Fundamentals of Pharmacology: Drug Treatment of Depression

Fundamentals of Pharmacology: Drug Treatment of Depression

Overview

  • Instructor: Professor Susan Duty

  • Institute: Institute of Psychiatry, Psychology & Neuroscience, Faculty of Life Science & Medicine

  • Focus: The pharmacological treatment of clinical depression.

Learning Outcomes

  • After this lecture, students should be able to:
      - Define clinical depression and describe its key symptoms.
      - Outline the "monoamine theory of depression" and use it to explain the clinical actions of current antidepressant drugs, including:
        - MAOIs (Monoamine Oxidase Inhibitors)
        - TCAs (Tricyclic Antidepressants)
        - SSRIs (Selective Serotonin Reuptake Inhibitors)
        - SNRIs (Serotonin and Noradrenaline Reuptake Inhibitors)
      - List the main problems with the monoamine theory of depression.
      - Recognize the challenges associated with the development of drugs to treat psychiatric disorders, including depression.

Clinical Depression

  • Also known as major depressive disorder (MDD).

  • Classified as a psychiatric affective disorder.

  • Epidemiology:
      - Second leading cause of disability among adults, following cardiovascular disease.
      - Average age of onset is in the mid to late 30s.
      - Female to male ratio: 2:1.

  • Sub-classes of Depression:
      - Endogenous Depression: Occurs without an obvious stressor.
      - Reactive Depression: Triggered by identifiable stressors.

  • Diagnosis Criteria: Symptoms must be present daily for more than 2 weeks.

Symptoms of Clinical Depression

Emotional Symptoms:

  • Sadness or low mood.

  • Anhedonia: Loss of enjoyment in previously pleasurable activities.

  • Low self-esteem characterized by feelings of hopelessness, worthlessness, and guilt.

  • Suicidal thoughts.

Biological Symptoms:

  • Significant changes in weight (either gain or loss).

  • Sleep disturbances: can be either insomnia or excessive sleeping.

  • Fatigue characterized by loss of energy.

  • Psychomotor retardation: Slowness of thought and action.

  • Diagnosis: At least five symptoms required for a clinical diagnosis.

Neurobiological Basis of Depression

  • Involvement of Brain Regions:
      - Anterior Cingulate Cortex
      - Hippocampus
      - Hypothalamus
      - Amygdala: Regulates emotions, influences memory processing (impairs recollection of positive events), mood, appetite, and energy.
      - Prefrontal Cortex: Influences cognitive aspects like feelings of worthlessness and guilt, and shapes personality and social behavior.

Discovery of Antidepressant Drugs

  • The first antidepressant was discovered by chance: Iproniazid
      - Originally tested as a treatment for tuberculosis.
      - Observed to improve mood and appetite in patients despite not curing tuberculosis.
      - Mechanism: Blocks Monoamine oxidase (MAO), preventing the breakdown of monoamines such as serotonin, norepinephrine, and dopamine.

Monoamine Hypothesis of Depression

Origin:

  • Proposed by Schildkraut in 1965.

  • Suggests that depression is linked to decreased monoaminergic transmission, specifically:
      - Noradrenaline
      - Serotonin (5-HT)
      - Dopamine

Supporting Evidence:

  • Reduced monoamine metabolites found in the cerebrospinal fluid (CSF) of depressed patients.

  • Antidepressant drugs that increase levels of norepinephrine (NA), serotonin (5-HT), and dopamine (DA) lead to improved mood.
      - Mechanisms:
        - Reduced reuptake of neurotransmitters.
        - Reduced intracellular breakdown of neurotransmitters.

  • Drugs that deplete monoamine stores (e.g., reserpine) can induce depressive symptoms.

Contradictory Evidence:

  • Some drugs that elevate NA, DA, and 5-HT levels do not exhibit antidepressant activity.
      - Examples include:
        - Amphetamine: Releases NA, DA, and 5-HT and reduces reuptake, but is not an antidepressant.
        - Cocaine: Reduces reuptake of NA, DA, and 5-HT but similarly lacks antidepressant effects.

  • Observations show that monoamine levels rise quickly upon antidepressant administration, yet clinical relief from depression may take 2-4 weeks, suggesting a lag time possibly due to secondary neuroplastic changes over a longer timescale (e.g., gene expression changes).

Mechanism of Monoamine Neurotransmission

  • Components:
      - Monoamines: Norepinephrine (NA), Serotonin (5-HT), Dopamine (DA).
      - Monoamine Oxidase (MAO): Enzyme responsible for degrading monoamines.
      - Monoamine Transporters (e.g., NET, SERT, DAT): Responsible for the reuptake of monoamines from synaptic cleft.
      - Post-synaptic Monoamine Receptors: Activated following neurotransmitter binding.

  • Potential Sites for Antidepressant Action: Many areas could be targeted to enhance monoamine signaling.

Types of Antidepressants

Monoamine Oxidase Inhibitors (MAOIs): Phenelzine

  • Mechanism: Inhibit Monoamine Oxidase to prevent degradation of monoamines.

  • Patient Guidelines: Must avoid tyramine-rich foods (e.g., mature cheese, chianti, fermented soy products) to prevent hypertensive crisis.

  • Current Use: These are prescribed when other antidepressants have failed.

Tricyclic Antidepressants (TCAs): Amitriptyline

  • Mechanism: Block monoamine reuptake transporters, allowing increased levels of monoamines in the synaptic cleft.

  • Additional Uses: Increasingly used for chronic pain management by enhancing NA and 5-HT levels in the spinal cord to decrease pain transmission.

  • Safety Concerns: Not a first-line treatment due to potential cardiovascular side effects.

Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs): Venlafaxine

  • Mechanism: Selectively block the reuptake of norepinephrine and serotonin.

  • Side Effects: Can cause panic attacks and increased blood pressure due to elevated norepinephrine levels.

  • Current Use: Less common than SSRIs.

Selective Serotonin Reuptake Inhibitors (SSRIs): Fluoxetine

  • Mechanism: Selectively block the reuptake of serotonin (5-HT) with a significantly higher affinity for SERT compared to NET.

  • Prevalence: Most prescribed class of antidepressants due to favorable side effect profiles.

Noradrenaline Reuptake Inhibitors (NRIs): Reboxetine

  • Mechanism: Selectively block the reuptake of norepinephrine.

  • Usage: Rarely used, primarily for cases where SSRIs are ineffective.

Development Challenges for Antidepressant Drugs

  • All current treatments are based on the monoamine hypothesis of depression.

  • Clinical efficacy of various antidepressants tends to be similar; approximately 30-40% of patients may not experience improvement.

  • Selection of antidepressants is based on several factors:
      - Patient’s treatment history.
      - Patient’s risk of suicide.
      - Adverse effect profile of the drug.

Questions and Discussion

  • Open floor for questions related to the pharmacological treatment of depression and the content covered in this lecture.