Pharmacology of

Antidepressants
PHCL411

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Depression

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

◼ Depression is the most common of the affective disorders

(Changes in mood associated with depression and/or mania)

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Classification of Depressive Disorders
❑ Traditional classification
1. Reactive (or neurotic) depression
2. Endogenous (or biological) depression

❑ Current classification (DSM-IV-TR) now DSM V

1. Major depressive disorder, single episode
2. Major depressive disorder, recurrent episode
3. Dysthymic disorder
4. Disruptive mood dysregulation disorder (<18yrs)
5. Premenstrual dysphoric disorder
6. Depressive disorder not otherwise specified

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Epidemiology
❑ Generally affect ~10% of the population
❑ 1 in 15 adults will suffer MD in any given year
❑ More prevalent in women than men (~2:1)
❑ Genetic predisposition increases both risk and incidence
❑ Highest risk of depression is between 25-44 years but can
occur at any age

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Aetiology
❑ No known cause
❑ Theories
✓Genetic theory
✓Biogenic theory
✓Dysregulation theory

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Theories of depression

❑ Genetic theory suggests that a genetic link exists for the

development of depression

❑ Biogenic theory suggests that depression is associated with

decreased levels of NE, 5-HT & DA in the brain

❑ Dysregulation theory suggests that depression is associated

with impaired regulation/homeostasis of NE, 5-HT & DA in the
brain

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Etiology of depression
• “The monoamine theory" (proposed in 1965) suggests that
depression is due to a deficiency of monoamines at certain sites
in the brain, while mania is caused by an overproduction of
these neurotransmitters.

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Pharmacological evidence supporting The Monoamine Theory of
Depression

Drug Principal action Effect in depressed

patients
TCA Block NA and 5-HT Increase MOOD
reuptake
MAO Inhibitors Increase stores of NA and Increase MOOD
5-HT
Reserpine Inhibits NA and 5-HT Decrease MOOD
storage
Methyldopa Inhibits NA synthesis Decrease MOOD

ECT Increase CNS response to Increase MOOD

NA and 5-HT
Tryptophan Increase 5-HT synthesis Increase MOOD

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Monoamine Hypothesis of Depression

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Limitation of Monoamine Theory of
Depression
Effect of Antidepressants
Biochemical
Clinical
(increase in
(Resolution
level of NT
of Depressive
(NA, 5HT and
Symptoms)
DA)

??? Secondary
Adaptive
Changes

Immediately 2-3 weeks

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 The Need to Modify the Biogenic Amine
Hypothesis
◼ Iprindole has no effect on monoamine metabolism or uptake but is an
antidepressant.

◼ Amphetamine increases NA release and inhibits NA uptake but is not effective

against endogenous depression.

◼ Cocaine inhibits NA & DA uptake but is not antidepressant.

◼ Methysergide is a 5-HT antagonist but does not affect mood in depressed

patients.

◼ L-Dopa increases NA synthesis but does not affect mood in depressed patients.

◼ Poor correlation between the rate of onset of action of antidepressants (rapid)

and the rate at which depressed patients improve (slow).

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Gene Expression Hypothesis of Depression

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Brain-derived neurotrophic factor (BDNF)

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Postulated Adaptive Mechanisms at
Gene Exprerssion

CREB (cAMP response

element-binding
protein) is a
cellular transcription
factor.

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-
-

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 Noradrenaline 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.

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 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 involved in:
• Anxiety.
• Sleep.
• Sexual behavior.
• Temperature regulation.
• CSF production.
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 Treatment of Depression
Treatment Options

1. Psychotherapy
2. Pharmacotherapy
3. Electroconvulsive therapy (ECT)

Choice of treatment option should be patient-specific

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 Psychotherapy of Depression
Indication

1. Treatment of mild-moderate depression (comparable efficacy

with pharmacotherapy)
2. Treatment of severe depression (In conjunction with
pharmacotherapy)

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 Psychotherapy of Depression

Cognitive-Behavioral • short-term, goal-oriented psychotherapy treatment

that takes a hands-on, practical approach to problem-
Therapy (CBT) solving

Interpersonal • a brief, attachment-focused psychotherapy that

centers on resolving interpersonal problems and
Therapy symptomatic recovery.

Psychodynamic • is a form of depth psychology, the primary focus of

which is to reveal the unconscious content of a client's
Therapy psyche in an effort to alleviate psychic tension.

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 Psychotherapy of Depression
Limitations

1. Delayed effect
2. Cost
3. Non-availability of trained therapists

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 Electroconvulsive Therapy (ECT)
Indications

1. Patients with treatment-resistant

depression
2. Severe suicidal depression
3. Psychotic depression
4. Depression in pregnancy

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 Electroconvulsive Therapy (ECT)
Procedure

❑ Involves passing brief electric pulse through the brain

between two electrodes attached to the skull to produce
controlled seizures

❑ Frequency of treatment is variable but most commonly three

sessions can be used once or twice weekly for 3-4 weeks

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 Electroconvulsive Therapy (ECT)

❑ ECT is generally safe, rapid-acting and highly effective

❑ Adverse effects are minimal and may consist of confusion,

headache, muscle aches, temporary loss of recent memory
and rarely cardiovascular effects

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•Pharmacotherapy of Depression

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Mechanism of Action of Antidepressants
• Most antidepressants are believed to work by slowing the
removal of certain neurotransmitters from the brain.
• NTs are needed for normal brain function and are involved in
the control of mood and other functions, such as eating, sleep,
pain and thinking.
• Antidepressants work by making these natural chemicals more
available to the brain.

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 Antidepressants

Monoamine Inhibitors of
Actors at α2, 5-
Oxidase Monoamine
HT receptors
Inhibitors Reuptakes

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Monoamine Oxidase (MAO)
There are two forms of monoamine oxidase enzyme; MAO-A and MAO-B

MAO-A
• found predominantly in peripheral adrenergic nerve ending, Intestinal mucosa, human
placenta and liver
• has substrate preference for 5-HT and is the main target for antidepressant MAOIs

MAO-B
• found in brain (basal ganglia), platelet and liver
• has substrate preference for phenylethylamine

Both enzymes act on NA and dopamine

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Monoamine Oxidase (MAO)
• Catalyses oxidative deamination of extravesicular NA, DA or 5-
HT.

• MAO regulates the free intraneuronal concentration of NA, 5-HT

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 Antidepressants

Monoamine Inhibitors of
Actors at α2, 5-
Oxidase Monoamine
HT receptors
Inhibitors Reuptakes

Selective

Non Selective

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 Antidepressants

Monoamine Inhibitors of
Actors at α2, 5-
Oxidase Monoamine
HT receptors
Inhibitors Reuptakes

Selective Non Selective

Reversible

Irrevesible

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Classification of MAOIs based on
Selectivity of Action
MAOIs

Non selective
Selective agents
agents

Phenelzine, MAO-A MAO-B

Tranylcypromine Selective Selective

Moclobemide,
Selegiline
iproniazid

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Classification of MAOIs based on
Reversibility of actions
MAOIs

Irreversible Reversible
agents agents (RIMA)

Drug examples
Drug example
Tranylcypromine
Moclobemide
Phenelzine
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Side effects
• Decreased sleep/insomnia, Nausea, Diarrhoea, Dry mouth,
Hypertension (high BP) and Hypotension (low BP), Dizziness,
Weight gain, Oedema (water retention), Sexual dysfunction,
Muscle spasms, Weakness and Confusion

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 Nonselective MAOIs not favorable (Cheese Reaction)

Cheese, beer, wine, Due to irreversible block of MAO

meat, fish, yeast, These escape degradation in
(contain large amount of tyrammine intestinal wall and liver
and other indirectly acting amines)

◼ Hypetensive crises, CVA Reach to circulation Displace large

amount of noradrenalin from
◼ Medical Emergency
loaded nerves

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 Reversible inhibitor of MAO-A
(RIMAs)
◼ Moclobemide
◼ Reversible and selective MAO-A inhibitor
◼ Short duration of action
◼ Competitive enzyme inhibition
◼ Tyramine is able to displace it
◼ Cheese reaction is less likely
◼ Devoid of anticholinergic, sedative, cognitive,
cardiovascular effects
◼ Good for elderly with heart diseases
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 Antidepressants
Inhibitors of
Monoamine Actors at α2, 5-
Monoamine
Oxidase HT receptors
Reuptakes
Inhibitors

Selective SSRI Non- Selective

TCA HCA

TECA

SNRI

NDRI

SARI

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 Selective SSRI

TCA
Inhibitors of
Monoamine
Reuptakes
TeCA

Non-Selective SNRI

NDRI

SARI

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A. Tricyclic Antidepressants (TCAs)
• TCAs are divided into 2 major groups: tertiary amines &
secondary amines.
• MOA: Act to inhibit the reuptake of biogenic amines by
inhibiting norepinephrine transporter, mostly NE, as well as 5-
HT and block action of ACh.
• The tertiary amines inhibit the reuptake of NE as well as 5HT,
whereas the secondary amines are relatively selective NE
reuptake inhibitors.

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• Examples: Amitriptyline, Imipramine, Clomipramine (Anafranil),
Doxepin (Silenor), Trimipramine (Surmontil), Protriptyline
(Vivactil), Desipramine (Norpramin), Nortriptyline (Pamelor),
Amoxapine (Asendin).
• Uses: Several types of depression, OCD, and Enuresis.
• Other off-label uses include: Panic disorder, Bulimia, Chronic
pain (for example, migraine, tension headaches, diabetic
neuropathy, and post herpetic neuralgia), Phantom limb pain,
Chronic itching, and Premenstrual symptoms.

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2. TeCAs
• Maprotiline is a tetracyclic antidepressant approved for depression.
• It may alternatively be classified as a tricyclic antidepressant, specifically a
secondary amine.
• Maprotiline is similar to TCAs in inhibition of neuronal noradrenaline
reuptake, anticholinergic activity display and does not affect monoamine
oxidase activity.
• It differs from TCAs in that it does not appear to block serotonin
reuptake.
• May be used to treat depressive affective disorders, including dysthymic
disorder (depressive neurosis) and major depressive disorder.
• It is effective in reducing anxiety symptoms associated
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3. Selective Noradrenaline Reuptake Inhibitors
(SNRIs)
• SNRIs are among the newer types of antidepressant.

• They act to block the reuptake of both serotonin and norepinephrine.

• They include duloxetine (Cymbalta), venlafaxine (Effexor), desvenlafaxine

(Khedezla, Pristiq), levomilnacipran (Fetzima)

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Duloxetine
• Duloxetine is used to treat depression and anxiety.
• It can also be used to relieve nerve pain (peripheral neuropathy) in
patient with diabetes or ongoing pain due to medical conditions such
as arthritis, chronic back pain, or fibromyalgia
• May improve your mood, sleep, appetite, and energy level, and
decrease nervousness.
• It acts to restore the balance of serotonin and norepinephrine in the
brain.
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S/E
• Nausea, dry mouth, constipation, loss of appetite, tiredness,
drowsiness, or increased sweating, dizziness or light
headedness, especially from start or on increase dose, Increase
in BP, confusion, easy bruising/bleeding, decreased interest in
sex, changes in sexual ability, muscle cramps/weakness, tremor,
difficulty urinating, signs of liver problems (such as
stomach/abdominal pain, persistent nausea, vomiting, yellowing
eyes/skin, dark urine) can also occur.

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Pharmacokinetics
• Drugs that can cause bleeding/bruising interact with duloxetine.

• Medications like cimetidine, certain quinolone antibiotics affects the

removal of duloxetine from the body.

• Affects clearance of drugs like antiarrhythmics (such as

propafenone, flecainide, quinidine), antipsychotics (such as
thioridazine), tricyclic antidepressants (such
as desipramine, imipramine)

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Pharmacokinetics cont’d

• The risk of serotonin syndrome increases when taken with

other drugs like street drugs such as MDMA, St. John's wort,
certain antidepressants like SSRIs, other SNRIs (such as
desvenlafaxine/venlafaxine), tryptophan, among others.

• The risk of serotonin syndrome/toxicity is more likely when

dose of the drug is started or increased.

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4. NDRIs
• Bupropion is the only drug in this class mainly used to treat
depression.
• It is an aminoketone, chemically unrelated to TCAs, TeCAs and SSRI
• It can also be used to help people stop smoking.
• It was first approved for clinical use in the United States (U.S.) in
1985 and became one of the most frequently prescribed
antidepressants in the English-speaking world.

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NDRI……

• The exact mechanism of action of bupropion is not fully understood.

• However, it enhances both noradrenergic and dopaminergic

neurotransmission via reuptake inhibition of the norepinephrine
transporter and the dopamine transporter.

• It also act to induce weight loss in addition to antidepressant activity

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5. SARIs
• SARIs act in two ways.
i. Prevention of serotonin reuptake.
ii. Also prevention of serotonin particles released in a synapse from
binding at certain undesired receptors and redirect serotonin
instead to other receptors that can maintain nerve cells within
mood circuits to function better.
• Examples include Nefazodone (serzone) and trazodone.

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SSRIs
• The first-line treatment for moderate-to-severe depression
• MOA: Alter serotonin levels in the brain
• Superior to others in children, teens and the elderly depression and
anxiety.
• Side effects often include nausea, Headache, Anxiety, Dry mouth,
Insomnia, a variety of sexual dysfunctions and Menstrual changes
• Examples: Escitalopram (lexapro), Citalopram (celexa), Fluoxetine
(prozac), Paroxetine (paxil, Pexeva), Sertraline (Zoloft), Vilazodone
(Viibryd)

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SSRI cont’d
• Each SSRI has a certain profile of its own particular
• Other Uses -Anxiety disorders including panic attacks, OCD,
PTSD and social anxiety disorder; Eating disorders; Chronic
pain; Premenstrual dysphoric disorder
• Interact with tryptophan, Blood-thinners like warfarin or
aspirin, Alcohol, Other antidepressants such as MAOIs
• Serotonin syndrome is caused by medications that increase
5-HT levels

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SSRI cont’d
• Taking an SSRI medication within two weeks of an MAOI may
cause serious side effects.
• SSRI withdrawal is more common for people who have taken
medication for longer than six weeks.
• Withdrawal symptoms may include: Irritability, Anxiety,
Insomnia, Headaches, Dizziness, Fatigue, Nausea
• Should be used with caution in patients with liver disease,
kidney disease, mania, lactation and pregnancy and in patients
with history of seizure or bipolar disorders
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 Antidepressants

Inhibitors of
Monoamine Actors at α2, 5-
Monoamine
Oxidase HT receptors
Reuptakes
Inhibitors

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Mianserin
• Unique not inhibit NA and 5-HT uptake
• Blocks pre-synaptic alpha 2 receptors increases release and
turnover of NA
• Antagonist at 5HT2, 5HT1c, and H1 receptors
• Has sedative effect
• Damages liver and bone marrow
• Cognitive impairment
• Weight gain
• Agranulocytosis

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Mirtazapine
• A noradrenergic and specific serotonergic antidepressant
(NaSSA)
• No effects as monoamine reuptake inhibitor.
• Has significant feature is its effect as histamine 1 antagonist
(linked to sedation and weight gain).

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• It is commonly used in the elderly population.
• It has no significant drug-drug interactions making it
attractive for use in combination with other antidepressants
as augmenting option

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 Other Clinical Uses
• Anxiety disorder (Generalised, panic and Social anxiety
disorders)
• Add-on to antipsychotics in Schizophrenia (negative
symptoms)
• Emesis
• Insomnia

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Pharmacokinetics
• Half-life:20-40h
• No active metabolites
• Not a significant inhibitor
• Metabolised by CYP1A2, CYP2D6 and CYP3A4
• No significant DDI

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Adverse Effects
• Agranulocytosis
• Dry mouth
• Weight gain
• Sexual dysfunction
• Insomnia
• GI disturbance

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Agomelatine
• Agomelatine is an atypical antidepressant
• It is a structural analogue of Melatonin developed in 2005

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Mechanism of Action
Agonism at MT1
Enhancement of
and MT2 melatonin 5HT2C antagonism 5HT2A agonism
BDNF
receptor

Resynchronization Increase in the

Reduction in 5HT Promotion of
of circadian level of NA and DA
firing neurogenesis
rhythm in the cortex

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 • Treatment of Acute
Depression and
Maintenance
Therapy
Clinical • Seasonal Depression
• Bipolar Depression
Indications • Generalised Anxiety
Disorder
• Circadian rhythm
sleep disorder
• Night eating disorder

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 • Nausea
• Dizziness
• Somnolence
• Insomnia
• Migraine
• Anxiety
Adverse • Constipation
Effects • Diarrhoea
• Fatigue
• Back pain
• Hyperhidrosis
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Contraindications Drug Interactions

• Alcoholism • Fluvoxamine
• Non-alcohol fatty liver disease • Ciprofloxacin
• Mania/Hypomania • Estrogen
• Dementia • Propranolol
• Obesity
• Children
• Pregnancy and Lactation

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