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.