Antidepressant Drugs

Anti-Depressant Drugs

• Dr. Aliena Edun, BPharm, M.D

Introduction to Depression

• Commonality: Depression is one of the most widespread psychiatric disorders.

• Types of Depression:

  • Reactive or Secondary Depression:

    • Most common type.

    • Occurs in response to real-life stimuli (e.g., grief, illness).

    • Affects 60% of diagnosed patients.

  • Major Depression or Endogenous Depression:

    • A genetically determined biochemical disorder often linked to family history.

    • Affects 25% of patients.

    • Typically responds to antidepressants or electroconvulsive therapy.

Types of Depression (continued)

• Bipolar Disorder (Manic-Depressive):

  • Depression associated with bipolar affective disorder.

  • Affects 10-15% of patients.

  • Lithium Bicarbonate is used to stabilize mood; mania may need antipsychotic drugs while depression is managed with antidepressants.

Etiology of Depression

• Caused by a deficiency of monoamines (noradrenaline, serotonin, dopamine) in specific brain regions.

• Mania results from overproduction of these neurotransmitters:

  • Symptoms include enthusiasm, rapid thoughts, impaired judgment.

Symptoms of Depression

• Persistent sadness.

• Hopelessness and tearfulness.

• Loss of energy (fatigue).

• Self-criticism and feelings of guilt.

• Worthlessness and irritability.

• Inability to concentrate and decreased interest in daily life.

• Changes in appetite, sleep issues (insomnia or excessive sleep).

• Recurrent thoughts of death or suicide.

• Chronic neuropathic pain.

Treatment of Depression

• Effective approaches include psychotherapies, behavioral therapies, electroconvulsive therapies, and psychoactive drugs.

• All antidepressant medications enhance the action of noradrenaline, dopamine, or serotonin in the brain.

• Led to biogenic amine theory linking depression to monoamine deficiencies.

Classification of Antidepressant Drugs

1. First Generation (Tricyclic Antidepressants - TCA’s):

• Examples:

  • Imipramine (Tofranil)

  • Desipramine

  • Trimipramine

  • Clomipramine (Anafranil)

  • Amitriptyline

  • Nortriptyline

  • Protriptyline

  • Doxepin

2. Second Generation Antidepressants:

• Examples:

  • Amoxapine

  • Maprotiline

3. Atypical Antidepressants:

• Examples:

  • Nefazodone

  • Mirtazapine

  • Bupropion (Wellbutrin, Zyban)

  • Trazodone

4. Selective Serotonin Reuptake Inhibitors (SSRI’s):

• Examples:

  • Fluoxetine (Prozac)

  • Fluvoxamine

  • Paroxetine (Paxil)

  • Sertraline (Zoloft)

  • Citalopram (Celexa)

  • Escitalopram

5. Serotonin/Norepinephrine Reuptake Inhibitors (SNRI's):

• Examples:

  • Venlafaxine (Effexor)

  • Duloxetine (Cymbalta)

6. Monoamine Oxidase Inhibitors:

• (a) Irreversible Inhibitors (Non-Selective):

  • Isocarboxazide

  • Tranylcypromine

  • Phenelzine

• (b) Reversible Inhibitors:

  • Moclobemide

  • Brofaromine

Mechanism of Action of Tricyclic Antidepressants (TCA’s)

• Mechanism: Block the reuptake of serotonin and noradrenaline in the presynaptic nerve terminal, increasing levels in the synaptic cleft.

• Additional effects include binding to alpha, histamine, and cholinergic receptors leading to side effects.

• Actions:

  • Elevates mood, enhances mental alertness, increases physical activity.

  • Selection based on side effect tolerance and drug duration of action.

Uses of Tricyclic Antidepressants (TCA’s)

• Indications:

  • Major depressive disorder

  • Panic disorder

  • Obsessive-compulsive disorder

  • Imipramine used for bed-wetting control in older children.

  • Attention deficit hyperactivity disorder.

Side Effects of Tricyclic Antidepressants (TCA’s)

• Anticholinergic effects:

  • Dry mouth, constipation, blurred vision, urinary retention.

• Cardiac effects:

  • Orthostatic hypotension, reflex tachycardia, arrhythmias.

• Endocrine effects:

  • Weight gain, sexual disturbances (like delayed ejaculation), sexual dysfunction.

• Other side effects:

  • Sedation (during early treatment), convulsions, confusion, hallucinations, allergic reactions, headache, drowsiness, tremors.

Drug Interactions of Tricyclic Antidepressants (TCA’s)

• Concurrent use with MAO inhibitors can lead to severe reactions (e.g., convulsions, hyperpyrexia, coma).

• Mixing with ethanol may cause toxic sedation.

• Caution advised in patients with cardiovascular disease, glaucoma, BPH, seizures, urinary retention.

• Contraindications: Liver impairment and cardiac issues.

Second Generation Antidepressants

• Amoxapine: Metabolite of loxapine with antipsychotic action and dopamine receptor antagonism.

• Maprotiline: Tetracyclic drug, potent norepinephrine uptake inhibitor; fewer sedative and antimuscarinic effects compared to older tricyclics.

• Side Effects: Dopamine antagonism can lead to akathisia, parkinsonism, amenorrhea-galactorrhea, somnolence, dry mouth, weight gain, constipation, sedation.

Atypical Antidepressants

• General Characteristics: Diverse actions at dopamine and norepinephrine receptors.

• Bupropion: Unique as it also decreases nicotine cravings; has a short half-life.

• Mirtazapine: Blocks 5-HT2 and α2 receptors; sedative; minimal antimuscarinic side effects.

• Trazodone: Acts on the 5-HT2A receptor; sedating, associated with priapism risks.

Selective Serotonin Reuptake Inhibitors (SSRIs)

• Mechanism of Action: Inhibit serotonin reuptake in presynaptic terminals, increasing synaptic concentration.

• Advantages: Fewer toxicities compared to TCAs, minimal action on other receptor types.

• Onset: Two weeks for improvement; maximum benefit may take 12 weeks.

Side Effects of SSRIs

• Common: Loss of libido, delayed ejaculation, anorgasmia, seizures (high doses), anxiety, insomnia, headaches, loss of appetite, weight loss.

• Notably, paroxetine and fluvoxamine can be more sedating.

• Discontinuation Syndrome: Abrupt withdrawal can lead to flu-like symptoms, headaches, malaise.

• Risks: Higher risk with SSRIs having shorter half-lives.

Drug Interactions of SSRIs

• Risk of serotonin syndrome if combined with MAOIs leading to hyperthermia and mental status changes.

• Fluoxetine inhibits metabolism of several drugs (e.g., haloperidol, TCAs).

• Uses: Treat obsessive-compulsive disorders, bulimia nervosa, panic disorder, and premenstrual dysphoric disorder.

Pharmacokinetics of SSRIs

• Generally well absorbed orally.

• Sertraline undergoes significant first-pass metabolism.

• Fluoxetine: Long half-life, and its metabolite has a very long half-life requiring a washout period.

Serotonin/Norepinephrine Reuptake Inhibitors (SNRIs)

• Mechanism of Action: Inhibit the reuptake of both serotonin and norepinephrine.

• Indications: Effective for patients where SSRIs fail; also treat chronic neuropathic pain.

• SNRIs have dual action similar to TCAs without activity on other receptor types.

Specific SNRIs

• Venlafaxine: Potent serotonin reuptake inhibitor; at high doses, norepinephrine reuptake is inhibited too.

  • Side Effects: Nausea, dizziness, insomnia, constipation; high doses may increase blood pressure.

• Duloxetine: Inhibits serotonin and norepinephrine reuptake at all dosages; avoid in hepatic impairment; food delays absorption.

  • Side Effects: Sexual dysfunction, nausea, dry mouth, insomnia.

Monoamine Oxidase Inhibitors (MAOIs)

• Mechanism of Action: Prevent inactivation of monoamines within the neuron, increasing neurotransmitter concentrations in synaptic space.

• Enzyme Selectivity: MAO-A metabolizes norepinephrine and serotonin; MAO-B is more selective for dopamine.

• Risk: Irreversible inhibitors block both enzymes, risking hypertensive reactions with tyramine-rich foods; reversible MAOIs, such as Moclobemide, pose lower risks.

Side Effects of MAOIs

• Common: Headaches, dry mouth, blurred vision, constipation, weight gain, sexual dysfunction, postural hypotension.

• Drug Interactions: Avoid tyramine-rich foods (e.g., cheese, meats, beer, red wine), as they can lead to hypertensive crises.

• Potentiate effects of various drugs (alcohol, TCA, etc.).

• Contraindications: Use is restricted in patients with hepatic or renal impairment and cardiovascular diseases.