Psychopharmacology of mood/anxiety disorders Flashcards Preview

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Flashcards in Psychopharmacology of mood/anxiety disorders Deck (50):
1

Serotonin metabolism at synaptic cleft

Autoreceptors: 5HT1A, 1B/D
SERT: serotnonin transpoter
MAO-B: destroys 5HT at high concentrations in presynaptic membrane
MAO-A/B destroys 5HT at synaptic cleft

2

Norepinephrine metabolism at synaptic cleft

Autoreceptor: presynaptic alpha-2 autoreceptor
NET: norepinephrine transporter
VMAT on NT vesicles

3

Dopamine metabolism at synaptic cleft

Autoreceptor: presynaptic D2 autoreceptor
VMAT on vesicles
D1-5 receptors on postsynaptic membrane
DAT transporter

4

GABA metabolism at synaptic cleft

GABAA, B, C receptor complexes on postsynaptic membrane
GABA transporter: GAT

5

Glutamate metabolism ta synaptic cleft

Transporter: EAAT
vGluT on vesicles
Presynaptic metabotropic receptor (autoreceptor)
Post: NMDA, AMPA, kainate, postsynaptic metabotropic receptors

6

Neurochemistry of Mania

5HT, NE, DA hyperactivity: elevated/expansive or irritable mood, risk-taking/poor impulse control, decreased need for sleep
5HT/DA hyperactivity: grandiosity/flight of ideas, increased goal-directed activity or agitation
DA/NE hyperactivity: distractibility/concentration issues

7

Prefrontal cortex in manic symptoms

racing thoughts
grandiosity
distractiliby
talkative/pressured speech
mood
risk

8

Thalamus in manic symptoms

decreased sleep/arousal

9

Nucleus accumbens in manic symptoms

racing thoughts
goal-directed
grandiosity

10

Time course of antidepressant effects

NT increases, receptor sensitivity decreases
clinical effect afterwards due to chronic adaptations in brain function, rather than increase in NT

11

SSRI examples

fluoxetine
sertraline
paroxetine
citalopram
escitalopram
fluvoxamine

12

SSRI MOA

blocks SERT
interferes with recycling of serotonin back to presynaptic neurons
increases 5HT availability in synapse

13

SSRI side effects

GI
CNS:initial agitation/worsening of anxiety, tremors, insomnia, headache
Reproductive: sexual dysfunction
Hematologic: bleeding (decreased platelet aggregation)
Fatigue/apathy: longer term use --> serotonergic influence on NA/DA release

14

SNRI examples

venlafaxine
duloxetine
desvenlafaxine

15

SNRI MOA

blocks SERT and NET

16

SNRI side effects

similar to SSRIs
additional potential to affect blood pressure/pulse (peripheral NE effects)

17

NDRI examples

Buproprion (SR/XL)

18

NDRI MOA

blocks NET, DAT

19

NDRI MOA

No serotonergic involvement (less effect on sexual functioning)
may include insomnia if dosed too closely to bedtime

20

NaSSA example

Mirtazapine

21

NaSSA MOA

noradrenergic serotonin specific antidepressant
Alpha-2 antagonism --> 5HT/NE disinhibition --> release of both
Blocks 5HT3: antiemetic
Blocks 5HT2A/2C: Sleep restoring, anxiolytic, antidepressant (increased NE/DA release in PFC)
Blocks histamine: hypnotic, anxiolytic effect, particularly at low doses

22

SARI examples

Trazodone
usually used as a sedative rather than a antidepressant

23

SARI MOA

low doses (

24

SARI side effect

histamine blockade
post-synaptic alpha-1 blockade: tiredness, dizziness/orthostasis
Post-synaptic alpha-2 blockade: priapism

25

TCA exapmles

Amitriptyline (SNRI) - Pain
Desipramine (NRI)
Clomipramine (SRI) - OCD

26

TCA MOA

classification based more on chemical structure
Antihistaminergic
Anticholinergic
Post-synaptic alpha-1 blockade
Na channel blockade

27

TCA side effects

Anti-histamine
Anticholinergic: constipation, blurry vision, dry mouth, drowsiness
Post-synaptic alpha1 block: tiredness, dizziness, orthostasis
Na channel block in brain: coma, seizures
Na channel block in heart: arrhythmia, death

28

MAOI examples

Phenelzine
Tranylcypromine - both nonselective, irreversible
Moclobemide (MAOI-A selective)

29

MAOI MOAs

MAO-A: metabolizes NE, 5HT, tyramine
MAO-B> preferentially metabolizes dopamine
enhance monoamine function by interfering with metabolism

30

Mood stabilizer examples

Valproic acid
Carbamazepine
Lamotrigine
Oxcarbazepine
Less commonly used adjuncts: gabapentin, topiramate

31

Lithium MOA

inhibits 2nd messenger enzyme systems (inositol monophosphatase)
modulates G proteins
interacts with various sites within downstream signal cascades (regulation of gene expression for GFs, neuronal plasticity)

32

Valproic acid salt MOA

Inhibits NaV channels (non-specific sites), boosts GABA actions
regulates downstream signal transduction cascades

33

Carbamazepine/oxcarbazepine MOAs

inhibits alpha unit of VSSC, CaV channel, nonspecific K channel, can enhance GABA

34

Lamotrigine MOA

inhibits alpha unit of VSSC
diminishes glutamate release
additional synaptic effects on glutamate

35

NaV/CaV channels in mania

too much Na/Ca flow in mania leading to excessive glutamate release
binding to channels helps reduce Na/Ca influx, lowering glutamate transmission

36

GABA/glutamate imbalance

restored in pharmacologic treatment
decrease glutamate/increase GABA

37

Agents that increase GABA

benzodiazepines
Zolpidem
Valproate
Carbamazepine
Topiramate

38

Agents that decrease glutamate

memantine
amantadine
topiramate
clozapine

39

Atypical antipsychotics in bipolar mania

5-HT2a antagonism --> reduces glutamate hyperactivity
can be beneficial for either mania or depression
D2 blockade useful for psychotic states

40

Atypical antipsychotics in bipolar/unipolar depression

5HT2/5HTc antagonism useful for reducing apathy/fatigue
--> in combo with SSRIs, releases brake that chronic 5HT effects hae on NE/DA release
Alpha-adrenergic blockade may improve mood via NE/5HT disinhibition
Dopamine partial agonism - useful for mood/cognition
5HT1A partial agonism - mood/anxiety
positive impacts on neurogenesis, sleep, cognition

41

Side effects of atypical antipsychotics

anticholinergic
antihistaminergic
alpha-1 antagonism (orthostasis), EPS due to excessive D2 blockade

42

Pertinent NTs in anxiolytics

Serotonin
NE
GABA

43

Anxiety disorder initiation of treatment

SSRI/SNRIs both 1st line, but initiating dose is lower than depression
May use benzodiazepine to manage short-term when starting therapy

44

SNRI usefulness in anxiety

NE may contribute to some of the related symptoms of anxiety, but could be useful due to:
Phasic reactivity
- anxiety: increase in phasic noradrenergic firing
- stress or threatening stimuli: extracellular NE very high

Tonic activity
- at rest, basal noradrenergic firing rate lower than would be expected in non-anxious individuals --> low levels of NE in synaptic cleft and at somatodendritic end of neuron

After several weeks of therapy:
Rest: basal NE firing rate low, extracellular NE levels increased --> blockade of reuptake/desensitization of alpha-2 autoreceptors
In response to stress: NE firing rate attenuated: likely due to somatodendritic alpha-2 autoreceptors failing to desensitize
--> inhibition of dramatic increase in NE usually observed with stress

45

SSRI usefulness in anxiety

enhances 5HT neurotransmission
5HT has little phasic reactivity (unlike NE)

46

Buspirone

primarily functions as partial 5HT-1A agonist
No GABA effects
not useful for as needed treatment of anxiety
useful for GAD

47

Benzodiazepine MOA

all bind to gamma subunit of GABAA receptors --> increase in receptor activity due to structural modification
do not substitute for GABA ( bind at alpha subunit), but increase freq of channel opening events --> increased chloride conductance --> hyperpolarization/inhibition of AP
Sedative/hypnotic, amnestic, anxiolytic, myorelaxant, anticonvulsant
Available benzodiazepines are non-selective; multiple benzos are additive rather than distinct
Clinically important differences due to PK properties
do not affect GABA-B on presynaptic mem (no effect on GABA release)

48

Benzodiazepine examples

lorazepam
clonazepam
diazepam
alprazolam
triazolam
oxazepam

49

Benzodiazepine indication

as needed/routine management of anxiety symptoms
management of insomnia

50

Anticonvulsants and anxiety

activation of fear circuits (amygdala) --> anxiety
Gabapentin/pregabalin
- not Health Canada indicated for anxiety
possible adjuncts for managing anxiety symptoms
Directly blocks alpha2delta subunits of CaV --> decrease Ca flow --> reduction in presynaptic NT release of glutamate