DEPRESSION

MONOAMINES

endogenously synthesized transmitter with amine groups

ex: catecholamines, indolamines

CATECHOLAMINES

☼ DA, NE, Epi (synthesized from tyrosine)

INDOLAMINES

☼ Serotonin (5-HT) (synthesized from tryptophan)

Describe the neurochemical changes in Depression​: Monoamine hypothesis

☼ Brain of depressed patients seem to have lower levels of DA, NE & 5-HT

5-HT DISREGULATION

☼ Changes in appetite and sleep

☼ Decreased libido and motor function

☼ Presence of Anxiety

☼ Aggression & Melancholy

NE & DA DISREGULATION

☼ Anhedonia: inability to experience pleasure

☼ Decreased Energy

☼ Memory Impairment

☼ Deficits in Executive Function

Analyze the pharmacological options for treatment of Depression.​

Monoamine Oxidase Inhibitors (MAO-I)

Classical Tricyclic Antidepressants (TCA)

Selective Serotonin Reuptake Inhibitors (SSRI)

Serotonin-Norepinephrine Reuptake Inhibitors (SNRI)

Serotonin Receptor Antagonists

Atypical Antidepressants

Compare various classes of antidepressants, their characteristics and adverse effects and how such analysis will help determine the best therapeutic option for patients with depression.​

MONOAMINE OXIDASE INHIBITORS (MAO-Is) MOA

block the degradation of monoamines inside the presynaptic terminal

RESULT

• increases the amount of NE & 5-HT in the presynaptic terminals

• Leads to GREATER amounts of transmitters released

MONOAMINE OXIDASE INHIBITORS (MAO-Is) TYPES

Selegiline (Deprenyl, Ensam Patch)

Tranylcypromine (Parnate)

Phenelzine (Nardil)

MONOAMINE OXIDASE INHIBITORS (MAO-Is) SIDE EFFECTS

Insomnia, Orthostatic (Postural) HYPOTENSION, Weight Gain, Tyramine Toxicity (rapid HYPERTENSION) (dairy, meat, etc)

TYRAMINE TOXICITY

MAO is found in liver and breaks down/metabolize tyramine. When you take a pill that is a MAO-I it goes everywhere in the body including the liver and blocks the MAO enzymes in the liver it causes an increase in tyramine levels since MAO can’t break down the tyramine due to the MAO-I. Tyramine has the ability to cause significant release of Epinephrine.

TOO MUCH EPINEPHRINE = RAPID INCREASE OF BP (HYPERTENSION) = CAN BE LETHAL

If you take MAO-I what should you avoid?

Avoid eating foods rich in tyramine such as Dairy, meat and meat alternatives, breads, cereals, grains, vegetable and fruits

TRICYCLIC ANTIDEPRESSANTS MOA

Blocks NE & 5-HT transporters → WE GET MORE NE & 5-HT in the synapse  

Dirty drug → off target effects

What happens on a cellular level w/o drugs

Normally without drugs

• NE is released in synapse & binds to alpha & beta receptors post & presynaptically

• NE & 5-HT are cleared from the synapse by transporters/reuptake pumps that pump the neurotransmitter from the synapse to presynaptic terminal

WHY DO WE HAVE MORE NE & 5-HT IN SYNAPSE BY USING TRICYCLICS?

• Preventing NE & 5-HT from being reuptake into the presynaptic terminal by the transporters/reuptake pumps thus increasing NE & 5-HT in synapse

• Because the transporters/reuptake pumps are blocked by the tricyclics therefore they cannot put NE & 5-HT back into presynaptic terminal so there’s more NE & 5-HT that remain in synapse

TRANSPORTER/REUPTAKE PUMP

Transporter sucks the neurotransmitter in the synapse and moves it into the presynaptic terminal and clear synapse of neurotransmitters (ex: NE & 5-HT)

People with depression have too little _____ so our goal is to _____ 5-HT & NE

5-HT; increase

TRICYCLIC ANTIDEPRESANTS TYPES

Imipramine (Deprimin)

Desipramine (Norpramin)

Trimipramine (Surmontil)

Amitriptyline (Elavil)

Nortriptyline (Pamelor)

TRICYCLIC ANTIDEPRESANTS SIDE EFFECTS

☼ ANTIHISTAMINE: sedation, weight gain, confusion

☼ ANTICHOLINERGIC:  dry mouth, constipation, blurred vision, dizziness, nausea, vomiting, confusion, tachycardia, urinary retention

☼ ANTIADRENERGIC: orthostatic hypotension, reflex tachycardia, drowsiness

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) MOA

☼ inhibits 5-HT transporters, more selective than tricyclic

(ONLY increase 5-HT not NE)

WHAT IS FIRST-LINE FOR TREATING DEPRESSION

SSRIs

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) DRUGS

Fluoxetine (Prozac)

Citalopram (Celexa)

Escitalopram (Lexapro)

Fluvoxamine (Luvox)

Paroxetine (Paxil)

Sertraline (Zoloft)

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) SIDE EFFECTS

Much MILDER SIDE EFFECTS compared to TRICYCLICS

ACTIVATING EFFECTS: enhanced energy; more wide awake

GI DISTURBANCES: Nausea, vomiting, pain

SEXUAL ADVERSE EFFECTS: Decreased libido, delayed ejaculation

Out of all the SSRIs which has the MOST ACTIVATING EFFECT?

Fluoxetine (Prozac)

SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs) MOA

Blocks 5-HT & NE transporters same MOA of Tricyclics

WHAT’S THE DIFFERENCE BETWEEN SNRI’s & Tricyclics

SNRIs DO NOT have OFF-TARGET EFFECTS LIKE TRICYCLICS

SNRIs: NO off target effect

Tricyclics: HAVE off target effect

SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs) DRUGS

Duloxetine (Cymbalta): Inhibits NE & 5-HT to equal extent

Venlafaxine (Effexor):

• Low Dose: ONLY blocks 5-HT transporters

• High Dose: BLOCK BOTH 5-HT & NE transporters

Desvenlafaxine: Active metabolite of venlafaxine

SEROTONIN NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIs) SIDE EFFECTS

☼ Palpatations, tachycardia, increased BP, hyperhidrosis, hot flashes

• Due to increase in epinephrine & norepinephrine

GI DISTURBANCES: Nausea, vomiting, pain

SEXUAL ADVERSE EFFECTS: Decreased libido, delayed ejaculation

WHY DO WE HAVE DESVENLAFAXINE?

basically profit

Patent for venlafaxine ran out so they made a generic venlafaxine so the company that had the rights for venlafaxine made the active metabolite & called Pristiq to sell it

• Pharmacology same

• Efficacy same

WHY ARE SNRI’s AREN’T FIRST LINE WHILE SSRI’S ARE?

• SSRIs came first & kind of stuck as first line therapy

• In many cases SSRIs & their effects are sufficient to produce relief from the depression

• Whenever you add more MOA you increase probability of getting more side effects

SEROTONIN RECEPTOR DRUGS MOA

Trazodone (Oleptro):

☼ Serotonin 5-HT2 receptor antagonist

☼ weak inhibitor of 5-HT transporter

☼ weak antagonist alpha-1 adrenoceptors & H1 histamine

Gepirone

☼ Serotonin 5-HT1A receptor agonist

☼ Yes antidepressant → TBD if it is effective

SEROTONIN RECEPTOR ADVERSE EFFECTS

Trazodone (Oleptro):

☼ Orthostatic Hypotension

☼ Sedation (due to alpha1 & H1 antagonism)

Gepirone:

☼ Nausea, darrhea

☼ Headache

☼ Insomnia

What is the primary effect of Trazodone?

By blocking/antagonizing 5-HT2 receptors

Ligands

(neurotransmitter/drug)

Bind to receptor & can activate the receptor & cause signal transduction/cell membrane effects

RECEPTOR VS TRANSPORTER (PUMPS)

RECEPTOR

• protein that’s on the surface of a cell membrane that ligands bind to

• pre or postsynaptic

• When a molecule/ligand/neurotransmitter binds to the receptor they can activate receptor → changes in signal transduction and membrane potential

• Ex: GPCRs like alpha-1

TRANSPORTER

• pore that allows neurotransmitters to go from one side of the cell to the other side of the cell

• Typically take neurotransmitters from extracellular space & push into intracellular space

• drugs block these transporters

AGONIST VS ANTAGONIST

AGONIST

• When an agonist molecule (drug) binds to a receptor it activates the receptor

• causes receptor to do what its suppose to do

ANTAGONIST

• When an antagonist molecule (drug) binds to a receptor it prevents receptor from being activated

• blocks any effect of the receptor

ATYPICAL ANTIDEPRESSANTS DRUGS

Buproprion (Wellbutrin): weight LOSS

Mirtazapine (Remeron): weight GAIN

Aripiprazole (Abilify)

Zuranolone: POSTPARTUM

Esketamine: NASAL - SCHEDULE 3

BUPROPION (WELLBUTRIN) MOA + ADVERSE EFFECT

MOA: ☼ Inhibits DA & NE transporters

ADVERSE EFFECT: ☼ nausea, insomnia, jitteriness ☼ can cause weight LOSS

MIRTAZAPINE (REMERON) MOA + ADVERSE EFFECT

causes weight GAIN and sedation /// good for elderly

MOA: ☼ tetracyclic antidepressant // NET EFFECT: increased 5-HT & NE levels

ANTAGONIST TO …

Histamine 1

Alpha 2 Nonadrenergic Receptor

5-HT2 Receptors (5-HT_{2A & C})

Norepinephrine Transporter

ADVERSE EFFECT:

☼ causes WEIGHT GAIN and sleep inducing (sedation)

☼ sedation due to antihistamine properties

☼ increases triglyceride and total cholesterol levels

ARIPIPRAZOLE (ABILIFY) MOA

☼ ATYPICAL antipsychotic // used in combination therapy with other antidepressants!!!

D2 Partial Agonist

5-HT1A Partial Agonist

5-HT2 Antagonist

What is the primary effect of Aripiprazle

D2 Partial Agonist

ZURANOLONE MOA

☼ neurosteroid hormone, increases effects of GABA on GABA_A receptors

positive allosteric modulator

☼ used for treating POSTPARTUM DEPRESSION

• Injectable Form: Brexanolone (Zulresso)

What happens if you give zuranalone to a person w/ just depression?

Not really effective in treating depression

NON-COMPETITIVE VS COMPETITIVE ANTAGONIST

NON-COMPETITIVE

• It doesn’t matter what other drug you throw at its receptor once non-competitive antagonist is bound there’s no change in concentration that’s going to kick this drug off the receptor

COMPETITIVE ANTAGONIST

• The drug w/ the higher concentration will bind to the receptor

ESKETAMINE (Spravato) MOA

☼ non-competitive NMDA receptor antagonist

[used for ADJUNCT THERAPY - ADULTS ONLY]

☼ Nasal spray that’s applied in an outpatient setting

• DOSING: low doses given 2x/weekly and gradually increase dose and reduce frequency over several weeks

• ONSET: within hours of initial dosing

treatment resistant depression - schedule 3 drug

ESKETAMINE (Spravato) ADVERSE EFFECT

☼ Potential for abuse / misuse  [SCHEDULE 3]

☼ increase in suicidal thoughts, short term cognitive impairment

☼ increase in blood pressure 

☼ sedation, dizziness, vertigo, hypesthesia

☼ dissociative disorder

ALL antidepressants we have gone over so far have delayed onset of clinical effect what is the EXCEPTION?

Esketamine

Downregulate

If on the cell membrane you use to have 10 receptors the cell decides to reduce the number of receptors

ex: 10 receptors → 5 receptors

fewer # of receptors to control how much those receptors are being activated

Describe why antidepressants have a delay in onset of clinical efficacy?

EARLY IN TREATMENT [weeks 1-2]

☼ Antidepressant produces a transient increase in synaptic levels of NE and 5-HT. The transmitters bind to presynaptic autoreceptors and reduce further release of the transmitter. ​

☼ The autoreceptors also downregulate the activity of the rate limiting enzymes (TH and TPH), reduce the rate of neuronal firing, and thus reduce transmitter release.​

☼ The net effect is that acute treatment of antidepressants can somewhat reduce NE & 5-HT release.​

LATE IN TREATMENT [weeks 3-4]

☼ Repeated use of antidepressant results in the down-regulation of the

autoreceptors, leading to an increase in transmitter release.​

☼ Increase in transmitter level results in increase in postsynaptic receptor

activation, leading to an increase in activation of intracellular signaling proteins

leading to a therapeutic response.​

What would happen if Trazodone is put into this picture

We know trazodone is a 5-HT2 antagonist so if we antagonize the autoreceptors we know for an autoreceptor for it to work it needs to be activated but if we apply trazodone to the autoreceptor trazodone will block the neurotransmitter from binding to the autoreceptor resulting in a increase (5-HT) of neurotransmitters b/c the neurotransmitter is not binding to the auto receptor

auto receptor CANNOT block neurotransmitter release

Will there be downregulation of postsynaptic receptor if you have a lot of 5-HT around? If so why?

Yes, b/c receptor downregulates if their overstimulated

How do you continue to treat patients if receptors are downregulated?

• receptor downregulation isn’t the end all be all

• Wide range of transduction cascades underneath receptors

• some of the transduction cascades become hypersensitize so you don’t need a lot of receptor activation to still trigger activation of transduction cascades

• In patients who have been taking antidepressants for a long time their brain adapts to the way it functions

DEPRESSION MEDS

MAO-Is

• Selegiline

• Tranylcypromine

• Phenelzine

Tricyclic Antidepressants

• Imipramine

• Desipramine

• Trimipramine

• Amitriptyline (Elavil)

• Nortriptyline (Pamelor)

SSRIs

• Fluoxetine (Prozac)

• Citalopram (Celexa)

• Escitalopram (Lexapro)

• Fluvoxamine

• Paroxetine (Paxil)

• Sertraline (Zoloft)

SNRIs

• Duloxetine (Cymbalta)

• Venlafaxine (Effexor)

• Devenlafaxine

5-HT Receptor Drugs

• Trazodone (Oleptro)

• Gepirone

Atypical Antidepressants

• Buproprion (Wellbutrin)

• Mirtazapine (Remeron)

• Aripiprazole (Abilify)

• Zuranolone

• Esketamine