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

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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 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
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?.


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


1 [neurotransmitters] in the synapseST GENERATION ANTIDEPRESSANTS ; TRICYCLIC ANTIDEPRESSANTS


2 [neurotransmitters] in the synapsend GENERATION ANTIDEPRESSANTS ; TETRACYCLIC / HETEROCYCLIC ANTIDEPRESSANTS


3 [neurotransmitters] in the synapserd GENERATION ANTIDEPRESSANTS ; HETEROCYCLIC ; SNRI ;


Selective Serotonin Reuptake Inhibitor [neurotransmitters] in the synapse


OUT [neurotransmitters] in the synapse

Cl-

Na+

Glu

GABA

Cl-

Na+

GABAA receptor

Glutamate/AMPA

receptor

Inhibition

Excitation

IN


Cerebral cortex [neurotransmitters] in the synapse

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


  • Arousal: [neurotransmitters] in the synapse

  • Processing signals relate to plain & pleasure. Regulating

  • body homeostasis

  • Emotion and feeling

  • Attention

  • Wakefulness & sleep

  • 5. learning

  • The construction of consciousness.


Fast: GABA, glutamate, acetylcholine [neurotransmitters] in the synapse

Slow: biogenic amines

Dopamine

Serotonin/5-HT

NE

Acetylcholine

Peptides


Ionotropic [neurotransmitters] in the synapse and metabotropic receptors

Fast

Ion flow in/out

milliseconds

Slow

Second messenger cascades

seconds

1/1000 of a second !


7 transmembrane [neurotransmitters] in the synapse

domain receptor

Out

NH2

In

2nd messengers

G

COOH


Ionotropic [neurotransmitters] in the synapse

Metabotropic


The monoamines [neurotransmitters] in the synapse

Dopamine

Epinephrine (adrenergic)

Norepinephrine (noradrenergic)

Serotonin


Neurotransmitter [neurotransmitters] in the synapse

receptors

Neurotransmitter

receptors

Ion pumps

Second messengers

Protein kinases

Transcription Factors

Cell nucleus

Ion channels


7-transmembrane-domain receptors [neurotransmitters] in the synapse


Excitatory input [neurotransmitters] in the synapse

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


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 purely excitatory or inhibitory.

Norephinephrine


Ne system
NE System purely excitatory or inhibitory.

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) purely excitatory or inhibitory.


MAO Inhibitors purely excitatory or inhibitory.

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


NE potentiation of responses to GABA purely excitatory or inhibitory.

Purkinje cells


Cl purely excitatory or inhibitory.-

Cl-

Cl-

Cl- Cl- Cl- Cl- Cl-

Out

GABA

GABA

PO4

In


GABA + cAMP purely excitatory or inhibitory.

GABA + NE

GABA

GABA

response

time

Noradrenergic potentiation of cerebellar Purkinje cell responses

to GABA: cAMP as intracellular intermediary.


PKA reg purely excitatory or inhibitory.

PKA cat

NE

GABAA receptor

b-adrenergic

receptor

b1

AC

PO4

Gs

cAMP

ATP


Cl purely excitatory or inhibitory.-

Cl-

Cl-

Cl- Cl- Cl- Cl- Cl-

Out

GABA

GABA

PO4

In

POSTSYNAPTIC MODULATION


Why does a purely excitatory or inhibitory.small amount of stress help you learn better?

But, too much chronic, severe stress  DEPRESSION


Before LTP purely excitatory or inhibitory.

Presynaptic

Postsynaptic

After LTP

More glutamate receptors

= bigger response

b-adrenergics and memory


LTP decays purely excitatory or inhibitory.

Presynaptic

Postsynaptic

After LTP

More glutamate receptors

= bigger response

After several hours…….


Unless purely excitatory or inhibitory.b-adrenergic activation of postsynaptic cell takes place…

Active during memory

formation

NE

Glu

Stabilization of LTP

cAMP

PKA

Inhibition of

protein phosphatase I


  • b purely excitatory or inhibitory.-adrenergic receptor activation helps memories

  • better memories when you are paying attention

  • because of higher emotional stimulation


INDOLEAMINE purely excitatory or inhibitory.

SEROTONIN (5-HT)


Serotonin system
Serotonin System purely excitatory or inhibitory.

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 purely excitatory or inhibitory.

MODULATION


Noradrenergic control of serotonergic release
Noradrenergic Control of Serotonergic Release purely excitatory or inhibitory.

Receptors

NE

2-AR

5-HT

1-AR

5-HT1

5-HT2

5-HT3

NE

1

2

3

Mianserin


Humans purely excitatory or inhibitory.

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 purely excitatory or inhibitory.


A synapse that uses serotonin/5-HT purely excitatory or inhibitory.


Fluoxetine/Prozac blocks the SERT purely excitatory or inhibitory.

Treatment of depression.

anxiety disorders,

obsessive-compulsive disorders

Re-uptake of 5-HT/serotonin


Genetic variation in the gene promoter region of the purely excitatory or inhibitory.

serotonin transporter.

risk factor for anxiety, alcoholism, mood disorders

slight differences in level of expression


Catecholamines purely excitatory or inhibitory.

Dopamine


Dopamine pathways in the brain purely excitatory or inhibitory.


Dopamine pathways purely excitatory or inhibitory. 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.


DARP-32 purely excitatory or inhibitory.

Dopamine and cAMP-regulated phosphoprotein

Molecular weight, 32 kDa

DARP-32 is a molecular integrator


Other neuromodulators (NE, serotonin) probably purely excitatory or inhibitory.

work in a similar way to dopamine

They assist with the selection/maintenance of different

neural ensembles.


Molecular actions of dopamine purely excitatory or inhibitory.


Genetics
Genetics purely excitatory or inhibitory.

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 purely excitatory or inhibitory.

16 amino acid repeat sequence present in two

to 11 copies - minisatellite phrase


D4 dopamine receptor purely excitatory or inhibitory.

The larger the number of repeats, the more

ineffective is the dopamine D4 receptor

in signalling


Genetics1
Genetics purely excitatory or inhibitory.

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? purely excitatory or inhibitory.

The current prevailing hypothesis…


Neurotrophin hypothesis

Neurotrophin Hypothesis purely excitatory or inhibitory.


Chronic, severe purely excitatory or inhibitory.


Mechanism for the Delay in purely excitatory or inhibitory.

Onset of the therapeutic

Effect of Antidepressant

Medications.


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