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PCL470 > Antidepressants > Flashcards

Antidepressants Flashcards

1
Q

What are the affective or mood disorders in the DSM-V?

A
  • group of diagnoses with disturbances in affect (expressed vs observed emotional response)
    1. depressive disorders
    2. anxiety disorders
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2
Q

What are the types of anxiety disorders?

A
  • GAD
  • PTSD
  • panic disorders
  • phobia
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3
Q

What are the 6 types of depression and how are they treated (only first 2)?

A
  1. major depressive disorder/unipolar depression
    - clinical depression (no manic episodes)
    - treated by antidepressant drugs
    - characterized by recurring depressive episodes
  2. bipolar disorder/manic depression
    - periods of depression alternating with periods of mania
    - treated by mood stabalizers
  3. dysthymia/persistent depressive disorder
  4. seasonal affective disorder
    - recurring depressive episodes that occur during a season
  5. postpartum depression and menopausal depression
    - hormone changes
  6. adjustment disorder with depression/stress response syndrome
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4
Q

What is the etiology of depression?

A
  • exact mechanism not known
  • related to chronic stress and disease of limbic system
  • complex polygenic mechanism with contributing environmental factors
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5
Q

What is the lifetime prevalence of depression?

A
  • 17% of adults in the US at least once in their lifetime
  • women affected 2x as frequently as men
  • leading cause of disability
  • can lead to suicie (800 000 people a year), second most common cause of death 15-29 year olds
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6
Q

What conditions are often comorbid with depression (secondary depression)

A
  • chronic pain
  • cancer
  • stroke
  • CV disease
  • depresison can also be a risk factor for these conditions
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7
Q

How is depression diagnosed?

A
  • clinical patient interview
  • must have at least 5 symptoms present in same 2 week period
  • depressed mood
  • loss of pleasure and interest in daily acitivities
  • altered eating
  • altered sleeping
  • fatigue or loss of energy
  • feelings of wotthlessness
  • suicidal thoughts
  • etc
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8
Q

What are the current available treatments for depression?

A
  • psychotherapy
  • chemical antidepressants
  • electroconvulsive therapy
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9
Q

What are the drawbacks of chemical antidepressants?

A
  • delay of therapeutic response: takes weeks ot regular dosing, patients can stop taking it because they think it doesn’t work
  • side effects can limit use: elderly are equally responsive but are more likely to experience adverse effects (prefer SSRIs) because of age –> BP changes, CV effects, GI
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10
Q

Monoamine hypothesis

A
  • depression is related to a deficiency in the levels of 5HT, NE and DA projecting from pontine and midbrain areas to cortical and limbic structures
  • changes in downstream signalling at postsynaptic sites is also likely involved
  • reserpine 1950s: antihypertensive that depeleted monoamines in the brain by blocking VMAT, people taking the drug started to develop depression
  • imipramine 1958: first tricyclic antidepressant that transports all 3 monoamines
  • al current available antidepressants enhance synaptic availability of monoamines

(monoamines are made fro AAs and packaged into vesicles by VMAT and act on metabotripic GPCRs_

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11
Q

Neurotrophic hypothesis

A
  • loss of neurotrophic growth factors (BDNF) leads to neuronal atrophy and death
  • BDNF is important in cell survival and synaptic plasticity
  • may be due to decrease in monoamine as they are involved in new synapses (NE and 5HT)
  • may be due to stress –> increased glucocorticoid levels –> decreased trophic support
  • when BDNF binds to TRK-B receptors it leads to increased neuronal survival and growth
  • antidepressants increase BDNF in the brain (as well as exercise and therapy)
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12
Q

MAOIs: clinical use

A
  • first modern class of antidepressants
  • iproniazid –> developed in early 1950s for TB
  • primarily used in treatment resistant MDD
  • atypical depressions
  • anxiety states including social anxiety and panic disorder
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13
Q

MAOIs: mechanism of action

A
  • increased synaptic availability of NE and 5HT by blocking their catabolism via inhibiting MAO enzymes (MAO A: targets tyramine, NE, 5HT, DA and MAO B: targets mainly DA)
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14
Q

MAOI drugs

A

phenelzine (nardil) and tranylcypromine (parnate)
- irrversible, non selective MAO-A and MOA-B inhibitors
- worse side effects than other MAOIs

maclobemide (aurorix, amira, clobemix, depnil)
- reversible MAO-A inhibitor

selegiline (deprenyl)
- irreversible MAO-B inhibitor at low dose
- non selective MAOI at higher dose

  • iproniazid –> first one developed in 1950s and was used for TB
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15
Q

Why are MAOIs not used as first line treatment?

A
  • hypertensive crisis due to increased tyramine
  • increased circulation of active bioamines (can’t combine with SSRIs)
  • narrow theraprutic range
  • generalized effects
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16
Q

Side effects of MAOIs (reversible and irreversible)

A

most common: orthostatic hypotension (due to tyramine) and weight gain
other: dry mouth, constipation, blurry vision, headache and drowsiness, insomnia, restlessness, sexual dysfunction

  • reversible: side effects are more transient
  • irreversible non selective: highest rate of sexual dysfunction
  • potentiate the action of other sedatives such as alcohol
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17
Q

Drug interactions with MAOIs

A

drugs that increases 5HT and NE
- SSRIs
- TCAs

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18
Q

MAOI overdose

A
  • uncommon but can cause hyperthermia, seizures, shock, delerium, and comatose state
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19
Q

MAO-A inhibitors and tyramine interaction

A
  • MAOI inhibits MAO-A which breaks down tyramine
  • high levels of tyramine and low MAO-A levels lead to increased NE circulation because it is displaced from vesicles by tyramine
  • this causes overwhelming vasoconstriction leading to hypertensive crisis
  • headaches, intracranial bleeding, stroke, myocardial infarction
  • this can be fatal
  • foods containing tyramine
  • cheese, smoke meat and fish, wines, chocolate, coffee, beans
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20
Q

5HT reuptake bloackade side effects

A

GI disturbances, anxiety, sexual dysfunction

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21
Q

NE reuptake bloackade side effects

A

tremors, tachycardia

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22
Q

DA uptake blockade side effects

A

psychomotor activation, antiparkinsonian effects, psychosis, increased attention, concentration

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23
Q

H1 receptor blockade side effects

A

sedation, drowsiness, weight gain, hypotension

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24
Q

muscarinic Ach receptor blockade side effects

A

blurred vision, dry mouth, sinus tachycardia, constipation, urinary retention, memory dysfunction

25
Q

alpha 1 adrenergic receptor blockade side effects

A

postural hypotesion, reflex tachycardia, dizziness

26
Q

TCA clinical use

A
  • major depression if SSRIs are not effective
  • phobic and panic anxiety states
  • chronic pain conditions
  • OCD
  • imipramine was the first TCA discovered in 1950s
  • dominant antidepressant until introduction of SSRIs in 1980s
  • 3 ringed structure
27
Q

TCA mechanism of action

A
  1. block reuptake of 5HT and NE by inhibition of SERT and NET
  2. desensitize presynaptic autoreceptors to further promote release of 5HT and NE
  3. reduce central beta adrenergic receptor responsiveness and density
  4. potent antagonist at cholinergic, histaminergic and alpha-adrenergic receptors
28
Q

TCA drugs

A

Imipramine (tofranil)
- prototype TCA
- anticholinergic - used to treat enuresis (bedwetting)
- strong 5HT and NE reuptake inhibition

Desipramine (norpramin)
- weaker anticholinergic action
- stronger NE than 5HT properties
- more effective at neuropathic pain

Amitriptyline (elavil)
- highly anticholinergic
- high alpha adrenergic blocking properties
- sedative effects

29
Q

Imipramine

A

TCA
- (tofranil)
- prototype TCA
- anticholinergic - used to treat enuresis (bedwetting)
- strong 5HT and NE reuptake inhibition

30
Q

desipramine

A

TCA
- (norpramin)
- weaker anticholinergic action
- stronger NE than 5HT properties
- more effective at neuropathic pain

31
Q

amitriptyline

A

TCA
- (elavil)
- highly anticholinergic
- high alpha adrenergic blocking properties
- sedative effects

32
Q

TCA side effects - antagonist actions

A
  1. antagonist action
    - histaminic (H1): sedation and weight gain
    - adrenergic (alpha 1): orthostatic intolerance/hypotension
    - muscarinic receptor: anticholinergic –> most common: dry mouth, constipation, blurred vision, urinary retention, confucion
33
Q

TCA side effects

A
  1. cardiac toxicity - MOST SERIOUS
    - blocks Na and Ca channels
    - lethal cardiac arrhythmias
  2. CNS toxicity
    - delerium (more in elderly patients)
    - lower threshold for seizure, tremor
  3. sexual dysfunction
  4. antagonist action
  5. overdose
    - convulsions, coma, cardiac arrhythmia (3 Cs)
    - can be fatal
  6. drug interaction: MAOI, SSRI
34
Q

Why are TCAs not used as first line treatment?

A
  • serious side effects (arrhythmia)
  • blockade of other receptors
    -therapeutic effects take 2-3 weeks, side effects are immediate
  • high protein binding and hepatic metabolism –> CYPs
  • narrow therapeutic range
  • risk of suicide by OD –> only need 4 day dose
35
Q

SSRI Clinical Use

A

Major depression
- ease of use, safety in OD, relative tolerability, low cost, broad spectrum of use

Other conditions
- GAD, PTSD, OCD, panic disorder, pre menstrual dysphoric disorder, bulimia

  • used as first line antidepressants
  • fluoxetine is the first SSRI in 1988 (prototyoe)
  • most commonly prescribed antidepressant
36
Q

SSRI Drug Names

A

sertaline
fluoxetine
paroxetine
fluvoxamine
citalopram
escitalopram

37
Q

SSRI Mechanism of Action

A
  • selectively inhibiting SERT and blocking reuptake of 5HT into presynaptic terminal
  • this increases synaptic 5Ht
  • downregulates or desensitizes presynaptic autoreceptors on serotonergic neurons
  • this further promotes neuronal firing and 5HT release
38
Q

SSRI Side Effects

A
  • increase both central and peripheral 5HT tone

short term (1st week): nausea, GI upset, diarrhea

long term:
- sexual dysfunction (30-40%)
- headaches, agitation, insomnia, nervousness, sweating, fatigue, weight loss/gain

OD: low risk of fatal OD
- safest of all antidepressants

39
Q

What can be causing the delayed onset of SSRI effects?

A
  • normally serotonergic receptors is firing/releasing serotonin acutely
  • acute treatment with SSRIs causes more release but AUTORECEPTORS CHANHE FIRING serotonergic neurons so they fire much less
  • after 2-3 weeks the autoreceptor is desensitized and firing goes back to normal –> firing the normal amount of serotonin and now preventing reuptake so there is a lot more in the synapse
  • see therapeutic effect after these 2-3 weeks –> higher levels of serotonin in cleft
40
Q

SSRIs and neurogenesis

A
  • autoreceptor desensitization
  • receptor upregulation/downregulation
  • increase trophic factors (takes 3 weeks)
  • increased neurogenesis
  • increased synaptogenesis
  • neurogenesis and synaptogenesis are decreased in animal models of depression and increased with antidepressants
  • chronic stress decreases neurogenesis in HPC leading to smaller hippocampal volume
41
Q

SNRI Clinical Use

A

Used more for MDD than anxiety
severe depression
chronic pain (fibromyalgia, diabetic neuropathy, back pain, arthiritis)

42
Q

SNRI Drugs, Mechanism of Action, Use

A
  • inhibit reuptake of serotonin and norepinephrine by SERT and NET

Venlafaxine
- weak inhibitor of NET, greater affinity for SERT
- used for severe depression

Duloxetine
- balanced 5HT/NE reuptake blockade
- inceasing use for chronic pain over TCAs (fibromyalgia, diabetic neuropathy, back pain, arthiritis)

43
Q

SNRI Side Effects

A

More selective than TCAs
- fewer less severe side effects than TCAs
- restlessness, insomnia, sexual dysfunction, nausea

  • low potential for OD
  • longer half life
44
Q

SNRI Drugs

A

venlafaxine
duloxetine
desvenlafaxine
milnacipran
levomilacipran

45
Q

How does psychological stress affect the brain?

A
  • HPA axis activated during fight or flight
  • chronic stress and sustained activation of HPA increases glucocorticoids and changes gene expression
  • this changes neuron physiology
  • glucocorticoids activate steroid homrone receptors that modulate several gene expressions
  • gene expression profile affects cell function and supports depressive state
  • production of glucocorticoids causes a decrease in BDNF expression
  • this causes decrease in neurogenesis and synaptic loss which leads to less branching and retraction of dendrites
  • this is reversed by antidepressants which increase branching of neurons
46
Q

How does the volume of the cortical region, hippocampus and amygdala change in MDD?

A

decreases in brain volume is greater in patients who have depression the longest and most severe –> fixed by antidepressants

not losing neurons - just synapses and neuronal packaging

cortical region (PFC and cingulate areas)
- decreased volume
- impaired connectivity
- reduction in number of glia size of neurons

hippocampus
- volume change
- size decreased
- no hippocampal cell loss
- impaired connectivity

amygdala
- mixed results on volume changes
- glial density reduction
- no neuron density change
- strengthened connectivity

47
Q

How does GABA, glia, astrocyte, and synapse marking change in MDD?

A

GABA
- reduced GABA marker expression
- altered GABA neurotransmission

astroglia
- reduced number, reduced marker

astrocytes
- less in number
- smaller in size
- less complex

synapses
- decrease in number
- decrease in synaptic markers

48
Q

Ketamine as an acute antidepressant treatment

A
  • ketamine is an
  • effect within 24-48 hours and lasts two weeks
  • causes significant decrease in depressive symptoms and suicidal cognition
  • studies show esketamine nasal spray given with oral antidepressant used for relapse prevention in patients with treatment resistant depression
  • FDA approved esketamine with oral antidepressant
49
Q

Where does ketamine increase spine densitity?

A
  • increase in spine density in cingulate cortex in the limbic system
  • reverses decrease in spines induced by chronic stress
  • increase due to activation of mTOR pathway that causes new synaptic proteins production
50
Q

Ketamine mechanism of action and disinhibition hypothesis

A
  • ketamine is an NMDA receptor antagonist - binds inside channel at PCP site
  • ketamine blocks NMDA receptor on GABAergic neuron
  • blocking GABA decreases the amount released to the GABAa receptor on glutamate neuron
  • less inhibition of glutamate neuron so more glu is released
  • glutaminergic surge causes rise in BDNF
51
Q

Scopolamine - disinhibition hypothesis

A
  • anticholinergic drug used to treat motion sickness and post on nausea
  • binds to Ach M1 receptors on GABAergic neuron which decreases GABA release thus less binds to GABAa receptors on glutamate neuron
  • more release of Glutamate that bind to AMPA receptors on post synaptic neuron
  • increased Ca in neuron leads to increased BDNF
  • studies showed that the drug increased spines through synaptogenesis
52
Q

Riluzole synaptic properties

A
  • blocks voltage dependent Na channels
  • reduces synaptic Glu release
  • increases glial Glu uptake
  • increases BDNF
  • increases synaptogenesis
53
Q

Cannabis varieties and compounds

A
  • sativa
  • indica
  • ruderalis

delta-9-tetrahydrocannabinol (THC) is the most common compound
- first identified
- main psychoactive compound
- respnsible for high associated with use

cannabidiol (CBD)
- psychoactive but not an intoxicant

routes of administration
- inhalation, oral, sub lingual, transdermal

54
Q

Cannabis use and Anxiety and Depression

A
  • decrease in anxiety and depression during high
  • worsen symotoms when cannabis is wearing off
  • can exacerbate symptoms in in people who have predisposition to anxiety and depression
  • clear link between schizophrenia and chronic cannabis use in young adults
  • CBD has potential for anxiety treatment
  • can provide sense of wellbeing, introspection and relief from stress for depression
  • but cannabis use more than once a month increases risk of depressive episodes in depressed patients, risk of suicide and no response to antidepressants
55
Q

Functional effects of cannabis

A

cognitive: decreased attention, concentration, short term memory
behavioural: decreased movement, increased/decreased talkitiveness
perceptual: altered pain, visual and time perception

56
Q

How does cannabis alter neuronal communication? What are the endocannabinoids?

A
  • CB1 and CB2 receptors
  • anandamide (AEA) and 2-arachidonoylglycerol (2AG)
  • bind to CB1 and CB2
  • CB1 is highly expressed in basal ganglia, hippocampus, cortex
  • CB2 mostly expressed in periphery
  • produce similar effects as cannabis: analgesia, decreased activity, disruption of memory formation
57
Q

Endocannabinoid system potential targets for antidepressants

A

CB1 receptors
- agonist and antagonist have been shown to have antidepressant properties in rodents
- study showed CBD has antidepressant effects even in CB1 KO

Fatty acid amide hydrolase (FAAH)
- preclinical finding: genetic or pharmacological inactivation of FAAH produced analgesic, anti inflammatory, anxiolytic, and antidepressant phenotypes without undesirable side effect of CB1 agonist

58
Q

What is the role of synaptic vesicle 2 A (SV2A)

A
  • synaptic vesicle membrane protein present in most synapses in the brain
  • involved in NT release
  • there is less seen in depressed patients (MDD and PTSD)
    HC > low severity > high severity
59
Q

Drawback of ketamine treatment for depression

A
  • ketamine has high abuse potential so it has to be administered in the clinic
  • ketamine only has an effect in MDD patients with detectable synaptic deficits

PCL470 (14 decks)

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