Transcript Antidepressant Drugs

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 don’t seem to be
working properly).
• They increase the activity of these chemicals in
our brains
Available Antidepressants
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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
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++
0
Amoxapine
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+
++
+
Bupropion
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0
+, 0
+, 0
?
Citalopram
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0
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++
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0
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0
Doxepin (Sinequan)
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Fluoxetine (Prozac)
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0, +
0, +
Fluvoxamine (Luvox)
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0
0
Imipramine (Tofranil)
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0
Maprotiline
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Mirtazapine2
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Nefazodone
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+, 0
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Nortriptyline
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Paroxetine (Seroxat)
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Protriptyline
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?
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?
Sertraline (Zoloft)
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0
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Trazodone (Mesyrel)
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Venlafaxine (Efexor)
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0, +
Drug
Amitriptyline
Clomipramine
Desipramine
2nd GENERATION ANTIDEPRESSANTS ; TETRACYCLIC / HETEROCYCLIC ANTIDEPRESSANTS
Block of Amine Pump for:
Sedation
Anti-muscarinic
Serotonin
Norepinephrine
Dopamine
+++
+++
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++
0
Amoxapine
++
++
+
++
+
Bupropion
0
0
+, 0
+, 0
?
Citalopram
0
0
+++
0
0
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++
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+++
0
+
+
0
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0
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0
Fluoxetine
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+
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0, +
0, +
Fluvoxamine
0
0
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0
0
Imipramine (Tofranil)
++
++
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++
0
Maprotiline
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0
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0
Mirtazapine2
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0
0
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Nefazodone
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+, 0
0
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Nortriptyline
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++
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++
0
Paroxetine
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0
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0
0
Protriptyline
0
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?
Sertraline
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0
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0
0
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0
++
0
0
0
0
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++
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
+++
+++
+++
++
0
Amoxapine
++
++
+
++
+
Bupropion
0
0
+, 0
+, 0
?
Citalopram
0
0
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0
0
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++
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0
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0
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0
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0
Fluoxetine
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0, +
0, +
Fluvoxamine
0
0
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0
0
Imipramine (Tofranil)
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++
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++
0
Maprotiline
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0
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0
Mirtazapine2
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0
0
0
0
Nefazodone
++
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+, 0
0
0
Nortriptyline
++
++
+++
++
0
Paroxetine
+
0
+++
0
0
Protriptyline
0
++
?
+++
?
Sertraline
+
0
+++
0
0
Trazodone (Mesyrel)
+++
0
++
0
0
Venlafaxine (Efexor)
0
0
+++
++
0, +
Drug
Amitriptyline
Clomipramine
Desipramine
Doxepin (Sinequan)
Block of Amine Pump for:
Selective Serotonin Reuptake Inhibitor
Sedation
Anti-muscarinic
Serotonin
Norepinephrine
Dopamine
+++
+++
+++
++
0
Amoxapine
++
++
+
++
+
Bupropion
0
0
+, 0
+, 0
?
Citalopram
0
0
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0
0
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++
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+++
0
+
+
0
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0
Doxepin (Sinequan)
+++
+++
++
+
0
Fluoxetine (Prozac)
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+
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0, +
0, +
Fluvoxamine (Luvox)
0
0
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0
0
Imipramine (Tofranil)
++
++
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++
0
Maprotiline
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++
0
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0
Mirtazapine2
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0
0
0
0
Nefazodone
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+, 0
0
0
Nortriptyline
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++
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++
0
Paroxetine (Seroxat)
+
0
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0
0
Protriptyline
0
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?
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?
Sertraline (Zoloft)
+
0
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0
0
Trazodone (Mesyrel)
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0
++
0
0
Venlafaxine (Efexor)
0
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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
G
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:
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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
1
2
3
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 brain’s 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 body’s own
movement. Parkinson’s disease. Time stops.
L-DOPA therapy. ‘Awakenings’ film. (Oliver Sachs)
Excess dopamine, more arousal. Attention defecit
disorder. May cause schizophrenia.
Dopamine’s 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.
Don’t 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.