Serotonin Reuptake Inhibitors and Similar Antidepressant Medications

Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Antidepressants are indicated as the 1st-line treatment for anxiety disorders and major depressive disorder (MDD) and are contraindicated in cases of current or recent use of monoamine oxidase inhibitors. Therapeutic response to antidepressants takes 2–4 weeks and complete benefit is not seen until up to 8 weeks, which is attributed to downstream cellular responses necessary for eliciting a physiologic response. In general, serotonin-affecting antidepressants are well tolerated, but caution must be taken while prescribing them in combination with other drugs that inhibit or induce the same hepatic cytochrome P450 enzymes to prevent increased levels of both drugs. An overdose can be life-threatening. It is important to recognize the signs and symptoms of SSRI/SNRI overdose to enable prompt treatment in an emergency setting.

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Chemistry and Pharmacodynamics

Mechanisms of action

  • Selective serotonin reuptake inhibitors (SSRIs):
    • Vary considerably in their chemical structures
    • Have similar mechanisms of action, which result in increased synaptic serotonin (also known as 5-hydroxytryptamine (5-HT))
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs) have a similar mechanism of action to SSRIs:
    • Chemical structures of duloxetine, milnacipran, and venlafaxine are dissimilar.
    • Desvenlafaxine and venlafaxine are bicyclic phenylethylamines with a similar structure.
    • Duloxetine is a naphthalene derivative.
  • Serotonin antagonist and reuptake inhibitors (SARIs): trazodone and nefazodone
    • Inhibit reuptake of serotonin by blocking the 5-HT2A receptor (antagonist)
    • Induce significant changes in the 5-HT presynaptic receptor adrenoreceptors
    • Block histamine (H₁) and α-1 adrenergic receptors
  • 5-HT1A receptor partial agonist: vilazodone
    • Inhibits CNS neuron serotonin uptake
    • No significant effect on the reuptake of norepinephrine (NE) or dopamine
  • Serotonin modulator and stimulator (SMS): vortioxetine
    • Inhibits serotonin reuptake
    • Has agonist activity at the 5-HT1A receptor and antagonist activity at the 5-HT3 receptor
Mechanisms antidepressants

Mechanisms of antidepressants:
The basic mechanisms of action of commonly prescribed antidepressants are listed. These medications include monoamine oxidase (MAO) inhibitors, the α-2 antagonist mirtazapine, the selective serotonin reuptake inhibitor fluoxetine, the serotonin antagonist and reuptake inhibitor trazodone, the tricyclic antidepressant desipramine, and the tetracyclic drug maprotiline.

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Pharmacodynamics

  • SSRIs:
    • “Selective”: have affinity for the serotonin receptor and very little affinity for other receptors
    • Many types of pre- and postsynaptic serotonin receptors exist (e.g., 5-HT2A and 5-HT2C).
    • SSRIs decrease the action of the presynaptic serotonin reuptake pump by 60%–80% → increased 5-HT levels in the synaptic cleft
    • Increased levels of serotonin are not sufficient to treat depression. The beneficial effect on mood takes several weeks and occurs due to:
      • Increased production of neuroprotective proteins
      • Treatment with an SSRI for weeks modifies the serotonergic receptors.
  • SNRIs:
    • Vary in their affinity for the serotonin and NE transporters → ↑ NE and 5-HT levels in the synaptic cleft
    • The degree to which serotonin and NE reuptake is inhibited depends on the dose and drug.
  • SARIs:
    • Relatively targeted at the 5-HT2A and 5-HT2C receptors
    • 5-HT2A and 5-HT2C are G-protein-mediated receptors located in the neocortex → antidepressant action
    • Also block H₁ receptors
  • Physiologic effects:
    • Physical symptoms may improve in the 1st 1–2 weeks (energy, sleep, appetite).
    • Affective symptoms improve after physical symptoms (mood, concentration, self-esteem).

Pharmacokinetics

Secondary serotonin reuptake inhibitors

  • Absorption:
    • Well-absorbed in the GI tract, not affected by food
    • Reach peak plasma levels in a few hours
  • Distribution:
    • Lipophilic
    • Widely distributed throughout the body (including the brain)
  • Metabolism:
    • Via cytochrome P450 (CYP)2D6, CYP3A4, and CYP2C19 pathways: significant for drug interactions
    • Half-lives vary from 21 hours (paroxetine) to 5 days (fluoxetine after long-term use).
    • Fluoxetine may be dosed every other day owing to its very long half-life.
    • All SSRIs except fluvoxamine produce pharmacologically active metabolites.
    • Fluoxetine is the only drug with an active metabolite that has antidepressant activity.
  • Excreted in the urine and feces

Serotonin-norepinephrine reuptake inhibitors

  • Absorption:
    • Food decreases the rate but not the degree of absorption.
    • Taking with meals may reduce nausea, which is generally the most common side effect of SNRIs.
  • Distribution:
    • Duloxetine is highly protein bound and primarily undergoes hepatic clearance.
    • Other SNRIs are not as highly protein bound as duloxetine. Renal excretion plays a significant role in their clearance.
  • Metabolism:
    • Significant interindividual differences in the clearance of SNRIs
    • Doses may vary substantially among individuals.
  • Excretion:
    • Partially metabolized by the kidneys and excreted in the urine
    • Dosage adjustments may be required in individuals with CKD.

Serotonin antagonist and reuptake inhibitor = trazodone (nefazodone is not currently available in the US)

  • Short-acting drug with a half-life of 7 hours
  • Metabolized via the CYP3A4 pathway
  • Excreted in the urine

5-Hydroxytryptamine1A receptor partial agonist = vortioxetine

  • Protein binding: 98%
  • Hepatic metabolism mainly via oxidation by CYP450 isoenzymes, primarily CYP2D6, and subsequent glucuronic acid conjugation to an inactive carboxylic acid metabolite
  • Long elimination half-life: approximately 66 hours (causes fewer withdrawal symptoms if doses are missed)
  • Excreted in the urine and feces

Serotonin modulator and stimulator = vilazodone

  • Protein binding: approximately 96%–99%
  • Metabolism: extensively hepatic via CYP3A4 (major pathway) and CYP2C19 and CYP2D6 (minor pathways)
  • Elimination half-life: approximately 25 hours

Classification and Indications

Antidepressant medications that affect serotonin levels in the brain to treat depression, anxiety, and other conditions are classified into several groups. The most commonly prescribed antidepressants are SSRIs. Other important classes of antidepressants include monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), and the NE/dopamine reuptake inhibitor (NDRI) bupropion.

Classification

The brand names of commonly used medications are listed in parentheses for further understanding.

  • SSRIs:
    • Citalopram (Celexa)
    • Escitalopram (Lexapro)
    • Fluoxetine (Prozac)
    • Fluvoxamine (Luvox)
    • Paroxetine (Paxil)
    • Sertraline (Zoloft)
  • SNRIs:
    • Duloxetine (Cymbalta)
    • Venlafaxine (Effexor)
    • Desvenlafaxine (Pristiq)
    • Milnacipran (Savella)
  • SARIs:
    • Trazodone (generic)
    • Nefazodone: not currently available in the US (August 2021), but may soon be made available
  • SMS: vortioxetine (Trintellix)

Indications

Antidepressants are used to treat several psychiatric conditions, and SSRIs/SNRIs/SARIs/SMS are most commonly used to treat major depressive disorder (MDD) such as unipolar depression and anxiety disorders, and also to treat chronic pain.

General indications for antidepressant medications:

  • MDD:
    • SSRIs are usually the preferred 1st-line agents (except fluvoxamine).
    • Concomitant therapy with psychosocial/behavioral therapy should be considered.
  • Anxiety disorders:
    • Generalized anxiety disorder
    • Social anxiety disorder
    • Panic disorder
  • OCD: SSRIs and SNRIs are effective.
  • Chronic pain:
    • Neuropathic pain
    • Chronic musculoskeletal pain
    • Fibromyalgia:
      • Duloxetine
      • Milnacipran (Savella) indicated for fibromyalgia, not depression
  • Unique uses for some medications that may be preferred over other similar drugs:
    • Premature ejaculation: sertraline
    • Vasomotor symptoms of menopause: paroxetine, venlafaxine, escitalopram
    • Vulvodynia may respond to SNRIs.
    • Migraine prophylaxis in individuals without depression: escitalopram, venlafaxine
    • PTSD: venlafaxine, paroxetine
    • Bulimia nervosa: fluoxetine
    • Premenstrual dysphoric disorder (PMDD): fluoxetine, sertraline
    • Insomnia: Trazodone is used more as a sleep aid than to treat depression.
    • Atomoxetine (Strattera) is used for ADHD and narcolepsy:
      • The exact mechanism of action is unknown; however, it selectively inhibits NE reuptake.
      • Not used for depression

Adverse Effects and Contraindications

None of the SSRIs significantly affect the α-adrenergic, histaminic, or cholinergic receptors, except for paroxetine, which has a weak antagonistic effect on the cholinergic receptors. The side effects of all SSRIs are due to their effects on the serotonin receptors.

Adverse effects

SSRIs:

  • GI:
    • Nausea
    • Diarrhea (most common with sertraline)
    • Xerostomia (dry mouth)
  • Diaphoresis
  • Sexual dysfunction:
    • Anorgasmia in women or delayed orgasm in men (sertraline may be used as a treatment for premature ejaculation)
    • Decreased libido
    • Erectile dysfunction
  • Weight changes: also may be due to depression itself
    • Weight gain may be seen with paroxetine.
    • Weight loss may be seen with fluoxetine.
  • Neurologic:
    • Dizziness
    • Headache
    • CNS depression
  • Insomnia
  • Increased risk of bleeding due to inhibition of platelet serotonin uptake (and drug interaction with clopidogrel)
  • Hypoglycemic effects (and drug interactions with sulfonylureas)
  • Hyponatremia
  • Cardiovascular: Citalopram may cause QT prolongation.

SNRIs, vilazodone, and vortioxetine:

  • Similar side effects as SSRIs
  • SNRIs may cause a slight increase in blood pressure.

Trazodone (SARI):

  • GI:
    • Constipation
    • Nausea
  • Xerostomia (dry mouth)
  • Neurologic/psychiatric:
    • Dizziness
    • Headache
    • Sedation
  • Blurred vision

Discontinuation syndrome:

  • Occurs more often in individuals taking higher doses
  • Commonly observed in drugs with shorter half-lives
  • Least risk with fluoxetine
  • Greatest risk with paroxetine and venlafaxine
  • Risk can be reduced by slowly tapering over several weeks.
  • Abruptly stopping SSRIs or SNRIs may cause:
    • Dizziness
    • Fatigue
    • Headache
    • Nausea
    • Insomnia
    • Irritability
    • Paresthesias: including a feeling of “electric-like” shocks

Serotonin syndrome (a potentially life-threatening side effect):

  • Usually caused by > 1 medication affecting the serotonin receptor
  • Was 1st described as a reaction between SSRIs and MAOIs
  • Drug combinations with SSRIs/SNRIs/other serotonergic antidepressants:
    • To treat migraine: triptans and ergots
    • Antidepressants: TCAs, MAOIs, antipsychotics
    • Anticonvulsants: carbamazepine, valproic acid
    • Antianxiety drug: buspirone
    • Opioid analgesics: tramadol, methadone, codeine
    • Over-the-counter cough medication: dextromethorphan
    • Herbal supplements for depression: St. John’s Wort, 5-HTP
    • Antibiotic: linezolid
    • Muscle relaxant: cyclobenzaprine
    • Street drugs: cocaine, methamphetamine
  • Symptoms include CNS stimulation, cardiovascular stimulation, and GI stimulation:
    • Severe muscle rigidity
    • Mydriasis
    • Myoclonus
    • Hyperreflexia
    • Hyperthermia
    • Seizures
    • Tachycardia
    • Unstable blood pressure
    • Diarrhea

Mnemonic to recall serotonin syndrome manifestations: “Madam’s tips”

  • M = mental status changes
  • A = agitation
  • D = diarrhea
  • A = ataxia
  • M = myoclonus
  • S = shivering
  • T = tachycardia
  • I = increased reflexes
  • P = pyrexia
  • S = sweating

Drug interactions

  • Both drug factors and patient factors can contribute to the toxicity of SSRIs/SNRIs in some individuals.
    • Drug factors: Some SSRIs and SNRIs are moderate-to-potent inhibitors of hepatic cytochrome P450 → drug-drug interactions by altering blood levels of other medications that depend on these enzymes for clearance or activation
    • Patient factors: Enzyme may function differently in individuals with significant variations in the CYP2D6 gene.
      •  “Slow metabolizers”
      •  “Extensive metabolizers”
  • CYPs are hepatic enzymes that metabolize several drugs:
    • Render the drug either more or less active
    • Combinations of drugs using the same metabolic pathway can cause serious adverse effects.
    • Examples of the CYP450 family of proteins used by antidepressants:
      • CYP2D6
      • CYP3A4 
      • CYP2C9
      • CYP1A2
  • SSRI drug interactions with other drugs that are metabolized by CYP450 enzymes:
    • Citalopram and escitalopram inhibit liver enzymes much less than other SSRIs.
    • Fluoxetine and paroxetine are potent inhibitors of CYP2D6 causing ↑ 2D6 substrate levels
    • Other CYP2D6 inhibitors that can interact with SSRIs and should be used with caution:
      • Antiarrhythmic agents: amiodarone, quinidine
      • H₂ histamine receptor antagonist: ranitidine
      • Bupropion (an antidepressant in its own class)
      • Cinacalcet (used for hyperparathyroidism)
    • Other CYP2D6 substrates (SSRIs can interact with other drugs and lead to increased drug levels and adverse effects):
      • β-blockers:
        • Used for hypertension or cardiac conditions: propranolol, metoprolol, atenolol, bisoprolol 
        • Combination with SSRIs can ↑ drug levels and cause hypotension
      • Tamoxifen: used to treat breast cancer
      • Antinausea medications: ondansetron, metoclopramide
      • Other antidepressants:
        • Tricyclic (amitriptyline, imipramine, nortriptyline)
        • Combination with SSRIs can ↑ drug levels and lead to serotonin syndrome
      • Antipsychotics:
        • Aripiprazole, haloperidol, olanzapine, quetiapine, risperidone
        • Combination with SSRIs can ↑ drug levels and lead to serotonin syndrome
      • 1st-generation antihistamines/H₁-receptor antagonists: chlorpheniramine, diphenhydramine
      • Muscle relaxants: cyclobenzaprine
      • Pain medications/opioid analgesics: codeine or tramadol
  • CYP3A4 substrates: SSRIs can interact with:
    • Some calcium channel blockers
    • Statins
    • Benzodiazepines
    • Hypnotics: zopiclone and zolpidem
    • Macrolide antibiotics: clarithromycin and azithromycin
    • Psychiatric medications: haloperidol, mirtazapine
    • Antivirals used in the management of HIV
  • CYP3A4 inhibitors and inducers: SSRIs can also interact with:
    • Antifungals: ketoconazole
    • Calcium channel blockers: specifically diltiazem and verapamil
    • Grapefruit juice
    • Antivirals used in the management of HIV (note that they are also CYP34 substrates, as listed above)
    • Anticonvulsants: carbamazepine, phenytoin, barbiturates
    • Rifampin
    • St. John’s wort
  • CYP2C9 pathway: fluoxetine can also interact with:
    • Antifungals: voriconazole
    • Some TCAs
    • Benzodiazepines
    • Proton pump inhibitors: omeprazole
    • Sulfonylureas: glipizide or glimepiride
  • Fluvoxamine (a different SSRI) is a potent CYP2C9 inhibitor:
    • ↑ Levels of the antipsychotics clozapine, thioridazine, and olanzapine
    • Contraindicated with the hypnotic drug ramelteon (Rozerem), melatonin, and the muscle relaxant tizanidine (Zanaflex) due to the risk of causing increased drug levels and CNS depression
  • SNRI drug interactions:
    • Duloxetine is a moderately potent inhibitor of CYP2D6 and may interact with other drugs:
      • ↑ Metoprolol levels
      • ↑ Thioridazine levels and risk of QT prolongation
    • Other SNRIs (venlafaxine, desvenlafaxine, and milnacipran) do not have significant effects on CYP enzymes.
  • SARI (trazodone) drug interactions:
    • Some sedatives or CNS depressants can cause increased sedation:
      • Opioids
      • Benzodiazepines
      • Barbiturates
      • Ethanol
    • Potent CYP2D6 inhibitors (paroxetine, tamsulosin): ↑ trazodone levels
  • 5-HT1A receptor partial agonist (vilazodone) drug interactions:
    • Similar adverse effects and contraindications as with SSRIs
    • Drug interactions: potent CYP3A4 inhibitors ↑ vilazodone levels
      • Antibiotics: clarithromycin, azithromycin
      • Antifungals: itraconazole, ketoconazole
      • Antivirals: indinavir, nelfinavir, ritonavir, saquinavir used in the management of HIV infection
      • Not all drugs within a class of medications inhibit CYP3A4.
  • Vortioxetine drug interactions: Use with other CYP2D6 inhibitors can ↑ vortioxetine levels

Contraindications

  • All SSRIs are contraindicated in individuals currently taking MAOIs to treat depression.
    • The combination may increase the risk of serotonin syndrome.
    • Additive risks of CNS depression and psychomotor impairment
  • SSRIs/SNRIs/SARIs/SMS are not recommended for individuals with bipolar depression as these drugs may induce mania (except for fluoxetine).
  • SNRIs:
    • Contraindicated with MAOIs
    • Duloxetine is contraindicated in individuals with narrow-angle glaucoma.

Overdose

Generally, an overdose of SSRI/SNRI/similar drugs can cause signs and symptoms of neuromuscular excitation and autonomic stimulation.

  • Signs:
    • Clonus
    • Agitation
    • Diaphoresis
    • Tremors
    • Hyperreflexia
    • Hyperthermia
  • Treatment:
    • Supportive care:
      • Discontinue serotonergic therapies.
      • Benzodiazepines may be needed for severe agitation.
      • Intubation may be required if there is a concern to protect the airway.
    • Cooling for individuals with hyperthermia
    • Individuals exhibiting refractory symptoms can be treated with cyproheptadine.

References

  1. O’Donnell, J.M., Bies, R.R., Shelton, R.C. (2018). Drug Therapy of Depression and Anxiety Disorders. In: Brunton LL, Hilal-Dandan R, Knollmann BC.(Eds.) Goodman & Gilman’s: The Pharmacological Basis of Therapeutics [Internet], 13th ed. New York, NY: McGraw-Hill. 
  2. Schatzberg, A.F., Nemeroff, C.B. (Eds.) (2017). The American Psychiatric Association Publishing Textbook of Psychopharmacology [Internet], 5e. Arlington, VA: American Psychiatric Association Publishing. https://doi.org/10.1176/appi.books.9781615371624 
  3. Stahl, S.M. (2013). Stahl’s Essential Psychopharmacology: Neuroscientific Basis and Practical Applications [Internet], 4th de. Cambridge University Press.
  4. Neurotransmitters and Neuromodulators. (2019). In: Nelson, L.S., et al. Goldfrank’s Toxicologic Emergencies [Internet], 11th ed. New York, NY: McGraw-Hill.
  5. Smink, F.R., van Hoeken, D., Hoek, H.W. (2013). Epidemiology, course, and outcome of eating disorders. Curr Opin Psychiatry. 26(6):543-8. https://doi.org/10.1097/yco.0b013e328365a24f
  6. American Geriatrics Society. (2019). 2019 Updated AGS Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. https://doi.org/10.1111/jgs.15767
  7. Hirsch, M., Birnbaum, R.J. (2021). Selective serotonin reuptake inhibitors: Pharmacology, administration, and side effects. UpToDate. Retrieved August 11, 2021, from https://www.uptodate.com/contents/selective-serotonin-reuptake-inhibitors-pharmacology-Administration-and-side-effects

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