Augmenting the Effects of MAO Inhibitors with Other Medications

Augmenting MAO Inhibitors

This article discusses how to augment the effects of MAO inhibitors with other medications or supplements.

As with any antidepressant, MAO inhibitors may lose effectiveness over time in some people. This phenomenon is sometimes called “pooping out.” This decline may occur relatively quickly, over a few weeks to months, or gradually, over years or decades. In these instances, it is important to evaluate whether there are modifiable factors contributing to the return of symptoms of depression. For example, increased life stressors can be addressed with counseling and new onset hypothyroidism can be treated with thyroid hormone supplementation. Your provider may make dosing adjustments, change medications, and/or augment your MAO inhibitor with a second medication. All augmenting strategies carry some potential for benefits and risks. Some common augmentation choices are discussed below.

Of note, we have found the following combinations to be highly effective:

Parnate + Lithium Carbonate + Ketamine
MAOI + L-Tryptophan + Lithium Carbonate (added after the L-Tryptophan is added since Lithium Carbonate may induce presynaptic release of serotonin)

L-Tryptophan

L-Tryptophan is an over-the-counter supplement and precursor to 5-HTP. It is an amino acid or building block of protein. [1, 2]
While we have observed therapeutic effects typically require doses >2,500 mg, patients should be started on no more than 125 mg per day and should very slowly increase the daily dose.
Patients should be educated about the high likelihood of experiencing serotonin syndrome and should only supplement a MAOI in the ambulatory setting with a L-Tryptophan if adequate monitoring can occur including monitoring by family or roommates.
In patients not on MAOIs, PET scan studies have found that taking 2 grams of L-Tryptophan every 8 hours would maximize serotonin production (i.e., no significant benefit was observed at higher doses in the average subject) and taking 3 grams at once would maximize serotonin production for 8-12 hours. [3] Researchers also noted that taking high doses of L-Tryptophan induced production of more Tryptophan 2,3-dioxygenase (TDO), an enzyme that degrades L-Tryptophan before it enters the brain.
L-Tryptophan also competes with other amino acids, the building blocks of protein, to enter the blood brain barrier and thus should be taken on an empty stomach or with foods containing low protein content. [4] This is particularly important because delayed absorption into the blood brain barrier allows L-Tryptophan to be degraded by TDO or diverted into other pathways such as building proteins and niacin. Interestingly, carbohydrates have been found to increase the absorption of L-Tryptophan to the blood brain barrier.
L-Tryptophan may help promote sleep which has an added value for patients on MAOIs since MAO inhibitors frequently cause temporary insomnia. [5, 6]

5-HTP

Similar to L-Tryptophan, 5-HTP is a precursor to serotonin. [4]
Unlike L-Tryptophan, 5-HTP does not compete with other amino acids for entrance through the blood brain barrier and avoids the rate-limiting step in the synthesis of serotonin from L-Tryptophan: the conversion of L-Tryptophan to 5-HTP. [7] Despite this theoretical benefit, however, we have anecdotally observed L-Tryptophan to typically be more effective than 5-HTP in augmenting the effects of MAOIs. And due to its short half life, it is has been proposed that extended-release 5-HTP may be necessary to obtained a sufficient and sustained increase in serotonin necessary to produce a clinical effect. [8] Nevertheless, a study looking at immediate-release 5-HTP, found this supplement to be a successful adjunctive treatment to an MAO inhibitor. [9]
Consistent with these studies, we have found an effective dose range of 5-HTP for augmentation of a MAO inhibitor to be 100-400 mg. Similar to L-Tryptophan, 5-HTP should be added slowly and patients should be educated to carefully monitor for signs and symptoms of serotonin syndrome and only done in the ambulatory setting if appropriate monitoring, typically with family members or roommates, can occur.
Supplementation with L-Tryptophan or 5-HTP, some argue, should be done with addition of other neurotransmitter precursors since increasing production of serotonin may deplete dopamine and other neurotransmitters. [10 – note that this article has been retracted by the journal due to undisclosed conflicts of interests; however, we believe this section of it provides a well-written summary of other non-retracted studies that have argued for a neurotransmitter precursor cocktail]

Wellbutrin (Bupropion) XL

Well-supported by the literature for MAO inhibitor augmentation, Wellbutrin has successfully been used in the literature and in our experience has a high success rate in patients who responded to wellbutrin monotherapy prior to trying a MAO inhibitor. [11, 12]
Wellbutrin also is effective in treating a wide range of addictions including addictions to nicotine, methamphetamine, and cocaine [13-15] as well as treating ADHD. [16]
Wellbutrin is contraindicated in patients with a history of seizures, seizure disorder, or epilepsy.

NAC (N-Acetylcysteine)

NAC is an over-the-counter medication with doses up to 1 g twice per day used to augment MAO inhibitors. [17]
Like all supplements, NAC is not regulated by the FDA and thus the quality and accuracy of the product label is not guaranteed.
There is very limited evidence suggesting NAC may be linked to the potential development of lung cancer; however, a much larger body of evidence suggests it is protective against lung cancer. [18-20]
NAC decreases inflammation of the liver and may improve mood through decreasing oxidative degradation of dopamine. [21, 22]

Lithium Carbonate

Lithium is highly effective option for some patients and is well-supported by the literature.
Given it’s narrow window for optimal therapeutic effects relative to side effects, Lithium requires regular lab monitoring.
Long-term use of lithium is associated with kidney damage. [23, 24] This risk may be mitigated by dosing lithium once per day at night instead of twice daily as it is commonly dosed. Once daily dosing may allow for greater time periods where lithium levels are low to maximize improved kidney regeneration and may be tolerable due to its long half-life. [25, 26]
Those who may be more sensitive to lithium, such as the elderly and those taking diuretics or “water pills” are generally advised to start with 150 mg nightly while others often started at 300 mg nightly. The daily dose is often increased by 150-300 mg each week. When at daily doses is 600-900 mg, blood level should be checked to ensure they are not in excess of 0.8 mmol/L. To minimize kidney damage, attempts should be made to keep doses lower than 0.6 mmol/L. However, in cases of severe depression or mania, doses may be increased to up to 1.2 mmol/L for a brief period of time. Lithium levels should be checked 24 hours (at trough) after last dose. As this is inconvenient with nighttime dosing, the blood level may be checked 12 hours after the last dose and the result should be divided by 1.3 prior to interpretation. [27]

Atypical Antipsychotics

In addition to augmenting the effects of MAOIs, second-generation or atypical antipsychotics may promote sleep, reduce anxiety, and reduce obsessive thoughts or compulsive behaviors. [28]
These drugs are associated with short-term motor or muscle problems that are often treatable to medications such as Benadryl or propranolol.
These drugs are associated with tardive dyskinesia, a permanent side effect that typically involves involuntary twitching of facial muscles. The risk of developing tardive dyskinesia is typically 1-10% per year of antipsychotic medication use and dependent on several factors including the type of antipsychotic, length of use, dose used, and age of the patient.
Additional side effects include sedation, weight gain, increased risk of developing diabetes, and increased cholesterol. However, these risks can be minimized with low, infrequent doses taken at night and with the use of metformin off-label to suppress appetite.
Several atypical or second-generation antipsychotics are listed below. [29]

Seroquel (Quetiapine)

Major Effects: Highly sedating and minimally-to-moderately effective for anxiety and psychosis
Risk of Tardive Dyskinesia (permanent but treatable side effect): Minimal with some studies even suggesting that Seroquel may be protective against tardive dyskinesia
Risk of Other Muscle Issues (temporary and treatable side effects): Minimal, however, some patients experience restless legs
Risk of Diabetes or Increased Cholesterol (typically easily preventable and treatable): Minimal-to-Moderate if only taken before bed. Moderate-to-High if taken during the day.

Abilify (Aripiprazole)

Major Effects: Significant antidepressant effects, minimally sedating, moderately effective for anxiety, and minimally-to-moderately effective psychosis
Risk of Tardive Dyskinesia (permanent but treatable side effect): Low
Risk of Other Muscle Issues (temporary and treatable side effects): Minimal
Risk of Diabetes or Increased Cholesterol (typically easily preventable and treatable): Minimal

Risperdal (Risperidone)

Major Effects: Highly effective for anxiety and psychosis and minimally sedating.
Risk of Tardive Dyskinesia (permanent but treatable side effect): Moderate
Risk of Other Muscle Issues (temporary and treatable side effects): Moderate
Risk of Diabetes or Increased Cholesterol (typically easily preventable and treatable): Very minimal

Latuda (Lurasidone)

Major Effects: Moderately sedating and moderately effective for anxiety and psychosis.
Risk of Tardive Dyskinesia (permanent but treatable side effect): Low
Risk of Other Muscle Issues (temporary and treatable side effects): Minimal
Risk of Diabetes or Increased Cholesterol (typically easily preventable): Low

Rexulti (Brexpiprazole)

Major Effects: Minimally sedating and moderately effective for anxiety, and psychosis
Risk of Tardive Dyskinesia (permanent but treatable side effect): Low
Risk of Other Muscle Issues (temporary and treatable side effects): Low
Risk of Diabetes or Increased Cholesterol (typically easily preventable): Low

Zyprexa (Olanzapine)

Major Effects: Very sedating (although typically less than seroquel) and moderately effective for anxiety and psychosis.
Risk of Tardive Dyskinesia (permanent but treatable side effect): Minimal-to-Moderate
Risk of Other Muscle Issues (temporary and treatable side effects): Minimal-to-Moderate
Risk of Diabetes or Increased Cholesterol (typically easily preventable and treatable): Moderate if only taken before bed. High if taken during the day.

Clozapine

Major Effects: Typically a last-line antipsychotic because in addition to risk of significant weight gain and significant anticholinergic side effects (detailed above), Clozapine requires weekly labs to monitor for a life-threatening reactions
Risk of Tardive Dyskinesia (permanent but treatable side effect): Low
Risk of Other Muscle Issues (temporary and treatable side effects): Minimal
Risk of Diabetes or Increased Cholesterol (typically easily preventable and treatable): High

Geodon (Ziprasidone) & Caplyta (Lumateperone) – Not recommended for MAOI augmentation as a case study found the drug may have been linked to a case of serotonin syndrome. [30]

Norpramin (Desipramine) or Pamelor (Nortriptyline)

These secondary amine tricyclic antidepressants are effective options for augmenting the norepinephrine system with minimal risk of serotonin syndrome. [31]
Both Desipramine (at doses of 100 mg per day) and Nortriptyline (at doses of 50 mg per day) protect against tyramine-induced hypertension by preventing tyramine from entering cells via the norepinephrine transporter. [32]
Anecdotally, we have noticed increased blood pressure (independent of tyramine consumption) with the addition of these drugs to MAOIs likely due to augmentation of norepinephrine activity.
When tricyclic antidepressants are combined with MAO inhibitors, there is a significant risk of anticholinergic side effects, including dizziness, urinary retention, constipation, and hardened stools. [33] These side effects are often treatable.
Desipramine and Nortriptyline are also effective in promoting sleep which may be of extra utility in patients on MAO inhibitors given MAO inhibitors frequently cause temporary insomnia. [34, 35]
These medications should be used with caution or avoided in patients with heart conditions or diseases.

Anticonvulsants (e.g., Topomax/Topiramate)

Anticonvulsants are frequently used off-label for a wide range of anxiety disorders including social anxiety and generalized anxiety disorder as they are highly effective in monotherapy and adjunctive treatment. [36-38]
Anticonvulsants are sometimes limited by their side effects including fatigue, brain fog, and weight gain; however, most patient do not experience these side effects, particularly at lower doses. [39]

Spravato (Esketamine) Nasal Spray or Ketamine Infusions

Ketamine, as a nasal spray, IV infusion, intramuscular or subcutaneous injection, is an effective medication for augmenting the therapeutic effects of MAO inhibitors. [40-42]
Ketamine is typically more effective when given intravenously, subcutaneously, or intramuscularly compared to intranasally in our experience.
The medication is most appropriate for individuals with depression with some individuals began experiencing relief from depression as early as a few hours after receiving Ketamine although most commonly the benefits are noticed after several days to weeks.
Limitations to Ketamine use include potential worsening of anxiety disorders, vivid dreams or nightmares, and dissociative symptoms. These side effects typically occur within 30 minutes of using the medication and rarely lasts more than 1-2 hours but can be debilitating for some.
Ketamine is usually not used daily but instead one or more times per week.
There is a theoretical risk of increased blood pressure when combining Ketamine with a MAOI and thus blood pressure should be monitored closely.

Synthroid (Levothyroxine) or Thyroid Hormone

Supplemental thyroid hormone may be an effective option but few studies exist explore its role as an augmenting agent for MAOIs.
Endocrinologist often should be involved.
This option should be avoided or used with caution in patients with heart diseases and osteopenia or osteoporosis. [43, 44]

Testosterone

Low testosterone is known to cause depression and depression can cause low testerone.
Endocrinologists often should be involved.
Testosterone has been found to be an effective medication for augmenting antidepressants but its use is restricted due to its status as a controlled substance. [45-47]
Patients taking testosterone, typically prescribed as a gel placed on both shoulders after showering, must get prostate exams yearly due to the slight increased risk of prostate cancer, having regular monitoring of testosterone and other hormone levels, and must avoid having females or children touch their shoulders or other regions of skin where the testosterone may have been applied.

L-Methylfolate

Although little literature exists exploring L-Methylfolate augmentation of antidepressants, it is known to aid in the synthesis of tetrahydrobiopterin (THB) and thus enhance the production of norepinephrine, dopamine, and serotonin. Thus, there is an increased risk of serotonin syndrome when used in combination with a MAOI. [48]
When used to augment antidepressants, including MAO inhibitors, doses of 7.5 mg to 15 mg per day are typically used.

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