Antidepressants: Types, Mechanisms, and Side Effects

Depression, which is sometimes called depressive disorder or clinical depression, is a prevalent mental health condition that affects individuals worldwide. While the symptoms of depression can vary between individuals, the disorder is typically characterized by persistently low mood, loss of pleasure in activities, and feelings of hopelessness or despair. Depression is a serious mood disorder which can significantly affect a person’s life and relationships. Fortunately, there are a variety of antidepressant medications available to treat the symptoms of depression. This article will introduce you to several common types of antidepressants and explain their mechanisms, benefits, potential side effects, and relevant considerations.
Faith Wershba

Faith Wershba

Postgraduate researcher at the University of Cambridge.

A blue image with text saying "Antidepressants"

What are antidepressants?

Antidepressants are a type of medication used to treat depression and associated mood disorders. Broadly speaking, these drugs function by affecting neurotransmitters, which are molecules produced by the brain that regulate various neural processes and behaviours [2]. There are several types of antidepressant medications, which are categorised according to the neurotransmitter system that they target [2, 3].

Types of antidepressants

Common antidepressants include [2, 3]:

  • Selective serotonin reuptake inhibitors (SSRIs)

SSRIs are one of the most commonly used and well-known types of antidepressant. Fluoxetine (Prozac), Sertraline (Zoloft), Citalopram (Cipramil), Escitalopram (Cipralex), Paroxetine (Paxil, Lexapro) are all examples of SSRIs.

  • Serotonin-noradrenaline reuptake inhibitors (SNRIs)

SNRIs are also regularly used to treat depression. Duloxetine (Cymbalta), Venlafaxine (Efexor), Desvenlafaxine (Pritstiq), and Milnacipran are examples of SNRIs.

  • Tricyclic antidepressants (TCAs)

TCAs are an older class of drug which includes Amitriptyline (Elavil), Clomipramine (Anafranil), Dosulepin (Prothiadin), Imipramine (Tofranil), Trimipramine (Norpramin), Desipramine (Norpramin), Lofepramine (Gamanil, Lomont), Nortriptyline (Palemor), Maprotiline (Ludiomil), and Amoxapine (Asendin).

  • Monoamine oxidase inhibitors (MAOIs)

MAOIs include drugs such as Selegiline (Eldepryl, Selgin), Moclobemide (Amira, Depnil), Tranylcypromine (Parnate), Isocarboxazid, and Phenelzine (Nardil).

  • Serotonin modulators

Some examples of serotonin modulators are Nefazodone (Serzone), Trazodone, Vilazodone (Viibryd), and Vortioxetine (Trintellix, Brintellix).

  • Norepinephrine-dopamine reuptake inhibitors (NDRIs)

Currently, there are not a large number of NDRIs used to treat depression. Examples of NDRIs include Bupropion (Wellbutrin, Zyban) and Amineptine (Survector). The ADHD medication Methylphenidate (Ritalin) also functions as a norepinephrine and dopamine reuptake inhibitor; however, this drug is not typically used for depression treatment [4].

How do antidepressants work?

Most antidepressants work by inhibiting the reuptake of neurotransmitters by presynaptic neurons. This is why many of the antidepressants listed above are referred to as “reuptake inhibitors.” Reuptake inhibitors bind and inhibit receptors on the surface of presynaptic neurons that reabsorb excess neurotransmitters from the synaptic cleft [2]. As a result of this action, there remains a greater concentration of neurotransmitter in the synaptic cleft during neural transmission, which helps boost neural signalling and promote stimulation of important brain regions. However, some antidepressants function by modulating the activity of postsynaptic neurons in addition to inhibiting presynaptic uptake receptors [5].

Antidepressant mechanisms of action

The specific mechanism of action depends on the type of antidepressant under consideration. Basic molecular mechanisms of antidepressant classes include [2]:

  • Inhibiting serotonin reuptake: SSRIs work by blocking the serotonin reuptake receptor SERT, which is located on the membrane of presynaptic neurons. This enhances and sustains serotonergic signalling in the synapse and thereby reduces depressive symptoms which are caused by insufficient serotonin levels. There is also evidence that continuous SSRI administration leads to increases in cyclic AMP and phosphorylation of various neural transcription factors involved in neuronal growth and BDNF expression [6].
  • Inhibiting norepinephrine reuptake: SNRIs work by blocking both serotonin and norepinephrine reuptake receptors on presynaptic neurons, though the serotonin reuptake inhibitor targeted by SNRIs differs from that targeted by SSRIs. This dual action helps boost serotonergic and noradrenergic activity in the synapse. Interestingly, some formulations of SNRIs (e.g., Milnacipran) exhibit slight receptor selectivity, inhibiting norepinephrine reuptake more strongly than serotonin reuptake.
  • Antagonism of cholinergic, muscarinic, and histamine receptors: in addition to inhibiting serotonin and norepinephrine reuptake, TCAs also inhibit cholinergic (α1, α2), muscarinic, and histamine (H1) receptors on the surface of postsynaptic neurons [7]. TCAs therefore operate via multiple neurotransmitter pathways and can have more wide-ranging effects than drugs which target only one or two pathways. However, this also means that TCAs have a wider range of potential adverse effects; because of this, TCAs are usually not recommended as a first-line of treatment [7].
  • Inhibiting monoamine oxidase activity: MAOIs target a type of enzyme called monoamine oxidase (MAO). MAO breaks down serotonin, norepinephrine, and dopamine molecules following reuptake into presynaptic neurons or within the synaptic cleft. MAOIs prevent this catabolic process by inhibiting MAO, which leads to greater concentrations of the mood-boosting neurotransmitters within the synapse [8]. MAOIs were one of the first types of antidepressants discovered; however, they are generally not used as a first option due to associated adverse effects and interactions with other drugs [2].
  • Modulating serotonin signalling: like SSRIs and SNRIs, serotonin modulators affect serotonergic signalling within the brain. Beyond inhibiting serotonin reuptake by presynaptic neurons, serotonin modulators regulate the activity of serotonin receptors on postsynaptic neurons, further boosting serotonergic signalling. Serotonin modulators may be used as an alternative to SSRIs in non-responsive individuals with depression [5].
  • Inhibiting norepinephrine and dopamine reuptake: NDRIs function by dual-inhibition of presynaptic norepinephrine and dopamine reuptake inhibitors. This boosts norepinephrine and dopamine signalling and can help diminish depression-associated symptoms and behaviours. NDRIs do not have serotonergic activity and do not act on postsynaptic neurons, which gives them a distinct functional profile from SNRIs, TCAs, and MAOIs [9].

Effectiveness of antidepressants

Antidepressants are regularly used for treating depression and are often beneficial in reducing symptoms, especially when combined with psychotherapy [1]. However, the effectiveness of these drugs is not a given, and some individuals try several types of antidepressants without experiencing an improvement in symptoms. Such individuals are considered to have treatment-resistant depression, which means that their symptoms do not decline after trying two or more antidepressant medications [1].

Additionally, individuals should take the correct dose of antidepressants

Treatment-resistant depression

Treatment-resistant depression occurs in individuals whose symptoms do not improve after trying two or more antidepressants. It is estimated that treatment-resistant depression affects 30% of individuals diagnosed with major depressive disorder [10].

In recent years, researchers have begun to test alternatives to antidepressants in order to treat cases of treatment-resistant depression. For example, deep brain stimulation (DBS) and transcranial magnetic stimulation (TMS), which deliver electric impulses to the brain in order to promote neural activity, have shown some promise in treating treatment-resistant depression [10]. In addition, psychedelics such as psilocybin and psychedelic-like drugs such as ketamine have demonstrated therapeutic effects for the treatment of severe depression [10].

While these treatments are more experimental and not as accessible as antidepressant medications, they may provide substantial benefit for individuals with severe treatment-resistant depression.

Side effects of antidepressants

Most antidepressants have a fairly well-established safety profile. However, antidepressants are associated with a host of side effects that range in their severity and prevalence.

Antidepressant side effects

While antidepressants are generally safe, they can cause adverse side effects. The range of side effects depends on several factors, including the class of antidepressant, the dose of medication, and individual differences in drug metabolism.

SSRI side effects

Side effects of SSRIs include:

  • Agitation, shakiness, or anxiety
  • Nausea
  • Indigestion
  • Constipation or diarrhea
  • Headaches, dizziness
  • Insomnia
  • Drowsiness
  • Reduced sex drive or sexual dysfunction

SNRI side effects

Side effects of SNRIs include:

  • Hypertension
  • Nausea
  • Indigestion
  • Anxiety or agitation
  • Constipation or diarrhea
  • Headaches, dizziness
  • Changes in sleep pattern
  • Excessive sweating

TCA side effects

Side effects of TCAs include:

  • Dry mouth
  • Blurred vision
  • Constipation
  • Urinary retention
  • Weight gain
  • Drowsiness
  • Irregular heart rhythm (arrhythmia) and palpitations
  • Fast heart rate (tachycardia)
  • Excessive sweating, particularly at night

MAOI side effects

Side effects of MAOIs include:

  • Dry mouth
  • Nausea, diarrhea, or constipation
  • Headache
  • Drowsiness
  • Insomnia
  • Dizziness or lightheadedness
  • Reduced blood pressure (hypotension)
  • Weight gain
  • Sexual dysfunction

NDRI side effects

Side effects of NDRIs include:

  • Agitation, anxiety
  • Headache
  • Dizziness
  • Insomnia
  • Excessive sweating
  • Dry mouth
  • Nausea
  • Stomach aches
  • Weight loss
  • Constipation
  • Hypertension
  • Tremors, shakiness

While the list of side effects might appear overwhelming, most individuals taking antidepressants only experience one or a few, while others experience no side effects. Side effects usually improve within several weeks of starting the medication as the body adjusts [3]. However, if side effects persist or are severe, it is best to contact your healthcare provider right away.

How do I know which antidepressant to take?

Choosing the right antidepressant will depend on your symptoms, any comorbid conditions or medical concerns, your tolerance of side effects, and various other personal considerations. Some antidepressants have contraindications with other medications or lifestyle habits, such as drinking alcohol. Such contraindications, along with any other concerns, are important to discuss with your medical provider before starting a new antidepressant medication.

On the other hand, some antidepressants have off-label benefits—that is, they improve symptoms of other disorders for which they are not technically marketed. For example, there is evidence that certain antidepressants are effective for individuals suffering from anxiety, obsessive compulsive disorder (OCD), or substance use disorders.

Antidepressants for anxiety

Depression and anxiety frequently occur as comorbid conditions. While there medications have been developed for specifically treating anxiety disorders, there is evidence that using antidepressants for anxiety can be beneficial. A meta-analysis of 29 trials found that SSRIs (Paroxetine, Fluoxetine) and SNRIs (Duloxetine) were beneficial for patients with general anxiety disorder and social anxiety disorder []. Compared to patients treated with placebos, those who received SSRIs or SNRIs had significantly reduced ratings on general anxiety and social anxiety scales.

Antidepressants for OCD

SSRIs are often used in combination with cognitive behavioural therapy (CBT) for the treatment of OCD. FDA-approved SSRIs for treating OCD include Fluoxetine (Prozac), Fluvoxamine (Luvox), Paroxetine (Paxil), Sertraline (Zoloft), and Clomipramine (Anafranil).

Antidepressants for substance abuse

Some classes of antidepressants have shown promise in treating specific types of substance abuse. For example, there is evidence that the SNRI Bupropion (Wellbutrin) is beneficial in reducing nicotine dependence in addicted individuals (with or without comorbid depression). However, there is less evidence supporting the use of antidepressants for alcohol, cocaine, or opioid abuse. Further research is needed to determine whether other classes of antidepressants, such as SSRIs and TCAs, may benefit individuals with various types of substance use disorders.

Conclusion

Depression is a common mental health condition that can significantly impact one’s quality of life. Fortunately, there are therapeutic resources that can help manage its symptoms. Antidepressants are commonly used medications for mood regulation, and they can be highly beneficial in combination with psychotherapy and other emotional supports. There are various classes of antidepressants, which function by targeting specific neurotransmitter pathways in the brain. SSRIs, SNRIs, TCAs, MAOIs, and NDRIs are some examples of various antidepressant types. It is important to note that some antidepressants are contraindicated with other medications or with alcohol consumption, such as Fluoxetine (Prozac), Venlafaxine (Efexor), Duloxetine (Cymbalta), Sertraline (Zoloft), and Amitriptyline. As such, it is important to discuss your medical history and lifestyle habits with a healthcare practitioner before starting antidepressant treatment. Although antidepressants work for many people, approximately 30% of individuals with depressive disorder experience treatment-resistant depression, meaning that their condition does not improve in response to antidepressants. As such, developing alternatives to antidepressants is an important goal of psychiatric research.

Resources for depression

If you or a loved one are suffering from symptoms of depression, you are not alone. There are a variety of mental health resources which may help lessen your burden. You are deserving of compassionate care and full well-being.

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Faith Wershba

Faith Wershba

Faith obtained her Honour’s Bachelor Degree in Human Biology, Immunology and History & Philosophy of Science at the University of Toronto. Currently, she is a postgraduate researcher at the University of Cambridge, focusing on the philosophy of medicine, science, biomedical research methods, and bioethics.