Lecture 3: Depression

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Major Affective Disorders
Affective disorder = mood disorder
8% of population, Indigenous: 13% (16% females, 10% males)
Main types of affective disorders:
Unipolar depression (major depressive disorder)
Bipolar depression (manic depression)
Major affective disorder: Depression
Depressed mood
Reduced interest in pleasure (anhedonia)
Sleep disorders (insomnia or hypersomnia)
Loss of energy
Feelings of guilt or worthlessness
Decreased attention
Altered eating patterns
Recurrent thoughts of death
Persists for weeks or months
Impairs the ability to function in society
Endogenous: no apparent cause
Reactive: external cause
2 x more prevalent in women
15 % suicide rate if left untreated (30% with bipolar)
High probability of relapse off treatment
Neuropathology of Depression
Prefrontal Cortex
Reduced number of glia
Reduced neuron size
Reduced volume
Hippocampus
Reduced number of GABA interneurons
Reduced volume
Amygdala
Overactivation
Neurotransmission to Alleviate Depression
Iproniazid (1950’s) elevated mood in tuberculosis patients
Increases monoamines in synaptic cleft
Monoamine oxidase inhibitor
Monoamine oxidase is an enzyme that breaks down monoamines (serotonin; dopamine; norarenaline) after re-uptake
It's inhibitor increases monoamines - prevents break down
Depression = decreased metabolites of monoamines in their CSF
Suicide victims
Increased beta (β) adrenoceptors in cortex
Increased 5-HT2A receptors in limbic regions
Decreased serotonin metabolites in several brain regions
Because of less serotonin to actually even make metabolites
Low level 5HIAA (serotonin metabolite) in CSF
Recent metanalyses shows reduced monoamine metabolites in CSF
Monoamine Hypothesis
The effectiveness of a monoamine oxidase inhibitor to elevate mood in depressed patients indicated that the depletion of monoamines contributed to the pathology of depression
Post mortem examination of depressed suicide victims supported this
Monoamines involved in depression
Noradrenaline (norepinephrine)
Dopamine
Serotonin
Monoamines: The Catecholamines
Dopamine
locus coeruleus
Noradrenaline
caudal raphe nuclei
Monoamines: Indolamine
Serotonin
rostral raphe nuclei
caudal raphe nuclei
Serotonin Involvement In Depression
Reducing tryptophan in the diet will produce symptoms of depression (meats; dairy; grains)
Tryptophan --> 5-Hydroxytryptophan --> 5-Hydroxytryptamine
Depression
People with depression have an overall reduction in the neurotransmitters
Serotonin
Noradrenaline
Dopamine
Mania
Elevated or irritable mood
Aggressive
Hyperactive
Distractible
Hyposomnia
Increased & forced speech
Fleeting ideas
Grandiose ideas
Neurotransmitters in Mania (just the reverse of depression!)
Increases in noradrenaline metabolites (CSF)
Dopamine-like drugs produce mania
Increases in dopamine metabolites
Excess serotonin may trigger mania
Mania: The Catecholamines
Dopamine
Noradrenaline
Mania: Indolamine
Serotonin
Mania: GABA
GABA neurotransmission is reduced
Neurons & Interneurons
Treatments for Depression
Monoamine neurotransmission is reduced in depression
How can we alleviate this?
Stop re-uptake!
Enhancing Monoamine Neurotransmission
First Generation Anti-depressants
Tricyclic Antidepressants (TCA’s)
Block re-uptake of all monoamines
Monoamine Oxidase Inhibitors
Block the metabolism of active monoamines
Normal Monoamine Neurotransmission
Action potential releases monoamines (noradrenaline/dopamine/serotonin) and each bind to own receptor
Noradrenaline=alpha or beta adrenoceptors
Dopamine=D1 or D5 receptor
Serotonin=5-HT1A receptor
Receptors couple to G-proteins
Gs: noradrenaline & dopamine
Gi: serotonin
Gs activate second messenger systems=EPSP; Gi inhibits=IPSP
Monoamines leave receptor & G-proteins uncouple
Monoamines reuptake w/transporter
Noradrenaline=NET; Dopamine=DAT; Serotonin=SERT
Monoamines broken down by monoamine oxidase into monoamine metabolites (inactive NTs) or repackaged
Tricyclic Antidepressants
Mood elevators
Tricyclic Antidepressants (TCA’s) block the re-uptake of ALL monoamines
Depressed people have reduced monoamine levels
TCA’s restore the monoamine levels to ‘normal’
How Tricyclic Antidepressants (TCAs) Work
They BLOCK transporters of ALL monoamines
Prevents reuptake = more monoamines left in synapse (and levels will increase with more action potentials) = more effect on next neuron
TCAs restore monoamine levels in depressed people
Tricyclic Antidepressants
Side Effects:
Sympathetic/antimuscarinic
Dry mouth, impaired vision, increased heart rate, difficult to pee
Memory and learning impairments
Antihistamine
Sedation
Blocks alpha 1 adrenoceptors - periphery)
Postural hypotension (low blood pressure on standing)
Adverse effect: CARDIOTOXIC (blocks ability for heart to pump – A-V block)
15 % depressed patients suicide - 25% by TCA overdose
Monoamine Oxidase (MAO) Inhibitors
Mood elevators
MAOI’s block the metabolism of ALL monoamines
Depressed people have reduced monoamine levels
MAOI’s restore the monoamine levels to ‘normal’
How Monoamine Oxidase Inhibitors (MAOI) Work
MAOI block the metabolism of monoamines once they're transported back to the presynaptic terminal through re-uptake
Prevents monoamines from being broken down by monoamine oxidase (MAO)
ALL of the monoamines are repackaged so more monoamines are in the vesicles
Instead of the normal amount of monoamine per vesicle to be released by action potential, a LOT MORE monoamines are waiting to be released into synaptic cleft
MAOIs Restore Monoamine Levels in People with Depression
Monoamine Oxidase (MAO) Inhibitors
Side Effects:
Tremors, excitement, insomnia (CNS overstimulation:convulsions)
Food & drug interactions
Foods to avoid:
Cheese/Concentrated yeast products/red wine that contain Tyramine
Hypertension - headaches or intracranial haemorrhage
Cardiotoxic (less than TCA’s)
Needed to develop better pharmacotherapies
40% non-compliance
Selective Re-uptake Inhibitors
Second Generation Antidepressants
These focus the re-uptake of serotonin or noradrenaline or both (Reduced Dopamine is not a major problem in depression)
Selective Serotonin Reuptake Inhibitors (SSRI’s) Noradrenaline Reuptake Inhibitors (NRI’s) Serotonin and Noradrenaline Reuptake Inhibitors (SNRI’s)
More selective = less side effects
Treatments for depression
Tricyclic Antidepressants
Not selective - blocks all monoamine transporters
Monoamine oxidase inhibitors
Prevents metabolism of all monoamines
Selective Reuptake Inhibitors
Selective for either serotonin, dopamine, or noradrenaline
Selective Serotonin Reuptake Inhibitors ONLY block Serotonin Re-uptake
Monoamines leave their receptor binding sites
Selective Serotonin Reuptake Inhibitors (SSRIs) prevent reuptake of serotonin through blocking the SERT transporter
Serotonin remains in synapse and levels increase with more action potentials
Noradrenaline Re-uptake Inhibitors ONLY block noradrenaline re-uptake
Monoamines leave their receptor binding sites
Noradrenaline Re-uptake Inhibitors (NRIs) prevent reuptake of noradrenaline by blocking NET transporter
Noradrenaline remain in synapse and levels increase with more action potentials
Serotonin and Noradrenaline Re-uptake Inhibitors Increase Levels of Noradrenaline and Serotonin (not Dopamine)
By blocking both the NET and SERT transporters
Selective Serotonin Reuptake Inhibitors
Side Effects:
Nausea, vomiting, gastrointestinal upset, insomnia, tremor, headache
NOT cardiotoxic (?safer? if OD)
Little memory & learning impairment
Better compliance
*Has increased suicide rates in children/adolescents*
Clinical trials have used adults
These treatments should be used with caution in younger population
Examples
Fluvoxamine; Fluoxetine
SSRIs are the most prescribed (2009-2013)
Sertraline & Escitalopram for Depression
SSRIs are the most prescribed (2019-2023)
Escitalopram & Sertraline for Depression
Noradrenaline Reuptake Inhibitors
Side Effects:
Not cardiotoxic
Less side-effects than TCAs and SSRIs
Although effective anti-depressants, less development of NRIs
Drug companies concentrating on SSRIs and combined SNRIs
SNRIs have less side effects, yet work as well as TCAs
Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)
Side Effects/Adverse effects:
Venlafaxine - SSRI side-effects (and hypertension/cardiotox?)
SNRI not cardiotoxic like TCAs
Less side-effects than TCA’s and SSRI’s
Other Antidepressant Pharmacotherapies
Tetracyclic (not Tricyclic!) antidepressants
Act on NA and 5-HT
Melatonergic antidepressants
MT1; MT2 Agonist; 5HT2C Antagonist
Atypical antidepressants
5-HT uptake bock (not good affinity)
Sedative effects (not work for severe depression)
SERT inhibitor
5HT receptor modulator
Herbal antidepressants
Inhibits reuptake of NA, 5HT & DA
Exercise in Depression
Decreases the symptoms of depression
Increases the release of monoamines
Increases ‘endorphins’ - natural opioid peptides
Thought to enhance Brain Derived Neurotrophic Factor (BDNF)
Not greatly ‘prescribed'
Mounting evidence that it may be a promising treatment
Suggest: weekly 3 x 30 min session at 60-80% max HR
2024 Meta analysis says exercise is as effective as therapy
Exercise and BDNF
BDNF is a key regulator of neurogenesis
BDNF allows brain to be more neuroplastic
Antidepressants work through BDNF and its receptors to lessen depression
In rats, exercise enhanced BDNF levels in hippocampus
Increased BDNF levels reduced depression
Antidepressants also increase BDNF function! How?
Antidepressant drugs act by directly binding to TRKB neurotrophin receptors
Psychedelics for depression
Ketamine is TGA approved for use as an anaesthetic, recently as antidepressant --> TRK B agonist?
Glutamate binds NMDA receptor --> Turns on GABA --> Shuts down pyramidal cells --> NMDA antagonist (i.e. ketamine) disinhibits pyramidal cell to fire in PFC
Ketamine allows pyramidal cells to not be inhibited anymore by GABA
Acute effects of Ketamine for treatment resistant depression (>2 unsuccessful treatments)
Esketamine (Spravato Nasal Spray), highly regulated
Chronic Ketamine use may be associated with hepatotoxicity
Psilocybin (magic mushrooms) will be available for TRD
5HT2A receptor agonist, allows greater frontal functional connectivity and flexibility
Ketamine and barbituates precipitate if placed in the same syringe
Mania
Increased noradrenaline
Increased serotonin
Increased dopamine
Decreased GABA
Treatments need to decrease overall neurotransmission