Anti-depressants

Monoamine oxidase inhibitors (MOAIs)

• Irreversible inhibitors of MAOa and MOAb

  • Irreversibly causes long washout period 

  • Selegiline is MAOb selective at low dose; mostly nonselective at high doses 

• MOA: 

  • Molecular: irreversible inhibition of MAOa and MAOb

  • Cellular: blocks breakdown DA, 5HT, and NE

  • Clinical: increase synaptic levels of DA, 5HT, NE

• Drugs:

  • Selegiline (Emsam)

  • Phenelzine (Nardil)

  • Tranylcypromine (Parnate)

• NTs:

  • At low dose of selegiline DA levels are raised.

  • At high dose of selegiline NE/5HT/DA levels are raised.

Drug interactions

• Any drug that increases NE/Adrenaline or 5HT 

• Hypertensive crisis

  • Sever htn

  • Sweating 

  • Anxiety 

  • Tachycardia

  • Chest pain 

  • Too much adrenalin, ne, tyramine

• Serotonin syndrome 

  • Mental state

  • dry mouth

  • muscle rigidity 

  • Tremor

  • N/V, diarrhea

  • Hyperthermia

  • Too much 5HT

Dietary Restriction 

• MAOIs at higher doses used for depression come with dietary restrictions including:

  • Aged cheese

  • Salami

  • Wine and tap bee

  • Miso and soy sauce 

• Cheese reaction

  • Sevre HTN

  • Sweating anxiety 

  • Tachycardia

  • Chest pain  

• Hypertensive crisis 

  • Sever htn

  • Sweating anxiety 

  • Tachycardia

  • Chest pain 

• These foods all contain high levels of tyramine, which competes with NE and adrenaline at MAOA 

• MAOA normally breaks down NE effectively. However, both MAOA inhibitors and high levels of tyramine can compete at MAOA with NE and reduce its breakdown. Normally neither is enough to be dangerous, but with combination, the resulting high levels of NE/adrenaline can cause hypertensive crises

Tricyclic antidepressants 

• Inhibitors of SERT and NET

• TCAs very nonselective

  • Large number of ADEs

• MOAs:

  • Molecular: inhibit SERT and NET

  • Cellular: Block reuptake of 5HT and NE

  • Clinical: increases synaptic levels of 5HT and NE

• Drugs:

  • Nortriptyline (Pamelor)

  • Desipramine (Norpramin) -more selective NET>SERT

  • Amitriptyline (Elavil)

  • Imipramine (Tofranil)

  • Doxepin (Sinequan, Silenor)

Serotonin and NE reuptake inhibitors (SNRI)

• Inhibit SERT and NET

• More selective than tricycles, fewer ADEs than TCA

• MOAIs:

  • Molecular: Inhibit SERT and NET

  • Cellular: Block reuptake of 5HT and NE

  • Clinical: Increases synaptic levels of 5HT and NE

• Drugs: 

  • Venlafaxine (Effexor, Effexor  XR) – SERT preferring

  • Desvenlafaxine  (Pristiq) – R-enantiomer only

  • Duloxetine  (Cymbalta)

  • Levomilnacipran (Fetzima)

  • Milnacipran (Savella)

Selective 5HT reuptake inhibitors (SSRIs)

• SSRIs inhibit SERT only 

• Each drug has widely different binding profile and ADEs

• All have latency to antidepressants effect

• MOAs:

  • Molecular: inhibits SERT

  • Cellular: blocks reuptake of 5HT

  • Clinical: increases synaptic levels of 5HT

• Drugs:

  • Fluoxetine  (Prozac)

  • Paroxetine  (Paxil)

  • Sertraline  (Zoloft)

  • Citalopram  (Celexa) – racemic; active and non-active enantiomers 

  • Escitalopram  (Lexapro) - active enantiomer (S)

NE and DA Reuptake inhibitors (NDRI)

• Inhibits NET and DAT

• Increases NE with no 5HT increases make this more activating than SSRIs: anxiety, tremors, decreased seizure threshold 

• MOAs:

  • Molecular: Inhibit NET and DAT

  • Cellular: Block reuptake of NE and DA

  • Clinical: Increases synaptic levels of NE and DA

• Drugs: Bupropion (Wellbutrin SR, XL)

5HT1A agonist 

• Azapirone serotonin 1a receptor partial agonist 

  • Partial agonist at presynaptic receptors with predominant antagonist effect 

  • Block of presynaptic auto-receptor negative-feedback loop increases 5HT release 

  • Antidepressant action due to increased 5HT 

  • Primarily used to treat anxiety disorders

• MOAs:

  • Molecular: Partial agonist with antagonist-like effect at presynaptic 5HT1A auto-receptors

  • Cellular: Disinhibits (increases) further 5HT release

  • Clinical: Increases synaptic levels of 5HT

• Drugs: buspirone

Serotonin Modulator 

• Tetracyclic serotonin modulator antidepressants

  • Antagonist presynaptic a2 adrenergic auto-receptors to increase NE release 

  • Antagonist presynaptic 5HT2 auto-receptors to increase 5HT release 

  • Significant non-selective binding and ADEs 

• MOA:

  • Molecular: Inhibit presynaptic α2 receptors and 5HT2 receptors

  • Cellular: disinhibits (increases) further NE and 5HT release

  • Clinical: Increases synaptic levels of 5HT and NE

• Drugs: Mirtazapine (Remeron)

Mixed Serotonergics 

• Mixed serotonergics are several related classes

• All mixed serotonergic have dual MOAs:

1. SERT inhibition 

2. Disinhibition of 5HT release: antagonism/partial agonism of presynaptic inhibitory 5HT auto-receptors increases further 5HT release 

NMDA receptor agonist 

• Glutamate NMDA receptor antagonists

• Antidepressant action due to increase in synaptic health and function

• MOAs:

  • Molecular: Antagonism of NMDA receptors

  • Cellular: Increases Glu and BDNF release

  • Clinical: Increases neural health/plasticity

• Drugs:

  • Esketamine (Spravato) (nasal spray) -active isomer of ketamine

  • Dextromethorphan

GABAA R positive allosteric modulator 

• GABAA R positive allosteric modulator aka allosteric potentiator

  • Analogues of neurosteroid allopregnanolone

  • For POST-PARTUM depression only

  • Reduces post-birth drop in allopregnanolone

  • Treats upstream cause of depression, not the mechanisms of depression

• Drugs:

  • Brexanolone (Zulresso) iv

  • Zuranolone (Zurzuvae) PO

Recognize that TCAs are less selective drugs than SNRIs, and therefore have increased ADEs

• TCAs are less specific drugs and have activity at a lot more receptors. This means they will have more ADEs

Recognize that venlafaxine is a pro-drug of desvenlafaxine and how effectiveness will depend on CYP activity. 

• Venlefaxine = racemic of active (r) and prodrug (s) 

• Desvenlafaxine = active R-enatomer only 

• CYP 2D6 activates pro-drug to activate drug 

Recognize that escitalopram consists only of the active enantiomer of citalopram.

• Citalopram is the racemic  (active and non-active enantiomer) of the active enantiomer of escitalopram 

• Ex: Is 20mg daily citalopram the same as 20mg daily escitalopram? 

  • NO. 20mg citalopram consists of 50% inactive enantiomer and 50% active enantiomer escitalopram. It has half the amount of active drug.

Explain how disinhibition at a synapse works.

• Disinhibition = removal of inhibitory pressure

• Presynaptic disinhibition → increased NT release

• Inhibitory auto-receptors on serotonergic terminals inhibit further 5HT release 

• Turning off these receptors increases 5HT release:

  

  • Antagonist 

  • Partial agonist = partial antagonist 

• Several drugs use about MOA

Explain the dual mechanisms shared by the Mixed Serotonergics and how this is different from SSRI MOA.

• Mixed seronergics MOA:

  • SERT inhibition 

  • Disinhibition of 5HT release: antagonism/partial agonism of presynaptic inhibitory 5HT auto-receptors increases further 5HT release 
    
    

• SSRI MOAs:

  • Molecular: inhibits SERT

  • Cellular: blocks reuptake of 5HT

  • Clinical: increases synaptic levels of 5HT

• SSRIs only inhibit SERT, while mixed agents inhibit SERT AND cause disinhibition and increased 5HT release.

• difference between disinhibition by buspirone and trazodone seen on this slide. Explain how these can both produce disinhibition of serotonin release.

  • Trazodone is an antagonist at presynaptic receptors, while buspirone is a partial agonist. These have the same effect because a partial agonist is also a “partial antagonist.” It just depends on which effect predominates.