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

1ST GENERATION ANTIDEPRESSANTS ; TRICYCLIC ANTIDEPRESSANTS Sedation Drug Anti-muscarinic

Block of Amine Pump for: Norepinephrine Dopamine

Serotonin

Amitriptyline Amoxapine Bupropion Citalopram Clomipramine Desipramine

+++ ++ 0 0 +++ +

+++ ++ 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 +, 0

++ ++ +, 0 0 +++ +++ + 0, + 0 ++ +++ 0 0

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, +

3rd GENERATION ANTIDEPRESSANTS ; HETEROCYCLIC ; SNRI ; Sedation Drug Anti-muscarinic

Block of Amine Pump for: 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 +, 0

++ ++ +, 0 0 +++ +++ + 0, + 0 ++ +++ 0 0

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, +

Selective Serotonin Reuptake Inhibitor Sedation Drug Anti-muscarinic

Block of Amine Pump for: Serotonin Norepinephrine Dopamine

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 +, 0

++ ++ +, 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, +

OUT

Cl-

Na+

ClGABAA receptor

Na+
Glutamate/AMPA receptor

Inhibition
IN

Excitation

Cerebral cortex

Sensory input

Information integration cognition, thought, mood, emotion

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

Ionotropic and metabotropic receptors

Fast Ion flow in/out milliseconds 1/1000 of a second !

Slow Second messenger cascades seconds

Out

NH2

7 transmembrane domain receptor

In

2nd messengers
COOH

Ionotropic

Metabotropic

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

Neurotransmitter receptors Neurotransmitter receptors

Second messengers

Ion pumps

Protein kinases

Ion channels

Transcription Factors Cell nucleus

7-transmembrane-domain receptors

Excitatory input Neuromodulatory inputs NE b1 DA D1

Glutamate Neuromodulatory inputs ACh M1 Ca2+ IP3 + DG 5-HT

GluR

cAMP
Hist PKA

Ca2+-dependent Kinases/phosphatases

PKC
Down-stream substrates

5-HT2C

Hist

H2

Gene expression

H1
Long-term synaptic modification

Short-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 ClGABA

GABA

Cl-

PO4 Cl-

Cl- Cl- Cl- Cl- 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-

Cl- Cl- Cl- Cl- Cl-

In

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
NE
2-AR

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.