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Transcript
Sean Lynch Consultant Psychiatrist and Honorary Associate Professor, University of Exeter Medical School Summary of Main Objectives for Session Aims Today Awareness of antidepressant types, efficacy, activity and adverse effects Basic awareness of transmitters implicated in depression. Novel antidepressants Examples of possible MCQ AND CASC type questions How psychopharmacology comes into MRCPsych exams Basic sciences EBM analysis of papers related to drug treatments CASC questions on treatment / treatment resistance Suggested Background Reading and Resources Stahl – Pharmacology of Antidepressants Maudsley Prescribing Guidelines NICE guidelines for anxiety and depression Gaskell series (College) Recent BMJ and BJPsych/APT review articles BAP website RCPsych website (look for Psychopharmacology links) ABPI 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 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 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 (e.g. endocrine, immune changes, increased risk of some physical illnesses)? • Dysregulation of stress-response system • Alteration in environmental adaptation and learning • Role of 5HT1a and 5HT2 • Role of NA, Dopamine • More recent interest in NMDA and glutamate 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 Effects on plasticity and neural growth Other systems may have changes (glutamate, cholinergic) Receptor types 1. lonotropic receptors Ion channels - permeable to Ca2+ , Na+ K+ Cl- Strong electrical response e.g. GABA, Nicotinic Ach 2. Metabotropic receptors Receptor signal via metabolism. Most are G-protein coupled receptors where NT binds leading to activation of second messenger e.g. CAMP - adenylyl cyclase CGMP - guanylyl cyclase 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 Not fully understood ? partial agents Inactivation of Neurotransmitters • Diffusion • Enzymatic degradation • Re-uptake Antidepressant Mechanisms • • • • • Reuptake inhibition MAO inhibition Receptor Antagonism Receptor Antagonism Novel Neurotransmitters implicated in depression 1. Amino acids amino butyric acid – GABA Glutamate 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 4. Acetyl Choline 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 Opioids? Glutamate The problem of which theoretical model of brain function to use 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 Effectiveness in depression • All antidepressants appear to be as effective in moderate severity illness (outpatient level), we are not sure about in different severities or subtypes of depression, however. • Previous response to one class does not necessarily predict future response • In some patients response can occur in subsequent episodes with different antidepressant classes • Antidepressants might differ in effectiveness in long-term maintenance and relapse prevention Effectiveness in depression • Highest in moderate severity - 60-80% in trials but high placebo response (40-60%) • Lower in mild severity and also high placebo response • Lower in severe (?50+% but few good trials), however lower placebo response • Issues about what constitutes a response versus remission • Issues about placebo design and “unblinding” in RCTs 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 Can suppress REM Some doubts expressed about efficacy in more severe depression SSRIs • Side Effects and Other Concerns – Serotonin Syndrome – Serotonin Withdrawal Syndrome – SSRI-Induced Sexual Dysfunction – Gastrointestinal Bleeding – Effects in Pregnancy/Breast-Feeding – Recent increases in reports of fetal malformations – Suicidality and aggression 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. Some have questioned whether anticholinergic effects may be related to effectiveness. Reputedly, held by some authorities to be more effective than other classes in severe depression 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, – Similar properties in trazadone • Mirtazepine – 5-HT2/5-HT3 receptor antagonist; potent antihistamine, α2 antagonist • Venlafaxine 5HT > NA reuptake • 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, reportedly fewer pressor and cardiac risks. 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 MONOAMINE OXIDASE INHIBITORS 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 Have we made any progress with antidepressants? Future Antidepressants? • • • • • • Buspirone group Tianeptine Omega-3 Fatty Acids NK1 antagonists DHEA (glucocorticoid hormone) or modulators Glutamate modulators? (Recent trial of IV ketamine, rapid and sustained effects in TRD) 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 Differential 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” 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 (some debate about this and some suggest second drug within same class e.g. if SSRI and then change) • Some patients respond with any switch (?placebo response) • Augmentation therapy:- Lithium, L-tryptophan • Cocktail approach - 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 49 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 50 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 51 See you back in twenty minutes 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 Simvastatin Evening Primrose Oil Chinese Herbal Medicine Multivitamins Premarin (Equine conjugated oestrogens) 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. NOW FOR SOME PRACTICE MCQs!!! RECAP OF FUNCTION OF MAIN TYPES OF NEUROTRANSMITTER READING /REVISION OUTSIDE OF LECTURE Amino Acids Glutamate Synthesised in 50% of synapses •Most important CNS excitatory neurotransmitter •Neurotoxicity •Major efferent transmitter from cerebral cortex to basal ganglia, thalamus, limbic system •Both receptor subtypes i.e. metabotropic and ionotropic glutamate receptors Inotropic glutamate receptors - N-methyl-D-aspartate (NMDA) Distribution of NMDA receptors. NR2A - throughout brain. NR2B – Striatum. NR2C - cerebellum involved in •Neuronal plasticity - learning and memory •Development of the CNS •Anaesthesia Activation of NMDA implicated in pathological states as excess glutamate activation messengers increased Ca2+ neuronal death Stroke, head injury, epilepsy, Parkinson's disease excitotoxicity. Possible therapeutic effects of NMDA receptor antagonists? Depression ? Schizophrenia e.g. PCP-induced psychosis GABA Predominant inhibitory neurotransmitter in the brain and spinal cord - 30 % synapses utilise GABA •GABA removal is via a high affinity transporter. •Modulate and control flow of sensory information •Interneurons - within all CNS structures e.g. stellate cells in cochlear •Striatal projection neurons to the globus pallidus and substantia nigra •One brain structure may receive many GABAergic inputs from different structures GABA receptors GABAA receptor Ion channel selective for Cl-. GABA binding leads to activation of the channel,and hyperpolarisation Barbiturates Benzodiazepines - binds to subunit Agonists – Muscimol, Picrotoxin Antagonists - Bicuculline, Flumazenil (BZ site), Penicillin - blocks open channel GABAB receptors G-protein coupled. Inhibit CAMP Increase K - inhibitory post synaptic potential. Decrease Ca flux Pre and post synaptic.Pre - inhibit NT release Agonists Baclofen Glycine Inhibitory NT. Co-expressed with GABA and coreleased •Found in spinal Cord Renshaw cells (+ GABA) and la inhibitory interneurons. •Recurrent and reciprocal inhibition of spinal motor neurons •Auditory and cerebellum. Cochlear -large glycine input •Forebrain -coagonist at NMDA receptor Acetylcholine Widely distributed and found at following sites:Neuromuscular junction Sympathetic and parasympathetic preganglionic Parasympathetic post ganglionic •CNS Acetylcholine receptors • Nicotinic – NMJ and also present within the CNS • Muscarinic - Ml, M2, M3, M4, M5 Ml - cortex M2 - thalamus, hypothalamus M3 - limbic cortex, striatum, hippocampus, M4 - striatum M5 mRNA only - Substantia nigra and VTA •Excitatory - suppress inward currents e.g. K+ currents, facilitates NMDA responses •Inhibitory - increase K+ conductance e.g. vagal inhibition of heart and few sites in the CNS e.g. thalamus and brain stem Function of cholinergic system •Cognition Reduced cholinergic activity in dementia. Loss of neurons in nucleus basalis. Cell loss correlates with dementia in PD. Decrease in choline acetyltransferase actvitly and upregulation of ACh receptors in cortex. Decreased M2 receptor pre synaptic and increased M4 receptors -post synaptic. Anticholinergic agents cause confusion Mood regulation (reciprocal relationship with monoamines or modulator???) •Movement/Tremor/dystonia •Interaction with dopamine receptors:Dopamine D1 receptors stimulate ACh release and Dopamine D2 receptors inhibit ACh release. Dopamine D2 receptor antagonists e.g. anti-psychotics, anti-emetics cause acute dystonia Biogenic amines • • • • Dopamine, 5-HT, NA, A Functions:Cortical- behaviour, mood, perception Subcortical- Basic functions sleep, appetite and motor EMOTIONAL RESPONSE STRESS RESPONSE Serotonin 5-HT function in the brain •Sleep-wake cycle and level of arousal e.g. in R.E.M. sleep there is little activity of serotonergic neurons in the DRN (dorsal raphe nucleus), but maximal discharge during arousal •Satiety. Feeding increases 5-HT levels in the lateral hypothalamus of the rat. •Regulation of anterior pituitary hormone control, growth hormone, prolactin and corticotrophin APPETITE CONTROL Serotonin receptors Classification based on receptor structure, transduction mechanisms and pharmacology All G-protein coupled except 5-HT3 5-HT1 family - 5-HTlA, 5-HTlB, 5-HTlD, 5-HT1E 5-HT1F 5-HT2 family – 5-HT2A , 5-HT2B , 5-HT2C 5-HT3 , 5-HT4, 5-HT5 family- 5-HT5A ,5-HT5B 5-HT6 5-HT7 PLEASURE RESPONSE The 5-HT1 receptor family 5-HT1A,B,D,E and F coupled to adenylyl cyclase. Autoreceptors - control of 5-HT, or other NT release. •5-HT1A receptor:- limbic system, amygdala, septum and hippocampus. 5-HT cell bodies within the DRN and inhibits 5-HT release and cell firing. Effect mood and emotion. •5-HT1B and 5-HTlD receptors distributed in hippocampus, cortex and pre-synaptically on the striatal projections 5-HT1B important in controlling 5-HT release and release of acetylcholine, glutamate and dopamine. Reduced sensitivity and 5-HT levels in alcoholism shown in man. SSRI's use in alcoholism mediated via 5-HTlB The 5-HT2 receptor family 5-HT2A receptor- widely distributed in the brain and periphery, cortex, limbic system, caudate. •Hallucinatory properties of the 5-HT2A agonist, LSD. Mixed dopamine D2/5-HT2A antagonist clozapine used in schizophrenia. •A decrease in 5-HT2A receptor numbers in the frontal cortex of schizophrenic patients. •Anti-psychotic effects via action within the GABAergic interneurons in the cortex. •Decreases in the level of 5-HT and 5-HIAA and compensatory increase in 5-HT2 binding in ventral prefrontal cortex of violent suicide victims 5-HT2B receptor:- Wide peripheral distribution. Animal studies have suggested roles in anxiety 5-HT2C receptor:- Located exclusively within the CNS, highest levels in the choroid plexus. Agonist, 1-(3-chlorophenyl) piperazine (MCPP) - induced anxiety in humans. •Obsessive-compulsive disorders: two newly developed, selective 5-HT2C agonists reduce behviour in animal models •Satiety - Weight loss - mCPP-induced hypophagia. SSRI's. Other 5-HT receptors 5-HT3 receptor:- In lower brain stem, cortex, hippocampus, amygdala. sensory and autonomic nervous system. •Vasodilatation •Pain •5-HT3 receptor antagonists ?anxiolytic and antagonist ondansetron effective in treating some psychotic symptoms? 5-HT4 receptor anxiety ? altering 5-HT release in the hippocampus 5HT6 - possibly in striatum, high affinity for typical and atypical neuroleptic drugs