Antidepressants and Major Depressive Disorder

What is respirine?

Respiring is a drug isolated from the snakeroot plant which has been used as an herbal remedy for thousands of years.

While Respirine worked to treat high blood pressure, what side effect did it cause?

Respirine caused severe depression

Resperine works by preventing the loading of monoamine transmitters into synaptic vesicles, which leads to a depletion of what?

A depletion of monoamines such as 5-HT and NE

What is the monamine hypothesis of Depression?

The monoamine hypothesis of depression suggests that a reduced level of monoamines such as dopamine, norepinephrine, and serotonin in the central nervous system can be responsible for depression.

True or false: the Monoamine Hypothesis of Depression engendered much research and drug development, but is too simplistic.

True.

What were the three cons to the monoamine theory of depression?

1) Antidepressants take weeks to become effective, even though the increase in 5-HT and NE occurs within days.

2) lowering levels of monoamines does not always produce depression

3) raising levels of monoamines does not always alleviate depression

When looking at the changes in the brain due to major depression, there are decreased volumes in which parts of the brain and what causes it?

The hippocampus, Amygdala, and Cortex have reduced volume. This is caused by the decrease in size in the Gila and neurons.

When looking at the changes in the brain due to major depression, there is changes of blood flow and metabolism in which two parts of the brain?

The frontal cortex and Amygdala

What happens to HPA axis (maintains homeostasis in mood, etc) function in those with major depression?

The HPA function is impaired and there is stress.

True or False: In the brains of those who have major depression, there is an adverse impact on neurotrophic support (mechanisms on which the NS maintains neuronal growth), neurogenesis, and cell survival.

TrueW

Neuronal connectivity changes in depression and following treatment. This is shown through an abundance of dendritic ______ and proteins acting _____.

spines; normally

PET scans of depressed patients show overall ____ in brain activity.

decreases

True or false: Serotonin dysfunction contributes to mood disorders.

True

(Proof that 5-HT dysfunction contributes to mood disorders):

A polymorphism in the ________ ________ ______ gene may contribute to the development of depression.

Serotonin reuptake transporter (SERT)

If inheritance plays a role in risk of developing an affective disorder, the concordance rate will be the highest in…

A) fraternal twins

B) identical twins

c) non-twin family members

B

Evidence of how genetics and environment interact to potentially produce a greater risk of depression is shown through a stress interaction which is what?

A stress interaction is based on alleles and environment. If you have two short alleles and stress, your risk for depression is increased vs. having two long alleles and stress. Without an environmental stressor, the risk of depression does not change.

Which statement about risk factors for mood disorders is true?

A) psychiatric disorders develop due to genetic factors alone

B) in the case of affective disorders, environmental triggers alone are enough to cause serious mood changes

C) The genetic factors involved in mood disorders indicate that an individual may be more susceptible to a disorder, not that they will definitely develop it.

D) Environmental Stress does not appear to play a role in mood disorders.

C

(Proof that 5-HT dysfunction contributes to mood disorders):

In depressed individuals, ____ levels of metabolite 5-HIAA are found in the CSF and postmortem brains.

low

(Proof that 5-HT dysfunction contributes to mood disorders):

True or False: 5-HT funcitioning is indicated by the levels of the metabolite 5-HIAA in the brain.

True

(Proof that 5-HT dysfunction contributes to mood disorders):

What is tryptophan hydroxylase?

Why do Tryptophan hyroxylase and 5-HT receptor knockout mice have depression like symptoms?

It is the enzyme that controls the rate of serotonin production.

Both types of knockout mice will have either reduced serotonin levels or serotonin, but no where for it to bind to leading to depression.

(Proof that 5-HT dysfunction contributes to mood disorders):

What is the study called where someone engages in a tryptophan deficient diet after fasting? What are the results of the study?

The Tryptophan Depletion Challenge. A tryptophan deficient diet causes depression in individuals with family history of it or relapse in patients on antidepressants.

(Proof that 5-HT dysfunction contributes to mood disorders):

In receptor binding studies, brains of depressed individuals show increased density of 5-HT receptors (an up regulation). Why is this?

The brain makes an incorrect compensatory response to try and fix the low 5-HT levels, however, there is not enough 5-HT to bind to the abundance of receptors.

(Proof that 5-HT dysfunction contributes to mood disorders):

Most antidepressants increase 5-HT by doing what?

BLOCKING serotonin reuptake by either blocking the SERT or by inhibiting MAO.

When looking at the acute effects of antidepressants, how do auto receptors reduce 5-HT synthesis?

When an antidepressant is taken, there is an acute influx of 5-HT in the synapse. The presynaptic auto receptors sense this and INHIBIT NT release, in this case 5-HT.

Chronic treatment results in auto receptor ______. This explains the delay in therapeutic _____. The acute effects cancelled each other out, so when the chronic effect finally takes place, therapeutic effect will as well.

down regulation; onset

The efficacy of Fluoxetine or many antidepressants depends on the level of pretreatment ______ function and stress level of the environment.

5-HT

Is norepinephrine activity altered by antidepressants?

Yes.

What is the evidence to NE activity being altered by antidepressants?

Many treatments lead to a down regulation (lower number) of beta (type of NE) receptors. Other untreated depressed individuals and those with bipolar have INCREASED density of a2 (another type of NE) auto receptors.

What does it mean that NE and 5-HT modulate one another?

These two neurons (noradrengergic and serotonergic) overlap. where they project. A change in one will lead to a change in another.

What is the evidence for the serotonin-norepinephrine hypothesis of depression?

When looking at the chronic, consistent effects of antidepressants there is BOTH a down regulation of B receptors and 5-HT receptors, and enhanced response to 5-HT. This means that without medication too many receptors leads to a lack of 5-HT.

True or false: in 2/3 of cases, several classes of antidepressants can eliminate the symptoms of affective disorders.

False. They can reduce, not eliminate.

When is maximal effectiveness usually reached in therapies for affective disorders?

4-6 weeks

If total remission is rare, then why do we continue treatments?

To prevent relapse.

What do MAOs do?

They metabolize monoamine neurotransmitters that are presynaptically contained in vesicles.

What does inhibiting MAOs do (the function of MAOIs)?

It increases the amount of neurotransmitters available for release.

What else must play a role in MAOI effectiveness?

Neuronal adaption involving the changes in number (density) of receptors and with second messenger functions.

What are MAOI side effects?

Changes in BP, sleep disturbances, and overeating/weight gain

Why is it dangerous to do drugs like cocaine or take cold medicines while on MAOIs?

MAOIs enhance NE levels which intensifies drugs that enhance NE function (cocaine, cold meds).

Elevated levels of _______ (which is normally metabolized by MAO) releases higher than normal stores of NE at nerve endings, causing dangerous increases in BP.

Tyramine

What effect do MAOIs have on liver enzymes?

MAOIs inhibit other liver enzymes.

What are Tricyclic antidepressants (TCAs)?

They are antidepressants that bind to presynaptic transporter proteins, inhibiting reuptake of neurotransmitters (NE and 5-HT), prolonging the duration of NT action.

Do all TCAs have the same NE and 5-HT reuptake blocking potencies?

No, different TCAs have Different NE and 5-HT blocking potencies.

In terms of TCAs, what is the first step in antidepressant action?

Acute increase in synaptic activity.

TCAs have ______ and _______ activity.

anticholinergic; antihistaminergic

Overdose on TCAs leads to what effects?

Cardiovascular problems, delirium, convulsions, coma, death, and low therapeutic index

Side effects of TCA:

Histamine receptor blockade causes ____.

sedation

Anticholinergic effects from TCAs cause what?

dry mouth, constipation, dizziness.

A1 blockade coupled with NE reuptake-blocking leads to potentially _______ effects.

cardiovascular

What generation are SSRIs (selective serotonin reuptake inhibitors)?

Second generation antidepressants

True or false: Second gen antidepressants have different side effects.

True

What do SSRIs do?

They block presynaptic 5-HT reuptake transporters.

Side effects of SSRIs:

Increased 5-HT function at some serotonergic receptors causes …

anxiety, movement disorders, insomnia, headache, muscle rigidity, nausea, sexual dysfunction

What is serotonin syndrome?

When on SSRIs, potentially life threatening effects when combined with other serotonergic agonists or drugs.

Can SSRIs cause physical dependence?

Yes

What do Dual NE/ 5-HT modulators (SNRIs) do?

They enhance both NE and 5-HT function.

Example of an SNRI:

Mirtazapine blocks a2 autoreceptors, ____ synaptic NE and a2 receptors on serotonergic cells, _____ serotonin release.

increasing; increasing