Antidepressant drugs
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Antidepressant Drugs. What are Antidepressants?. Drugs that are used to relieve or prevent psychic depression.

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Antidepressant Drugs

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Antidepressant drugs

Antidepressant Drugs


What are antidepressants

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

Available Antidepressants

  • 1) Tricyclics and Tetracyclics (TCA)

    Imipramine Doxepin Desipramine AmoxepineTrimipramine

    Maprotiline Clomipramine Amitriptyline NortriptylineProtriptyline

  • 2) Monoamine Oxidase Inhibitors (MAOIs)

    TranylcypraminePhenelzineMoclobemide

  • 3) Serotonin Selective Reuptake Inhibitors (SSRIs)FluoxetineFluvoxamine

    SertralineParoxetineCitalopram

  • 4) Dual Serotonin and Norepinephrine Reuptake Inhibitor (SNRI)

    Venlafaxine Duloxetine

  • 5) Serotonin-2 Antogonist and Reuptake Inhibitors (SARIs)

    NefazodoneTrazodone

  • 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

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

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?.


Antidepressant drugs

Amine neurotransmitters are

either degraded (metab)

or reuptaken

MAO

Mito

COMT


The purpose of antidepressants is the increase the neurotransmitters in the synapse

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


Antidepressant drugs

1ST GENERATION ANTIDEPRESSANTS ; TRICYCLIC ANTIDEPRESSANTS


Antidepressant drugs

2nd GENERATION ANTIDEPRESSANTS ; TETRACYCLIC / HETEROCYCLIC ANTIDEPRESSANTS


Antidepressant drugs

3rd GENERATION ANTIDEPRESSANTS ; HETEROCYCLIC ; SNRI ;


Antidepressant drugs

Selective Serotonin Reuptake Inhibitor


Antidepressant drugs

OUT

Cl-

Na+

Glu

GABA

Cl-

Na+

GABAA receptor

Glutamate/AMPA

receptor

Inhibition

Excitation

IN


Antidepressant drugs

Cerebral cortex

Cerebral cortex

Information integration

cognition, thought,

mood, emotion

Motor output

Sensory input

Information integration

cognition, thought,

mood, emotion

Motor output

Sensory input

norepinephrine

acetylcholine

histamine

dopamine

serotonin


Antidepressant drugs

  • Arousal:

  • Processing signals relate to plain & pleasure. Regulating

  • body homeostasis

  • Emotion and feeling

  • Attention

  • Wakefulness & sleep

  • 5.learning

  • The construction of consciousness.


Antidepressant drugs

Fast: GABA, glutamate, acetylcholine

Slow: biogenic amines

Dopamine

Serotonin/5-HT

NE

Acetylcholine

Peptides


Antidepressant drugs

Ionotropic and metabotropic receptors

Fast

Ion flow in/out

milliseconds

Slow

Second messenger cascades

seconds

1/1000 of a second !


Antidepressant drugs

7 transmembrane

domain receptor

Out

NH2

In

2nd messengers

G

COOH


Antidepressant drugs

Ionotropic

Metabotropic


Antidepressant drugs

The monoamines

Dopamine

Epinephrine (adrenergic)

Norepinephrine (noradrenergic)

Serotonin


Antidepressant drugs

Neurotransmitter

receptors

Neurotransmitter

receptors

Ion pumps

Second messengers

Protein kinases

Transcription Factors

Cell nucleus

Ion channels


Antidepressant drugs

7-transmembrane-domain receptors


Antidepressant drugs

Excitatory input

Glutamate

Neuromodulatory

inputs

Neuromodulatory

inputs

ACh

GluR

NE

M1

b1

Ca2+

5-HT

DA

IP3 + DG

D1

Ca2+-dependent

Kinases/phosphatases

cAMP

PKC

5-HT2C

Hist

Hist

PKA

Down-stream substrates

H2

H1

Gene expression

Short-term synaptic modification

Long-term synaptic modification


Antidepressant drugs

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.


Antidepressant drugs

Catecholamines

Norephinephrine


Ne system

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.


Antidepressant drugs

A synapse that uses norepinephrine (NE)


Antidepressant drugs

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

Stimulant

Cocaine blocks the NET

Reuptake of NE


Antidepressant drugs

NE potentiation of responses to GABA

Purkinje cells


Antidepressant drugs

Cl-

Cl-

Cl-

Cl- Cl- Cl- Cl- Cl-

Out

GABA

GABA

PO4

In


Antidepressant drugs

GABA + cAMP

GABA + NE

GABA

GABA

response

time

Noradrenergic potentiation of cerebellar Purkinje cell responses

to GABA: cAMP as intracellular intermediary.


Antidepressant drugs

PKA reg

PKA cat

NE

GABAA receptor

b-adrenergic

receptor

b1

AC

PO4

Gs

cAMP

ATP


Antidepressant drugs

Cl-

Cl-

Cl-

Cl- Cl- Cl- Cl- Cl-

Out

GABA

GABA

PO4

In

POSTSYNAPTIC MODULATION


Antidepressant drugs

Why does a small amount of stress help you learn better?

But, too much chronic, severe stress  DEPRESSION


Antidepressant drugs

Before LTP

Presynaptic

Postsynaptic

After LTP

More glutamate receptors

= bigger response

b-adrenergics and memory


Antidepressant drugs

LTP decays

Presynaptic

Postsynaptic

After LTP

More glutamate receptors

= bigger response

After several hours…….


Antidepressant drugs

Unless b-adrenergic activation of postsynaptic cell takes place…

Active during memory

formation

NE

Glu

Stabilization of LTP

cAMP

PKA

Inhibition of

protein phosphatase I


Antidepressant drugs

  • b-adrenergic receptor activation helps memories

  • better memories when you are paying attention

  • because of higher emotional stimulation


Antidepressant drugs

INDOLEAMINE

SEROTONIN (5-HT)


Serotonin system

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.


Antidepressant drugs

PRESYNAPTIC

MODULATION


Noradrenergic control of serotonergic release

Noradrenergic Control of Serotonergic Release

Receptors

NE

2-AR

5-HT

1-AR

5-HT1

5-HT2

5-HT3

NE

1

2

3

Mianserin


Antidepressant drugs

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.


Antidepressant drugs

The 5-HT neurons in the brain


Antidepressant drugs

A synapse that uses serotonin/5-HT


Antidepressant drugs

Fluoxetine/Prozac blocks the SERT

Treatment of depression.

anxiety disorders,

obsessive-compulsive disorders

Re-uptake of 5-HT/serotonin


Antidepressant drugs

Genetic variation in the gene promoter region of the

serotonin transporter.

risk factor for anxiety, alcoholism, mood disorders

slight differences in level of expression


Antidepressant drugs

Catecholamines

Dopamine


Antidepressant drugs

Dopamine pathways in the brain


Antidepressant drugs

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.


Antidepressant drugs

DARP-32

Dopamine and cAMP-regulated phosphoprotein

Molecular weight, 32 kDa

DARP-32 is a molecular integrator


Antidepressant drugs

Other neuromodulators (NE, serotonin) probably

work in a similar way to dopamine

They assist with the selection/maintenance of different

neural ensembles.


Antidepressant drugs

Molecular actions of dopamine


Genetics

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


Antidepressant drugs

D4 dopamine receptor

16 amino acid repeat sequence present in two

to 11 copies - minisatellite phrase


Antidepressant drugs

D4 dopamine receptor

The larger the number of repeats, the more

ineffective is the dopamine D4 receptor

in signalling


Genetics1

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.

Don’t oversimplify!


Why do antidepressants take so long to work

Why do antidepressants take so long to work?

The current prevailing hypothesis…


Neurotrophin hypothesis

Neurotrophin Hypothesis


Antidepressant drugs

Chronic, severe


Antidepressant drugs

Mechanism for the Delay in

Onset of the therapeutic

Effect of Antidepressant

Medications.


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