Antidepressants

Learning Objectives

1. Understand treatment approaches for depression.

2. Identify and describe current pharmacotherapies, including:

   • Monoamine oxidase inhibitors (MAOIs)

   • Tricyclic antidepressants (TCAs)

   • Selective serotonin reuptake inhibitors (SSRIs)

   • Other antidepressants

3. Discuss potential future treatments.

Treatment Options

• Main Treatments: Cognitive Behavioral Therapy (CBT) and Pharmacotherapy.

• Mild Depression Treatments:

  • Wait and See: Monitor patient’s condition for 2-4 weeks.

  • CBT: Helps patients alter negative thought patterns to improve their mood.

  • Interpersonal Therapy: Addresses interpersonal issues contributing to depressive symptoms.

  • Exercise: Often recommended to improve mood.

  • Low-dose SSRIs: Sometimes used, but typically discontinued if ineffective after four weeks.

Antidepressants and Their Mechanisms

• Types of Antidepressants:

  • MAOIs (monoamine oxidase inhibitors)

  • TCAs (tricyclic antidepressant drugs)

  • SSRIs (selective serotonin reuptake inhibitors)

  • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

  • Noradrenergic and Specific Serotonergic Antidepressants (NaSSAs)

  • Serotonin Antagonists and Reuptake Inhibitors (SARIs)

• Mechanism of each type, focusing on modulation of neurotransmitters like serotonin (5-HT) and norepinephrine (NA).

Monoamine Oxidase Inhibitors (MAOIs)

• Mechanism: Inhibit the enzyme monoamine oxidase (MAO), increasing 5-HT and NA levels in the synapse.

• Early MAOIs: Phenelzine and Isocarboxazid (nonselective and irreversible) no NA degradation when needed.

• Side Effects: Postural hypotension, central nervous system (CNS) stimulation e.g. insomnia, increased appetite and weight gain (due to 5HT2 receptor downregulation), anticholinergic effects (e.g., dry mouth, constipation, blurred vision, tachycardia).

• Drug Interactions: Interact with tyramine (found in cheese and wine), leading to dangerous blood pressure elevations. irreversible MAOIs are non specific - reduce metabolism of opioid analgesics and alcohol.

• Reversible MAOIs: Reversible inhibitors of MAO-A (RIMAs), e.g., moclobemide, are safer + selective and allow excess NA degradation in emergencies.

• ONLY USED IN SEVERE DEPRESSION WHEN OTHER ANTIDEPRESSANTS DO NOT WORK.

Tricyclic Antidepressants (TCAs)

• Mechanism: Inhibit reuptake of 5-HT and NA, initially increasing their concentration at the synapse.

• Chronic Effects: Downregulation of β1 and 5-HT2 and auto receptors. (downregulate both pre and post synaptic receptors).

• Side Effects: Anticholinergic effects (constipation, dry mouth), antihistaminic effects (weight gain, sedation), a adrenergic antagonist effects (hypotension), risk of toxicity in overdose.

• Use Caution: Not recommended for elderly or individuals with cardiovascular issues, epilepsy, dementia or suicidal tendencies.

• Drug interaction: metabolism of TCAs inhibited by certain drugs e.g. antipsychotics, steroids. increase the effect of alcohol and anaesthetics.

• withdrawal symptoms e.g. sweating, flu like, vomiting.

• narrow therapeutic window

• NOT IDEAL DUE TO LONG TIME TO PRODUCE EFFECTS, USED FOR CHRONIC PAIN AND ANXIETY.

• Examples: amitriptylline, imipramine, lofepramine

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Mechanism: Inhibit serotonin reuptake, increasing 5-HT in the synapse. downregulate 5-HT1A/1D autoreceptors - presynaptic receptors (responsible for negative feedback mechanism) increasing the release of serotonin.

  • The increased release of 5-HT normalise post synaptic 5-HT receptors

• Benefits: Fewer side effects than TCAs, safer in overdose, better for long-term use and better compliance, broader therapeutic profile.

• Side Effects: Insomnia, sexual dysfunction, anti-OCD (5HT2A), nausea, headache, diarrhea, GI distress (5HT3), initial anxiety, weight gain or loss.

• Withdrawal Risks: Flu-like symptoms, emotional disturbance, and risk of increased suicidal behavior in those under 18.

• Drug interactions: interacts with TCA, MAO-I, St Johns Wart.

  • inhibit metabolism of TCA

  • risk of serotonin syndrome if overdosed - seizures, sweating, confusion, HBP.

  • SSRIs inhibit BZD metabolism - excessive sedation risk if combined.

  • risk of bleeding when taken with anticoagulant & NSAIDs

  • SSRIs may not be suitable for diabetics, heart/kidney problems, bipolar (mania phase)

• Additional Uses: Treat anxiety disorders, OCD, PTSD, and some chronic pain.

Other Antidepressant Drugs

1. SNRIs (e.g., venlafaxine):

   • Inhibit reuptake of both serotonin and norepinephrine, fewer anticholinergic, antiadrenergic, antihistaminic effects than TCAs.

   • Side effects: Headache, dry mouth, sweating, insomnia, increased blood pressure.

   • safer and more tolerated than TCAs

   • used for chronic pain & anxiety

2. SARIs (e.g., trazodone):

   • Acts as a serotonin antagonist and reuptake inhibitor, causing less initial anxiety than SSRIs.

   • strong sedative, less side effects associated with 5HT2A stimulation.

3. NaSSAs (e.g., mirtazapine):

   • Blocks certain serotonin receptors (5-HT2, 5-HT3), reduces anxiety, but can cause sedation and weight gain, lacks side effects linked to 5HT2/3.

4. Other agents:

   • Bupropion: Blocks NA and DA reuptake, used in nicotine addiction and ADHD.

   • contraindication for patients with a history of bulimia or anorexia nervosa

   • Mianserin: Weak NA reuptake inhibitor effects and a2, 5HT2A/3, a1, H1 antagonist, but can cause severe side effects like drowsiness, weight gain, tremor headache, agranulocytosis and bone marrow depression.

   • oestrogen (HRT): for treatment of menopause and associated depression caused by fluctuating oestrogen levels.

     • has action on monoamine system, GABAergic, glutamatergic.

Issues with Antidepressants

• Common Problems: Delayed effects, varied patient response, high side-effect profile, toxic with overdose, more efficacious than placebo.

• Pharmacogenomics: Genetic variations (e.g., CYP2C19, CYP2D6) affect antidepressant metabolism, guiding more personalized treatment.

Future Directions in Antidepressant Development

• New Drug Targets:

  • Monoamine Modulators: Including 5-HT2A antagonists, 5HT1A agonists, and D2 agonists.

  • Ion Channel Modulators: NMDA blockers (e.g., ketamine), neurosteroids.

  • Biological Treatments: Monoclonal antibodies, botulinum toxin, microbiota manipulation.