Transcript Antidepressant drugs - Dr Lynch

Psychopharmacology
- Antidepressant drugs
Dr. Sean Lynch
Reactions to stressful
experiences
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Acute reactions - immediate and brief responses to sudden
intense stressors in a person who does not have other psychiatric
disorder at time
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Post-traumatic stress disorder - prolonged and
abnormal response to exceptionally intense stressful circumstances
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Adjustment disorder - more gradual and prolonged
response to stressful changes in a person’s life
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Depression?
Reactions to stressful
experiences
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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?
The ten leading causes of disability
worldwide (1990)
Disability adjusted life years
All causes
Unipolar major depression
Iron deficiency anaemia
Falls
Alcohol use
COPD
Bipolar disorder
Congenital anomalies
Osteoarthritis
Schizophrenia
Obsessive compulsive disorders
Total (millions)*
472.7
50.8
22.0
22.0
15.8
14.7
14.1
13.5
13.3
12.1
10.2
% of total
10.7
4.7
4.6
3.3
3.1
3.0
2.9
2.8
2.6
2.2
Murray & Lopez eds. The Global Burden of Disease. Harvard University Press, 1996
Depression
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Depressive disorders are common, prevalence 25% (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
Depression
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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
Depression
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Multisystem disorder?
Dysregulation of stress-response system
Alteration in environmental adaptation and learning
Role of 5HT1a and 5HT2
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Role of NA, Dopamine
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Implications in depression
 Decision making capacity
 Ability to deal with stressful / threatening situations
 Learning
 Information processing
Possible changes in depression
5HT1a upregulation
5HT2 antagonism
ß adrenoceptor downregulation
Possible effects on dopamine
Possible effects on neuropeptides
Altered HPA / corticotrophin function
Basics of Receptor mechanisms
D- D7
5HT1a,b,c
5HT2 a,b,c
5HT3
NA
ß
α
Blockade in Psychosis, augmentation in
mood, reward/addiction
Agonism in anxiety, depression,
antagonism in migraine
Antagonism in depression, psychosis?
Antagonism in anxiety, psychosis?
Blockade ?depression
Antidepressant Mechanisms
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Reuptake inhibition
MAO inhibition
Receptor Antagonism
Receptor Antagonism
Novel
Neurotransmitters implicated in depression
1. Amino acids
 amino butyric acid - GABA
2. Amines - contain an amine group but no acid
5-Hydroxytryptamine (5-HT)
Dopamine (DA)
Noradrenaline (NA)
3. Peptides - small chains of amino acids
Neurokinins/ Substance P
Endogenous opioids
CCK
VIP
Neurotransmitters implicated in depression
GABA - Inhibitory , possible effects in anxiety and stress regulation?
5-Hydroxytryptamine (5-HT)
Sleep, reward, pain, learning, sexual drive, aggression
Dopamine (DA)
Drive, motivation, energy,
Noradrenaline (NA)
Aggression, drive
Acetyl choline – memory, cognitive function, sleep?
Peptides
“Master switch” ? adaptation, learning
Neurotransmitters implicated in depression
Dopamine?
Glutamate
Acetylcholine
Serotonin
Noradrenaline
-Aminobutyric acid
(GABA)
Neuropeptides
Corticotrophins
Antidepressant Classes and
Interactions
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Tricyclics
SSRI
SNRI
MAOI
Novel – NASSA, Melatonin Modulation
Experimental
CURRENT ANTIDEPRESSANTS
SSRI's
 paroxetine
 fluoxetine and norfluoxetine
 sertraline
 fluvoxamine
 citalopram and escitalopram
 (Clomipramine)
Antidepressants
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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
SSRI's
Differences in half-lives and dosage / schedules
Selectivity differs e.g., fluoxetine more noradrenergic than
citalopram.
Paroxetine has greater anticholinergic activity
Have activity on peripheral and central serotonin receptors e.g.
5HT1a, 5HT2 but also 5HT1b and 5HT3. Might have some activity
on NA receptors (but much weaker)
Down regulate 5HT2 and possible enhance 5HT1a
SSRIs
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Side Effects and Other Concerns
 Serotonin Syndrome
 Serotonin Withdrawal Syndrome
 SSRI-Induced Sexual Dysfunction
 Gastrointestinal Bleeding
 Effects in Pregnancy/Breast-Feeding
Serotonin Syndrome
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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)
TRICYCLIC ANTIDEPRESSANTS
Divided into “first” generation drugs (imipramine, amitriptyline)
and “second” and “third” generation drugs.
Came from developments of potential antipsychotic drugs
Sedative
“Neutral”
“Stimulating”
More noradrenergic
More serotonergic
amitriptyline, dothiepin
imipramine, lofepramine
protryptyline,
Desipramine
Clomipramine
This is defined by ratio of NA to 5HT reuptake inhibition e.g. around 40
times greater for clomipramine for 5HT
Reuptake inhibition is not their only possible mode of action i.e. antagonism
effects and effects on autoreceptors
TRICYCLIC ANTIDEPRESSANTS
As a group they are more “mixed” in monoamine activity than modern agents
e.g. closer ratio of noradrenaline / serotonin activity than NARIs or SSRIs
Main postulated action re-uptake inhibition, but have effects on 5HT1a, 5HT2
and NA ß receptors
Relatively little effect on dopamine
Have membrane stabilising effects
Anticholinergic, antiadrenergic and quinidine effects.
Cardiotoxicity possible.
Lower seizure threshold.
Act on all monoamines.
Effects on 5HT1a 5HT2, D2, H1 and α1 and α2
Muscarinic ACh activity
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
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Pharmacokinetics
well absorbed orally
long half-lives, metabolised in liver
can have active metabolites e.g. imipramine and
lofepramine
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Pharmacodynamic
Active metabolites
Calcium channel blockers?
Antihypertensives?
TRICYCLIC ANTIDEPRESSANTS
Protein binding can displace / effect availability of other bound-drugs
Can be interactions with other agents via cytochrome metabolism
CPY450 1A2 metabolises clomipramine and imipramine and can be potently
inhibited by fluovoxamine
CPY450 2D6 is involved in tricyclic metabolism and paroxetine and
fluvoxamine are most potent inhibitors, but citalopram and sertaline less
potent
Carbamazepine can induce CYP450
Dual Action Antidepressants
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Nefazodone
 5-HT2 receptor antagonist and 5-HT/NA reuptake
blocker; chronic use down regulates NA/5-HT
receptors., α1 and α2 activity,
Mirtazepine
 5-HT2/5-HT3 receptor antagonist; potent
antihistamine, α2 antagonist
Duloxetine
 5-HT/NA reuptake blocker, mild DA activity
NA specific and “Dual Action” Drugs
NASSAs
SNRIs
NARIs
- mirtazepine
- venlafaxine
- reboxetine
SNRIs and NARIs thought to rely on reuptake inhibition.
Venlafaxine SSRI - like until higher dosage and then NA activity
more potent – side effects (SSRI) plus headache, tremor, changes
in blood pressure (higher dosage). Duloxetine NA and 5HT activity
from low doses
NARI – dry mouth, blurred vision, sweatiness, sedation
Mirtazepine (like mianserin) does not rely on reuptake inhibition,
but has activity at 5HT and NA auto and presynaptic receptors
which regulate respective transmitter turnover. More sedative
NARIs
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Reboxetine
first NARI specifically developed for
depression.
 improved attention and speed of cognitive
functioning
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CURRENT ANTIDEPRESSANTS
2. MAOIs
Serendipitous find in TB treatment (isoniazid, iproniazid)
Irreversible and non-selective (for MAO subtype)
Phenelzine (Hydrazine)
Tranylcypromine (non-hydrazine) – more potent inhibitor
Reversible and selective
Moclobemide
Brofaromine
reversible (MAOA)
- some weak MAOB activity,not therapeutically significant
Selegiline
reversible MAOB – weak MAOA activity, little antidepressant
activity
Adverse effects similar to tricyclics but non-sedative. ? addiction syndrome for some
older MAOIs. Cheese reaction, drug interaction, hepatotoxicity,
neurotoxicity Fewer adverse effects for moclobemide
? Differential effects on dopamine turnover viz a viz other antidepressant
classes
Now “second-line”, less effective than other classes (except atypical
depression?)
MAOIs
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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
MAOIs
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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
Antidepressant Effectiveness
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Efficacy
Clinical Effectiveness
Safety and Adverse Outcomes
Clinical Effectiveness
Drug Efficacy depends upon:
 pharmacology,
 pharmacodynamics,
 pharmacogenetics
Clinical Effectiveness depends upon:
 efficacy,
 tolerability,
 adherence
SHOULD WE ALWAYS USE NEW DRUGS?
Ethical and practical issues
 Efficacy vs effectiveness
 Costs of treatment
 Toxicity of treatment
 Disease delayed or modified?
Antidepressant activity - evidence based?
1.Success rate of treatment for episode
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Severity of episode
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Dosage
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Compliance
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Duration
2. Effects on illness duration, risk of relapse and risk of recurrence
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Symptomatic
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Shorten episode
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Some prophylactic effects
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Hard to know who should take these and for how long i.e markers, how big
the effect
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Little scientific evidence regarding predictors of relapse or recurrence
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
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Antidepressant withdrawal syndromes
 Documented for all antidepressants
 Usually just physiological adaptation
 Some have psychological dependence (MAOI’s)
 Some produce EPS
Antidepressants - safe?
Discontinuation symptoms / syndrome
Suicidality
Aggression - “the Prozac Defence”
Treatment resistance
“Switching”
Serotonin Syndrome
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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)
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.
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Is diagnosis correct?
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Is drug treatment dose optimum? Compliance, pharmacokinetics,
pharmacodynamics
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Has drug been given for right period?
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High dosage regimens can be used with TDM and regular safety monitoring
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Rate response on recognised scale
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Change to a different antidepressant class
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Augmentation therapy:- Lithium, L-tryptophan
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Cocktail - little firm evidence they are helpful.
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
40
Trends in antidepressant-related deaths, England & Wales,
1993 to 2000
Numbers of deaths
600
500
400
Other
antidepressants
Amitriptyline
300
200
Dothiepin
100
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
0
Year of death
41
Deaths per million population
Antidepressant-related age-specific death rates, England &
Wales, 1993 to 2000
20
18
16
14
12
10
8
6
4
2
0
Male
Female
0-14
15-29
30-44
45-59
60-74 75 and
All
over
ages
Age group
42
Future Antidepressants?
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Buspirone group
NK1 antagonists
Tianeptine
DHEA (glucocorticoid hormone)
Omega-3 Fatty Acids
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?
ANTIDEPRESSANT DRUGS
CLINICAL PROBLEM ONE
Temazepam
Paroxetine
20mg
20mg
She is also taking:Omeprazole
Lipostat
Evening Primrose Oil
Chinese Herbal Medicine
Multivitamins
Premarin
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?
ANTIDEPRESSANT DRUGS
CLINICAL PROBLEM TWO
Warfarin
(variable as per clinic card)
Carbamazepine
Sodium Valproate
400mg tds
200mg qds
He is also taking:Multivitamins
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.