Treatment-Resistant Bipolar Disorder: A Formidable Foe

Treatment resistance in bipolar disorder is very common. Even with optimal care, which includes medication combinations, 50 percent of bipolar individuals who achieve symptom remission will relapse within two years. And although clinically familiar, the concept of treatment resistance lacks a standard definition upon which clinicians and diagnosticians can reliably agree. Another area of disagreement is pharmacological management. Combining medications is a routine practice and the number of potential combinations is considerable. There is little sound, clinical evidence to drive decisions about which medications to use first, and how these should be dosed. In short, both the notion and management of treatment-resistant BPD is all over the place.


When working with these patients, you’re likely to encounter some or even most of the following: suicide risk is highest among all psychiatric disorders at 20 percent; 25 percent have an alcohol problem. Most will find their way to your offices by way of the criminal justice system or because they’ve taken unreasonable risks and are considered a danger to themselves or others, particularly during the manic phase.

They typically don’t present to treatment during the manic phase because mania is a desired state, and if they do, ego concerns, arrogance, a sense of entitlement, a lack of awareness, and an inability to calculate the consequences of their behavior often accompany the classic manic symptoms. Confirming a diagnosis could literally take years because these patients don’t tend to volunteer information, are poor historians and need constant redirection. Clinicians who are intolerant of unruly behavior can be worn down quickly by these presentations. Clear boundaries should be established from the outset of treatment.

Treatment-resistant Bipolar Mania

Historically, lithium and certain anticonvulsants have been employed as first-line agents for acute mania with antipsychotics reserved for more resistant, very ill, psychotic patients. However, the spectrum of FDA-sanctioned uses for the second-generation antipsychotics in bipolar disorder continues to expand – with some prescribers now utilizing them for moderately ill manic individuals. For truly resistant conditions, Clozaril and ECT are recommended. Despite the innumerable mix-and-match medication strategies for treatment-resistant mania – many of which demonstrate little if any efficacy in comparative studies – the Lithium/Depakote combination still remains optimal in mania prevention.

Treatment-resistant Bipolar Depression

There are few treatments that have demonstrated efficacy in bipolar depression and it is proving to be a tough nut to treat successfully. Only two medications, Seroquel and Symbyax (a Prozac/Zyprexa combination) have been approved. Other recommended agents are lithium and Lamictal. Traditional antidepressants have little if any benefit in bipolar depression and may be associated with a switch to mania. In particular, the serotonin and norepinephrine (SNRI) agents are associated with an ever higher risk of switching. The SNRIs include Effexor, Cymbalta and Pristiq. For patients who do not respond to the drugs of choice listed above, prescriber creativity in finding a combination that can help becomes a must. Lithium, Seroquel and Lamictal can be used in combination with one another. Also, Vagus Nerve Stimulation (VNS) has demonstrated efficacy.

Other Remedies

Medication should always be combined with intensive cognitive-behavioral psychotherapies that include supportive family members whenever possible. Psychotherapy should appeal to patients’ “better angels” and help them harness their creativity by channeling it toward more productive outcomes. Neurofeedback has been associated with positive outcomes.



Treatment-resistant bipolar disorder is highly nuanced, complex and most certainly does not lend itself to black-or-white judgments when it comes to medication management. Polypharmacy will likely be necessary since complications and co-morbidities such as substance abuse are the rule rather than the exception. The most important consideration when employing multiple drug agents is to conceptualize a reason for each medication choice. And clinicians must stress medication compliance as a means to quality of life and survival.


Joe Wegmann is a licensed clinical social worker and a clinical pharmacist with over 30 years of experience in counseling and medication treatment of depression and anxiety. Joe’s new book, To learn more about Joe’s programs or to contribute a question for Joe to answer in a future article, visit his website at, or e-mail him at