Chapter 13: Antidepressants

Chapter 13: Antidepressants

Chapter Overview

• The chapter covers several components related to antidepressants:

  • The Nature of Depression

  • The Neurobiological Basis of Depression

  • Antidepressant Drugs: Neurophysiology

  • Pharmacokinetics of Antidepressants

  • Effects of Antidepressants

  • Tolerance; Withdrawal; Concluding Comments

The Nature of Depression

• Major Affective Disorders:

  • Major depressive disorder is classified as a major affective disorder (also termed mood disorder).

  • Characterized by disordered feelings and disturbances in mood/emotion.

• Definition of Depression:

  • Depression is often confused with the everyday feelings of "ups and downs" in life.

  • Serious medical illnesses known as mood disorders should not be conflated with these everyday experiences.

  • Types of depressive mood disorders include:

  • Bipolar Disorder (manic-depressive illness)

  • Post-partum Depression and Psychosis

  • Clinical Depression/Unipolar Disorder (most common)

• Prevalence:

  • Mood disorders are prevalent, with real illnesses that can have severe consequences on physical health.

  • Symptoms can include fatigue, stomach issues, muscle pain, etc.

  • According to Statistics Canada's 2002 Mental Health Survey:

  • 5.3% of Canadians aged 15+ reported symptoms meeting mood disorder criteria within the past 12 months:

    • 4.8% for major depression

    • 1.0% for bipolar disorder

  • Lifetime prevalence:

  • 1 in 7 adults (13.4%) met criteria for mood disorder:

    • 12.2% for depression

    • 2.4% for bipolar disorder.

  • Gender differences show higher rates of depression among women (female-to-male ratio approximately 2:1).

• Diagnostic Criteria:

  • The Diagnostic and Statistical Manual of Mental Disorders (DSM) serves as the authoritative guide for diagnosing mental disorders.

  • Includes symptoms, descriptions, and criteria for major depressive disorder outlined in DSM-5.

The Neurobiological Basis of Depression

• Neuroimaging Techniques:

  • Identifies abnormalities in the amygdala, prefrontal cortex (PFC), hippocampus, and nucleus accumbens associated with depression.

  • Imaging helps locate brain regions but does not specify neurochemical abnormalities.

• Monoamine Theory of Depression:

  • Suggests that mood is related to monoamines, particularly serotonin (5-HT) and norepinephrine (NE). A decrease in activity in these systems leads to depression.

• Evidence Supporting Monoamine Theory:

  • Substances enhancing monoamine neurotransmission (e.g., cocaine, amphetamine) elevate mood.

  • Decreased activity at monoamine synapses correlates with depressive symptoms.

  • Depression is often observed in patients with Parkinson’s disease.

  • Patients treated with reserpine (which blocks vesicular monoamine transporter, VMAT) experienced severe depression despite improvement in hypertension.

• Glucocorticoid Theory of Depression:

  • Characterizes hypercortisolemia (high cortisol levels) as a significant abnormality in major depression.

  • Chronic glucocorticoid receptor activation affects brain structure and function,

  • Causes dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis, leading to:

    • Reduced hippocampal volumes

    • Decreased PFC activity

    • Disruption of neurocircuitry homeostasis related to depression.

• Chronic Stress and Monoamines:

  • Chronic HPA activation influences monoamines, suggesting that monoamine abnormalities may be secondary to HPA overdrive rather than central to the causation of depression.

Antidepressant Drugs: Neurophysiology

• Mechanism of Action:

  • Antidepressants primarily increase activity in one or multiple monoamine systems in the brain.

  • They are classified based on their mechanisms:

  • First-Generation Antidepressants: MAOIs (Monoamine Oxidase Inhibitors) and TCAs (Tricyclic Antidepressants)

  • Second-Generation Antidepressants: SSRIs (Selective Serotonin Reuptake Inhibitors)

  • Third-Generation Antidepressants: SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors) / Atypicals

• Nerophysiology Categories:

  • MAOIs:

  • Inhibit MAO activity, preventing breakdown of DA, NE, and 5-HT so that they are available for vesicle storage and release.

  • TCAs:

  • Block reuptake of 5-HT and NE, and affect other systems (e.g., antagonistic actions on muscarinic, histamine, and α1 adrenergic receptors).

  • SSRIs:

  • Specifically block reuptake of 5-HT, minimally affecting other monoamines.

  • SNRIs:

  • Block reuptake of 5-HT and NE, and possibly dopamine.

  • Atypicals:

  • Vary in action; mechanisms may involve reuptake inhibition or autoreceptor antagonism.

Pharmacokinetics of Antidepressants

• Absorption:

  • Antidepressants generally exhibit similar pharmacokinetics regarding absorption timings:

  • TCAs: peak in 1-3 hours

  • SSRIs, SNRIs, Atypicals: peak in 4-8 hours.

  • First-pass metabolism is substantial in most antidepressants, significantly diminishing drug bioavailability, except SSRIs/SNRIs, which are less affected by alcohol inhibition.

• Distribution:

  • Antidepressants easily cross the blood-brain barrier.

• Metabolism / Elimination:

  • Half-life:

  • MAOIs: 2-4 hours

  • TCAs: Approximately 24 hours

  • Second- and Third-Generation Antidepressants: Generally shorter half-lives (15-25 hours).

Effects of Antidepressants

• MAOIs:

  • Side effects may include:

  • Tremors

  • Weight Gain

  • Blurry Vision

  • Dry Mouth

  • Low Blood Pressure and Postural Hypotension

  • "Cheese effect": Tyramine buildup causes sympathetic-like symptoms (e.g., increased blood pressure, nausea, potential for serious outcomes like strokes).

  • Serotonin Syndrome: A clinical triad of cognitive, autonomic, and somatic effects scrivened as a side effect.

• TCAs:

  • Anticholinergic effects leading to:

  • Dry Mouth

  • Constipation

  • Blurred Vision

  • Sweating Tremors

  • Possible dizziness, irregular heartbeat, increased appetite, and weight gain attributed to histamine activity.

• SSRIs:

  • Generally fewer side effects, mainly impacting serotonin pathways; potential side effects include nausea, GI issues, nervousness, agitation, but often decrease over time.

• Third Generation Antidepressants:

  • Side effects frequently arise from acetylcholine and histamine antagonism, and enhanced 5-HT2-3 receptor activity, including:

  • Increased appetite

  • Weight Gain

  • Changes in blood pressure

  • Dizziness

  • Dry Mouth

  • Restlessness

Tolerance, Withdrawal and Concluding Comments

• Tolerance:

  • Therapeutic effectiveness may show tolerance after several months, but clinical significance varies.

  • Tolerance to side effects often occurs within weeks except for SSRIs, which may cause lasting tiredness.

• Withdrawal Symptoms:

  • Abrupt discontinuation is discouraged;

  • TCAs: restlessness, anxiety, chills, muscle aches.

  • SSRIs: dizziness, insomnia, fatigue, nausea, headaches, sensory disturbances.

  • SNRIs: heart palpitations, nausea, delusions.

• Serotonin Discontinuation Syndrome:

  • Defined by six core somatic symptoms:

  • Flulike symptoms (fatigue, myalgia)

  • Insomnia (sleep disturbances)

  • Nausea (gastrointestinal symptoms)

  • Imbalance (dizziness, vertigo)

  • Sensory disturbances (electric shock-like sensations)

  • Hyperarousal (anxiety, agitation).

• Effectiveness in Treating Depression:

  • Efficacy across antidepressant classes is relatively similar, although responses vary significantly by individual and type of depression.

  • Roughly 60-70% of individuals with major depression experience relief:

    • Approximately 30-50% achieve full symptom remission.

• Limitations in Antidepressant Drug Effectiveness:

  • Antidepressants have long response times; significant effects often become apparent after two weeks, with full potential at four weeks.

  • Some patients are treatment-resistant, with a failure rate ranging from 29 to 46 percent for reducing depressive symptoms effectively.

Chapter 13: Review

• Topics covered include:

  • The Nature of Depression

  • The Neurobiological Basis of Depression

  • Antidepressant Drugs: Neurophysiology

  • Pharmacokinetics of Antidepressants

  • Effects of Antidepressants

  • Tolerance; Withdrawal; Concluding Comments