Screening of antidepressant agents

Dr. Partha Sarkar

(PGT, 1st Yr)

Department of Pharmacology

Medical College, Kolkata

Depression

Depression• It is a major affective or mood disorder.

• Characterized by extreme exaggerations and disturbances of mood.

• It may adversely affect cognition or psychomotor function.

Depression

The biogenic amine hypothesis proposes

Reduction in NEReduction in level of

5HT,DA,GABA

Antidepressant drugs• RIMAs: Moclobemide, clorgyline

• TCAs: Imipramine, Amitryptyline,

• SSRIs: Fluoxetine, Sertraline, Citalopram, Escitalopram

• NDRIs: Desipramine, Amoxapine, Nortryptyline

• ATYPICAL ANTIDEPRESSANT: Venalafexine, Trazodone, Duloxetine, Mianserine

Screening Method’s Principles

• To see the relationship between the Clinical efficacy of known antidepressants and their effects on various pharmacological test models.

• Motor activity of these tests also allow assessment of the specificity of antidepressant activity by establishing a ratio between the antidepressant dose and sedative or stimulant dose.

In vivo methods• Water Wheel Model

• Learned Helplessness Test

• Tail Suspension Test

• Reserpine Induced Hypothermia

• Amphetamine Potentiation

• Resident Intruder Paradigm

• Muricidal Behavior in Rats

Water Wheel Model• This model demonstrates the antidepressant

property of the test drug by use of the `Behavioral Despair Activity`

• The animal is forced to swim without any escape in a water tank. The rotating wheel in the water tank poses as an option for escape but add-on to the despair as it turns under the weight of the animal and it has to keep rotating it in order to stay afloat.

Water Wheel Model

Water Wheel Model

• The juncture when the animal is immobile and ceases to struggle and remains floating motionless in the water, making only those movements necessary to keep its head above the water is denoted as end point or

behavior despair.

Water Wheel ModelMice of either sex and weight range of 20 to25gm

are selected.

Animals are treated with standard drug like imipramine and rechallenged on water wheel.

A potential antidepressant will increase the number of counts of water wheel.

Indicating increased effort at escape behavior.

Water Wheel Model

Water Wheel Model• The classical tricyclic antidepressants reduce

immobility time in this model.

• However antidepressants acting selectively on 5HT system are inactive in this test.

• False positive are induced by opiates and antihistaminics.

Modified Traditional Porsolt Paradigm

• Lucki and co-workers have enchanced the sensitivity of the traditional porsolt paradigm and accuracy of its scoring.

• This enables to better detect SSRIs antidepressant activity

Forced Swim Test

Forced Swim TestThe adult male rats are forced to swim in a cylinder

with no escape.

The animals become immobile after an initial struggling phase.

The immobility has been equated to a despair reaction.

Antidepressants decrease the immobility time.

Forced Swim Test

Learned Helplessness Test

Learned Helplessness TestFirst Phase

Adult wister rat of either sex and in weight range from 200 to 250g are placed in a compartment with steel mesh grid floor.

This forms the first phase of the animal model where animal is exposed to `inescapable shock treatment`

Repeated shocks(15 sec duration,0.8mA every min)are applied this serves as stress to animals.

Rats are exposed for 1 hour without any escape route

Learned Helplessness TestFirst Phase

Learned Helplessness TestSecond Phase

After chronic exposure a cue(buzzer or light signal)precedes the shock.

This is termed as the escape response.

Simultaneously a door open for a safe chamber, which is unelectrified.

The animal is allowed to escape towards it and avoid the noxious stimulus.

Learned Helplessness TestSecond Phase

Learned Helplessness Test• Failure to exhibit escape response by an

animal is said to be an indicative of its depressive state.

• Antidepressants reduce escape failure.

• This classic paradigm has a variable Score of 30 to 80%

Tail suspension test

Tail suspension testMouse(20 to 30 gm, either sex) is hung on a wire in an upside down posture such that its nostril touches the water surface.

Initially the animal tries to escape by making vigorous movements, but is unable to escape and become immobile

Pretreatment with antidepressant drug reduces immobility time.

A computerized system with 16 channels are used to measure the time of activity, time of immobility of the animal in real time.

Tail suspension test

Amphetamine potentiation test

Amphetamine potentiation testRats(male wister,250 to 300g)are housed in a controlled

environment with temp 22±2A C,12 hr light/dark cycle and free access to food and water

90mins after the last dose of the test drug, D-amphetamine(5-10mg/kg,ip)is injected and 30mins later they are placed singly

into cages with photocells to record their activity.

The rat receives the test drug(antidepressants drugs) in their home cage usually for 2 weeks

Most antidepressants including TCA,MAOI potentiate amphetamine effects seen as increased locomotor activity.

Amphetamine potentiation test

Muricidal behavior model• Female rats of Holtzman strain exhibit

compulsive mouse killing behavior irrespective of their satiety status.

• Nonmuricidal rats can be rendered muricidal by pretreatment with pilocarpine(2.5-5mg/kg, ip).

• Agents reducing muricidal behavior exhibit antidepressant action.

Muricidal behavior in female rats of Holtzman strain.

Pitfalls of classical antidepressant methods

• A major problem in the search for new antidepressant drugs is the lack of animal models that resemble depressive illness in humans and are selectively insensitive to simulate effective antidepressant treatment.

• Also novel antidepressant like mianserin shows little or no antidepressant effect on laboratory animals.

Pitfalls of classical antidepressant methods

Thank you