Pharmacology of Antidepressants and Benzodiazepines

Antidepressants and Benzodiazepines

Overview of Anxiety Disorders

• Anxiety disorders are among the most common psychiatric illnesses with a lifetime prevalence of around 31%.
• They are frequently underdiagnosed and remain untreated in about 40% of diagnosed patients.

The Monoamine Hypothesis

• An incomplete theory attempting to describe the mechanisms of anxiety and depression and the mechanism by which antidepressants work.
• States that mood disorders result from abnormalities in serotonin, norepinephrine, and/or dopamine neurotransmission.
• Limitations:
  • Antidepressants only work in about 50 – 70% of people.
  • It takes several weeks before antidepressant effects are realized.
  • Changes to neurotransmitter levels occur with the first dose.

Reuptake Inhibitors

• Types:
  • Tricyclic antidepressants (TCA)
  • Selective serotonin reuptake inhibitors (SSRI)
  • Serotonin and Norepinephrine reuptake inhibitors (SNRI)

Tricyclic Antidepressants (TCA)

• Older class of reuptake inhibitors.
• Block neuronal reuptake of norepinephrine and serotonin.
• Increase the time neurotransmitters are present in the synapse and enhance neurotransmission.
• Limitations:
  • Rather non-specific for the serotonergic and noradrenergic neurons they target.
  • Affects more neuronal targets than necessary.
  • Cross reacts with cardiac adrenoreceptors.
  • Causes anticholinergic effects.

Imipramine (TCA)

• Indicated for:
  • Agoraphobia
  • Generalized anxiety disorder
  • Panic disorder
• Adverse effects:
  • CNS:
    • Drowsiness
    • Psychomotor impairment
    • Agitation
    • Headache
    • Myoclonus
    • Seizure
  • Anticholinergic:
    • Dry mouth
    • Constipation
    • Blurred vision
    • Urinary retention
    • Cognitive impairment
  • Cardiovascular:
    • Orthostatic hypotension
    • Palpitations
    • Dizziness
    • Tachycardia
    • Arrhythmias
    • QTc interval prolongation
• Contraindications:
  • Patients with suicidal ideation
  • Use with caution in patients with existing cardiovascular disease, cognitive impairment, or history of seizure.
  • Considered a second-line agent for anxiety and depression.

Selective Serotonin Reuptake Inhibitors (SSRI) and Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)

• Considered first-line agents for anxiety and depression.
• Examples:
  • Escitalopram (SSRI)
  • Venlafaxine (SNRI)

Escitalopram (SSRI)

• Indicated for:
  • Generalized anxiety disorder
  • Major depressive disorder
  • Agoraphobia
  • Panic disorder
  • Social anxiety disorder
• Adverse effects:
  • CNS:
    • Anxiety
    • Agitation
    • Insomnia
    • Headache
    • Extrapyramidal effects
  • GI:
    • Nausea
    • Vomiting
    • Diarrhea
    • Constipation
    • Increased risk of upper GI bleeding
  • Other:
    • Dry mouth
    • Increased sweating
    • Sexual dysfunction
    • May prolong QTc interval
• Dosing:
  • For anxiety disorders: 5-20 mg/day PO
  • For major depressive disorder: 10-20 mg/day PO

Venlafaxine (SNRI)

• Indicated for:
  • Generalized anxiety disorder
  • Major depressive disorder
  • Social anxiety disorder
• Adverse effects:
  • Similar to Escitalopram
• Dosing:
  • For anxiety disorders: 37.5-300 mg/day PO
  • For major depressive disorder: 37.5-375 mg/day PO

Serotonin Syndrome

• Range from mild symptoms to life-threatening.
• Symptoms:
  • Mild:
    • Mild hypertension
    • Tachycardia
    • Mydriasis
    • Diaphoresis
    • Shivering
    • Tremor
    • Myoclonus
  • Moderate:
    • Hyperthermia
    • Hyperactive bowel sounds
    • Horizontal ocular clonus
    • Mild agitation
    • Hypervigilance
    • Pressured speech
  • Severe:
    • More severe hyperthermia
    • Dramatic swings in pulse rate and blood pressure
    • Delirium
    • Muscle rigidity

Antidepressant Discontinuation Syndrome

• Occurs with rapid discontinuation or dose reduction.
• Symptoms:
  • Anxiety
  • Crying
  • Headache
  • Increased dreaming
  • Insomnia
  • Irritability
  • Myoclonus
  • Nausea
  • Electric shocks
  • Tremor
  • Flulike symptoms
  • Imbalance
  • Sensory disturbances
• Prevention:
  • Gradual tapering by approximately 25% per week
  • Slower tapering may be needed in some individuals

Benzodiazepines

• Act as positive allosteric modulators of GABA-A receptors.
• GABA-A receptors are found in high concentrations in the cortex and limbic system.
• GABA is inhibitory and reduces the excitability of neurons.
• Classification:
  • By elimination half-life:
    • Short acting: 1-12 hours
    • Intermediate acting: 12-40 hours
    • Long acting: 40-250 hours
  • By potency:
    • Lower potency options: fewer adverse effects
    • Higher potency options: faster onset of action, increased risk of adverse effects

Clonazepam

• Indicated for:
  • Generalized anxiety disorder
  • Agoraphobia
  • Panic disorder
  • Social anxiety disorder
• Characteristics:
  • High-potency long-acting benzodiazepine
  • Half-life: 18-50 hours
  • Onset of action: 20-60 minutes
  • Peak concentration: 1-4 hours
  • Duration: 6-8 hours
• Adverse effects:
  • CNS:
    • Drowsiness
    • Psychomotor impairment
    • Fatigue
    • Muscle weakness
    • Reduced concentration
    • Confusion
    • Dysarthria
    • Ataxia

Introduction to Antidepressants and Benzodiazepines

• Anxiety disorders are among the most common psychiatric illnesses, with a lifetime prevalence of around 31%.
• Major depressive disorder has a lifetime prevalence of 10% and accounts for over 5% of population illness-related productivity loss.

The Monoamine Hypothesis

• The monoamine hypothesis is an incomplete theory attempting to describe the mechanisms of anxiety and depression and the mechanism by which antidepressants work.
• The hypothesis states that mood disorders result from abnormalities in serotonin, norepinephrine, and/or dopamine neurotransmission.
• Limitations of the hypothesis include:
  • Antidepressants only work in about 50-70% of people.
  • It takes several weeks before antidepressant effects are realized.
  • Changes to neurotransmitter levels occur with the first dose.

Reuptake Inhibitors

• Tricyclic antidepressants (TCA) are an older class of reuptake inhibitors.
• Selective serotonin reuptake inhibitors (SSRI) and serotonin and norepinephrine reuptake inhibitors (SNRI) are other classes of reuptake inhibitors.

Tricyclic Antidepressants

• TCAs block neuronal reuptake of norepinephrine and serotonin, increasing the time neurotransmitters are present in the synapse and enhancing neurotransmission.
• TCAs are rather non-specific for the serotonergic and noradrenergic neurons they target, affecting more neuronal targets than necessary.
• Adverse effects of TCAs include:
  • Anticholinergic effects (dry mouth, constipation, blurred vision, urinary retention, cognitive impairment).
  • Cardiovascular effects (orthostatic hypotension, palpitations, dizziness, tachycardia, arrhythmias, QTc interval prolongation).

Imipramine

• Imipramine is a TCA indicated for agoraphobia, generalized anxiety disorder, and panic disorder.
• Adverse effects of imipramine include:
  • CNS effects (drowsiness, psychomotor impairment, agitation, headache, myoclonus, seizure).
  • Anticholinergic effects (dry mouth, constipation, blurred vision, urinary retention, cognitive impairment).
  • Cardiovascular effects (orthostatic hypotension, palpitations, dizziness, tachycardia, arrhythmias, QTc interval prolongation).

SSRIs and SNRIs

• SSRIs and SNRIs are considered first-line agents for anxiety and depression.
• Examples of SSRIs and SNRIs include:
  • Escitalopram (SSRI)
  • Venlafaxine (SNRI)

Escitalopram

• Escitalopram is a SSRI indicated for agoraphobia, panic disorder, social anxiety disorder, and major depressive disorder.
• Adverse effects of escitalopram include:
  • CNS effects (anxiety, agitation, insomnia, headache, extrapyramidal effects).
  • GI effects (nausea, vomiting, diarrhea, constipation, increased risk of upper GI bleeding).
  • Other effects (dry mouth, increased sweating, sexual dysfunction, and may prolong QTc interval).

Venlafaxine

• Venlafaxine is a SNRI indicated for generalized anxiety disorder, social anxiety disorder, and major depressive disorder.
• Adverse effects of venlafaxine include:
  • CNS effects (anxiety, agitation, insomnia, headache, extrapyramidal effects).
  • GI effects (nausea, vomiting, diarrhea, constipation, increased risk of upper GI bleeding).
  • Other effects (dry mouth, increased sweating, sexual dysfunction, and may prolong QTc interval).

Serotonin Syndrome

• Serotonin syndrome is a range of symptoms from mild to life-threatening, resulting from increased serotonin levels in the body.
• Symptoms of serotonin syndrome include:
  • Mild cases: mild hypertension, tachycardia, mydriasis, diaphoresis, shivering, tremor, myoclonus, and hyperreflexia.
  • Moderate cases: hyperthermia, hyperactive bowel sounds, horizontal ocular clonus, mild agitation, hypervigilance, and pressured speech.
  • Severe cases: severe hyperthermia, dramatic swings in pulse rate and blood pressure, delirium, and muscle rigidity.

Antidepressant Discontinuation Syndrome

• Antidepressant discontinuation syndrome occurs with rapid discontinuation or dose reduction of antidepressants.
• Symptoms of antidepressant discontinuation syndrome include:
  • Anxiety, crying, headache, increased dreaming, insomnia, irritability, myoclonus, nausea, electric shocks, tremor, flulike symptoms, imbalance, and sensory disturbances.
• The syndrome can be reversed by restarting the antidepressant and tapering more slowly.

Benzodiazepines

• Benzodiazepines act as positive allosteric modulators of GABA-A receptors, enhancing inhibitory neurotransmission.
• Benzodiazepines can be classified by:
  • Elimination half-life: short-acting (1-12 hours), intermediate-acting (12-40 hours), and long-acting (40-250 hours).
  • Potency: lower potency options have fewer adverse effects, while higher potency options have a faster onset of action but increase the risk of adverse effects.

Clonazepam

• Clonazepam is a high-potency long-acting benzodiazepine indicated for agoraphobia, panic disorder, and social anxiety disorder.
• Adverse effects of clonazepam include:
  • CNS effects: drowsiness, psychomotor impairment, fatigue, muscle weakness, reduced concentration, confusion, dysarthria, and ataxia.