depression

DEPRESSION: OVERVIEW

  • One in eight Canadians will experience a mood disorder at some time in their lives.

  • Factors contributing to depressive disorders:

    • Hormonal Changes:

    • Premenstrual syndrome

    • Pregnancy

    • Postpartum

    • Substance Abuse:

    • Alcohol

    • Other drugs

    • Illnesses:

    • Parkinson’s disease

    • Heart attack

    • Thyroid dysfunction.

    • Heredity:

    • Plays a significant role, particularly in bipolar disorder.

  • Suicide Risk:

    • As many as 12% of depressed patients contemplate or attempt suicide.

DEPRESSION AND ITS IMPACT

  • Depression influences most aspects of a person’s life and lifestyle, affecting:

    • Self-esteem

    • Mood

    • Thought processes

    • Eating habits

    • Sleeping patterns.

Signs and Symptoms:

  • Persistent feeling of sadness.

  • Loss of interest in activities once enjoyed.

  • Irritability or frustration.

  • Sleep disturbances:

    • Insomnia or hypersomnia (excessive sleep).

  • Fatigue:

    • Lack of energy and concentration.

  • Anxiety:

    • Feelings of worthlessness or guilt.

SUICIDE

  • A major concern in depression is suicide risk.

  • The overdose potential of medications used in treating depression must be carefully monitored.

  • Demographics:

    • While suicide deaths are more frequent in males, non-fatal self-inflicted injuries, many of which are suicide attempts, are more common in young females.

THREE PRIMARY TYPES OF DEPRESSION

  1. Major Depressive Disorder

  2. Bipolar Disorder

  3. Dysthymia

MAJOR DEPRESSION (CLINICAL DEPRESSION)

  • Characterized by:

    • Persistent feelings of intense sadness for weeks.

    • Lack of interest in activities that used to be pleasurable.

    • May include physical ailments such as fatigue and changes in sleep patterns.

    • Common feelings include emptiness and hopelessness.

    • Symptoms can include:

    • Fatigue

    • Irritability

    • Insomnia or hypersomnia.

BIPOLAR DISORDER (MANIC DEPRESSIVE DISORDER)

  • Characterized by:

    • Sudden swings in mood between depression and periods of mania.

  • Mania Symptoms Include:

    • Hyperactivity

    • Racing thoughts

    • Insomnia

    • Distractibility

    • Increased goal-directed behavior.

  • Proposed Example: Vincent Van Gogh.

DYSTHYMIA

  • Similar symptoms to Major Depression but less severe.

  • Results in chronic symptoms that prevent effective functioning and feelings of well-being.

OTHER TYPES OF DEPRESSION

  • Atypical Depression:

    • Increase in sleep, appetite, and weight.

  • Anxious Depression:

    • May be refractory to standard antidepressants.

  • Seasonal Affective Disorder (SAD):

    • Occurs during specific seasons, e.g., winter.

    • Often responds to light therapy.

    • Associated with decreased release of melatonin in the brain in response to the external environment; however, melatonin effectiveness for SAD remains unproven and requires further research.

  • Psychotic Depression:

    • Includes mood congruent delusions, often revolving around themes of sinful behavior or profound worthlessness.

NEUROCHEMISTRY OF DEPRESSION

  • Biogenic Amine Theory:

    • Clinical depression results from a decrease in monoamine neurotransmitters in the brain:

    • Norepinephrine

    • Dopamine

    • Serotonin.

    • The neurotransmitter ext{GABA} may also be involved.

    • Bipolar affective disorder (mania):

    • Believed to be associated with increased levels of monoamines.

DRUGS USED TO TREAT DEPRESSION: MECHANISMS OF ACTION

  • Mechanisms to Increase Neurotransmitter Levels:

    • Inhibition of neurotransmitter reuptake.

    • Decreased degradation of neurotransmitters.

ANTIDEPRESSANTS

  • Types of Antidepressants:

    1. Tricyclic Antidepressants (TCAs)

    2. Selective Serotonin Reuptake Inhibitors (SSRIs)

    3. Monoamine Oxidase Inhibitors (MAOIs)

    4. Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

    5. Atypical Antidepressant Drugs.

  • Selection Criteria:

    • Based on the patient’s ability to tolerate drug side effects; all antidepressants are equally effective.

TRICYCLIC ANTIDEPRESSANTS (TCAs)

  • Examples:

    • Amitriptyline

    • Imipramine

    • Nortriptyline

    • Desipramine

    • Trimipramine.

Characteristics of TCAs:

  • Oldest class of antidepressant medications.

  • Mechanism of Action:

    • Inhibit the reuptake of serotonin and norepinephrine into nerve terminals.

    • Also used for other conditions like nerve pain and enuresis.

    • Highly lipophilic, allowing them to cross the blood-brain barrier.

    • Variable pharmacokinetics.

Efficacy of TCAs:

  • Similar structures with comparable efficacy and adverse reactions.

  • Relieve depression after a minimum of 2 weeks; often take 4 to 8 weeks of treatment.

TCAs: ADVERSE REACTIONS

  • Side Effects Related to Receptor Binding:

    • Adrenergic Receptors:

    • Increased cardiovascular activity (can be lethal in overdose due to narrow therapeutic index).

    • Hypotension and rebound tachycardia.

    • Histaminic Receptors:

    • Sedation (tolerance may develop).

    • Weight gain.

    • Hypotension can lead to falls in older adults.

    • Muscarinic Receptors (anticholinergic effects):

    • Blurred vision.

    • Dry mouth.

    • Constipation.

    • Urinary retention.

    • Confusion and delirium.

TCAs: LOOK-ALIKE/SOUND-ALIKE DRUGS

  • Similar names to other medications can cause confusion:

    • Clomipramine, chlorpromazine, clomiphene.

    • Desipramine and imipramine.

    • Doxepin and digoxin.

    • Imipramine and desipramine.

    • Nortriptyline and amitriptyline.

    • Trimipramine, imipramine, and triamterene.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)

  • Examples:

    • Citalopram

    • Escitalopram

    • Fluoxetine

    • Fluvoxamine

    • Paroxetine

    • Sertraline

    • Vilazodone

    • Vortioxetine.

Characteristics of SSRIs:

  • Most widely prescribed antidepressant class.

  • Mechanism of Action:

    • Selective blockade of serotonin reuptake at the synaptic cleft.

    • Little to no effect on other receptors, resulting in fewer side effects.

  • Equally effective as TCAs but lack cardiotoxic effects.

  • Typically well-tolerated; dosage should be increased gradually to avoid adverse effects.

SSRIs: DISCONTINUATION SYNDROME

  • Symptoms:

    • Flu-like symptoms: fatigue, lethargy, malaise, muscle aches.

    • Insomnia.

    • Nausea.

    • Imbalance: dizziness, gait instability, vertigo.

    • Sensory disturbances: "electric shock" sensations, paresthesias.

    • Hyperarousal: anxiety, agitation.

SSRIs: ADVERSE EFFECTS

  • Potential side effects:

    • Insomnia

    • Decreased appetite

    • Nausea

    • Agitation or anxiety

    • Diarrhea

    • Sexual dysfunction.

  • Serotonin Syndrome:

    • Caused by excessive amounts of serotonin; symptoms include:

    • Muscle spasms

    • Fever

    • Sweating

    • Confusion

    • Seizures

    • Cardiovascular collapse and death.

    • Often results from inadvertent administration of multiple medications affecting serotonin levels such as TCAs, anti-psychotics, and St. John’s wort.

SSRIs: WARNING LABELS

  • May impair ability to drive.

  • Avoid alcohol.

  • May cause dizziness.

  • Should be swallowed whole; do not crush or chew (if delayed release).

  • Do not discontinue without medical supervision.

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs)

  • Examples:

    • Desvenlafaxine

    • Duloxetine

    • Venlafaxine

    • Levomilnacipran.

Characteristics of SNRIs:

  • Blocks both serotonin (5-HT) and norepinephrine (NE).

  • Similar side effects to SSRIs.

MONOAMINE OXIDASE INHIBITORS (MAOIs)

  • Examples:

    • Moclobemide

    • Phenelzine

    • Tranylcypromine.

Mechanism of Action of MAOIs:

  • Mechanism:

    • Block MAO enzyme, which interferes with the degradation of monoamine neurotransmitters and dietary amines.

    • Results in more norepinephrine, serotonin, and dopamine available to bind at receptor sites.

  • Two forms of MAO:

    • MAO-A, used for major depression, preferentially metabolizes norepinephrine and serotonin.

    • MAO-B, used for treating Parkinson's disease.

MAOIs: ADVERSE REACTIONS

  • Possible side effects:

    • Sedation

    • Dry mouth

    • Urinary retention

    • Constipation

    • Orthostatic hypotension

    • Impotence

    • Weight gain

    • Risk of hypertensive crisis, potentially life-threatening due to many food-drug and drug-drug interactions.

  • Slow elimination occurs over days to weeks; generally not a first-line agent.

Examples of Foods That Contain Tyramine (which interact with MAOIs)

Type of Food

Examples

Alcohol

Beer, red wines

Dairy Products

Cheese, yogurt

Fruits

Avocados, bananas

Meats

Hot dogs, salami

Vegetables

Fava beans

Other

Chocolate

Yeast

All yeast or yeast extracts

MAOIs: WARNING LABELS

  • Take with food for moclobemide.

  • Avoid alcohol.

  • May cause dizziness or drowsiness.

  • Do not discontinue without medical supervision.

ATYPICAL ANTIDEPRESSANTS

  • Examples:

    • Bupropion

    • Mirtazapine

    • Nefazodone

    • Trazodone.

Characteristics of Atypical Antidepressants:

  • Elevate mood by increasing levels of dopamine, serotonin, and norepinephrine.

  • Indicated for depression, often in patients with bipolar disorder.

Atypical: Mirtazapine

  • A tetracyclic antidepressant that increases norepinephrine and serotonin release.

  • Adverse effects:

    • Drowsiness

    • Dizziness

    • Dry mouth

    • Constipation

    • Blurred vision

    • Increased risk of diabetes

    • Suicidal ideation.

Atypical: Trazodone

  • Weak reuptake inhibitor of serotonin.

  • Adverse effects:

    • Sedation

    • Hypotension

    • Nausea

    • Risk of priapism.

Bupropion

  • Inhibits reuptake of serotonin, norepinephrine, and dopamine.

  • Used for both depression and as an aid in quitting smoking.

  • Different brand names, drug coverage, and dosing based on usage:

    • Wellbutrin for depression: 100-300 mg/day.

    • Zyban for smoking cessation: 150 mg twice a day for 7-12 weeks.

  • Adverse effects:

    • Insomnia

    • Higher doses (greater than 450 mg/day or 150 mg/dose) increase the risk for seizures in people with seizure disorders.

OTHER: ST. JOHN’S WORT

  • A popular herbal remedy for depression.

  • Available without prescription at health food stores.

  • May be effective for mild depression.

  • Issues concerning the quality of herbal products.

  • Dosage varies depending on the form.

  • Interacts with other agents that alter serotonin levels.

BIPOLAR DISORDER (MANIC DEPRESSION)

  • Characterized by:

    • Sudden mood swings between depression and mania.

    • Symptoms of mania may result from excessively high levels of norepinephrine.

    • Patients may shift quickly between mood states or remain in one for extended periods.

  • Treatment typically includes mood stabilizers.

MOOD ALTERING DRUGS (MOOD STABILIZERS)

  • Principal mood stabilizers:

    • Lithium

    • Valproic acid

    • Carbamazepine

    • Lamotrigine.

  • All drugs indicated for bipolar disorder have anti-manic actions.

LITHIUM

  • The oldest of the mood stabilizers.

  • Reduces current symptoms of both mania and depression and prevents future episodes.

  • Thought to alter the activity of norepinephrine, dopamine, and serotonin.

LITHIUM: PHARMACOKINETICS

  • Very narrow therapeutic index requires proper monitoring.

  • Competitive interaction between lithium and sodium may lead to lithium toxicity.

  • Plasma lithium levels and renal function should be regularly monitored to prevent toxicity.

  • Salt-free diets can increase lithium excretion.

  • Lithium has a long half-life (approximately 24 hours), which increases with prolonged therapy.

LITHIUM: ADVERSE EFFECTS

  • Early Usage:

    • Sedation

    • Nausea

    • Increased urination

    • Dry mouth

    • Difficulty concentrating

    • Tremors.

  • Long-term Usage:

    • Weight gain

    • Acne

    • Impotence

    • Hypothyroidism

    • Rashes

    • Hair loss.

  • Contraindications:

    • Not recommended during pregnancy.

ANTISEIZURE DRUGS USED TO TREAT BIPOLAR DISORDER

  • Used as mood stabilizers:

    • Adjunct to lithium therapy or when lithium is ineffective or produces adverse effects.

SIDE EFFECTS OF ANTISEIZURE DRUGS

  • Valproic Acid:

    • Sedation

    • Nausea

    • Ataxia

    • Liver dysfunction.

  • Carbamazepine:

    • Sedation

    • Dizziness

    • Ataxia

    • Visual disturbances.

  • Lamotrigine:

    • Sedation

    • Nausea

    • Ataxia

    • Blurred vision

    • Double vision

    • Rash.

WARNING LABELS FOR MOOD STABILIZERS

  • May cause dizziness or drowsiness; may impair ability to drive.

  • Avoid alcohol.

  • Take with food (for certain medications).

  • Drink plenty of fluids (for lithium).

  • Controlled-release products should not be crushed or chewed.

  • May contraindicate in pregnancy (except lamotrigine).

  • Do not discontinue without medical supervision.