Types of Antidepressants and How They Work

Antidepressants are medications primarily used to treat depression, though they can also help manage anxiety disorders and other conditions.

They work by altering brain chemistry, particularly neurotransmitters that regulate mood. While chemical imbalance is one theory behind depression, biological, psychological, and social factors also contribute.

There are several main classes of antidepressants: SSRIs, SNRIs, TCAs, and MAOIs. Newer atypical antidepressants fit none of these groups.

Each type varies in how it works, its side effects, and what conditions it treats best. Prescribing depends on severity, other health conditions, and individual response.

This article is for informational and educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment.

Always seek the advice of your physician, therapist, or other qualified health provider with any questions you may have regarding a medical or mental health condition. Never disregard professional advice or delay in seeking it because of something you have read on this site.

How antidepressants work

Antidepressants work by acting on some part of neurotransmission within the brain.

Neurotransmission involves neurotransmitters, which are brain chemicals that travel around the brain and influence mood and behavior.

After a neuron releases a neurotransmitter, it normally takes some of it back up. This is called reuptake. Reuptake inhibitors block that step, so more of the neurotransmitter stays in the synapse, the gap between neurons. An SSRI, for example, blocks serotonin reuptake.

There are three main neurotransmitters that are influenced by antidepressants and are believed to be involved in the regulation of mood:

• Serotonin: Believed to play a role in mood, feelings of happiness, appetite, and sleep.
• Dopamine: Plays a role in how we feel pleasure, motivation, rewards, arousal, and decision-making.
• Norepinephrine: Plays a role in regulating cognition, motivation, alertness, and heart rate and blood pressure during stressful periods.

The mechanism is not fully understood. MAOIs, for example, block their target enzyme almost immediately, yet mood typically lifts only after weeks. That mismatch has long puzzled researchers.

The popular “chemical imbalance” explanation is also contested.

According to Moncrieff’s (2008) historical analysis, the idea of an antidepressant as a drug that corrects a specific chemical deficiency was largely a mid-20th-century marketing and classification decision. It was not a finding that came first and justified the drugs.

Antidepressants can still help many people. A treatment can work through a mechanism that is not yet understood. The debate challenges only the confident claim that a drug corrects a proven biological cause of depression.

Types of antidepressants

The table below compares the five classes covered in this section.

Class	Main action	Examples	Key cautions
SSRIs	Block serotonin reuptake	Fluoxetine (Prozac), sertraline (Zoloft), citalopram (Celexa)	Headaches, nausea, insomnia, sexual dysfunction
SNRIs	Block serotonin and norepinephrine reuptake	Duloxetine (Cymbalta), desvenlafaxine (Pristiq)	Raised blood pressure, dizziness, nausea
Tricyclics (TCAs)	Block serotonin and norepinephrine reuptake	Amitriptyline, nortriptyline	Stronger side effects, including heart rhythm effects
MAOIs	Block monoamine oxidase, the enzyme that breaks down serotonin and norepinephrine	Phenelzine (Nardil)	Dangerous interactions with tyramine-rich foods and some drugs
Atypical	Vary by drug	Bupropion, mirtazapine, agomelatine	Drowsiness or insomnia, weight gain, dry mouth

Selective serotonin reuptake inhibitors (SSRIs)

Selective serotonin reuptake inhibitors (SSRIs) were developed in the 1980s and 1990s and work on affecting the use of the neurotransmitter serotonin in the brain.

SSRIs increase serotonin levels by blocking its reuptake into the presynaptic neuron. They are the most commonly prescribed antidepressants, used for depression, anxiety disorders, obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), and panic disorder.

Common SSRIs include fluoxetine (Prozac), sertraline (Zoloft), and citalopram (Celexa). These medications are typically well tolerated and have fewer side effects than older classes.

Side effects may include headaches, nausea, insomnia, sexual dysfunction, and weight changes. Rarely, SSRIs may cause serotonin syndrome or increased suicidal thoughts in young people, especially when first starting treatment.

SSRIs were designed rather than discovered by chance. Wong et al. (1995) describe how Eli Lilly researchers deliberately screened for a compound that blocked serotonin reuptake far more selectively than the tricyclics of the time. The result was fluoxetine, sold as Prozac from 1988.

SSRIs are also much safer in overdose than tricyclics and MAOIs, a large part of why they became the most widely prescribed class.

SSRIs are used beyond depression, too. In a small double-blind crossover trial of 15 people with pathological gambling, Hollander et al. (2000) found that fluvoxamine reduced gambling urges and behavior more than placebo. The sample was small, so the result needs replication.

Concern about suicidal thoughts began early. Teicher, Glod and Cole (1990) described six patients who developed intense suicidal preoccupation during fluoxetine treatment.

It was a small case series without a control group. It could not show that the drug caused the reaction.

Whittington et al. (2004) later compared published with unpublished trials of SSRIs in children and adolescents. Once the unpublished trials were included, the balance of benefit and risk looked less favorable for most SSRIs, with fluoxetine the exception. Efficacy appeared weaker, and self-harm-related events appeared more common.

The UK restricted most SSRIs, other than fluoxetine, for under-18s in 2003.

Monoamine oxidase inhibitors (MAOIs)

Monoamine oxidase inhibitors (MAOIs) were developed in the 1950s and were one of the earliest classifications of antidepressants.

MAOIs were discovered by accident. Iproniazid, the first MAOI, was trialled in the early 1950s for tuberculosis. Patients became unusually cheerful and energetic, even when their lung disease did not improve. Crane (1956) documented the effect. It helped establish MAOIs as psychiatric treatments.

MAOIs increase levels of serotonin, dopamine, and norepinephrine by blocking the enzyme monoamine oxidase.

MAOIs are primarily used for depression but also help relieve other conditions associated with depression or anxiety, such as agoraphobia, social phobia, and posttraumatic stress disorder.

Interactions are the main danger with MAOIs. They carry three risks:

• Tyramine foods: Aged cheeses, cured meats, and alcohol can push blood pressure to dangerous levels.
• Other medications: Dangerous interactions occur with other antidepressants and some over-the-counter cold remedies.
• Serotonin syndrome: A risk when MAOIs are combined with certain drugs.

The food risk has a clear cause. The enzyme MAOIs block also breaks down tyramine, so a tyramine-rich meal on a non-selective MAOI can cause a sudden spike in blood pressure. Rarely, this “cheese reaction” can cause a cerebral hemorrhage.

Newer reversible MAOIs bind the enzyme less permanently and carry a much lower risk of the cheese reaction. Even so, they are usually reserved for depression that has not responded to other drug classes.

Tricyclics (TCAs)

Tricyclic antidepressants (TCAs) are known as a first generation of antidepressant drugs, invented after MAOIs.

TCAs were originally tested on people who had schizophrenia and became a popular antidepressant treatment in the 1960s.

Tricyclics are named for their three fused carbon rings. The first, imipramine, was chemically related to the antipsychotic chlorpromazine, so it was tested in people with schizophrenia. It did not help psychosis.

Kuhn (1958) then reported a dramatic lift in mood in depressed patients at a Swiss psychiatric hospital. That launched tricyclics as an antidepressant class.

TCAs block the reuptake of serotonin and norepinephrine. Though once widely used, they are now less common due to stronger side effects. TCAs are sometimes used for chronic pain, insomnia, migraines, OCD, and irritable bowel syndrome (IBS).

Examples include amitriptyline and nortriptyline. Side effects may include dizziness, fatigue, weight gain, dry mouth, nausea, sexual dysfunction, and irregular heartbeat.

TCAs may also elevate blood sugar and interact poorly with alcohol or certain emergency medications, making them unsuitable for some people with heart conditions or diabetes.

The most serious risk is cardiovascular. Tricyclics can have toxic effects on the heart, which makes overdose far more dangerous than with newer classes. Modified compounds such as lofepramine and trazodone keep much of the mechanism with fewer of the classic side effects.

Serotonin-norepinephrine reuptake inhibitors

Serotonin-norepinephrine reuptake inhibitors (SNRIs) were introduced as a class of antidepressants in the mid-1990s.

SNRIs block the reuptake of both serotonin and norepinephrine (a chemical that plays a role in alertness, motivation, heart rate, and blood pressure).

They are used to treat depression. They can also help with other conditions, including:

• Bipolar depression
• Obsessive-compulsive disorder (OCD)
• Generalized anxiety disorder (GAD)
• Attention deficit hyperactivity disorder (ADHD)
• Chronic nerve pain
• Fibromyalgia

Common SNRIs include duloxetine (Cymbalta) and desvenlafaxine (Pristiq).

Side effects can include increased blood pressure, dizziness, nausea, muscle weakness, and agitation. Prolonged use may cause manic or hypomanic episodes, so they are often prescribed short-term or with caution in people with high blood pressure.

Atypical antidepressants

Atypical antidepressants are mostly newer medications that do not fit under the other classes.

Bupropion boosts dopamine and norepinephrine, making it helpful for depression. Mirtazapine is used to block the receptors of the hormone epinephrine (also known as adrenaline, a stress hormone). Agomelatine affects melatonin and serotonin, supporting circadian rhythm regulation.

Side effects vary but often include drowsiness or insomnia, weight gain, nausea, dry mouth, or sexual dysfunction. These medications may be used when standard options are ineffective or poorly tolerated.

Ketamine and esketamine

Ketamine and esketamine work differently from every class above. They act on glutamate, the brain’s main excitatory neurotransmitter, rather than on serotonin or norepinephrine, and can work within hours.

In a double-blind crossover trial, Zarate et al. (2006) gave 18 people whose depression had resisted standard treatment ketamine and, on another occasion, a saline placebo. Symptoms improved significantly within two hours. Some patients still benefited a week later.

The trial was small, and one dose’s effect is temporary. Even so, it reshaped psychiatric drug research.

Ketamine blocks the NMDA receptor, which responds to glutamate and helps drive synaptic plasticity, the strengthening and weakening of connections between neurons.

Duman and Aghajanian (2012) propose that this triggers a burst of new connections in the prefrontal cortex. On this account, ketamine repairs neural circuits. It does not correct a chemical shortfall.

Esketamine, a closely related form of ketamine, is a nasal spray approved for treatment-resistant depression. It is used alongside an oral antidepressant. Popova et al. (2019) found it improved symptoms significantly more than a nasal placebo, with benefit appearing within days.

A pooled analysis of patient-level data found that one ketamine infusion reduced suicidal thoughts within a day (Wilkinson et al., 2018).

Both drugs carry distinct risks:

• Dissociation: A sense of detachment from one’s own body, and occasionally hallucinations, during and shortly after treatment.
• Misuse potential: Ketamine has a history as a recreational drug.
• Supervised use: Both need monitored administration, so treatment is limited to specialist clinics.

How Effective Are Antidepressants?

Asking how well antidepressants work really means asking how much better they do than a placebo, an inactive treatment. Depression often improves on its own, and placebo response is substantial. The question has divided researchers for decades.

Antidepressants Versus Placebo

Cipriani et al. (2018) ran the largest comparison to date. Their systematic review and network meta-analysis, which pools direct and indirect comparisons, covered 522 trials and 116,477 participants. It included unpublished trials, which limits publication bias.

Every one of the 21 antidepressants studied beat placebo for short-term treatment of adults with major depression. The advantage was modest, though, and varied between drugs.

Most trials lasted only weeks, so the findings say little about long-term benefit.

Kirsch et al. (2008) analyzed data submitted to the US Food and Drug Administration, including unpublished negative trials. Patients improved substantially on both drug and placebo.

The gap between them was small. It fell below the clinical significance threshold set by the UK’s National Institute for Health and Care Excellence (NICE), except in the most severely depressed patients.

Why the Gap May Be Smaller Than It Looks

A double-blind trial keeps patients and raters unaware of who receives the drug.

Fisher and Greenberg (1993) argued that side effects such as dry mouth or sweating undermine this, because an inert placebo causes none. Guessing correctly can inflate the apparent benefit through expectation. Researchers call this unblinding.

Thomson (1982) compared tricyclic trials that used an inert placebo with the few that used atropine, an active placebo that causes side effects too. The drug’s advantage was much smaller in the atropine studies. Those studies were few, and atropine itself might have some antidepressant effect.

Williams et al. (2026) tested the idea in a systematic review and meta-analysis. Open-label antidepressant trials, where everyone knows the treatment, outperformed blinded ones.

Psychedelic therapy, open-label by nature, showed no equivalent boost. So part of the gap appears to reflect expectation, not pharmacology alone.

Patient Reports and Real-World Outcomes

Trials mostly measure physical side effects. Read et al. (2014) instead asked 1,829 New Zealand adults who had been prescribed antidepressants in the previous five years about 20 possible adverse effects.

Eight of the 20 effects were reported by more than half of the sample. Reported effects included:

• Sexual difficulties: 62% of respondents.
• Emotional numbing: 60%.
• “Not feeling like myself”: 52%.
• Suicidal feelings attributed to the drug: 39%.

These are self-reports, so they cannot prove cause. The authors suggest such effects may be more common than trials imply, because trials rarely ask about them.

The STAR*D trial (Sequenced Treatment Alternatives to Relieve Depression) followed depressed outpatients through up to four treatment steps, switching or adding medication whenever a step failed (Rush et al., 2006). Remission rates fell at each step:

• Step 1: 36.8%.
• Step 2: 30.6%.
• Step 3: 13.7%.
• Step 4: 13.0%.

The investigators reported a cumulative remission rate of about 67%. Patients who needed more steps also relapsed more often. Pigott et al. (2010) reanalyzed the data against the trial’s original pre-registered outcome criteria. They argued that the true cumulative rate was substantially lower.

Practical Considerations When Taking Antidepressants

The best antidepressant depends on individual symptoms, medical history, and how the body responds.

Antidepressants typically take two to four weeks to start working. SSRIs, for instance, may first improve energy or reduce anxiety before mood lifts.

If there’s no improvement after six weeks, a doctor may adjust the dosage or switch medications. Sometimes, combinations are used.

Antidepressants are not the only option. Medication tends to bring faster initial relief than cognitive behavioral therapy (CBT) alone, but CBT typically catches up over several months.

Combining the two usually outperforms either alone. UK guidance from the National Institute for Health and Care Excellence (NICE) recommends psychological therapy as a first-line option for many people.

Take antidepressants consistently and under supervision. High doses or drug interactions can trigger serotonin syndrome, a serious condition marked by confusion, high heart rate, and high blood pressure.

Do you need mental health support?

USA

Contact the National Suicide Prevention Lifeline for support and assistance from a trained counselor. If you or a loved one are in immediate danger: https://suicidepreventionlifeline.org/

1-800-273-8255

UK

Contact the Samaritans for support and assistance from a trained counselor: https://www.samaritans.org/; email jo@samaritans.org.

Available 24 hours a day, 365 days a year (this number is FREE to call):

116-123

Rethink Mental Illness: rethink.org

0300 5000 927

Further Reading

Depression: How effective are antidepressants? Institute for Quality and Efficiency in Health Care, National Center for Biotechnology Information, U.S. National Library of Medicine. January 12, 2017.

Marken, P. A., & Munro, J. S. (2000). Selecting a selective serotonin reuptake inhibitor: clinically important distinguishing features. Primary care companion to the Journal of clinical psychiatry, 2(6), 205.

Hillhouse, T. M., & Porter, J. H. (2015). A brief history of the development of antidepressant drugs: from monoamines to glutamate. Experimental and clinical psychopharmacology, 23(1), 1.

Friedman, R. A. (2014). Antidepressants” black-box warning—10 years later. New England Journal of Medicine, 371(18), 1666-1668.

Ramachandraih, C. T., Subramanyam, N., Bar, K. J., Baker, G., & Yeragani, V. K. (2011). Antidepressants: from MAOIs to SSRIs and more. Indian journal of psychiatry, 53(2), 180.

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