ANTI-PSYCHOTIC DRUGS (since 1950’s) Mainly age range, but increasing in kids! Stop PANIC, HOSTILITY, FEAR Before 1950’s in the WEST: Dr. Freeman (US) popularized lobotomies for curing many mental illnesses >18,000 lobs US ( ) Rosemary Kennedy had one Lived to 86 but suffered as a result

East: Extract of the Indian Snakeroot plant (used as antidote to snake bites) RAUWOLFIA was used Depletes serotonin and catecholamines but many side effects: nausea, nightmares

THE TRICYCLIC ANTIDEPRESSANTS R = CH 2 CH 2 CH 2 NMe 2 X = Cl CHLORPROMAZINE [aka: Thorazine, Promactil, Prozil, Sanopron,...] Chloropromazine was a cheap, failed anti-histamine, which was unbelievably effective: withdrawn patients became active violent patients became calmed 95% of those institutionalized could go home ( mg daily)

Chlorpromazine is a so-called ‘dirty drug’: antagonist for many different postsynaptic receptors: dopamine receptors (subtypes D1, D2, D3 and D4): account for antipsychotic properties serotonin receptors (5-HT1 and 5-HT2): antiaggressive properties but also leading to weight gain, fall in blood pressure, sedation histamine receptors (H1 receptors): accounts for sedation, antiemetic effect, vertigo, fall in blood pressure and weight gain M1 and M2 muscarinic acetylcholine receptors: symptoms such as dry mouth, blurred vision, constipation, difficulty or inability to urinate, loss of memory dopamine reuptake inhibitor: (mild) antidepressive

Dopamine present in greater amounts in brains of schizophrenics, so all tricyclic antidepressants antagonize the D 2 site ~ 20 second-generation drugs are in use and they are more specific for the desired D 2 receptor (as well as 5- HT 2, see next slide) eg. Fluphenazine (dose 2-10 mg): Current Canadian Tricyclic Anti-Depressants: maprotiline, amitryptyline,clomipramine desipramine, doxepin, imipramine, nortryptyline, trimipramine, chlorpromazine, methotrimeprazine, fluphenazine, perphenazine, prochlorperazine, thioproperazine, trifluoperazine, mesoridazine, pericyazine,pipotiazine, thioridazine,flupenthixol, thiothixene, zuclopenthixol, mirtazapine

Additional binding to the 5-HT 2 (serotonin) sites helps to control POSITIVE (voices) and NEGATIVE (withdrawal) symptoms egs. HALDOL (Haloperidol) and CLOZARIL (Clozapine) 2-6 mg 25 mg initially There are many variants of each, and all have reduced side effects, but Clozapine gives reduced white blood cell counts and therefore needs weekly blood tests

ZYPREXA (olanzapine) is a more expensive version of clozapine $8/day, but 17 US veteran hospitals reported that haldol + benztropine (10 cents per day) is just as good

ANOTHER STATEGY: Selective Serotonin Re-uptake Inhibitors (SSRI’s) (first anti-depression drugs by design from 1980’s on) PROZAC (±) ZOLOFT PAXIL (1988, Lilly) (Pfizer) (Glaxo) > one million Rx/month mg/day/once 50 mg/day/once 20 mg/day/once

COMT = catechol-O- methyl transferase MAO = Monoamine oxidase

ACTION: blocks serotonin re-uptake (binds 5-HT 1A receptors): serotonin stays around longer, nerve impulse more likely to be transmitted – overdose does not appear to be possible however Main side effects: nausea (Paxil < Zoloft < Prozac), dry mouth, dizziness, weight loss... PAXIL (SEROXAT in UK, paroxetine): only shows side effects early on but they diminish after a few weeks Sales increased 5x in less than a decade (2.7B$) ALL SSRI’s now have a black box warning: DO NOT GIVE TO PATIENTS ALSO USING MAO (monoamine oxidase) INHIBITORS DO NOT GIVE TO SUICIDAL PATIENTS, WITH EPILEPSY OR SEIZURES

Current Canadian Drugs in this Class and Related SSRI’s: citalopram, fluoxetine, paroxetine, sertraline fluvoxamine, venlafaxine (also SNRI) Monoamineoxidase inhibitors: phenelzine, tranylcypromine, moclobemide. Other: bupropion, trazodone, l-tryptophan SSRI's linked to serious lung disorder in newborns – avoid during pregnancy Paroxetine [PAXIL] in First Trimester of Pregnancy May Have Small Increased Risk of Heart-Related Birth Defects, Compared to Other Antidepressants

RITALIN (Methylphenidate) (Novartis (CIBA)) (±) Stimulant for ADHD (attention deficit hyperactive disorder) Unruly children behave ‘properly’ within minutes Why a stimulant for ‘hyperactivity’? ADHD patients have decreased brain activity in areas critical to concentration ACTION: increases dopamine levels in brain, injected or orally, which activates motivation and drive (like ‘speed’!); main effect is on behaviour rather than body motor function Only tested on kids > 6 years age

Side effects: nervousness, insomnia, tics, loss of appetite, stomach pain; some suppression of growth with long-term use Not tested during pregnancy Dose: Children 5-10 mg, 3 x per day Adults 5-20 mg, 3 x per day About 5% of US kids estimated on drug!!! Also approved in Canada: dexamphetamine, atomoxetine

MANIC DEPRESSION - LITHIUM Suffer mood swings: 3 months ‘up’: excess drink, grand plans, impulse spending, quit job, give away possessions then 6-9 months ‘down’: rejection, suicidal feelings FIX: Li 2 CO 3 LITHANE (Pfizer) Lithium carbonate Mechanism not known but has many measurable effects: decreases dopamine in brain (changes metabolism), alters c-AMP formation, alters Na + transport in nerve & muscle cells DOSE: 3 x 600mg day is close to the toxic dose!