MAOIs

What are MAOIs?

Monoamine oxidase inhibitors (MAOIs) are a type of antidepressant medication. They were the first antidepressants developed in the 1950s and are still used today to treat depressive disorders and neurological conditions ^[1].

MAOIs can cause various side effects, dietary restrictions, and health risks, so they are not typically used as a first-line treatment but are still used in necessary circumstances, as they can be effective treatments ^[2].

What are MAOIs used to treat?

The FDA has approved some MAOIs to treat major depressive disorder ^[3]. It is advised not to use MAOIs as a first-line treatment for depression due to their potential risks. However, MAOIs may be the preferred treatment for treatment-resistant depression or atypical depression, with symptoms such as anxiety, increased sleep, or changes in appetite ^[4][5].

Other MAOIs have been FDA-approved for use in treating Parkinson’s disease. They may be used alone or alongside levodopa, a commonly used medication for Parkinson’s, and help to reduce motor symptoms ^[6][7].

MAOIs are occasionally used off-label for uses that are not FDA-approved. This includes ^[1][8]:

• Depressive episodes in bipolar disorder
• Anxiety disorders, particularly social phobia and panic disorder
• Attention-deficit/hyperactivity disorder (ADHD)
• Narcolepsy

How do MAOIs work?

Monoamine oxidase is an enzyme in the brain responsible for degrading and regulating several neurotransmitters, including serotonin, dopamine, and norepinephrine. These neurotransmitters are known as amine neurotransmitters and help regulate several functions, including mood, behavior, energy, cognition, and sleep ^[1][9].

MAO inhibitors prevent the monoamine oxidase enzyme from breaking down these neurotransmitters, thereby increasing their levels. Reduced levels of amine neurotransmitters, particularly serotonin, are known to be involved in the development of depression, so by increasing these levels, MAOIs cause an antidepressant effect ^[10].

There are two types of monoamine oxidase enzymes, called MAO-A and MAO-B. MAO-A impacts serotonin, dopamine, and norepinephrine. In contrast, MAO-B does not impact serotonin but also affects dopamine and norepinephrine ^[1].

There are three types of MAOIs: ones that selectively inhibit MAO-A, ones that selectively inhibit MAO-B, and ones that are not selective, thus inhibiting both MAO-A and MAO-B. As such, each of these MAOIs can cause different effects, with those that inhibit MAO-A having a more substantial antidepressant effect than those that only inhibit MAO-B ^[10].

However, as MAO-A also metabolizes dietary tyramine, MAO-A inhibitors prevent this from occurring, allowing tyramine to enter the bloodstream. This triggers the release of norepinephrine, which results in an increase in blood pressure and a hypertensive crisis, commonly referred to as the ‘cheese effect’ ^[2][10].

Most MAOIs are administered as an oral tablet, which enters the gastrointestinal tract. But a transdermal patch has been developed to provide the antidepressant effects of MAOIs while preventing the ‘cheese effect’, as the medication is absorbed directly into the bloodstream ^[2][11].

Types of MAOIs

There are various types of MAOIs, categorized as MAO-A inhibitors, MAO-B inhibitors, and nonselective MAOIs ^[3][6][10]:

MAO-A inhibitors

• Clorgyline: Clorgyline is not used clinically.
• Moclobemide: Moclobemide is not approved for use in the US but is used in other parts of the world for depression and social phobia.

MAO-B inhibitors

• Selegiline: Selegiline is FDA-approved in the treatment of Parkinson’s disease. It is available as an oral tablet to be swallowed whole under the brand names L-deprenyl and Eldepryl. It is also available as an orally disintegrating tablet under the brand name Zelapar.
• Rasagiline: Rasagiline is FDA-approved for treating Parkinson’s disease. It is available as a tablet under the brand name Azilect.
• Safinamide: Safinamide is FDA-approved for treating Parkinson’s disease. It is available as a tablet under the brand name Xadago.

Nonselective MAOIs

• Phenelzine: Phenelzine is FDA-approved for the treatment of depression. It is available as a tablet under the brand name Nardil.
• Tranylcypromine: Tranylcypromine is FDA-approved for the treatment of depression. It is available as a tablet under the brand name Parnate.
• Isocarboxazid: Isocarboxazid is FDA-approved to treat depression. It is available as a tablet under the brand name Marplan.
• Transdermal Selegiline: Transdermal selegiline is FDA-approved to treat depression. It is available as a skin patch under the brand name Emsam.

Side effects of MAOIs

Common short-term side effects of MAOIs include ^[2][3][6]:

• Nausea
• Drowsiness
• Dizziness
• Insomnia
• Stomach upset, including diarrhea and constipation
• Increased suicidal ideation: This risk is higher in people under the age of 24 and within the first few weeks or months of a new treatment. If you notice emerging or increasing thoughts of self-harm or suicide when commencing MAOI treatment, inform your doctor or mental health professional immediately.

Possible side effects of long-term MAOI use include ^[2][4]:

• Weight gain
• Sexual dysfunction
• Muscle pain
• Muscle spasms
• Numbness and tingling
• Difficulty passing urine

MAOI withdrawal symptoms can occur when abruptly stopping the medication. This can include ^[1][12]:

• Nausea
• Vomiting
• Fatigue
• Agitation
• Irritability
• Insomnia
• Psychotic symptoms such as delusions and hallucinations

To prevent withdrawal, your doctor will likely reduce your dose gradually. It is important not to suddenly stop MAOI treatment, as this can increase the risk of withdrawal symptoms.

Possible interactions with MAOIs

Serotonin syndrome

MAOIs can contribute to the onset of serotonin syndrome if used alongside other antidepressants or medications that increase serotonin. Dangerously high serotonin levels can cause serotonin syndrome and can, in some cases, be fatal. Symptoms of serotonin syndrome include ^[2][11]:

• Fatigue
• Change in mental state
• Hallucinations
• Stomach pain
• Diarrhea
• Kidney failure
• Shaking
• Irregular heartbeat
• Fever
• Sweating

It is advised not to use MAOIs while using SSRIs, SNRIs, TCAs, other MAOIs, bupropion, and amphetamines. When changing between one of these medications and an MAOI, it is advised to wait at least 14 days between the last dose of the previous medication and the first dose of the next. For medicines with longer half-lives, such as fluoxetine, it is necessary to wait longer ^[2].

‘Cheese effect’

The hypertensive crisis that MAOIs can cause is often called the ‘cheese effect’. It is caused by the impact MAOIs have on tyramine metabolization in the intestines. The ‘cheese effect’ can cause severe and potentially fatal issues, including ^[4][10]:

• Increased blood pressure
• Headaches
• Irregular or fast heartbeat
• Nausea
• Stroke

As such, it is required to follow a restricted diet when taking an MAOI to help prevent this. Foods high in tyramine should be avoided or limited, such as ^[2]:

• Soy products
• Certain cheeses
• Bananas
• Certain types of meat and fish
• Broad bean pods

Dietary restrictions are not necessary when taking MAO-B inhibitors or the MAOI transdermal patch in a low dose, as these types of MAOIs are not likely to cause this effect.

Drug interactions

Some medications can also cause a hypertensive crisis when combined with MAOIs and should be avoided. This includes ^[1][2]:

• Parkinson’s medications
• Medications that increase dopamine, serotonin, or epinephrine
• Stimulants
• Amphetamines
• Opioids
• Tryptophan
• Vasoconstrictors

Always inform your doctor of all medications you take, whether prescribed or over the counter, before starting a new treatment.

Precautions

People with heart, liver, or kidney conditions may not be able to take MAOIs safely. It is advised to inform your doctor of any existing conditions before starting MAOI treatment, as it may be unsafe to do so, or your doctor may wish to prescribe you a reduced dose and ensure careful monitoring of your physical health ^[4].

Alternatives to MAOIs

Before being prescribed MAOIs, your doctor will likely try an alternative medication that carries fewer risks.

Alternative medications for depression

Several other antidepressant medications are available that will likely be prescribed before trying an MAOI. This includes ^[3][13]:

• Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, and citalopram
• Serotonin and norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine, duloxetine, and levomilnacipran
• Tricyclic antidepressants (TCAs), such as imipramine, amitriptyline, and desipramine
• Atypical antidepressants, such as mirtazapine and bupropion

Alternative treatment for depression

Alongside antidepressant medication, utilizing therapy and self-help techniques is often very helpful. Available therapies that can be effective at managing symptoms of depression include ^[13]:

• Cognitive behavioral therapy (CBT)
• Interpersonal therapy (IPT)
• Psychodynamic therapy
• Mindfulness-based therapy
• Behavioral activation
• Family therapy

Self-help techniques that can be beneficial for managing symptoms of depression include ^[13][14]:

• Talking to others
• Keeping a mood diary
• Relaxation techniques
• Mindfulness
• Avoiding drugs and alcohol
• Spending time outside in nature
• Improving physical health, such as eating a healthy diet, regularly exercising, and following a sleep schedule

Alternative medications for Parkinson’s disease

Many alternative medications can be used to treat Parkinson’s disease, which can be used alongside or instead of MAOIs. This includes ^[6]:

• Dopamine precursors, such as levodopa
• Dopamine agonists, such as pramipexole and ropinirole
• Anticholinergics, such as benztropine and trihexyphenidyl

Additional treatments for Parkinson’s disease include ^[15]:

• Speech therapy
• Physical therapy
• Occupational therapy
• Deep brain stimulation (DBS)