How Do Other Antidepressants Work?

Antidepressants are medications that are primarily prescribed to treat depression. Antidepressants that do not fall into any specific class of antidepressant drugs are typically categorized as “other antidepressants.” Some of the other antidepressants work in multiple ways, useful for treating disorders other than depression.

Each of the other antidepressant drugs works in a unique way in treating depression and other disorders. The other antidepressants work by regulating the levels and activity of various neurotransmitters in the brain such as:

• Serotonin
• Dopamine
• Norepinephrine
• Glutamate
• Gamma-aminobutyric acid (GABA)
• Histamine

Neurotransmitters are chemical messengers that nerve cells (neurons) release to communicate with each other. Neurotransmitters regulate most physiological functions including breathing, heart rate, and digestion, and are also responsible for learning, memory, sleep, emotions, and behavior.

Neurons have protein molecules known as receptors on their surfaces which initiate appropriate action within the cell when stimulated by neurotransmitters. Each neurotransmitter stimulates specific types of receptors that respond to them and initiate excitatory or inhibitory action.

The medications that are grouped under other antidepressants include:

• Brexanolone: Brexanolone is a synthetic form of allopregnanolone, a breakdown product of the female sex hormone progesterone. Brexanolone is used to treat postpartum depression which occurs in some women due to a sudden drop in hormone levels after childbirth. Brexanolone works by modulating the activity of GABA-A receptors.
• Gepirone: Gepirone is a new drug in clinical trials to treat the major depressive disorder (pending FDA approval). Gepirone is believed to improve mood by binding to serotonin 5-HT1A receptors, which are inhibitory, and by modulating serotonin neurotransmission.  
• Trazodone: Trazodone increases levels of serotonin by inhibiting its reabsorption (reuptake), which improves mood. Trazodone also blocks histamine, inducing sedation.
• Vortioxetine: Vortioxetine is thought to work for depression by increasing serotonin levels and enhancing its activity in the central nervous system.
• Bupropion: Bupropion increases the levels of dopamine and norepinephrine by inhibiting their reuptake, which improves mood, concentration, and energy.
• Esketamine intranasal: Esketamine inhibits the activity of glutamate, an excitatory neurotransmitter, by blocking N-methyl-D-aspartate (NMDA) receptors, which respond to glutamate. It is not clear how esketamine intranasal works for depression, but is usually used for treatment-resistant depression.
• Maprotiline: Maprotiline is a tetracyclic antidepressant, so named because of the four rings of atoms in its molecular structure. Maprotiline relieves depression and anxiety by increasing the levels of serotonin and norepinephrine and modulating their receptors’ activity.
• Mirtazapine: Mirtazapine blocks alpha-2 receptors which are inhibitory, and increases the levels of norepinephrine and serotonin. Mirtazapine also blocks the activity of serotonin receptors 5HT2 and 5HT3 which increase anxiety, and histamine receptors to produce a calming effect.
• Nefazodone: Nefazodone is a selective serotonin reuptake inhibitor (SSRI)/antagonist antidepressant. Nefazodone enhances the availability and activity of norepinephrine and serotonin by inhibiting their reuptake and blocking 5HT-2 and alpha-1 receptors.
• Vilazodone: Vilazodone is a partial SSRI/5HT-1A agonist which works by inhibiting serotonin reuptake and stimulating 5HT-1A serotonin receptors, producing a calming effect.

Other antidepressants may be administered as oral tablets, intranasal sprays, or intravenous (IV) injections. Other antidepressants are used in varying conditions that include the following:

FDA-approved

• Depression
• Postpartum depression
• Major depressive disorder
• Seasonal affective disorder
• Smoking cessation
• Treatment-resistant depression

Off-label

• Insomnia
• Aggressive behavior
• Cocaine withdrawal
• Alcohol withdrawal
• Prevention of migraine
• Attention deficit hyperactivity disorder (ADHD)
• Neuropathic pain
• Anxiety associated with depression
• Posttraumatic stress disorder
• Hot flashes

Orphan designation

• Dravet syndrome (rare drug-resistant epilepsy in children)

Side effects of other antidepressants vary with each type of antidepressant. A few of the most common side effects include:

Brexanolone:

• Sedation and somnolence (drowsiness)
• Dizziness, vertigo, and presyncope (faint feeling)
• Dry mouth

Gepirone:

• Nausea
• Dizziness
• Lightheadedness

Trazodone:

• Drowsiness
• Dizziness
• Headache and fatigue
• Dry mouth
• Blurred vision
• Nausea and vomiting

Vortioxetine:

• Nausea
• Diarrhea/constipation/vomiting
• Dizziness

Bupropion:

• Headache
• Dry mouth
• Nausea and weight loss
• Insomnia and agitation
• Dizziness
• Pharyngitis (throat inflammation)

Esketamine intranasal:

• Dissociation
• Dizziness and vertigo
• Nausea and dysgeusia (taste disorder)
• Sedation and lethargy
• Headache
• Hypoesthesia (numbness)
• Anxiety

Maprotiline:

• Fatigue and weakness
• Sedation and lethargy
• Constipation
• Dry mouth
• Blurred vision

Mirtazapine:

• Somnolence
• Weight gain
• Xerostomia (dry mouth)
• Increased appetite
• Constipation

Nefazodone:

• Headache
• Somnolence
• Nausea
• Xerostomia
• Dizziness and asthenia (weakness)
• Constipation
• Insomnia

Vilazodone:

• Diarrhea
• Nausea
• Dizziness
• Insomnia

Information contained herein is not intended to cover all possible side effects, precautions, warnings, drug interactions, allergic reactions, or adverse effects. Check with your doctor or pharmacist to make sure these drugs do not cause any harm when you take them along with other medicines. Never stop taking your medication and never change your dose or frequency without consulting your doctor.

Generic and brand names of some of the other antidepressants include:

• Aplenzin
• brexanolone
• bupropion
• esketamine intranasal
• Forfivo XL
• gepirone (pending FDA approval)
• maprotiline
• mirtazapine
• nefazodone
• Remeron
• Remeron SolTab
• Spravato
• Travivo (pending FDA approval)
• trazodone
• Trazodone D
• Trintellix
• Viibryd
• vilazodone
• vortioxetine
• Wellbutrin SR
• Wellbutrin XL
• Zulresso