Pharmacology of Mood and Anxiety Disorders

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1

Describe the characteristics of a depressive episode

  1. Sadness, indifference, apathy, irritability
  2. Δ in sleep, appetite, and weight
  3. Fatigue
  4. Feeling shame/guilt
  5. Anhedonia
  6. Thoughts of death/dying
2

Describe the Amine hypothesis

  • ↓ in aminie-dependent neurotransmission
  • May result in upregulation of amine receptors
3

What drug is the amine hypothesis based on?

Reserpine

4

Reserpine MOA

Inhibits VMAT (inducing depression)

5

T/F: An increase in amine function would relieve depression

True

6

Describe the neurotrophic hypothesis

  • Low Brain Derived Neurotrophic Factor (BDNF) due to loss in dendritic spines and branches
  • Antidepressants ↑ BDNF over time
7

What is the responsibility of BDNF?

Promote growth of neurons

8

In anxiety disorders, dysfxnl 5HT and NE NTMsn has been implicated, particularly in which systems?

  • Limbic
  • Basal Ganglia
9

Characterized by motor tension, autonomoic hyperactivity, vigilance

Generalized Anxiety Disorder (GAD)

10

Which NT is thought to be overactive in GAD?

NE

11

Non-sedative non-bzd agent that can treat GAD w/ no anticonvulsant/ muscle relaxation effects

Buspirone

12

Buspirone MOA

5HT1A partial agonist

13

T/F: Buspirone anxiolytic effects are typically seen immediately.

False

14

What is an advantage of buspirone?

No rebound anxiety / withdrawal signs w/ abrubt cessation

15

Recurring episodes involving sympathetic crisis (racing heart, dizziness, chest pain, flushes, chills)

Panic disorder

16

Yohimbine MOA

α2 antagonist

17

T/F: Yohimbine precipitates panic attacks in pts and control subjects, potentially due to an abnormality in biogenic amines

False

18

Involves increased noradrenergic activity in the hippocampus and amygdala triggered by stimulus/stressor

PTSD

19

T/F: Vietnam vets were shown to have high levels of circulating DA and exposure to combative stimuli causes increase in BP and HR.

False

20

Recurrent obsessions (i.e. germs) and compulsive behaviors (i.e. hand washing)

OCD

21

Disturbance of ___________ is thought to be involved in OCD

Basal ganglia

22

Before treatment, NT are released at pathologically low levels and exert ss levels of autoinhibitory feedback. What is the net effect of this?

Abnormally low baseline level of postsynaptic receptor activity (signaling)

23

T/F: Chronic use of antidepressants results in desensitization of the postsynaptic autoreceptors, causing inhibition of NT synthesis and reducing exocytosis = enhanced NTm

False

24

List SSRIs:

  1. Fluoxetine
  2. Paroxetine
  3. Sertraline
  4. Citalopram
  5. Escitalopram
  6. Fluvoxamine
25

Fluoxetine brand name

Prozac

26

Paroxetine brand name

Paxil

27

Sertraline brand name

Zoloft

28

Citalopram brand name

Celexa

29

Escitalopram brand name

Lexapro

30

Fluvoxamine brand name

Luvox

31

Proposed adaptive presynaptic changes from chronic use of SSRIs

  • 5HT1 desensitization and down-reg. = ↑ in presyn activity of 5HT
  • SERT down-reg = ↓ clearance of 5HT
32

Proposed adaptive postsynaptic changes from chronic use of SSRIs

  • 5HT2a desensitization and down-reg = Antidepressant effects
  • ↑ cAMP --> ↑ CREB and ↑ BDNF (neurogenesis)
33

Which SSRIs produce active metabolites?

Fluoxetine and sertraline

34

T/F: Fluoxetine and it's metabolite, norfluoxetine, have long t1/2 (50 and 240 hrs)

True

35

SSRI metabolism

  • CYP2D6
  • 2C9
  • 2C19
  • 3A4
36

Fluoxetine and paroxetine have been shown to inhibit which enzyme?

2D6

37

Fluvoxamine has been shown to inhibit which enzyme?

1A2

38

SSRI SEs

  • GI upset, N
  • Sex dysfxn
  • Potential teratogen (paroxetine)
39

SSRI discontinuation syndrome characteristics

  • Irritability
  • GI disturbances
  • Paresthesia
40

When does SSRI discontinuation syndrome occur?

After abrupt discontinuation of SSRI

41

Why is fluoxetine generally not associated w/ SSRI discontinuation syndrome ?

Long t1/2 and active metabolite w/ long t1/2

42

T/F: SSRIs have little or no affinity for various NT receptors such as M, α, and H1.

True

43

Serotonin syndrome can be caused by a combo of SSRIs and ______

MAOIs

44

Specific agents that can cause serotonin syndrome when combined w/ SSRIs:

  1. Sumatatriptan
  2. MDMA
  3. LSD
  4. St. John's wort
45

Signs of Serotonin syndrome:

  • HTN
  • Hyperreflexia
  • Tremor
  • Clonus
  • Hyperthermia
  • Hyperactive bowel sounds
  • Diarrhea
  • Mydriasis
  • Agitation
  • Coma
46

T/F: Serotonin syndrome is a pharmacokinetic drug-drug interaction because it refers to the MOA of the drug.

False

47

List examples of SNRIs

  • Venlafaxine
  • Desvelnafaxine
  • Duloxetine
  • Levomilnacipran
48

Venlafaxine brand name

Effexor

49

Desvelnafaxine brand name

Pristiq

50

Venlafaxine/Desvelnafaxine MOA

  • Block SERT
  • Block NET (weak)
51

Duloxetine brand name

Cymbalta

52

Duloxetine MOA

  • Block SERT
  • Block NET
53

Duloxetine metabolism

CYP1A2 and 2D6

54

T/F: SNRIs have strong affinity for M, α, and H1 receptors as well as SERT and NET

False

55

Levomilnacipran brand name

Fetzima

56

Levomilnacipran is the more active enantiomer of milacipran, an SNRI for what condition?

Fibromyalgia

57

Levomilnacipran MOA

  • Block SERT
  • Block NET (slightly greater potency)
58

Levomilnacipran metabolism

CYPs(3A4), then glucuronidation

59

List atypical SNRIs

  • Bupropion
  • Trazadone
  • Nefazodone
  • Mirtazapine
  • Vilazodone
  • Vortioxetine
60

Bupropion brand name

Wellbutrin

61

Bupropion MOA

Blocks NET and DAT (weakly)

62

T/F: Bupropion has active metabolites and is also used for smoking cessation

True

63

Bupropion inhibits which enzyme?

CYP2D6

64

Trazadone and nefazodone MOA

  • Inhibit 5HT2
  • Weak SERT inhibition
  • H1 blockade (cause sleepiness)
  • α1 blockade (cause ortho hypotn)
65

Mirtazapine brand name

Remeron

66

Mirtazapine MOA

  • 5HT2 antagonist
  • α2 antagonist
  • H1 antagonist
67

Vilazodone brand name

Viibryd

68

Vilazodone MOA

  • inhibit SERT
  • 5HT1A partial agonist (this is thought to overcome acute presyn autoinhibition of 5HT neurons)
69

Vilazodone metabolism

CYP3A4, 2C19, 2D6

70

Vortioxetine brand name

Trintellix

71

T/F: Vortioxetine is an antidepressant with a mixed MOA, including being a SERT inhibitor.

True

72

List examples of TCA tertiary amines

  • Imipramine
  • Amitriptyline
  • Clomipramine
  • Doxepin
  • Trimipramine
73

TCA Tertiary amines inhibit NET and SERT with a higher affinity for _______

SERT

74

Imipramine brand name

Tofranil

75

Clomipramine brand name

Anafranil

76

Doxepin brand name

Silenor

77

TCA secondary amines inhibit NET and SERT w/ a higher affinity for _______

NET

78

List examples of TCA secondary amines

  • Desipramine
  • Nortriptyline
  • Protriptyline
79

Desipramine brand name

Norpramin

80

Nortriptyline brand name

Pamelor

81

Protriptyline brand name

Vivactil

82

TCA tetracyclic examples:

  • Amoxapine (NE and DA)
  • Maprotiline (NE)
83

Other pharmacodynamic actions of TCAs

  • α1 blockade
  • H1 blockade
  • M blockade
84

What effects would α1 blockade cause?

Ortho hypotn, reflex tachycardia

85

What effects would H1 blockade cause?

Somnolence, weight gain

86

What effects would M blockade cause?

Dry mouth, constipation, blurred vision

87

Describe TCA absorption

Mostly well absorbed, first pass metabolism can affect bioavailability

88

T/F: TCAs are not widely distributed because they are ptn bound.

False

89

Where do TCAs accumulate in the body?

Cardiac tissue -- could cause toxic effects

90

TCA metabolism

CYP1A2, 2C19, 2D6, 3A4

91

Imipramine is active on its own and is metabolized to the active metabolite __________

Desipramine

92

Amitriptyline is active on its own and is metabolized to the active metabolite __________

Nortriptyline

93

TCA SEs:

  1. Somnolence
  2. Confusion, delerium
  3. Dry mouth, blurred vision, constipation, urinary hesitancy
  4. Ortho hypotn, conduction defects, arrhythmias
  5. Seizures
  6. weight gain
  7. sexual disturbances
94

TCAs can cause hypertensive crisis when combined with ______

MAOIs

95

Describe symptoms of DC/withdrawal syndrome of TCAs

  • Malaise
  • Chills
  • Coryza
  • Muscle aches
  • Sleep disturbances
96

MAOI metabolism

Acetylation and hydroxylation

97

Examples of MAOIs

  • Tranylcypromine
  • Phenelzine
  • Selegiline
  • Isocarboxazid
98

Tranylcypromine brand name

Parnate

99

Phenelzine brand name

Nardil

100

Selegiline brand name

EMSAM

101

T/F: MAOIs are reversible inhibitors of MAO-A and MAO-B.

False

102

Selegiline is selective for which MAO (at low doses)

MAO-B

103

Hypertensive crisis can be caused if MAOIs are combined w/ what drugs/compounds?

  • SSRIs (↑ catecholamines and inhibition of reuptake)
  • Tyramine (fermented foods)
  • OTC cold remedies containing sympathomimetics
104

St. John's wort MOA

Inhibit reuptake of 5HT, DA, NE

105

St. John's wort induces:

CYP450s

106

Esketamine brand name

Spravato

107

Esketamine indication

Resistant depression

108

Esketamine MOA

NMDA antagonist

109

Esketamine administration

Intranasal (↑ bioavailability than oral)

110

Brexanolone brand name

Zulresso

111

Brexanolone indication

postpartum depression

112

Brexanolone MOA

GABAa +allosteric mod.

113

Brexanolone admin:

Continuous IV over 60 hrs

114

Which bipolar:

  • Formarly manic-depressive disorder
  • Cycles of mania and depressed mood

Biploar I

115

Defined as gradiosity, paranoid thoughts, overactivity

Mania

116

Which bipolar:

  • Hypomania (less severe than mania)
  • No hospitalization/fxnl impairment
  • No psychotic symptoms
  • Depression

Bipolar II

117

Lithium MOA

Inhibits formation of inositol = depletes cell of PIP2

118

T/F: Before therapy, levels of PIP2 may be increased in a person experiencing mania.

True

119

Other effects of lithium:

  • ↓ fxn of glycogen synthase kinase-3 (GSK-3)
  • Can replace Na but does not maintain membrane potentials
120

What process is GSK-3 involved in

Regulating neuroplasticity

121

↓ GSK-3 fxn is seen with lithium and what other drug?

Valproic acid

122

Time to lithium peak plasma levels

30 min-2 hrs

123

Lithium metabolism:

No metabolism; renal excretion

124

Lithium AE

  • Acne
  • CNS (tremor)
  • Renal (polyuria and polydipsia due to ADH inhibition)
  • Thyroid (benign goiter)
  • CV effects
  • Leukocytosis
  • Pregnancy affects (Ebstein's malformation)
125

Other drugs used for bipolar disorder

  • Valproic acid
  • Carbamazepine
  • lamotrigine