Types of Antidepressants

by eMedExpert staff
Medical references reviewed: August, 2018

The history of antidepressants begins with the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). Both of these successful classes of antidepressants were discovered by chance. The first antidepressants became available in the late 1950s.

Newer antidepressants such as the SSRIs have largely replaced older TCAs and MAOIs as first-line depression drugs. However, Tricyclic antidepressants and MAOIs remain valuable alternatives for patients with moderate to severe depression.

All antidepressants work on the principle of enhancing one or more of the neurotransmitters in the brain. Neurotransmitters are molecules that specialize in delivering packets of information from one neuron to another.

Important to know: Neurotransmitters cannot be taken orally or intravenously because they cannot pass the brain-blood barrier.

Classification of Antidepressants

There are many different types of antidepressant. Antidepressants are put into groups based on which chemicals in the brain they affect. Main classes of antidepressant include:

Non-selective Antidepressants

  • Tricyclic antidepressants (serotonin and noradrenalin reuptake inhibition with effects on multiple receptor system and sodium conductance)
  • Monoamine oxidase inhibitors (MAOIs)

Selective Reuptake Inhibitors

  • Selective serotonin reuptake inhibitors (SSRIs)
  • Selective noradrenaline reuptake inhibitors (NARI)
  • Serotonin and norepinephrine reuptake inhibitors (SNRIs)
  • Norepinephrine and dopamine reuptake inhibitors (NDRIs)

Receptor Blockers

  • Noradrenergic and specific serotonergic antidepressants (NaSSA) (serotonin (5-HT2A and 2C, 5-HT3) receptor blockade with noradrenalin (alpha-2) receptor blockade)
  • Serotonin (5-HT2A) receptor blockade with serotonin reuptake inhibition (nefazodone, trazodone)

Selective Serotonin Reuptake Inhibitors

  • Citalopram (Celexa)
  • Escitalopram (Lexapro)
  • Fluoxetine (Prozac)
  • Paroxetine (Paxil)
  • Sertraline (Zoloft)

Selective Serotonin Reuptake Inhibitors (SSRIs) act only on the neurotransmitter serotonin, while tricyclic antidepressants and MAO inhibitors act on both serotonin and another neurotransmitter, norepinephrine, and may also interact with other chemicals throughout the body. Selective serotonin reuptake inhibitors have fewer side effects than tricyclic antidepressants and MAO inhibitors. Some of the side effects that can be caused by SSRIs include dry mouth, nausea, nervousness, insomnia, headache and sexual problems.


Tricyclic Antidepressants

Tertiary amines:

  • Amitriptyline (Elavil)
  • Clomipramine
  • Imipramine (Tofranil)
  • Trimipramine (Surmontil)
  • Doxepin (Sinequan)

Secondary amines:

  • Nortriptyline (Pamelor)
  • Desipramine (Norpramin)
  • Protriptyline (Vivactil)

The tricyclics have been used to treat depression for a long time. Imipramine was discovered in the early 1950s, and was the first tricyclic antidepressant.

TCAs act on both serotonin and norepinephrine neurotransmitters, and may also interact with other chemicals throughout the body. Common side effects caused by these medicines include dry mouth, blurred vision, constipation, difficulty urinating, worsening of glaucoma, impaired thinking and tiredness.

Amoxapine (Asendin) is very rarely used because of severe extrapyramidal side effects.

Serotonin and Norepinephrine Reuptake Inhibitors

Serotonin and norepinephrine reuptake inhibitors (SNRIs) works by slowing down the reuptake of both serotonin and noradrenaline, but more selectively than other antidepressant drugs.

Norepinephrine and Dopamine Reuptake Inhibitors

  • Bupropion (Wellbutrin)

NDRIs block the reuptake of neurotransmitters norepinephrine and dopamine, increasing the levels of these neurotransmitters in the synapses.

Combined reuptake inhibitors and receptor blockers

  • Trazodone (Desyrel)
  • Nefazodone (Serzone)

Trazodone and nefazodone are phenylpiperazine antidepressants.

Trazodone is a serotonin reuptake inhibitor and is also a 5-HT2 receptor antagonist. This results in more serotonin to stimulate other nerves. This medication has sedative and antidepressant properties.

Nefazodone works by inhibiting the uptake by nerves of serotonin and norepinephrine. Nefazodone is chemically related to trazodone, and shares its actions. Nefazodone has a lesser risk of priapism.

Noradrenergic and Specific Serotonergic Antidepressants

  • Mirtazapine (Remeron)

The novel antidepressant mirtazapine has dual mode of action. It is a noradrenergic and specific serotonergic antidepressant that enhances noradrenergic and serotonergic neurotransmission. Mirtazapine has been proved effective in the treatment of patients who were resistant or intolerant to SSRIs.

Monoamine oxidase inhibitors (MAOIs)

  • Phenelzine (Nardil)
  • Tranylcypromine (Parnate)
  • Isocarboxazid (Marplan)
  • Selegiline (Emsam)

MonoAmine Oxidase Inhibitorsare are the oldest class of antidepressants developed in the 1950s. MAOI work by increasing the availability of the monoamine transmitters; norepinephrine (NE), dopamine (DA), and 5- hydroxytryptamine (5-HT), by blocking their metabolism.

Relative Toxicity with Overdose
Toxicity of Antidepressants with Overdose
Relative toxicity Antidepressant
Very high Amoxapine
Tricyclic antidepressants (inhibit sodium channels at overdose levels, causing potentially lethal cardiac arrhythmias and seizures)
High Monoamine oxidase inhibitors
Medium Venlafaxine
Low Bupropion
Selective serotonin reuptake inhibitors
Therapeutic and Adverse Effects of Antidepressants
Therapeutic and Adverse Effects of Transporter and Receptor Blocking Effects of Antidepressants 4
Transporter / Receptor Blocking Therapeutic Adverse
Norepinephrine transporter Antidepressant Tremors
Blockade of antihypertensive effects of guanethidine and guanadrel
Augmentation of pressor effects of sympathomimetic amines
Serotonin transporter Antidepressant Gastrointestinal disturbances (including weight loss early in treatment, weight gain late in treatment)
Increase or decrease in anxiety (dose dependent) Sexual dysfunction (including decreased libido)
Extrapyramidal adverse effects
Interactions with tryptophan, monoamine oxidase inhibitors, and fenfluramine
Dopamine transporter Antidepressant
Psychomotor activation
Precipitation or aggravation of psychosis
α1 -Adrenoceptors   Potentiation of antihypertensive effect of prazosin, terazosin, doxazosin, and labetalol
Postural hypotension and dizziness Reflex tachycardia
Dopamine D2 receptor Amelioration of signs and symptoms of psychosis Extrapyramidal movement disorders: dystonia, parkinsonism, akathisia, tardive dyskinesia, rabbit syndrome.
Endocrine effects: prolactin elevation (galactorrhea, gynecomastia, menstrual changes, sexual dysfunction in men).
Histamine H1 receptors Sedation Sedation, drowsiness, weight gain
Potentiation of central depressant drugs
Muscarinic receptors Antidepressant Blurred vision
Attack or exacerbation of narrow-angle glaucoma
Dry mouth
Sinus tachycardia
Urinary retention
Memory dysfunction
5-HT 2A receptors Antidepressant
Reduction of anxiety Promotion of deep sleep
Prophylaxis of migraine headaches
SSRI-induced anxiety and even occasional panic attacks are hypothetically mediated by stimulating 5-HT2 receptors.

Properties of the Ideal Antidepressant

  • High rate of efficacy
  • Rapid onset of antidepressant effect
  • Intermediate half-life - not too long (like fluoxetine), not too short (like paroxetine)
  • Predictable blood level
  • Lack of adverse effects
  • Negligeble potential for drug interactions
  • Low toxicity in overdose

References & Resources

  • 1. The Merck Manual of Medical Information. Mark H. Beers et al., eds. 2nd Home Edition. Whitehouse Station, NJ: Merck; 2003.
  • 2. Stephen M. Stahl. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. (2nd ed.), Cambridge: Cambridge University Press.
  • 3. Physicians' Desk Reference. 59th ed. Montvale, N.J.: Thomson PDR, 2005.
  • 4. Elliott Richelson. Pharmacology of Antidepressants. Mayo Clin Proc . 2001;76:511-527

Published: May 05, 2007
Last updated: January 19, 2019


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