What is treatment resistant bipolar disorder?

There is no single, official or clinical definition for this term.

Basically it means refractory, intractable, difficult or unmanageable in the sense that the patient is not responsive to the standard, and usually
successful, treatments.

Some studies have shown increasing treatment resistance with number of episodes.

This is consistent with the kindling theory of bipolar disorder whereby episodes become more serious and more frequent without effective treatment.

A typical threshold will be the failure to respond to 2, 3 or 4 of the most recognized and proven bipolar medications (mood stabilizers).

Treatment resistant bipolar disorder is an urgent problem. Why?

Three seems to be emerging as the most common measure but there is a lot of variance.

For example, someone who tries lithium, Depakote, Lamictal and Zyprexa with no relief could be fairly classified as treatment resistant.

The best overview I have found is from Molecular Psychiatry on Treatment Resistance in Bipolar Disorder.

There are many factors that make the issue more complicated.

The three main sources of confusion are:

1. What stage of the illness the patient is at. It is now well established that some medications work best for treating mania but different medications are better for treating bipolar depression, and still others are best suited for ongoing maintenance.


It is NOT unusual to try a few meds before finding your best bipolar treatment.

2. The difference between treatment resistance and treatment intolerance. What does mean? The issue is, is it fair to categorize someone as treatment resistant if they abandon their medication not because of ineffectiveness but because of disliking the side effects?

3. What role does misdiagnosis pay? If I don’t respond to my bipolar medication, perhaps it is because I am sick with something else. Instead of asking “Why doesn’t this work?”, ask “Am I bipolar?”

Different treatments for mania, depression and maintenance


What looks like treatment resistant bipolar disorder can arise when we try to treat the wrong phase of the illness.

For example, for severe bipolar depression, lithium or Lamictal plus an antidepressant should be considered. Alternatives are quetiapine (Seroquel) or a olanzapine/fluoxetine combination (i.e Symbyax).

However, in acute mania when traditional mood stabilizers are inadequate, an atypical antipsychotic with strong anti-manic properties such as risperidone (Risperdal), aripiprazole (Abilify), or ziprasidone (Geodon).

For maintenance where lithium or Depakote are ineffective, olanzapine (brand name Zyprexa) can be tried.

Alternatives in treatment resistant bipolar

What do psychiatrists usually try in the face of treatment resistant bipolar disorder? The main “fall-back” positions are:

1. Combining traditional mood stabilizers such as lithium and Depakote with the newer atypical anti-psychotics.


2. Trialling alternative drugs such as clozapine – the first of the atypical anti-psychotics developed in 1971 to treat schizophrenia and widely regarded as a medication of “last resort”.

3. Electroconvulsive therapy (ECT).

4. Calcium channel blockers.

5. High-dose thyroid augmentation.

It is also worth reading about emerging treatment alternatives, such as Mexiletine in treatment-resistant bipolar disorder.

(Mexiletine is used to treat certain types of abnormal heart rhythms. It works by blocking certain electrical signals in the heart to stabilize the heart rhythm and by blocking sodium channels.)

Improve compliance to improve results

There are many reasons why people are not medication compliant, even when the medications are actually very effective and it would be an excellent idea to take them.

However, it is not unusual for people with poor medication compliance to claim that “nothing works” and present themselves as having treatment resistant bipolar disorder.

It is very important not to confuse non-compliance with treatment resistance in bipolar disorder.


Research findings differ, but a UCLA study found that from a patient’s perspective, they did not take their bipolar medications because:

1. They disliked the idea of medication controlling their moods.

2. They missed their highs.

3. They felt depressed.

4. They disliked the idea of having a chronic illness, symbolized by the necessity for drug therapy.

In Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression, 2nd Edition, Doctors Goodwin and Jamison suggest the following to improve bipolar medication adherence:

1. Minimize dosage to the lowest possible effective dose.


2. Aggressively treat side effects.

3. Track compliance.

4. Examine concerns about long-term medication.

5. Educate patient and families about the role of medication and the dangers of “kindling”.

6. Encourage psychotherapy as well as medication.

Misdiagnosis – Am I bipolar?

Seemingly treatment resistant bipolar disorder may in fact be misdiagnosed “some other disorder”.

Researchers at Rhode Island discovered that many patients diagnosed as bipolar actually had borderline personality disorder instead. In fact, it appears to be becoming one of the most common misdiagnosis traps.

How to tell? Bipolar disorder is episodic, whereas borderline personality is a more pervasive and constant state.

Often “treatment resistant” really means “misdiagnosed”!

After beginning treatment, Am I Bipolar? will answer itself in that if mood stabilizers make you “better”, (remove bipolar symptoms) then it is probably the underlying condition.

However, consider that if the traditional bipolar disorder treatment of mood stabilizers does not help, that there may be an alternative underlying condition.