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.