psychopharmacology - antidepressant drugs dr. sean lynch
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PsychopharmacologyPsychopharmacology- Antidepressant drugs- Antidepressant drugs
Dr. Sean LynchDr. Sean Lynch
Reactions to stressful Reactions to stressful experiencesexperiences
Acute reactions - Acute reactions - immediate and brief responses to sudden immediate and brief responses to sudden intense stressors in a person who does not have other psychiatric intense stressors in a person who does not have other psychiatric
disorder at timedisorder at time Post-traumatic stress disorder -Post-traumatic stress disorder - prolonged and prolonged and
abnormal response to exceptionally intense stressful circumstancesabnormal response to exceptionally intense stressful circumstances
Adjustment disorder - Adjustment disorder - more gradual and prolonged more gradual and prolonged response to stressful changes in a person’s liferesponse to stressful changes in a person’s life
Depression?Depression?
Reactions to stressful Reactions to stressful experiencesexperiences
There are implications for mechanism of action There are implications for mechanism of action of antidepressants and effectivenessof antidepressants and effectiveness
Will antidepressants alter an intact but activated Will antidepressants alter an intact but activated stress-response system?stress-response system?
Will continued stress overcome the Will continued stress overcome the effectiveness of antidepressants?effectiveness of antidepressants?
The ten leading causes of The ten leading causes of disabilitydisability
worldwide (1990)worldwide (1990)
Murray & Lopez eds. The Global Burden of Disease. Harvard University Press, 1996
Total (millions)* % of total
472.750.8 10.722.0 4.722.0 4.615.8 3.314.7 3.114.1 3.013.5 2.913.3 2.812.1 2.610.2 2.2
All causesUnipolar major depressionIron deficiency anaemiaFallsAlcohol useCOPD
Bipolar disorderCongenital anomaliesOsteoarthritisSchizophrenia
Obsessive compulsive disorders
Disability adjusted life years
DepressionDepression Depressive disorders are common, Depressive disorders are common,
prevalence 2-5% (5-10% primary care prevalence 2-5% (5-10% primary care settings). It affects around 121 million settings). It affects around 121 million people worldwide (WHO)people worldwide (WHO)
Associated with significant morbidity and Associated with significant morbidity and mortality. Recently the WHO have mortality. Recently the WHO have announced it is likely to be the single announced it is likely to be the single cause for burden of any disease by 2030 cause for burden of any disease by 2030 due to years lost of life or through severe due to years lost of life or through severe disability.disability.
More prevalent in developing countries More prevalent in developing countries
DepressionDepression
Pathophysiology Pathophysiology Structural, neurochemical changes in hippocampus, Structural, neurochemical changes in hippocampus,
frontal cortexfrontal cortex once thought to be a result of neurotransmitter once thought to be a result of neurotransmitter
deficiencies (e.g., NA, 5-HT)deficiencies (e.g., NA, 5-HT) More recent evidence suggests reductions in More recent evidence suggests reductions in
neurotrophic hormones and reduced neuronal neurotrophic hormones and reduced neuronal plasticityplasticity
DepressionDepression
Multisystem disorder?Multisystem disorder? Dysregulation of stress-response systemDysregulation of stress-response system Alteration in environmental adaptation and learningAlteration in environmental adaptation and learning Role of 5HT1a and 5HT2Role of 5HT1a and 5HT2 Role of NA, Dopamine Role of NA, Dopamine
Implications in depression
Decision making capacity
Ability to deal with stressful / threatening situations
Learning
Information processing
Possible changes in depressionPossible changes in depression
5HT1a upregulation5HT1a upregulation
5HT2 antagonism5HT2 antagonism
ß adrenoceptor downregulationß adrenoceptor downregulation
Possible effects on dopaminePossible effects on dopamine
Possible effects on neuropeptidesPossible effects on neuropeptides
Altered HPA / corticotrophin functionAltered HPA / corticotrophin function
Basics of Receptor mechanismsBasics of Receptor mechanisms
DD- D7- D7 Blockade in Psychosis, augmentation in Blockade in Psychosis, augmentation in mood, reward/addiction mood, reward/addiction
5HT1a,b,c5HT1a,b,c Agonism in anxiety, depression, Agonism in anxiety, depression, antagonism in migraineantagonism in migraine
5HT2 a,b,c5HT2 a,b,c Antagonism in depression, psychosis?Antagonism in depression, psychosis?
5HT35HT3 Antagonism in anxiety, psychosis?Antagonism in anxiety, psychosis?
NA NA ßß Blockade ?depressionBlockade ?depression
αα
Antidepressant Antidepressant MechanismsMechanisms
Reuptake inhibitionReuptake inhibition MAO inhibitionMAO inhibition Receptor AntagonismReceptor Antagonism Receptor AntagonismReceptor Antagonism NovelNovel
Neurotransmitters implicated in depression
1. Amino acids amino butyric acid - GABA
2. Amines - contain an amine group but no acid5-Hydroxytryptamine (5-HT)Dopamine (DA)Noradrenaline (NA)
3. Peptides - small chains of amino acidsNeurokinins/ Substance PEndogenous opioidsCCKVIP
Neurotransmitters implicated in depression
GABA - Inhibitory , possible effects in anxiety and stress regulation?
5-Hydroxytryptamine (5-HT)Sleep, reward, pain, learning, sexual drive, aggressionDopamine (DA)Drive, motivation, energy,Noradrenaline (NA)Aggression, drive
Acetyl choline – memory, cognitive function, sleep?
Peptides“Master switch” ? adaptation, learning
Neuropeptides
Noradrenaline
Acetylcholine
Dopamine?
Serotonin
-Aminobutyric acid (GABA)
Glutamate
Corticotrophins
Neurotransmitters implicated in depression
Antidepressant Classes Antidepressant Classes and Interactionsand Interactions
TricyclicsTricyclics SSRISSRI SNRISNRI MAOIMAOI Novel – NASSA, Melatonin Novel – NASSA, Melatonin
ModulationModulation ExperimentalExperimental
CURRENT ANTIDEPRESSANTS
SSRI's
paroxetine
fluoxetine and norfluoxetine
sertraline
fluvoxamine
citalopram and escitalopram
(Clomipramine)
AntidepressantsAntidepressants Selective serotonin reuptake inhibitors: SSRIsSelective serotonin reuptake inhibitors: SSRIs 1st line: citalopram, sertraline, fluoxetine, 1st line: citalopram, sertraline, fluoxetine,
paroxetine ad fluvoxamineparoxetine ad fluvoxamine Max effect 4-6 weeksMax effect 4-6 weeks Side effects: commonest GI side effects, Side effects: commonest GI side effects,
headaches, insomniaheadaches, insomnia Few anticholinergic side effectsFew anticholinergic side effects Low cardiotoxicity so safer in overdose.Low cardiotoxicity so safer in overdose. Withdrawal effects; worse if stopped suddenly: Withdrawal effects; worse if stopped suddenly:
nausea, dizziness, agitation, insomnianausea, 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
SSRIsSSRIs
Side Effects and Other ConcernsSide Effects and Other Concerns Serotonin SyndromeSerotonin Syndrome Serotonin Withdrawal SyndromeSerotonin Withdrawal Syndrome SSRI-Induced Sexual DysfunctionSSRI-Induced Sexual Dysfunction Gastrointestinal BleedingGastrointestinal Bleeding Effects in Pregnancy/Breast-FeedingEffects in Pregnancy/Breast-Feeding
Serotonin SyndromeSerotonin Syndrome
Due to excess serotoninDue to excess serotonin Can be due to SSRIs and other antidepressantsCan be due to SSRIs and other antidepressants Causes: overdose, drug Causes: overdose, drug
combinations/interactions, sometimes at combinations/interactions, sometimes at normal dosesnormal doses
Can be fatalCan be fatal Symptoms: Neurological (confusion, agitation, Symptoms: Neurological (confusion, agitation,
coma), Neuromuscular (rigidity, tremors, coma), Neuromuscular (rigidity, tremors, myoclonus, hyperreflexia), Autonomic myoclonus, hyperreflexia), Autonomic (hyperthermia, tachycardia, (hyperthermia, tachycardia, hyper/hypotension, GI upset)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 amitriptyline, dothiepin “Neutral” imipramine, lofepramine “Stimulating” protryptyline, More noradrenergic Desipramine More serotonergic 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
TCAsTCAs AdrenergicAdrenergic - postural hypotension - postural hypotension Anticholinergic - dry mouth, blurred vision, constipationAnticholinergic - dry mouth, blurred vision, constipation Antihistaminic - sedationAntihistaminic - sedation OtherOtherCardiovascular - tachycardia, blockade, arhythmiasCardiovascular - tachycardia, blockade, arhythmiasEpileptic thresholdEpileptic thresholdWeight gainWeight gainSexual dysfunctionSexual dysfunctionTremorTremorParkinsonian effectsParkinsonian effects
TCAsTCAs PharmacokineticsPharmacokinetics
well absorbed orallywell absorbed orallylong half-lives, metabolised in liverlong half-lives, metabolised in livercan have active metabolites e.g. imipramine andcan have active metabolites e.g. imipramine andlofepraminelofepramine
PharmacodynamicPharmacodynamicActive metabolitesActive metabolitesCalcium channel blockers?Calcium channel blockers?Antihypertensives?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 potentlyinhibited by fluovoxamine
CPY450 2D6 is involved in tricyclic metabolism and paroxetine andfluvoxamine are most potent inhibitors, but citalopram and sertaline lesspotent
Carbamazepine can induce CYP450
Dual Action AntidepressantsDual Action Antidepressants
NefazodoneNefazodone 5-HT2 receptor antagonist and 5-HT/NA reuptake 5-HT2 receptor antagonist and 5-HT/NA reuptake
blocker; chronic use down regulates NA/5-HT blocker; chronic use down regulates NA/5-HT receptors.,receptors., α α1 and 1 and αα2 activity,2 activity,
MirtazepineMirtazepine 5-HT2/5-HT3 receptor antagonist; potent 5-HT2/5-HT3 receptor antagonist; potent
antihistamine, antihistamine, αα2 antagonist2 antagonist DuloxetineDuloxetine
5-HT/NA reuptake blocker, mild DA activity5-HT/NA reuptake blocker, mild DA activity
NA specific and “Dual Action” Drugs NASSAs - mirtazepine SNRIs - venlafaxine NARIs - 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
NARIsNARIs
ReboxetineReboxetine first NARI specifically developed for first NARI specifically developed for
depression.depression. improved attention and speed of cognitive improved attention and speed of cognitive
functioningfunctioning
CURRENT ANTIDEPRESSANTS
2. MAOIsSerendipitous find in TB treatment (isoniazid, iproniazid)
Irreversible and non-selective (for MAO subtype)Phenelzine (Hydrazine)Tranylcypromine (non-hydrazine) – more potent inhibitor
Reversible and selectiveMoclobemideBrofaromine reversible (MAOA)- some weak MAOB activity,not therapeutically significantSelegiline reversible MAOB – weak MAOA activity, little antidepressantactivity
Adverse effects similar to tricyclics but non-sedative. ? addiction syndrome for someolder MAOIs. Cheese reaction, drug interaction, hepatotoxicity,neurotoxicity Fewer adverse effects for moclobemide
? Differential effects on dopamine turnover viz a viz other antidepressantclasses
Now “second-line”, less effective than other classes (except atypicaldepression?)
MAOIsMAOIs
PharmacologyPharmacology Inhibition of monoamine oxidaseInhibition of monoamine oxidase MAO-A (depression) MAO-B (Parkinsons)MAO-A (depression) MAO-B (Parkinsons)
Side EffectsSide Effects potentially serious interactions with adrenergic drugs potentially serious interactions with adrenergic drugs
some anaesthetics and opiates.some anaesthetics and opiates. Recent advancesRecent advances
Transdermal delivery of selegilineTransdermal delivery of selegiline
MAOIsMAOIs
Monoamine oxidase inhibitorsMonoamine oxidase inhibitors Isocarboxazid, PhenelzineIsocarboxazid, Phenelzine ““Cheese reaction”: tyramine rich Cheese reaction”: tyramine rich
food can cause a hypertensive crisis: food can cause a hypertensive crisis: need to avoid foods rich in tyramine need to avoid foods rich in tyramine e.g. cheese, red wine, liver, yeast e.g. cheese, red wine, liver, yeast products.products.
RIMA: moclobemideRIMA: moclobemide
Antidepressant Antidepressant EffectivenessEffectiveness
EfficacyEfficacy Clinical EffectivenessClinical Effectiveness Safety and Adverse OutcomesSafety and Adverse Outcomes
Clinical EffectivenessClinical Effectiveness
Drug EfficacyDrug Efficacy depends upon: depends upon: pharmacology, pharmacology, pharmacodynamics, pharmacodynamics, pharmacogeneticspharmacogenetics
Clinical EffectivenessClinical Effectiveness depends upondepends upon: : efficacy, efficacy, tolerability, tolerability, adherenceadherence
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 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
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 (MAOI’s) Some produce EPS
Antidepressants - safe?Antidepressants - safe?
Discontinuation symptoms / syndromeDiscontinuation symptoms / syndrome
SuicidalitySuicidality
Aggression - “the Prozac Defence”Aggression - “the Prozac Defence”
TreatmentTreatment resistanceresistance
““Switching”Switching”
Serotonin SyndromeSerotonin Syndrome
Due to excess serotoninDue to excess serotonin Can be due to SSRIs and other antidepressantsCan be due to SSRIs and other antidepressants Causes: overdose, drug Causes: overdose, drug
combinations/interactions, sometimes at combinations/interactions, sometimes at normal dosesnormal doses
Can be fatalCan be fatal Symptoms: Neurological (confusion, agitation, Symptoms: Neurological (confusion, agitation,
coma), Neuromuscular (rigidity, tremors, coma), Neuromuscular (rigidity, tremors, myoclonus, hyperreflexia), Autonomic myoclonus, hyperreflexia), Autonomic (hyperthermia, tachycardia, (hyperthermia, tachycardia, hyper/hypotension, GI upset)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. 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 & Drug-related poisoning deaths, England & Wales, 1993 to 2000Wales, 1993 to 2000
21,63121,631 drug-related poisoning deaths drug-related poisoning deaths
50%50% of these suicides of these suicides
3,959 -3,959 - deaths which mention deaths which mention antidepressantsantidepressants
79% 79% of theseof these suicidessuicides
41
Trends in antidepressant-related deaths, Trends in antidepressant-related deaths, England & Wales, 1993 to 2000England & Wales, 1993 to 2000
0
100
200
300
400
500
600
Year of death
Nu
mb
ers
of
death
s
Otherantidepressants Amitriptyline
Dothiepin
42
Antidepressant-related age-specific death Antidepressant-related age-specific death rates, England & Wales, 1993 to 2000rates, England & Wales, 1993 to 2000
0
2
4
6
8
10
12
14
16
18
20
0-14 15-29 30-44 45-59 60-74 75 andover
Allages
Age group
Death
s p
er
millio
n p
op
ula
tio
n
Male
Female
Future Future Antidepressants?Antidepressants?
Buspirone groupBuspirone groupNK1 antagonistsNK1 antagonistsTianeptineTianeptineDHEA (glucocorticoid hormone)DHEA (glucocorticoid hormone)Omega-3 Fatty AcidsOmega-3 Fatty Acids
ANTIDEPRESSANT DRUGSANTIDEPRESSANT DRUGS CLINICAL PROBLEMCLINICAL PROBLEM
A 46 year old woman has an 8 week history of poor sleep, weightA 46 year old woman has an 8 week history of poor sleep, weight
loss and reduced social contact. She has not complained ofloss and reduced social contact. She has not complained of
depressed mood, however. She is menopausal and has pepticdepressed mood, however. She is menopausal and has peptic
ulcer disease and has recently started treatment for highulcer disease and has recently started treatment for high
cholesterol. Two weeks ago her G.P. started her on paroxetine. Hercholesterol. Two weeks ago her G.P. started her on paroxetine. Her
sleep and appetite have not improved and she has becomesleep and appetite have not improved and she has become
restless. Her medication is shown overleaf. restless. Her medication is shown overleaf.
Discuss the appropriateness of the medication. Discuss the appropriateness of the medication.
Why could the drug have had this effect?Why could the drug have had this effect?
Would you change this and if so why?Would you change this and if so why?
ANTIDEPRESSANT DRUGSANTIDEPRESSANT DRUGS CLINICAL PROBLEM ONECLINICAL PROBLEM ONE
TemazepamTemazepam 20mg20mg ParoxetineParoxetine 20mg20mg
She is also taking:-She is also taking:-
OmeprazoleOmeprazole
LipostatLipostat
Evening Primrose OilEvening Primrose Oil
Chinese Herbal MedicineChinese Herbal Medicine
MultivitaminsMultivitamins
PremarinPremarin
ANTIDEPRESSANT DRUGSANTIDEPRESSANT DRUGS CLINICAL PROBLEM TWOCLINICAL PROBLEM TWO
A 44 year old man has a long history of generalised motor seizuresA 44 year old man has a long history of generalised motor seizures
which have been well-controlled. He has a 5 week history ofwhich have been well-controlled. He has a 5 week history of
low mood, lack of energy, sleep disturbance with early morninglow mood, lack of energy, sleep disturbance with early morning
wakening, poor concentration and pessimistic thoughts. He haswakening, poor concentration and pessimistic thoughts. He has
tried dothiepin (dosulepin) but developed excessive sedation andtried dothiepin (dosulepin) but developed excessive sedation and
had possible petit mal seizures.He tried fluoxetine which was nothad possible petit mal seizures.He tried fluoxetine which was not
effective and also caused sedation. He is currently takingeffective and also caused sedation. He is currently taking
venlafaxine at a dosage of 225mg daily. He also takes warfarin forvenlafaxine at a dosage of 225mg daily. He also takes warfarin for
a previous deep venous thrombosis.He is complaining of stomacha previous deep venous thrombosis.He is complaining of stomach
upset and diarrhoea.upset and diarrhoea.
Discuss the appropriateness of the medication. Discuss the appropriateness of the medication.
Why could the drug have had this effect?Why could the drug have had this effect?
Would you change this and if so why?Would you change this and if so why?
ANTIDEPRESSANT DRUGSANTIDEPRESSANT DRUGS CLINICAL PROBLEM TWOCLINICAL PROBLEM TWO
WarfarinWarfarin (variable as per clinic card)(variable as per clinic card)
Carbamazepine Carbamazepine 400mg tds400mg tds Sodium ValproateSodium Valproate 200mg qds200mg qds
He is also taking:-He is also taking:-
MultivitaminsMultivitamins
ProblemsProblems
1. A 50 year old woman with depressive illness has been taking 1. A 50 year old woman with depressive illness has been taking fluoxetine but noticed increasing tiredness and nausea and a fluoxetine but noticed increasing tiredness and nausea and a deterioration in her mood. It comes to light that she has been deterioration in her mood. It comes to light that she has been taking a mixture of natural herbal medicines for depression in taking a mixture of natural herbal medicines for depression in addition. Discuss the importance of this new information using addition. Discuss the importance of this new information using psychopharmacological principles.psychopharmacological principles.
2. A 39 year old man with depressive illness has had olanzapine 2. A 39 year old man with depressive illness has had olanzapine added to his sertraline antidepressant. After 8 days treatment his added to his sertraline antidepressant. After 8 days treatment his symptoms worsen. Discuss why this might have occurred.symptoms worsen. Discuss why this might have occurred.