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• 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

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.

• 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

MAO

COMT

Amine neurotransmitters areeither degraded (metab)

or reuptaken

Mito

The purpose of antidepressants is the increase the

[neurotransmitters] in the synapse

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


Drug




Bupropion 0 0 +, 0 +, 0 ?





Fluoxetine + + +++ 0, + 0, +

Fluvoxamine 0 0 +++ 0 0




Nefazodone ++ +++ +, 0 0 0


Paroxetine + 0 +++ 0 0


Sertraline + 0 +++ 0 0


Venlafaxine 0 0 +++ ++ 0, +

2nd GENERATION ANTIDEPRESSANTS ; TETRACYCLIC / HETEROCYCLIC ANTIDEPRESSANTS


Drug




Bupropion 0 0 +, 0 +, 0 ?





Fluoxetine + + +++ 0, + 0, +

Fluvoxamine 0 0 +++ 0 0




Nefazodone ++ +++ +, 0 0 0


Paroxetine + 0 +++ 0 0


Sertraline + 0 +++ 0 0



3rd GENERATION ANTIDEPRESSANTS ; HETEROCYCLIC ; SNRI ;


Drug




Bupropion 0 0 +, 0 +, 0 ?





Fluoxetine (Prozac) + + +++ 0, + 0, +

Fluvoxamine (Luvox) 0 0 +++ 0 0




Nefazodone ++ +++ +, 0 0 0


Paroxetine (Seroxat) + 0 +++ 0 0


Sertraline (Zoloft) + 0 +++ 0 0



Selective Serotonin Reuptake Inhibitor

OUT

IN

Cl-

Cl-

Na+

Na+

GABAA receptor Glutamate/AMPAreceptor

GA

BA

Gl

u

Inhibition Excitation

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

Arousal:

1. Processing signals relate to plain & pleasure. Regulatingbody homeostasis

2. Emotion and feeling3. Attention4. Wakefulness & sleep5. learning

The construction of consciousness.

Fast: GABA, glutamate, acetylcholine

Slow: biogenic aminesDopamineSerotonin/5-HTNEAcetylcholinePeptides

Ionotropic and metabotropic receptors

Fast

Ion flow in/out

milliseconds

Slow

Second messenger cascades

seconds

1/1000 of a second !

Out

In

G

7 transmembrane domain receptor

2nd messengers

NH2

COOH

Ionotropic

Metabotropic

The monoamines

Dopamine

Epinephrine (adrenergic)

Norepinephrine (noradrenergic)

Serotonin

Second messengers

Protein kinases

Transcription FactorsCell nucleus

Ion pumps

Ion channels

Neurotransmitterreceptors

Neurotransmitterreceptors

7-transmembrane-domain receptors

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

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 receptors.

A synapse that uses norepinephrine (NE)

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

NE potentiation of responses to GABA

Purkinje cells

PO4

Cl-

Cl-

GABACl-

Cl- Cl- Cl- Cl- Cl-

GABA

Out

In

time

GABAresponse

GABA

GABA + NE

GABA + cAMP

Noradrenergic potentiation of cerebellar Purkinje cell responsesto GABA: cAMP as intracellular intermediary.

1

NE

Gs AC

ATP

cAMP

PKA reg

PKA cat

PO4

GABAA receptor-adrenergicreceptor

PO4

Cl-

Cl-

GABACl-

Cl- Cl- Cl- Cl- Cl-

GABA

Out

In POSTSYNAPTIC MODULATION

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

-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 -adrenergic activation of postsynaptic cell takes place…

NE

Glu

cAMPPKA

Inhibition ofprotein phosphatase I

Active during memoryformation

Stabilization of LTP

-adrenergic receptor activation helps memories

-better memories when you are paying attention because of higher emotional stimulation

INDOLEAMINESEROTONIN (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.

PRESYNAPTICMODULATION

Noradrenergic Control of Serotonergic Release

NE5-HT

NE

2-AR

1-AR

1 2 3

Mianserin

5-HT1

5-HT2

5-HT3

Receptors

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.

The 5-HT neurons in the brain

A synapse that uses serotonin/5-HT

Re-uptake of 5-HT/serotonin

Fluoxetine/Prozac blocks the SERT

Treatment of depression.anxiety disorders, 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 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.

DARP-32

Dopamine and cAMP-regulated phosphoproteinMolecular weight, 32 kDa

DARP-32 is a molecular integrator

Other neuromodulators (NE, serotonin) probablywork in a similar way to dopamine

They assist with the selection/maintenance of differentneural ensembles.

Molecular actions of dopamine

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

D4 dopamine receptor

16 amino acid repeat sequence present in twoto 11 copies - minisatellite phrase

D4 dopamine receptor

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

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

Why do antidepressants take so long to work?

The current prevailing hypothesis…

Neurotrophin Hypothesis

Chronic, severe

Mechanism for the Delay inOnset of the therapeuticEffect of AntidepressantMedications.

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Antidepressant Drugs