PMCOL 412 - major depressive disorder

emotion

• caused by a specific event

• usually aware of cause

• starts and end quickly

• brief duration (min to hrs)

• expression displayed

• intense

mood

• usually no specific cause

• may be unaware of cause

• gradual start and end

• chronic duration (hrs to days)

• expression not displayed

• mild

affective disorders make up more than 10% of

disability-adjusted life years worldwide

affective disorders fall on a

spectrum

depression is a

unipolar mood disorder (lies on one pole of the spectrum)

types of depression

• major depressive disorder

• minor depression disorder

• anxious depression

• post partum depression

• postmenopausal depression

• seasonal depression disorder

• psychotic depression

major depressive disorder is defined by the

diagnostic and statistical manual of mental disorders, 5th edition (DSM-5)

risk factors for depression

• age

• genetics

• stress

• sex

• education

• childhood trauma

examples of aversive gene environment interactions

• prenatal factors

• childhood trauma

• stress

• medical illness

• drug abuse

protective gene environment interactions

• social support

• coping

• exercise

disease course of depression

• variable

• episodes last between 13-30 weeks

• most inpatients recover within a year

• most outpatients do not recover after 2 years

• chance of recurrence is high

• relative risk (RR) of other diseases is increased in MDD patients

brain areas affected in depression

the prefrontal cortex and the limbic system (amygdala, hippocampus, hypothalamus)

the limbic system regulates

emotions, motivation, memory

the limbic system is highly innervated by

noradrenergic and serotonergic projections

hypothalamus

controls body temp, hunger, fatigue, sleep

amygdala

memory, decision-making, emotional responses

hippocampus

memory, navigation

basal ganglia

control of movements, learning, habit, cognition, emotion

thalamus

regulation of sleep, consciousness, alertness

our brains are much more complex than mice, however there are

many useful similarities

what are the two models used to look at modeling depression

1. forced swim test (FST)

2. tail suspension test (TST)

rodents forced to swim or suspended by their tail eventually

give up on attempting escape

the FST and TST are tests of

learned helplessness

models of depression are used to predict

efficacy of anti-depressant drugs for humans

acute treatment with classical antidepressants reduces

time immobile

unpredictable chronic mild stress model (UCMS)

• rodents are subjected to unpredictable and mild stressors over an extended period of time

• rodents show decreased sucrose preference, grooming, aggression, sex

• show increased immobility in FST and TST

• respond to chronic antidepressant treatment

what are the 3 theories of MDD etiology

• monoamine hypothesis

• HPA axis and immune involvement

• neuroplasticity

what is the monoamine hypothesis

depression is caused by monoamine deficiency

examples of monoamines

DA, 5HT, NA

IPRONIAZID

• TB medication

• monoamine oxidase inhibitor

RESERPINE

• anti-noradrenergic used to treat high blood pressure

• depletes catecholamines

MAO-A inhibitors

prevent the degradation of DA, NA, 5HT resulting in more monoamine available to release into the synaptic cleft

MAO-B inhibitors

prevent the degradation of DA and exogenous monoamines resulting in more dopamine available to release in the synaptic cleft

irreversible MAO-A and MAO-B inhibitors

covalently bind to flavin in MAOs

examples of MAO-Is

• IPRONIAZID

• PHENELZINE

major side effect of MOA-I

the cheese effect

what is the cheese effect

increase in tyramine leads to increase in blood pressure

MACLOBEMIDE

• reversible MAO-A inhibitor

• no cheese effect

• better side effect profile than irreversible inhibitors

• approved in canada

tricyclic antidepressants

block 5HT and NO reuptake to increase the latency of the monoamines in the synaptic cleft

side effects of tricyclic antidepressants

off target blockade of the histamine H1 receptors, muscarinic Ach receptors and alpha adrenoreceptors causes confusion, sedation, dry mouth, blurred vision, postural hypotension

examples of tricyclic antidepressants

• IMIPRAMINE

• AMITRIPTYLINE

selective serotonin reuptake inhibitors (SSRIs)

block presynaptic uptake of 5HT - this increases 5HT accumulation in the synaptic cleft

side effects of SSRIs

nausea, anorexia, loss of libido, less anticholinergic effects compared to MAO-Is

example of SSRIs

fluoxetine

selective serotonin and noradrenaline reuptake inhibitors (SNRIs)

block presynaptic uptake of 5HT and NA - this increases the accumulation of 5HT and NA in the synaptic cleft

side effects of SNRIs

headache, nausea, hypertension, loss of libido

example of SNRIs

venlafaxine

NA and DA reuptake inhibitors (NDRIs)

block presynaptic uptake of NA and DA - more NA and DA present int he synaptic cleft bind to post synaptic receptors

side effects of NDRIs

hypertension, increased heart rate, tremor, decreased appetite

example of NDRIs

bupropion

problem with monoamine hypothesis - therapeutics targeting monoamines lead to changes in NT levels over a short time course, however antidepressant effects of these drugs take weeks to develop —>

therapeutic lag

other drugs that enhance monoamine transmission are not

antidepressants (problem with monoamine hypothesis)

the effects of these antidepressants (monoamine hypothesis associated) are more likely due to

secondary adaptive changes in the brain rather than their immediate effects on neurotransmission through monoamines

the hypothalamic-pituitary-adrenal (HPA) axis regulates

the body’s response to stress

pathway of the HPA axis

corticotropin releasing hormone (hypothalamus) —> adrenocorticotropin hormone (pituitary) —> cortisol (adrenal cortex)

HPA axis in MDD

• elevated cortisol

• desensitized cortisol receptors

• impaired monoamine transmission

• increased immune response

• reduced BDNF

chronic glucocorticoid treatment can result in

depressive in patients

interferon treatment causes

depressive symptoms

MIFEPRISTONE

glucocorticoid receptor antagonist - no beneficial effect in depression

CELECOXIB

may enhance the antidepressant effects of SSRIs

synaptic plasticity

• long term stress results in the weakening of synapses

• similar findings have been observed in depression

• this process is mediated, in large part, by impaired glutamate signaling through AMPA receptors

brain derived neurotrophic factor (BDNF)

• plays a role in synaptic plasticity in the mature brain

• induces widespread structural changes at synapses

• promotes insertion of AMPA receptors at postsynaptic terminals

ketamine

uncompetitive NMDA receptor antagonist - works through disinhibition of glutamatergic neurons by blocking the tonic firing of GABAergic inhibitory interneurons

ketamine results in a

“glutamate burst” that promotes synaptic strengthening

a single IV dose of ketamine produces

immediate anti-depressant response in patients with treatment resistant depression

ketamine has high

abuse potential —> hydroxynorketamine

lysergic acid diethylamide (LSD)

• weak partial agonist of 5-HT2A, 5-HT2B and 5-HT2C receptors

• agonist of D2 receptors

• beneficial effects of MDD likely due to glutamatergic effects and acute changes to gene transcription that promote plasticity

• used in conjunction with therapy

side effects of LSD

physiologically safe, potential to do unsafe things while using, low abuse potential, increased BP, vasoconstriction, sweating, dilated pupils, increased salivation

psilocybin (magic mushrooms)

• psilocybin —> psilocin

• strong agonist for 5HT2A receptors

• weak agonist for other 5HT receptors

• does not bind to D2 receptors

• mechanisms similar to LSD

• used in conjunction with therapy

side effects of magic mushrooms

physiologically safe, potential to do unsafe things while using, low abuse potential