1. Antidepressant Drugs

2. 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

3. 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
SertralineParoxetine 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

4. 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.

5. • 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

6. MAO
COMT
Amine neurotransmitters are
either degraded (metab)
or reuptaken
Mito

7. The purpose of antidepressants is
the increase the
[neurotransmitters] in the
synapse

8. 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

9. 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

10. 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 ;

11. 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

12. OUT
IN
Cl-
Cl-
Na+
Na+
GABAA receptor Glutamate/AMPA
receptor
G
A
B
A
G
l
u
Inhibition Excitation

13. Information integration
cognition, thought,
mood, emotion
Cerebral cortex
Sensory input Motor output
acetylcholine norepinephrine
serotonin dopamine histamine
Information integration
cognition, thought,
mood, emotion
Cerebral cortex
Sensory input Motor output

14. 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.

15. Fast: GABA, glutamate, acetylcholine
Slow: biogenic amines
Dopamine
Serotonin/5-HT
NE
Acetylcholine
Peptides

16. Ionotropic and metabotropic receptors
Fast
Ion flow in/out
milliseconds
Slow
Second messenger cascades
seconds
1/1000 of a second !

18. Out
In
G
7 transmembrane
domain receptor
2nd messengers
NH2
COOH

19. Ionotropic
Metabotropic

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

21. Second messengers
Protein kinases
Transcription Factors
Cell nucleus
Ion pumps
Ion channels
Neurotransmitter
receptors
Neurotransmitter
receptors

23. 7-transmembrane-domain receptors

24. Glutamate
Ca2+
Ca2+
-dependent
Kinases/phosphatases
Down-stream substrates
Gene expression
Short-term synaptic modification Long-term synaptic modification
cAMP
PKA
Hist
DA
NE
ACh
5-HT
Hist
PKC
IP3 + DG
GluR
β1
D1
H2
M1
5-HT2C
H1
Excitatory input
Neuromodulatory
inputs
Neuromodulatory
inputs

25. 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.

26. Catecholamines
Norephinephrine

27. 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.
α and β receptors.

28. A synapse that uses norepinephrine (NE)

29. Reuptake of NE
Monoamine oxidase, located on outer membrane
of mitochondria; deaminates catecholamines free in
nerve terminal that are not protected by vesicles
Selective inhibitor,
reboxetine
Cocaine blocks the NET
Antidepressant
MAO Inhibitors
Stimulant

30. NE potentiation of responses to GABA
Purkinje cells

31. PO4
Cl-
Cl-
GABA
Cl-
Cl-
Cl-
Cl-
Cl-
Cl-
GABA
Out
In

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

33. β1NE
Gs AC
ATP
cAMP
PKA reg
PKA cat
PO4
GABAA receptorβ-adrenergic
receptor

34. PO4
Cl-
Cl-
GABA
Cl-
Cl-
Cl-
Cl-
Cl-
Cl-
GABA
Out
In
POSTSYNAPTIC MODULATION

35. 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

36. β-adrenergics and memory
Presynaptic Postsynaptic
Before LTP
After LTP
More glutamate receptors
= bigger response

37. After LTP
More glutamate receptors
= bigger response
After several hours…….
Presynaptic Postsynaptic
LTP decays

38. Unless β-adrenergic activation of postsynaptic cell takes place…
NE
Glu
cAMP
PKA
Inhibition of
protein phosphatase I
Active during memory
formation
Stabilization of LTP

39. β-adrenergic receptor activation helps memories
-better memories when you are paying attention
because of higher emotional stimulation

40. INDOLEAMINE
SEROTONIN (5-HT)

41. 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.

43. PRESYNAPTIC
MODULATION

44. Noradrenergic Control of Serotonergic Release
NE
5-HT
NE
α2-AR
α1-AR
1 2 3
Mianserin
5-HT1
5-HT2
5-HT3
Receptors

45. 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
Humans
The purpose of antidepressants is to increase the levels of
circulating neurotransmitters in the synapse.

46. The 5-HT neurons in the brain

47. A synapse that uses serotonin/5-HT

48. Re-uptake of 5-HT/serotonin
Fluoxetine/Prozac blocks the SERT
Treatment of depression.
anxiety disorders,
obsessive-compulsive disorders

49. Genetic variation in the gene promoter region of the
serotonin transporter.
risk factor for anxiety, alcoholism, mood disorders
slight differences in level of expression

50. Catecholamines
Dopamine

51. Dopamine pathways in the brain

52. 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.

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

54. Other neuromodulators (NE, serotonin) probably
work in a similar way to dopamine
They assist with the selection/maintenance of different
neural ensembles.

55. Molecular actions of dopamine

58. 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
Genetics

59. D4 dopamine receptor
16 amino acid repeat sequence present in two
to 11 copies - minisatellite phrase

60. D4 dopamine receptor
The larger the number of repeats, the more
ineffective is the dopamine D4 receptor
in signalling

61. 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!
Genetics

62. Why do antidepressants take so
long to work?
The current prevailing hypothesis…

64. Neurotrophin Hypothesis

66. Chronic, severe

67. Mechanism for the Delay in
Onset of the therapeutic
Effect of Antidepressant
Medications.