Pharmacology of antidepressant agents

1. DRUG THERAPY OF
DEPRESSION
DR HTET HTET
MBBS, MMEDSC, PGCERTHPE

2. LESSON OUTCOMES
After this session, you should be able to:
1.Enlist the groups of antidepressants
2.Describe their mechanism of action and adverse
effects
3.Explain cheese reaction

3. LECTURE OUTLINE
1. What is depression?
2. Types & theories of depression
3. Management of depression
4. Classification of antidepressants
5. Pharmacology of drugs

4. WHAT IS DEPRESSION?
• most common of the affective disorders (disorder of mood).
• may range from a very mild condition, to severe (psychotic) depression accompanied
by hallucinations and delusions.
• Worldwide, depression is a major cause of disability and premature death.
• In addition to the significant suicide risk, depressed individuals are more likely to die
from other causes, such as heart disease or cancer.
• often associated with other psychiatric conditions including anxiety, eating disorders
and drug addiction

5. LECTURE OUTLINE
1. What is depression?
2. Types & theories of depression
3. Management of depression
4. Classification of antidepressants
5. Pharmacology of drugs

6. TYPES OF DEPRESSION
• Unipolar depression (Major depressive disorder)
• Depressed mood, loss of interest or pleasure in life, sleep disturbances, feeling of
worthlessness, diminished ability to think or concentrate, recurrent thoughts of
suicide. They can be irritable or anxious.
• Bipolar disorder (Manic-depressive disorder)
• Recurrent fluctuations in mood, energy, behaviour that encompass the extremes of
human experience.
• Dysthymia
• low-grade depressed mood without sufficient other symptoms to count as “clinically
significant” or major depression

7. TYPES OF DEPRESSION
Classification based on aetiology
• Reactive depression (external stimuli)
• Endogenous depression (caused by the factors within
individual independent of outside stimuli)

8. THEORIES OF DEPRESSION
• Monoamine hypothesis (main biochemical theory of depression)
• first proposed in 1965,
• which states that depression is caused by a functional deficit of the
monoamine transmitters, noradrenaline and 5-hydroxytryptamine (5-
HT) at certain sites in the brain,
• deficit in function or amount of monoamines
• while mania results from a functional excess

9. The monoamine hypothesis of
depression (Figure) suggests that
depression is related to a deficiency
in the amount or function of cortical
and limbic serotonin (5-
HT), norepinephrine (NE),
and dopamine (DA).

10. THEORIES OF DEPRESSION
• Neurotrophic hypothesis
• brain-derived neurotrophic factors (BDNF) are critical in the regulation of
neural plasticity, resilience, and neurogenesis
• depression is associated with the loss of neurotrophic support and that
effective antidepressant therapies increase neurogenesis and synaptic
connectivity in cortical areas such as the hippocampus.
• BDNF is thought to exert its influence on neuronal survival and growth
effects by activating the tyrosine kinase receptor B in both neurons and glia

11. NEUROTROPIC HYPOTHESIS OF DEPRESSION

12. LECTURE OUTLINE
1. What is depression?
2. Types & theories of depression
3. Management of depression
4. Classification of antidepressants
5. Pharmacology of drugs

13. MANAGEMENT OF DEPRESSION
Pharmacological
• Anti-depressant drugs
Psychological
• CBT
• Interpersonal therapy
Choice
depends on
Patient
preference
and local
availability
Very severe
depression
with psychotic
symptoms, e.g.
suicidal risk –
ECT

14. TREATMENT OF DEPRESSION RELATED
DISORDERS
A. Acute anxiety with depression:
e.g. benzodiazepines (Separate Lecture)
mild, neurotic depression, esp. with anxiety.
Short-term for acute onset, not effective for long-term treatment of
psychotic depression.
B. Antidepressants:
for psychotic depression, severe neurotic depression; long- term
treatment.

15. OVERVIEW OF DRUG THERAPIES
• Drugs that are used to treat depression acts by enhancing the
neurotransmission at serotonergic and/or noradrenergic neurons
• Most of the drugs does this by inhibiting the reuptake of these
neurotransmitters (5HT, NA) and hence enhancing their effects in
the CNS.

16. CLASSIFICATION OF ANTIDEPRESSANT
DRUGS
• 1.Monoamine uptake inhibitors
• 1.tricyclic antidepressants, (TCA)
• 2.selective serotonin reuptake inhibitors (SSRI)
• 3. Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI)
• 4. NA reuptake inhibitor
• 3.Monoamine receptor antagonists
• 5.Monoamine oxidase (MAO) inhibitors

17. DRUG CLASSES USED IN TREATMENT OF DEPRESSION
AND ANXIETY DISORDERS
1. Selective serotonin reuptake inhibitors (SSRI)
2. Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI)
3. Tricyclic antidepressants
4. Monoamine oxidase (MAO) inhibitors
5. Atypical antidepressants
6. Atypical antipsychotics

18. 1. TRICYCLIC ANTIDEPRESSANTS (TCA)
Mechanism of action:
• inhibits the reuptake of NA and 5HT into the presynaptic neuron,
• increased availability of NA and 5HT at the receptors, increasing their concentration
in the synaptic cleft in the CNS and periphery  mood elevation
• TCAs additionally block muscarinic, alpha adrenergic, histaminergic receptors which
are responsible for adverse effects
Onset
• Therapeutic effect is noticeable in a week or two (onset of action)

20. TRICYCLIC ANTIDEPRESSANTS (TCA)
• Pharmacological actions:
• CNS:
• mood elevation of depressed patients
• may extend to excitement, hypomania, mania with sufficient dose; agitation, seizures
• no mood elevation or euphoria, but causes anxiety in normal persons.
• lowers seizure threshold, convulsions in overdose
• Respiratory symptoms
• respiratory depression with overdose
• CVS:
• orthostatic hypotension, sinus tachycardia; arrhythmias and cardiac conduction defect with
overdose
• Others
• anticholinergic action  atropine-like effects
• potentiates exogenous & endogenous noradrenaline, sympathomimetics

21. 1. Severe endogenous depression
2. Nocturnal enuresis (Imipramine)
3. Panic Disorder
4. Obsessive-Compulsive Disorders
5. Chronic Neuropathic Pain (e.g., Trigeminal Neuralgia/ Diabetic
Neuropathy/ Tabetic Neuropathy)
6. Others (Eating Disorders (Bulimia)/ Narcolepsy/ School Phobia/
ADHD)
Tricyclic antidepressants (TCA)

22. Adverse effects
• Atropine like side effects: dry mouth, blurring of vision, constipation,
urinary retention
• α adrenergic blocking effect: postural hypotension, tachycardia,
cardiac arrhythmias
• H1 blocking effects: sedation, confusion
• Others: increased appetite, weight gain, seizures
Tricyclic antidepressants (TCA)

23. DRUG CLASSES USED IN TREATMENT OF DEPRESSION
AND ANXIETY DISORDERS
1. Selective serotonin reuptake inhibitors (SSRI)
2. Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI)
3. Tricyclic antidepressants
4. Monoamine oxidase (MAO) inhibitors
5. Atypical antidepressants
6. Atypical antipsychotics

24. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
Citalopram, Escitalopram, Fluoxetine, Paroxetine, Sertraline
MOA
• SERT mediates the reuptake of serotonin into the presynaptic terminal;
neuronal uptake is the primary process by which neurotransmission via
5-HT is terminated.
• SSRI blocks reuptake and results in enhanced and prolonged
serotonergic neurotransmission.

25. Uses
• Anxiety and depression disorders
• Impulse control disorders (OCD: impulsive buying,
kleptomania)
• Post traumatic stress disorder (PTSD)
Selective serotonin reuptake inhibitors

26. Adverse effects
• headache, insomnia,
• GI disturbances
• sexual dysfunction
• May increase risk of suicidal thoughts or behavior
• Serotonin syndrome with MAOIs (“rare, neuromuscular hyperactivity,
agitation, potential seizures, hyperthermia, delirium, death”)
Selective serotonin reuptake inhibitors

27. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
Advantages of SSRI
a) Less cardiotoxic and less sedative than TCA
• Acute toxicity (especially cardiotoxicity) is less than that of MAOIs or TCAs, so
overdose risk is reduced.
• SSRIs are less sedating and have fewer antimuscarinic side effects than the older
TCAs.
b) Lesser chance of food and drug interaction
• No food reactions,
• but dangerous 'serotonin reaction' (hyperthermia, muscle rigidity, cardiovascular
collapse) can occur if given with MAOIs.
c) No weight gain
• in general, SSRIs DO NOT: **** cause weight gain
d) Side effect profile
• No postural hypotension, no sedation, do not precipitate seizures, no cardiac

28. SSRI
• Disadvantages:
• Mild side-effects: nervousness, restlessness, insomnia, anorexia,
headache, diarrhoea
• Impair performance of skilled tasks, e.g. driving;
• sexual dysfunctions
• May produce withdrawal symptoms  needs tailing off -Indication :
better tolerated and safer in overdose than other classes, should be
considered first-line drugs for treating depression.
Selective serotonin reuptake inhibitors

29. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
• Status
• most commonly prescribed group of antidepressants
• overall antidepressant efficacy similar to TCA, less efficacious in more
severe depression

30. DRUG CLASSES USED IN TREATMENT OF DEPRESSION
AND ANXIETY DISORDERS
1. Selective serotonin reuptake inhibitors (SSRI)
2. Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI)
3. Tricyclic antidepressants
4. Monoamine oxidase (MAO) inhibitors
5. Atypical antidepressants
6. Atypical antipsychotics

31. WHAT IS MAO?
• What are MAOs?
• enzymes involved in deamination (degradation) of monoamines which include
NA and 5-HT
• Two sub-types: –MAO-A, preferentially deaminates 5-HT and NA –MAO-B,
preferentially deaminates phenylethylamine and dopamine.
• Types of MAOI 1.Non selective MAOI 2.Selective MAOI

32. MONOAMINE OXIDASE INHIBITORS
Meclobemide
• inhibits MAO-A selectively and reversibly
• effective antidepressant, except in severe cases
• lacks anticholinergic, sedative, psychomotor and cardiaovascular adverse
effects of typical TCAs Status:
• well tolerated alternative to TCAs in mild to moderate depression;
• especially suitable for elderly patients and those with heart disease.

33. MONOAMINE OXIDASE INHIBITORS
• Status: •much less frequently used, because of
(i) Interactions:
• “cheese reaction” with food containing tyramine, dopamine etc.,
- cheese, beer, wines, pickled meat and fish, yeast extract 
hypertensive crisis
• with TCAs  severe toxicity resembling atropine poisoning -
with many others including: (indirect sympathomimetic drugs)
cold & cough remedies, antiparkinsonian drugs,
• MAOI + SSRI – serotonin syndrome

34. DRUG CLASSES USED IN TREATMENT OF DEPRESSION
AND ANXIETY DISORDERS
1. Selective serotonin reuptake inhibitors (SSRI)
2. Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI)
3. Tricyclic antidepressants
4. Monoamine oxidase (MAO) inhibitors
5. Atypical antidepressants
6. Atypical antipsychotics

35. SEROTONIN-NOREPINEPHRINE REUPTAKE
INHIBITORS
Venlafaxine, duloxetine
• Inhibitors of SERT and NET
• Use in anxiety and depression, ADHD, autism, fibromyalgia,
PTSD, menopause symptoms

36. DRUG CLASSES USED IN TREATMENT OF DEPRESSION
AND ANXIETY DISORDERS
1. Selective serotonin reuptake inhibitors (SSRI)
2. Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI)
3. Tricyclic antidepressants
4. Monoamine oxidase (MAO) inhibitors
5. Atypical antidepressants
6. Atypical antipsychotics

37. ATYPICAL ANTIDEPRESSANTS
Mirtazapine, trazodone, and nefazodone
• 5HT2 receptor antagonists (blocks 5-HT2C receptors)
Mirtazapine also blocks α2 adrenoreceptors
• Block of α2 adrenoceptors will not only increase noradrenaline
release but will also enhance 5-HT release

38. DRUG CLASSES USED IN TREATMENT OF DEPRESSION
AND ANXIETY DISORDERS
1. Selective serotonin reuptake inhibitors (SSRI)
2. Newer inhibitors of noradrenaline and 5-HT reuptake (SNRI)
3. Tricyclic antidepressants
4. Monoamine oxidase (MAO) inhibitors
5. Atypical antidepressants
6. Atypical antipsychotics

39. ATYPICAL ANTIPSYCHOTICS
Aripiprazole, Olanzapine, Quetiapine …
• Use for
• Resistant major depression and psychotic disorders
• Schizophrenia
• Bipolar depression

40. TREATMENT OF DEPRESSION
• Mild depression - non-drug measures,
• antidepressant drugs – used - if the response is poor.
• antidepressant drugs have similar efficacy but different side effects.
• Choice of drug is based on
• individual aspects including concomitant disease (TCAs in particular have several
indications) and
• treatment (MAOIs and TCAs cause important interactions), suicide risk and
previous response to treatment.

41. TREATMENT OF DEPRESSION
• Other things being equal, an SSRI is preferred (better tolerated, less
dangerous in overdose.)
• take several weeks before taking effect (so decisions on dose increment or
switching to another class should not be made precipitately)
• In urgent situations, specialist consideration - possible use of
electroconvulsive therapy.
• Anxiolytic (e.g. benzodiazepine), or antipsychotic drugs are useful adjuncts
in some patients.

42. TREATMENT OF DEPRESSION
• Important points for drug therapy:
• reviewed every 1 – 2 weeks at start of therapy
• continued for at least 4 weeks (6 weeks in elderly) before contemplating
switch
• following remission, continue same dose for at least 6 months
• withdrawal symptoms if stopped suddenly after 8 weeks or more, (physical
dependence);  needs tailing off (4 weeks or longer) –at least 2 weeks gap
in-between, when switching drugs
• Both CBT and interpersonal therapy are as effective as antidepressants for
mild to moderate depression.
• Antidepressant drugs are, however, preferred for severe depression. Drug

43. OTHER USES OF ANTIDEPRESSANTS
• neuropathic pain (e.g. amytriptyline, nortryptyline)
• anxiety disorders (e.g. SSRIs, venlafaxine, duloxetine)
• fibromyalgia
• bipolar depression
• smoking cessation (e.g. buproprion)
• attention-deficit hyperactivity disorder
• Premature ejaculation

44. REFERENCES
• Brunton, L. Chabner, B. Knollman, B. Goodman & Gilman’s
Pharmacological Basis of Therapeutics. 12th Edition. United
States: The McGraw-Hill Companies, Inc.
• Rang, HP, Dale, MM, Ritter, JM, Flower, RJ, Henderson, G (2012).
Rang and Dale's Pharmacology. 7th ed. London: Elsevier
Churchill Livingstone