SSRIs: Mechanism, Indications

• Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressants
• SSRIs treat depression and anxiety disorders

Mechanism of Action

• SSRIs work by increasing the extracellular level of serotonin
• This is done by inhibiting its reuptake into the presynaptic cell
• SSRIs block the serotonin transporter (SERT) protein
• SERT usually transports serotonin from the synaptic cleft back into the presynaptic neuron
• Blocking SERT increases the availability of serotonin in the synaptic cleft
• This allows serotonin to bind to postsynaptic receptors for a longer duration
• This enhances serotonergic neurotransmission, improving mood and reducing anxiety

Indications

• Major depressive disorder (MDD): SSRIs are a first-line treatment
• Generalized anxiety disorder (GAD): Effective in reducing excessive worry and anxiety
• Panic disorder: Helps to reduce the frequency and severity of panic attacks
• Obsessive-compulsive disorder (OCD): Reduces obsessions and compulsions
• Social anxiety disorder (SAD): Reduces fear and avoidance of social situations
• Post-traumatic stress disorder (PTSD): Helps manage symptoms like flashbacks and hyperarousal
• Premenstrual dysphoric disorder (PMDD): Alleviates mood symptoms related to menstruation
• Bulimia nervosa: Can reduce binge eating and purging behaviors (fluoxetine only)

Common SSRIs

• Fluoxetine: One of the first SSRIs, known for its long half-life
• Sertraline: Commonly prescribed, with a relatively balanced side effect profile
• Paroxetine: Can be effective but has a higher risk of withdrawal symptoms
• Citalopram: Generally well-tolerated, but has dose limitations due to potential cardiac effects
• Escitalopram: The S-enantiomer of citalopram, often considered to have fewer side effects
• Fluvoxamine: Also used for OCD, can have more drug interactions

Side Effects

• Nausea: Common initially, usually resolves within a few weeks
• Diarrhea: Can occur due to increased serotonin in the gastrointestinal tract
• Insomnia: Some individuals experience difficulty sleeping
• Somnolence: Others may feel excessively tired or drowsy
• Sexual dysfunction: Including decreased libido, erectile dysfunction, and anorgasmia
• Weight changes: Can vary; some experience weight gain, others weight loss
• Increased sweating: Excessive perspiration is a possible side effect
• Dry mouth: Reduced saliva production can occur
• Headache: Common, especially at the beginning of treatment
• Anxiety or agitation: Some individuals may feel more anxious initially
• Serotonin syndrome: A rare but serious condition due to excessive serotonin activity

Serotonin Syndrome

• A rare but potentially life-threatening condition
• Typically occurs when SSRIs are combined with other serotonergic drugs
• Symptoms include:
  • Agitation: Restlessness and irritability
  • Confusion: Disorientation and difficulty thinking clearly
  • Increased heart rate: Tachycardia
  • Increased blood pressure: Hypertension
  • Muscle rigidity: Stiffness and tension in the muscles
  • Hyperreflexia: Overactive reflexes
  • Tremor: Shaking or trembling
  • Sweating: Excessive perspiration
  • Dilated pupils: Enlargement of the pupils
  • Diarrhea: Frequent, loose stools
• Severe cases can lead to:
  • High fever: Hyperthermia
  • Seizures: Uncontrolled electrical activity in the brain
  • Coma: Loss of consciousness
  • Death
• Treatment involves:
  • Stopping the serotonergic medications
  • Supportive care (e.g., cooling blankets, IV fluids)
  • Medications to block serotonin production

Discontinuation Syndrome

• Can occur when SSRIs are abruptly stopped
• Not the same as addiction or dependence, but can be uncomfortable
• Symptoms include:
  • Flu-like symptoms: Fatigue, muscle aches, and chills
  • Insomnia: Difficulty sleeping
  • Nausea: Feeling sick to the stomach
  • Imbalance: Dizziness, vertigo, and lightheadedness
  • Sensory disturbances: "Brain zaps" or electric shock sensations
  • Anxiety: Increased feelings of worry or unease
  • Depression: Worsening of mood
  • Irritability: Feeling easily annoyed or frustrated
• To minimize discontinuation symptoms, SSRIs should be tapered gradually
• Gradual dose reduction allows the brain to readjust to lower serotonin levels

Drug Interactions

• MAOIs: Combining SSRIs with MAOIs can lead to serotonin syndrome
• Other serotonergic drugs: Caution should be exercised when combining with other drugs that increase serotonin activity
• Warfarin: SSRIs can increase the risk of bleeding when taken with warfarin
• NSAIDs: Increased risk of gastrointestinal bleeding when combined with SSRIs
• Antiplatelet drugs: Such as aspirin or clopidogrel; can increase bleeding risk
• CYP450 inhibitors: Some SSRIs can inhibit CYP450 enzymes, affecting the metabolism of other drugs
• Alcohol: While not a direct interaction, alcohol can worsen the side effects of SSRIs

Precautions

• Suicidal thoughts: SSRIs can increase the risk of suicidal thoughts in young adults
• Bipolar disorder: SSRIs can trigger mania or hypomania in individuals with bipolar disorder
• Pregnancy: SSRIs can potentially affect the fetus; benefits and risks should be carefully considered
• Breastfeeding: Some SSRIs can pass into breast milk; benefits and risks should be discussed
• Cardiac issues: Citalopram and escitalopram have been associated with QT interval prolongation

Administration

• SSRIs are typically taken orally in tablet or capsule form
• They are usually taken once daily
• Dosage varies depending on the specific SSRI and the individual's condition
• It may take several weeks (4-6) to experience the full therapeutic effects
• Consistent adherence to the prescribed regimen is important
• If a dose is missed, it should be taken as soon as remembered
• Unless it is almost time for the next scheduled dose
• Doses should not be doubled
• Regular follow-up appointments with a healthcare provider are necessary
• To monitor progress and manage any side effects

Selective serotonin reuptake inhibitors (SSRIs) are antidepressants that increase serotonin levels in the synaptic cleft by blocking the serotonin transporter (SERT). This mechanism enhances serotonergic neurotransmission, improving mood and reducing anxiety. SSRIs treat major depressive disorder, generalized anxiety disorder, panic disorder and obsessive-compulsive disorder.