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Psychopharmacology - Antidepressant drugs

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Title: Psychopharmacology - Antidepressant drugs


1
Psychopharmacology- Antidepressant drugs
  • Dr. Sean Lynch

2
Reactions to stressful experiences
  • Acute reactions - immediate and brief responses
    to sudden intense stressors in a person who does
    not have other psychiatric disorder at time
  • Post-traumatic stress disorder - prolonged and
    abnormal response to exceptionally intense
    stressful circumstances
  • Adjustment disorder - more gradual and prolonged
    response to stressful changes in a persons life
  • Depression?

3
Reactions to stressful experiences
  • There are implications for mechanism of action of
    antidepressants and effectiveness
  • Will antidepressants alter an intact but
    activated stress-response system?
  • Will continued stress overcome the effectiveness
    of antidepressants?

4
The ten leading causes of disabilityworldwide
(1990)
Total (millions)
of total
472.7
50.8
10.7
22.0
4.7
22.0
4.6
15.8
3.3
14.7
3.1
14.1
3.0
13.5
2.9
13.3
2.8
12.1
2.6
10.2
2.2
Murray Lopez eds. The Global Burden of Disease.
Harvard University Press, 1996
5
Depression
  • Depressive disorders are common, prevalence 2-5
    (5-10 primary care settings). It affects around
    121 million people worldwide (WHO)
  • Associated with significant morbidity and
    mortality. Recently the WHO have announced it is
    likely to be the single cause for burden of any
    disease by 2030 due to years lost of life or
    through severe disability.
  • More prevalent in developing countries

6
Depression
  • Pathophysiology
  • Structural, neurochemical changes in hippocampus,
    frontal cortex
  • once thought to be a result of neurotransmitter
    deficiencies (e.g., NA, 5-HT)
  • More recent evidence suggests reductions in
    neurotrophic hormones and reduced neuronal
    plasticity

7
Depression
  • Multisystem disorder?
  • Dysregulation of stress-response system
  • Alteration in environmental adaptation and
    learning
  • Role of 5HT1a and 5HT2
  • Role of NA, Dopamine

8

9
  • Possible changes in depression
  • 5HT1a upregulation
  • 5HT2 antagonism
  • ß adrenoceptor downregulation
  • Possible effects on dopamine
  • Possible effects on neuropeptides
  • Altered HPA / corticotrophin function

10
Basics of Receptor mechanisms
  • D?- D7 Blockade in Psychosis, augmentation in
    mood, reward/addiction
  • 5HT1a,b,c Agonism in anxiety, depression,
    antagonism in migraine
  • 5HT2 a,b,c Antagonism in depression, psychosis?
  • 5HT3 Antagonism in anxiety, psychosis?
  • NA ß Blockade ?depression
  • a

11
Antidepressant Mechanisms
  • Reuptake inhibition
  • MAO inhibition
  • Receptor Antagonism
  • Receptor Antagonism
  • Novel

12

13

14
Neurotransmitters implicated in depression
Dopamine?
Acetylcholine
Glutamate
Noradrenaline
Serotonin
Neuropeptides
?-Aminobutyric acid (GABA)
Corticotrophins
15
Antidepressant Classes and Interactions
  • Tricyclics
  • SSRI
  • SNRI
  • MAOI
  • Novel NASSA, Melatonin Modulation
  • Experimental

16

17
Antidepressants
  • Selective serotonin reuptake inhibitors SSRIs
  • 1st line citalopram, sertraline, fluoxetine,
    paroxetine ad fluvoxamine
  • Max effect 4-6 weeks
  • Side effects commonest GI side effects,
    headaches, insomnia
  • Few anticholinergic side effects
  • Low cardiotoxicity so safer in overdose.
  • Withdrawal effects worse if stopped suddenly
    nausea, dizziness, agitation, insomnia

18

19
SSRIs
  • Side Effects and Other Concerns
  • Serotonin Syndrome
  • Serotonin Withdrawal Syndrome
  • SSRI-Induced Sexual Dysfunction
  • Gastrointestinal Bleeding
  • Effects in Pregnancy/Breast-Feeding

20
Serotonin Syndrome
  • Due to excess serotonin
  • Can be due to SSRIs and other antidepressants
  • Causes overdose, drug combinations/interactions,
    sometimes at normal doses
  • Can be fatal
  • Symptoms Neurological (confusion, agitation,
    coma), Neuromuscular (rigidity, tremors,
    myoclonus, hyperreflexia), Autonomic
    (hyperthermia, tachycardia, hyper/hypotension, GI
    upset)

21

22

23
TCAs
  • Adrenergic - postural hypotension
  • Anticholinergic - dry mouth, blurred vision,
    constipation
  • Antihistaminic - sedation
  • Other
  • Cardiovascular - tachycardia, blockade,
    arhythmias
  • Epileptic threshold
  • Weight gain
  • Sexual dysfunction
  • Tremor
  • Parkinsonian effects

24
TCAs
  • Pharmacokinetics
  • well absorbed orally
  • long half-lives, metabolised in liver
  • can have active metabolites e.g. imipramine and
  • lofepramine
  • Pharmacodynamic
  • Active metabolites
  • Calcium channel blockers?
  • Antihypertensives?

25

26
Dual Action Antidepressants
  • Nefazodone
  • 5-HT2 receptor antagonist and 5-HT/NA reuptake
    blocker chronic use down regulates NA/5-HT
    receptors., a1 and a2 activity,
  • Mirtazepine
  • 5-HT2/5-HT3 receptor antagonist potent
    antihistamine, a2 antagonist
  • Duloxetine
  • 5-HT/NA reuptake blocker, mild DA activity

27

28
NARIs
  • Reboxetine
  • first NARI specifically developed for depression.
  • improved attention and speed of cognitive
    functioning

29

30
MAOIs
  • Pharmacology
  • Inhibition of monoamine oxidase
  • MAO-A (depression) MAO-B (Parkinsons)
  • Side Effects
  • potentially serious interactions with adrenergic
    drugs some anaesthetics and opiates.
  • Recent advances
  • Transdermal delivery of selegiline

31
MAOIs
  • Monoamine oxidase inhibitors
  • Isocarboxazid, Phenelzine
  • Cheese reaction tyramine rich food can cause a
    hypertensive crisis need to avoid foods rich in
    tyramine e.g. cheese, red wine, liver, yeast
    products.
  • RIMA moclobemide

32
Antidepressant Effectiveness
  • Efficacy
  • Clinical Effectiveness
  • Safety and Adverse Outcomes

33
Clinical Effectiveness
  • Drug Efficacy depends upon
  • pharmacology,
  • pharmacodynamics,
  • pharmacogenetics
  • Clinical Effectiveness depends upon
  • efficacy,
  • tolerability,
  • adherence

34

35
  • Antidepressant activity - evidence based?
  • 1.Success rate of treatment for episode
  • Severity of episode
  • Dosage
  • Compliance
  • Duration
  • 2. Effects on illness duration, risk of relapse
    and risk of recurrence
  • Symptomatic
  • Shorten episode
  • Some prophylactic effects
  • Hard to know who should take these and for how
    long i.e markers, how big
  • the effect
  • Little scientific evidence regarding predictors
    of relapse or recurrence

36
  • Antidepressant activity - evidence based?
  • 3. Basic properties of antidepressants
  • All equally effective in moderate illness
  • Similar lag phase before therapeutic activity
  • Differentail responses occur
  • May not all be as effective in different types of
    depression, OCD, anxiety disorders
  • Antidepressant withdrawal syndromes
  • Documented for all antidepressants
  • Usually just physiological adaptation
  • Some have psychological dependence (MAOIs)
  • Some produce EPS

37
  • Antidepressants - safe?
  • Discontinuation symptoms / syndrome
  • Suicidality
  • Aggression - the Prozac Defence
  • Treatment resistance
  • Switching

38
Serotonin Syndrome
  • Due to excess serotonin
  • Can be due to SSRIs and other antidepressants
  • Causes overdose, drug combinations/interactions,
    sometimes at normal doses
  • Can be fatal
  • Symptoms Neurological (confusion, agitation,
    coma), Neuromuscular (rigidity, tremors,
    myoclonus, hyperreflexia), Autonomic
    (hyperthermia, tachycardia, hyper/hypotension, GI
    upset)

39
  • Antidepressant activity - evidence based?
  • Antidepressant augmentation
  • Evidence for Li, L-tryptophan
  • Less evidence for T3, anticonvulsants
  • Treatment resistance
  • The basic principles are similar to those for any
    treatment resistance.
  • Is diagnosis correct?
  • Is drug treatment dose optimum? Compliance,
    pharmacokinetics, pharmacodynamics
  • Has drug been given for right period?
  • High dosage regimens can be used with TDM and
    regular safety monitoring
  • Rate response on recognised scale
  • Change to a different antidepressant class
  • Augmentation therapy- Lithium, L-tryptophan
  • Cocktail - little firm evidence they are helpful.

40
Drug-related poisoning deaths, England Wales,
1993 to 2000
  • 21,631 drug-related poisoning deaths
  • 50 of these suicides
  • 3,959 - deaths which mention
    antidepressants
  • 79 of these suicides

41
Trends in antidepressant-related deaths, England
Wales, 1993 to 2000
42
Antidepressant-related age-specific death rates,
England Wales, 1993 to 2000
43
Future Antidepressants?
  • Buspirone group
  • NK1 antagonists
  • Tianeptine
  • DHEA (glucocorticoid hormone)
  • Omega-3 Fatty Acids

44
(No Transcript)
45
ANTIDEPRESSANT DRUGS CLINICAL PROBLEM
  • A 46 year old woman has an 8 week history of poor
    sleep, weight
  • loss and reduced social contact. She has not
    complained of
  • depressed mood, however. She is menopausal and
    has peptic
  • ulcer disease and has recently started treatment
    for high
  • cholesterol. Two weeks ago her G.P. started her
    on paroxetine. Her
  • sleep and appetite have not improved and she has
    become
  • restless. Her medication is shown overleaf.
  • Discuss the appropriateness of the medication.
  • Why could the drug have had this effect?
  • Would you change this and if so why?

46
ANTIDEPRESSANT DRUGS CLINICAL PROBLEM ONE
  • Temazepam 20mg
  • Paroxetine 20mg
  • She is also taking-
  • Omeprazole
  • Lipostat
  • Evening Primrose Oil
  • Chinese Herbal Medicine
  • Multivitamins
  • Premarin

47
ANTIDEPRESSANT DRUGS CLINICAL PROBLEM TWO
  • A 44 year old man has a long history of
    generalised motor seizures
  • which have been well-controlled. He has a 5 week
    history of
  • low mood, lack of energy, sleep disturbance with
    early morning
  • wakening, poor concentration and pessimistic
    thoughts. He has
  • tried dothiepin (dosulepin) but developed
    excessive sedation and
  • had possible petit mal seizures.He tried
    fluoxetine which was not
  • effective and also caused sedation. He is
    currently taking
  • venlafaxine at a dosage of 225mg daily. He also
    takes warfarin for
  • a previous deep venous thrombosis.He is
    complaining of stomach
  • upset and diarrhoea.
  • Discuss the appropriateness of the medication.
  • Why could the drug have had this effect?
  • Would you change this and if so why?

48
ANTIDEPRESSANT DRUGS CLINICAL PROBLEM TWO
  • Warfarin (variable as per clinic card)
  • Carbamazepine 400mg tds
  • Sodium Valproate 200mg qds
  • He is also taking-
  • Multivitamins

49
  • Problems
  • 1. A 50 year old woman with depressive illness
    has been taking fluoxetine but noticed increasing
    tiredness and nausea and a deterioration in her
    mood. It comes to light that she has been taking
    a mixture of natural herbal medicines for
    depression in addition. Discuss the importance of
    this new information using psychopharmacological
    principles.
  • 2. A 39 year old man with depressive illness has
    had olanzapine added to his sertraline
    antidepressant. After 8 days treatment his
    symptoms worsen. Discuss why this might have
    occurred.
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