Pharmacology I 6.3 Serotonin and Depression

What is major depressive disorder?

Behavioral despair and anhedonia"...presence of sad, empty, or irritable mood, accompanied by somatic and cognitive changes that significantly affect the individual's capacity to function"

What is MDD known to be?

Most common mental health disorder

Men

12%

Women

20%

What is the population percentage?

10-15%

What is MDD described to be?

Continuous cycling depression episode

How can it be treated?

With pharmacotherapy

What is the diagnostic criteria for depression?

1. Depressed mood or lost of interest or pleasure

2. Significant weight loss or gain

3. Hypersomnie or insomnia

4. Recurrent thoughts of death, suicidal ideation.

What is does major mean?

Significant continuation of severe depressive emotional state

What must be present in a person to be diagnosed with MDD?

Have 5 or more of the symptoms during a 2 week period or more than 2 weeks

What is the pathogenesis for depression?

Serotonin hypofunction

Fault of serotonin

Not enough serotonin--> monoamine hypothesis

If a sample of CSF was taken in people with MDD, what would is show?

- Decreased amount of NT and metabolites which decreases serotonin

What happens if NT was replaced with pharmacotherapy?

Increased mood

If it was a top free diet?

There would be a relapse in symptoms since serotonin is derived from tryptophan

What is Moma (ecstasy)?

Acts like amphetamine and is a love drug; there is increase serotonin release so it gets broken down so much that there is a significant drop in mood

Where does it work?

At the 5-HT system, after using it--> signs of MDD

Why is MDD not treated solely with monoamine replacement?

Neurotransmitter levels rise immediately after medicate start but clinical efficacy not seen for weeks

In people with MDD, there is less serotonin in CSF, but once they start therapy, what happens?

Levels will increase with immediate use of therapy but there will be noooo clinical improvement in depressive symptoms

Why does it take a while?

In people with MDD< it might take 6 weeks to feel better in behavioral despair

What are side effects in therapy use?

Sexual dysfunction, weight gain, sedation

What is happening in the neuron?

The presence of the NT is not the only factor but the neuron function as well

What is the neurotrophic hypothesis?

Secondary hypothesis that is complementary to the monoamine hypothesis where it explains the lag time in initiation of txt and clinical effects

Why is there low underlying neurological signaling?

Due to low neurons levels so to bring back signaling back, the nerves have to grow and differentiate and start signaling at higher levels

What does the vascularization look like in a depressed state?

There is not a lot of vascularization and not a lot of connections

What does the vascularization look like in a treat state?

More vascularization and connections to make new neuronal pathways; angiogenesis

How long does it take for new vasculature to occur?

6 weeks

What is the growth factor in neurons?

BDNF

Storage inhibitor

Reserpine, Amphetamine, Modafinil

Metabolism inhibitor

Iproniazid, phenelzine, selegelin

Reuptake inhibitors: SSRI, SNRI, NRI

Fluoxetine

Venlafaxine

Atomoxetine

Tricyclic Antidepressant (TCA)

Imipramine, Amitriptyline

Atypical

Bupropion, Mirtazepine, Ketamine

What does reserpine do?

It is a hypertensive medication which prevents transporter of NT; makes them sad; reversible

MAOi

Irreversible enzyme inhibition; inhibit tyramine metabolism

What are the food interactions that can occur?

Wine, cheese, cured meats

What can eating these food lead to?

Tyramine buildup that can lead to cardiovascular effects

Example of MAOi

phenelzine

TCAs

Potential overdose; non-selective (5-HT, NE, mACh)

What is the structure like?

- Has three rings

Examples of TCA

amitriptyline or imipramine

SSRIs

Improved safety profile over TCA; most commonly used

What is it more selective for?

10x more selective for SERT than DAT/NET

What does SSRIs do?

Finds serotonin re-uptake transporter to inhibit it to increase serotonin synaptic concentration

examples of SSRIs

fluoxetine and paroxetine

SNRIs

Combined blockade is dose-dependent

What do SNRIs do?

Serotonin and norepinephrine reuptake inhibitors which are 10 times more selective

NRI

used for ADHD by blocking NE uptake

Examples of SNRIs

Venlafaxine

What is an example of an NRI?

Atomoxetine (only NR) used for ADHD which increase focus

What is the anti-depressant ADR?

Serotonin syndrome

What are symptoms of serotonin syndrome?

- hyperreflexia

- tremor

- clonus

- inc. bowel sounds

- autonomic instability

- agitation

- Inc. HR

- mydriasis

- diaphoresis

What is mirtrazepine?

Used in non-responsive MDD

What is the structure of mirtazepine like?

Not TCA structure but similar complex pharmacology

What class is mirtazepine?

NASSA

What are the effects of mirtazepine?

- Antagonist alpha 2 adrenergic auto-receptor so it increases nor-adrenergic in synapse to increase serotonin incidence

- Antagonist 5HT2 and 5HT3 receptors (inotropic)

- Antagonist H1 histamine receptors which produce sedative effects

What happens to serotonin?

Is funneled to 5 HT receptors to increase mood and stability

What is the goal of mirtazepine?

Improve serotonin signal and improve noradrenaline signal

Binding of mirtazepine

- Prevent suppression of subsequent NT release to increase norpepi release

- Increase in norepinephrine release leads to increase cell activity and synthesis and release

Serotonin syndrome symptoms?

- Hyperreflexia, clonus, tremor

- dilated pupils

- diarrhea, increased bowel spunds

- CK can be raised but more with NMS

Neuroleptic malignant syndrome

- Hyporeflexia, lead pipe rigidity

- Normal pupils

- Normal GI

- CK is raised and can cause acute kidney injury

How can patient be treated?

Stop all meds

Fix what's wrong

Keep in hospital until better