Treatment Resistance in Bipolar Disorder

A growing body of evidence indicates treatment resistance is extremely common in bipolar disorder. Even when psychopharmacologic treatment is optimal, nearly 50% of bipolar individuals with symptom remission experience a recurrence in two years. Oftentimes it is not known whether a person is resistant to specific medications or whether poor treatment adherence plays a role. For example, some people stop taking their medication as soon as they feel better or because they want to experience the productivity and creativity associated with mania.

The concept of treatment-resistant bipolar disorder is clinically familiar, although it lacks a standard definition. The general agreement is that no response to standard, evidence-based therapies equates to treatment resistance. In order to attain a formal definition, clarification is needed regarding non-responsiveness to one or more standard treatments, dosages and phases. In lieu of a formal definition, treatment resistance in bipolar disorder needs to be assessed by clinicians based on the specific phase of treatment: mania or depression and acute or maintenance.

Treatment for Bipolar Disorder

The dual nature of bipolar disorder and the three different types create unique treatment challenges. Bipolar treatments must adequately address both depressive and manic episodes and the specific type of bipolar. Mood stabilizers play a key role in preventing or reducing the risk of recurring episodes. Antipsychotics and antidepressants are also commonly used to treat bipolar disorder.

Mood Stabilizers

Lithium is one of the most commonly prescribed mood stabilizers for the treatment of bipolar disorder. Anticonvulsants including valproic acid (Depakene), divalproex sodium (Depakote), carbamazepine (Tegretol, Equetro and others) and lamotrigine (Lamictal) are often effective for controlling manic and depressive episodes.


Antidepressant medications, in particular selective serotonin reuptake inhibitors (SSRIs) such as Paxil, Zoloft and Prozac, can be effective for controlling depressive episodes. An antidepressant can sometimes trigger a manic episode, so it is often prescribed in combination with a mood stabilizer or antipsychotic.


If symptoms of depression or mania continue despite treatment with other medications, atypical antipsychotics may be prescribed. Olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), aripiprazole (Abilify), ziprasidone (Geodon), lurasidone (Latuda) or asenapine (Saphris) may help reduce psychotic symptoms associated with manic episodes.


Symbyax combines the antidepressant fluoxetine and the antipsychotic olanzapine to treat depression and stabilize moods.

Causes of Treatment Resistance

Decades of research have identified risk factors for treatment-resistant depression, including older age, duration and severity of episodes and co-occurring disorders. Treatment resistance is more prevalent in bipolar depression than in major depressive disorder, with subthreshold manic symptoms playing a pivotal role. Evidence indicates genetic, infectious and immunologic influences play a role in the development and treatment resistance of specific psychiatric disorders including bipolar. In addition, the following variables may be the underlying cause of treatment-refractory depression.

  • Sub-therapeutic antidepressant dosing (about 20%)
  • Treatment non-adherence (about 40%)
  • Intolerable adverse effects (20% to 30%)
  • Incorrect diagnosis (10% to 15%) (e.g. thyroid disease, nutritional deficiencies, sleep apnea or “latent” bipolarity)

Research on Alternative Treatments for Refractory Cases

Knowledge about brain circuits involved in depression and other psychiatric disorders has greatly evolved over the last few decades. Deep brain stimulation (DBS) for treatment-resistant depression has been the subject of clinical trials for more than a decade. A DBS trial involving 17 individuals (10 with major depressive disorder, seven with bipolar disorder) showed promise. Significant improvements were realized in all measures, and no large clinically meaningful or statistically significant differences occurred between the two groups. Based on positive results of multiple trials, some experts believe DBS may become a first-line or second-line treatment for treatment-refractory depression and bipolar disorder in the next five years.

A 2000 study found that 17 out of 22 individuals with treatment-refractory bipolar disorder with symptoms of mania and psychosis showed at least 20% improvement in several major measurement scales after treatment with clozapine. More recently, a case study was published involving a 17-year-old male diagnosed with bipolar mania, who, 2 ½ years prior, functioned with medications but experienced frequent relapses, in part due to noncompliance. After being admitted to an inpatient psychiatric unit, he was treated first with risperidone (12 mg daily for four weeks), followed by olanzapine (30 mg daily for three weeks), and haloperidol (30 mg daily for three weeks), along with 1,500 mg of valproate, daily. After being unresponsive to these drugs, he responded adequately to 100 mg clozapine and 1,500 mg valproate, with remission occurring within two weeks. Clozapine should be considered as a viable option for resistant mania.


Choose a better life. Choose recovery.