Antidepressants

A power point presentation on drugs used in depressive disorders for the undergraduate MBBS students of Pharmacology

1. DRUGS USED IN AFFECTIVE
DISORDERS
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

2. Introduction

3. What are affective Disorders?
1.Mania
2.Depression
•Reactive
•Endogenous or Major Depression
•Depressive syndromes – Unipolar or Bipolar

4. Bipolar Disorder - imageBipolar Disorder - image

5. Bipolar Disorder - image

6. Drugs used in Mania – Mood Drugs used in Mania – Mood
StabilizersStabilizers
Lithium CarbonateLithium Carbonate
Alternative Drugs:Alternative Drugs:
–CarbamazepineCarbamazepine
–Sodium ValproateSodium Valproate
–LamotrigineLamotrigine
–TopiramateTopiramate
–Atypical anyipsychotics – Olanzapine, risperidoneAtypical anyipsychotics – Olanzapine, risperidone

7. Lithium Carbonate – Pharmacological Lithium Carbonate – Pharmacological
actions actions
CNS:CNS:
–No discernible psychotropic effect in normal No discernible psychotropic effect in normal
individualsindividuals
–Similarly, no effect on Manic-depressive Similarly, no effect on Manic-depressive
patientspatients
–On prolonged administration – acts as mood On prolonged administration – acts as mood
stabilizerstabilizer
–Suppresses the episodes af attackSuppresses the episodes af attack

8. Effect of
Lithium
Salts in
Mania:

9. Lithium Carbonate – Mechanism of Lithium Carbonate – Mechanism of
actionaction
1.1.Effect on Electrolyte and ion transport:Effect on Electrolyte and ion transport:
–Li is the lightest of the alkali metal atomsLi is the lightest of the alkali metal atoms
–Na+ and K+ are important in this familyNa+ and K+ are important in this family
–Li distributes evenly in extracellular and intracellular fluids Li distributes evenly in extracellular and intracellular fluids
(contrast to Na+ and K+)(contrast to Na+ and K+)
–Build up a small concentration gradient across cell Build up a small concentration gradient across cell
membranemembrane
–But, cannot be transported via Na+/K+ ATPase But, cannot be transported via Na+/K+ ATPase
–Interfere with transuducer mechanism of cell membraneInterfere with transuducer mechanism of cell membrane

10. Lithium Carbonate – Mechanism Lithium Carbonate – Mechanism
of actionof action
2.2.Effects on 2Effects on 2
ndnd
Messenger Messenger
–IPIP33 and DAG are important 2 and DAG are important 2
ndnd
messenger for alpha and messenger for alpha and
Muscarinic transmissionMuscarinic transmission
–Lithium inhibits several enzymes in the normal recycling of Lithium inhibits several enzymes in the normal recycling of
PhosphoinositidePhosphoinositide
–These include IPThese include IP22 to IP to IP11 and IP to Inositol and IP to Inositol
–These leads to depletion of PIPThese leads to depletion of PIP22, the membrane precursor , the membrane precursor
of IPof IP33 and DAG and DAG
–Ultimate effect may be in G-protein receptors – may Ultimate effect may be in G-protein receptors – may
uncouple receptors from G-protein uncouple receptors from G-protein

11. Lithium Carbonate, Mechanism – Lithium Carbonate, Mechanism –
contd.contd.

12. Lithium Carbonate, Mechanism – Lithium Carbonate, Mechanism –
contd.contd.
3.3.Neurotransmitters:Neurotransmitters:
–Enhances the action of SerotoninEnhances the action of Serotonin
–Decrease the noradrenaline and dopamine Decrease the noradrenaline and dopamine
turnover – antimanic actionturnover – antimanic action
–Augment synthesis of AcetylcholineAugment synthesis of Acetylcholine

13. Lithium Carbonate - PharmacokineticsLithium Carbonate - Pharmacokinetics
•Initial Dose is 600 mg/day and gradually increased (600 to
1200 mg/day
Well absorbed orally, but slowlyWell absorbed orally, but slowly
Not metabolized and not protein boundNot metabolized and not protein bound
Attains uniform distribution in total body Attains uniform distribution in total body
waterwater
Apparent Vd – 0.8L/kg at steady state Apparent Vd – 0.8L/kg at steady state

14. Lithium, Pharmacokinetics – Lithium, Pharmacokinetics –
contd.contd.
Li is actively reabsorbed from proximal tubule in the Li is actively reabsorbed from proximal tubule in the
kidney similar to Na+kidney similar to Na+
When Na+ is restricted larger portion of Na+ is When Na+ is restricted larger portion of Na+ is
reabsorbed - similar is in case of Lireabsorbed - similar is in case of Li
Initially rapid excretion, then slower in later phase.Initially rapid excretion, then slower in later phase.
T1/2 is 16 to 30 HrsT1/2 is 16 to 30 Hrs
Clearance is 20% of creatinineClearance is 20% of creatinine
Steady state is attained in 5-7 daysSteady state is attained in 5-7 days
Available as 300 and 400 mg tabletsAvailable as 300 and 400 mg tablets

15. Lithium – Monitoring of TreatmentLithium – Monitoring of Treatment
Individual variation in the rate of excretionIndividual variation in the rate of excretion
Narrow margin of safetyNarrow margin of safety
Done 5 days after the start of treatmentDone 5 days after the start of treatment
Measurement is done 12 Hrs after the last doseMeasurement is done 12 Hrs after the last dose
If no therapeutic improvement, chnge the doseIf no therapeutic improvement, chnge the dose
New dose = desired plasma level/present levelNew dose = desired plasma level/present level
Monitor the new dose level after 5 days againMonitor the new dose level after 5 days again
If steady state (0.5 to 0.8 mEq/L – increase the If steady state (0.5 to 0.8 mEq/L – increase the
interval of monitoringinterval of monitoring

16. Lithium – Adverse EffectsLithium – Adverse Effects
1.1.CNS:CNS:
–Tremor is frequentTremor is frequent
–Coarse tremor, giddiness, ataxia, motor incoordination, Coarse tremor, giddiness, ataxia, motor incoordination,
nystagmus etc. – delirium, comanystagmus etc. – delirium, coma
–Occurs mainly when plasma level is high (2mEq/L)Occurs mainly when plasma level is high (2mEq/L)
–Treat with propranolol, atenolol etc.Treat with propranolol, atenolol etc.
–If required – Osmotic diuretics for Li excretionIf required – Osmotic diuretics for Li excretion
1.1.Renal: Polyuria and PolydipsiaRenal: Polyuria and Polydipsia
–Loss of ability of collecting tubules to conserve water by influence Loss of ability of collecting tubules to conserve water by influence
of ADH (G protein)of ADH (G protein)
–Excessive free water clearanceExcessive free water clearance
–Nephrogenic Diabetes InsipidusNephrogenic Diabetes Insipidus

17. Lithium, Adverse Effects – contd.Lithium, Adverse Effects – contd.
3.3.Cardiac Effects:Cardiac Effects: Sick-sinus syndrome – Sick-sinus syndrome –
contraindicated – flattening of T wavecontraindicated – flattening of T wave
4.4.Thyroid Function:Thyroid Function: Decrease in thyroid Decrease in thyroid
Function – goitre (G protein)Function – goitre (G protein)
5.5.Pregnancy Pregnancy – contraindicated– contraindicated
–Foetal goitre, congenital abnormalities (cardiac) Foetal goitre, congenital abnormalities (cardiac)

18. Lithium – Drug InteractionsLithium – Drug Interactions
Diuretics: Renal clearance of Lithium is reduced by Diuretics: Renal clearance of Lithium is reduced by
25% with Diuretic e.g. furosemide, Thiazides25% with Diuretic e.g. furosemide, Thiazides
NSAIDS: Renal clearance of Lithium is reduced by NSAIDS: Renal clearance of Lithium is reduced by
25%25%
All Neuroleptics, except clozapine – increased EPSAll Neuroleptics, except clozapine – increased EPS
Insulin and oral hypoglycaemics: enhance Insulin and oral hypoglycaemics: enhance
hypoglycaemiahypoglycaemia

19. Antimanic – Other Drugs
Carbamazepine:
–Prolong remission
–Relapse with Li+ therapy and rapid cycling of
Mood – Li + CBZ
Sodium Valproate:
–Ist line in acute mania
–Lithium resistance cases
–Lithium + Valproate – resistance to monotherapy

20. Antimanic Drugs - contd.
Lamotrigine:
–Not for acute cases but Bipolar disorders
–Used as monotherapy as well as with Lithium
Atypical antipsychotics:
–1st line in acute mania in combination with BZD
except patient requiring parenteral therapy
–Olanzapine in maintenance therapy and
prophylaxis

21. ANTIDEPRESSANTS
A
N
T
ID
E
P
R
E
S
S
A
N
T
S
Drugs which can Elevate Mood (Mood Elevators)

22. ANTIDEPRESSANTS
1.MAO inhibitors:
–Irreversible: Isocarboxazid, Iproniazid, Phenelzine and
Tranylcypromine
–Reversible: Moclobemide and Clorgyline
1.Tricyclic antidepressants (TCAs)
NA and 5 HT reuptake inhibitors – Imipramine,
Amitryptiline, Doxepin, Dothiepin and Clomipramine
NA reuptake inhibitors – Desimipramine, Nortryptyline,
Amoxapine
1.Selective Serotonin reuptake inhibitors:
–Fluoxetine, Fluvoxamine, Sertraline and Citalopram
1.Atypical antidepressants:
–Trazodone, Mianserin, Mirtazapine, Venlafaxine, Duloxetine,
Bupropion and Tianeptine

23. Causes of Depression and
Mechanism of antidepressants
The Monoamine Theory:
Adrenaline, Noradrenaline, Dopamine and 5-HT
are neurotransmitters (Biogenic amines)
Called Noradrenergic, Serotonergic or
Dopaminergic etc. neurones
Normally NA and 5 HT are in adequate numbers
at post synaptic region
In DEPRESSION – Deficiency of NA or 5 HT or
BOTH

24. Mechanism of antidepressants –
contd.
Drugs act by increasing the local availability of NA or
5 HT
MAO Inhibitors: MAO is a Mitochondrial Enzyme
involved in Oxidative deamination of these amines
MAO-A: Peripheral nerve endings, Intestine and
Placenta (5-HT and NA)
MAO-B: Brain and in Platelets and Mainly
Serotonergic (Phenylalanine)
Selective MAO-A inhibitors (RIMA) have
antidepressant property

25. Mechanism of antidepressants –
contd.
TCAs:
–NA, 5 HT and Dopamine are present in Nerve endings
–Normally, there are reuptake mechanism and termination of
action
–TCAs inhibit reuptake and make more monoamines
available for action
SSRIs:
–Serotonins also reuptaken by Nerve terminals
–SSRIs inhibit the reuptake mechanism and make more 5
HT available for action

26. Mechanism of
Antidepressants

27. MAO inhibitors
Drugs: Irreversible: Isocarboxazid, Iproniazid, Phenelzine and
Tranylcypromine, Reversible: Moclobemide and Clorgyline
Not popular now except irreversible selective MAO-A
inhibitors:
–Strict dietary restrictions
–Irreversible action
–Drug-drug interactions
–Safer drugs are available now
Major drawbacks:
–Manic state or hypertensive crisis
–Cheese reactions
–Other drug interactions

28. MAO inhibitors (Drawbacks) – contd.
Drug Interactions:
–Ephedrine (drugs of cold and cough): hypertensive reaction
–Reserpine, guanethidine: excitement and rise in BP
–Levodopa: excitement and rise in BP (delayed degradation
of NA and DA)
–Antiparkinsonian anticholinergics: Hallucinations and
symptoms of atropine poisoning
–MAOI and SSRI: Serotonin Syndrome (Mental confusion,
hallucinations, sweating, hyperthermia, twitching of muscle,
clonus and convulsion)

29. MAO inhibitors – contd.
Moclobomide: Advantages
–Reversible action (1-2 days after stoppage)
–Potentiation of pressor response to dietary
amines is weak
–Dietary restriction not required
–Lack of anticholinergic, sedative,, cognitive and
CVS adverse effects
–Used in elderly patients and with heart diseases
–Mild to moderate depression - alternative to TCAs

30. Tricyclic Antidepressants - Imipramine
NA and 5 HT reuptake inhibitors –
Imipramine, Amitryptiline, Doxepin, Dothiepin and
Clomipramine; NA reuptake inhibitors –
Desimipramine, Nortryptyline, Amoxapine
Analogue of CPZ
Inhibit NET and SERT
Interacts with variety of receptors – alpha, H1,
5HT1, 5HT2 and D2

31. Imipramine – contd.
Early effects – sedation, no other CNS effect
After 2-4 wks:
–Elevation of mood, more communicative
–REM sleep suppressed and no night awakening
–More sedative ones are for agitated and anxiety
patients (amitriptyline, doxepin)
–Withdrawn patients – less sedative Imipramine,
Nortriptyline
–Induce seizure (Clomipramine, bupropion)

32. Imipramine - Mechanism of action
Inhibit uptake of Biogenic amines – NA and 5-HT
No inhibition of DA uptake except Bupropion
Cocaine and amphetamines are inhibitors of DA
uptake – strong CNS stimulant
May facilitate DA transmission in forebrain –
elevation of MOOD
Reuptake inhibition causes – increase amines in
synaptic cleft
Inhibition of DA – stimulant action
Inhibition of NA and 5-HT – antidepressant action

33. Imipramine - Mechanism of action –
contd.
But, antidepressant action starts after few weeks, whereas
blockade starts immediately
Inhibition of uptake is an early step but cascade of events that
follow are important
Initially, auto receptors - α2 and 5-HT1 are activated by excess
of NA/5HT – negative feed back
Limiting of synaptic availability of NA - homeostasis
On repeated exposure – α2 receptor response diminishes -
desensitization of these pre-synaptic receptors
Adaptive changes – in number and sensitivity of pre and
postsynaptic pre-synaptic production and release of NA -
normal or more
No reuptake and no negative feed back

34. Imipramine – Pharmacological actions
ANS: Dry mouth, blurring of vision,
constipation and urinary hesitancy
CVS: Tachycardia –
–NA and anticholinergic action
–Postural hypotension
–ECG – T wave suppression
–Arrhythmia

35. Effect of
Antidepressants
Deficient Drive of
MOOD to -
Normal Rhythmic
Drive on
Prolonged
Treatment

36. Imipramine - Pharmacokinetics
Good oral absorption but undergo 1st pass effect –
variable bioavailablity
Highly bound to plasma protein and high Vd
Metabolized in Liver: Active metaboites: Imipramine
– desipramine and amitriptyline – nortriptyline
Excreted via urine, t1/2 – 16 to 24 Hrs
One daily dose – because of active metabolites
Therapeutic window phenomenon: Optimal effect at
50-200 ng/ml
Doses to be individualized and titrated

37. Imipramine – Adverse effects
1.Anticholinergic effects: Dry mouth, bad taste,
constipaton, urinary retention etc.
2.Dysphoric state or mania - suicide
3.CVS:
Postural hypotension – older patient and overdose
Arrhythmia – with IHD
1.Weight gain – not with bupropion and SSRI
2.Seizure – in children
3.Sedation, mental confusion etc. – more with
amitriptyline
4.Sweating and fine tremor

38. Imipramine – Drug Interactions
1.TCAs and Sympathomimetics (Cough and
cold)
2.TCAs and MAO inhibitors – Hypertensive
crisis
3.TCAs and SSRIs – SSRIs inhibit
metabolism of TCAs
4.Anticholinergic property – delay absorption
of other drugs

39. Imipramine - Drawbacks
Low safety margin
Anticholinergic, CVS and neurological side
effects
Therapeutic lag (2-4 wks)
Variable patient response

40. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
Drugs: Fluoxetine, Fluvoxamine, Sertraline and
Citalopram
Similar antidepressant action
Relatively safe and better patient acceptability
Some patients not responding to TCAs may respond
with SSRIs
Because of absence of psychomotor and cognitive
impairment - Preferred in prophylaxis of recurrent
depression

41. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
Relative advantages:
–No sedation, so no
cognitive or psychomotor
function interference
–No anicholinergic effects
–No alpha-blocking action,
so no postural hypotension
and suits for elderly
–No seizure induction
–No arrhythmia
Drawbacks:
–Nausea is common
–Interfere with ejaculation
–Insomnia, dyskinesia,
headache and diarrhoea
–Impairment of platelet
function – epistaxis
–Serotonin Syndrome:
Mental confusion,
hallucinations, sweating,
hyperthermia, twitching of
muscle, clonus and
convulsion.

42. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS
Fluoxetine:
–Prototype of SSRIs
–Slow action and not used for rapid effects
–Longest acting – 2 days, t1/2 = 2 days
–Used in depression and OCDs in adult and
children

43. SSRIs – Pharmacokinetic comparison
Dose
mg/day
Drug
interaction
Half life Steady
state
(Days)
Fluoxetine5-20 high 2-4 days 30-60
Sertraline50 low 26 Hrs 7-14
Paroxetime20 high 20 Hrs 10-14
Citalopram20-40low 35 Hrs 7

44. Atypical Antidepressants
1.Trazodone:
Weak 5-HT uptake block, α – block, 5-HT2 antagonist
No anticholinergic action
No arrhythmia
No seizure
ADRs: Priapism, Postural Hypotension
2.Venlafaxine:
SNRI (Serotonin and NA uptake inhibitor)
Fast in action
No cholinergic, adrenergic and histaminic interference
Raising of BP

45. Atypical Antidepressants – contd.
3. Mirtazapine:
NaSSA action (Noradrenaergic and specific serotonergic
antidepressant) – enhancement of NA release and specific 5-
HT1 receptor action
Blockade of 5-HT2 and 5-HT3
No anticholinergic or antidopaminergic action
4. Bupropion:
Inhibitor of DA and NA uptake (NDRI)
Non-sedative but excitant property
Used in depression and cessation of smoking
Seizure may precipitated

46. Antidepressants - Uses
1.Endogenous Major Depression:
Aim: Relieve symptoms of depression and restore Normal
social Behavior
1
st
choice – SSRI (atypical ones also may be considered)
TCAs – in non-responsive cases
(TCAs have to be used in severe depression in adults)
MAO –A inhibitors in mild and moderate cases
Maintenance – by TCAs (Imipramine 100 mg)
Combined with Lithium in Bipolar disorder
Newer ones are not recommended in children – suicide
chance

47. Antidepressants (Uses) – contd.
2. Obsessive Compulsive Disorder (OCD) and Phobic states:
(SSRIs are useful)
–Compulsive eating in Bulimia
–Body dysmorphic disorder
–Compulsive buying
–Kleptomania
3.Anxiety Disorders: BZD
4.Neuropathic pain: Imipramine, Amitriptyline – post herpetic neuralgia
4.Attention Deficit Hyperactivity Disorder: TCAs
5.Enuresis
6.Migraine: Amitryptiline as prophylactic

48. Antianxiety Drugs

49. What is anxiety?
Anxiety is a normal reaction to stress
It helps one deal with a tense situation in the
office, study harder for an exam, keep
focused on an important speech
In general, it helps one cope
But when anxiety becomes an excessive,
irrational dread of everyday situations, it has
become a disabling disorder

50. Antianxiety Drugs – contd.
Five major types of anxiety disorders are:
–Generalized Anxiety Disorder (GAD)
–Obsessive-Compulsive Disorder (OCD)
–Panic Disorder
–Post-Traumatic Stress Disorder (PTSD)
–Social Phobia (or Social Anxiety Disorder)
GAD:
–Excessive, exaggerated anxiety and worry about everyday life
events with no obvious reasons for worry
–always expect disaster and can't stop worrying about health,
money, family, work, or school
–interferes with daily functioning, including work, school, social
activities, and relationships.

51. Antianxiety Drugs – contd.

52. What are the Drugs?
Benzodiazepines: Alprazolam, Diazepam,
Chlordiazepoxide, Oxazepam and Lorazepam
Older Drugs: Barbiturates, Chloral hydrate and
Meprobamate
Azapirones: Buspirone, Gepirone and Isapirone
Others: Propranolol, Imipramine Fluoxetine and
Zolpidem etc.

53. Antianxiety Drugs – BZDs
High potency BZDs are useful
Slow and Long duration of action
Relieve anxiety at low doses – no generalized CNS depression
Prescribed for short period – especially for alcohol and drug
abuse persons
Less cognitive impairment
At low dose – CVS and Respiratory side effects are less
Withdrawal syndrome – tapering of Doses
Clonazepam - social phobia and GAD
Lorazepam - panic disorder
Alprazolam - panic disorder and GAD
Diazepam – acute panic state and organic disease anxiety

54. Antianxiety Drugs – Buspirone
No marked sedation and euphoria
No direct effect on GABA or BZD receptors
No physical dependence or tolerance
No muscle relaxant, no anticonvulsant or no
extra pyramidal effects
No functional and cognitive impairment
No cross tolerance to other anxiolytics and
little abuse potential

55. Buspirone – contd.
Partial agonist action on presynaptic auto receptor 5-
HT1A – reduces serotonergic activity in dorsal raphe
Antagonist of certain 5-HT1A post synaptic receptors
Weak D2 action but no antipsychotic effect
Adaptive changes after chronic treatment – reduction
in 5-HT2 receptors in cortex
Given orally, absorbed rapidly – high 1
st
pass
metabolism, active metabolite – urine and faeces
Dose: 5-15 mg dose

56. Antianxiety Drugs - Propranolol
Reduces symptoms of anxiety
Symptoms: Sympathetic overactivity –
palpitation, tachycardia, rise in BP, sweating,
tremor, GIT hurrying etc
No action on psychological symptoms – fear,
tension etc.
Useful in examination fear, public
appearance etc.

57. Pharmacotherapy of Anxiety
Anxiety is a Physiological phenomenon
Start medication only when marked impairment of performance
Start with a BZD according to the type of disorder at smallest
dose possible
Doses are found out by titrating with the symptoms
Usually start with ½ or 2/3
rd
of the normal dose at bed time
If required the rest of the doses be given at day time
Simultaneously treat the primary cause – hypertension, Peptic
ulcer etc.
SSRIs and Buspirone may be used in severe cases but not in
acute cases

58. Pharmacotherapy of Anxiety – contd.
Beta-blockers may be given as adjuncts
Withdraw anxiolytics, if required in tapering doses
Lifelong therapy may be required for some patients
but avoid short acting drugs for long therapy
Monitor for Drug interactions
In GAD – counseling, mental relaxations and
Behavioural therapy
Avoid:
–Excess of Cola or Coffee (stimulants)
–Combination of alcohol, antihistamines, anticholinergics

59. Thank you / Khublei