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Psychopharmacology - Antidepressant drugs Dr. Sean Lynch 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 person’s life Depression? 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? 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 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 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 Multisystem disorder? Dysregulation of stress-response system Alteration in environmental adaptation and learning Role of 5HT1a and 5HT2 Role of NA, Dopamine 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 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 Tricyclics SSRI SNRI MAOI Novel – NASSA, Melatonin Modulation Experimental CURRENT ANTIDEPRESSANTS SSRI's paroxetine fluoxetine and norfluoxetine sertraline fluvoxamine citalopram and escitalopram (Clomipramine) 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 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 Side Effects and Other Concerns Serotonin Syndrome Serotonin Withdrawal Syndrome SSRI-Induced Sexual Dysfunction Gastrointestinal Bleeding Effects in Pregnancy/Breast-Feeding 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) 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 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? 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 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 Reboxetine first NARI specifically developed for depression. improved attention and speed of cognitive functioning 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 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 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 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 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? Discontinuation symptoms / syndrome Suicidality Aggression - “the Prozac Defence” Treatment resistance “Switching” 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) 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. 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? 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.