Bipolar disorder is being better understood each day. There is also ongoing research into its treatment.

But successfully treating bipolar disorder can involve several medication trials, and it can take years to achieve remission. Even if remission is attained, recurrence is the rule — not the exception. It’s not uncommon for all first-line treatments to be exhausted.

People in this situation may be considered by mental health professionals to be treatment-resistant. Luckily, there are treatments that can be tried when first-line, and even second-line, treatments for bipolar disorder fail.

What is Treatment Resistance?

There is no consensus among clinicians and researchers on one definition of treatment resistance. Generally, patients in an acute state (manic, depressed or mixed) whose symptoms do not improve after at least two evidence-based medication trials are considered treatment-resistant in research studies. In the maintenance phase, patients are considered treatment-resistant if they continue cycling despite several adequate medication trials.

In some studies additional criteria must be met in order to truly be considered treatment-resistant. These include functional measures of remission.

Dr. Prakash Masand, psychiatrist and founder of Global Medical Education argues, however, that “Treatment-resistance is more common than most clinicians think since a sustained response to treatment rarely includes an assessment of functioning. When functioning and residual depression are taken into consideration, far more patients would be considered treatment-resistant.”

First-Line Treatments for Bipolar Disorder

First-line treatments for bipolar disorder have been shown to be the most reliable. They are approved by the Food and Drug Administration (FDA). First-line treatments vary, depending on the phase of bipolar disorder the patient is in.

First-line treatments for mania include:

  • Valproate (Depakote)
  • Carbamazepine (Tegretol, extended release)
  • Lithium
  • All atypical antipsychotics such as risperidone (Risperdal), quetiapine (Seroquel) and aripiprazole (Abilify)

In the depressed phase of bipolar disorder, only quetiapine and an olanzapine (Zyprexa)/fluoxetine (Prozac) combination are approved as first-line treatments, although lurasidone (Latuda) is awaiting FDA approval.

For mixed episodes of bipolar disorder, carbamazepine and most atypical antipsychotics are approved. For the maintenance phase of bipolar treatment, lamotrigine (Lamictal), lithium, aripiprazole and olanzapine are FDA-approved.

Second-Line Treatments for Bipolar Disorder

According to Dr. Masand, many treatments are still available for people considered treatment-resistant. “People should not give up hope just because several treatments have failed. We have many tools in the toolbox outside of first-line monotherapy treatment.”

Primary second-line treatments in bipolar disorder include adjunctive treatments such as the addition of an atypical antipsychotic to lithium or valproate or vice versa. Dr. Masand notes that “patients in a manic or mixed state may actually respond more quickly to lithium or an anticonvulsant combined with an atypical antipsychotic.”

And while antidepressants should never be used alone to treat bipolar disorder, adding them to an existing mood stabilizer or antipsychotic is considered a second-line treatment and is sometimes helpful for bipolar depression. “Additionally, adjunctive armodafinil (Provigil) may also be useful in bipolar depression,” Dr. Masand. said

Additional Treatments for Bipolar Disorder

There are additional therapies that can be considered even if both first-line and second-line treatments fail. According to Dr. Masand, third-line treatments include clozapine (Clozaril), electroconvulsive therapy (ECT), repetitive transcranial magnetic stimulation (rTMS), calcium channel blockers, high-dose thyroid augmentation, omega-3 fatty acids and other anticonvulsants.

“Novel treatments are also being researched,” Dr. Masand said. “Agents such as n-acetylcysteine, mexiletine (Mexitil), pramipexole (Mirapex), ketamine and others have shown promise for the treatment of the various phases of bipolar disorder. It’s also critical that all patients with bipolar disorder receive an adjunctive proven psychotherapy such as psychoeducation, family-focused therapy, interpersonal and social rhythm therapy or cognitive behavioral therapy (CBT), as relapse rates have been shown to be lower when therapy is added to medication treatment.”