ANTI-DEPRESSANT DRUGS

Deo L. Panganiban, MD, FPSECP

March 7, 2014; 3:00 5:00 PM
Pharmacology
February 4, 2014, 3:00-5:00 PM
Pediatrics
Definition: depression

OUTLINE

Antidepressants
Mechanisms of Antidepressants
SSRIs
SNRIs

DEPRESSION
Early detection of psychosis and depression can
minimize the of these disorders
SYMPTOMS
Sadness intense
Hopelessness
Despair
No pleasure in usual activities
Sleep pattern & appetite changes
Loss of energy
Suicidal thoughts
Mania is characterize by the opposite behaviour
that there is over enthusiasm, rapid thinking and
speech patterns, extreme self-confidence and
impaired judgement
Mania and depression are different from
schizophrenia. Schizophrenic has disturbances in
thought (delusion, hallucination)

ANTIDEPRESSANTS
SELECTIVE SEROTONIN RE-UPTAKE INHIBITORS
Citalopram
Escitalopram
Fluoxetine
Fluvoxamine
Paraxetine
Sertraline
SEROTONIN/NOREPINEPHRINE RE-UPTAKE
INHIBITORS
Duloxetine
Venlafaxine
ATYPICAL ANTIDEPRESSANTS
Bupropion (very important)
Mirtazapine
Nefazodone
Trazodone (very important)
TRICYCLIC ANTIDEPRESSANTS (POLYCYCLIC
ANTIDEPRESSANTS)
Amitriptyline
Amoxapine
Clomipramine
Desipramine
Doxepine
Imipramine
Transcriber/s: Team HRH
Formatting: Jan Cynric Cacao
Editor/s: Jan Monzon

Atypical Antidepressants
Tricyclic Antidepressants
MAO Inhibitors
Mania and Bipolar Disorders
Other Mood Stabilizers
Maprotiline
Nortriptyline
Protriptyline
Trimipramine
MONOAMINE OXIDASE INHIBITORS
Phenelzine
Selegiline
Trancyclopramine
MANIA & BIPOLAR DRUGS
Carbamazipine (important)
Lithium salts(older drug)
Valproic acid
*Most effective antidepressants will potentiate either
directly or indirectly the actions of neurotransmitter
NOREPINEPHRINE or SEROTONIN. In some of the
drugs both of the neurotransmitters are affected. This
leads to Biogenic amine theory.

MECHANISMS
BIOGENIC AMINE THEORY
Depression is associated with deficiency of
monoamines, especially Norepinephrine and
Serotonin, at functionally important receptor sites
in the brain and that elation(opposite of
depression) is associated with excess of such
amines
Conversely, the theory states that mania is caused
by overproduction of NE and 5HT. However this
theory does not explain why the pharmacological
effects of any antidepressants and anti-mania
drugs on neurotransmission occurs immediately
whereas the time course of therapeutic response
occurs over several days.
We have to modify the biogenic amines here. The
potency of antidepressant drugs in blocking our
neurotransmitters does not correlate with
clinically anti-depressant effects; its not all about
the binding but the modification of effect
Some of them may be mild or attenuated others
would not be attenuated at all. So this suggests
that there is decreased uptake of
neurotransmitters NE or 5HT as the only initial
effect of the drugs

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It has been proposed that presynaptic inhibitory

receptor actually decrease in the brain over a 2-4
weeks period with our antidepressant drugs.
This is what we call down regulation of our
inhibitory receptors. This permits greater
synthesis and also permits the release of
neurotransmitters into the synaptic cleft and
therefore enhances the signalling in the post
synaptic neurons presumably leading to a
treatment or therapeutic response that is stable
and long-term

SELECTIVE SEROTONIN RE-UPTAKE

INHIBITORS (SSRI)
The NTs have been already released from our
presynaptic nerves and all you have to do is to
inhibit their reuptake specifically serotonin
This is a group of diverse antidepressant drugs
and they specifically inhibit the reuptake of
serotonin and they have 300-3000 fold greater
selectivity for serotonin transporters as to
compared to the NE transporters
This is contrast with your tricyclic antidepressants
(TCAs) that will non-selectively inhibit the
reuptake of Epinephrine and serotonin
Both tricyclic and SSRIs actually exhibits very little
activity to block dopamine receptors. SSRIs have
little activity in blocking muscarinic, alpha
adrenergic receptors and histaminic (H1)
receptors. Therefore the common side effects
that are seen with your TCAs (because TCAs
occupy these receptors) like orthostatic
hypotension, sedation, xerostomia (dryness of the
mouth and blurring of vision) are NOT commonly
seen in SSRIs. Therefore SSRIs, have largely
replaced TCAs and MAO inhibitors for DOC for
depression
Citalopram and Fluoxetine- are both racemic
mixture with their S-enantiomers being more
potent inhibitors of 5HT reuptake.
Escitalopram is a pure S-enantiomer of citalopram
that thus have higher POTENCY.
ACTIONS OF SSRIs
Blocks RE-UPTAKE of Serotonin Increased
Serotonin (synaptic cleft) Greater post-synaptic
neuronal activity
Effects: 2 weeks (meaning not for very acute
symptoms)
Maximum benefit: 12 weeks or more
NOT uniformly effective (one may respond to a
anti-depressive drug but not respond to other
drug; know what is effective for your patient)
80 %of the patients have positive response
to one drug, there is still other patients you
need to design for treatment
No CNS stimulation or mood elevation in
NORMAL persons (only effective in patients with
depression)
THERAPEUTIC USES
Treatment of DEPRESSION(as effective as TCAs)
Treat other Psychiatric disorders:
Obsessive-Compulsive - Fluvoxamine (only
approved drug)
Transcriber/s: Team HRH
Formatting: Jan Cynric Cacao
Editor/s: Jan Monzon

Panic
Generalized Anxiety
Post-traumatic Stress
Social anxiety disorder
Premenstrual dysphoric disorder
Bulimia nervosa - Fluoxetine (only approved
drug)

PHARMACOKINETICS
ORAL: ALL well absorbed
Peak levels: 2 8 hours
Food: little effect on absorption
SERTRALINE food increases absorption;
significant First-pass metabolism
Well distributed; large volumes of
distribution(excess of our body weight 15-30kg)
Plasma half-lives: 16 -36 hours
Metabolism = Hepatic: P450 enzymes
Extensive glucoronide or sulfate conjugation
(metabolites does not contribute to the activity of
the parent drug)
FLUOXETINE:
Much longer half-life: 50 hours
(sustained release preparations which
will allow the doctors to dose a patient
only once a week)
S-norfluoxetine (S-enantiomer): potent
(half-life: parent drug: 50 hours,
metabolite: average is 10 days and as
potent as the parent compound)
Along with Paroxetine very potent
inhibitors of CYP2D6 (elimination of
TCA drugs, neuroleptic drugs, some
anti-arrhythmic, adrenergic as well as
adrenergic antagonist drugs. SO if you
inhibit CYP2D6, this will cause toxicity.
It also notable that Caucasians
metabolize Paroxetine and Fluoxetin.
There also isoenzymes that are involve
in metabolism of SSRIs, this will affect
multiple medications.
Excretion of SSRIs is primarily
through the kidneys except for
Sertraline and Paroxetine (fecal
excretion,50% for Sertraline). Dosages
of these drugs should be adjusted
downward if with liver impairment
ADVERSE EFFECTS
SSRIs have less severe adverse effects compared
to TCAs and MAO inhibitors
Headaches
Sweating
Anxiety & agitation
GIT effects: nausea, vomiting, diarrhea
Weakness & fatigue
Sleep disturbances (insomnia, somnolence)
Sexual dysfunction
Weight changes (gain weight most often)
Drug-drug interactions
CAUTIONS & CONTRAINDICATIONS
Sleep disturbances
Paroxetine and Fluvoxamine are more
sedating than activating drugs, useful in
depressed and patients with difficulty in
sleeping. Conversely patients who are

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fatigue or with excessive somnolence may

benefit from activating antidepressants
(Sertraline and Fluoxetine)
Sexual dysfunction
Manifests as loss of libido, delayed
ejaculation (male) and anorgasmia (female).
These cases are not reported to the doctors
because patients are shameful of these
SOLUTIONS:
Replace the offending drug with fewer
sexual side effects (Bupropione and
Mirtazepine)
Lower the dose of the current drug
used
For men with erectile dysfunction (give
Sildenafil or Vardenafil)
Use in children and teenagers
Use cautiously because 1:50 children
becomes more suicidal. Monitor closely their
behaviors that might lead to more
depression and suicidal thinking especially
when you increase or decrease the dose of
the drug
Overdoses
Does not cause any cardiac arrhythmia but
lower the seizure threshold especially in
patients with history of seizures and epilepsy
Serotonin syndrome
All SSRIs might cause Serotonin
syndrome. Component symptoms
include:
Hyperthermia
Muscle rigidity
Increase sweating
Myoclonic muscle twitching
Changes in mental status and vital
signs
*These complications happen when you combine
SSRIs with MAO inhibitors or another highly
serotogenic drugs)
*You need extended time (2 weeks) to wash out these
drugs before you administer another antidepressant or
another class of drugs
Discontinuation syndromes
Occur with abrupt drug withdrawal. Agents
with short half-lives and those having
inactive metabolites have higher risk of this
syndrome
Fluoxetine lowest risk
Components include:
Headache
Nervousness
Changes in sleep pattern

SEROTONIN/NOREPINEPHRINE REUPTAKE INHIBITORS (SNRI)

SNRIs (second-line) are used when SSRIs are not
any more effective. Depression accompanied by
chronic painful symptoms (backaches, muscle
aches) are decreased by SNRIs
SNRIs and TCAs with their dual actions in
inhibiting 5HT and NE reuptake are effective in
Transcriber/s: Team HRH
Formatting: Jan Cynric Cacao
Editor/s: Jan Monzon

relieving physical symptoms which may be due to

neuropathic pain or peripheral diabetic
neuropathy
SNRIs differ from TCAs because they have very
little activity on adrenergic, muscarinic or
histaminic receptors. SNRI thus have fewer
effects in these receptors, and thus elicit LESS
side effects than TCAs.
Duloxetine & Venlafaxine
Both these drugs may cause
DISCONTINUATION SYNDROME if the
treatment is stopped abruptly
VENLAFAXINE
Potent inhibitor of serotonin re-uptake
Inhibitor of Norepinephrine re-uptake:
Medium or higher doses
Mild Dopamine re-uptake inhibitor:
High doses
Minimal inhibition of Cytochrome P450
isoenzymes: substrate of CYP2D6
Parent drug + active metabolite half-life: 11 hours
27% plasma protein bound
SIDE EFFECTS
Nausea, headache, sexual dysfunction
Dizziness, insomnia, sedation, and constipation
High doses: increase BP and HR
DULOXETINE
Inhibitor of Serotonin & Norepinephrine reuptake at ALL doses
Extensive hepatic metabolism
Contraindicated in hepatic insufficiency
Urinary excretion of metabolites
Use is not for renal end-stage patients
Food: delays absorption
Half-life: approx. 12 hours
Highly bound to plasma proteins
SIDE EFFECTS
GIT: nausea, dry mouth, constipation
Diarrhea and vomiting are less commonly
seen
Insomnia, dizziness, somnolence & sweating
Sexual dysfunction
Increase in BP and HR

ATYPICAL ANTIDEPRESSANTS
Mixed group of drugs that have actions on several
different sites
Not more efficacious than TCAs or SSRIs but
differ in their side effect profiles
BUPROPION
Weak dopamine & Norepinephrine re-uptake
inhibitor
Short half-life dosing frequency; extendedrelease formulation
Assists in decreasing craving & attenuates
nicotine withdrawal symptoms in patient who are
trying to quit smoking
Metabolism: CYP2D6 pathway
Low risk of drug to drug interactions

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SIDE-EFFECTS
Dry mouth (xerostomia), sweating, nervousness
Tremors
Low sexual dysfunction incidence
INCREASED Seizure risk when given at high
doses
MERTAZAPINE
ENHANCES Serotonin and Norepinephrine
neurotransmission
Blocks 5-HT2 receptors
Sedative due to anti-histaminic activity
(markedly seen)
Does not occupy muscarinic receptors
Does not have anti-muscarinic side effects or
interferes with sexual functioning which are
seen in SNRIs
Advantage on patients who are depressed
and have difficulty in sleeping
INCREASES appetite and weight gain
NEFAZODONE & TRAZODONE
Weak inhibitors of Serotonin re-uptake
Ability to block POSTSYNAPTIC 5-HT2A
receptors
Chronic use: DESENSITIZE 5-HT2A
PRESYNAPTIC receptors increased
SEROTONIN release
Both drugs are sedating due to potent antihistaminic activity
SIDE-EFFECTS:
Priapism Trazodone
Hepatotoxicity Nefazodone

TRICYCLIC ANTIDEPRESSANTS
Blocks norepinephrine and serotonin reuptake
into the neuron
If discovered today, may be classified under SNRIs
except for their difference in adverse effects
Tertiary amines
Imipramine prototype
Amytriptyline
Clomipramine
Doxepine
Trimipramine
Secondary amines
Desipramine
Nortriptyline
Protryptyline
Marprotiline and Amoxapine related tetracyclic
antidepressants; also known as polycyclics
all have similar therapeutic effects and choice of
the drug depends on how the patient will tolerate
the side effects or any pre-existing medical
conditions or the duration of action of the drug
MECHANISM OF ACTION
Inhibition of neurotransmitter re-uptake
Potent inhibitors of NE & Serotonin into
presynaptic neurons
Therapeutic doses: DOES NOT block
Dopamine transporters
Increases Monoamine concentrations in
synaptic cleft results in antidepressant
effects
Transcriber/s: Team HRH
Formatting: Jan Cynric Cacao
Editor/s: Jan Monzon

MAPROTILINE & DESIPRAMINE selective

inhibitors of NE re-uptake
Blocking of receptors
Also blocks serotogenic, alpha-adrenergic,
histaminic & muscarinic receptors
Unknown therapeutic effects
Responsible for untoward effects
AMOXAPINE: blocks D2 receptors
ACTIONS
Elevates mood
Improves mental alertness
Increases physical activity
Reduces morbid pre-occupation in about 50-70%
of patients with major depression
Onset of mood elevation is every slow
Should be treated for at least TWO weeks
Does not cause central nervous stimulation or
mood elevations in normal individuals
Physical and psychological dependence: rarely
reported
Necessitates very slow withdrawal or
termination to minimize discontinuation
syndrome
THERAPEUTIC USES
Treats MODERATE to SEVERE DEPRESSION
Panic disorder
Bed-wetting (in children) IMIPRAMINE
Treat migraine headache & chronic pain AMITRIPTYLINE
PHARMACOKINETICS
ORAL: well-absorbed
Widely distributed; penetrates CNS readily
Variable half-lives
Variable first-pass metabolism: low or
inconsistent bioavailability
4-8 weeks initial treatment period
Metabolism: hepatic microsomal system;
conjugated with glucuronic acid
ADVERSE EFFECTS
Blurred vision, xerostomia, urinary retention,
constipation, aggravation of narrow-angle
glaucoma anti-muscarinic effects
Slows cardiac conduction
Orthostatic hypotension: dizziness & reflex
tachycardia (IMIPRAMINE)
Nortriptyline causes less orthostatic
hypotension
Sedation prominent in the first several weeks of
treatment due to blockade of histamine H1
receptors
Weight gain: very common adverse effect
Sexual dysfunction: evidenced by erectile
dysfunction in men and anorgasmia in women
PRECAUTIONS
In Manic-Depressive patients: may cause a switch
to manic behavior
Narrow therapeutic index
5-6 daily low dose of Imipramine can be
lethal
In Suicidal patients: limit dose; monitor closely

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May exacerbate unstable angina, benign prostatic

hyperplasia, epilepsy & pre-existing arrhythmias
Caution use in very young & in elderly

EFFECT OF MAO INHIBITORS

MAO inhibitors prevent inactivation of monoamines
within a neuron, causing excess neurotransmitter to
diffuse into the synaptic space.

MONOAMINE OXIDASE INHIBITORS

Phenelzine
Selegiline previously approved for Parkinson's
disease now also approved for depression
Trancyclopramine

Monoamine oxidase (MAO) is an enzyme found in the

mitochondria, the nerves and other tissues
(gastrointestinal tract and the liver.)
In the neuron, MAOs function as safety valves to
oxidatively deaminate any excess neurotransmitter
molecules (NE, DA, Serotonin) that may leak out of the
synaptic vesicles.
MAOIs irreversibly or reversibly inactivate the enzymes
permitting neurotransmitter molecules to escape
degradation and therefore to both accumulate within
the presynaptic neuron and leak into the presynaptic
space.
This is believed to cause activation of NE, and
Serotonin receptors and may be responsible for the
indirect antidepressant actions of these drugs.
Use of MAOIs is now limited because of complicated
dietary restrictions required for patients taking these
drugs.
MECHANISM OF ACTION

*NORMAL MONOAMINE TRANSMISSION

Diagram shows how MAO inactivates monoamines
(norepinephrine, serotonin, and dopamine) that leaks from
a synaptic vesicle.

Forms stable complexes with Monoamine oxidase

IRREVERSIBLE INACTIVATION (Phenelzine)
Increased NE, Serotonin, and Dopamine
stores (excess neurotransmitter will
subsequently diffuse into the synaptic space)
Drugs also inhibit HEPATIC & GIT MAO
High drug-drug & food- drug interactions.
Both tissues catalyze the oxidative
deamination of the drug and potentially
toxic substances such as tyramine which is
found in certain foods
SELEGILINE, administered as a transdermal
patch may produce less inhibition of hepatic
MAO at low doses, avoiding the first pass
metabolism
ACTIONS
Fully inhibited = days after treatment
Actions are delayed several weeks
Agitation or insomnia: SELEGILINE &
TRANCYCLOPROMINE (have amphetamine-like
stimulant effect)
THERAPEUTIC USES
Treatment of DEPRESSION
Unresponsive or Allergic to TCAs
Strong anxiety
Low psychomotor activity patients
Treat PHOBIC states
ATYPICAL DEPRESSION (manifested as very
labile moods, rejection sensitivity, and appetite
disorders)
*Note: MAO Inhibitors = LAST-LINE AGENTS

Transcriber/s: Team HRH

Formatting: Jan Cynric Cacao
Editor/s: Jan Monzon

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PHARMACOKINETICS
ORAL: well-absorbed
EFFECTS ONSET require 2-4 weeks treatment
Enzyme regeneration weeks after drug
termination
SWITCHING Antidepressant drug : allow for 2
weeks delay
METABOLISM: Hepatic
EXCRETION: Urinary

ADVERSE EFFECTS
Drug-Drug interactions:
TYRAMINE (from diet) NOT degraded =
release of large amounts of stored
CATECHOLEAMINES = occipital headache,
stiff neck, tachycardia, nausea,
hypertension, cardiac arrhythmias, seizures,
even stroke
Tyramine-induced HPN: Treat with
PHENTOLAMINE or PRAZOSIN
Drowsiness, orthostatic hypertension,
blurring of vision, xerostomia, dysuria &
constipation
SEROTONIN Syndrome:
MAO INHIBITOR + SSRIs (Should not
be co-administered)
Washout period: 2 weeks
FLOUXETINE: 6 weeks
MAO Inhibitors + BUPROPION = SEIZURES

MANIA & BIPOLAR DISORDERS

LITHIUM SALTS prophylactic, mood stabilizer
EFFECTIVE: 60-80% of MANIA & HYPOMANIA
Mode of Action UNKNOWN: Attenuate
signalling via receptors @ phosphatidylinositol
biphosphate (PIP2) 2nd-messenger system
INTERFERES with re-synthesis of PIP2
LITHIUM
ORAL
Excretion: Urinary
Safety factor & Therapeutic index = LOW

ADVERSE EFFECTS:
Headache, xerostomia, polydipsia, polyuria,
polyphagia, GIT distress (nausea and vomiting),
tremors, dizziness, fatigue, skin reaction &
sedation
HIGH LEVELS: Ataxia, slurred speech, coarse
tremors, confusion, seizures

SIDE EFFECTS

*Diabetes insipidus that results from Lithium can be

treated with Amiloride.
Thyroid function can also be decreased therefore
monitoring thyroid levels is essential
Causes no noticeable effect on normal individuals

OTHER MOOD STABILIZERS

ANTI-EPILECTICS: Carbamazepine, Valproic acid,
Lamotrigine (have been successful in treatment
of Bipolar disorders)
ATYPICAL ANTIPSYCHOTICS:
Improve Manic symptoms) Benzodiazepines
as adjuncts or acute stabilization;
Risperidone, Olanzapine, Ziprasidone,
Aripiprazole & Quetiapine
Foods that contain tyramine include aged cheese,
aged meat (ham), chicken liver, pickled or smoked fish
(anchovies, sardines), red wine These should be
avoided when taking MAOIs.
Treatment using MAOI may be dangerous in severely
depressed patients with suicidal tendencies. They
might attempt suicide by taking foods containing
tyramine.
From Wikipedia:
Serotonin syndrome is not an idiopathic drug reaction;
it is a predictable consequence of excess serotonergic
activity at central nervous system (CNS) and
peripheral serotonin receptors.[1] For this reason,
some experts strongly prefer the terms serotonin
toxicity or serotonin toxidrome because these more
accurately reflect the fact that it is a form of
poisoning.
The symptoms are often described as a clinical triad of
abnormalities:
Cognitive effects: headache, agitation, hypomania,
mental confusion, hallucinations, coma
Autonomic effects: shivering, sweating,
hyperthermia, hypertension, tachycardia, nausea,
diarrhea.
Somatic effects: myoclonus (muscle twitching),
hyperreflexia (manifested by clonus), tremor.

ANTIDEPRESSANT DRUGS: SUMMARY OF SIDE EFFECTS

DRUG CLASS
DRUG
FLUVOXAMINE
SSRIs
PAROXETINE
ATYPICAL ANTIDEPRESSANTS

SEDATION
TRICYCLIC/POLYCYCLIC
ANTIDEPRESSANTS

Transcriber/s: Team HRH

Formatting: Jan Cynric Cacao
Editor/s: Jan Monzon

MIRTAZAPINE
NEFAZODONE
TRAZODONE
AMITRIPTYLINE
AMOXAPINE
CLOMIPRAMINE
DOXEPIN
IMIPRAMINE
MAPROTILINE
NORTRIPTYLINE
TRIMIPRMINE

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TRICYCLIC/POLYCYCLIC
ANTIDEPRESSANTS

ORTHOSTATIC HYPOTENSION

MAO INHIBITORS

TRICYCLIC/POLYCYCLIC
ANTIDEPRESSANTS

WEIGHT GAIN

ATYPICAL ANTIDEPRESSANTS

SSRIs
GIT DISTRESS
SEROTONIN/NE
RE-UPTAKE INHIBITORS
ATYPICAL ANTIDEPRESSANTS
TRICYCLIC/POLYCYCLIC

AMITRIPTYLINE
DOXEPIN
IMIPRAMINE
PHENELZINE
TRANCYCLOPROMINE
AMITRIPTYLINE
CLOMIPRAMINE
IMIPRAMINE
DOXEPINE
TRIMIPRAMINE
MIRTAZAPINE
CITALOPRAM
ESCITALOPRAM
FLUOXETINE
FLUVOXAMINE
PAROXETINE
SERTRALINE
DULOXETINE
VENLAFAXINE
NEFADOZONE
CLOMIPRAMINE

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RECORDINGS

NOTES

DEVIATIONS

810%

CREDITS

To two of my friends who wants to remain

anonymous

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Transcriber/s: Team HRH

Formatting: Jan Cynric Cacao
Editor/s: Jan Monzon

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