CPPS 306 Mood Sabilizers

What is major depressive disorder

A heterogenous genetic disorder with onset at anytime of life

Recurring

Affects 10% of the population

The WHO predicts by 2030 MDD will be the #1 health issue world-wide

What are symptoms of major depressive disoder

Emotional - APATHETIC

Cognitive - Impaired concentration

Neurovegetative - lack of motivation, cant experience or anticipate pleasure

What non-pharmacological (non-drug) biological interventions have been used to treat depression

Insulin-induced hypoglycemic convulsions

• Historic only

Electro Convulsive therapy

• Currently safe and effective

What are the five major pharmacological/drug classes of antidepressants

MonoAmin Oxidase Inhibitors (MAOIs)

Tricyclic antidepressants (TCAs)

Seretonin and norepinephrine reuptake inhibitors. (SNRIs)

Selective seretonin reuptake inhibitors (SSRIs)

Atypical antidepressant

What is monoamin oxidase responsible for

a mitochondrial enzyme that breaks dwon monoamines to prevents buildup of toxic neuroactive amines (tyramine)

What are the monoamines that monoamine oxidase breaks down?

• Serotonin (5-HT)

• Norepinephrine (NE)

• Dopamine (DA)

• Tyramine (From food)

Compare and Contrast Monoamine-A (MAO-A) vs Monoamine-B (MAO-B)

MAO-A

• found in neurons, liver, and GI tract

• Highest affinity for 5HT

• mainly. metabolizes serotonin in gut and brain

MAO-B

• Found in neurons, liver, and platelets

• Highest affinity for DA

• mainly metabolizes dopamine in bain

What is tyramine?

Found in food (cheese + wine)

• Normally broken down by MOA-A in gut = harmless

What happens when you take non-selective Monoamine oxidase inhibitors (MOI)

• Tyramine is not boken down

• Tyramine enters blood

• Displaces noradrenalin from sympathetic terminals → increases heart rate, BP, and throbbing headache

Trancyclypromine

A MOI

• Non selective inhibitor of both MOA-A and B

• Increases 5HT/NE in brain

• Increases absorption of tyramine into blood stream

Moclobemide

A Monoamin Oxidase inhibitors

• Selective inhibitor of MOA-A

• Increases 5HT/NE in brain without affecting blood tyramine

  • Take in morning because it disrupts sleeping pattern

Why is moclobemide safer than non-selective MAO inhbitors

Because it selectively inhibits MAO-A in the brain, increasing serotonin and norepinephrine to treat depression, while largely preserving gut tyramine metabolism and reducing the risk of hypertensive crisis.

What are tricyclic antidepressents (TCAs) and name them

Imipramine and Amitriptyline

• Both block reuptake of NE and 5-HT

• Increases NE and 5-HT in the synapses which alleviates depression

What are side effects of TCA/s

They are non-selective meaning not only do they block 5-HT and NE reuptake, but they also block

• Muscarininc receptors = anticholingergic effect = memory impairment, dry mouth, constipation, blurry vission

• A1-adrenergic receptors = postural hypotension

What happens to imipramine and amitriptyline after liver metabolism?

Imipramine → desipramine

Amitriptyline →nortriptyline

• Both TCAs and have less affinity for muscarnic and a-receptors meaning its more NE-selective and have less side effects

Why are desipramine and nortriptyline better tolerated than their original form imipramine and amitriptyline

Because they are more selective for NE (leave more NE in synaspe) reuptake and have less muscarnic and a receptor blockage

What do Serotonin Norepinephrine reupatke inhibitors (SNRIs) do and name them

Inhibit both NE and 5HT reuptake and lack affinity for any NT receptors

• Venlafaxine

• Duloxetine

Cleaner and better than TCAs

Why are SNRis useful for chronic and neuropathic pain?

Because increasing norepinephrine and serotonin enhances descedning inhibitory pain pathways in the spinal cord

What are selective serotonin reuptake inhibitors (SSRIs) and give an exammple

Inhibit only 5HT reuptake and lack affinity for NT receptors

• Fluoxetine

Why is fluoxetine considered dangerous

Fluoxetine inhibits the cytochrome p450 2D6 causing potential fatal drug interactions with narcotics and beta blockers

Since Fluoxetine is considered dangerous due to increasing fatal drug-drig interactions, what are safer SSRi alternatives

Citalopram

Escitalopram

• Both have less serious p450 related drug interactions

Why are atypical antidepressents considered a separate class from SSRI,s SNRIs, TCAs

because they improve depression through diverse, non standard mechanisms (receptor anatognism, partial agonism, or weak reuptake inhibition) rather than primarily bloclking monoamine reuptake or MOA

What are the atypical atidepressants drugs

Mirtazapine

Amoxapine

Nefazodone

Trazodone

Bupropion

Mirtazapine

Atypical Antidepressant

• Pre-synaptic alpha receptor antagonist

• Blocks several types of post-synaptic 5HT/NE/DA/HA receptors

Amoxapine

Atypical Antidepressant

• Moderate reuptake inhibitor of 5HT

• Strong reuptake inhibitor of NE

• Antagonist/inverse agonist of select 5HT, NE, and DA receptors

  • Binds and prevents 5HT, NE, and DA from binding to thier receptors

Nefazodone

Atypical Antidepressant

• Strong anatagonist of 5HT_2A (blocks this specific serotonin receptor)

  • Reduces anxiety, insomnia, sexual side effects, over-activation from serotonin

• Weak inhibitor of 5HT, NE, and DA reuptake (slightly increase the amount of NT in the synapse)

Trazodone

• Weak reuptake inhibitor of 5HT

• antagonizes

  • 5HT

  • alpha adrenergic receptors

    • reducing arousal and anxiety

Bupropion

Weak reuptake inhibitor for DA/NE

NAChR antagonist = blocks Ach from activating nicotinc receptos

Effective alone, but often added with SSRIs

What does the delay in antidepressant response indicate?

Since antidepressants increase neurotransmitters within hours, but clinical imporvement takes weeks (feeling better), this suggests that the benefit depends on slow adaptive brain changes, not acute monoamine elevation

What common receptor change occurs with chronic or long term antidepressent treatment

Down regulation of Beta adregernic receptors which (receptors that respond to NE and become less senstivie to their signaling) suggesting receptor adaptatoin contirbutes to mood normalization

What is considered the key mediator of antidepressant efficiency

BDNF

• Chronic antidepressants increase BDNF expression, promoting neuroplasticity and synaptic remodelling linked to mood improvement

What is esketamine, and why is it important in treatment of depression?

A rapid-acting antidepressant used for treatment-resistant depression that increases BDNF and synaptic plasticity, producing clinical imporvement within hours instead of weeks

What is mania in bipolar disorder?

a pathological state of elevated or irritable modd with increased arousal and energy, opposite to depression

What is the main treatment goal in bipolar disorder

To remove or stop acute mania, prevent futue manix episodes, and stablize long-term mood

What are the three majore drug classes used to treat bipolar disorder

Lithium

Anticonvuisants

Atypical antipsychotics

Why is lithium critical for biopolar disorder

Because it treats acute mania, prevents future manic episdoes, and has a mild antidepressant effect for long term mood stabilization

What are the early signs of lithium overdoes

Nausea and vomitting

What are the anticonvulsant drugs used as mood stabilizers in bipolar disorder

Carbamazepine

Valproic Acid

Lamotrigine

How does carbamazepine stabilize mood in bipolar disorder

Blocks voltage gated Na channels

Enhances GABA signaling

• Similar benefits to lithium but with fewer side effects

How does valproic acid stabilize mood in bipolar disorder

Blocks voltage gated Na channels

Enhances GABA receptor currents

• Used in patients with rapid cycling of manic and depressive episodes

How does Lamotrigine stabilize mood in bipolar disorder

Blocks voltage-gated Na channels

Also blocks L-, N, and P-type Ca channels

• Most effective in the depressed phase

When are atypical antipsychotics used in bipolar disorder?

For acute, mania, or mixed episodes, epscially when psychosis, delusions, or severe agitation are present

Why is antidepressent monotherapy dangerous in bipolar disorder?

Because it can cause a manic episode, worsening the disease course

Which drug combination is used to treat bipolar depression while reducing the risk of mania

Olanzapine + fluoxetine

20-40% of patients do not respond to or tolerate lithium, what is the general treatment strategy when lithium is ineffective or not telerated?

Switch to anticonvulsants and/or add atyipical antipsychotics for acute mania or mixed states