AntidepressantsDepression is one the most treatable mental

illness*

*Foye's principle of medicinal chemistry

Depression

It is a mental illnesses characterized by pathological changes in mood (in contrast schizophrenia is disorder in thought)Two types of mood disorders

1) Unipolar disorders• Depression – lacking enthusiasm• Mania – excessive or unreasonable

enthusiasm2) Bipolar disorder (Alteration between manic-

depressive phase)

What does CLINICAL Depression feel like?

Confessions of depressed people“an empty hole (in ur heart)” “ life not being worth anything”“don’t feel sad or happy, feel numb”“can’t make simple decision, can’t communicate”“feels tiring”“like the whole world is in your shoulder”https://www.youtube.com/watch?v=K-F9f1nJAW0

How severe can depression be physiologically?

• Depression isn’t just a psychological state that can drive to suicide. It has physiological consequences too that can interfere with quality of life

• Insomnia (lack of sleep) – Weakens immune system, fatigue

• Increases pain perception• To suppress depression people do– Excessive eating obesity related heart problem– Excessive alcohol liver damage and withdrawal

symptoms

Cause of Depression• Like schizophrenia , the exact cause is unknown• 1) Monoamine Hypothesis : The accepted cause is deficiency

of Neuro transmission by biological amines Nor-adrenaline (NE) and Dopamine (DA) and Serotonin(5HT) in the CNS

• Evidence – Reserpine, which has antihypertensive actions due to its ability to deplete catecholamines (DA and NE) and 5HT from peripheral sympathetic nerve endings, caused depression

• Drugs that promote catecholamines and serotonin in the synapse relieved depression– MAOI – block metabolism of DA and NE – TCA – block reuptake of NE and 5HT

• However not all monoamine reuptake inhibitors are anti-depressant eg Cocaine is a potent inhibitor of noradrenalin and dopamine reuptake. However it is not an anti-depressant but an addictive

2) Receptor Sensitivity HypothesisTo compensate the deficiency of NE and 5HT in the

synapse, the post synaptic receptors become hypersensitive to these neurotransmitters and also they increase in number. This explains the delay in anti-depression therapy where drug effects are seen only after few weeks. The drugs need to first increase the NE and 5HT in synapse enough to normalize the hypersensitivity and increased number of their receptors and then only they start to show anti-depression action.

*Foye's principle of medicinal chemistry

Antidepressants Classification1) Tricyclics and Tetracyclics (TCA)

Imipramine Doxepin AmoxepineAmitriptyline Nortriptyline

2) Monoamine Oxidase Inhibitors (MAOIs)Phenelzine Moclobemide

3) Selective Serotonin Reuptake Inhibitors (SSRIs)Fluoxetine

Sertraline Citalopram4) Dopamine and Norepinephrine Reuptake Inhibitor (DNRI)

Bupropion5) Mood stabilizer- Lithium Carbonate

There are 5 Gen of antihistaminesGeneration Property eg1st Effect various NT with no selectivity TCA, maprotilline

2nd No anticholinergic actionWeak antihistaminic and adrenolytic action

mianserine, mirtazapine, trazodone

3rd Selective inhibition of NE,DA or 5HTdoes not affect muscarine, histamine and adrenergic cerebral systems

SSRI, ipsapirone, viloxazine, reboxetine, bupropione

4th Selective (5HT and NE) or (DA and NE) milnacipran, befloxatone5th Selective 5HT and NE and DA venlafaxine, cericlamine

Ref: Cesk Psychiatr.1994 Feb;90(1):3-19.

Discovery of TCA’s

•Chlorpromazine (CPZ) was the first anti-phycotic drug.•TCA’s were the first anti-depressents. They were accidentally discovered while searching for better derivative of CPZ. Hence they appear similar in structure

Imipramine

AmitriptylineProtriptyline

Doxepin

Chlorpromazine

Maprotiline

• TCA’s refer to a general structural class seen in – NE and 5HT Selective Reuptake Inhibitor (NSRI)

• Contains 3o terminal amine group

– Selective NE Reuptake Inhibitor (SNRI)• Contains 2o terminal amine group

• TCA’s generally have a wide side effect profile due to potency for other receptors such as – muscarinic– histamine – alpha1-adrenergic– sodium channels (causes cardiotoxicity)

• Thus selective inhibitor such as Serotonin/ Noradrenaline Reuptake Inhibitors (SSRI/SNRI) are preferred

SAR of TCA’s1) It consist of 3 ring in 6-7-6 or 6-6-6 format,

with two phenyl rings fused by a central 6 or 7 membered ring that can be homocyclic or heterocyclic. The central ring can be bridged to form a tetracyclic rings

Homocyclic (contains only carbon in central ring)

Heterocyclic (contains other atoms than carbon like N/O/S in central ring)

ImipramineAmitriptyline

Maprotiline

• They differ form antipsychotics in that instead of a sulphur, the rings are connected by two carbon units

ImipramineAnti-depressent

PromazineAnti-psycotic

• The three rings do not contribute to receptor binding but are responsible for various CNS side effects due to high lipophilicity. (Thus this feature is absent in later inhibitors)

2) The methylene linker to the terminal amine must be 3 carbon units and can side chain can be attached by any carbon on the central ringIt can be saturated or unsaturated. It should not be branchedCis form is potent than trans form

ImipramineAmitriptyline

Saturated (no double bond) 3 carbon linker

Unsaturated (has Double bond)3 carbon linker

Amoxepine has terminal amine attached to a different carbon

Imipramine

Branching reduces potency of Trimipramine by 100 times relative to Imipramine

Cis form is more potent than trans

3) Substituting a halogen or CN (cyano) group in 3 position of either phenyl ring increase selectivity for 5HT transportor

Clomipramine Selectivity Ratio of 5HT/NE

132

ImipramineSelectivity Ratio 5HT/NE

26

Clomipramine is considered the most powerful antidepressant ever made

4) The terminal group has to be a amine and it controls pharmacodynamics

Secondary amine group have more potency to NE transportorsTertiary amine group are non-selective to NE or 5HT transporter’s

potency1 Des-

ipramineMore NE

2 Ipramine NE/5HT3 Nortryptilli

neMore NE

4 Amitrpytilline

NE/5HT

Imipramine

It is a tricyclic antidepressant (TCA) of the di-benzazepine group. It was the first compound of it’s type.It is used in the treatment of

– Depression– Bedwetting

• Within the body, Imipramine is demethylated to desipramine, another TCA.

• MOA: It blocks transporters of 5HT and NE which prevents their reuptake from the synapse and thus prevents depression in agreement to monoamine hypothesis

Doxepin

• It is a TCS of dibenzoxepine group with an unsaturated heterocyclic central ring containing oxygen

• Two isomers are possible and is marketed in 85:15 mixture of Trans : Cis • Cis form inhibits reuptake of 5HT and Trans form inhibits reuptake of NE• The isomers do not differ in bioavailability but the Trans is metabolized to a larger degree such that the demethylated (3o amine converts to 2o amine by loss of a methyl group) metabolite of both trans and cis exist in 1:1 ratioIt is used in the treatment of Depression and also Itch and insomniaMOA: It blocks transporters of 5HT and NE which prevents their

reuptake from the synapse and thus prevents depression in agreement to monoamine hypothesis

• is a TCA of the dibenzoxazepine group with unsaturated heterocyclic central ring that has both N and O and the terminal amine is with a cyclic piperazinyl ring

• Comparatively it has a faster onset of action (four to seven days instead of 2-3 weeks) and shortest elimination (8 hr)

• It has anti-depressive and anti-psycotic property• Used in major depression and in delusional depression• MOA: It blocks transporters of 5HT and NE which prevents

their reuptake from the synapse and thus prevents depression in agreement to monoamine hypothesis

Amoxepin

Amitriptyline

• It is a TCA of the dibenzocycloheptene group and has unsaturation in both the central ring and propyl

linker• It is metabolized into Nortriptyline by demethylation

and it also is a TCA• It is used in – Major Depression

MOA: It blocks transporters of 5HT and NE which prevents their reuptake from the synapse and thus prevents depression in agreement to monoamine hypothesis

Nortriptyline• It is a TCA of the dibenzocycloheptene group and has unsaturation in both the central ring and propyl

linker• It is a major demethylated metabolite of

Amitriptyline• It is used in – Depression – bedwetting and neuropathic pain

MOA: It blocks transporters of 5HT and NE which prevents their reuptake from the synapse and thus prevents depression in agreement to monoamine hypothesis

SSRI (Selective Serotonin Reuptake Inhibitors)

Discovery • The need for SSRI was due to high side effect

profile of TCA’s which had potency for various receptors other than NE and 5HT transporters

• It was discovered that the antihistaminic drug Pheniramine was also a selective inhibitor of 5HT transporter without any cardio toxic effects

• Thus structural manipulation was done on Pheniramine to result the first SSRI- Zimeldine

• SSRI and SNRI represent 2nd Gen Antidepressents

Antihistaminic Antidepressants

Zimeldine was withdrawn from market due to Gullian Barre symptom (immune system attacking nerves)

Further research lead to discovery of Fluoxetine.Fluoxetine and it’s derivatives are successful SSRI

• SSRI have many therapeutic uses (this reflects the involvement of 5HT in many physiologic process)– depression, – OCD, obesity, personality disorder , anxiety– panic disorder, migraine, alcoholism, rheumatic pain,

premenstrual disorder, bulimia (over eating)• They are claimed to be better tolerated than

TCA’s with fewer side effects• They are expensive and this has lead to patient

again falling into depression because they could not continue with this drug

• SSRI have a history of increased risk of suicide for unknown reasons

• Selectivity and potency for 5-HT uptake do not coincide

• Citalopram is the most selective 5-HT-uptake inhibitor, whereas paroxetine is the most potent

• SSRI are not perfect!• Side effects include nausea, diarrhea, anxiety,

agitation, insomnia and sexual dysfunction• But no anticholinergic or cardiotoxic effects like

TCA’s

SAR of SSRI• Mono susbtitution in para position of phenoxy

group by electron withdrawing group results gain in 5HT selective inhibition

• But – bi-substitution – or mono-substitution at other places or – use of electron donating group

• causes loss in selective inhibition

CF3 is mono-subs in para position

• Introducing ring in the fluoxetine derivatives maintains selectivity for 5HT transporter but lowers the potency, except in paroxetine which is more potent than fluoxetine

• The amine group shows maximum potency when in 2o form ie 3o amine reduce potency for 5HT transportors

NOTEGENERAL Effect of Amine on potency

Amine PotencyTCA’s Secondary NE

Tertiary NE/5HT

SSRI Secondary 5HTPrimary Reduced 5HT

Tertiary Reduced 5HT

Locate chiral carbons

HN

Cl

Cl

Fluoxetine

Sertraline

Citalopram

Fluoxetine

• It is an antidepressent of the SSRI class• The S enantiomer is 100 times more selective but R

enatiomer is 8 times more potent and has longer duration of action (ie selectivity and potency do not correlate for SSRI)

• It’s N-demethylated metabolite, NorFluoxetine has weaker activity but is responsible for it’s long half life

• Uses - major depressive disorder, OCD, post-traumatic stress disorder, premenstrual disorder, bulimia nervosa, panic disorder, and obesity

• MOA- It selectively blocks presynaptic 5HT transporter which inhibits reuptake of 5HT leading to antidepressent effects in accordance to monoamine hypothesis

Sertraline

• It is an antidepressent of the SSRI class• It has two chiral centers and only the S,S diastereomer is

active • It’s N-demethylated hepatic metabolite, NorSertraline, is 5-

10 times weaker than sertraline• Uses - Major Depression, OCD, body dysmorphic disorder,

post-traumatic stress disorder, premenstrual disorder, panic disorder and social phobia

• MOA- It selectively blocks presynaptic 5HT transporter which inhibits reuptake of 5HT leading to antidepressent effects in accordance to monoamine hypothesis

Citalopram• It is an antidepressent of the SSRI class• Only the S enantiomer is active (27 times more active than R)• Citalopram is the most selective 5-HT uptake inhibitor but

not the most potent• Unlike other SSRI, it doesn’t undergo 1st pass metabolism • It’s N-demethylated metabolite, desmethylcitalopram

retains 50% potency• Uses: Major depressive disorder, chronic depression, OCD,

anxiety, panic disorder, premenstrual disorder, Body dysmorphic disorder

• MOA- It selectively blocks presynaptic 5HT transporter which inhibits reuptake of 5HT leading to antidepressent effects in accordance to monoamine hypothesis

Bupropion

• It is an amino ketone antidepressent of the DNRI class• The tertiary butyl group prevents N-demethylation like

in other antidepressents• It’s property to antagonize nicotine at therapeutic doses is

used to combat smoking withdrawal symptoms• Uses- Depression, 2nd line treatment in Smoking cessation • MOA – It primarily inhibits pre-synaptic DA and, to a

lesser extent, NE transporters and increases their levels in the synapse which results antidepressant effect in accordance to monoamine Hypothesis

Lithium Carbonate (Li2CO3)• Lithium (Li) is a simple monovalent cation, which as

a salt, carbonate or citrate, is used in the – treatment of mania – in the augmentation treatment of depression – and in the prophylaxis of bipolar disorder

• It is the only drug that has shown to reduce suicidal tendency in depression

Ref: Can J Psy chi a try, Vol 48, No 7, August 2003

• But it is not without side effects• EPS, Hair loss, Hypothyroidism• Nausea, Vomitting, Leukocytosis, Dry mouth,

increased thirst, Decreased memory

• They were used since 1894 for depression and is very effective but we don’t yet know the actual MOA

• The postulated MOA is Lithium in therapeutic concentrations blocks the activity of the enzyme, inositol-1-phosphatase, resulting in a depletion of neuronal inositol and ultimately decrease levels of phosphatidylinositol biphosphate(PIP2) and it’s 2nd dary messenger IP3 and DAG

Thank You

There are 5 Gen of antihistaminesGeneration

Property

1st Effect various NT with no selectivity TCA, maprotilline

2nd No anticholinergic actionWeak antihistaminic and adrenolytic action

mianserine, mirtazapine, trazodone

3rd Selective inhibition of NE,DA or 5HTdoes not affect muscarine, histamine and adrenergic cerebral systems

SSRI, ipsapirone, viloxazine, reboxetine, bupropione

4th Selective (5HT and NE) or (DA and NE) milnacipran, befloxatone

5th Selective 5HT and NE and DA venlafaxine, cericlamine