The document discusses the amine hypothesis of mood and various classes of antidepressant drugs. It proposes that neurotransmitters like norepinephrine and serotonin play a role in mood, and that antidepressants work by enhancing their actions. The classes covered include tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, monoamine oxidase inhibitors, and others. Their mechanisms of action, clinical uses, toxicity, and drug interactions are described.

1. By:M.Usman Khalid
DPT,MS-NMPT
Antidepressants

2. The Amine Hypothesis of Mood
• The amine hypothesis of mood postulates that brain amines,
particularly norepinephrine (NE) and serotonin (5-HT), are
neurotransmitters in pathways that function in the expression of
mood.
• According to the hypothesis, a functional decrease in the activity of
such amines is thought to result in depression; a functional increase
of activity results in mood elevation.
• The amine hypothesis is largely based on studies showing that many
drugs capable of alleviating symptoms of major depressive
disorders enhance the actions of the central nervous system (CNS)
neurotransmitters 5-HT and NE.

3. DRUG CLASSIFICATION &
PHARMACOKINETICS
• A.Tricyclic Antidepressants: Tricyclic antidepressants
(TCAs; e.g, imipramine, amitriptyline) are
structurally related to the phenothiazine
antipsychotics.
• Orally absorbed.
• Hepatic metabolism.
• Plasma half-lives of 8–36 h

4. B. Selective Serotonin Reuptake Inhibitors:
• Fluoxetine is the prototype of a group of drugs that are
selective serotonin reuptake inhibitors (SSRIs).
• Hepatic metabolism
• Half-lives of 18–24 h.
• Other members of this group (e.g, citalopram,
escitalopram, fluvoxamine, paroxetine, and sertraline)
do not form long-acting metabolites.

5. C. Heterocyclics:
• These drugs have varied structures and include the serotonin-
norepinephrine reuptake inhibitors (SNRIs, duloxetine, venlafaxine,
levomilnacipran), 5-HT2 receptor antagonists (nefazodone, trazodone)
and miscellaneous other heterocyclic agents including amoxapine,
bupropion, maprotiline, and mirtazapine. Pharmacokinetics is same as
TCA.

6. D. Monoamine Oxidase Inhibitors:
• Monoamine oxidase inhibitors (MAOIs; e.g, phenelzine,
tranylcypromine) are structurally related to amphetamines
and are orally active.
• The older, standard drugs inhibit both MAO-A (monoamine
oxidase type A), which metabolizes NE, 5-HT, and tyramine,
and MAO-B (monoamine oxidase type A), which metabolizes
dopamine.
• In spite of the prolonged actions, the MAOIs are given daily.

7. MECHANISMS OF ANTIDEPRESSANT
ACTION
• Most antidepressants cause potentiation of the
neurotransmitter actions of NE, 5-HT, or both.
A. TCAs
• The acute effect of tricyclic drugs is to inhibit the
reuptake mechanisms (transporters) responsible for the
termination of the synaptic actions of both NE and 5-HT
in the brain. This presumably results in potentiation of
their neurotransmitter actions at postsynaptic receptors.

8. B. SSRIs
• The acute effect of SSRIs is a highly selective action
on the serotonin transporter (SERT). SSRIs
allosterically inhibit the transporter, binding at a site
other than that of serotonin. They have minimal
inhibitory effects on the NE transporter, or blocking
actions on adrenergic and cholinergic receptors.

9. C. SNRIs
• SNRIs bind to transporters for both serotonin and NE,
presumably enhancing the actions of both
neurotransmitters.
• Venlafaxine has less affinity for the NE transporter than
desvenlafaxine or duloxetine.
• The SNRIs differ from the TCAs in lacking significant
blocking effects on peripheral receptors including
histamine H1, muscarinic, or α-adrenergic receptors.

10. D. Serotonin 5-HT2 Receptor Antagonists
• The major antidepressant actions of nefazodone and
trazodone appear to result from block of the 5-HT2A
receptor, a G protein-coupled receptor located in
several CNS regions including the neocortex.
Antagonism of this receptor is associated with both
the antianxiety and antidepressant actions of these
drugs.

11. E. Other Heterocyclic Antidepressants:
• Mirtazapine has a unique action to increase amine
release from nerve endings by antagonism of
presynaptic α2 adrenoceptors involved in feedback
inhibition.
• The drug is also an antagonist at serotonin 5-HT2
receptors.

12. • F. MAOIs:The MAOIs increase brain amine levels by
interfering with their metabolism in the nerve
endings, resulting in an increase in the vesicular
stores of NE and 5-HT.
• When neuronal activity discharges the vesicles,
increased amounts of the amines are released,
presumably enhancing the actions of these
neurotransmitters.

13. SITES OF ACTION OF ANTIDEPRESSENT DRUGS

14. PHARMACOLOGIC EFFECTS
A. Amine Uptake Blockade
• The drugs that block NE transporters in the CNS (e.g,
tricyclics, maprotiline, venlafaxine) also inhibit the
reuptake of NE at nerve endings in the autonomic
nervous system. Likewise, MAOIs increase NE in
sympathetic nerve terminals.
• Peripheral autonomic sympathomimetic effects.

15. • Sedation
• Muscarinic receptor blockade
• Cardiovascular effects
• Seizures

16. CLINICAL USES
• A. Major Depressive Disorders: (SSRIs, SNRIs, 5-HT
antagonists, and certain heterocyclics) are now the most
widely prescribed agents.
• Tricyclic drugs continue to be most useful in patients with
psychomotor retardation, sleep disturbances, poor appetite,
and weight loss.
• MAOIs are thought to be most useful in patients with
significant anxiety, phobic features, and hypochondriasis.
Selegiline, the MAO type B inhibitor used in parkinsonism.

17. • TCAs are also used in the treatment of bipolar
affective disorders, acute panic attacks, phobic
disorders; enuresis, attention deficit hyperkinetic
disorder, and chronic pain states.
• The SNRIs (e.g, duloxetine, venlafaxine) are effective
in patients with neuropathic pain and fibromyalgia;
duloxetine is also approved for the pain of diabetic
neuropathy.

18. TOXICITY & DRUG INTERACTIONS
• Tricyclic antidepressants
• α block, M block.
• Sedation
• Weight gain
• Overdose
• Arrhythmias
• Seizures
DRUG INTERACTION:
• Reversal of the antihypertensive action of guanethidine by blocking its transport into sympathetic nerve
endings.
• Depression of the CNS with other central depressants, including ethanol, barbiturates, benzodiazepines,
and opioids.

19. • SSRI Toxicity:
• Nausea
• Headache
• Anxiety
• Agitation
• Insomnia
• Sexual dysfunction
• QT prolongation.

20. • Certain SSRIs are inhibitors of hepatic cytochrome
P450 isozymes, an action that has led to increased
activity of other drugs, including TCAs and warfarin
• Fluoxetine inhibits CYP2D6 and to a lesser extent
CYP3A4 isoforms; fluvoxamine inhibits CYP1A2 and
paroxetine CYP2D6.

21. Serotonin Syndrome
• This life-threatening syndrome includes severe
muscle rigidity, myoclonus, hyperthermia,
cardiovascular instability, and marked CNS
stimulatory effects, including seizures.
• Antiseizure drugs, muscle relaxants, and blockers of
5-HT receptors (e.g, cyproheptadine) have been used
in the management of the syndrome.

22. TOXICITY
• Serotonin-norepinephrine reuptake inhibitors
(SNRIs):
• Anticholinergic
• Sedation
• Hypertension (venlafaxine)

23. TOXICITY
• Monoamine oxidase inhibitors (MAOIs):
• Hypertensive reactions
• Hyperthermia
• CNS stimulation leading to agitation and convulsions