What The Current Research Says About Treatment-Resistant Bipolar Depression
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Treatment-resistant bipolar depression (TRBD) occurs when symptoms of bipolar disorder do not respond well to typical pharmacological treatments, such as antidepressants, antipsychotics, and mood stabilizers. Current scientific research is exploring the effectiveness of alternative methods that may be effective for TRBD when the standard mechanisms are not adequately effective. While research into these new modes of treatment is relatively scarce, some treatment methods are emerging as promising. Below, learn more about these options and the symptoms of treatment-resistant bipolar disorder and depression.
Understanding treatment-resistant bipolar depression
Bipolar disorder (previously called “manic depression”) is characterized by mood states called hypomania, mania, and depression. Mania describes a condition of abnormally elevated energy levels that can affect mood, emotions, and activity level.
A major depressive episode may follow a period of mania. Symptoms of bipolar depression may include:
- Sadness, emptiness, or hopelessness
- A loss of interest in previously enjoyed activities
- Weight fluctuations
- Sleep disturbances
- Low energy
- Difficulty concentrating
- Suicidal thoughts or behaviors
Symptoms of bipolar depression are similar to those of major depressive disorder (also known as unipolar depression). However, bipolar and unipolar depression are distinct conditions.
The criteria for treatment-resistant bipolar depression include “failure to reach sustained remission or tolerate at least two different adequate treatment trials after at least eight weeks at therapeutic doses with acceptable adherence.” Mood stabilizers, antipsychotics, and other standard treatments for bipolar disorder may be used in these trials. Treatment-resistant depression may lead to prolonged depressive episodes that may become difficult to manage.
The challenges of treating TRBD
Because TRBD mimics other mood disorders, diagnosing and treating symptoms may be challenging. Symptoms such as persistent low mood, fatigue, and cognitive impairment often overlap with those of major depressive disorder (MDD), sometimes making an accurate and assured diagnosis complicated.
However, unlike MDD, which is characterized solely by depressive episodes, TRBD involves the cyclical mood swings of bipolar disorder, including manic or hypomanic episodes. Additionally, the fluctuating nature of bipolar disorder can complicate the assessment of treatment efficacy.
Individuals with treatment resistance are at an increased risk of social isolation, functional impairment, and self-harm, underscoring the need for innovative therapeutic methods and personalized approaches to improve treatment outcomes and enhance individuals’ overall well-being.
Current research on the underlying mechanisms of bipolar disorder
Treatment-resistant bipolar depression has been reported in approximately one-fourth of individuals with diagnosed bipolar disorders. Genetic and neurobiological research has shed light on some mechanisms that may cause or intensify TRBD, including the following:
- Genetic factors: Polygenetic risk scores and familial inheritance patterns suggest a strong genetic component of TRBD.
- Neurobiological mechanisms: Neurotransmitter dysregulation and altered brain circuitry may contribute to mood instability.
- Role of inflammation: Elevated cytokine levels and immune system dysfunction are associated with depressive episodes.
The likelihood of being diagnosed with treatment-resistant bipolar depression may be affected by the presence of the above risk factors, chronic stress, and the presence of comorbid conditions like anxiety disorders or a substance use disorder. Understanding these mechanisms may help scientists develop targeted therapies that are tailored to the root causes of each individual’s needs and improve their treatment response. In addition, treatments for co-occurring conditions can be developed, such as anxiety treatments that also support bipolar disorder.
Neurotransmitter imbalances in TRBD
Neurotransmitters like dopamine, serotonin, and norepinephrine transmit signals between nerve cells in the brain. Depressive symptoms are associated with low levels of serotonin, a pleasure hormone, which can cause low mood, lack of pleasure, and sleep disturbances. Dopamine transmission is also often dysregulated in cases of TRBD, which can cause mood instability and anhedonia, reinforcing the symptoms of low mood associated with decreased serotonin levels.
Some research supports that high concentrations of glutamate, an amino acid, may contribute to the onset of depressive symptoms by contributing to excitotoxicity and mood episodes. Homing in on the specific hormonal imbalances associated with TRBD may make way for novel treatments like ketamine and Esketamine to restore neurotransmitter function and alleviate symptoms of TRBD.
Genetic factors contributing to bipolar disorder
Like many mental health conditions, TRBD is associated with genetic risk factors. For example, having a family history of bipolar disorder increases an individual’s risk of having the disorder. The heritability of bipolar disorder is estimated to be between 79% and 93%.
However, research has identified several specific genetic markers associated with mood instability. Variations in the CACNA1C and ANK3 genes have been linked to bipolar disorder in European populations, but contradictory results have been found in other populations. Analysis of a more diverse sample population may be required to solidify the link between these genes and bipolar disorder. Further genetic testing based on specific genetic profiles can help identify which medications are most likely to be effective for individual patients with TRBD.
Innovative approaches for treating TRBD
Ketamine and Esketamine are rapid-acting NMDA receptor antagonists that may reduce symptoms of depression quickly—often within a matter of hours. While these therapies have been approved for treatment-resistant depression, they have not yet been approved for treatment-resistant bipolar depression. However, preliminary studies support that Esketamine therapy may be effective for TRBD.
Transcranial magnetic stimulation (TMS) is another novel treatment method for treatment-resistant depression that involves noninvasive brain stimulation that targets mood-regulating regions. Researchers hypothesize that TMS could be effective for TRBD, but further research is required to determine whether this lack of significant differences in outcomes is scientifically supported.
Another emerging therapy for treatment-resistant bipolar depression is psilocybin-assisted therapy. Randomized controlled trials of repeated doses of psilocybin to individuals found that psilocybin-assisted therapy was effective, safe, and tolerable to subjects with TRBD—without serious adverse events.
The BetterHelp platform is not intended to provide any information regarding which medication or medical treatment may be appropriate for you. The content provides generalized information that is not specific to one individual. Do not take any action without consulting a qualified medical professional.
Study insights: The role of brain stimulation in reducing bipolar depression
Vagus nerve stimulation (VNS) is another emerging therapy, with one 2020 study finding that 63% of those treated with VNS in addition to standard methods had a significant reduction in depressive symptoms. However, more research is needed as this study was not a placebo-controlled trial.
Pointedly stimulating other brain regions associated with mood and cognitive function—such as the subgenual anterior cingulate cortex and nucleus accumbens—with magnetic seizure therapy and other methods may also be helpful in future TRBD approaches. Deep brain stimulation could potentially be used in cases where an individual meets multitherapy-resistant criteria for bipolar depression. However, more research into these alternative methods is necessary.
Study insights: Efficacy of lithium augmentation for bipolar disorder
A 2022 review of clinical trials and meta-analyses explored the effectiveness of lithium augmentation in individuals with TRBD. The results of the study found that lithium:
- Improved response rates to treatments
- Reduced relapse frequency into future manic episodes
- Could be relatively safe and tolerable regarding side effects
The study also notes that while lithium is particularly effective in preventing the onset of future manic episodes, it is less effective in preventing depressive episodes. This study suggests that lithium treatments are best used in conjunction with other methods as part of a holistic treatment plan.
Emerging treatments for treatment-resistant bipolar depression and major depressive disorder
Ongoing research is exploring innovative treatment solutions, including:
- Psychedelic-assisted treatment, focusing on psilocybin and MDMA
- Neurostimulation technologies, including transcranial direct current stimulation and closed-loop deep brain stimulation
- Digital tools that integrate artificial intelligence to improve mental health monitoring and offer virtual support communities that enhance personalized treatment plans
Role of psychotherapy in major depressive episodes
Specific psychotherapeutic approaches may supplement prescription medications for TRBD. These include cognitive-behavioral therapy (CBT), which addresses harmful thought patterns and coping strategies, and dialectical behavior therapy (DBT), which enhances emotional regulation and distress tolerance. Therapy may become critical to improving treatment adherence and long-term outcomes of TRBD.
Addressing major depressive episodes in bipolar disorder
Research supports that a comprehensive approach to managing depressive episodes of bipolar disorder might include:
- Mood stabilizers to prevent mood swings (talk to your doctor about the best options for you)
- Psychotherapy, which can enhance emotional regulation and treatment adherence
- Lifestyle modifications, such as healthy sleeping levels, regular exercise, and nutritious eating to support overall well-being
Consulting with a licensed health practitioner is advisable when treating bipolar disorder.
Online therapy for TRBD symptoms
Online therapy through a platform like BetterHelp may be beneficial for individuals with TRBD who have difficulty leaving their homes due to their depressive symptoms. Digitally administered therapy allows patients to connect with a mental healthcare specialist from wherever they have secure, reliable internet access, practically eliminating geographical limitations associated with commuting to time-inflexible in-person appointments.
Certain long-term studies, like the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder, work to analyze the effectiveness of a combination approach that includes pharmacological and psychosocial methods of treating bipolar disorder. This particular NIMH study found that participants who received intensive psychotherapies had a more successful recovery rate (64%) than others.
Online therapy is equally as effective in treating bipolar depression alongside lithium as its in-person counterpart, suggesting that it is a viable alternative for individuals living with TRBD. However, more research is necessary to determine its overall effectiveness for TRBD.
Takeaway
Can bipolar disorder become treatment-resistant?
Treatment-resistant bipolar disorder can occur in some people, especially those who experience longer depressive episodes. For example, some people with unipolar and bipolar depression experience depressive episodes for months that do not improve with traditional treatment methods like psychotropic medications, antidepressants, adjunctive therapy, and other treatments. They may only respond to complex treatment regimens, which can be more invasive, such as magnetic seizure therapy, electroconvulsive therapy, ketamine, psychadelics, and intense adjunctive topiramate treatment. Do not try, change, or stop any treatment without consulting a medical doctor.
Why do people with bipolar disorder isolate themselves?
Not everyone with bipolar disorder has the same symptoms. However, some people may experience symptoms similar to other mental disorders, like major depressive disorder, which can cause isolation and social withdrawal. Depression can reduce motivation, which can impact every aspect of daily life, including hygiene, self-care, eating, sleeping, and socializing. Socialization may seem overwhelming or difficult because the person struggles to care for themselves, work, and get their daily tasks done. They may also have negative thoughts about themselves or convince themselves that people in their lives don’t love or care about them. If you love someone with bipolar disorder, reach out when you notice them retreating, and remind them they are important to you.
What happens when bipolar meds don't work?
In cases of treatment-resistant unipolar depression or treatment-resistant cases of bipolar disorder, people often don’t respond to multiple medications. Acute mania can occur frequently, or the person may have acute bipolar depression that is difficult to control and severe. Previously referred to as a “manic-depressive illness,” bipolar disorder is considered severe, and finding the proper maintenance treatment for symptoms can be a process. Suppose your doctor notices that no medications or therapy are helping you. In that case, they might recommend alternative treatments, such as ECT, TMS, Ketamine, anxiety treatments, and other options that were developed to treat long-term refractory bipolar disorder and medication-resistant bipolar depression.
What is the best medication for treatment-resistant depression?
Every person responds differently to different medications. Antipsychotics, antidepressants, and mood stabilizers are the most common medications prescribed for bipolar disorder. According to the American Psychiatric Association and multiple systematic reviews in journals like Arch Gen Psychiatry, those with bipolar I disorder who struggle with manic episodes may be prescribed lithium, which is one of the most common and widely used medications for severe bipolar disorder. However, research all options before starting, and consult your doctor.
How do you deal with a bipolar person not on medication?
Medication adherence can be difficult for people with bipolar disorder, as they may go off their medications when they start to feel better, leading to a manic or depressive episode. If you’re worried about the individual, let them know. Remind them of the benefits of taking their medication and tell them to talk to their psychiatrist if they’re concerned about side effects like a dull mood.
Can bipolar depression go into remission?
Bipolar disorder tends to cause episodes of depression, hypomania, and mania. People with this condition aren’t depressed or manic every day forever. Instead, they may go through a few months of depression, followed by a couple of weeks of mania or a few days of hypomania. In these cases, treatment can be essential to target the episodes and stop them from worsening.
What is the life expectancy of someone with bipolar depression?
The life expectancy of people with bipolar disorder is 11 to 20 years less than average. However, those who seek treatment, continue to care for themselves, and work on healthy behaviors may increase their chances of long-term success and livelihood.
Can you stop a bipolar depressive episode?
You can prevent depression when you live with bipolar disorder by practicing healthy lifestyle habits, adhering to your treatment plan, and seeking help when symptoms arise. If you are on medication, take your medication as prescribed. If it helps, get a weekly pill counter where you can track when you’ve taken your medications to keep yourself accountable. In some cases, depression may arise even if you’re doing everything on your treatment plan. If you notice worsening symptoms or a depressive episode, talk to your therapist or doctor about options.
What is the new hope for treatment-resistant depression?
Researchers are always looking for new methods of treatment for treatment-resistant conditions like treatment-resistant depression. Transcranial magnetic stimulation therapy (TMS), electroconvulsive therapy (ECT), and ketamin-assisted therapy are a few popular new options.
How do you snap out of a bipolar depressive episode?
You can’t “snap out” of a mental illness. However, you can try treatment options like medication, therapy, and others to reduce the severity of your symptoms or prevent an episode altogether. Talk to a therapist or psychiatrist to learn more.
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