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Psychopharmacology What you should know to survive the LMCC and Internship. Kate Huntington, MD April 2008. Objectives. To review: indications for mechanism of action side effects (remember not everyone gets these) monitoring parameters for the major classes of psychotropic medications.
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PsychopharmacologyWhat you should know to survive the LMCC and Internship Kate Huntington, MD April 2008
Objectives To review: • indications for • mechanism of action • side effects (remember not everyone gets these) • monitoring parameters for the major classes of psychotropic medications
SSRI’s: Indications • MDD • GAD • Social phobia • PTSD • OCD • Augmentation in BD • Premenstrual Dysphoric Disorder • Panic Disorder
SSRI: Mechanism of Action • In depression, the serotonin neuron has a relative deficiency of serotonin and the autoreceptors and postsynaptic receptors are increased in number & sensitivity • When the reuptake pump is blocked, the level of serotonin increases in the somatodendritic area, causing autoreceptors (the brakes) to decrease in number & sensitivity • This turns off the brake on the serotonin neuron and electrical impulses flow down the axon, releasing more serotonin at the axon terminal • Increased levels of serotonin in the synapse leads to down regulation (decreased number and sensitivity) of postsynaptic receptors & other downstream changes
SSRI: Side Effect Profile • Headache • Anxiety (limbic projections) and Agitation (basal ganglia projections) • Nausea (chemoreceptor trigger zone) • Diarrhea (peripheral GI 5HT3 & 5HT4 receptors) • Sexual dysfunction (spinal projections) and Sleep disruption or Somnolence (Brainstem sleep centre)
SSRI: Rare but Dangerous Side Effects • UGI bleeding (platelet dysfunction) • SIADH • SSRI discontinuation syndrome (slow taper) • Serotonin syndrome
Norepinephrine & Dopamine Reuptake Inhibitor:Mechanism of Action (Bupropion/Wellbutrin) • Blockade of norepinephrine and dopamine reuptake pumps, leads to similar cascade as with SSRI’s
NDRI: Side Effect Profile • Seizures (not with SR formulation & following correct dosing; contraindicated with Bulimia or electrolyte disturbances) • Headache • Agitation (limbic cortex) • Rash • Emesis • Sleep disruption (limbic cortex) and Shaking (cerebellum)
Serotonin & Noradrenergic reuptake Inhibitors: Mechanism of Action(Venlafaxine/Effexor) • Blockade of serotonin reuptake up to about 150 mg • Blockade of serotonin and norepinephrine reuptake from about 150-225mg • Blockade of serotonin, norepinephrine and dopamine reuptake above 225 mg
SNRI: Side Effect Profile • Same as SSRI up to 150 mg • >150 mg, may also see sustained increase in diastolic BP & other noradrenergic-type side effects (see NDRI)
SNRI: Rare but Dangerous Side Effects • As with SSRI’s
NaSSA: Mechanism of Action • Blocks Alpha 2 autoreceptors on norepinephrine neurons & heteroreceptors on Serotonin neurons, causing more NE & 5HT to be released (puts the brakes on the brakes) • NE neurons from the locus coeruleus innervate midbrain raphe 5HT neurons. Therefore, increased NE causes a further increase in 5HT release • Blocks 5HT2 receptors, having an anxiolytic effect & blocking sleep & sexual side effects • Blocks 5HT3, blocking GI side effects from peripheral receptors & from brainstem chemoreceptor trigger zone • Blocks H1 histamine receptors, causing sedation & weight gain
NaSSA: Side Effect Profile • Weight gain (H1 blockade) • Anticholinergic: constipation, urinary retention, dry mouth, blurred vision, drowsiness, sinus tachycardia, confusion/delirium, fever (red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare; bowel & bladder lose their tone & the heart goes off alone) • Drowsiness (H1 blockade) • Equilibrium
NaSSA: Rare but Dangerous Side Effects • Neutropenia • Serotonin syndrome • Hepatotoxicity • Possibly SIADH
SARI: Mechanism of ActionSerotonin 2A antagonists/reuptake inhibitors (Trazadone/Desyrel) • Primarily blocks 5HT2A, reducing sexual dysfunction & sleep disruption & increasing effect of 5HT1A stimulation (5HT2A & 5HT1A oppose one another) • Weak 5HT reuptake inhibitor, increasing 5HT stimulation of 5HT1A (therapeutic effects) • H1 blockade causes sedation • Alpha One blockade leads to orthostatic hypotension
SARI: Side Effect Profile • Orthostatic hypotension • Sedation
SARI: Rare but Dangerous Side Effects • Serotonin syndrome
TCA: Mechanism of ActionTricyclic antidepressants: 3° amines (eg amitriptyline, imipramine, doxepine) 2° amines (eg nortriptyline, desipramine) • Therapeutic effects and side effects from blocking Serotonin, Norepinephrine & Dopamine Reuptake • Some also have 5HT2 blocking ability (blocks sex & sleep side effects) • Side effects from blocking H1 histamine receptors, muscarinic receptors, alpha one adrenergic receptors & sodium channels in the heart & brain
Antihistamine – weight gain & sedation Anticholinergic – (remember toxidrome from NaSSA) Anti-alpha adrenergic – dizziness, orthostatic hypotension Blockade of fast sodium channels – prolongation of QTc (risk of Torsades) TCA: Side Effect Profile
TCA: Rare but Dangerous Side Effects • Torsades de Pointes • EKG – rule out bradycardia and prolonged QTc • Lytes – rule out electrolyte imbalance • Make sure not on type 1 or 3 antiarrythmic drugs • SIADH • Serotonin Syndrome
MAOI: Mechanism of ActionMonoamine oxidase inhibitors: “the classics” (phenylzine/nardil, tranylcypromine/parnate)Reversible inhibitor: (moclobemide/mannerix) • Irreversibly bind MAO (2 wks) & destroy its function, therefore decrease monoamine breakdown, increasing 5HT, NE & DA
MAOI: Side Effect Profile • Side effects related to increase in serotonin norepinepherine & dopamine (see SSRI’s & NDRI’s) • Orthostatic hypotension
MAOI: Rare but Dangerous Side Effects • Blood dyscrasias • Hepatotoxicity • Teratogenicity • Serotonin Syndrome - (even more susceptable than with other serotenergic antidepressants) • When you see an MAOI, get a pharmacy consult, the patient should consult their pharmacist about any over - the – counter medications • Hypertensive crisis • Consult the dietician Re: MAOI diet • Patients need to avoid all foods with tyramine (aged foods such as cheese and wine)
Serotonin Syndrome Co-incidence with the addition or increase of a serotenergic agent Development of at least 4 major or 3 major plus 2 minor criteria
Hypertensive Crisis • Norepinephrine is the amine most closely linked with control of blood pressure • MAO normally inactivates norepinepherine • Tyramine, an amine present in aged foods, causes release of norepinepherine • In the presence of MAOI, this increased NE cannot be broken down, resulting in a hypertensive crisis
Starting Antidepressants: General Guidelines • Start with a reuptake inhibitor or mirtazepine (not a TCA or MAOI) • Start at lowest possible dose (half of this with anxiety and in the elderly and medically frail) • Increase by this increment about every five half lives (or about once a week) until one of the following endpoints: • Intolerable side effects • Full response • Maximum dose • Continue to monitor for therapeutic effects, side effects and safety
Course of Recovery From Depression Response 2-3 weeks: Improved sleep, appetite, vegetative shifts 3-4 weeks: objective improvement energy suicidal ideation may 6-8 weeks: subjective improvement
Stimulants: Indications • ADHD • Narcolepsy • (treatment resistant depression)
Stimulants: Mechanism of action • Increases dopamine and NE actions by blocking their reuptake and facilitating their release • Action in DL prefrontal cortex improves attention, concentration, executive function and wakefulness • Action in Basal Ganglia may improve hyperactivity • Action in medial prefrontal cortex may improve depression, fatigue and sleepiness
Stimulants: Common Side Effects • Headaches and Heart concerns(palpitations, tachycardia and hypertension) • Insomnia, Irritibility and Increased stimulation • Dizziness • Exacerbation of tics, tremor • Stomach: anorexia, nausea, abdo pain, weight loss, possibly slowing of normal growth in children
Stimulants: Rare Side Effects • Psychosis
Stimulants:Ongoing Monitoring • Blood pressure at baseline and with dose increases • In children, ongoing monitoring of height and weight
Common MDE Mania Mixed state Catatonia Schizophenia with prominent affective symptoms Schizoaffective disorder Uncommon Delirium NMS Parkinson’s Disease ECT: Indications
ECT: Indications (cont.) • Indications for First Line Use: • Need for rapid improvement (suicide, malnutritian, catatonia, severe psychosis or agitation) • When other treatments are more risky (elderly, pregnant) • Patient preference • Psychotic depression (gold standard – 95% response)
ECT: Relative Contraindications(weigh pros & cons) • Space occupying cerebral lesions • Increased ICP • Recent MI • Recent CVA • Aneurysm • Retinal detachment • Pheochomocytoma
ECT: Mechanism of Action • Neurotransmitter theory • Enhances DA, 5HT & NE neurotransmissiom • Neuroendocrine theory • Increased release of neurohormones including prolactin, TSH, ACTH & endorphins • Anticonvulsant theory • Increase in seizure threshold during course of ECT; CSF of animals receiving ECS is anticonvulsant when given IV to recipient animals
ECT: Side Effect Profile • Common • Headache • Muscle ache • Nausea • Memory impairment • Delirium • Amnesia (anterograde & retrograde) • No longterm deficits
ECT: Side Effect Profile • Rare: • Mortality 1/10,000-0.2 / 100 000 • Cardiovascular • 2° initial vagal stimulation • Bradycardia / asystole / ectopic activity • 2° sympathetic stimulation • Increased HR & increased BP • Prolonged apnea • Pseudocholinesterase deficiency • Prolonged seizure • Treat with IV benzo