Depression Pharmacology

Which amino acid is serotonin derived from?

Tryptophan

Simplified pathway of serotonin derivation

Tryptophan → 5-hydroxytryptophan → 5-hydroxytryptamine (5-HT)

Which enzyme converts tryptophan to 5-hydroxytryptophan?

Tryptophan hydroxylase

Which enzyme converts 5-hydroxytryptophan to 5-hydroxytryptamine?

Tryptophan decarboxylase

How is 5-HT broken down?

MAO and aldehyde dehydrogenase

Which neurotransmitters are monoamines?

• 5-HT

• NE

• DA

Serotonin functions throughout the body

• GI tract signalling and nausea

• CV system including vasoconstriction and platelet aggregation

• CNS function - regulating emotions

Which monoamine has the most receptors?

5-HT (therefore most complex signalling)

Monoamine Hypothesis of Depression

First modern hypothesis about the cause of depression

• reserpine depletes vesicular NE and can induce depression

• alterations in the 3 monoamines are observed in depression

• changes in gene transcription and mRNA levels of monoamine receptors, transporters, metabolic enzymes, etc

• Drugs that affect monoamine systems are effective in treating depression

Neurotrophic Factor Hypothesis of Depression

• neurotrophic factors: growth factors that act primarily on neurons and support cells in CNS

• alterations in their signalling are present in depression

• changes in neurotrophic factor signalling and synaptic activity are evident with tx that cause rapid antidepressant effect (ketamine, ECT)

Neuroendocrine and Neuroinflammation Hypothesis of Depression

• several endocrine disorders are associated with increased incidence of depression

• elevated corticotropin-releasing hormone and other hormones

• altered responses to dexamethasone suppression test

• neuroendocrine changes more strongly associated with mod-severe depression or depression with psychosis

• are a significant portion of depressed pts simply hypothyroid?

Traditional models of animal studies on depression

Forced swim test and tail suspension test (can’t ask animals how they feel)

Newer model of animal studies on depression and what it suggests

Social defeat test

• suggests that the pathophysiology of depression doesn’t involve a deficit or abnormal neurotransmitter signalling, rather it is the manifestation of the absence of resilience

What is the serotonin transporter and what does it do?

• 12-transmembrane protein

• moves 5-HT, sodium, and chloride into nerve terminal

• intracellularly, binding of K+ causes release of 5-HT and returns transporter to resting state

How are SSRIs different from TCAs?

• Have affinity for serotonin transporter without significant antagonist activity at alpha1, histamine, or muscarinic receptors

• better tolerated but not more effective

SSRI SE

• GI (increased 5-HT signalling in gut)

• sleep disturbance

• sexual dysfunction

• weight gain

• QT prolongation

• bleeding

How do SSRIs cause sleep disturbances?

• depression itself modulates the sleep architecture, as well as SSRIs

• Change in REM onset, delayed total REM and other sleep period lengths, increased number of awakenings

How do SSRIs cause sexual dysfunction?

• 5-HT2A activation possibly in spinal cord

• disruptions of NO signalling (would explain ED)

• central cross-talk/disruptions with the dopaminergic system

  • would explain delayed ejaculation and reduced libido

• desensitization of 5-HT1a receptors on oxytocin-producing neurons would reduce oxytocin secretion

How do SSRIs cause weight gain?

• would think they would have anorexic effects due to serotonergic effects

• thought to be due to off-target effects but poorly understood

How do SSRIs prolong QT?

1. direct blockade of hERG potassium ion channels

2. disruption of hERG protein expression on cell membrane

   • reduces K+ flow by decreasing number of hERG K+ ion channels

How do SSRIs cause bleeding?

5-HT (along with TXA2 and ADP) is a signalling molecule released from platelets once they become activated

(block reuptake of 5-HT by platelets )

What is arginine vasopressin?

Another name for ADH (antidiuretic hormone)

Function of arginine vasopressin

• increased urine concentration

• reduced urine volume

• possible hyponatremia

When is ADH normally secreted?

In response to high plasma osmolality

Cause of SSRI-associated SIADH

Unknown

Who may be at higher risk of SSRI-induced SIADH?

Older adults

When does SIADH usually occur with SSRI use?

A few weeks after initiating therapy

Which SSRI has the longest half-life? Why?

Fluoxetine - active metabolite norfluoxetine

What is NET?

NE transporter - has affinity for both NE AND DA

(unlike SERT which is selective for 5-HT)

ADRs of NDRIs

• anxiety

• agitation

• insomnia

• seizures at high doses

(all low incidence)

Example of NDRIs

Bupropion

Which major antidepressant SE do NDRIs lack?

Sexual dysfunction

MOA of TCAs

Most are NE and 5-HT reuptake inhibitors (same MOA of SNRIs)

TCA SE

• anticholinergic

• altered cardiac function (orthostatic hypotension, tachycardia, palpitations)

• Drowsiness

• Weight gain

How do SSRIs and TCAs compare with respect to overdose?

SSRIs lack serious fatal toxicity in overdose

TCA overdose

• restlessness and excitement

• cardiac arrhythmias

  • risk lasts several days

• tonic-clonic seizures

• dystonia

• rapid onset coma

  • coma may last 1-3 days

  • afterwards, excitement and restlessness may return

• resp depression

• hypothermia

• hypotension

Which antidepressants are 5-HT selective?

• Venlafaxine

• Paroxetine

• Fluvoxamine

• Sertraline

• Fluoxetine

• Citalopram

Which antidepressants are non-selective?

• Amitriptyline

• Imipramine

• Clomipramine

Which antidepressants are NE-selective?

• Desipramine

• Nortriptyline

• Others

Mirtazepine MOA

• weak inhibitor of NET

• antagonist or inverse agonist at:

  • 5-HT2A/B/C

  • 5-HT3

  • 5-HT7

  • alpha2a/c

  • alpha1

  • H1

  • muscarinic receptors

Trazodone MOA

• weak inhibitor of SERT and NET

• -5-HT2 receptor antagonist (specifically 5-HT2A)

• alpha1 antagonist

• some H1 receptor antagonism

Which antidepressant has the same MOA of trazodone?

Nefazodone

What else does 5-HT2A antagonism result in, besides anti-depressant effects?

• anxiolytic

• antipsychotic

Most common ADRs of trazodone

• sedation

• GI

Nefazodone ADR

May cause hepatotoxicity

Vortioxetine (Trintellix) MOA

• serotonin modulator (non-selective, multi-targeted)

  • SERT and NET inhibitor

  • 5-HT1a receptor agonist

  • 5-HT1b partial agonist

  • 5-HT1d, 3, 7 antagonist

Effect of vortioxetine in addition to antidepressant effects

Improves cognition

Major AE of vortioxetine

N/V

Vilazodone MOA

5-HT reuptake inhibition and partial agonist at 5-HT1A receptors

Most common AE of vilazodone

GI - may be mitigated by titrating the dose and taking with food

Where is MAO located?

In synapse and presynaptic neuron where it breaks down monoamines

Function of MAO-A

Metabolizes 5-HT, NE, and DA

Function of MAO-B

Metabolizes DA and phenylethylamine

Example of irreversible MAOI

Phenelzine

AE of MAOI

• postural hypotension

• anticholinergic

• weight gain

• insomnia

At what point do antidepressants require a taper to d/c?

~2 months of use

Antidepressant withdrawal sx

• GI

• anxiety

• insomnia

(others - varies b/w antidepressants and b/w people)

FINISH mnemonic:

F: flu-like

I: insomnia

N: nausea

I: imbalance

S: sensory disturbances

H: hyperarousal

Which antidepressant produces withdrawal the quickest (sometimes after only 1 missed dose)?

Venlafaxine

Serotonin Syndrome Symptoms

Rapid onset of:

• fever

• increased HR

• shivering

• sweating

• dilated pupils

• tremor or twitching

• hyper reflexes

• acidosis

• seizures

What is ECT?

Electroconvulsive therapy - electrodes on head under mild anesthesia with ventilation with succinylcholine and neuromuscular blocker to reduce injury

Efficacy of ECT

Highly effective - up to 80% response rate in depression and drug-resistant depression or depression with suicidal ideation

• rapid onset (no delay)

Primary AE of ECT

• confusion

• memory loss

Ketamine MOA

• NMDA receptor antagonist

• also interacts with hyperpolarization-activated, cyclic nucleotide-modulated channels (HCN)

• effects on monoamine reuptake and GPCRs inclusing muscarinic, sigma, and opioid receptors

Which enantiomer of ketamine is more active at sigma receptors?

R-enantiomer

Which enantiomer of ketamine is more active at NMDA receptors and HCN channel?

S-enantiomer (marketed as esketamine)

Ketamine effects in animal studies

Rapidly reverses stress-induced phenotypes and neuronal architecture

Ketamine effects on epigenetics

Alters non-coding RNA levels and alters histone deacetylase activity

What is BDNF?

Brain-derived neurotrophic factor

What is the growing evidence regarding BDNF and depression?

• ECT increases BDNF levels

• BDNF itself is an antidepressant in rodent models

• BDNF-deficient mice display depressive behaviours

• Depressed humans have reduced serum BDNF levels

What is Brexanolone

AKA allopregnanolone

• neurosteroid related to progesterone

• allosteric GABA-A receptor modulator - has rapid antidepressant effects like ketamine - effects may last longer

• approved in USA for post-partum depression