ANTI DEPRESSANTS

Drugs

Dr. Muhammad Tariq

 Lecture Contents #1

1.What is Depression?
2.What the causes of Depression?
3.Types of depression and symptoms
4.Treatment for depression
5.Gernal mechanism of Depression
6.Classification of antidepressant Drugs
2

7.Book References
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 Depression
"Depression" is a very common psychiatric disorder that is related to the "mood" (affective
disorder).

“An affective disorder characterized by loss of interest or pleasure in almost all a person’s usual
activities or pastimes.”

• Changes in mood are associated with depression and/or mania.

• Disorders of mood rather than disturbance in thought or cognition.

• Clinical depression: feeling sad for more than two weeks.

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5
 DEPRESSION

• Types
• Symptoms
• Diagnosis
• Causes
• Treatment

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 TYPES OF DEPRESSION
• Major depression
• Chronic depression (Dysthymia)
• Atypical depression
• Bipolar disorder/Manic depression
• Seasonal depression (SAD)

Atypical depression
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Bipolar disorder/Manic depression
 SYMPTOMS
Persistently sad, anxious, or empty moods
Loss of pleasure in usual activities (anhedonia)
Feelings of helplessness, guilt, or worthlessness
Crying, hopelessness, or persistent pessimism
Fatigue or decreased energy
Loss of memory, concentration, or decision-making capability
Restlessness, irritability
Sleep disturbances
Change in appetite or weight
Physical symptoms that defy diagnosis and do not respond to treatment
(especially pain and gastrointestinal complaints)
Thoughts of suicide or death, or suicide attempts
Poor self-image or self-esteem (as illustrated, for example, by verbal self-
reproach) 8
  DIAGNOSIS
Extensive patient and family history
Blood test for hypothyroidism
Current medication
DSM-IV
One of the first two symptoms
Five other symptoms
 CAUSES OF DEPRESSION
Genetics
Death/Abuse
Medications

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 Symptoms of "mania" are exactly the opposite:

• Happy, excited, euphoric , self-confidence, lack of judgment

• Sudden odd decisions that are mostly of disastrous consequences

• Excessive rapid talking , moving quickly from one

to another (Flight of ideas)

• Hyperactive & full of energy, unable or unwilling to sleep

• Sudden irritability, rage or paranoia

• Impatience, Aggression

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 TREATMENT FOR DEPRESSION
• Psychotherapy
• Electroconvulsive therapy
• Natural alternatives
• Medication Psychotherapy
SSRIs
MAOIs
TCAs Electroconvulsive therapy

SNRIs
NDRIs
TeCAs (Tetracyclic antidepressant)

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Potential Side Effects of Antidepressant Therapy
Central Nervous System
Cardiac Dizziness, cognitive impairment,
sedation, light-headedness,
Orthostasis,
somnolence, nervousness,
hypertension,
insomnia, headache, tremor,
heart block,
changes in satiety and appetite
tachycardia
Gastrointestinal
Nausea, constipation,
Urogenital vomiting, dyspepsia,
Erectile dysfunction, diarrhea
ejaculation disorder,
anorgasmia, priapism Autonomic Nervous System
Dry mouth, urinary retention,
blurred vision, sweating
Monoamine nerves: Neurotransmission

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 Normal synapse, no depression. Neurotransmitter deficiency
lead to Depression

• 5-HT deficiency may cause the sleep problems, irritability and anxiety associated with
depression
• Decreased level of NE, which regulates mood, alertness, arousal, appetite, reward & drives,
may contribute to the fatigue and depressed mood of the illness
• However, dopamine is important for pleasure, sex & psychomotor active

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Sites of Action for Antidepressants

1- Monoamine (NE or/ and 5-HT) re-uptake pump inhibitors

2- Blockade of pre-synaptic a2 receptors
3- Inhibition of MAO enzyme 17
 Antidepressants
• Antidepressants do not act immediately (show clinical effects after 2 weeks) indicating that
secondary adaptive changes in the brain are important.

• The most consistent adaptive change seen with antidepressant drugs is the downregulation of
beta-, alpa-2 and 5-HT2 receptors. Alpha-1 is not affected.

• Affect only people who are depressed.

• Effect does not increase with increasing doses.

• Antidepressants are not habit-forming.

• Antidepressants differ widely in side effects.

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 Lecture Contents #2

1.Selective Serotonin Reuptake Inhibitors (SSRIs)?

2. SSRIS On the market
3.Mechanism of Action of SSRIs
4.Fluoxetine (Prozac)
5.Therapeutic Uses of SSRIs
6.SSRIS Side effects 2

7.Book References
 Part: 1
Selective Serotonin Reuptake Inhibitors
(SSRIs)
SSRIs are preferred to TCAs:
• Lower anticholinergic effects
• Lower sedation
• Lower weight gain
• Lower cardiovascular effects 20
• Available for the past 15 years
• Allows for more serotonin to be available to stimulate
postsynaptic receptors
• Available to treat depression, anxiety disorders, ADHD,
obesity, alcohol abuse, childhood anxiety, etc.
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 SSRIS ON THE MARKET
• Citalopram (Celexa)
• Dapoxetine (Priligy)
• Escitalopram (Lexapro)
• Fluoxetine (Prozac)
• Fluvoxamine (Luvox)
• Paroxetine (Paxil)
• Sertraline (Zoloft)

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 Fluoxetine
Fluvoxamine
Citalopram
Sertraline
Paroxetine

Binds to SERT   5-HT levels in synapse

No effect on NET (noradrenaline transporter)

No block to mAch, H, or a1 Adrenoceptor 
so no antimuscarinic nor sedative effects

They are nearly of comparable efficacy but of preferential response in each individual
 Mechanism of Action of SSRIs

Reuptake blocking antidepressant

(TCA, SSRI ) causes increase in
neurotransmitters
25
 Fluoxetine (Prozac)

• The body eliminates Fluoxetine very slowly. The half-life of fluoxetine after a single dose is 2
days and after multiple dosing 4 days.

• The liver then metabolizes fluoxetine into norfluoxetine, a desmethyl metabolite, which is also
a serotonin reuptake inhibitor.

• Norfluoxetine has an even longer half-life, i.e. 8.6 and 9.3 days for single and repeated dosage
respectively.

• Because fluoxetine's metabolism involves the P450IID6 system, concomitant therapy with
drugs also metabolized by this enzyme system (such as the tricyclic antidepressants) may lead
to drug interactions.
• Fluoxetine is approved for use in children & adolescence, is relatively safe in pregnancy.
 Therapeutic Uses of SSRIs
Same as for TAC, in addition effective in the following conditions
• Depression.
• Anxiety Disorder.
• Eating disorders- bulimia nervosa (fluoxetine).
• Post traumatic stress disorder.
• Premenstrual dysphoric disorder.
• Attention Deficit Hyperkinetic Disorder.
• Treatment of premature ejaculation.
 SSRIS SIDE EFFECTS
Anhedonia Fatigue
Apathy Changes in sexual behavior
Nausea/vomiting Suicidal thoughts
Drowsiness or somnolence
Headache
Bruxism (involuntarily grinding of
the teeth)
Extremely vivid and strange
dreams
Dizziness

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 Lecture Contents # 3

1.Serotonin-norepinephrine reuptake inhibitors (SNRIS)?

2.Mechanism of Action of (SNRIS)?
3.Venlafaxine
4.Norepinephrine-dopamine Reuptake Inhibitors (NDRIS) or Atypical Antidepressant
5. Bupropion
6. Therapeutic Uses of Bupropion
2

7.Book References
 Part:2
SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS (SNRIS)

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 Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)

Serotonin norepinephrine reuptake inhibitors (SNRIs) are a class of

antidepressant used in the treatment of clinical depression and other affective
disorders.
Inhibit both serotonin and noradrenergic reuptake like the TCAs but without the
Antihistamine, Antiadrenergic Or Anticholinergic side effects

They act upon two neurotransmitters in the brain that are known to play an
important part in mood, namely, 5HT and NE. This can be contrasted with the
more widely-used selective serotonin reuptake inhibitors (SSRIs), which act only
on serotonin.
Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)

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 Serotonin-norepinephrine reuptake inhibitors (SNRIS)
• Slightly greater efficacy than SSRIs
• Slightly fewer adverse effects than SSRIs
• Current drugs
Venlafaxine (Effexor)
Duloxetine (Cymbalta)
Desvenlafaxine (PRISTIQ)
Levomilnacipran (FETZIMA) Venlafaxine 1:1
Duloxetine
• Mechanism of Action
• Very similar to SSRIs
• Works on both neurotransmitters (Serotonin & Nor-epinephrine)
• Effective in relieving pain.
• Side effects
• Similar to SSRIs
• Suicide 33
 Serotonin and Noradrenaline Reuptake Inhibitors (SNRIs)

Venlafaxine
• It is used primarily for the treatment of depression, generalized anxiety disorder, and social
anxiety disorder in adults. Venlafaxine is the first and most commonly used SNRI.

• Selective 5HT and NE uptake blockers Combines the action of SSRI and NRI.

• Causes dual action on serotonin and adrenergic

systems, thus amplifying these two systems
synergistically.

• But without α1, M1 cholinergic or H receptor blocking properties.

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Venlafaxine
Side Effects
• Because of its relatively short half-life of 4 hours, Effexor should be administered
in divided dosages throughout the day.

• Side effects may include

• nausea, dizziness, sleepiness, abnormal ejaculation, sweating, dry mouth, gas or

stomach pain, abnormal vision, nervousness, insomnia, loss of appetite,
constipation, confusion/agitation, tremors, and drowsiness.
 Part:3
Norepinephrine-Dopamine Reuptake Inhibitors (NDRIS) or Atypical Antidepressant

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 Norepinephrine-dopamine reuptake inhibitors (NDRIS) or Atypical Antidepressant
• Current drugs
Bupropion (Wellbutrin)
Mirtazapine ( REMERON)
Nefazodone
Trazodone (DESYREL)
Vilazodone (VIIBRYD)
Vortioxetine (BRINTELLIX)
• Mechanisms of Action
• Similar to SSRIs and SNRIs
• More potent in inhibiting dopamine
• Also an α3-β4 nicotinic antagonist
• Adverse effects
• Lowers seizure threshold
• Suicide
• Does not cause weight gain or sexual dysfunction (even used to treat the two) 38
Mechanism of Action Norepinephrine and Dopamine Reuptake Inhibitor

 These are a class of antidepressants that are not really

categorized as a special group of antidepressants.

 The only antidepressant in this group is Bupropion

(Wellbutrin), which is an antidepressant of the
aminoketone class, chemically unrelated to tricyclics
or SSRIs.

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 Bupropion
• Bupropion is a selective catecholamine (norepinephrine and dopamine) reuptake
inhibitor. It has only a small effect on serotonin reuptake. It does not inhibit MAO.

• Bupropion is metabolised in the liver. It has at least three active metabolites;

hydroxybupropion, threohydrobupropion and erythrohydrobupropion. These
active metabolites are further metabolised to inactive metabolites and eliminated
through excretion into the urine.

• Partial agonist at 5-HT type IA receptors (decrease 5HT activity ) but enhances
dopaminergic and noradrenergic activity
41
 Bupropion

Advantages
Sexual side effects normally accompanying SSRI's do not accompany bupropion.
Interestingly, patients commonly report increased libido, perhaps evidence of its
dopaminergic properties.
No weight gain, loss of appetite.

• Common side effects

Dry mouth, tremors, anxiety, agitation, dizziness, headache, excessive
sweating, increased risk of seizures and insomnia.
 Therapeutic Uses of Bupropion

Major depression.

Bupropion is useful in ADHD (attention deficient disorder).

Bupropion also helps in reducing craving & attenuating the withdrawal

symptoms for Nicotine in tobacco users trying to quit smoking.
 Lecture Contents # 4

1.Tricyclic antidepressants (TCAs)?

2. Mechanism of action of TCAs
3.Pharmacokinetics of TCAs
4.Therapeutic uses of TCAs
5. TCAs Side effects
6. Monoamine oxidase (MAos) and depression
2

7.MAO Enzyme
8.MAOIs Mechanism Of Action
9.Book References
Part:4
TRICYCLIC ANTIDEPRESSANTS (TCAs)

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 Tricyclic Antidepressants
• Effectively relieve depression with anxiolytic and analgesic action
• First choice for treatment of depression
• Pharmacological properties
Block presynaptic NE reuptake transporter
Block presynaptic 5-HT reuptake transporter
Block postsynaptic histamine receptors
Block postsynaptic ACh receptors
 MECHANISM OF ACTION of TCAs:

• All tricyclics block reuptake pumps for both 5HT and NE in nerve terminals by
competing for binding site of the transport protein
So ↑ conc. of NE & serotonin in the synaptic cleft & at the receptor site
Facilitation of NE & serotonin transmission ---- improves symptoms of depression
• Some have more potency for inhibition of 5HT uptake pump; clomipramine,
imipramine, amitryptyline

• Others have more potency for inhibition of NE uptake pump: nortriptyline,

desipramine
TCAs inhibit serotonin, norepinephrine, and dopamine transporters, slowing reuptake
• TCAs also allow for the downregulation of post-synaptic receptors

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Tricyclic Antidepressants (TCAs)

TCAs


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 PHARMACOKINETICS of TCAs

• Peak levels: 2-6 hours post ingestion

• TCAs are "lipophilic" in nature, therefore they are well absorbed from the GIT
and readily cross the blood brain barrier to penetrate the CNS.

• Elimination: hepatic oxidation

• TCAs are metabolized in the liver by demethylation (Imipramine to

Desipramine, Amitriptyline to Nortriptyline) and by hydroxylation into
metabolites that retain the biological activity of the parent compounds.

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 Therapeutic uses of TCAs
Endogenous (Major) Depression -- moderate to severe.
Panic attack /acute episode of anxiety.
Imipramine is used for treatment of nocturnal enuresis in children and geriatric
patients as it constricts internal urethral sphincter ( anti-muscarinic effect).
Generalized Anxiety Disorder (GAD).
Obsessive Compulsive Disorder (OCD)
Attention Deficit Hyperkinetic Disorder (ADHD).
 Chronic neuropathic pains or Unexplained body pains.

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 TCAs Side Effects

Muscarinic M1 receptor antagonism - anticholinergic effects including dry

mouth, blurred vision, constipation, urinary retention and impotence

Histamine H1 receptor antagonism - sedation and weight gain

Adrenergic α receptor antagonism - postural hypotension
Direct membrane effects - reduced seizure threshold, arrhythmia
Serotonin 5-HT2 receptor antagonism - weight gain (and reduced anxiety)

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 TCAs Side effects
Non selectivity results in greater side effects
TCAs can also lead to cardiotoxicity
Increased LDH leakage Lactate Dehydrogenase (LDH)
Slow cardiac conduction
High potency can lead to mania
Contraindicated with persons with bipolar disorder or
manic depression

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 Part:5
Monoamine oxidase (MAos) and depression

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 Monoamine Oxidase
MAO is found in nearly all tissues and is located intracellularly associated with mitochondria.

Present in nerve terminals that release NA, DA (Dopamine) or 5-HT.

Located on outer surface of mitochondrial membranes.

In neurons, MAO oxidatively deaminates and inactivates any excess norepinephrine, serotonin
and dopamine, that may leak out of synaptic vesicles.
 MAO is not involved in the inactivation of released transmitter
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 MONOAMINE OXIDASE INHIBITORS (MAOIs)

MAOIs ON THE MARKET

• MAO Inhibitors (nonselective)

• Phenelzine (Nardil)
• Tranylcypromine (Parnate)
• Isocarboxazid (Marplan)
• MAO-B Inhibitors (selective for MAO-B)
• Selegiline (Emsam)

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 MAO Enzyme
MAO exists in tow forms coded by separate genes

• MAO-A: Metabolizes norepinephrine, Serotonin and Tyramine.

Inhibition of MAO-A produces Antidepressant effect .

• MAO-B: specific for dopamine.

Inhibition of MAO-B produces Anti-parkinsonian effect.

Monoamine Oxidase Inhibitors (MAOIs)
 monoamine oxidase (MAo) and depression

• MAO catalyze deamination of intracellular monoamines

• MAO-A oxidizes epinephrine, norepinephrine, serotonin
• MAO-B oxidizes phenylethylamine
• Both oxidize dopamine non preferentially
• MAO transporters reuptake extracellular monoamine

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 MAOIS MECHANISM OF ACTION

MAO contains a cysteinyl-linked flavin

MAOIs covalently bind to N-5 of the
flavin residue of the enzyme

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 MAOIs SIDE EFFECTS

Drowsiness/Fatigue Muscle twitching

Constipation Weight gain
Nausea Blurred vision
Diarrhea Headache
Dizziness Increased appetite
Low blood pressure Restlessness
Lightheadedness, Shakiness
Decreased urine output Weakness
Decreased sexual function Increased sweating
Sleep disturbances

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 Summary

Book References

1.Whalen, K., Lippincott illustrated reviews: pharmacology. 2018: Lippincott Williams & Wilkins.
2.Tripathi, K., Essential of Medical Pharmacology; 2008. New Delhi, 2008: p. 235-236.
3.Katzung, B.G., Basic and clinical pharmacology. 2012: Mc Graw Hill.
4.Brenner, G.M. and C.W. Stevens, Brenner and Stevens’ Pharmacology E-Book. 2017: Elsevier Health Sciences.
5.Shanbhag, T., S. Shenoy, and V. Nayak, Pharmacology. 2017: Elsevier Health Sciences.

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Think Positive!

Thank You