1. Antidepressant, Anti-anxiety Drugs
Dr. R. K. Dixit
Professor
Pharmacology and Therapeutics
C. S. M. Medical University Lucknow,

4. Classification of Major Affective Disorders

5. Episodal (reactive) Depression
Adverse life events.
Physical illness.
Drugs.
Other psychiatric disorders.

6. Reactive (episodal) Depression
More than 60% of all depressions.
Core depressive syndrome: feelings of misery, apathy, inadequacy, pessimism, anxiety, tension, guilt. Ugliness, Low self –esteem,
Bodily complaints

7. Withdrawn.
Loss of interest in pleasurable activities.
Indecisiveness, loss of motivation.
Retardation of thought and action.
Sleep disturbance

8. In severe cases, it is accompanied by hallucinations and delusions.
Recurrent suicidal ideation, a suicide attempt or a specific suicide plan.
significant weight change (without dieting )
Psychomotor agitation or retardation.

9. 2. Depression can be drug-induced.
1. Has a genetic component.
2. Depression can be drug-induced.
3. Depression can be drug-repressed.
4. Depression can be treated with drugs.
5. Depression can be treated with
Electroconvulsive Therapy (ECT).

10. (Manic-Depressive Disease, Bipolar Disorder).
Mania
Mania alone is rare (10%) and most frequently cycles with Major/endogenous depression
(Manic-Depressive Disease, Bipolar Disorder).
Core Symptoms:
Characterized by an elevated “high” mood.
Talkative, go on-and-on about the things they will do.
Increased self-esteem.
Auditory hallucinations.
Decrease need to sleep. Expensiveness, unnecessary buying.
Lack judgment, Supermen

11. The precise cause of affective disorders remains elusive.
Evidence implicates alterations in the firing patterns of a subset of biogenic amines in the CNS,
Norepinephrine (NE) and Serotonin (5-HT).
 Activity of NE and 5 -HT systems?.

12. (hippocampus, amygdala, hypothalamus, thalamus).
Almost all NE pathways in the brain originate from the cell bodies of neuronal cells in the locus coereleus in the midbrain, which send their axons diffusely to the cortex, cerebellum and limbic areas
(hippocampus, amygdala, hypothalamus, thalamus).
Mood: -- higher functions performed by the cortex.
Cognitive function: -- function of cortex.
Drive and motivation: -- function of brainstem
Memory and emotion: -- function of the hippocampus and amygdala.
Endocrine response: -- function of hypothalamus.

13. (in groups known as raphe nuclei) This system is also involved in:
Serotonin System
As with the NE system, serotonin neurons located in the pons and midbrain
(in groups known as raphe nuclei)
send their projections diffusely to the cortex, hippocampus, amygdala, hypothalamus, thalamus, etc. --same areas implicated in depression.
This system is also involved in:
Anxiety.
Sleep.
Sexual behavior.
Temperature regulation.
CSF production.

16. Blocked by antidepressants

17. Serotonin receptors 5–HT1 5–HT2 subtypes
5–HT1A, 5–HT1B, 5–HT1D, 5–HT1E, 5–HT1F
primarily responsible for the therapeutic (antidepressant) effects of increased intrasynaptic serotonin
5–HT2
5–HT2A, 5–HT2B, 5–HT2C
primarily responsible for the toxic effects of increased intrasynaptic serotonin

18. Serotonin receptors
Over all 14 types divided in to 1, 2, 3, and 4-7 family
All are G-protein coupled receptors except 3
1- decreases cAMP while 4-7 increase
3- ligand gated cation channel

19. Alternative Therapies
No way of a priori knowing which therapy will be best for a patient.
Light Therapy
Psychological Treatment
ECT (patients with suicidal tendency and for quick action)
St. John’s Wort (Plant)

20. Antidepressants TCAs SSRIs doxepin TCAs MAOIs MAOIs MAOIs TCAs TCAs
isocarboxazide
MAOIs
TCAs
Venflaxine
maprotiline
MAOIs
Venflaxine
MAOIs
MAOIs
SSRIs
SSRIs
Amoxepine
SSRIs
Venflaxine
MAOIs
Nortriptyline

21. Reversible inhibitor of MAO-A (RIMAs)
Moclobemide ,Clorgyline
(Isocarboxacid, phenelzine, tranylcypromine.) CM
RITA-Don't- Copy
Exams-For-PCS
MAD-Boy-turned-violent
ANT IDEPRES SANT S
Tricyclic antideprssants (TCAs)
NA + 5 HT reuptake inhibitor
Imipramine, Amitriptyline
Trimipramine, Doxepin
Dothiepin, Clomipramine
Predominantly NA reuptake inhibitor
Desipramine, Nortriptyline
Amoxapine, Reboxetine
Selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine, Fluvoxamine
Paroxetine, Sertraline
Citalopram, Escitalopram
Atypical antidepressants
Trazodone, Mianserine
Mirtazapine, Venlafaxine Duloxetine,Tianeptine
Amineptine, Bupropion

22. Mechanism of Action ATYPICAL (MAOIs).
1. Inhibition of MAO enzymes.
(MAOIs).
2. Inhibition of NE and 5-HT reuptake.
(TCAs, SSRIs, Newer TCAs).
3. Prominent alpha blocking and weak 5-HT antagonists.
(Nefazodone, trazodone,)
4. Serotonin and noradrenalin reuptake inhibitor (SNRIs)
(venlafaxine, duloxetine)
5. Noradrenergic and specific serotonergic antidepressants (NaSSA)
(Mirtazapine)
6. Inhibitor of Dopamine and Noradrenalin
(Bupropion)
7. Blockade of pre-synaptic alpha 2 receptors
(Mianserin)
8. Increases rather than inhibiting 5-HT uptake
(Tianeptine, Amineptine)
ATYPICAL

23. MAO ( monoamine oxidase) an enzyme Two types
MAO – A
-Peripheral adrenergic nerve endings
-Intestinal mucosa
-Human placenta
-Liver
-Serotonin , Noradrenalin and dopamine
-Inhibited by moclobemide
and clorgyline
MAO-B
-brain ( basal ganglia)
-Platelets
-Liver
-Deaminates dopamine
-Inhibeted by selegiline (deprenyl)
A-B
C-D
Isoniazide, iproniazide, phenelzine, isocarboxazide,tranylcypromine were non selective and irreversible inhibitors (Hit and run drugs) used previously but not used now due to drug drug and drug food interactions. Linezolide (new drug against MRSA) Cheese and serotonin syndrome

25. Nonselective MAOIs not favorable Cheese Reaction
Cheese, beer, wine,
meat, fish, yeast,
(contain large amount of tyrammine and other indirectly acting amines)
Due to irreversible block of MAO These escape degradation in intestinal wall and liver
Hypertensive crises, CVA
Medical Emergency
Reach to circulation Displace large amount of noradrenalin from loaded nerves
Tt. I.V. Phentolamine, Prazosin

26. Nonselective MAOIs not favorable
Cold and Cough medicines contain Ephedrine
(Same result as cheese reaction)
Levodopa- excitement and hypertension
Tricyclic antidepressants- excitement, rise in BP, temperature

27. Reversible inhibitor of MAO-A (RIMAs)
Moclobemide-
Reversible and selective MAO-A inhibitor
Short duration of action
Competitive enzyme inhibition
Tyramine is able to displace it
Cheese reaction is less likely
Devoid of anticholenergic, sedative, cognitive, cardiovascular effects
Good for elderly with heart diseases

28. Tricyclic Antidepressants (TCAs)
Imipramine represents the class (Prototype)
Inhibit monoamine reuptake
(serotonin and noradrenalin)
Increase the concentration of Serotonin and NA at synapse and potentiate the action (therapeutic effects)
Other receptors acted (Adverse effects)
Muscarinic- Anticholinergic side effects (dryness etc.) #
Alpha- alpha blocking actions (postural hypotension etc.) #
Histamine-Antihistaminic (sedation) #
Dopamine- antipsychotic (amoxapine, maprotiline)

29. TCAs actions (CNS) In Normal person In Depressed
Tiredness
Light-headedness
Sleepiness
Difficulty in thinking
Difficulty in concentration,
Gait disturbances
Provoke anxiety
Unpleasant
In Depressed
-Sedation immediately
-Elevation of mood (2-4Weeks)
-Suppresses REM prolongs total sleep duration
Lower seizure threshold and produce convulsions in overdose Don’t carry abuse potential, Development of dependence is less

30. TCAs uptake blockade is not directly responsible for antidepressant action?
Uptake blockade occurs quickly but antidepressant action occurs after months
Initially
Pre synaptic alpha 2 and 5-HT1 auto receptors are activated by increased amount of NA and Serotonin in synaptic cleft resulting in decreased firing
But on long term
desensitize and down regulation of these receptors and induce adaptive changes in the number and sensitivity of receptors and amine turnover leading to enhanced NA and Serotonin transmission required for antidepressant action.

31. Tolerance to Anticholinergic and hypotensive actions develop latter on
TCAs on other systems
ANS
Potent anticholinergic
(dry mouth, blurring of vision,, constipation, urinary hesitancy)
Weak alpha 1 blocking
(postural hypotension, impairment of ejaculation,)
H1 antihistaminic
(sedation)
CVS
Tachycardia
Postural hypotension
Cardiac arrhythmias (T wave suppression or inversion) due to intra ventricular conduction interference due to NA and Anti cholinergic actions
Tolerance to Anticholinergic and hypotensive actions develop latter on

32. TCAs (Pharmacokinetics)
Good oral absorption
Highly bound to Proteins (plasma and tissue)
Metabolized in liver (oxidation, glucuronide conjugation and CYP2D6, CYP3A4, CYP1A2
Many active metabolites may be produced
Mostly can be given once a day (at bed)
Have Therapeutic Window phenomenon (50-200ng/ml of imipramin)

33. TCAs Adverse effects
Anticholinergic- dry moth, bad taste, constipation, epigastric fullness, urinary retention (more common in elderly male), blurred vision, palpitation
Sedation, mental confusion, weakness
Increased appetite and weight
Sweating, fine tremors
Precipitation of seizures
Postural hypotension
Cardiac arrhythmias
Rashes and jaundice

34. TCAs (Acute Poisoning)
Usually suicidal attempt
Presents as
Excitement
delirium,
Anticholinergic symptoms like atropine poisoning
Muscle spasm
Convulsions
Respiratory depression
Coma
Treatment
Gastric lavage
I.V. line
Oxygen
Maintenance of BP and Temperature
Diazepam iv
Propranolol / lignocain

35. TCAs (Interactions) Potentiation of sympathomimetics (direct acting)
Reduce action of sympathomimetics (indirect acting)
Reduce antihypertensive action of guanethidine and
clonidine ( by preventing their transport in to neurons)
Potentiate other CNS sedatives
SSRIs inhibit metabolism of TCAs
With MAO inhibitors dangerous hypertensive crisis with excitement and hallucinations
Retard the absorption of other drugs
Phenytoin, phenylbutazone, chlorpromazine, aspirin, displace TCAs and produce toxicity
Phenobarbitone induce metabolism and inhibit the effect of the drug

36. Miscellaneous Amoxapine Reboxetine Tetra cyclic compound
Blocks D2 reuptake also
Has mixed antidepressant and neuroleptic effects
Good for psychotic depression
Reboxetine
Selective NA reuptake blocker
Weak action on 5-HT mechanism
Anticholinergic effects are minimal

37. Selective Serotonin Reuptake Inhibitors (SSRIs)
Limitations of TCAs
Anticholinergic effects
Alpha blocking action
Cardio toxicity
Sedation, seizures ppt
Low safety margin
Weight gain
Therapeutic window
Overdose poisoning common
Lag of 1 month period
Incomplete response to Tt
Answers may be given by SSRIs
Selectively inhibit membrane associated SERT (serotonin transporter)
More tolerability and better acceptability
Used in depression as well as in OCD, phobias
No sedation, No seizure ppt
No alpha blocking action
Less chances of arrhythmia
No weight gain
Now 1st choice for OCD, Panic disorders, Social Phobia, Eating disorders, Premenstrual syndrome, Post traumatic stress

38. Important points TCAs have slightly more efficacy
Some patients not responding to TCAs may respond to SSRIs,
SSRIs preferred in prophylaxis of recurrent depression
In severe depression TCAs appear to be more efficacious

39. Individual compounds Fluoxetine Fluvoxamine Paroxetine Sertraline
Prototype of SSRIs
Longest acting
Fluvoxamine
Short acting
Commonly used in indoor patients
Paroxetine
Short acting
More GI side effects
Sertraline
Less chances of drug interactions due to low potency to cause cytochrome enzyme depression
Escitalopram
Active enantiomer of citalopram side effects are less
Citalopram
Similar to sertraline but should be avoided in patients attempting suicide

40. SSRIs Side effects Others Gastric upset Nausea
Interfere with ejaculation
Nervousness
Restlessness
Insomnia
Anorexia
Headache
Diarrhea
Epistaxis
Ecchymosis
Others
Inhibit cytochrome enzymes and elevate the plasma level of other drugs
Other serotonergic drug ( MAOIs) is taken may precipitate Serotonin Syndrome manifesting as agitation, restlessness, sweating, twitching, convulsions

41. Atypical Antidepressants
Trazodone
Blocks 5-HT uptake
Has prominenent alpha blocking
Weak 5-HT2 antagonistic
No anticholinergic effect
Bradycardia
Has anxiolytic action also
Prolonged and painful
penile erection (priaprism)
Mianserin
Unique not inhibit NA and 5-HT uptake
Blocks pre-synaptic alpha 2 receptors increases release and turnover of NA
Antagonist at serotonin 2, 1c, and H1 receptors
Has sedative effect
Damages liver and bone marrow (Reserve drug)

42. Atypical Antidepressants
Tianeptine / and Amineptine
Increases rather inhibiting 5-HT uptake
Neither sedative nor stimulant
Effective in anxiodepressive states
Venlafaxine / Duloxetine
SNRI selective in action
Faster onset of action
Increases BP
Duloxetine increases uretheral tone used in urinary incontinence ( over active bladder)
Mirtazapine (NaSSA)
Noradrenergic and specific serotonergic antidepressant
Blocks alpha 2 auto receptor (on NA neuron) and hetero- (on 5-HT neuron) receptors increasing both NA and serotonin release.
Bupropion
Inhibits DA and NA uptake has excitant effect
Used to reduce smoking

43. Antidepressant uses
Depression (ECT may be needed in severely depressed and patients having suicidal tendency)
Bipolar affective disorders TCAs and lithium or SSRIs with lithium or valporate/ lamotrigine
SSRIs with atypical antipsychotic in psychotic depression
Obsessive compulsive disorders (SSRI and Clomipramine)
Eating disorders

44. Anxiety disorders
Neuropathic pain
Attention deficit hyperactivity disorder in children
Enuresis- (Imipramine 25mg at night)
Overactive bladder (stress incontinence)
Migraine prophylaxis
Pruritus (Topical doxepin)

45. Antianxiety Drugs Anxiety - emotional state Unpleasant
Associated with uneasiness
Discomfort
Fear
Undefined threat
Fear about future
Some amount of anxiety is must for progress
When it becomes excessive, disproportionate, hampers performance
then only
needs treatment

46. Have anticonvulsant activity
Antianxiety Drugs
Drugs producing restful state of mind without interfering with normal mental or physical functions.
Have no effect on thought control
Don’t produce extra pyramidal side effects
Can Produce physical dependence
May Have abuse potential
Don’t selectively block conditioned avoidance response in animals
Have anticonvulsant activity

47. Antianxiety Drugs Benzodiazepine Azapirones Others Diazepam
Chlordiazepoxide
Oxazepam
Lorazepam
Alprazolam
Azapirones
Buspirone
Gepirone
Ispapirone
Others
Beta blocker- Propranolol
Antihistaminics- Hydroxyzine
SSRIs and other antidepressant drugs
PHO/BIG/DOCLA

48. Benzodiazepines
Relieve anxiety at low dose ( higher dose induce sleep and impair performance )
Selective taming effect
More selective to limbic system
Have low side effects in Antianxiety dose
Lorazapam and clonazepam IM for psychotic and manic patients
Act by facilitating GABAergic transmission

49. Benzodiazepine MOA Extra-tracellular Intracellular Cl Diazepam +
DMCM –
Flumazenil- 0
α subunit
Extra-tracellular
Others
δεθπ
Facilitator
γ subunit
Barbiturates
Mimetic
Intracellular
Facilitator
GABA
β subunit
GABA- A Receptor
More Cl- intracellular more polarized more refractory Cl

50. Benzodiazepines Adverse effects Sedation Light headedness
Psychomotor impairment
Cognitive impairment
Vertigo
Confusional state
Increased weight
Impaired sexual functions
Potential to produce dependence
All are almost similar selection is empirical

51. Benzodiazepines (Individual drugs)
Chlordiazepoxide
First BZD
Long lasting effect
Chronic anxiety
Diazepam
Has two phase of metabolism
Broken in to active metabolites
Long duration of action
Oxazepam
Polar compound
Penetration In brain is slow
No active metabolite
Used in short lasting anxiety state
Lorazepam
Less lipid soluble
Slow entry in brain
No active metabolite IM
Alprazolam-
high potency, mood elevating in depressed pt. less drowsiness

52. Buspirone Does not produce sedation, cognitive impairment,
Does not interact with BZD receptor or modify GABAergic transmission
No tolerance
No physical dependence
No muscle relaxant
No anticonvulsant property

53. Buspirone Relieves mild to moderate generalized anxiety
Effects develop slowly (not used for acute)
Partial agonist on 5HT1A (pre-synaptic) and antagonist on 5HT postsynaptic receptors
Presynaptic auto-receptors stimulated leading to reduced activity of dorsal raphe serotonergic neurones
Also has weak D2 blocking effect

54. Hydroxazine Propranolol H1 antihistaminic
Sedative, anti -emetic and spasmolytic
Anti - Pruritus
Propranolol
Reduces sympathetic symptoms like rise in BP, Tremors, sweating etc.
Performance or situational anxiety
(like examination fear, social phobia, public lecture)

55. Questions Classify antipsychotic drugs Classify antidepressant drugs
Pharmacological actions of chlorpromazine
Pharmacological actions of amitriptyline
Drug indued parkinsonism
MOA of antipsychotic
MOA of antidepressants
Lithium

56. Questions Drug of choice of cheese reaction-Phentolamine
Moclobemide is reversible and selective MAO-A inhibitor
All antidepressants don’t inhibit DA uptake except amoxapine, maprotiline, Bupropion
Antidepressants don’t carry abuse potential
SSRIs are inhibitor of CYP enzymes
Serotonin syndrome
Trazodone – may produce priaprism due to high α1 blocking property
Mianserin unique not inhibiting NA or 5HT but blocks Pre-synaptic α2 receptors
Tianeptine, Amineptine - unique increase 5-HT uptake
Venlafaxine, Duloxetine – SNRI
Mirtazapine- NaSSA- blocks α2 auto and hetro receptors and enhance NA and 5HT release
Nocturnal enuresis- Imipramine
Benzodiazepines- GABA facilitatory
Buspirone- partial agonist at 5HT1A autoreceptors,antagonist at 5HT1A postsynaptic
DOC of performance or situational anxiety- B-blockers

57. Thanks