How Do SNRI Antidepressants Work?

Serotonin-norepinephrine reuptake inhibitor (SNRI) antidepressants are medications prescribed to treat depression and conditions such as fibromyalgia, which cause chronic widespread pain. SNRIs increase the levels of serotonin and norepinephrine and regulate their activity.

Serotonin and norepinephrine are chemicals (neurotransmitters) released by nerve cells (neurons) in the brain to transmit nerve signals. Serotonin and norepinephrine play important roles in mood regulation and pain modulation, and abnormality in their functioning can cause chronic pain, fatigue, depression, and anxiety. 

SNRI antidepressants raise the levels of serotonin and norepinephrine by preventing their reabsorption (reuptake), a natural process in the brain. An increase in serotonin and norepinephrine levels improves mood and increases energy, and regulation of their activity alters pain perception and pain threshold.

SNRI antidepressants are oral tablets or capsules approved by the FDA for the treatment of the following conditions:

• Major depressive disorder
• Generalized anxiety disorder
• Social anxiety disorder
• Panic disorder
• Fibromyalgia
• Diabetic peripheral neuropathic pain
• Chronic musculoskeletal pain

Off-label uses include:

• Hot flashes due to hormonal chemotherapy
• Posttraumatic stress disorder (PTSD)
• Attention deficit hyperactivity disorder (ADHD)
• Neuropathic pain

Side effects of SNRI antidepressants may include the following:

• Nausea
• Dry mouth
• Hyperhidrosis (excessive sweating)
• Dizziness
• Insomnia
• Constipation
• Somnolence (drowsiness)
• Headache
• Fatigue
• Hot flush
• Asthenia (weakness)
• Anorexia (loss of appetite)
• Diarrhea
• Vomiting
• Dyspepsia (indigestion)
• Abdominal pain
• Gastritis
• Flatulence
• Ejaculation disorder
• Anorgasmia (difficulty reaching orgasm)
• Decreased libido
• Sexual dysfunction
• Erectile dysfunction
• Testicular pain
• Impotence
• Increase in cholesterol levels
• Increase in triglycerides
• Nervousness
• Agitation
• Mood swings
• Tremor
• Vertigo
• Anxiety
• Poor quality sleep
• Abnormal dreams
• Depersonalization
• Hallucinations
• Activation of mania or hypomania
• Seizure
• Delirium
• Loss of consciousness
• Suicide ideation and attempt
• Homicidal ideation
• Mydriasis (dilation of pupils)
• Blurred vision
• Diplopia (double vision)
• Abnormal vision
• Accommodation disorder (difficulty in eye focus)
• Dry eyes
• Visual impairment
• Narrow-angle glaucoma (a condition with high intraocular pressure that damages the optic nerve)
• Musculoskeletal stiffness and pain
• Muscle spasm
• Twitching
• Paresthesia (prickling sensation)
• Hypoesthesia (reduced sensation)
• Parkinsonism
• Impaired coordination and balance
• Convulsions
• Catatonia (inability to move normally)
• Dystonia (involuntary muscle contractions)
• Trismus (lockjaw)
• Vasodilation
• Syncope (fainting)
• Bruxism (teeth grinding)
• Tinnitus
• Ear pain
• Dysgeusia (taste disorders)
• Migraine
• Chills
• Yawning
• Thirst
• Malaise
• Throat pain
• Nasopharyngitis (inflammation of nasal passage and pharynx)
• Laryngitis (inflammation of the larynx)
• Upper respiratory tract infection
• Cough
• Influenza
• Interstitial lung disease and eosinophilic pneumonia
• Dyspnea (shortness of breath)
• Palpitations
• Supraventricular arrhythmia (irregular heartbeat that begins in the areas above the ventricles)
• Tachycardia (rapid heartbeat)
• Hypertension (high blood pressure)
• Hypotension (low blood pressure)
• Ischemic cardiac events in people with cardiac risk factors
• Myocardial infarction (heart attack)
• Takotsubo cardiomyopathy (sudden weakness of the heart muscles)
• Weight gain
• Weight loss
• Colitis (inflammation of the colon)
• Pancreatitis (inflammation of the pancreas)
• Hepatitis (inflammation of the liver)
• Gastroenteritis (infection and inflammation of the digestive system)
• Abnormal liver function test results
• Hyperprolactinemia (increase in prolactin levels)
• Galactorrhea (abnormal milk production and leakage)
• Gynecologic bleeding
• Hypothyroidism
• Hyperglycemia (increased glucose in the blood)
• Urinary retention
• Dysuria (painful urination)
• Anuria (lack of urine output)
• Acute kidney failure
• Hypersensitivity reactions such as:
  • Rash
  • Urticaria (hives)
  • Pruritus (itching)
  • Dermatitis
  • Alopecia (hair loss)
  • Photosensitivity
  • Erythema multiforme (round lesions like a bullseye)
  • Angioedema (swelling in the tissue under the skin or mucous membranes)
  • Stevens-Johnson syndrome (a rare medical emergency with flu-like symptoms and a painful rash)
  • Toxic epidermal necrolysis (a severe skin condition with widespread redness, skin cell death, and exfoliation which can lead to sepsis)
  • Anaphylaxis (severe allergic reaction)
• Increased tendency to bruise
• Cutaneous vasculitis (inflammation of blood vessels in the skin)
• Reduced blood cell count conditions such as:
  • Neutropenia (low neutrophils, a type of immune cell)
  • Leukopenia (low leukocytes, a type of immune cell)
  • Agranulocytosis (low granulocytes, immune cells with granules)
  • Thrombocytopenia (low platelet count)
  • Anemia
• Hyponatremia (low sodium in the blood)
• Aneurysm (weakened area and bulging in the blood vessel)
• Deep vein thrombophlebitis (blood clot in the vein with inflammation)
• Bacteremia (bacterial infection in the blood)
• Gastrointestinal bleeding
• Abnormal bleeding
• Serotonin syndrome
• Drug discontinuance symptoms
• Restless leg syndrome
• Aggression and anger after treatment discontinuation
• Seizures on discontinuance of treatment
• Extrapyramidal disorders (movement disorders)
• Rhabdomyolysis (breakdown of skeletal muscle cells)

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 SNRI antidepressant drugs include:

• Cymbalta
• desvenlafaxine
• Drizalma Sprinkle
• duloxetine
• Effexor XR
• Fetzima
• levomilnacipran
• milnacipran
• Pristiq
• Savella
• venlafaxine