Antidepressants

Question 0

What is general information in FIRST generation antidepressants?

Answer 0

• Progress in DECREASE adverse effects
• It has improved by being more selected and tolerated.

*Major unknown, the biochemical mechanism by which antidepressants cause their efficacy in treating unipolar depression disorder is still UNKNOWN.

Question 1

What is some general information or statistics on Antidepressants?

Answer 1

• 40-50% have improvement such as showing few remaining symptoms
• Additional 20-30% have clinical improvement
• Drawback: 25-35% show minimal improvement and it takes weeks to months for effects to occur. Also there is side effects and toxcity associated

Question 2

What is PROPHYLACTIC TREATMENT OF DEPRESSION used for?

Answer 2

Unipolar depression does not reoccur in 50% of patients (just single episode). Prophylactic Treatment is used to prevent recurrence of disease.

Question 3

What are characteristics of UNIPOLAR DEPRESSION?

Answer 3

Dysphoric mood, hopelessness, sadness, morbidness,

- Mood disturbance must be PROMINENT AND PERSISTANT, AND 4 symptoms must occur nearly everyday for 2 weeks.

Question 4

What is the NEUROCHEMICAL basis of depression?

Answer 4

Serotonin and/or norepinephrine is deficient. This is shown when certain drugs that deplete serotonin and/or norepinephrine, it causes depression.
Also drugs that help with serotonin and/or norepinephrine, helps in 2/3 of depressed patients.
-They are involved in majority of depression BUT NOT all.

Question 5

How does serotonergic transmission occur?

Answer 5

Antidepressant work at presynaptic serontonin autoreceptors. These are located on the 1. cell body(somatic dendrite) and 2. axon terminal (terminal autoreceptor).

2 Aspects of their action in AXON TERMINAL Receptor: 1. ACTIVATION of these receptor, DECREASES serontonin release.
2.If you BLOCK or DOWNREGULATE the receptors, you INCREASE release.

In the CELL BODY aka Dendritic autoreceptos: 1. ACTIVATION, DECREASES neuron fireing
2.BLOCK or DOWNREGULATION, INCREASES fireing of neuron.

Question 6

How is serontonin synthesize and released?

Answer 6

It is made form L-TRYPTOPHAN. Serotonin can 1. bind to post synaptic receptor 2. it can feedback to bind to presynaptic 3. reuptake via membrane transporter (specfic for serontonin). It can also be repackage in a vessicle or metabolize by MAO-Type A.

Question 7

How does nonadrenergic transmission occur?

Answer 7

Alpha 1 and Beta 1 on postsynaptic.1. Activate Alpha 2 autorecepto (presynaptic) and inhibit norepinphrine release. It can be 1) taken up by post synaptic side to be metabolize by COMT 2) taken up by active transporters protein (norepinphrine specific) or metabolize by MAO-type A .

Question 8

What enzymes metabolize serotonin and norephnephrine?

Answer 8

Norepinephrine is metabolize by COMT and MAO-Type A enzyme. Whereas Serotonin is metabolize by just MAO-TYPE A.

Question 9

What groups are competitive inhibitors of serotonin and norepinephrine?

Answer 9

Tricyclics and Atypical drugs

Question 10

Do antidepressants work immediately?

Answer 10

Nope, it takes days or weeks to see effects.
Acutely: there is a efficacy delay.

ACCUTELY:STEPS:

1. Block reuptake of NE and 5HT.
2. Initially, this will increase NE and 5HT activity (short lived) because it then ACTIVATE autoreceptors at the terminal, which decreases NE and 5HT release. It also ACTIVATE autoreceptors in cell body, which DECREASE fireing.
3. Initial decrease is offset by subsequent decrease=NET effect

Question 11

How does Chronic Antidepressants work?

Answer 11

These DOWNREGULATE presynaptic autoreceptors, which causes INCREASE NE neuron fireing, INCREASE Serotonin fireing, increase activity in both in cell body.

Question 12

How does Tricyclics work?

Answer 12

INCREASE in nonadrenergic neurotransmission, DECREASE the number of ALPHA 2 receptors on terminal and cell body which lead to INCREASE in NE neuron fireing and release.

Question 13

How does Selective Serotonin Reuptake (SSRIs) work?

Answer 13

Increase serotonergic transmission, decreases serotonin autoreceptor on axon terminal causing an increase in serotonin release, and decrease in serontonin receptors on cell body causing increase in fireing rate and increase serotonin release.

Question 14

What is the new explanation for efficacy delay?

Answer 14

The hippocampus is involved in mood regulation. Antidepressants cause proliferation of neurons in hippocampus (hippocampal neurogenesis) This takes weeks to occur, which coincides with efficacy delay in antidepressant action. By blocking antidepressants, induced hippocampus neurogenesis blocks the adverse effects

Question 15

What drugs are ATYPICAL drugs?

Answer 15

These are weak inhibitors of NE and 5HT reuptake.

1. BUPROPION: it counteracts the concurrent effects of alcohol. It will block sedative effect of alcohol.
2. MIRTAZAPINE: NE neuron which can innervate a 5HT neuron. The 5HT neuron also has a alpha 1 neuron which cause release of serotonin (see pic).

Question 16

What are Monoamine Oxidase Inhibitors?

Answer 16

They decrease metabolism of norepinephrine, serotonin, epinnephrine and dopamine.

Question 17

How was the first generation of MAO inhibitors?

Answer 17

It inhibited ALL forms on Monoamine Oxidase, which cause an increase in neurotransmission of NE and 5HT. These early MAO inhibitors where IRREVERSIBLE such as PHENELZINE.

The enzyme blocks to MAO active site, MAO breaks down phenelzine and products of the breakdown binds irreversibly to the enzyme. This is known as suicide inhibitor. This works on BOTH MAO Type A and Type B.

Question 18

How is second generation of MAO inhibitors?

Answer 18

These are reversible such as MOCLOBEMIDE. These sit at acitve site and stop enzyme from breaking down anything but does NOT bind permanently. It inhibits only ONE form of MAO, that is Type A.

It is not at toxic as the irreversible inhibitor.

MAO-type A inhibititors are effective antidepressants in that it increase serotonin more than NE in brain (because NE as two enzymes that break it down)

Question 19

What is some other general information about antidepressants?

Answer 19

acute effect: efficacy delay
chronic: antidepression

They are alll equal in treating depression however SSRI has more use and patient compliance. And SSRI have low side effects than tricyclics

Question 20

What are the clinical indications?

Answer 20

unipolar (major) depression
panic disorder: use IMIPRAMINE
OCD: use FLUVOXAMINE (SSRI) and CLOMIPRAMINE

Question 21

What is VELAFAXINE?

Answer 21

It is the first 5HT and NE reuptake inhibitors called SSNRI. It is very powerful and has selective blockade of NE and serotonin reuptake. Use in majore depression, general anxiety disorder and social anxiety.

Side effects: nausea (37%), still not as bad as tricyclics.

Question 22

Drugs and Mechanism of Action

Answer 22

Tricyclic Antidepressants (TCAs): Competitive reuptake inhibitors of norepinephrine and serotonin
eg. Imipramine *, Desipramine * 

Atypical Antidepressants: Weak reuptake inhibitors of NE and 5-HT.Increase noradrenergic or serotonergic transmission by other mechanisms
eg. Bupropion *, Mirtazapine *

Selective Serotonin Reuptake Inhibitors (SSRIs)
More potent inhibitor of serotonin reuptake than norepinephrine reuptake
eg.Fluoxetine *, Sertraline *

Monoamine Oxidase Inhibitors (MAOIs): Inhibitor of NE and 5-HT metabolizing enzyme MAO
Phenelzine * -IRREVERSIBLE

Reversible monoamine oxidase inhibitor (RIMA)
Moclobemide *