Serotonergics + Adrenergics- AUSTIN

Symptoms of depression:

• anhedonia (ex: what used to be fun, now is not)

• avolition (lack of goal directed behavior)

• apathy (don’t care)

• lethargy (change in energy levels)

• cognitive

• sadness, anxiety, guilt, worthlessness

• thoughts of self, harm, self-destruction

What is the most important part of the brain effected in depression?

hippocampus—> important for forming, and maybe storage of episodic memories

What brain changes are seen in depression:

• structural changes—> decrease neuron density and atrophy

  • associated w/ HPA axis activation and BDNF

• connectivity changes

  • amygdala, ACC, hippocampus

  • changes in NT activity

• activity changes

  • baseline changes

  • response to stress

What is the monoamine hypothesis associated with depression?

what evidence is there for and against this hypothesis?

• pathophys of depression is associated w/ decreased activity of monoamines in the CNS

  • monoamines: serotonin, dopamine, NE

• evidence for:

  • any substance that increases monoamine has antidepressant properties

  • inhibiting MAO improves mood

  • reserpine (blocks VMAT) causes depression

• evidence against:

  • delay in clinical efficacy following increased levels of monoamines

  • only 50-70% of pts. experience full response to therapies that target monoamines (think: if monoamine hypothesis was 100% true than all pts. should respond)

There is no known single underlying cause of depression.

What are some things associated/observed with depression?

• genetic

• environment (ex: stress, trauma)

• HPA-axis abnormalities

  • increased cortisol associated

• Sickness behavior

  • increased level of pro-inflammatory mediators associated

What is the neurotrophic hypothesis associated with depression?

• basically—> Longitudinal Changes are seen

• Early depressive episodes are often "reactive" (triggered by stress), but later episodes become more "endogenous" (spontaneous), suggesting cumulative brain changes

  • austin ex: say your house burns down—> okay youre upset… but then shortly after you crash your car, lose your job—> you start to think “endogenously” or to yourself that bad things are going to happen to you

• Hippocampus and other parts of the brain volume decrease correlates with the duration of untreated depression, implying a positive feedback loop (“sad makes more sad”)

Altered signaling of what transmitters in addition to monoamines is associated with depression?

glutamate and GABA

What is the role of SERT?

removes serotonin from the synapse by reuptake

What is the role of NET?

removes NE from the synapse by reuptake

which autoreceptors of 5-HT and NE are inhibitory?

• a2 autoreceptors—> inhibitory

• 5HT1B—> inhibitory

Why does the clinical effect seen with reuptake inhibition take weeks to see?

• OVERALL THEORY: chronic use leads to downregulation of inhibitory autoreceptors

  • when we take acute treatment—> autoreceptors are flooded and shuts down pre synpase= doesn’t allow NT release DESPITE inhibiting reputake

  • over time—> downregulate autoreceptors and now the synapse can flood with NTs

• other theories: long-term tx may increase transcription factors and growth factors—> leading to neurogenesis (brain growth)

All antidepressants have what BBW?

suicidality

What different classes of drugs can be used for depression:

• reuptake inhibitors

  • TCAs

  • SSRIs

  • SNRIs

• degradation inhibitors

  • MAOIs

• others:

  • bupropion

  • mirtazapine

  • trazodone

  • serotonin modulators

TCAs are extremely hydrophilic or lipophilic?

• what are the advantages/disadvantages to this?

• TCAs= extremely LIPOphilic

  • advantages: good PK, can cross the BBB

  • disadvantages: low selectivity for receptors

MOA of TCAs:

• Inhibits Serotonin and NE reuptake

  • selectivity depends on whether it’s a tertiary or secondary amine (tertiary TCAs have increased selectivity for 5HT)

In addition to its main MOA, TCAs also have activity at what receptors?

• antagonist: 5HT, NMDA, a1, histamine, muscarinic receptors

• agonist: sigma

• blocks sodium and L type calcium channels

BBW of TCAs:

suicidality in children, adolescents, and young adults (24 and younger)

What are the effects seen with TCAs?

• explain each pharmacologically when applicable (aka what receptor is responsible for that effect)

• antidepressant (from NE and 5-HT reuptake inhibition)

• analgesic

• sedation (H1, M)

• orthostatic hypotension (a1)

• dry mouth (M)

• weight gain (H1)

• sexual dysfunction

• arrhythmias (sodium and calcium channel blockade)

• lower seizure threshold

Names of the TCAs:

• which are tertiary amines? which are secondary?

• amitriptyline- tertiary

• clomipramine

• Doxepin

• Imipramine

• desipramine- secondary

• nortriptyline

Why do we want to avoid abrupt discontinuation with SSRIs?

• exception to this?

• avoid abrupt d/c bc may cause flu-like symptoms, mood changes, tremor, n, dizziness, palpitations

• EXCEPTION: fluoxetine bc of its long t ½

MOA of SSRIs:

INHIBIT SEROTONIN REUPTAKE

SSRIs have less activity at other receptors compared to TCAs. What is the implication of this?

SSRIs have decreased risk of ADRs

List the SSRIs:

• Citalopram

• Fluoxetine

• Fluvoxamine

• paroxetine

• sertraline

Because SSRIs are so structurally different from each other, how do we compare them?

• SERT selectivity (aka we look for how high of an affinity the drug has to SERT)

What are the common shared structural features between all SSRIs?

• e- withdrawing group (nitro, acetyl, halogen) at para position of non-fused aromatic ring

Where do SSRIs bind to on SERT?

• exception?

• bind to primary/orthosteric site

• exception: escitalopram ALSO binds to allosteric site

  • (makes it work better)

What SSRI is the most selective?

What SSRI is the most potent?

• most selective—> escitalopram

• most potent—> paroxetine

The #1 thing we use to determine what SSRI to use is the ADRs.

What ADRs are seen from SSRIs? BBW?

• GI

  • n/v/d

  • GI bleed risk

  • appetite/weight changes (can be ↑ or ↓)

• CNS

  • HA

  • insomnia/fatigue

  • anxiety/agitation/mania

  • tremors/seizures

• BBW for suicidal thoughts and behaviors in pediatric and young adult pts.

• others:

  • serotonin syndrome

  • sweating

  • sexual dysfunction

  • hyponatremia

  • withdrawal symptoms

  • anticholinergic effects*

  • arrhythmias*

  • *= not seen in all

Most SSRIs are pregnancy category __. What is the exception?

• most are pregnancy cat C

• exception: paroxetine is cat D—> risk of heart defects, esp in 1st trimester

Do SSRIs have any food considerations?

Metabolized by what main CYP?

• can take w/ or w/out food (austin recommends with)

• metabolized by CYP2D6, 2C19, 3A4

Answer the following about specific SSRIs:

• which has the longest t ½ ?

• has the greatest probability of weight loss/anorexia?

• most likely to cause diarrhea?

• does not inhibit CYP3A4/ has the least enzyme interactions?

• most likely to prolong the QT interval?

• which are basic?

• fluoxetine

• fluoxetine

• sertraline

• citalopram

• citalopram

• ALL SSRIs are basic

MOA of SNRIs:

Inhibits serotonin and NE reuptake

REVIEW:

Compare the MOAs of TCAs, SSRIs, and SNRIs

TCAs	SERT + NET + other receptors
SSRIs	SERT
SNRIs	SERT + NET

Which is preferred—> SSRIs or SNRIs?

either or—> studies found no clinically significant difference between the two

How do SNRIs play a role in neuropathic pain?

NET inhibition

List the SNRIs:

• Venlafaxine

• Duloxetine

• Desvenlafaxine

• Milnacipran

• Levomilnacipran

ADRs of SNRIs:

• Similar to SSRIs!!!

• GI, CNS, sexual dysfunction, serotonin syndrome

• INCREASE in blood pressure (bc of NET/adrenergic)

• SWEATING

• bleeding risk

• withdrawal syndrome

SNRIs are metabolized by what CYP?

CYP2D6, 3A4, 1A2

MOA of MAOIs:

• difference between MAO-A and MAO-B

• inhibit of monoamine oxidase

  • prevents intracellular of monoamines

  • MAO-A: metabolizes DA, NE, 5-HT, tyramine

  • MAO-B: metabolizes DA, tyramine

What antidepressant reacts with cheese, beer, and wine? (known as the “cheese” reaction)

MAOIs

Explain why the cheese reaction occurs:

• these foods contain tyramine

• tyramine is metabolized by MAO

• if we inhibit MAO with MAOIs then tyramine (which is structurally similar to NE)—> displaces vesicular NE—> NE is not metabolized

• SHORT term results:

  • risk of HTN, tachycardia, arrhythmias (hypertensive crisis)

• LONG term results:

  • tyramine stored in vesicles and hydroxylated to octopamine (instead of NE)

  • when the SNS is activated—> octopamine is released instead of NE, which does not have any vasoconstriction/contraction = decrease BP

austin simplied example: basically blocks metabolism of these foods—> gets into CNS/PNS and displaces NE= makes NE flood out —> heart problems

For MAOIs:

• BBW

• ADRs

• Interactions

• BBW—> suicidal thoughts and behavior in pediatric and young pts.

• ADRs:

  • CNS (HA, drowsiness, lighthead)

  • GI (n/v/d)

  • sexual dysfunction

  • others: orthostatic hypotension, anticholinergic, paresthesia

• Interactions

  • SO MANY THINGS

  • significantly increases risk of serotonin syndrome

List the MAOIs:

• Isocarboxazid

• Phenelzine

• Tranylcypromine

• Selegiline

• Rasagiline

Are most MAOIs reversible or irreversible inhibitors?

irreversible

What is the triad of effects seen with serotonin syndrome?

• cognitive: mental status changes, HA, hallucinations

• somatic: hyperrflexia, tremor, myoclonus

• autonomic: hyperthermia, n/v/d, tachycardia, sweating

Serotonin Syndrome and NMS are difficult to differentiate. What are the key differences?

In serotonin syndrome—> there will be pupil dilation and reflexes not seen in NMS

Tx for serotonin syndrome?

• ciproheptadine (5-HT antagonist)

• SUPPORTIVE CARE—> #1 is GET RID OF THE CAUSE

WHAT IS THE WORST COMBO WHEN IT COMES TO SEROTONIN SYNDROME?

MAOI inhibitor + SSRI

MOA OF BUPROPION?

• HAS NO EFFECT ON WHAT????? UNIQUE!!!!!!!!!

• inhibits reuptake of NE and DA

  • NO EFFECT ON SEROTONIN

ADRs of Bupropion:

• DOSE-DEPENDENT DECREASE OF SEIZURE THRESHOLD

• stimulant-like effect

• n/v/d

• weight loss, INCREASED LIBIDO

• diaphoresis, blurred vision

What functional groups on Bupropion are essential for function? why?

• bulky t-butyl group prevents oxidative metabolism

  • protects the Nitrogen for drug efficacy

• prevents drug from forming metabolites that act like meth

MOA and ADRs of Trazodone and Nefazodone?

• net effect?

MOA:

• 5-HT1A partial agonist

• 5-HT2A, a, H1 antagonist/inverse agonist

• minimal SERT inhibition

• net effect: enhance 5-HT and NE release

ADRs:

• extreme drowsiness

• CV

What is a rare ADR associated with trazodone?

priapism

MOA and ADRs of Mirtazapine?

• net effect?

MOA:

• a2 antagonist (primary)

• 5-HT_2A,2C,3 ,H1 antagonist/inverse agonist

• net effect: enhance 5-HT and NE activity

ADRs:

• increased appetite/weight gain

• sedation

Note: decreased risk of sexual ADRs and serotonin syndrome

How does a2 antagonism with Mirtazapine lead to enhancement of 5-HT and NE activity?

• increases release of monoamines (inhibits the inhibitor)

• a1 activation by NE on serotonin is excitatory

• net effect: decrease in inhibition of serotonergic signaling

What is the MOA of Vilazodone and Vortioxetine?

• ADRs?

• CYP?

• MOA: SERT inhibition, 5-HT1A partial agonists

  • vortioxetine: 5-HT3 antagonism, 5-HT1B antagonism/partial agonism

• ADRs: n/v/d

• CYP2D6

What is Allopregnanolone approved for?

• BBW?

• MOA?

• approved for POSTPARTUM depression

• BBW: excessive sedation, loss of consciousness

• MOA: positive allosteric modulator at GABA-A receptor, antidepressant MOA unclear

For Ketamine:

• MOA?

• ADRs?

• NMDA receptor antagonist, antidepressant mechanism unclear

• ADRs: CV, rash, GI, dependence