antidepressant drugs
TRANSCRIPT
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Antidepressant Drugs
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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
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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
FluvoxamineSertralineParoxetine 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 EnhancerTianeptine
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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.
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• 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?.
Biogenic Theory of Depression
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MAO
COMT
Amine neurotransmitters areeither degraded (metab)
or reuptaken
Mito
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The purpose of antidepressants is the increase the
[neurotransmitters] in the synapse
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Block of Amine Pump for:
Drug
Sedation Anti-muscarinic Serotonin Norepinephrine Dopamine
Amitriptyline +++ +++ +++ ++ 0
Amoxapine ++ ++ + ++ +
Bupropion 0 0 +, 0 +, 0 ?
Citalopram 0 0 +++ 0 0
Clomipramine +++ ++ +++ +++ 0
Desipramine + + 0 +++ 0
Doxepin (Sinequan) +++ +++ ++ + 0
Fluoxetine (Prozac) + + +++ 0, + 0, +
Fluvoxamine (Luvox) 0 0 +++ 0 0
Imipramine (Tofranil) ++ ++ +++ ++ 0
Maprotiline ++ ++ 0 +++ 0
Mirtazapine2 +++ 0 0 0 0
Nefazodone ++ +++ +, 0 0 0
Nortriptyline ++ ++ +++ ++ 0
Paroxetine (Seroxat) + 0 +++ 0 0
Protriptyline 0 ++ ? +++ ?
Sertraline (Zoloft) + 0 +++ 0 0
Trazodone (Mesyrel) +++ 0 ++ 0 0
Venlafaxine (Efexor) 0 0 +++ ++ 0, +
1ST GENERATION ANTIDEPRESSANTS ; TRICYCLIC ANTIDEPRESSANTS
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Block of Amine Pump for:
Drug
Sedation Anti-muscarinic Serotonin Norepinephrine Dopamine
Amitriptyline +++ +++ +++ ++ 0
Amoxapine ++ ++ + ++ +
Bupropion 0 0 +, 0 +, 0 ?
Citalopram 0 0 +++ 0 0
Clomipramine +++ ++ +++ +++ 0
Desipramine + + 0 +++ 0
Doxepin (Sinequan) +++ +++ ++ + 0
Fluoxetine + + +++ 0, + 0, +
Fluvoxamine 0 0 +++ 0 0
Imipramine (Tofranil) ++ ++ +++ ++ 0
Maprotiline ++ ++ 0 +++ 0
Mirtazapine2 +++ 0 0 0 0
Nefazodone ++ +++ +, 0 0 0
Nortriptyline ++ ++ +++ ++ 0
Paroxetine + 0 +++ 0 0
Protriptyline 0 ++ ? +++ ?
Sertraline + 0 +++ 0 0
Trazodone (Mesyrel) +++ 0 ++ 0 0
Venlafaxine 0 0 +++ ++ 0, +
2nd GENERATION ANTIDEPRESSANTS ; TETRACYCLIC / HETEROCYCLIC ANTIDEPRESSANTS
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Block of Amine Pump for:
Drug
Sedation Anti-muscarinic Serotonin Norepinephrine Dopamine
Amitriptyline +++ +++ +++ ++ 0
Amoxapine ++ ++ + ++ +
Bupropion 0 0 +, 0 +, 0 ?
Citalopram 0 0 +++ 0 0
Clomipramine +++ ++ +++ +++ 0
Desipramine + + 0 +++ 0
Doxepin (Sinequan) +++ +++ ++ + 0
Fluoxetine + + +++ 0, + 0, +
Fluvoxamine 0 0 +++ 0 0
Imipramine (Tofranil) ++ ++ +++ ++ 0
Maprotiline ++ ++ 0 +++ 0
Mirtazapine2 +++ 0 0 0 0
Nefazodone ++ +++ +, 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, +
3rd GENERATION ANTIDEPRESSANTS ; HETEROCYCLIC ; SNRI ;
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Block of Amine Pump for:
Drug
Sedation Anti-muscarinic Serotonin Norepinephrine Dopamine
Amitriptyline +++ +++ +++ ++ 0
Amoxapine ++ ++ + ++ +
Bupropion 0 0 +, 0 +, 0 ?
Citalopram 0 0 +++ 0 0
Clomipramine +++ ++ +++ +++ 0
Desipramine + + 0 +++ 0
Doxepin (Sinequan) +++ +++ ++ + 0
Fluoxetine (Prozac) + + +++ 0, + 0, +
Fluvoxamine (Luvox) 0 0 +++ 0 0
Imipramine (Tofranil) ++ ++ +++ ++ 0
Maprotiline ++ ++ 0 +++ 0
Mirtazapine2 +++ 0 0 0 0
Nefazodone ++ +++ +, 0 0 0
Nortriptyline ++ ++ +++ ++ 0
Paroxetine (Seroxat) + 0 +++ 0 0
Protriptyline 0 ++ ? +++ ?
Sertraline (Zoloft) + 0 +++ 0 0
Trazodone (Mesyrel) +++ 0 ++ 0 0
Venlafaxine (Efexor) 0 0 +++ ++ 0, +
Selective Serotonin Reuptake Inhibitor
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OUT
IN
Cl-
Cl-
Na+
Na+
GABAA receptor Glutamate/AMPAreceptor
GA
BA
Gl
u
Inhibition Excitation
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Information integrationcognition, thought,
mood, emotion
Cerebral cortex
Sensory input Motor output
acetylcholine norepinephrineserotonin dopamine histamine
Information integrationcognition, thought,
mood, emotion
Cerebral cortex
Sensory input Motor output
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Arousal:
1. Processing signals relate to plain & pleasure. Regulatingbody homeostasis
2. Emotion and feeling3. Attention4. Wakefulness & sleep5. learning
The construction of consciousness.
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Fast: GABA, glutamate, acetylcholine
Slow: biogenic aminesDopamineSerotonin/5-HTNEAcetylcholinePeptides
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Ionotropic and metabotropic receptors
Fast
Ion flow in/out
milliseconds
Slow
Second messenger cascades
seconds
1/1000 of a second !
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Out
In
G
7 transmembrane domain receptor
2nd messengers
NH2
COOH
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Ionotropic
Metabotropic
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The monoamines
Dopamine
Epinephrine (adrenergic)
Norepinephrine (noradrenergic)
Serotonin
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Second messengers
Protein kinases
Transcription FactorsCell nucleus
Ion pumps
Ion channels
Neurotransmitterreceptors
Neurotransmitterreceptors
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7-transmembrane-domain receptors
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Glutamate
Ca2+
Ca2+-dependentKinases/phosphatases
Down-stream substrates
Gene expression
Short-term synaptic modification Long-term synaptic modification
cAMP
PKAHist
DA
NE ACh
5-HT
HistPKC
IP3 + DG
GluR
1
D1
H2
M1
5-HT2C
H1
Excitatory input
Neuromodulatory inputs
Neuromodulatory inputs
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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.
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Catecholamines
Norephinephrine
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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 receptors.
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A synapse that uses norepinephrine (NE)
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Reuptake of NE
Monoamine oxidase, located on outer membraneof mitochondria; deaminates catecholamines free innerve terminal that are not protected by vesicles
Selective inhibitor,reboxetine Cocaine blocks the NET
Antidepressant
MAO Inhibitors
Stimulant
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NE potentiation of responses to GABA
Purkinje cells
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PO4
Cl-
Cl-
GABACl-
Cl- Cl- Cl- Cl- Cl-
GABA
Out
In
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time
GABAresponse
GABA
GABA + NE
GABA + cAMP
Noradrenergic potentiation of cerebellar Purkinje cell responsesto GABA: cAMP as intracellular intermediary.
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1
NE
Gs AC
ATP
cAMP
PKA reg
PKA cat
PO4
GABAA receptor-adrenergicreceptor
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PO4
Cl-
Cl-
GABACl-
Cl- Cl- Cl- Cl- Cl-
GABA
Out
In POSTSYNAPTIC MODULATION
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Why does a small amount of stress help you learn better?Why does a small amount of stress help you learn better?
But, too much chronic, severe stress DEPRESSION
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-adrenergics and memory
Presynaptic Postsynaptic
Before LTP
After LTP
More glutamate receptors= bigger response
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After LTP
More glutamate receptors= bigger response
After several hours…….
Presynaptic Postsynaptic
LTP decays
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Unless -adrenergic activation of postsynaptic cell takes place…
NE
Glu
cAMPPKA
Inhibition ofprotein phosphatase I
Active during memoryformation
Stabilization of LTP
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-adrenergic receptor activation helps memories
-better memories when you are paying attention because of higher emotional stimulation
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INDOLEAMINESEROTONIN (5-HT)
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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.
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PRESYNAPTICMODULATION
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Noradrenergic Control of Serotonergic Release
NE5-HT
NE
2-AR
1-AR
1 2 3
Mianserin
5-HT1
5-HT2
5-HT3
Receptors
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Serotonin - a chemical manifestation of personality
High level of serotonin: compulsivesobsessive-compulsive disorderse.g. compulsive hand-washing
Low levels of serotonin: depression, suicide.
Listening to Prozac, P.D. Kramer, 1993
Humans
The purpose of antidepressants is to increase the levels ofcirculating neurotransmitters in the synapse.
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The 5-HT neurons in the brain
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A synapse that uses serotonin/5-HT
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Re-uptake of 5-HT/serotonin
Fluoxetine/Prozac blocks the SERT
Treatment of depression.anxiety disorders, obsessive-compulsive disorders
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Genetic variation in the gene promoter region of the serotonin transporter.
risk factor for anxiety, alcoholism, mood disorders
slight differences in level of expression
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Catecholamines
Dopamine
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Dopamine pathways in the brain
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Dopamine pathways do many things:Control flow of blood through the brain Motor control (nigrostriatal) system
Behavioural controlDopamine is the brain’s motivational chemical. It works onglutamate synapses to modulate their excitability.
A shortage of brain dopamine causes an indecisivepersonality, unable to initiate even the body’s ownmovement. 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.
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DARP-32
Dopamine and cAMP-regulated phosphoproteinMolecular weight, 32 kDa
DARP-32 is a molecular integrator
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Other neuromodulators (NE, serotonin) probablywork in a similar way to dopamine
They assist with the selection/maintenance of differentneural ensembles.
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Molecular actions of dopamine
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Polymorphisms of genes involved in aminergic (dopamine/serotonin) neurotransmission
Effects on personality?
Dopamine D4 receptor - novelty seekingPromoter of serotonin transporter gene - harm avoidance/anxiety
Genetics
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D4 dopamine receptor
16 amino acid repeat sequence present in twoto 11 copies - minisatellite phrase
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D4 dopamine receptor
The larger the number of repeats, the more ineffective is the dopamine D4 receptor in signalling
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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 tolife 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!
Genetics
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Why do antidepressants take so long to work?
The current prevailing hypothesis…
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Neurotrophin Hypothesis
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Chronic, severe
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Mechanism for the Delay inOnset of the therapeuticEffect of AntidepressantMedications.
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