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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.
Amine neurotransmitters are either degraded (metab) or reuptaken MAO Mito COMT
Serotonin
+++ ++ 0 0 +++ +
+++ ++ 0 0 ++ +
++ ++ +, 0 0 +++ +++
0 + ? 0 0 0
Doxepin (Sinequan)
Fluoxetine (Prozac) Fluvoxamine (Luvox) Imipramine (Tofranil) Maprotiline Mirtazapine2 Nefazodone
+++
+ 0 ++ ++ +++ ++
+++
+ 0 ++ ++ 0 +++
++
+++ +++ +++ 0 0 +, 0
+
0, + 0 ++ +++ 0 0
0
0, + 0 0 0 0 0
Nortriptyline
Paroxetine (Seroxat) Protriptyline Sertraline (Zoloft) Trazodone (Mesyrel) Venlafaxine (Efexor)
++
+ 0 + +++ 0
++
0 ++ 0 0 0
+++
+++ ? +++ ++ +++
++
0 +++ 0 0 ++
0
0 ? 0 0 0, +
2nd GENERATION ANTIDEPRESSANTS ; TETRACYCLIC / HETEROCYCLIC ANTIDEPRESSANTS Block of Amine Pump for: Sedation Drug Anti-muscarinic Serotonin Norepinephrine Dopamine
Amitriptyline Amoxapine Bupropion Citalopram Clomipramine Desipramine Doxepin (Sinequan) Fluoxetine Fluvoxamine Imipramine (Tofranil) Maprotiline Mirtazapine2 Nefazodone
0 + ? 0 0 0 0 0, + 0 0 0 0 0
Nortriptyline
Paroxetine Protriptyline Sertraline Trazodone (Mesyrel) Venlafaxine
++
+ 0 + +++ 0
++
0 ++ 0 0 0
+++
+++ ? +++ ++ +++
++
0 +++ 0 0 ++
0
0 ? 0 0 0, +
Amitriptyline Amoxapine Bupropion Citalopram Clomipramine Desipramine Doxepin (Sinequan) Fluoxetine Fluvoxamine Imipramine (Tofranil) Maprotiline Mirtazapine2 Nefazodone
0 + ? 0 0 0 0 0, + 0 0 0 0 0
Nortriptyline
Paroxetine Protriptyline Sertraline Trazodone (Mesyrel) Venlafaxine (Efexor)
++
+ 0 + +++ 0
++
0 ++ 0 0 0
+++
+++ ? +++ ++ +++
++
0 +++ 0 0 ++
0
0 ? 0 0 0, +
Amitriptyline Amoxapine Bupropion Citalopram Clomipramine Desipramine Doxepin (Sinequan) Fluoxetine (Prozac) Fluvoxamine (Luvox) Imipramine (Tofranil) Maprotiline Mirtazapine2 Nefazodone
0 + ? 0 0 0 0 0, + 0 0 0 0 0
Nortriptyline
Paroxetine (Seroxat) Protriptyline Sertraline (Zoloft) Trazodone (Mesyrel) Venlafaxine (Efexor)
++
+ 0 + +++ 0
++
0 ++ 0 0 0
+++
+++ ? +++ ++ +++
++
0 +++ 0 0 ++
0
0 ? 0 0 0, +
OUT
Cl-
Na+
ClGABAA receptor
Na+
Glutamate/AMPA receptor
Inhibition
IN
Excitation
Cerebral cortex
Sensory input
Motor output
acetylcholine norepinephrine
serotonin
dopamine
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
Out
NH2
In
2nd messengers
COOH
Ionotropic
Metabotropic
Ion pumps
Protein kinases
Ion channels
7-transmembrane-domain receptors
GluR
cAMP
Hist PKA
Ca2+-dependent Kinases/phosphatases
PKC
Down-stream substrates
5-HT2C
Hist
H2
Gene expression
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.
MAO Inhibitors Monoamine oxidase, located on outer membrane of mitochondria; deaminates catecholamines free in nerve terminal that are not protected by vesicles
Reuptake of NE
Out ClGABA
GABA
Cl-
PO4 Cl-
In
GABA + cAMP
GABA + NE
GABA response
GABA
time Noradrenergic potentiation of cerebellar Purkinje cell responses to GABA: cAMP as intracellular intermediary.
NE b1 Gs
b-adrenergic receptor
GABAA receptor
AC
cAMP
PO4
PKA reg
ATP
PKA cat
Out ClGABA
GABA
Cl-
PO4 Cl-
In
POSTSYNAPTIC MODULATION
Presynaptic
Postsynaptic
Before LTP
After LTP
After LTP
More glutamate receptors = bigger response After several hours. Presynaptic Postsynaptic
LTP decays
NE
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
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
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
The purpose of antidepressants is to increase the levels of circulating neurotransmitters in the synapse.
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 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.
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
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!
Neurotrophin Hypothesis
Chronic, severe
Mechanism for the Delay in Onset of the therapeutic Effect of Antidepressant Medications.