Treatment-Resistant Bipolar Disorder — Symptoms and Next Steps| bpHope.com

Finding stability isn’t always straightforward, and for some, bipolar symptoms remain difficult to manage despite treatment. Here’s what can help.

If you’re living with bipolar disorder and standard treatments aren’t bringing relief, your provider might use the term “treatment-resistant.” It’s a label that can sound worryingly like “untreatable,” a deeply discouraging prospect. 

But you should know that what treatment-resistant actually means is that your bipolar care plan is ready to take a new direction, one that might include medication combinations, brain stimulation therapies, and emerging treatments. 

Understanding what treatment resistance really is — and what comes next — can help you and your care team create a plan that works better for you.

Understanding the Meaning of Treatment-Resistance

Treatment resistance in bipolar disorder — like treatment resistance for other mental health conditions — means that the treatments you’ve tried so far aren’t doing what they need to do, explains Andrew Nierenberg, MD, director of the Dauten Family Center for Bipolar Treatment Innovation at Massachusetts General Hospital and professor of psychiatry at Harvard Medical School in Boston. 

You won’t find “treatment-resistant bipolar disorder” listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR), says Dr. Nierenberg. It’s not a formal diagnosis. It’s clinical shorthand for when someone isn’t responding well to first-line treatments. 

But “treatment-resistant” is a loaded term, and there’s a movement within expert and patient circles to adopt the term “difficult to treat” instead, according to an article published by the American Psychiatric Association (APA). This is the term Nierenberg prefers. “Something just doesn’t feel right about treatment-resistant. What we want to do is avoid any harmonics around blame. There’s no blaming for it,” he says.

Importantly, treatment-resistant describes how things are now, not how they will always be. “It does not mean untreatable,” says Mauricio Tohen, MD, DrPH, professor and chairman of psychiatry and behavioral sciences at the University of New Mexico School of Medicine in Albuquerque.

Treatment-resistant bipolar disorder means your condition isn’t responding well to the first medications you’ve tried, but that you may respond to different combinations or other treatments, Dr. Tohen explains. “So in other words, do not lose hope.”

Defining Treatment Resistance in Bipolar Disorder

There is no single standard definition for treatment resistance in bipolar disorder, but most providers follow similar guidelines that match the definitions used for treatment resistance in other psychiatric conditions, like major depressive disorder, per Cleveland Clinic. 

Generally, your bipolar disorder would be considered treatment resistant if you’ve tried at least two medications without enough improvement.

But those medication trials must meet three criteria, notes Tohen:

• Right Dose You need to reach the standard therapeutic dose, not just start the medication. Many medications require a taper period where you gradually increase the dose over time. If you stop before reaching that target dose, it doesn’t count as a full trial. 
• Right Duration You’d need to stay on the medication long enough for it to work. Depending on the medication, this is typically at least six to eight weeks. 
• Approved Medication The medication should be approved by a regulatory agency, like the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA), for treating your specific bipolar symptoms (depression, mania, or maintenance).

Types of Treatment-Resistant Bipolar Disorder

When you talk about treatment resistance in bipolar disorder, you need to be specific in terms of what aspect of bipolar disorder isn’t responding to treatment, says Tohen. You can have three types of treatment-resistant bipolar disorder, he says:

• Treatment-resistant bipolar depression: When bipolar depression episodes don’t respond to treatment.
• Treatment-resistant bipolar mania: When manic or hypomanic episodes don’t respond to treatment.
• Treatment-resistant relapse prevention: When you continue having breakthrough mood episodes despite taking maintenance medication.

Treatment-resistant bipolar depression is the most common form, and bipolar depression tends to be the most challenging to treat, says Nierenberg. 

In part out of recognition of this, the International Society for Bipolar Disorders convened a task force of 30 international experts, including Tohen, to establish a standardized definition. Their scientifically-grounded criteria include:

• No meaningful, lasting improvements after trying at least two approved medications for acute bipolar depression.
• Meaningful improvement means at least a 50 percent reduction in symptoms for at least two to four weeks, as measured on standard mood surveys.
• Medications were taken at the right dose for the right amount of time. 

Prevalence of Treatment Resistance 

Treatment resistance is common, but — partly due to the lack of a standard definition — there’s no good data on exactly how common it is. 

One research review put the percentage of people living with bipolar disorder who have treatment-resistant bipolar depression — just one of the three types — at about 33 percent.

Another way to consider its prevalence is by examining how many people recover from an acute mood episode and then continue to be well five years later, which Nierenberg notes is a relatively small number. A related study of more than 25,000 Canadians diagnosed with bipolar disorder found that only 23 percent had mild or no symptoms in the past year.

Ruling Out Pseudo-Resistance

Not responding to treatment for bipolar disorder doesn’t always mean you have treatment resistance. 

“If somebody is not getting an adequate dose for an adequate duration of a medication and they’re not responding, they’re not difficult to treat. It’s that the treatment is inadequate,” says Nierenberg. This is called pseudo-resistance.

Two main factors can contribute to pseudo-resistance, according to a scientific paper:

• Inadequate Treatment If you’re not able to take the doses in the standard amounts for the required length of time — due to challenges with side effects or being consistent with medications — then it’s not possible to say for sure that standard medications don’t work for you.
• Diagnostic Problems If you aren’t responding to bipolar disorder treatment, you might have another untreated condition alongside bipolar disorder, like anxiety, attention deficit and hyperactivity disorder (ADHD), or substance use disorder, says Nierenberg. Or it could be that what has been diagnosed as bipolar disorder is really another health condition.

Risk Factors for Difficult-to-Treat Bipolar Disorder

Scientists don’t yet fully understand the biology of bipolar disorder, including why some cases respond well to certain medications while others don’t.

Someday, psychiatry may move to a more personalized medicine model, similar to cancer treatment, where once your specific type is identified, it can be matched with a therapy known to work best for it, explains Tohen.

For example, research on lithium suggests it may be possible to someday use your genetic profile to tell if you’re likely to respond to the mood stabilizer. But psychiatry is likely to remain complex because its causes are both biological and nonbiological, he says. 

Having factors that make treatment more difficult will make it more likely that your case is considered treatment-resistant. These include having more severe symptoms, comorbid psychiatric or medical conditions, and not having access to a stable environment with stable relationships, says Nierenberg. 

Recognizing Signs of Treatment Resistance

If you aren’t getting better despite treatment, that’s how you know your bipolar disorder is difficult to treat, says Nierenberg. On some level, it’s self-evident. 

Your provider may talk to you about the concept of “treatment resistance” or “difficult to treat,” but they might not. “It’s not necessarily something that one would have to give a label to,” he adds.

At the same time, you also don’t need to wait for your provider to bring it up. If you’re concerned about your progress, speak up, says Tohen. This helps everyone understand where you are and whether it’s time to try something different.

“I encourage patients to bring up the point that I’m not responding to antidepressant A or antipsychotic B. What can we do next?” says Tohen.

Potential Complications of Treatment Resistance

Like any chronic disease that’s not getting better, when bipolar disorder isn’t responding to treatment, it can affect every area of your life. “It’s extremely disruptive,” says Nierenberg. 

Complications might include: 

• Difficulty Functioning Professionally and personally, treatment-resistant bipolar disorder makes it difficult — if not impossible — to do the things you need and want to do. 
• Suicidal Thoughts or Behaviors It can be incredibly difficult to keep going when you’re trying things and taking the medications you’re supposed to take and not feeling any better.

These are serious complications. If you notice symptoms like these, tell your care team immediately. It’s likely time to escalate the aggressiveness of treatment, says Nierenberg. 

What to Do for Treatment-Resistant Bipolar

If first-line treatments aren’t working, there are many other options to explore. Here’s what your provider might suggest:

Medication Combinations 

Combining medications can be effective when a single drug isn’t enough. For example, adding lamotrigine (Lamictal) to lithium is a common strategy, Tohen says. Since adding medications can also increase the risk of side effects, it’s something you’ll have to decide together with your treatment team.

Emerging Pharmaceuticals 

Intravenous ketamine and the related nasal spray esketamine aren’t yet approved by the FDA for bipolar disorder, but they show promise for treating bipolar depression, says Tohen. One study found that just four ketamine infusions significantly reduced depression and suicidal thoughts in adults with treatment-resistant unipolar and bipolar depression. 

Brain Stimulation Therapies 

With treatment-resistant bipolar disorder, you need to consider options beyond medications, says Tohen. One category to consider is brain stimulation therapies, which change brain activity to address symptoms, per the National Alliance on Mental Illness (NAMI). 

The two with the most evidence for bipolar disorder are electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS), Tohen says. Researchers are also studying intermittent theta-burst stimulation (iTBS), deep brain stimulation (DBS), and vagus nerve stimulation (VNS), according to a review of the research.

Metabolic Therapy 

A review of the research suggests that some people living with bipolar disorder may have mitochondrial dysregulation, says Nierenberg. This means their cells have trouble producing the energy their bodies need to function properly. Researchers are studying whether treatments that support mitochondrial function in the brain — including ketogenic diets and GLP-1s — might help. “We are exploring whether a type of triglyceride-lowering drug could also be beneficial,” he says. The research is early but promising.

Talk Therapy 

Psychotherapy approaches like cognitive behavioral therapy (CBT) and interpersonal and social rhythm therapy (IPSRT) can be extraordinarily helpful for those who can engage, says Nierenberg. But the more severe your symptoms, the less you might be able to benefit from psychotherapy. Sometimes you may need another type of treatment to get better enough that you can then do therapy, he says. 

Lifestyle Changes 

When you’re able, consistent daily routines — particularly around sleep — can help support stability in cases of difficult-to-treat bipolar disorder. Research suggests that exercise may be an especially effective add-on treatment for bipolar depression, says Tohen. 

Whatever you try, the best path forward involves partnering with your care team to create an individualized plan. Express what matters most to you, negotiate around side effects, and make decisions together, says Nierenberg. Connecting with peer support through organizations like the Depression and Bipolar Support Alliance (DBSA) and NAMI — can also really help, he says. 

Outlook for Treatment-Resistant Bipolar Depression

If your bipolar symptoms have been difficult to treat, it may be time to take your care in a different direction. Remember: First-line treatments are just a starting point. 

Many innovative treatments are already available, and more are on the way thanks to scientific research and other knowledge-sharing efforts, like The Bipolar Action Network — where Nierenberg serves as a principal investigator — which helps healthcare systems share what’s working for their patients living with bipolar disorder. 

By working together, the outcomes for complex chronic bipolar disorders will get better and better over time, Nierenberg says.

Frequently Asked Questions

Understanding treatment resistance often starts with asking the right questions — and here are some of the most important ones:

1. Is treatment-resistant bipolar disorder untreatable? 

No, treatment-resistant bipolar disorder does not mean the condition is untreatable. It means your symptoms haven’t responded to at least two medications, but they may improve with medication combinations or other treatments, such as brain stimulation therapies. 

2. Is it a problem if my bipolar disorder isn’t responding to treatment?

Yes, inadequately treated bipolar disorder can be extremely disruptive, making it difficult or impossible to function professionally and personally. It can also lead to suicidal thoughts or behaviors, making it essential to work with your care team to find effective treatment.

3. Why are some cases of bipolar disorder so hard to treat?

Having more severe symptoms, other psychiatric or medical conditions, and lacking access to a stable environment can make bipolar disorder more difficult to treat. But much is still unknown about the biology of bipolar disorder and why some cases respond to certain medications while others don’t. 

4. How do I know if I have treatment-resistant bipolar?

If you aren’t getting better despite treatment, that’s how you know your bipolar disorder is “treatment-resistant.” Generally, that means you’ve tried at least two approved medications at the right dose for long enough (typically six to eight weeks) without meaningful improvement. 

5. What can I do if bipolar meds don’t work?

If bipolar medications aren’t working, ask your care team what you can try next. Other options include medication combinations, brain stimulation therapies like ECT or rTMS, emerging pharmaceuticals like ketamine, and metabolic therapies. 

If you or a loved one is experiencing significant distress or having thoughts about suicide and need support, call or text 988 to reach the 988 Suicide & Crisis Lifeline, available 24–7. If you need immediate help, call 911.

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