1. Psychopharmacology: Part 1 Antidepressants and Anxiolytics
Dr. Prashant Tibrewal

2. LITTLE BIT OF HISTORY
Serendipitous discovery in the 1950s led to the development of the first antidepressant agents:
Iproniazid (for tuberculosis)
Imipramine (for psychosis)
Further investigations revealed their pharmacological activity on monoamine systems.

3. A BIT MORE……
In 1960s specific search for serotonin reuptake inhibitors started
Culminating in the derivation of first SSRI- Zimelidine (withdrawn)
Further search for specific SSRIs led to the development of landmark SSRI- Fluoxetine

4. CLASSIFICATION
Since then more than two dozen antidepressants, which work by seven distinct mechanisms, have been developed
TCA
SSRI
NDRI
NaSSA
SNRI
SARI
MAOI

5. MECHANISM
Given the structural diversity of the members of each class, they may not resemble each other in terms of their pharmacokinetics, metabolism or toxicity.
However, most have an action on the metabolism and at the receptor for monoamine neurotransmitters:
Norepinephrine
Serotonin
Dopamine

6. ADDITIONAL MECHANISMS
Augmentation of intracellular cyclic AMP
Augment levels of neurotrophic and transcription factors such as CREB and BDNF
Modulate excitatory transmission by decreasing binding at NMDA receptors or by inducing changes at AMPA receptors.

7. MONOAMINE HYPOTHESIS NORMAL STATE -- no depression
MAO enzyme destroying neurotransmitter
monoamine neurotransmitter
NORMAL STATE -- no depression
DEPRESSION -- caused by neurotransmitter deficiency
Stahl S M, Essential Psychopharmacology (2000)

8. Increase in neurotransmitters causes return to normal state
MAO inhibitor blocks the enzyme from destroying monoamine neurotransmitter
reuptake pump blocked by antidepressant
Increase in neurotransmitters causes return to normal state
Stahl S M, Essential Psychopharmacology (2000)

9. Monoamine Receptor Hypothesis of Depression
Normal functioning
Decrease in NT
Receptors up-regulate due to lack of NT
Stahl S M, Essential Psychopharmacology (2000)

10. CIRCUIT 10

11. CIRCUIT 11

12. CIRCUIT
Ser Ne 12

13. CIRCUIT
Ser Ne 13

14. CLASSICAL ANTIDEPRESSANTS
MAO inhibitors
and
Tricyclics

16. TYPES OF MAOI Irreversible and non selective
Phenelzine, Tranylcypromine, Isocarboxazid
RIMAs- Moclobemide
Selective for MAO B-- Deprenyl

17. MAOI
Fell out of fame due to ‘cheese reaction’ – dietary tyramine metabolism inhibited by MAOI leading on to hypertensive crisis
Rigid dietary restrictions
RIMAs – Moclobemide fewer restrictions
Reserved for resistant or atypical cases

18. MAOI Risk of SSRI syndrome Do not combine with TCAs or SSRIs
Never with an SSRI
RIMA can be better tolerated but less effective.

19. TRICYCLICS First agents marketed in 1950’s Amitryptiline Doxepine
Imipramine
Clomipramine
Trimipramine
Desipramine
Nortriptyline

20. TCAs

21. Therapeutic action

22. Psychopharmacology of antidepressants: Stephen Stahl
Therapeutic action
Psychopharmacology of antidepressants: Stephen Stahl

23. Psychopharmacology of antidepressants: Stephen Stahl
Side effects
Psychopharmacology of antidepressants: Stephen Stahl

24. Psychopharmacology of antidepressants: Stephen Stahl
Side effects
Psychopharmacology of antidepressants: Stephen Stahl

25. Psychopharmacology of antidepressants: Stephen Stahl
Side effects
Psychopharmacology of antidepressants: Stephen Stahl

26. Mechanism
Block reuptake of Serotonin (5HT) and Norepinephrine (NE) Onset of antidepressant effect: 3-4 weeks

27. SIDE EFFECTS Alpha-1 Blockade: Histamine Blockade:
Orthostasis, Sexual Dysfunction, Potential for cardiac conduction delays (QT prolongation)
Histamine Blockade:
Potential for weight gain, Sedation
Acetylcholine Blockade:
Cognitive Dulling
Blurring of Vision
Tachycardia
Exacerbation of Asthma
Sexual Dysfunction

28. CONTRAINDICATIONS Hypertensive patients
Cardiac conduction abnormalities (esp. prolonged QT)
Acute narrow angle glaucoma
GI dysmotility syndromes
Benign Prostatic Hypertrophy

29. PROS AND CONS Strengths Effective, especially in severe depression.
Low cost.
Sedation perceived as a benefit.
Can be used in pain, fibromyalgia and migraine
Weaknesses
Anticholinergic SEs.
Cardiovascular toxicity in overdose.
weight Gain.
Multiple daily dosing.
Titration.
Overall SE Profile.

30. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)
Fluoxetine
Fluvoxamine
Sertraline
Citalopram
Escitalopram
Paroxetine

31. No or only weak effects at other monoamine transporter
That distinguishes them from the older TCAs, thus they are named selective.

32. Widely used, first-line treatments for depression and anxiety
Multiple FDA indications
Safety in overdose
Tolerability- better side effect profiles than older drugs like TCAs and MAOIs

33. tryptophan transporter
SEROTONIN IS PRODUCED
tryptophan transporter
AAADC
5HTP
Tryptophan
TRY-OH
5HT (Serotonin)
5--34
Stahl S M, Essential Psychopharmacology (2000)

34. SEROTONIN IS DESTROYED serotonin transporter
MAO
5--35
Stahl S M, Essential Psychopharmacology (2000)

35. serotonin transporter
SEROTONIN RECEPTORS
5HT1D autoreceptor
alpha 2 hetero receptor
serotonin transporter
5HT3
5HT4
5HT2C
5HTX
5HT2A
5HTY
5HT1A
5HTZ
5--36
Stahl S M, Essential Psychopharmacology (2000)

36. 5HT1A Presynaptic and post synaptic Antidepressant action OCD Panic
Social phobia
Bulimia

37. 5HT1D
Anti- migraine actions

38. 5HT2 Agitation Akathisia Anxiety Panic attacks Insomnia
Sexual dysfunction

39. 5HT3
Nausea
GI distress
Diarrhoea
Headache

40. Serotonin Pathways Raphe Nucleus
Stahl S M, Essential Psychopharmacology (2000)

41. PATHWAYS INVOLVED
Depression: disinhibition of pathway to prefrontal cortex
OCD: to basal ganglia
Panic Disorder: To limbic cortex and hippocampus
Bulimia: to hypothalamus

42. Frontal Cortex Mood Stahl S M, Essential Psychopharmacology (2000)
Usual onset is 3-8 weeks
Stahl S M, Essential Psychopharmacology (2000)

43. OCD Akathisia/ Agitation Basal Ganglia
Stahl S M, Essential Psychopharmacology (2000)

44. Limbic
Anxiety
Stahl S M, Essential Psychopharmacology (2000)

45. Hypothalamus Appetite/bulimia
Stahl S M, Essential Psychopharmacology (2000)

46. Sleep Centers Insomnia
Stahl S M, Essential Psychopharmacology (2000)

47. Spinal Cord Sexual Dysfunction
Through mesolimbic dopaminergic pathway
Descending pathway down the spinal cord to spinal neurons. Via 5HT2 receptors
Stahl S M, Essential Psychopharmacology (2000)

48. Brainstem Vomiting Center
Nausea and vomiting
Stahl S M, Essential Psychopharmacology (2000)

49. Gut GI cramps/Diarrhea
Stahl S M, Essential Psychopharmacology (2000)

50. COMMON FEATURES Similar mechanism of action
Efficacy equivalent to TCAs
Higher therapeutic index than TCAs
Safer and better tolerated
- minimal cardiac effects
- fewer anticholinergic effects
Better patient compliance

51. ARE THEY IDENTICAL? Differ structurally pharmacodynamically
- potency & selectivity
pharmacokinetically
- half-life, metabolic activity
- Cytochrome P450 enzyme inhibition

52. SELECTIVITY Differ in selectivity & potency
Citalopram is the most selective
- inhibits 5-HT uptake 3400 times more than NE
Paroxetine : inhibits uptake of NE
Sertraline: inhibits uptake of DA

53. PHARMACOKINETICS Half-life: FLX longest half-life
- FLX & SER: metabolites with long half-lives
Time to steady-state: 3-4 weeks for FLX
- 5 to 10 days for other SSRIs
All highly plasma bound
- Citalopram the least (80%)

54. PHARMCOKINETICS (CONTD)
Nonlinear for most
Citalopram: linear pharmacokinetics across all dose ranges
Up-titration predictable with citalopram

55. EFFECT ON CYTOCHROME P450 Potent inhibitors Exception: Citalopram
Least drug-drug interactions with citalopram

56. ADVANTAGES OF FLX Discontinuation symptoms least
Reemergence of depression slower

57. ADVERSE EFFECTS Paroxetine: - highest anticholinergic effects
- weight gain
- delayed ejaculation
Citalopram:
- higher sedation

58. ADVERSE EFFECTS….. Fluoxetine - anxiety, nervousness & agitation
- weight loss
- Headache
Fluvoxamine & sertraline
- GI symptoms
- tremors

59. SEXUAL DYSFUNCTION Prospective multicenter study (n=1022).
Spanish working group for the study of psychotropic related sexual dysfunction.
All had normal sexual function previously.
Fluoxetine - 58%, Sertraline - 63%
Paroxetine - 71%, Fluvoxamine - 62%
Citalopram - 73%

60. Look for alternatives in patients with
Sexual dysfunction
Consistent insomnia and agitation
Nocturnal myoclonus

61. NDRI
BUPROPION
The only antidepressant that ignores the serotonin system.
Therefore, the therapeutic profile, side effects and clinical applications are different from and complementary to others.

62. Dopamine deficiency could lead to symptoms such as psychomotor retardation, anhedonia, cognitive slowing, inattention, pseudodementia and craving.
These could be the target symptoms.
To amplify therapeutic effects
To eliminate side effects (esp sexual dysfunction)

63. Other uses: ADHD, nicotine cessation
Side effects: Proadrenergic. Therefore possibility of overstimulation, agitation, insomnia, nausea, seizures.

64. AVOID USE IN PATIENTS WITH
Seizure disorder
Non compliance to twice daily dosing
Agitated patient with insomnia

65. SNRI Venlafaxine Desvenlafaxine Duloxetine
Milnacipran (not available in Australia)

66. VENLAFAXINE Dose dependent pharmacology
At low doses , it is essentially an SSRI
At medium to high doses,additional NE reuptake occurs
At very high doses some DA reuptake inhibition also occurs.
Dual mechanism of action leads to better remission when compared to SSRIs

67. 5.5% incidence of rise in BP at doses above 200 mg/day.
Risk increases to 13% above 300 mg.
Indicated for GAD and social anxiety as well.
Initial dose 75 mg
Recommended upper dosage is 225 mg/day. However, can be titrated up to 375 mg/day

68. DESVENLAFAXINE
DVS is the salt form of the isolated major active metabolite of venlafaxine.
Developed for the treatment of depression and for the alleviation vasomotor symptoms associated with menopause.
Initial dose 50 mg. Titrate up to 200 mg/day.
Can be safer than Venlafaxine in hepatic dysfunction.

69. DULOXETINE Indicated for the treatment of depression,
generalized anxiety disorder,
and painful diabetic neuropathy
? stress urinary incontinence

70. Formulated as a delayed-release capsule to reduce the risk of severe nausea associated with the drug.
Extensive hepatic metabolism—avoid in alcoholism.
Initial dose 20 mg. titrate up to 60 mg/day.
Dose can be divided to minimise side effects.

71. SARI - NEFAZODONE
Serotonin-2 receptor antagonism with serotonin reuptake blockade.
SSRIs with a difference.
Block 5HT2 in addition leading to amelioration of 5HT2 related side effects.
So, less sexual side effects and sleep disruption associated with the SSRIs

72. Nevertheless found to produce problematic sedation, nausea, dizziness, and visual disturbances
Consequently, Nefazodone was never extensively adopted in clinical practice.

73. NASSA- MIRTAZAPINE Designer antidepressant Four principle actions
Proadrenergic as well as proserotonergic action – due to ά 2 antagonism
Serotonin 2 and 3 antagonist
Strong antihistamine properties

75. Useful in depression with
Anxiety
Agitation
Insomnia
Also useful in counteracting side effects of SRIs such as:
Sexual dysfunction
Nausea, GI disturbances, agitation , panic weight loss.

76. SHOULD NOT BE USED IN Hypersomnia Motor retardation Cognitive slowing
Overweight patients

77. BUSPIRONE AND BZDS Buspirone Presynaptic agonist at 5HT1a receptors
Thrice daily dosing
Not first line drugs
Benzodiazepines
GABA facilitatory drugs
Good anxiolytics but addiction potential, sedation
Long acting agents preferred
Propranolol – for isolated anxious situations

78. Newer Antidepressants
Agomelatine:
Agomelatine is a novel antidepressant that is both a melatonergic agonist and a 5-HT 2C antagonist. Agomelatine also enhances dopaminergic and adrenergic input to the frontal cortex. Dose 25 – 50 mg at bedtime. Not avaialble in US.
Vortioxetine is a 5-HT3, 5-HT1D, and 5-HT7 antagonist, a 5-HT1A agonist, and a 5-HT1B partial agonist. Dose 5mg – 20 mg/day.

79. Conceptualising the current scenario
Major depressive disorder accounts for 4.4 percent of the total overall global disease burden.
Affects 5-13% of medical outpatients
Yet often undiagnosed and untreated
Often under treated when correctly diagnosed

80. Conceptualising the current scenario
Among persons both with major depressive disorder and bipolar disorder, 75 to 85 percent have recurrent episodes.
10 to 30% recover incompletely and have persistent, residual depressive symptoms, or dysthymia.

81. Conceptualising the current scenario
Patients who have diabetes, epilepsy, or ischemic heart disease with concomitant major depression have poorer outcomes than do those without depression.
The risk of death from suicide, accidents, heart disease, respiratory disorders, and stroke is higher among the depressed.

82. Conceptualising the current scenario
The prescription and use of anti-depressants has received a lot of attention in the medical literature, the media and legislation
The task for medical professionals is made more complex by the bewildering array of apparently efficacious drugs from which to choose
GPs diagnose most episodes of depression amongst Australians and prescribe more than 85% of antidepressants
Mant A, Hickie IB et al MJA 2004

83. HOW TO CHOOSE ? Largely based on your clinical assessment.
Side effects, tolerability, safety and convenience play a major role in decision making.
Differential efficacy plays little role.

84. INITIAL CLINICAL ASSESSMENT
Should include an evaluation of :
Patient’s previous treatment outcomes
Mood-disorder subtype
Severity of the current episode of depression
Risk of suicide
Coexisting psychiatric and physical conditions,
Non psychiatric medications and substance abuse
Psychosocial stressors
Family history

85. How to choose? Consider some of the following questions:
The patient’s particular symptoms
Possible side effects
Whether it worked for a close relative
Interaction with other medications
Pregnancy and breast feeding
Co-existing health conditions
Cost and health insurance coverage

86. The patient’s particular symptoms
Poor sleep/ global insomnia
Agitation and anxiety
Sedative AD- TCA, Mirtazapine
Atypical depression-
weight gain, hypersomnolence
SNRI, MAOIs
Obsessive symptoms
SSRIs
Low energy
Stimulating AD- Bupropion, Venlafaxine, Desvenlafaxine, Nortriptyline
Pain, Weight loss and GI symptoms
TCAs

87. Interaction with other medications
SSRIs reduce platelet aggregation- adds to the effect of NSAIDs/Aspirin
SSRIs increase levels of medications metabolized by cytochrome p450 isoenzymes in the liver eg losartan, chlorpheniramine, diazepam, risperidone
MAOIs and TCAs- lower blood pressure and cause tachycardia, potential interaction with antihypertensive medications
MAOIs and hypertensive crisis-tyramine reaction

88. Co-existing medical condition
Potential interactions:
Drug-illness interaction
Drug-drug interaction
Parkinson’s disease- MAOIs slows down dopamine metabolism
Use Venlafaxine with care in patients with established hypertension
Avoid TCAs and Paroxetine in people with angle closure glaucoma, benign prostatic hypertrophy
Citalopram drug of choice in individuals on multiple medical medications

89. Suicide and antidepressant treatment
All antidepressants reduce risk of suicide
TCAs and SNRIs have lower safety thresholds in OD
SSRIs may initially worsen anxiety and agitation and suicidal ideation (particularly in <25 years )

90. BIPOLAR DEPRESSION
Bipolar patients are three times more likely to experience depression than mania.
Patients are 30 times more likely to suicide during the depressed phase of their illness.
Three agents are FDA approved:
Olanzapine+ Fluoxetine
Quetiapine
Lurasidone

91. BIPOLAR DEPRESSION Largest study till date: STEP BD
Supportive evidence for Lithium, Lamotrigine, Olanzapine
Lack of evidence and potential for harm with traditional antidepressants
They should therefore be avoided as first line treatment for Bipolar Depression.

92. In case of resistance Ensure adequate compliance/dosage/duration
Reconsider your diagnosis
Look for co-morbid GMC
Look for co-morbid Psychiatric conditions
Psychosocial stressors/Family EE

93. In case of resistance Optimizing antidepressant dose
Augmenting or combining therapies
Switching therapies

94. FUTURE CHALLENGES Identification of antidepressants
That act more quickly than those currently available,
That do not require continuation and maintenance treatment.
A biologic classification system of subtypes of major depression is needed to facilitate the selection of the best antidepressant for each patient.

95. PHASES OF TREATMENT Acute Continuation Maintenance
Jan June Jan June 05
Acute
Continuation
Maintenance

96. PHASES OF TREATMENT Acute Continuation Maintenance
Jan June Jan June 05
Acute
Continuation
Maintenance

97. PHASES OF TREATMENT Acute Continuation Maintenance
Jan June Jan June 05
Acute
Continuation
Maintenance

98. PHASES OF TREATMENT