Psychopharmacology - Antidepressant drugs

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Psychopharmacology- Antidepressant drugs

• Dr. Sean Lynch

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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?

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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?

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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
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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

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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

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Depression

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

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

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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

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Antidepressant Mechanisms

• Reuptake inhibition
• MAO inhibition
• Receptor Antagonism
• Receptor Antagonism
• Novel

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Neurotransmitters implicated in depression
Dopamine?
Acetylcholine
Glutamate
Noradrenaline
Serotonin
Neuropeptides
?-Aminobutyric acid (GABA)
Corticotrophins
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Antidepressant Classes and Interactions

• Tricyclics
• SSRI
• SNRI
• MAOI
• Novel NASSA, Melatonin Modulation
• Experimental

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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

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SSRIs

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

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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)

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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

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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?

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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

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NARIs

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

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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

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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

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Antidepressant Effectiveness

• Efficacy
• Clinical Effectiveness
• Safety and Adverse Outcomes

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Clinical Effectiveness

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

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• 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

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• 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

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

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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)

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• 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.

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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

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Trends in antidepressant-related deaths, England
Wales, 1993 to 2000
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Antidepressant-related age-specific death rates,
England Wales, 1993 to 2000
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Future Antidepressants?

• Buspirone group
• NK1 antagonists
• Tianeptine
• DHEA (glucocorticoid hormone)
• Omega-3 Fatty Acids

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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?

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ANTIDEPRESSANT DRUGS CLINICAL PROBLEM ONE

• Temazepam 20mg
• Paroxetine 20mg
• She is also taking-
• Omeprazole
• Lipostat
• Evening Primrose Oil
• Chinese Herbal Medicine
• Multivitamins
• Premarin

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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?

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ANTIDEPRESSANT DRUGS CLINICAL PROBLEM TWO

• Warfarin (variable as per clinic card)
• Carbamazepine 400mg tds
• Sodium Valproate 200mg qds
• He is also taking-
• Multivitamins

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• 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.