Depression and Dementia

What are Ach and glutamates roles in Alzheimer's disease?

low Ach

excessive glutamate (sometimes low glutamate)

What are the goals of treating dementia/alzheimers?

Increase acetylcholine signaling (AChEsterase Inhibitors)

Decrease glutamate signaling (Inhibit the NMDA receptor)

Why is glutamate signaling needed to be reduced to treat dementia? (synaptic and extrasynaptic NMDA) 

Synaptic NMDA is needed for survival but excess glutamate decreases receptors. Extra-synaptic NMDA receptor activity (glutamate binding) promotes apoptosis (cell is overstimulated) leading to loss of neurons 

MOA of Aricept (Donepezil)?

Inhibit AchE to increase Ach signaling

How does Namenda (Memantine) work?

NMDA receptor antagonist, blocks glutamate binding

What are two main drugs used to treat Dementia?

Aricept

Namenda

What are Aricept (donepezil) and Namenda (memantine) used to treat?

Dementia

What is major depressive disorder (MDD)? 

A recurring and disabling disorder with symptoms lasting for at least two weeks that interfere with a persons ability to work, sleep, study, eat, and enjoy once-pleasurable activities

What are the three factors that play into the pathology of major depression?

Neurotrophic hypothesis, neuroendocrine factors, monoamine hypothesis 

What is the Neurotrophic hypothesis? 

The thought that major depressive disorder is associated with loss of neurotrophic

What factors play into the neurotrophic hypothesis?

Brain-derived neurotrophic factor impacts neuronal growth and survival by helping nerves get the signaling they need to grow and make connections 

How do antidepressants play into the neurotrophic hypothesis?

Increase BDNF and neurogenesis

How do neuroendocrine factors play a role in dpression?

Major depressive disorder is associated with hormonal abnormalities such as elevated cortisol, thyroid disregulation, and sex steroids deficiency 

How do monoamines play a role in depression (Monoamine Hypothesis)?

In someone with depression there are more MAO present, resulting in increased metabolism of monoamines which means less neurotransmitters like serotonin/dopamine available

What are examples of monoamines?

Dopamine, norepinephrine, serotonin etc.

What does MAO-A oxidize/metabolize? MAO-B? 

Epinephrine, norepinephrine, serotonin; Dopamine and Tryptophan 

What are the three ways in which most anti-depressants act?

1. Block transmitter reuptake

2. Inhibit presynaptic autoreceptors (increase release of NT)

3. Inhibit MAO (decrease NT degradation)

How does someones neuroanatomy dictate that they will have mild/moderate depression symptoms?

If they have low monoamine reuptake transporters, more monoamines will stay in the cleft (less degraded) and therefore less depression symptoms

How does someones neuroanatomy dictate that they will have severe depression symptoms?

If they have normal number of monoamine reuptake transporters, they will be took inside the cell and degraded easier resulting in less monoamines in the cleft causing more depression symptoms

Examples of Tricyclic Antidepressants?

Amitriptyline (Elavil)

Nortriptyline (Pamelor)

How do tricyclic antidepressants work?

blocks serotonin and NE reuptake

blocks many NT receptors throughout body

What are the side effects of TCAs?

Blurred vision (Muscarinic M1 antagonism)

Orthostatic/postural hypotension (Histamine H1 receptor antagonism)

Sedation (Adrenergic A1 receptor antagonism)

Weight gain (Serotonin 5-HT2 receptor antagonism)

Seizures (Direct membrane effects)

What specific serotonin receptor is found to be low in depression?

5-HT₂

What are the downsides to using TCAs?

Lots of side effects and has a delayed effect (takes weeks to work)

What is an example a tetracycline?

Mirtazapine (Remeron)

MOA of Mirtazapine (Remeron)

blocks presynaptic alpha-2 receptors to increase NE

What are the side effects of Mirtazapine?

sedation

cardiovascular side effects

Examples of SSRIs?

Fluoxetine (Prozac)

Sertraline (Zoloft)

Citalopram (Celexa)

Paroxetine (Paxil)

Escitalopram (Lexapro)

Drugs that end in -oxetine, are what?

SSRIs

Drugs that end in -opram are what?

SSRIs

MOA of SSRIs

block reuptake of serotonin to increased serotonin in the cleft

What is the most commonly used antidepressant??

SSRIs

What are the early onset side effects of SSRIs?

nausea

anxiety, agitation

insomnia

What are the late onset side effects of SSRIs?

weight Gain

weakeness

sexual dysfunction

withdrawal syndrome

What are the potential drug interactions with SSRIs?

serotonin syndrome with other drugs that increase serotonin

drugs that are also metabolized by CYPs

What are examples of SNRIs?

Venlafaxine (Effexor)

Duloxetine (Cymbalta)

Desvenlafaxine (Pristiq)

What kind of drug are Venlafaxine (Effexor), Duloxetine (Cymbalta), and Desvenlafaxine (Pristiq)?

SNRIs

What kind of drugs are Prozac, Zoloft, Celexa, Paxil, and Lexapro?

SSRIs

What is the MOA of SNRIs?

block reuptake of serotonin and norepinephrine --> increasing serotonin and NE in the cleft

What other uses besides depression are SNRIs used for?

anxiety disorders

chronic nerve pain

What are the side effects of SNRIs?

blurred vision

dry mouth

insomnia

What a specific side effect of duloxetine (Cymbalta)?

seizures

What kinds of drugs can be used to treat depression?

TCAs

tetracyclines

SSRIs

SNRIs

NDRIs

5HT2 modulators

MOAIs

What kind of drugs is Bupropion (Wellbutrin)?

NDRI

What is an example of an NDRI?

Bupropion (Wellbutrin)

What is the MOA of NDRIs (Wellbutrin)?

blocks reuptake of NE and dopamine --> increased NE and dopamine in the cleft

What monoamine does NDRIs have a higher effect on?

dopamine > NE

What are the side effects of NDRIs?

dry mouth

insomnia

nausea

seizures

What is the benefit to NDRIs?

they dont cause weight gain or sexual dysfunction

What is an example of at 5HT2 modulators

Trazodone (Desyrel)

What kind is the MOA of Trazodone (Desyrel)?

5HT2a receptor antagonist and a 5HT1A receptor agonist --> decreasing serotonin stimulation

and

serotonin and NE reuptake blocker --> increasing serotonin and NE in the cleft

Overall: balances serotonin stimulation

Whats the advantage of using Trazodone?

it balances serotonin stimulation resulting in less side effects

What are the side effects of Trazosone (Desyrel)?

dry mouth

fatigue, sedation

N/V

What are examples of nonselective MAOIs?

Phenelzine (Nardil)

What is the MOA of nonselective MAOIs (Phenelzine/Nardil)?

irreversibly bind and inhibit MAOAs and MOABs, causing and increase in NT

What is the downside to nonselective MAOIs?

lots of side effects

What is an example of a selective MAOI?

Selegline (Emsam)

What kind of drug is Selegline (Emsam)?

selective MAO-B inhibitor

MOA of selegiline (Emsam)?

MOA-B inhibitor --> increases dopamine

What is selegiline (emsam) used for?

Parkinson's disease

What are the side effects of MAOIs?

Drowsiness/fatigue

decreased BP

decreased sexual function

weight gain

blurred vision

What are the drug interactions wit MAOIs?

Can cause serotonin syndrome if taken with another drug that increases serotonin

can cause over effect if taken with high dose of St. Johns Wort

What does St. John's Wort do at high doses?

blocks MAOs