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What is bipolar disorder (manic depression) and how is it treated? This article explores treatments, including the use of MAOIs for bipolar disorder.
What is Bipolar Disorder?
Bipolar disorder (formerly called manic depression) is a mental disorder marked by dramatic shifts in mood. Individuals diagnosed with bipolar disorder shift from periods of emotional, euphoric highs, known as mania or hypomania depending on severity, to hopeless depressive lows.
In cases of bipolar disorder, these depressive episodes typically last longer than manic episodes. During the depressive episodes, the patient can experience persistent sadness, lack of motivation, changes in eating or sleeping habits, feelings of hopelessness, and suicidal thoughts.
The Diagnostic and Statistical Manual of Mental Disorders (DSM), Fifth Edition (DSM-5), defines a major depressive episode as having 5 or more of the following symptoms presenting over a two week period and at least one of the symptoms is one of the first two of the following:
In contrast, during a manic episode, they can experience feelings of extreme happiness, racing thoughts, talkativeness, overconfidence, impulsivity, and risky behaviors that are otherwise unusual for the patient. Hypomania is a less severe form of mania that does not significantly impair the patient’s social or occupational life. [1,2]
The DSM-5 defines a mania and hypomania by the following:
A. A distinct period of abnormally and persistently elevated, expansive, or irritable mood and increased activity or energy
B. During this period, 3 or more of the following symptoms (4 if the mood is only irritable) occur:
C. The episode is not due to a substance, medication, or other medical condition
The DSM-5 then notes the following differences between mania and hypomania:
Mania
Hypomania
How Does Bipolar Depression Compare with Major Depression?
Bipolar depression is unique. When compared to patients with unipolar major depressive disorder, bipolar patients, while no more severely depressed, are more likely to experience atypical depressive symptoms. [3] Symptoms such as anxiety, restlessness, insomnia or hypersomnia, and impulsivity, often associated with generally atypical and mixed-state depression, are common signifiers of bipolar depression. [4] These atypical and mixed-state symptoms make depressive states more difficult to treat and manage, and are often mismanaged due to outdated and misinformed clinical criteria. Properly treating these depressive states is vital.
What are the Different Types of Bipolar Disorder?
There are three main forms of bipolar disorder that usually have different clinical presentations. Bipolar I Disorder: is composed of major depressive episodes with manic episodes, Bipolar II Disorder: major depressive episodes with hypomanic episodes, and cyclothymic disorder: low-grade depressive episodes with hypomanic episodes. [5]
Major depressive episodes are common in bipolar I disorder but are not required for the diagnosis. However, patients with bipolar II disorder typically spend the majority of their time in a major depressive state.
What is the Cause of Bipolar Disorder?
The exact cause of bipolar disorder is unknown. It’s believed to be a combination of genetics and environmental factors that result in a cascade of neurological disturbances. Which includes inflammatory changes, oxidative stress, apoptosis, and cellular atrophy. These changes lead to abnormal monoamine signaling, mainly defective serotonin and dopamine pathways, as well as abnormal GABA and glutamate transmission. Resulting in decreased grey matter volume and activity in the prefrontal cortex on brain imaging. This is the part of the brain that’s involved in creative thinking, planning, impulse control, and emotion regulation. [5-8]
Why Does Bipolar Disorder Need Effective Treatment?
In bipolar disorder, the risk of suicide death is up to 30 times higher than in the general population. It is in these depressive states that the risk of suicide is the greatest. [9] Even in absence of suicidal behavior, the disorder causes distress and impairment in not only individuals, but their families. Yet, compared to the treatment of manic episodes, there is a dearth of clinical research into effective treatments for bipolar depression. [10]
What is the Cause of Bipolar Disorder?
The exact cause of bipolar disorder is unknown. It’s believed to be a combination of genetics and environmental factors that result in a cascade of neurological disturbances. Which includes inflammatory changes, oxidative stress, apoptosis, and cellular atrophy. These changes lead to abnormal monoamine signaling, mainly defective serotonin and dopamine pathways, as well as abnormal GABA and glutamate transmission. Resulting in decreased grey matter volume and activity in the prefrontal cortex on brain imaging. This is the part of the brain that’s involved in creative thinking, planning, impulse control, and emotion regulation. [5-8]
Is Bipolar Disorder Curable?
There is currently no definitive cure for bipolar disorder. However, multiple treatment options that are proven to be effective in symptom control are available. The choice of treatment varies with clinical presentation, phase of the disease, and patient’s response to any medications previously prescribed for their condition. The treatment plan for bipolar disorder consists of the resolution of an acute manic episode or depressive episode that the patient may be experiencing, and a long-term maintenance therapy in order to prevent future episodes.
How is Bipolar Disorder Commonly Treated?
The first-line therapy for an acute manic episode is monotherapy with a mood stabilizer such as lithium or valproic acid, an atypical antipsychotic such as quetiapine or risperidone, or a combination of a mood stabilizer and an antipsychotic. [11, 12] Acute depressive episodes are also treated with mood stabilizers and antipsychotics, in combination or in monotherapy. They’re usually more common and last longer than manic episodes. Antidepressants can be incorporated into the treatment regimen for patients who don’t respond well to the first-line therapy. They’re not prescribed alone and can only be used along with mood stabilizers or antipsychotics. [13-15] The antidepressants that can be used are selective serotonin reuptake inhibitors (SSRI) such as fluoxetine, combined serotonin and norepinephrine reuptake inhibitors (SNRI) such as duloxetine, tricyclic antidepressants (TCA) such as imipramine, and monoamine oxidase inhibitors (MAOIs).
The effectiveness of these more common antidepressants as treatments for bipolar depression is uncertain. Compared to typical unipolar depression, bipolar depression research into effective treatments is lacking. While no antidepressants, other than the combination of the SSRI fluoxetine with olanzapine, are specifically approved for bipolar disorder, small-scale research exists that indicates that the more common antidepressant classes (SSRIs, SNRIs) may be effective second-line medications for treating bipolar depression when mood stabilizers are ineffective at controlling symptoms alone. [8] The research into this topic however is limited, and evidence exists that indicates that an SSRI taken with a mood stabilizer is about as effective in influencing durable recovery from a depressive episode as a mood stabilizer taken alone. [16]
What Additional Risks Do These Treatments Have?
There are several risks associated with prescribing any antidepressant to treat episodes of bipolar depression. When treating bipolar disorder, typically antidepressants should not be prescribed or taken without a mood stabilizer. In those with bipolar disorder, particularly type I, antidepressants may worsen symptoms by causing patients to shift from a depressive state into states of mania or hypomania. Taking antidepressants alone may also lead to or worsen rapid cycling, where one experiences four or more distinct manic or depressive episodes within a year. Given this risk, and limited research indicating the actual effectiveness of commonly prescribed antidepressants, such as SSRIs and SNRIs, common antidepressants are recommended to only be prescribed when other better-understood treatment methods are exhausted. [12]
What is the Role of MAO Inhibitors in Bipolar Disorder?
Although bipolar depressive episodes present atypically to more standard unipolar depression cases, the use of similar diagnostic criteria for depressive episodes in both unipolar and bipolar depression cases has caused treating physicians to favor SSRIs and SNRIs for the treatment of bipolar depression. [25]. Bipolar depressive episodes tend to present with symptoms more congruent with atypical and treatment-resistant depressions, rather than the typical symptoms seen in most unipolar depression cases. This atypical presentation has been associated with poor treatment outcomes with standard antidepressant regimens. [4] In atypical depression cases like bipolar episodes, MAOIs are well documented as more effective than standard antidepressant treatments for depression (SSRIs and tricyclic antidepressants). [26]
A retrospective analysis of a clinical trial found that patients with bipolar disorder who were treated with a MAOI had a higher percentage, as well a higher speed of recovery than patients who were treated with paroxetine, which is an SSRI antidepressant. Suggesting that MAOIs may be more effective in treating bipolar depression than paroxetine. [16] This doesn’t necessarily mean that MAOI are more effective than SSRIs. A large meta-analysis that compared the safety and efficacy of multiple antidepressants, recommends starting with a MAOI or an SSRI other than paroxetine, if antidepressants are indicated. The study also advises against using tricyclic antidepressants (TCAs) as a first line therapy due to its side effects. [17] When a randomized clinical trial compared Moclobemide, a MAOI, to imipramine, a TCA, the researchers concluded that the two medications were similar in efficacy. They also found that side effects, including mania and anticholinergic symptoms, were more common in patients who were treated imipramine. [18] In another randomized clinical trial, Tranylcypromine, a MAOI, has been shown to be even more effective than imipramine in patients with anergic bipolar depression. [19] And another crossover study found that patients with bipolar depression that is resistant to imipramine respond well when switched to tranylcypromine. [20] A systematic review of the studies comparing tranylcypromine to placebo, imipramine and lamotrigine, which is a mood stabilizer used in bipolar depression [21], found that patients respond significantly better to tranylcypromine than they respond to the other medications. [22] These results suggest that MAOIs have favorable outcomes in terms of efficacy as well as the risk of mania induction when compared to TCAs. [23]
A 2015 expert review on the use of antidepressants in the treatment of bipolar disorder further reaffirms the evidence that antidepressant regimens of MAOIs are more effective at treating bipolar depression than other commonly prescribed antidepressants. [4] When combined with a mood stabilizer, MAOIs are also less likely to induce manic symptoms than standard antidepressant treatments. [4] Another study comparing the efficacy of MAOIs to treatment with the SSRI paroxetine found that compared to 24% of patients with durable remission in the control group, only 27% of patients treated with paroxetine and a mood stabilizer experienced durable remission. In contrast, 58% of patients treated with an MAOI and a mood stabilizer experienced durable remission. Patients treated with an MAOI also saw faster durable recovery than those treated with paroxetine. [16] Based on this research and other recent well-executed studies, MAOIs appear to be more effective for treating the depressive symptoms of bipolar disorder than other commonly prescribed antidepressants.
Unfortunately, despite the evidence that MAOIs are highly effective at treating bipolar depression compared to other existing treatments, MAOIs are chronically under-prescribed, even in cases where they may be an incredibly beneficial treatment. Because of the stigma surrounding MAOIs due to their side effects, many clinicians are hesitant to prescribe MAOIs in cases where they may be effective even though recent research indicates that MAOIs may be more effective at treating bipolar depression compared to other second and third-line prescriptions. [16] Many opt for treatments that have little research to back their effectiveness. [4, 12, 24] Worse, many physicians choose treatments that have proven adverse outcomes in bipolar disorder. Unfortunately, clinicians often rely on assumptions based on research into unipolar depression to treat bipolar patients. However, there is hope, with recent clinical research into atypical forms of depression, and there has been renewed interest and research into MAOIs. Information on the effectiveness of MAOIs in treating bipolar depression has begun to reach an expanded audience of treating clinicians.
What Other Measures Should Be Taken for Bipolar Disorder?
In addition to pharmacological treatment, psychosocial interventions can also be helpful for patients with bipolar disorder. They’re used along with medications and are known to improve disease progression and patient’s well-being. These interventions include cognitive behavioral therapy (CBT), which is a type of psychotherapy that aims to improve the patient’s behavior and help them better understand their mood changes by modifying their thoughts. CBT is more effective during depressive episodes than during manic episode. Patients with bipolar disorder can also benefit greatly from family-focused psychotherapy. Educating family members and giving them the tools to improve communication and mutual understanding can help the patient avoid certain stressors that can aggravate the course of their illness. Interpersonal and social rhythm therapy is another psychosocial intervention that focuses on the patient’s routine and helps stabilize their mood and prevent disturbances in their circadian rhythm. [27-30]
Conclusion
Not all patients experiencing bipolar disorder should be prescribed an antidepressant or an MAOI. In some cases, patients can manage their depressive episodes with mood stabilizers alone. MAOIs are not a cure-all for depressive episodes, but they are a key drug class in any physician’s arsenal when treating bipolar disorder. They are an important and effective treatment for hard-to-regulate bipolar depressive episodes. When administered properly under expert care they are generally safe and can help alleviate some of the difficulty that exists when treating bipolar depression.
Though more research needs to be conducted to identify the most effective MAOI treatment regimens and drug combinations to effectively treat bipolar depression, enough preliminary evidence and recommendations exist to serve as preliminary guidelines for treating physicians in cases of bipolar depression.
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