This document discusses antidepressants, including tricyclic antidepressants and selective serotonin reuptake inhibitors. It provides definitions of affective disorders and describes the neurobiological theory of depression. It discusses the pharmacology, indications, mechanisms of action, adverse effects and interactions of tricyclic antidepressants. It also discusses the pharmacology, mechanisms of action, important drugs, adverse effects and interactions of selective serotonin reuptake inhibitors. The document provides information on the treatment of depression and compares older tricyclic antidepressants to newer selective serotonin reuptake inhibitors.

1. ANTIDEPRESSANTS
•TricyclicAntidepressants
•Selective Seratonin
Reuptake Inhibitors

2. Definitions
• Affective disorders - mental illnesses characterized by
pathological changes in mood (not thought – compare
with schizophrenia)
1. Unipolar disorders
• Depression – pathologically depressed mood (life time prevalence
up to 17%)
• Mania – excessive elation and accelerated psychomotoric activity
(rare)
Bipolar disorder (manic-depressive illness) – „cycling mood“
• = severe highs (mania, event. hypomania) and lows (major
depressive episodes)
• prevalence 1-5%, life-time illness, stronger genetic background

3. Depression
• common mental disorder that presents with depressed mood, loss of
interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or
appetite, low energy, and poor concentration (WHO def.)
• Major Depressive Episode Criteria/Core symptoms
– Five (or more) of the following symptoms have been present during the
same 2-week period and represent a change from previous functioning; at
least one of the symptoms is either (1) depressed mood or (2) loss of
interest or pleasure.
• depressed mood most of the day…
• markedly diminished interest or pleasure
• significant weight loss /gain
• insomnia or hypersomnia
• psychomotor agitation or retardation, fatigue or loss of energy
• feelings of worthlessness or excessive or inappropriate guilt
• diminished ability to think or concentrate, or indecisiveness
• recurrent thoughts of death or suicidal ideation without a specific plan or a
suicide attempt (!)

4. Neurobiological theory of depression
• Monoamine (catecholamine) theory (1965) = the underlying biological or
neuroanatomical basis for depression is a deficiency of central
noradrenergic and/or serotonergic transmission in the CNS
Supported by:
• pharmacological effect of antidepressants (TCA, MAOI)
• In the past, medication of hypertension with reserpine induced
depression
Contradiction:
• several drugs (e.g. cocaine) increase the amount of these
neurotransmitters in the CNS but are unable to treat depression
• the effect of antidepressants on neurotransmitter levels is relatively
quick but onset of antidepressant action is significantly delayed
• „Receptor theory“ = the problem is in up-regulation of post-synaptic
receptors and alterations in their sensitivity
The antidepressant treatment increases the amount of monoamines in CNS
and thereby gradually normalize the density/sensitivity of their receptors
• The precise pathophysiology of depression remains unsolved

5. Therapy of depression
Pharmacotherapy/Mood Elevators
–
–
–
–
Tricyclic antidepressants (TCA)
Monoamine oxidase inhibitors (MAOI)
Selective Serotonin Re-uptake Inhibitors (SSRI)
Other and atypical antidepressant
• Serotonin-2 Antagonists/Reuptake Inhibitors (SARI)
• Serotonin and Noradrenaline Reuptake Inhibitors (SNRI)
• Noradrenaline and Dopamine Reuptake Inhibitors (NDRI)
• Noradrenaline Reuptake Inhibitors (NaRI)
• Noradrenergic/Specific Serotonergic Antidepressants (NaSSA)
Duration of treatment – 6 months after recovery (1st epizode), may
be even life-long treatment in recurrent depression
Non-pharmacological treatment
–
–
–
Psychotherapy
Light therapy
Electroconvulsive therapy (ECT)

7. • Chemical structure with characteristic
three-ring nucleus – lipophilic nature
• Originally developed as antipsychotics
(1949), but were found to have no effect in
this indication.
• Principal mechanism of action:
– blockade of re-uptake of monoamine neurotransmitters
noradrenaline (NA) and serotonin (5-HT) by competition for
binding site of the carrier protein. 5HT and NA neurotransmission
is similarly affected but the effect on the dopamine system is
much less important (compare with cocaine)
– in most TCA, other receptors (incl. those outside the CNS) are
also affected: blockade of H1-receptor, -receptors, M-receptors
I. Tricyclic Antidepressants (TCAs)
imipramine

8. Mode of action
• Block reuptake of NE,Serotonin and
Dopamine at nerve terminal,thus
increasing the NE,5HT or DA at the
extracellular and more of its action on at
receptor site.
• Down regulation of Beta-adregernic
receptors
• in most TCA, other receptors (incl. those outside the CNS) are
also affected: blockade of H1-receptor, -receptors, M-receptors

10. Pharmacological action
• CNS-mood elevation in depress
patient,can cause ataxia,epilepsy,seizures
and coma.
• CVS-orthostatic hypotension
• ANS-anticholinergic effects.Most potent
anticholinergic action

11. Classification
• A. Tertiary Amines: Amitriptyline,
Butriptyline, Clomipramine, Dosulepin,
Doxepin, Imipramine, Lofepramine,
Trimipramine
• B. Secondary Amines: Desipramine,
Nortriptyline, Protriptyline
• C. Others/Dibenzodiazepine derivitive:
Dibenzepin

12. Classification
A. NA and 5HT reuptake inhibitors
Imipramine,Amitryptaline,Clomipramine
B. Predominantly NA reuptake inhibitor
Desipramine,Nortriptyline,Amoxapine

13. Most important TCAs
• imipramine
• desimipramine
– demethylated form, the active metabolite of imipramine
• amitriptyline
• nortriptyline
– demethylated form, the active metabolite of amitriptyline)
Clinical use and efficacy is relatively close within the group
the more significant difference is in their adverse effects

14. INDICATIONS
• Clinical depression
• Neuropathic pain-Diabetic
neuropathy/Analgesia
• ADHD
• Nocturnal Enuresis
(Imipramine)
• Panic disorder(Imipramine)
• OCD(Clomipramine)
• Others like eating
disorder,narcolepsy

15. • Agranulocytosis
• Severe liver damage
• Glaucoma
• Prostatic hyperplasia
• Epilepsy
• lactation
Contraindication

16. Pharmacokinetics
•
• Administered orally – rapid absorption, however extensive
first pass effect  low and inconsistent BAV
Strong binding to plasma proteins (90-95% bound). They
are also bound in tissues + wide distribution (high
lipophilicity) = large distribution volumes (ineffectiveness of
dialysis in acute intoxications).
• Biotransformation – in the liver (CYP450, N-demethylation
and tricyclic ring hydroxylation) – most of these metabolites
are active! CYP450 polymorphisms ! Glucuronidation  inactive
metabolites excreted in the urine.
• Elimination half-lives - generally LONG (T1/2 =10-80h).
Elderly patients – even longer T1/2, risk of accumulation.

17. Drug interaction
•
• Tricyclic interaction includes additive depression of the CNS with
other antidepressents include ethanol, barbiturates,
benzodiazipines, and opioids.
• Tricyclic may also cause reversal of the anti-hypertensive action of
guanethidine by blocking its transport into sympathetic nerve
endings.
• Less commonly, tricyclics may interfere with the anti-hypertensive
actions of methylnorepinephrine( the active metabolite of
methyldopa) and clonidine.
• Tricyclics also share metabolic pathways with phenytoin, hence it
may increase concentrations of phenytoin.
Tricyclics also potentiate the pressor effects of adrenaline and
noradrenaline, so that there is a potantial hazard when a local
anaesthetic is used with a pressor amine.

18. Drug Dose
• It takes about 2-3 weeks before tricyclic antidepressents
has any evident action on depression( although sleep
and agitation may respond earlier).
• Hence, it is useless to give it as per needed only.They
must be administred regularly in sufficient doses to
achieve the desired effect.
• After remission of symptoms, it is essential to continue
the anti-depressents for 6-12 months in the 1st episode
and longer duration in subsequent episodes to prevent
reccurence of symptoms.
• A drug, e.g. imipramine is given in sufficient
doses(100-300 mg) for 6 weeks, can it be called as
ineffective for a particular patient.

19. • When starting the drug start with a low dose and
gradually increase it to prevent the side-effects.
• When stopping the drug, taper the dose over 2-3
weeks period. As if you were to stop it abruptly, it will
cause withdrawal symptoms such as:
-Nausea
-Tremor
-Headache
-Insomnia

20. Adverse Effects
Pharmacological Action Adverse Effect
Muscarinic receptor Blockage/
Anticholinergic
•Dry mouth, tachycardia, blurred
vision, glaucoma
•Constipation, Urinary retention,
Sexual dysfunction
•Cognitive impairement
ᾴ1 Adrenoceptor blockade •Drowsiness, Postural Hypotension,
Sexual dysfunction(loss of libido,
impaired erection)
•Cognitive Impairement
Histamine H1 receptor Blockade Drowsiness, Weight Gain
Membrane stabilizing properties Cardiac conduction defects, Cardiac
arrythmia, Seizures
Others Rash, Oedema, Leukopenia, Elevated
liver enzymes

21. Teratogenic effects
• Have not been proved
but it should be used
cautiously in the first
trimester of pregnancy.

22. Toxic Effects
• CVS: Ventricular fibrillation, Conduction
disturbances, Low BP, --- ecg shows
prolong PR and QT intervals, depressed
ST, flattened T waves. Heartblock
occasionally
• RS: Respiratory depression -> Hypoxia,
Aspiration pneumonia
• CNS: Agitation, twitching, convulsions,
hallucinations, delerium, coma.
Parasympathetic dry mouth, dilated pupil,
blurred vision, urine retention, pyrexia

23. Management of toxicity
• Supportive care
• Cardiac monitoring---if arrythmia, ICU
• Plasma level monitoring: Shudn go above
450ng/ml or 300ng/ml if concomitant
medical disorder
• TCA has delayed gastric emptyin, do
gastric lavage if several hours after
overdose
• Activated Charcoal 1gm/kg PO/NG

24. Newer Drugs
• Lofepramine-Has strong anti-cholinergic
side-effect than amitriptyline and is less
sedating; however, it may cause anxiety
and insomnia.In overdose it is also less
toxic than conventional tricyclics.
• Trazodone-Also has few anti-cholinergic
side effects, but has strong sedating
properties.

26. II. Selective Serotonin Re-uptake
Inhibitors (SSRI)
• More modern (1st drug fluoxetine available in 1988) and safe
antidepressants
• Principal mechanism of action:
– selective inhibition of 5-HT (serotonin) reuptake  more
extracellular seratonin → More action on seratonin receptors
on post synaptic → more stimulation
• Other indications of SSRI - anxiety disorders: generalized
anxiety, panic disorder, social anxiety disorder, obsessive-
compulsive disorder
+ bulimia nervosa, gambling

28. Most important SSRI
• (10-60mg/day)Fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem,
Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS)
(50-300mg/day) Fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox,
Favoxil, Movox)
(10-40mg/day) Paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat,
Rexetin, Xetanor, Paroxat)
(50-200mg/day) Sertraline (Zoloft, Lustral, Serlain)
(10-40mg/day) Citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital,
Emocal, Sepram, Seropram, Citox)
•
•
•
•

29. Pharmacokinetics
• Good absorption after oral administration
• Important biotransformation in the liver
– CYP450 - 2D6 and 2C19 isoforms (polymorphism 
interindividual variability in the clinical effect) and active
metabolites (e.g. fluoxetine)
• Long half-lives of elimination(s)
– fluoxetine (T1/2=50h) + active metabolite (T1/2 =240h)
• Drug interaction: based on plasma protein binding and CYP
blockade
– increased effect of co-administered TCA but also -blockers,
benzodiazepines etc.

30. HO
HO
NH2
Norepinephrine
(Noradrenaline)
HO
Serotonin
5-Hydroxytryptamine
(5-HT)
N
H
NH2
OH groups necessary for agonist activity
OH
C
N
O
N
F
Me
Me
Citalopram
(CelexaTM)
O
Fluoxetine
(ProzacTM)
N
H
CF3
Me
Neurotransmitters
N
O
Fluvoxamine
(LuvoxTM)
F3C
NH2
OCH3
O
O
O
H
N
F
Paroxetine
(PaxilTM)
Sertraline
(ZoloftTM)
Cl
Cl
H
N
O
N
Me Me
Dapoxetine
Commercial SSRI's

31. Adverse effects
• Relative improvement to other antidepressants (mostly mild)
• Less Cardiotoxic compared to TCA
• Generally, much safer in overdose
• Lack anticholinergic effects and are not Sedating
• GIT – nausea, vomiting, diarrhea
• Neuropsychiatry – Headache, Irritability, Restless
(Akathisia)-EPS more common in SSRI than TCA, Agitation,
Tremor, Insomnia and daytime somnolence, Seizures
Mania
• Sexual dysfunctions – Ejaculatory delay, anorgasmia
• Suicidal Behavior
• Serotonin syndrome upon intoxication or drug interactions

32. Serotonin Syndrome
• SSRIs are contraindicated with concomitant
use of MAOIs (monoamine oxidase inhibitors).
This can lead to increased serotonin levels
which could cause a serotonin syndrome.
• CF:-
– NEURO: Myoclonus, Nystagmus, Headache,
Tremors, Rigidity, Seizures
– MENTAL STATE: Irritability, Confusions, Agitations,
Hypomania, Coma
– OTHERS: Hyperpyrexia, sweating, diarrhea,
cardiac arrythmia, death

33. SSRI discontinuation syndrome
• not as significant as benzodiazepines
• little to no abuse potential
• Withdrawal symptoms: common
descriptions include dizziness, electric
shock-like sensations, sweating, nausea,
insomnia, tremor, confusion, and vertigo

34. THANK YOU