Antidepressant Drugs

What are Antidepressants?

Drugs that are used to relieve or prevent psychic
depression.
Work by altering the way in which specific
chemicals, called neurotransmitters, work in our
brains (i.e. in the case of depression, some of the
neurotransmitter systems dont seem to be
working properly).
They increase the activity of these chemicals in
our brains

Available Antidepressants

1) Tricyclics and Tetracyclics (TCA)

Imipramine
Doxepin

Desipramine

Amoxepine

Trimipramine

Maprotiline
Clomipramine Amitriptyline Nortriptyline Protriptyline
2) Monoamine Oxidase Inhibitors (MAOIs)
Tranylcypramine Phenelzine
Moclobemide
3) Serotonin Selective Reuptake Inhibitors (SSRIs)
Fluoxetine
Fluvoxamine
Sertraline Paroxetine
Citalopram
4) Dual Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)
Venlafaxine
Duloxetine
5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs)
Nefazodone
Trazodone
6) Norepinephrine and Dopamine Reuptake Inhibitor (NDRI)
Bupropion
7) Noradrenergic and Specific Serotonergic Antidepressant (NaSSAs)
Mirtazapine
8) Noradrenalin Specific Reuptake Inhibitor (NRI)
Reboxetine
9) Serotonin Reuptake Enhancer
Tianeptine

Amine Hypothesis

1950: Reserpine Induce depression

Study: Reserpine depletes storage or amine neurotransmitters
such as serotonin and norepinephrine
Break-through: MAOI and TCA
Then: Depression Amine-dependent synaptic
transmission
(Antidepressants Amine by means of reuptake and
metabolism)
Conclusion: Major model for the subsequent antidepressants,
except Buproprion.

Biogenic Theory of Depression

The precise cause of affective disorders
remains elusive.
Evidence implicates alterations in the firing
patterns of a subset of biogenic amines in
the CNS, Norepinephrine (NE) and
Serotonin (5-HT).
Activity of NE and 5 -HT systems?.

Amine neurotransmitters are

either degraded (metab)
or reuptaken
MAO
Mito
COMT

The purpose of antidepressants is

the increase the
[neurotransmitters] in the synapse

Block of Amine Pump for:

1ST GENERATION ANTIDEPRESSANTS ; TRICYCLIC ANTIDEPRESSANTS

Sedation

Anti-muscarinic

Serotonin

Norepinephrine

Dopamine

+++

+++

+++

++

Amoxapine

++

++

++

Bupropion

+, 0

+, 0

Citalopram

+++

+++

++

+++

+++

+++

Doxepin (Sinequan)

+++

+++

++

Fluoxetine (Prozac)

+++

0, +

0, +

Fluvoxamine (Luvox)

+++

Imipramine (Tofranil)

++

++

+++

++

Maprotiline

++

++

+++

Mirtazapine2

+++

Nefazodone

++

+++

+, 0

Nortriptyline

++

++

+++

++

Paroxetine (Seroxat)

+++

Protriptyline

++

+++

Sertraline (Zoloft)

+++

Trazodone (Mesyrel)

+++

++

Venlafaxine (Efexor)

+++

++

0, +

Drug

Amitriptyline

Clomipramine
Desipramine

2nd GENERATION ANTIDEPRESSANTS ; TETRACYCLIC / HETEROCYCLIC ANTIDEPRESSANTS

Block of Amine Pump for:
Sedation

Anti-muscarinic

Serotonin

Norepinephrine

Dopamine

+++

+++

+++

++

Amoxapine

++

++

++

Bupropion

+, 0

+, 0

Citalopram

+++

+++

++

+++

+++

+++

+++

+++

++

Fluoxetine

+++

0, +

0, +

Fluvoxamine

+++

Imipramine (Tofranil)

++

++

+++

++

Maprotiline

++

++

+++

Mirtazapine2

+++

Nefazodone

++

+++

+, 0

Nortriptyline

++

++

+++

++

Paroxetine

+++

Protriptyline

++

+++

Sertraline

+++

+++

++

+++

++

0, +

Drug

Amitriptyline

Clomipramine
Desipramine
Doxepin (Sinequan)

Trazodone (Mesyrel)
Venlafaxine

Block of Amine Pump for:

3rd GENERATION ANTIDEPRESSANTS ; HETEROCYCLIC ; SNRI ;

Sedation

Anti-muscarinic

Serotonin

Norepinephrine

Dopamine

+++

+++

+++

++

Amoxapine

++

++

++

Bupropion

+, 0

+, 0

Citalopram

+++

+++

++

+++

+++

+++

+++

+++

++

Fluoxetine

+++

0, +

0, +

Fluvoxamine

+++

Imipramine (Tofranil)

++

++

+++

++

Maprotiline

++

++

+++

Mirtazapine2

+++

Nefazodone

++

+++

+, 0

Nortriptyline

++

++

+++

++

Paroxetine

+++

Protriptyline

++

+++

Sertraline

+++

Trazodone (Mesyrel)

+++

++

Venlafaxine (Efexor)

+++

++

0, +

Drug

Amitriptyline

Clomipramine
Desipramine
Doxepin (Sinequan)

Block of Amine Pump for:

Selective Serotonin Reuptake Inhibitor

Sedation

Anti-muscarinic

Serotonin

Norepinephrine

Dopamine

+++

+++

+++

++

Amoxapine

++

++

++

Bupropion

+, 0

+, 0

Citalopram

+++

+++

++

+++

+++

+++

Doxepin (Sinequan)

+++

+++

++

Fluoxetine (Prozac)

+++

0, +

0, +

Fluvoxamine (Luvox)

+++

Imipramine (Tofranil)

++

++

+++

++

Maprotiline

++

++

+++

Mirtazapine2

+++

Nefazodone

++

+++

+, 0

Nortriptyline

++

++

+++

++

Paroxetine (Seroxat)

+++

Protriptyline

++

+++

Sertraline (Zoloft)

+++

Trazodone (Mesyrel)

+++

++

Venlafaxine (Efexor)

+++

++

0, +

Drug

Amitriptyline

Clomipramine
Desipramine

OUT

Cl-

Na+

Cl-

Na+

GABAA receptor

Inhibition
IN

Glutamate/AMPA
receptor

Excitation

Cerebral cortex

Sensory input

Information integration
cognition, thought,
mood, emotion

acetylcholine norepinephrine

serotonin

dopamine

Motor output

histamine

Arousal:
1. Processing signals relate to plain & pleasure. Regulating
body homeostasis
2. Emotion and feeling
3. Attention
4. Wakefulness & sleep
5. learning
The construction of consciousness.

Fast: GABA, glutamate, acetylcholine

Slow: biogenic amines
Dopamine
Serotonin/5-HT
NE
Acetylcholine
Peptides

Ionotropic and metabotropic receptors

Fast

Slow

Ion flow in/out

Second messenger cascades

milliseconds

seconds

1/1000 of a second !

Out

NH2

7 transmembrane
domain receptor

In

2nd messengers
COOH

Ionotropic

Metabotropic

The monoamines
Dopamine
Epinephrine (adrenergic)
Norepinephrine (noradrenergic)
Serotonin

Neurotransmitter
receptors
Neurotransmitter
receptors

Ion pumps
Second messengers

Protein kinases

Ion channels

Transcription Factors
Cell nucleus

7-transmembrane-domain receptors

Excitatory input

Glutamate

Neuromodulatory
inputs
NE

GluR
b1

DA

Neuromodulatory
inputs
ACh

D1

cAMP

M1
Ca2+
Ca2+-dependent
Kinases/phosphatases

PKC

Hist

PKA

H2

5-HT

IP3 + DG

5-HT2C

Down-stream substrates

Gene expression

Short-term synaptic modification

Hist

H1
Long-term synaptic modification

Particular modulator transmitters should not be

regarded as purely excitatory or inhibitory.
Their exact action depends on context.

On the same cell, they can be either excitatory or

inhibitory depending on the state of the cell.

Catecholamines
Norephinephrine

NE System
Almost all NE pathways in the brain originate from the cell
bodies of neuronal cells in the locus coereleus in the
midbrain, which send their axons diffusely to the cortex,
cerebellum and limbic areas (hippocampus, amygdala,
hypothalamus, thalamus).
Mood: -- higher functions performed by the
cortex.
Cognitive function: -- function of cortex.
Drive and motivation: -- function of brainstem
Memory and emotion: -- function of the
hippocampus and amygdala.
Endocrine response: -- function of hypothalamus.

and b receptors.

A synapse that uses norepinephrine (NE)

MAO Inhibitors Monoamine oxidase, located on outer membrane

of mitochondria; deaminates catecholamines free in
nerve terminal that are not protected by vesicles

Antidepressant
Selective inhibitor,
reboxetine

Cocaine blocks the NET Stimulant

Reuptake of NE

NE potentiation of responses to GABA

Purkinje cells

Out

GABA

ClGABA

Cl-

PO4
Cl-

In

Cl- Cl- Cl- Cl- Cl-

GABA + cAMP
GABA + NE

GABA
response

GABA
time
Noradrenergic potentiation of cerebellar Purkinje cell responses
to GABA: cAMP as intracellular intermediary.

NE

b-adrenergic
receptor

GABAA receptor

b1
Gs

PO4

AC
cAMP

PKA reg

ATP

PKA cat

Out

GABA

ClGABA

Cl-

PO4
Cl-

In

Cl- Cl- Cl- Cl- Cl-

POSTSYNAPTIC MODULATION

Why does a small amount of stress help you learn better?

But, too much chronic, severe stress DEPRESSION

b-adrenergics and memory

Presynaptic

Postsynaptic

Before LTP

After LTP

More glutamate receptors

= bigger response

After LTP

More glutamate receptors

= bigger response
After several hours.
Presynaptic

Postsynaptic
LTP decays

Unless b-adrenergic activation of postsynaptic cell takes place

NE

Active during memory

formation

Glu

Stabilization of LTP
PKA
Inhibition of
protein phosphatase I

cAMP

b-adrenergic receptor activation helps memories

-better memories when you are paying attention
because of higher emotional stimulation

INDOLEAMINE
SEROTONIN (5-HT)

Serotonin System
As with the NE system, serotonin neurons located
in the pons and midbrain (in groups known as
raphe nuclei) send their projections diffusely to the
cortex, hippocampus, amygdala, hypothalamus,
thalamus, etc. --same areas implicated in
depression. This system is also involve in:

Anxiety.
Sleep.
Sexual behavior.
Rhythms (Suprachiasmatic nucleus).
Temperature regulation.
CSF production.

PRESYNAPTIC
MODULATION

Noradrenergic Control of Serotonergic Release

Receptors
2-AR

NE

5-HT

1-AR
5-HT1
5-HT2
5-HT3

NE

Mianserin

Humans
Serotonin - a chemical manifestation of personality
High level of serotonin: compulsives
obsessive-compulsive disorders
e.g. compulsive hand-washing

Low levels of serotonin: depression, suicide.

Listening to Prozac, P.D. Kramer, 1993

The purpose of antidepressants is to increase the levels of

circulating neurotransmitters in the synapse.

The 5-HT neurons in the brain

A synapse that uses serotonin/5-HT

Fluoxetine/Prozac blocks the SERT

Treatment of depression.
anxiety disorders,
Re-uptake of 5-HT/serotonin
obsessive-compulsive disorders

Genetic variation in the gene promoter region of the

serotonin transporter.
risk factor for anxiety, alcoholism, mood disorders
slight differences in level of expression

Catecholamines
Dopamine

Dopamine pathways in the brain

Dopamine pathways do many things:

Control flow of blood through the brain
Motor control (nigrostriatal) system

Behavioural control
Dopamine is the brains motivational chemical. It works on
glutamate synapses to modulate their excitability.
A shortage of brain dopamine causes an indecisive
personality, unable to initiate even the bodys own
movement. Parkinsons disease. Time stops.
L-DOPA therapy. Awakenings film. (Oliver Sachs)
Excess dopamine, more arousal. Attention defecit
disorder. May cause schizophrenia.
Dopamines action is essential for drug addiction.

DARP-32
Dopamine and cAMP-regulated phosphoprotein
Molecular weight, 32 kDa
DARP-32 is a molecular integrator

Other neuromodulators (NE, serotonin) probably

work in a similar way to dopamine
They assist with the selection/maintenance of different
neural ensembles.

Molecular actions of dopamine

Genetics
Polymorphisms of genes involved in aminergic
(dopamine/serotonin) neurotransmission
Effects on personality?
Dopamine D4 receptor - novelty seeking
Promoter of serotonin transporter gene - harm avoidance/anxiety

D4 dopamine receptor

16 amino acid repeat sequence present in two

to 11 copies - minisatellite phrase

D4 dopamine receptor

The larger the number of repeats, the more

ineffective is the dopamine D4 receptor
in signalling

Genetics
The larger the number of loop 3 repeats, the more ineffective
the dopamine D4 receptor in signalling
Long D4DR genes imply low responsiveness to dopamine
short D4DR gene imply high responsiveness

The idea
People with long D4DR genes have low responsiveness to
dopamine, so they need to take a more adventurous approach to
life to get the same dopamine buzz that short-gened people get
from simple things.
Obviously, this is just one possible factor of many.
Dont oversimplify!

Why do antidepressants take so

long to work?
The current prevailing hypothesis

Neurotrophin Hypothesis

Chronic, severe

Mechanism for the Delay in

Onset of the therapeutic
Effect of Antidepressant
Medications.