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Treatment-Resistant Bipolar Disorder

Jul 30, 2021

Bipolar disorder is a mental condition that causes the mood to shift from emotional highs to depressive lows. There are a number of known treatments that work relatively well when taken as prescribed. However, when conventional treatments fail, the condition is known as treatment-resistant bipolar disorder.

Signs and Symptoms

The periods of emotional high are characterized by periods of mania where the person may:

  • Feel jumpy or wired
  • Have a decreased need for sleep
  • Experience a loss of appetite
  • Talk about a lot of things very quickly
  • Experience racing thoughts
  • Feel they can do anything
  • Experience feelings of grandeur
  • Spend, eat or drink excessively or engage in reckless sexual activity.

In contrast, the periods of emotional lows are usually characterized by:

  • Depressive episodes
  • Poor concentration
  • Inability to do even simple things
  • Increased appetite and associated weight gain
  • Loss of interest in things that usually bring enjoyment
  • Periods of self-isolation

First-Line Treatments of Bipolar Disorder

Most of the pharmacological agents used in the management of bipolar disorder focus on mood stabilization.


Lithium is used for the treatment of episodes of mania, including those experiencing psychosis. It is also the only mood stabilizer that has shown efficacy in treating depressive episodes and preventing suicidal ideations. The mitigation of relapse when taking Lithium is estimated to be between 40% and 64%.

Lithium has been the mainstay maintenance treatment for some time.


Anticonvulsants used in the treatment of bipolar disorder include Sodium Valproate, Divalproex, Carbamazepine, and Tegretol. Anticonvulsants work by decreasing brain excitation, enhancing inhibition by blocking low-voltage sodium gated channels. They also lower glutamate and other excitatory amino acids and potentiating GABA levels.

These medications typically work best during manic episodes as a general rule. The side effect of weight gain is often one of the primary reasons for non-adherence.

First Generation Atypical Anti Psychotics

These medications include risperidone, quetiapine, and aripiprazole. Anti-psychotics are especially effective in treating episodes of mania or hypomania.

Patients taking first-generation antipsychotics need to be monitored closely for metabolic syndrome, which includes weight gain, glucose intolerance, diabetes mellitus, and hyperlipidemia.

Anti Depressants

Anti-depressants are more commonly used for treating depressive episodes and are less effective in the treatment of mania.

Treatment-Resistant Bipolar Disorder

There is no precise definition of treatment-resistant bipolar disorder. Generally, several factors are taken into account when determining if a patient is resistant to treatment. These include the number of manic or depressive episodes, the number of times that treatment has failed, the attempts to use combined therapies, and the exclusion of factors such as non-compliance.

It is important to note that non-compliance is an issue among bipolar patients, especially during the maintenance phase, where many perceive the side effects of the pharmacological treatments to outweigh the benefits.

When the first-line treatments fail to be effective, there are several second-line treatments to consider. These have varying degrees of success.


The options for treatment-resistant bipolar include the anticonvulsants:

  • Phenytoin
  • Levetiracetam
  • Topiramate
  • Gabapentin
  • Tiagabine

Adjunctive Psychotherapies

Adjunctive psychotherapies that should also be considered include:

  • Family-focused treatment
  • Cognitive Behavioral Therapy
  • Group psychoeducation
  • Interpersonal and social rhythm therapy


Clozapine has been used for over 30 years in the management of treatment-resistant bipolar disorder. It is an atypical antipsychotic. There is increasing evidence to suggest it can modify the disease process and reduce the burden of the disease resulting in significant improvements.

Clozapine is often a reluctant choice due to its side effect profile which includes dry mouth, excessive drooling, weight gain, and increased seizure risk. Those taking clozapine should be monitored closely, especially when titrating the dosage for signs of tachycardia and prolonged QT interval. Clozapine is associated with cardiomyopathy. It is also vital to monitor white cell counts due to the risk of agranulocytosis.

Brain Stimulation Therapies

Brain stimulation therapies have shown some effect in the management of treatment-resistant bipolar.

ECT Therapy

Electroconvulsive therapy is an effective treatment for severe manic or depressive episodes associated with bipolar disorder. It is especially effective when the symptoms include increased risk of suicidality, psychotic symptoms, or when the other first-line treatments have been ineffective.

VNS Therapy

Adjunctive vagus nerve stimulation is an appropriate treatment for bipolar disorder when the patient has shown resistance to conventional treatments or cannot tolerate conventional treatments.

It is generally well tolerated by patients and has shown to be especially effective in patients suffering from treatment-resistant depressive episodes that are destabilizing.

TMS Therapy

Transcranial Magnetic Stimulation Therapy is another brain stimulation therapy that is becoming increasingly popular in managing treatment-resistant bipolar disorder.

It has been shown to improve cognition in patients suffering from depressive episodes. Despite some concerns from medical professionals, for some patients with bipolar depressive symptoms, TMS would be too stimulating and flip them into a period of mania. TMS has shown itself to be an effective intervention and is gaining in popularity among some members of the medical profession.

The nature of bipolar is such that it is often difficult to control the symptoms with medications alone. The added difficulty associated with the side effect profile of many medicines means that when patients are well, they become reluctant to take them. This makes patients non-compliance a significant issue, resulting in relapses.

This also makes it difficult to define precisely when someone is resistant to treatment when suffering from bipolar disorder. However, the promise shown by many of the brain stimulation therapies could in the future open a new pathway for patients who have bipolar and limit the need for some of the medications, which would undoubtedly win favor with many patients. The difficulty may be persuading patients to try these therapies, given their historical use.

Make a Choice

The bottom line is that bipolar disorders need treatment but deciding which one is right for you or a loved one is the key. Here at Brain Therapy TMS our staff stands ready to help and educate you on the many benefits of TMS for bipolar disorder, call us today.

Considering TMS Treatment? Schedule a Consultation!

Tired of the results you’re getting from your standard treatment? Transcranial Magnetic Stimulation may be able to increase your chances of long-term remission, reducing your symptoms and allowing you to live a more joyful life.




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