Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Adherence (medicine) wikipedia , lookup
Atypical antipsychotic wikipedia , lookup
5-HT3 antagonist wikipedia , lookup
5-HT2C receptor agonist wikipedia , lookup
Polysubstance dependence wikipedia , lookup
Pharmacogenomics wikipedia , lookup
Serotonin syndrome wikipedia , lookup
Neuropharmacology wikipedia , lookup
PSYCHOPHARMACOLOGY: PART 1 ANTIDEPRESSANTS AND ANXIOLYTICS Dr. Prashant Tibrewal LITTLE BIT OF HISTORY Serendipitous discovery in the 1950s led to the development of the first antidepressant agents: Iproniazid (for tuberculosis) Imipramine (for psychosis) Further investigations revealed their pharmacological activity on monoamine systems. A BIT MORE…… In 1960s specific search for serotonin reuptake inhibitors started Culminating in the derivation of first SSRIZimelidine (withdrawn) Further search for specific SSRIs led to the development of landmark SSRI- Fluoxetine CLASSIFICATION Since then more than two dozen antidepressants, which work by seven distinct mechanisms, have been developed 1. 2. 3. 4. 5. 6. 7. TCA SSRI NDRI NaSSA SNRI SARI MAOI MECHANISM 1. 2. 3. Given the structural diversity of the members of each class, they may not resemble each other in terms of their pharmacokinetics, metabolism or toxicity. However, most have an action on the metabolism and at the receptor for monoamine neurotransmitters: Norepinephrine Serotonin Dopamine ADDITIONAL MECHANISMS Augmentation of intracellular cyclic AMP Augment levels of neurotrophic and transcription factors such as CREB and BDNF Modulate excitatory transmission by decreasing binding at NMDA receptors or by inducing changes at AMPA receptors. MONOAMINE HYPOTHESIS MAO enzyme destroying monoamine neurotransmitter neurotransmitter NORMAL STATE -- no depression DEPRESSION -- caused by neurotransmitter deficiency Stahl S M, Essential Psychopharmacology (2000) MAO inhibitor blocks the enzyme from destroying monoamine neurotransmitter reuptake pump blocked by antidepressant Increase in neurotransmitters causes return to normal state Stahl S M, Essential Psychopharmacology (2000) Monoamine Receptor Hypothesis of Depression Normal functioning Receptors upregulate due to lack of NT Decrease in NT Stahl S M, Essential Psychopharmacology (2000) CIRCUIT CIRCUIT CIRCUIT Ser Ne CIRCUIT Ser Ne CLASSICAL ANTIDEPRESSANTS MAO inhibitors and Tricyclics 15 TYPES OF MAOI Irreversible and non selective Phenelzine, Tranylcypromine, Isocarboxazid RIMAs- Moclobemide Selective for MAO B-- Deprenyl MAOI Fell out of fame due to ‘cheese reaction’ – dietary tyramine metabolism inhibited by MAOI leading on to hypertensive crisis Rigid dietary restrictions RIMAs – Moclobemide fewer restrictions Reserved for resistant or atypical cases MAOI Risk of SSRI syndrome Do not combine with TCAs or SSRIs Never RIMA with an SSRI can be better tolerated but less effective. TRICYCLICS First agents marketed in 1950’s Amitryptiline Doxepine Imipramine Clomipramine Trimipramine Desipramine Nortriptyline TCAs Therapeutic action Therapeutic action Psychopharmacology of antidepressants: Stephen Stahl Side effects Psychopharmacology of antidepressants: Stephen Stahl Side effects Psychopharmacology of antidepressants: Stephen Stahl Side effects Psychopharmacology of antidepressants: Stephen Stahl Mechanism Block reuptake of Serotonin (5HT) and Norepinephrine (NE) Onset of antidepressant effect: 3-4 weeks SIDE EFFECTS Alpha-1 Blockade: Orthostasis, Sexual Dysfunction, Potential for cardiac conduction delays (QT prolongation) Histamine Blockade: Potential for weight gain, Sedation Acetylcholine Blockade: Cognitive Dulling Blurring of Vision Tachycardia Exacerbation of Asthma Sexual Dysfunction CONTRAINDICATIONS Hypertensive patients Cardiac conduction abnormalities (esp. prolonged QT) Acute narrow angle glaucoma GI dysmotility syndromes Benign Prostatic Hypertrophy PROS AND CONS Strengths Effective, especially in severe depression. Weaknesses Anticholinergic SEs. Low cost. Cardiovascular toxicity in overdose. Sedation perceived as a benefit. weight Gain. Can be used in pain, fibromyalgia and migraine Multiple daily dosing. Titration. Overall SE Profile. SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) Fluoxetine Fluvoxamine Sertraline Citalopram Escitalopram Paroxetine No or only weak effects at other monoamine transporter That distinguishes them from the older TCAs, thus they are named selective. Widely used, first-line treatments for depression and anxiety Multiple FDA indications Safety in overdose Tolerability- better side effect profiles than older drugs like TCAs and MAOIs SEROTONIN IS PRODUCED tryptophan transporter AAADC 5HTP Tryptophan TRY-OH 5HT (Serotonin) 5--34 Stahl S M, Essential Psychopharmacology (2000) SEROTONIN IS DESTROYED serotonin transporter MAO 5--35 Stahl S M, Essential Psychopharmacology (2000) SEROTONIN RECEPTORS 5HT1D autoreceptor alpha 2 hetero receptor serotonin transporter 5HT2C 5HT2A 5HT1A 5--36 5HT3 5HT4 5HTX 5HTY 5HTZ Stahl S M, Essential Psychopharmacology (2000) 5HT1A Presynaptic and post synaptic Antidepressant action OCD Panic Social phobia Bulimia 5HT1D Anti- migraine actions 5HT2 Agitation Akathisia Anxiety Panic attacks Insomnia Sexual dysfunction 5HT3 Nausea GI distress Diarrhoea Headache Serotonin Pathways Raphe Nucleus Stahl S M, Essential Psychopharmacology (2000) PATHWAYS INVOLVED Depression: disinhibition of pathway to prefrontal cortex OCD: to basal ganglia Panic Disorder: To limbic cortex and hippocampus Bulimia: to hypothalamus Frontal Cortex Mood Stahl S M, Essential Psychopharmacology (2000) Basal Ganglia Akathisia/ Agitation OCD Stahl S M, Essential Psychopharmacology (2000) Limbic Anxiety Stahl S M, Essential Psychopharmacology (2000) Hypothalamus Appetite/bulimia Stahl S M, Essential Psychopharmacology (2000) Sleep Centers Insomnia Stahl S M, Essential Psychopharmacology (2000) Spinal Cord Sexual Dysfunction Stahl S M, Essential Psychopharmacology (2000) Brainstem Vomiting Center Nausea and vomiting Stahl S M, Essential Psychopharmacology (2000) Gut GI cramps/Diarrhea Stahl S M, Essential Psychopharmacology (2000) COMMON FEATURES Similar mechanism of action Efficacy equivalent to TCAs Higher therapeutic index than TCAs Safer and better tolerated - minimal cardiac effects - fewer anticholinergic effects Better patient compliance ARE THEY IDENTICAL? Differ structurally pharmacodynamically - potency & selectivity pharmacokinetically - half-life, metabolic activity - Cytochrome P450 enzyme inhibition SELECTIVITY Differ in selectivity & potency Citalopram is the most selective - inhibits 5-HT uptake 3400 times more than NE Paroxetine : inhibits uptake of NE Sertraline: inhibits uptake of DA PHARMACOKINETICS Half-life: FLX longest half-life - FLX & SER: metabolites with long half-lives Time to steady-state: 3-4 weeks for FLX - 5 to 10 days for other SSRIs All highly plasma bound - Citalopram the least (80%) PHARMCOKINETICS (CONTD) Nonlinear for most Citalopram: linear pharmacokinetics across all dose ranges Up-titration predictable with citalopram EFFECT ON CYTOCHROME P450 Potent inhibitors Exception: Citalopram Least drug-drug interactions with citalopram ADVANTAGES OF FLX Discontinuation symptoms least Reemergence of depression slower ADVERSE EFFECTS Paroxetine: - highest anticholinergic effects - weight gain - delayed ejaculation Citalopram: - higher sedation - weight gain ADVERSE EFFECTS….. Fluoxetine - anxiety, nervousness & agitation - weight loss - Headache Fluvoxamine & sertraline - GI symptoms - tremors SEXUAL DYSFUNCTION Prospective multicenter study (n=1022). Spanish working group for the study of psychotropic related sexual dysfunction. All had normal sexual function previously. Fluoxetine - 58%, Sertraline - 63% Paroxetine - 71%, Fluvoxamine - 62% Citalopram - 73% Look for alternatives in patients with Sexual dysfunction Consistent insomnia and agitation Nocturnal myoclonus NDRI BUPROPION The only antidepressant that ignores the serotonin system. Therefore, the therapeutic profile, side effects and clinical applications are different from and complementary to others. Dopamine deficiency could lead to symptoms such as psychomotor retardation, anhedonia, cognitive slowing, inattention, pseudodementia and craving. These could be the target symptoms. To amplify therapeutic effects To eliminate side effects (esp sexual dysfunction) Other uses: ADHD, nicotine cessation Side effects: Proadrenergic. Therefore possibility of overstimulation, agitation, insomnia, nausea, seizures. AVOID USE IN PATIENTS WITH Seizure disorder Non compliance to twice daily dosing Agitated patient with insomnia SNRI Venlafaxine Desvenlafaxine Duloxetine Milnacipran (not available in Australia) VENLAFAXINE Dose dependent pharmacology At low doses , it is essentially an SSRI At medium to high doses,additional NE reuptake occurs At very high doses some DA reuptake inhibition also occurs. Dual mechanism of action leads to better remission when compared to SSRIs 5.5% incidence of rise in BP at doses above 200 mg/day. Risk increases to 13% above 300 mg. Indicated for GAD and social anxiety as well. Initial dose 75 mg Recommended upper dosage is 225 mg/day. However, can be titrated up to 375 mg/day DESVENLAFAXINE DVS is the salt form of the isolated major active metabolite of venlafaxine. Developed for the treatment of depression and for the alleviation vasomotor symptoms associated with menopause. Initial dose 50 mg. Titrate up to 200 mg/day. Can be safer than Venlafaxine in hepatic dysfunction. DULOXETINE Indicated for the treatment of 1. depression, 2. generalized anxiety disorder, 3. and painful diabetic neuropathy ? stress urinary incontinence Formulated as a delayed-release capsule to reduce the risk of severe nausea associated with the drug. Extensive hepatic metabolism—avoid in alcoholism. Initial dose 20 mg. titrate up to 60 mg/day. Dose can be divided to minimise side effects. SARI - NEFAZODONE Serotonin-2 receptor antagonism with serotonin reuptake blockade. SSRIs with a difference. Block 5HT2 in addition leading to amelioration of 5HT2 related side effects. So, less sexual side effects and sleep disruption associated with the SSRIs Nevertheless found to produce problematic sedation, nausea, dizziness, and visual disturbances Consequently, Nefazodone was never extensively adopted in clinical practice. NASSA- MIRTAZAPINE Designer antidepressant Four principle actions Proadrenergic as well as proserotonergic action – due to ά 2 antagonism Serotonin 2 and 3 antagonist Strong antihistamine properties Useful in depression with Anxiety Agitation Insomnia Also useful in counteracting side effects of SRIs such as: Sexual dysfunction Nausea, GI disturbances, agitation , panic weight loss. SHOULD NOT BE USED IN Hypersomnia Motor retardation Cognitive slowing Overweight patients BUSPIRONE AND BZDS Buspirone Presynaptic agonist at 5HT1a receptors Thrice daily dosing Not first line drugs Benzodiazepines GABA facilitatory drugs Good anxiolytics but addiction potential, sedation Long acting agents preferred Propranolol – for isolated anxious situations Newer Antidepressants Agomelatine: Agomelatine is a novel antidepressant that is both a melatonergic agonist and a 5-HT 2C antagonist. Agomelatine also enhances dopaminergic and adrenergic input to the frontal cortex. Dose 25 – 50 mg at bedtime. Not avaialble in US. Vortioxetine is a 5-HT3, 5-HT1D, and 5-HT7 antagonist, a 5-HT1A agonist, and a 5-HT1B partial agonist. Dose 5mg – 20 mg/day. Conceptualising the current scenario Major depressive disorder accounts for 4.4 percent of the total overall global disease burden. Affects 5-13% of medical outpatients Yet often undiagnosed and untreated Often under treated when correctly diagnosed Conceptualising the current scenario Among persons both with major depressive disorder and bipolar disorder, 75 to 85 percent have recurrent episodes. 10 to 30% recover incompletely and have persistent, residual depressive symptoms, or dysthymia. Conceptualising the current scenario Patients who have diabetes, epilepsy, or ischemic heart disease with concomitant major depression have poorer outcomes than do those without depression. The risk of death from suicide, accidents, heart disease, respiratory disorders, and stroke is higher among the depressed. Conceptualising the current scenario The prescription and use of anti-depressants has received a lot of attention in the medical literature, the media and legislation The task for medical professionals is made more complex by the bewildering array of apparently efficacious drugs from which to choose GPs diagnose most episodes of depression amongst Australians and prescribe more than 85% of antidepressants Mant A, Hickie IB et al MJA 2004 HOW TO CHOOSE ? Largely based on your clinical assessment. Side effects, tolerability, safety and convenience play a major role in decision making. Differential efficacy plays little role. INITIAL CLINICAL ASSESSMENT Should include an evaluation of : Patient’s previous treatment outcomes Mood-disorder subtype Severity of the current episode of depression Risk of suicide Coexisting psychiatric and physical conditions, Non psychiatric medications and substance abuse Psychosocial stressors Family history How to choose? Consider some of the following questions: The patient’s particular symptoms Possible side effects Whether it worked for a close relative Interaction with other medications Pregnancy and breast feeding Co-existing health conditions Cost and health insurance coverage The patient’s particular symptoms Poor sleep/ global insomnia Agitation and anxiety Atypical depression- Sedative AD- TCA, Mirtazapine SNRI, MAOIs weight gain, hypersomnolence Obsessive symptoms SSRIs Low energy Stimulating AD- Bupropion, Venlafaxine, Desvenlafaxine, Nortriptyline Pain, Weight loss and GI symptoms TCAs Interaction with other medications SSRIs reduce platelet aggregation- adds to the effect of NSAIDs/Aspirin SSRIs increase levels of medications metabolized by cytochrome p450 isoenzymes in the liver eg losartan, chlorpheniramine, diazepam, risperidone MAOIs and TCAs- lower blood pressure and cause tachycardia, potential interaction with antihypertensive medications MAOIs and hypertensive crisis-tyramine reaction Co-existing medical condition Potential interactions: 1. Drug-illness interaction Drug-drug interaction 2. Parkinson’s disease- MAOIs slows down dopamine metabolism Use Venlafaxine with care in patients with established hypertension Avoid TCAs and Paroxetine in people with angle closure glaucoma, benign prostatic hypertrophy Citalopram drug of choice in individuals on multiple medical medications Suicide and antidepressant treatment All antidepressants reduce risk of suicide TCAs and SNRIs have lower safety thresholds in OD SSRIs may initially worsen anxiety and agitation and suicidal ideation (particularly in <25 years ) BIPOLAR DEPRESSION Bipolar patients are three times more likely to experience depression than mania. Patients are 30 times more likely to suicide during the depressed phase of their illness. Three agents are FDA approved: Olanzapine+ Fluoxetine Quetiapine Lurasidone 1. 2. 3. BIPOLAR DEPRESSION Largest study till date: STEP BD Supportive evidence for Lithium, Lamotrigine, Olanzapine Lack of evidence and potential for harm with traditional antidepressants They should therefore be avoided as first line treatment for Bipolar Depression. In case of resistance Ensure adequate compliance/dosage/duration Reconsider your diagnosis Look for co-morbid GMC Look for co-morbid Psychiatric conditions Psychosocial stressors/Family EE In case of resistance Optimizing antidepressant dose Augmenting or combining therapies Switching therapies FUTURE CHALLENGES 1. 2. Identification of antidepressants That act more quickly than those currently available, That do not require continuation and maintenance treatment. A biologic classification system of subtypes of major depression is needed to facilitate the selection of the best antidepressant for each patient. PHASES OF TREATMENT Jan 04 June 04 Jan 05 June 05 Acute Continuation Maintenance PHASES OF TREATMENT Jan 04 June 04 Jan 05 June 05 Acute Continuation Maintenance PHASES OF TREATMENT Jan 04 June 04 Jan 05 June 05 Acute Continuation Maintenance PHASES OF TREATMENT