MB3057_2024_MDD_(L2)

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Definition of Depression

• Historical Perspective: Hippocrates attributed melancholia to an excess of black bile, originating from the four bodily humours.

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Causes of Depression

• Multi-faceted Nature: Depression is caused by a combination of genetic, environmental, and psychological factors.

• Neurochemical Imbalances: Low mood is associated with decreased levels of monoamine neurotransmitters, particularly focusing on noradrenergic transmission.

• Monoamine Hypothesis: Proposed by Schildkraut in 1965, connecting depression with neurotransmitter imbalances:

  • Key Neurotransmitters: Noradrenaline (norepinephrine), serotonin (5-Hydroxytryptamine or 5HT), and dopamine.

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Alec Coppen's Contribution

• Refining the Hypothesis: Coppen emphasized the importance of serotonin (5HT) in the biochemical changes related to depression, shifting focus from noradrenaline dominance.

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The Role of Neurotransmitters

• Monoamine Theory of Depression: Involves key neurotransmitters and their functions:

  • Noradrenaline: Related to attention, stress, wakefulness, and feeding.

  • Dopamine: Associated with motivation, reward, reinforcement, and movement coordination.

  • Serotonin (5HT): Influences mood, memory, sleep, appetite, and sexuality.

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Treatments for Major Depressive Disorder (MDD)

• Non-Pharmacological Approaches:

  • Talking Treatments:

    • Lifestyle modifications (e.g. exercise).

    • Cognitive Behavioral Therapy (CBT).

    • Interpersonal Therapy.

• Pharmacological Options:

  • Various medications.

  • Electroconvulsive Therapy (ECT) and non-invasive brain stimulation methods (e.g. tDCS, rTMS).

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Pharmacological Interventions

• Types of Antidepressants:

  • Selective Serotonin Reuptake Inhibitors (SSRIs): e.g., Citalopram, Escitalopram.

  • Tricyclic Antidepressants (TCAs): e.g., Amitriptyline, Desipramine.

  • Norepinephrine-Dopamine Reuptake Inhibitor (NDRI): Bupropion.

  • Serotonin Modulators: Nefazodone, Trazodone.

  • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): e.g., Venlafaxine, Duloxetine.

  • Novel Agents: e.g., Vilazodone, Vortioxetine.

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Monoamine Oxidase Inhibitors (MAOIs)

• Mechanism of Action: Inhibit isoenzymes responsible for monoamine metabolism (MAO-A for 5HT, MAO-B for dopamine).

• History: First effective antidepressants (Iproniazid, 1952; Tranylcypromine, 1959) but have slow onset and many side effects.

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Kinetics of Neurotransmitter Action

• Neurotransmitter Metabolism Dynamics: Importance of inhibition by MAOIs in neurotransmitter availability and subsequent vesicular uptake.

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Mechanism and Delivery

• Tricyclic Antidepressants: Act by inhibiting 5HT and noradrenaline transporters.

• Comparison to MAOIs: TCAs were developed soon after and share some limitations with MAOIs regarding side effects.

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Pharmacodynamics of TCAs

• Transporter Affinity: High affinity for noradrenaline (NET) or serotonin (SERT) transporters significantly affecting neurotransmission.

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SSRIs Introduction

• First Approved SSRI: Fluoxetine (Prozac) in 1986.

• Follow-On Drugs: Paroxetine, Sertraline, Citalopram.

• Advantages: Major advances but also associated with side effects (sexual dysfunction, insomnia).

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SNRIs and Atypical Antidepressants

• Introduction of SNRI: Venlafaxine (1993), followed by Duloxetine.

• Atypical Drugs: Bupropion (NDRI), Mirtazapine (α2-adrenoceptor antagonist), Trazodone (5HT2A antagonist).

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Mirtazapine Action

• Mechanism Explanation: Functions by antagonizing α2-adrenoceptors, enhancing neurotransmitter release in the post-synaptic neuron.

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NICE Guidelines for MDD Treatment

• Psychological Interventions: Along with physical activity programs.

• Effective Drug Treatments: Starting with SSRIs, then exploring alternative mechanisms if no improvement is observed.

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Drug Mechanism Considerations

• Pharmacological Selectivity: Many drugs are not selective and engage multiple targets, complicating therapeutic action and efficacy.

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Evidence Review of Serotonin Theory

• A comprehensive systematic review addresses the serotonin theory's current stance, showing inconsistent associations between serotonin and depression despite its influential role in treatment rationale.

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Systematic Review Findings

• Concluding observations suggest long-term antidepressant use potentially reduces serotonin concentrations, challenging existing theories on serotonin's role in depression.

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TRKB Receptor Insights

• Recent findings indicate antidepressants may bind to TRKB receptors, suggesting a new mechanism of action involving synaptic effects.

• Mechanism Explained: TRKB plays a role in promoting neuronal plasticity alongside traditional neurotransmitter pathways.

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Treatment Challenges

• Delayed therapeutic Effects: No immediate improvements observed upon drug initiation; a trial-and-error approach is often necessary due to varied patient responses.

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Efficacy of Treatments

• Evidence of Effectiveness: Existing therapies show positive outcomes and substantial support in treatment of MDD.

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Drug Effectiveness and Tolerability

• Comparison of different antidepressants in efficacy and tolerability versus placebo, highlighting significant differences in outcomes across various medications.

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Mechanism Delays and Drug Action

• Complexities of immediate neurotransmitter alterations versus the longer-term adaptations required for successful antidepressant effects require focused research on measurement techniques and assessment of treatment adaptations.

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Network Hypothesis of Depression

• Healthy Brain Function: Depicts successful overlapping neural networks in normal conditions.

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Dysfunction in Depression

• Impairments in Network Processing: Illustrates altered information processing pathways in depression.

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Neural Connectivity Enhancements

• Antidepressant treatments demonstrated to improve connectivity between neural networks, aiding recovery.

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Activity-Dependent Pruning

• Suggests that the recovery process involves selective stabilization of effective synapses, supporting healthy network connectivity post-treatment.

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Role of Neurogenesis

• Research supports the notion that enhanced hippocampal neurogenesis is vital for the efficacy of antidepressants, linking structural brain changes to therapeutic effects.

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Limitations of Current Treatments

• Treatment Resistance: About one-third of patients do not respond to existing therapies, necessitating alternative approaches like ECT and rTMS.

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Emerging Treatments Summary

• Ketamine: A previously established anesthetic that now demonstrates rapid antidepressant effects by blocking NMDA receptors.

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New Drug Developments

• Ketamine Alternatives: Ongoing efforts to synthesize ketamine-like drugs that retain its antidepressant effectiveness.

• Psychedelic Drugs: Notable findings regarding psilocybin as agonists of 5HT2A receptors point to their usefulness in treatment models.

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Recommended Readings

• Key literature on innovative treatments and the neurobiology behind depression can inform ongoing research and therapeutic strategies.

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Extra Slides

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Vortioxetine Overview

• Mixed mechanisms of action as an effective treatment choice for MDD. Approved for use in multiple countries, particularly beneficial for patients with significant cognitive symptoms.