Bipolar Disorder Treatment with Tricyclics and MAOIs

Among the range of antidepressant medications that have been used to treat bipolar patients experiencing depressive episodes, tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs) are among the oldest modern medicines.

With the advent of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), the use of these older antidepressants is declining. However, there may be advantages to prescribing TCAs and MAOIs to this day. This article explores the efficacy of older antidepressants for managing depressive episodes and outlines key concerns and controversies that surround their use.

What Are Tricyclic Antidepressants (TCAs)?

Tricyclic antidepressants and bipolar disorder have a long history, with TCAs first introduced as a pharmacotherapy for major depressive disorder in the late 1950s. This class of drugs works by inhibiting the reuptake of neurotransmitters in the brain. With neurotransmitters blocked from being reabsorbed, there’s a higher concentration of them in the brain. TCAs, therefore, can increase levels of serotonin and norepinephrine, which in turn helps modulate mood, attention, and pain.

TCAs that have been used to treat patients for depression include:

• Imipramine
• Amitriptyline
• Nortriptyline
• Desipramine
• Doxepin

TCAs were initially prescribed by clinicians to treat bipolar patients experiencing depressive episodes, which can be defined as more than 2 weeks of depressed mood or loss of enjoyment.^[1] While TCAs could be effective for some patients, the drugs weren’t without risks or adverse effects.

Today, TCAs are largely considered second-line treatment options alongside SSRIs for bipolar disorder. They are now more commonly used to treat neuropathic pain, insomnia, and migraines, among other conditions.^[2]

What Are Monoamine Oxidase Inhibitors (MAOIs)?

Monoamine oxidase inhibitors were the first antidepressants ever to be available, initially introduced as a drug in the 1950s. They were used to treat depression as well as other disorders impacting the nervous system, such as panic disorder and social phobia, when other antidepressants were ineffective or unsuitable for a patient.

MAOIs are a unique class of antidepressants that work by blocking the monoamine oxidase enzyme. This, in turn, prevents the enzyme from breaking down neurotransmitters including norepinephrine, serotonin, dopamine, and tyramine.

Similarly to TCAs, it’s this mechanism of preventing neurotransmitters from breaking down (thus increasing their concentration in the brain) that can help patients regulate their mood and overcome symptoms of depression.

Common MAOI drugs currently available for treatment include:

• Tranylcypromine
• Phenelzine
• Isocarboxazid

Historically, MAOI drugs were an option for treating bipolar patients experiencing depressive episodes. However, MAOI drugs used for bipolar disorder are not without controversy. Numerous drug interactions must be considered before prescribing MAOIs. They also require patients to make drastic dietary changes to prevent adverse effects or overdose. For this reason, SSRIs and SNRIs are more commonly prescribed today for depressive episodes than MAOIs.^[3]

How Effective Are TCAs and MAOIs in Treating Bipolar Disorder?

Both medications are effective at blocking serotonin as a method of easing depressive symptoms. However, they are less effective than SSRIs due to being less selective. They also come with more side effects, which is the primary reason they are not preferred over SSRIs and SNRIs.

Research exploring the effectiveness of these medications found that:

• Comparing patients with bipolar and unipolar depression who were prescribed MAOIs, the medication appeared to be more effective (and just as safe) for the bipolar patients.^[4]
• Tricyclic antidepressants are less effective than other antidepressants, with researchers concluding in The American Journal of Psychiatry that “It may be prudent to use a selective serotonin reuptake inhibitor or a monoamine oxidase inhibitor rather than a tricyclic antidepressant as first-line treatment.”^[5]

Ultimately, the mechanism of action for TCAs and MAOIs has proven effective. The primary reason these medications are falling to the wayside compared to modern antidepressants is the vast number of side effects they can elicit in bipolar patients and the dangers they pose.

Side Effects of TCAs and MAOIs

It is imperative that clinicians carefully monitor and manage the administration of any antidepressant, whether it be a TCA, MAOI, or SSRI, to ensure it is effectively treating the depressive episode and that adverse effects are not causing harm.

Common side effects of TCAs include:

• Constipation
• Dizziness
• Confusion
• Weight gain
• Xerostomia (dry mouth)

There’s also evidence that TCAs may increase the risk of cardiovascular complications in patients with preexisting ischemic heart disease and increase the risk of seizures in patients with epilepsy.^[2]

For bipolar patients, in particular, TCAs may induce rapid cycling, switching from depression to mania. This is more commonly associated with TCA antidepressants than it is with non-TCA antidepressants – possibly due to the anticholinergic activity of the drug. TCAs increase the risk of switching even when prescribed alongside a mood stabilizer.^[6][7][8]

As for MAOIs, common side effects include:

• Dizziness
• Sexual dysfunction
• Insomnia
• Headaches
• Weight gain^[9]

There’s also evidence that MAOIs may be linked to a higher risk of kidney disease when prescribed alongside lithium.^[10] Beyond these adverse effects, clinicians must also very carefully consider the drug interactions and dietary restrictions that must be imposed when prescribing MAOIs and the huge impact this can have on the patient’s lifestyle.

Drug Interactions and Dietary Restrictions

MAOIs work by blocking the monoamine oxidase enzyme, which prevents the breakdown of neurotransmitters, including tyramine. This is a problem, as high levels of tyramine can narrow the blood vessels, leading to very high blood pressure.

Bipolar patients who are prescribed MAOIs will need to follow strict dietary restrictions to keep tyramine levels low. Foods high in tyramine that should be avoided include:

• Fermented meats, including pepperoni, bacon, hot dogs, and soy-based meat alternatives
• Pickled or cured fish, including caviar and pickled herrings
• Citrus fruits, including tangerines, oranges, limes, lemons and grapefruits
• Overripe fruits, including avocados and bananas
• Yeast-rich foods, including sourdough bread, marmite, and miso paste
• Pickled foods, including tofu, kimchi, and pickles

As for drug-to-drug interactions, MAOIs should not be prescribed alongside other drugs that have serotonergic effects, such as analgesics, opioids, triptan migraine medications, SSRIs, SNRIs, trazodone, and clomipramine. MAOIs can also interact with drugs that have noradrenergic effects, so noradrenaline reuptake inhibitors and stimulant medications should also be avoided to prevent further increasing blood pressure in patients.^[11]

Like MAOIs, TCAs can also interact with other drugs, particularly those that have a serotonergic effect.^[12] It’s important to avoid this drug interaction as increased serotonin concentrations in the central nervous system can lead to serotonin syndrome, also known as serotonin toxicity. This adverse effect is characterized by autonomic overactivity, hypomania, restlessness, confusion, movement disorders, and, in some cases, rigidity and hyperthermia, which can be life-threatening.^[13]

Special Considerations for Bipolar Patients

For bipolar patients, careful consideration should be made before any antidepressants are prescribed, particularly MAOIs and TCAs, due to the aforementioned risk of triggering manic episodes and rapid cycling.

Although the risk of switching from a depressive to a manic state is considered lower with MAOIs than TCAs, the risk is still present and should be weighed by both clinician and patient.

With regards to predicting whether antidepressants will trigger switching, Michael J Gitlin, Department of Psychiatry, Geffen School of Medicine at UCLA, notes in the International Journal of Bipolar Disorders:

“We cannot know about the risk/benefit ratio of antidepressants for any individual patient. Thus, an antidepressant may be prescribed with [a] patient (and family, if involved) and psychiatrist aware of the potential risks. Both TEAS and cycle acceleration typically occur early in antidepressant treatment and can be monitored.”^[14]

TCAs and MAOIs vs Other Antidepressants

There are numerous antidepressants available for patients with bipolar – including both modern and older options. Research has generally found that:

• Tricyclic antidepressants are less selective than SSRIs, meaning that they have a stronger effect on the body with more side effects and a greater risk of overdose. SSRIs, on the other hand, are better tolerated and less likely to be discontinued as a course of treatment.^[15]
• SSRIs may be better suited for long-term and acute treatment of major depression, particularly as they don’t increase blood pressure or have anticholinergic effects.^[16]
• However, both SSRIs and TCAs have adverse effects. While TCAs may cause dizziness and sedation and prompt anticholinergic symptoms, SSRIs may be more prone to causing sexual dysfunction and gastrointestinal problems.^[17]
• Despite the notable drawbacks to MAOIs regarding dietary changes and drug interactions, they may be preferable for some patients as they induce less switching to mania compared to tricyclic antidepressants. But, overall, SSRIs may have greater efficacy and fewer side effects than either option.^[5]

Clinicians should carefully weigh the benefits and adverse effects of each antidepressant to find the best treatment for any individual patient.

Combining TCAs and MAOIs with Mood Stabilizers

Ultimately, clinicians today may be more likely to prescribe modern antidepressants, namely SSRIs, due to fewer adverse effects and drug interactions compared to traditional antidepressants such as tricyclics and MAOIs.

Regardless of which antidepressant is recommended, most official guidelines highlight that mood stabilizers should be used as the first-line treatment for bipolar depression. Antidepressant treatments can be provided alongside mood stabilizers or supplement them at a later stage in the treatment plan.^[18]

Individuals with bipolar disorder should seek advice from a qualified medical professional regarding antidepressants, mood stabilizers, and other viable treatments for bipolar depression so they can find a medication that works effectively for them.