Pharmacology - lecture 15 - Drug Treatment of Depression

Learning Outcomes

  • After this lecture, students should be able to:

    • Define clinical depression and describe key symptoms.

    • Outline the "monoamine theory of depression" and explain the clinical actions of current antidepressant drugs including MAOIs, TCAs, SSRIs, and SNRIs.

    • 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.

  • Classification: Psychiatric, affective disorder.

  • Prevalence: Second leading cause of disability in adults (following cardiovascular disease).

  • Age of Onset: Average age is mid/late 30s.

  • Gender Ratio: F:M ratio is approximately 2:1.

  • Sub-classes:

    • Endogenous: No obvious stress trigger.

    • Reactive: Identifiable stress trigger.

  • Diagnosis: Continuation of symptoms for more than 2 weeks.

Symptoms of Clinical Depression

Emotional Symptoms:

  • Sadness or low mood.

  • Loss of enjoyment in previously pleasurable activities (anhedonia).

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

  • Suicidal thoughts.

Biological Symptoms:

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

  • Sleep disturbances (insomnia or excessive sleep).

  • Fatigue or loss of energy.

  • Cognitive slowness or lethargy.

  • Diagnosis Requirement: At least 5 symptoms must be present.

Neurobiological Basis of Depression

  • Regions Involved:

    • Anterior cingulate cortex

    • Cortical and sub-cortical limbic regions:

      • Hippocampus: Involved in memory processing and emotional regulation.

      • Hypothalamus: Regulates mood, appetite, and energy levels.

      • Amygdala: Regulates emotions such as fear and aggression.

      • Prefrontal cortex: Cognitive processing related to feelings of worthlessness and guilt, influences personality and social behavior.

History of Antidepressants

  • Iproniazid: First antidepressant discovered by chance during tuberculosis treatment.

    • Initially did not cure TB but improved patients' mood, appetite, and sleep.

    • Mechanism: Blocks the enzyme monoamine oxidase (MAO) which breaks down key neurotransmitters.

Monoamine Hypothesis of Depression

  • Proposed by Schildkraut (1965):

    • Suggests that a decrease in monoaminergic transmission (serotonin, norepinephrine, dopamine) is responsible for depression.

    • These pathways are crucial for regulating mood and behavior.

    • Monoamines innervate forebrain areas and frontal cortex involved in mood/behaviour.

Evidence for and Against Monoamine Hypothesis

For:

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

  • Mood improvement is observed with drugs that increase levels of norepinephrine, serotonin, and dopamine.

    • Reduced reuptake

    • Reduced intracellular breakdown

  • Monoamine depletion (e.g., from reserpine) can induce depressive symptoms.

Against:

  • Some drugs that elevate monoamine levels do not show antidepressant effects (e.g., amphetamine, cocaine).

  • Monoamine levels increase quickly upon antidepressant administration, but clinical improvement takes 2-4 weeks.

  • Suggestion that initial monoamine increases lead to secondary neuroplastic changes over time.

Monoamine Neurotransmission

  • Monoamines: Norepinephrine (NA), serotonin (5-HT), dopamine (DA).

  • Inactive metabolites arising from these neurotransmitters are important indicators.

  • Impacts of drugs occur at various sites affecting neurotransmitter transporters and receptors.

Development of Antidepressants

  • All antidepressants are rooted in the monoamine hypothesis, showing similar clinical efficacy.

  • Effectiveness varies, with 30-40% of patients not improving.

  • Choice of drug influenced by:

    • Patient's treatment history.

    • Suicide risk assessment.

    • Profile of adverse effects.

Types of Antidepressants

MAO Inhibitors (MAOIs): Phenelzine

  • Mechanism: Blocks breakdown of monoamines, allowing monoamines to build up.

  • Increase of post-synaptic monoamine receptors activated.

  • Dietary restrictions: Avoid tyramine-rich foods to prevent hypertensive crisis.

  • Usage: Prescribed when other types have failed.

Tricyclic Antidepressants (TCAs): Amitriptyline

  • Mechanism: Blocks reuptake of monoamines, increasing levels in the synaptic cleft.

  • Currently more used for chronic pain treatment due to dangerous cardiovascular side effects.

Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs): Venlafaxine

  • Mechanism: Selectively blocks reuptake of NA and 5-HT.

  • Side effects: Panic attacks and increased blood pressure.

Selective Serotonin Reuptake Inhibitors (SSRIs): Fluoxetine

  • Blocks reuptake of 5-HT.

  • Most prescribed class of antidepressants.

  • Highly selective for serotonin reuptake.

Noradrenaline Reuptake Inhibitors (NRIs): Reboxetine

  • Mechanism: Selectively blocks reuptake of NA.

  • Usage: Generally reserved for cases where SSRIs are ineffective.