Psychopharmacology of mood/anxiety disorders Flashcards
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
Norepinephrine metabolism at synaptic cleft
Autoreceptor: presynaptic alpha-2 autoreceptor
NET: norepinephrine transporter
VMAT on NT vesicles
Dopamine metabolism at synaptic cleft
Autoreceptor: presynaptic D2 autoreceptor
VMAT on vesicles
D1-5 receptors on postsynaptic membrane
DAT transporter
GABA metabolism at synaptic cleft
GABAA, B, C receptor complexes on postsynaptic membrane
GABA transporter: GAT
Glutamate metabolism ta synaptic cleft
Transporter: EAAT
vGluT on vesicles
Presynaptic metabotropic receptor (autoreceptor)
Post: NMDA, AMPA, kainate, postsynaptic metabotropic receptors
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
Prefrontal cortex in manic symptoms
racing thoughts grandiosity distractiliby talkative/pressured speech mood risk
Thalamus in manic symptoms
decreased sleep/arousal
Nucleus accumbens in manic symptoms
racing thoughts
goal-directed
grandiosity
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
SSRI examples
fluoxetine sertraline paroxetine citalopram escitalopram fluvoxamine
SSRI MOA
blocks SERT
interferes with recycling of serotonin back to presynaptic neurons
increases 5HT availability in synapse
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
SNRI examples
venlafaxine
duloxetine
desvenlafaxine
SNRI MOA
blocks SERT and NET
SNRI side effects
similar to SSRIs
additional potential to affect blood pressure/pulse (peripheral NE effects)
NDRI examples
Buproprion (SR/XL)
NDRI MOA
blocks NET, DAT
NDRI MOA
No serotonergic involvement (less effect on sexual functioning)
may include insomnia if dosed too closely to bedtime
NaSSA example
Mirtazapine
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
SARI examples
Trazodone
usually used as a sedative rather than a antidepressant
SARI MOA
low doses (
SARI side effect
histamine blockade
post-synaptic alpha-1 blockade: tiredness, dizziness/orthostasis
Post-synaptic alpha-2 blockade: priapism
TCA exapmles
Amitriptyline (SNRI) - Pain
Desipramine (NRI)
Clomipramine (SRI) - OCD
TCA MOA
classification based more on chemical structure Antihistaminergic Anticholinergic Post-synaptic alpha-1 blockade Na channel blockade
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
MAOI examples
Phenelzine
Tranylcypromine - both nonselective, irreversible
Moclobemide (MAOI-A selective)
MAOI MOAs
MAO-A: metabolizes NE, 5HT, tyramine
MAO-B> preferentially metabolizes dopamine
enhance monoamine function by interfering with metabolism
Mood stabilizer examples
Valproic acid Carbamazepine Lamotrigine Oxcarbazepine Less commonly used adjuncts: gabapentin, topiramate
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)
Valproic acid salt MOA
Inhibits NaV channels (non-specific sites), boosts GABA actions
regulates downstream signal transduction cascades
Carbamazepine/oxcarbazepine MOAs
inhibits alpha unit of VSSC, CaV channel, nonspecific K channel, can enhance GABA
Lamotrigine MOA
inhibits alpha unit of VSSC
diminishes glutamate release
additional synaptic effects on glutamate
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
GABA/glutamate imbalance
restored in pharmacologic treatment
decrease glutamate/increase GABA
Agents that increase GABA
benzodiazepines Zolpidem Valproate Carbamazepine Topiramate
Agents that decrease glutamate
memantine
amantadine
topiramate
clozapine
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
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
Side effects of atypical antipsychotics
anticholinergic
antihistaminergic
alpha-1 antagonism (orthostasis), EPS due to excessive D2 blockade
Pertinent NTs in anxiolytics
Serotonin
NE
GABA
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
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
SSRI usefulness in anxiety
enhances 5HT neurotransmission
5HT has little phasic reactivity (unlike NE)
Buspirone
primarily functions as partial 5HT-1A agonist
No GABA effects
not useful for as needed treatment of anxiety
useful for GAD
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)
Benzodiazepine examples
lorazepam clonazepam diazepam alprazolam triazolam oxazepam
Benzodiazepine indication
as needed/routine management of anxiety symptoms
management of insomnia
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
