your doctor: “Is this FDA-approved for bipolar depression?”
• Ask: “What’s my risk of switching?”
• Ask: “Am I on a mood stabilizer or antipsychotic too?”
• Ask: “How long will I be on this?”

If your doctor says, “It’s working fine,” ask for data. Show them the numbers. Ask if they’ve read the ISBD guidelines. If they haven’t, it’s time to find someone who has.

And if you’ve ever had a manic episode after starting an antidepressant? That’s not a coincidence. That’s a red flag. Never take that drug again.

The Bigger Picture

We’re in a transition. For decades, bipolar depression was treated like unipolar depression. That was a mistake. Now, the science is catching up. Guidelines are clearer. Alternatives are better. And the risks of antidepressants are no longer debated-they’re proven.

The real challenge isn’t finding a new drug. It’s changing how we think. Bipolar disorder isn’t depression with mood swings. It’s a distinct illness with its own rules. Treating it like unipolar depression doesn’t just miss the mark-it can make things worse.

The goal isn’t just to lift mood. It’s to stabilize it. And that’s not something an antidepressant can do alone.