1. ANTIDEPRESSANTS

2. OVERVIEW OF DEPRESSION
 DepressionDepression is a state of low mood and
aversion to activity. Depression is a
syndrome.
 Depressive syndromes :Depressive syndromes :
- major depression(with subtypes)
- dysthymic disorder(low-grade but very
chronic form of depression, which lasts
for more than 2 years)
- minor depression

3. CLINICAL PRESENTATION
(SYMPTOMS)
 Emotions :Emotions :
 depressed mood
 loss of interest or pleasure in most or all activities
 IdeationIdeation
 thoughts of worthlessness or guilt
 recurrent thoughts about death or suicide
 Somatic symptomsSomatic symptoms
 change in appetite or weight
 low energy
 psychomotor retardation or agitation
 poor concentration

4. SOME DEPRESSION FEATURES
 Depression is an illness, not ais an illness, not a
choicechoice, and is just as socially
debilitating as coronary artery
disease and more debilitating than
diabetes mellitus or arthritis.
 Up to 15% of severely depressed
patients will ultimately commit
suicide.
 Depression can be successfullysuccessfully
treatedtreated.

5. DepressionDepression is episodic, with untreated episodes
commonly lasting 6 to 24 months, followed by
recovery or remission.

6. BIOCHEMICAL BASIS OF DEPRESSION
NoradrenergicNoradrenergic
synapsesynapse
structurestructure

7. SIMPLE PICTURE

8. BIOCHEMICAL BASIS OF DEPRESSION
Monoamine Hypothesis:Monoamine Hypothesis: depression was due to a
deficiency of monoamine neurotransmitters, notably
nor-epinephrine (NE) and serotonin (5-
hydroxytryptamine [5HT])

9. EVIDENCE FOR MONOAMINE HYPOTHESIS
 Certain drugs that depleted these neurotransmitters could induce
depression
 Known antidepressants at that time both had pharmacological
actions that boosted these neurotransmitters.
 The idea was that the "normal" amount of monoamine
neurotransmitters became somehow depleted, perhaps by an
unknown disease process, by stress, or by drugs leading to the
symptoms of depression.
 An overly simplified notion about depression

10. BIOCHEMICAL BASIS OF DEPRESSION
 Neurotransmitter ReceptorNeurotransmitter Receptor
HypothesisHypothesis
 The neurotransmitter receptor theory posits that something is wrong with
the receptors for the key monoamine neurotransmitters.

11. In this figure, monoamine neurotransmitter isIn this figure, monoamine neurotransmitter is
depleted (see red circle).depleted (see red circle).

12. The consequences of monoamine neurotransmitter
depletion could cause the postsynaptic receptors to
abnormally up-regulate (indicated in red circle). This up-
regulation or other receptor dysfunction is hypothetically
linked to the cause of depression.

13.  there is no clear and convincing evidence that monoamine deficiency
accounts for depression
 there is no clear and convincing evidence that excesses or deficiencies
of monoamine receptors account for depression;
 there is growing evidence that despite apparently normal levels ofthere is growing evidence that despite apparently normal levels of
monoamines and their receptors, these systems do not respond normallymonoamines and their receptors, these systems do not respond normally

14. MONOAMINE HYPOTHESIS OF
GENE EXPRESSION
The monoamine hypothesis of gene expression proposes that
depression itself is linked to abnormal functioning of
neurotransmitter-inducible gene expression, particularly neurotrophic
factors such as brain-derived neurotrophic factor (BDNF), leading to
atrophy and apoptosis of critical hippocampal neurons.

16. MECHANISM OF ACTION
All antidepressants have a common action on monoamine neurotransmitters:
they increase monoamine neurotransmission, leading to
changes in gene expression in the neurons
targeted by the monoamines. This includes desensitization of
neurotransmitter receptors, leading to both therapeutic action and tolerance
to side effects.

17. Effect
develops only
after 10-14
days.

18. ANTIDEPRESSANTS TYPES
 1 Selective serotonin reuptake inhibitors (SSRIs) Citalopram,
Escitalopram, Fluoxetine
 2 Serotonin-norepinephrine reuptake inhibitors (SNRIs) Duloxetine,
Venlafaxine
 3 Norepinephrine reuptake inhibitors (NRIs)
Atomoxetine, Reboxetine
 4 Norepinephrine-dopamine reuptake inhibitors (NDRIs) Bupropion,
Methylphenidate

19.  5 Tricyclic antidepressant (TCAs) Amitriptyline, Clomipramine, Imipramine
 6 Tetracyclic antidepressants (TeCAs) Mianserin, Maprotiline
 7 Monoamine oxidase inhibitors (MAOIs) – reversible and irreversible
Phenelzine, Selegiline(MAO-B),Moclobemide, Tranylcypromine

21. TRICYCLIC ANTIDEPRESSANTS(TCA)
- Their organic chemical structure
contains three rings.
- The majority of the TCAs act primarily as
serotonin-norepinephrine reuptake
inhibitors (SNRIs).
As other tricyclic drugs (antipsychotic) they have
antimuscarinic, antihistaminic and alfa-receptor blocking
activity.

22. TCA SIDE EFFECTS
Drowsiness
Dry mouth
Blurred vision
Constipation
Urinary retention
Dizziness
Impaired sexual functioning
Increased heart rate
Disorientation or
confusion
Headache
Low blood pressure
Sensitivity to sunlight
Increased appetite
Weight gain
Toxocity: 3 C’s – coma, convulsions,
cardiootoxicity.

23. MAO INHIBITORS
 Reversible or irreversible inhibition of monoaminooxydase.
 Monoamine oxidase exists in two subtypes, A and B.
 Both forms are inhibited by the original MAO inhibitors, which are
therefore nonselective
 The A form metabolizes the neurotransmitter monoamines most closely
linked to depression
 MAO A inhibition is linked both to antidepressant action and to the
troublesome hypertensive side effects of the MAO inhibitors.

24. MAO INHIBITORS CON’T
Nowadays we have selective inhibitors of MAO A or of MAO B and
reversible inhibitors.
Reversible inhibitors of MAO A called RIMAs.
Exogenous amines(tyramine in cheese) can markedly elevate blood
pressure in the presence of irreversible MAO inhibitors.

29. SELECTIVE SEROTONIN REUPTAKE INHIBITORS(SSRI)
Inhibition of serotonin reuptake into the presynaptic cell, increasing the
level of serotonin available to bind to the postsynaptic receptor

31. SSRIS PHARMACOLOGY
 Uses:
- Major depresion
- Bulimia
- Anxiety disorders
- Premenstrual dysphoric disorder
Side effects:
- Anxiety
- Bruxism(the habit of grinding the teeth)
- Agitation
- Weight loss
- Sexual dysfunction(delay ejaculation)

32. 1
2
3 4
Cytochrome P450 – CYP450

35. CNS STIMULANTS

36. CNS STIMULANTS
 Stimulants are psychoactive drugs which induce
temporary improvements in either mental or physical function or
both.
 Common effects:
Increased alertness, awareness, wakefulness, endurance,
productivity, and motivation, increased arousal, locomotion, heart
rate, and blood pressure, and the perception of a diminished
requirement for food and sleep.
Stimulants are widely used throughout the world(social drugs, OTC
drugs, illegal drugs).

37. CAFFEINE
 discovered by a German chemist
in 1819
 xanthine alkaloid
 Source : beans, leaves, and fruit
of some plants, where it acts as
a natural pesticide kills certain
insects feeding on the plants
 coffee plant, leaves of the tea,
kola nut, guarana berries

38. PHARMACOLOGY
Half-life—varies widely among individuals according to age, liver function,
pregnancy, some concurrent medications, and velocity of metabolism -
approximately 4.9 hours
In women taking oral contraceptives 5–10 hours
In pregnant women - 9–11 hours
Severe liver disease - up to 96 hours
Smoking can shorten caffeine's half-life

39. Caffeine is metabolized in the liver by the
cytochrome P450 1A2 into:
- Paraxanthine (84%): Has the effect of
increasing lipolysis, leading to elevated
glycerol and free fatty acid levels in the
blood plasma.
- Theobromine (12%): Dilates blood vessels
and increases urine volume. Theobromine is
also the principal alkaloid in the cocoa bean,
and therefore chocolate.
- Theophylline (4%): Relaxes smooth muscles
of the bronchi, and is used to treat asthma.

40. CNS EFFECTS
increased alertness and wakefulness,
faster and clearer flow of thought
increased focus and better general body coordination

41. readily crosses the blood–brain barrier
caffeine molecule is structurally similar to
adenosine
binds to adenosine receptors on the surface of cells
without activating them
caffeine acts as a competitive inhibitor
competitive nonselective phosphodiesterase
inhibitor which raises intracellular cAMP,
activates PKA
Mechanism of actionMechanism of action

43. AMPHETAMINE GROUP
Amphetamine
Methamphetamine
Levoamphetamine
Dextroamphetamine
Major neurobiological mechanisms:
-most widely studied neurotransmitter with regard to
amphetamine action is dopamine
-increasing dopamine release from pre-synaptic membrane
-amphetamine inhibit dopamine reuptake

44. PHYSICAL EFFECTS
Reduced appetite
Increased/distorted sensations,
Hyperactivity
Dilated pupils
Restlessness
Tachycardia
Increased blood pressure
Sweating
Uncontrollable movements or shaking

45. PSYCHOLOGICAL EFFECTS
 Euphoria (via increased dopamine)
 Increased anxiety (via increased
norepinephrine)
 alertness
 concentration
 energy
 self-esteem
 self-confidence
 aggression
Also:
-Dependence
-Tolerance
-Withdrawal
syndrome

46. MODAFINIL
treatment of narcolepsy, shift work sleep disorder and excessive daytime
sleepiness associated with obstructive sleep apnea
increase the levels of various monoamines dopamine, noradrenaline and
serotonin in synaptic cleft
activates glutamatergic circuits while inhibiting GABAergic neurotransmission

47. SIDE EFFECTS
The most common side effects of modafinil in clinical trials
are:
headache
upper respiratory tract infection
Nausea
Nervousness
Anxiety
insomnia