Lecture 8

Careful Clinical Observation – (Thorazine) to (Abilify) Psychosis and Schizophrenia What is Psychosis?

• Impaired reality testing - the inability to distinguish between what is real and not real. • Presence of characteristic symptoms:

– Disorders of perception (hallucinations)

– Disorders of thougg(ht (delusions )

– Disorganized speech (disordered associations)

– Disorganized or catatonic behavior (rituals) • Note that severe episodes of mood disorders may have psychotic features as secondary symptoms and are not a primary psychotic disorder,,jpp i.e. Major Depressive Episode with pypsychosis or acute mania • Patients with personality disorders (schizotypal, schizoid, borderline and paranoid) can present with psychotic symptoms Psychotic Disorders

Primary Psychiatric Disorders

• Schizophrenia • Schizophreniform disorder • Schizoaffective disorder • Brief psychotic disorder • Shared ppysychotic disorder • Delusional disorder Schizophrenia • Course of Illness – Onset – Most common initial presentation during adolescence • Imaging studies show this is a period with extensive CNS remodeling – Progression – Patients fall into three general groups • A single psychotic episode followed by good mentlhtal hea lth • A lifelong pattern of remission followed by relapse • Lifelong disease with no remission Schizophrenia Symptoms

• Positive syypmptoms (not normally experienced by healthy individuals) – Hallucinations – Delusions – Bizarre behavior • Negative symptoms (normally found in healthy individuals, but not present or diminished) – Social withdrawal – Apathy – Inability to experience pleasure – Loss of attention control Schizophrenia: Etiology • Genetics – Concordance for monozygotic twins about 50% v. dizygotes 10% – De novo mutations arising in paternal germ cells • Environmental factors – First and Second trimester pregnancy: Viral infections, Drug Exposure – Third trimester pregnancy: Hypertension, Diuretics • Neurological Abnormalities – Decreased size/activity of pre-frontal cortex; lateral and third ventricular enlargement; abnormal cerebral symmetry; decreased brain density; decreased volume of hippocampus, amygdala and parahippocampal gyrus – EEG shows decreased alpha waves, increased theta and delta waves, epileptiform activity. Also, saccadic eye movements (poor smooth visual pursuit • Neuro transmitt er Ab normaliti es: DA , 5-HT, NE , Gl u tama te Developments in Medical Treatments for Psychotic Disorders

’30s ’40s ’50s ’60s ’70s ’80s ’90s ’00 ‘05

Thioridazine ECT Chlorpromazine Typical Atypical antipsychotics

Aripiprazole – D2 partial agonist Drug Terminology

• • Major tranquilizer- a misnomer • NltiNeuroleptics - promitinent neurol lilidogical side effects (EPS) Structure of Chlorpromazine: First Neuroleptic Antipsychotic

Ethylamine Core Structure Chlorpromazine • Synthesized in 1951 by Paul Charpentier at the French pharmaceutical company Rhône‐Poulenc for use in anesthesia • Henri Laborit was French army surgeon interested in artificial hibernation for the prevention of surgical shock ‐ tested chlorpromazine because the compound had been reported to lower body temperature – Observed a tendency to go to sleep along with disinterest in what was going on • Cooling with water was used in France as a means to control agitation ‐ Chlorpromazine was ⇒ recommended to physicians in the psychiatric service at Val de Grâce military hospital in Chlorpromazine – cont. • First patient to receive chlorpromazine was Jacques Lh. ‐ a 24 year old severely agitated psychotic • After 20 days on therapy physicians reported that Jacques Lh. was “ ready to resume normal life” • An additional thirty‐eight patients were given chlorpromazine by Pierre Deniker at Saint‐ Anne’s Hospital with similar outcomes • Marketed by Rhône‐Poulenc in France in 1952 under the trade name Largactil False Hypotheses Behind Chlorpromazine Clllinical Development • are useful in anesthesia (they do have some slight sedative properties) • Artificial hibernation could prevent surgical shock (wrong) • The most important property of chlorpromazine was its ability to lower body temperature (irrelevant) • Patient cooling was an effective means to control agitation (wrong) 1957 Albert Lasker Award for Chlorpromazine • Henri Laborit ‐ initiated clinical studies • Pierre DDikeniker ‐ condtdducted the critica l clin ica l studies in schizophrenic patients • Heinz Lehmann ‐ disseminated the full practical significance of chlorpromazine to the medical community

Henri Laborit Pierre Deniker Heinz Lehmann Chlorpromazine in the Clinic

• Prevents hallucinations and delusions • Prophylactic: limits emergence of these symptoms Hospital Beds Occupied by Patients with Psychiatric Disorders

Yearly change in the number of hospitalized patients with psychiatric disorders (thousands)

16 Miracaceole of Chl opoorprom azin e? Limitations in Treatment with Chlorpromazine

• No decrease in negative symptoms • Patients often unable to function in society • Require medication – disease is not cured • Drop in number of institutionalized patients – No substitute support system provided Antipsychotic First Generation “Typical Anti ps ychotic Dru gs” Classification Prototype PhPhenothiazinesenothiazines Aliphatics Chlorpromazine (Thorazine) Fluphenazine (Prolixin) Perphenazine (Trilafon) Piperidine (Mellaril) (Serentil) Butyrophenone Haloperidol (Haldol) (Orap) Thioxanthine Thiothixene (Navane) Dibenzoxazepines Loxapine (Loxitane) Dihydroindolones (Moban) General Limitations of Conventional Antippysychotics* • Gaps in efficacy – Cognitive function – NtiNegative symp toms – Depressive symptoms • Profound number of side-effects with long-term health consequences – Anticholinergic (dry mouth, ocular changes, constipation, tachycardia, etc.) – Extrapyramidal (dystonia, akathisia, parkinsonian, dyskinesia,,) TD) – Sedation – Cardiovascular (arrhythmias, blood pressure changes) – Mtbli(Metabolic (we ihtight ga in, a ltere d g lucose, hliidihyperlipidemia) – Altered hormones (hyperprolactinemia, FSH, LH → sexual side effects) – Lowered seizure threshold

*Considerable differences exist among specific antipsychotic compounds Tardive Dyskinesia late appearing extrapyramidal symptom

• First evidenced at many weeks or years • Involuntary purposeless and repetitive movements (fly catching, lip smacking, etc.) •Higg,gh dose, long treatment times increase risk • Irreversible in 1/3 of patients; no proven therapy • Proposed mechanism is receptor super-sensitivity Parkinson’s Disease versus Tardive Dyskinesia

Michael J. Fox

Michael J Fox Parkinson's Disease - YouTube

Tardive Dyskinesia Patient

Tardive Dyskinesia Symptoms - (AIMSDVD.com) - YouTube What Constitutes an Ideal Antipsychotic

Mood-stabilizing Efficacious for properties positive and Low EPS, TD negative symptoms

Ideal Cognitive Affordable benefits antipsych oti c

No adverse Weight long-term health Neutral Improved consequences function and quality of life What is the Mechanism by Which Neuroleptic Antipsychotics Act? Dopamine Theory ofSf Schi zoph reni a

Hyperdo paminer gic Hypodopaminergic pathways pathways

Positive symptoms Negative symptoms Dopamine Hypothesis of Schizophrenia

Mesocortical pathway Nigrostriatal pathway Hypoactivity: (part of EP system) neggypative symptoms amotivation cognitive deficits

Mesolimbic pathway Hyperactivity: Tuberoinfundibular pathway positive symptoms (inhibits prolactin release)

* Antipsychotic Drugs Mechanism of Action

• Blockade of dopamine (D2) receptors is associated with positive symptom therapeutic efficacy. – A threshold value of 65‐70% of D2‐receptor occupancy is needed for therapeutic response. – EPS incidence rises as D2‐receptor occupancy increases above 80%. • Blockade of Serotonin (5HT 2a) receptors is associated with negative (or mood) symptom therapeutic efficacy. (Also 5HT2c?) (Farde L, et al.: Arch Gen 1992; 49:538‐544) • Elevation of prolactin levels show a threshold relationship to D2‐receptor occupancy. (Schlegel S, et al.: Psychopharmacology (Berl) 1996; 124:285‐287) • Blockade of other receptors is generally responsible for side‐effects.

Phenothiazines are Dirty Drugs

And They Need to be Dirty Drugs to Work Effectively Compppound Receptor Potencies (Ki values nM )

DOPAMINE SEROTONIN 5HT2A/D2 DOPAMINE MUSCAR ADRENERGIC HISTAMI INIC NE

D2 5-HT1A 5-HT2A 5-HT2C RATIO D1 D4 M11A2A H1

Typical Agents Haloperidol 1.2 2100 57 4500 47 120 5.5 >10,000 12 1130 1700 Fluphenazine 0.8 1000 3.2 990 3.9 17 29 1100 6.5 310 14 Thiothixene 0.7 410 50 1360 72 51 410 >10,000 12 80 8 Perphenazine 0.8 420 5.6 130 7.4 37 40 1500 10 810 8.0 LiLoxapine 11 2550 444.4 13 040.4 54 818.1 120 42 150 494.9 Molindone 20 3800 >5000 10,000 >250 >10,000 >2000 >10,000 2600 1100 2130 Thioridazine 8.0 140 28 53 3.5 94 6.4 13 3.2 130 16 Chlorpromazine 3.6 2120 3.6 16 1 76 12 32 0.3 250 3.1 Improving Therapeutic Index Animal Models • AhiApomorphine iidnduce d climbi ng – In vivo measure of dopamine receptor antagonism • Prepulse inhibition – Startle response is suppressed by warning tone – Schizophrenic patients show deficits in prepulse inhibition – Antipsychotic medications enhance prepulse inhibition • Elevated plus maze – Proposed as measure of anxiety – Benzodiazepines active Antipsychotic Next Generation “Atypi cal A nti psych oti c Drugs”

Classification Prototype

Dibenzodiazepines Clozapine (Clozaril) Benzisoazoles Risperidone (Risperdal) Thienbenzodiazepines Olanzapine (Zyprexa) Dibenzthiazepines Quetiapine (Seroquel) Benzisothiazolyls Ziprasidone (Geodon) Piperazinyl quinolinone Aripiprazole (Abilify) 5HT2a Antagonism can Help Block Extrapyramidal Symptoms Properties of conventional and atypical antipsyc ho tic drugs • All have equivalent clinical efficacy in treating positive symptoms

• None cause significant improvement in cognitive negative symptoms

• All take weeks to months to show effect

• Any single conventional will fail in about 30% of patients; these ppypypgatients may respond to atypical drugs. Atypical Anti ps ychotics Advanta ges

• May be more effective against negative symptoms

• Less likely to cause EPS and TDs

• More favorable side effect ppprofile improves compliance Metabolic syndrome and drugs

• Increased risk of diabetes

• Worsening lipid profile

• No clear association with weight gain; mechanism unknown

• Black box label on all atypical antipsychotics

• Caution and frequent monitoring in patients with family history of diabetes or cardiovascular disease Atypical Antipsychotics Have Improved Side Effect Profiles

First Generation/Conventional Antipsychotics Second Generation/Atypical Antipsychotics

Antipsychotic Extrapyramidal Antipsychotic

onders onders Extrapyramidal

pp effect pp Symptoms effect Symptoms AB CD EFGH res res of of

% %

Log Dose Log Dose Limitations of Current Atypical Antipsychotics* • Gaps in efficacy remain – Cognitive function – Negative symptoms (improved vs. conventional) – Depressive symptoms – Slower onset of th erapeuti c response • Improved motor side effects but now different adverse effects for some, but not all atypicals, with long-term health consequences – Significant weight gain – Increased risk of hyperglycemia and type 2 diabetes – Altered lipid profiles (non-specific and increases in CHO and TGL) – Cardiac effects (orthostatic hypotension, tachycardia and QTc prolongation) – Hyperprolactinemia *Considerable differences exist among drugs considered atypical antipsychotics Clozapine as a Prototype

– No EPS (acute or tardive)

– Mesolimbic/cortical (vs nigrostriatal) selectivity

– Does not increase prolactin release What is Wrong with Clozapine?

•Clozappgyine can lead to agranulocytosis

•Clozapine increases incidence of seizures

• Clozapine cause weight gain and metabolic changes

• Sedation, hypersalivation, orthostatic hypotension as addit iona l s ide e ffects Autonomic Side Effects of Antipsychotic Drugs

• α1 AdrR blockade-orthostatic hypotension

• mAChR blockade – dry mouth, blurred vision, constipation, urinary retention

• Histamine H1 blockade – sedation, increased appetite and weight gain, metabolic syndrome Research Programs Have Focused on Optimizing Receptor Activities Getting the RtiRatios Ri Rihtght

Roth et al, Nature Rev. Drug Discovery, 3, 353, (2004) Comparison of Antipsychotics ADR HPD ARI ZIP RIS CLZ OLZ QTP

EPS +++ + + ++ 0 + + TD +++ 0 0 + 0 + + Anti‐Ach + 00++++ ++ ++ Hypotension + + + ++ +++ + ++ AST/ALT + + + + + + + Sedation + + + + +++ ++ ++ QTc Prolongation +0++ ++ + + Metabolic syndrome + + + ++ +++ +++ ++ Diabetes + 0 0+ +++ +++ ++ Weight Gain + + + + +++ +++ ++ Prolactin +++ 0 0 +++ 0 + 0 Increased Lipids + 0 0 + +++ +++ ++ Hig h (()+++), MMdiedium (()++), Low (+), Very Low (0) First and Second Generation Antipsychotics May Cause Agranulocytosis, Although It Occurs More Frequently With Clozapine (leukopenia 3%, agranulocytosis 1.3%). Aripiprazole: the Latest and Greatest

Otsuka discovery BMS US development Intrinsic Activity at D2 Receptors Intrinsic Activity Describes the Ability of a Compound to Activate Receptors

D2 receptor Full activation Full agonist (dopamine)

No activation Antagonist (haloperidol, etc)

Partial activation Par tiltial agoni it(st (ari iipiprazol l)e)

* Dopamine Antagonism: Positi ve S ympt oms and EPS

EPS

DA Hyperprolactinemia inhibition Improvement of positive symptoms Dopamine Antagonism: NtiStNegative Symptoms

DA inhibition Min ima l improvemen t o f negative symptoms Dopamine Partial Agonism: Positi ve S ympt oms and EPS

No EPS

DA No hyperprolactinemia stabilization Improvement of positive symptoms Dopamine Partial Agonism: NtiStNegative Symptoms

Stabilized silignal ItfImprovement of negative symptoms, cognition and amotivation Aripiprazole: Activity at Cloned Human D2 Receptors

DA 100 onseonse

50 Partial activation ax. respax. resp MMMM

% % Aripiprazole 0 HHlaloper idlidol 10--1010 10--99 10--88 10--77 10--66 10--55 No activation Concentration (()M) Aripiprazole Is a Partial Agonist at Clone d H uman D2 RtReceptors

100 100 nM DA + aripiprazole

onseonse Receptor blockade needed for clinical response 50 100 nM DA Blocking, ax. respax. resp + haloperidol partial activation MMMM

% % Partial agonism 0 Full blockade

10--1010 10--99 10--88 10--77 10--66 10--55 Concentration (()M) Receptor Binding Profile of Aripiprazole and Reference Antipsychotics

Aripiprazole Olanzapine Risperidone Quetiapine Ziprasidone Clozapine Haloperidol Receptor (Abilify™) (Zyprexa®) (Risperdal®) (Seroquel®) (Geodon®)(Clozaril®) (Haldol®)

D1 265* 31 430 455 525 85 210

D2 0340.34* 11 4 160 5 126 070.7

D3 0.8* 49 10 340 7 473 2

D4 44* 27 9 1600 32 35 3

5-HT1A 171.7* >10, 000 210 2800 3 875 1100

5-HT2A 3.4* 4 0.5 295 0.4 16 45

5-HT2c 15* 23 25 1500 1 16 >10,000

α1 47 19 070.7 7 11 7 6

H1 61* 7 20 11 50 6 440

M1 >10,000 1.9 >10,000 120 >1000 1.9 >1500

Data represented as Ki (nM). *Data with cloned human receptors. Bymaster et al, 1996; Seeger et al, 1995; Daniel et al, 1999; Arnt and Skarsfeld, 1998. Aripiprazole Long-Term Trial 2 Time to Discontinuation Due to Lack of Efficacy or Adverse Events

1.00 ARIP-30MG 0.95 HALO-10MG 0.90

0.85

0.80 PATIENTS FF 0.75 p-value < 0.0001 0.70

PORTION O 0.65 OO

PR 0.60

0.55

0.50

050 100 150200 250 300 350 Days in Study * Aripiprazole Long‐Term Trial 2: Maintaining a Response Time to Failure to Maintain Response

1.0 Risk ratio = 0.697 (0.454, 1.069) P=0.098 ss

0.9 t event ortion uu pp 0.8

Pro Aripiprazole (n=447)

witho Haloperidol (n=189) 070.7 0 28 56 84 112 140 168 196 224 252 280 308 336 364 Days since randomization

Response = 30% decrease in PANSS, maintained for 28 days. Kujawa et al. Int J Neuropsychopharmacol. 2002;5(suppl 1):S186. * Aripiprazole Long‐Term Trial 2: Change in Negative Symptoms re

oo 0

-1 ative sc gg -2 Aripiprazole -3

NSS ne Haloperidol AA -4

-5

ease in P * * * * * * * -6

Decr 12345678101214182226303438424652 Week of therapy

*Aripiprazole significantly greater improvement: P<0.05, ANCOVA; LOCF. Baseline scores: aripiprazole = 24.7 (n=853); haloperidol = 24.7 (n=430). Kujawa et al. Int J Neuropsychopharmacol. 2002;5(suppl 1):S186. Aripiprazole Neurocognitive Function TiTria l: CCiomparison With Olanzap ine

Coggynitive Ability Better Verbal Learning 0.7 0.25 Aripiprazole (n=76) Aripiprazole (n=76) Olanzapine (n=93) 0.6 Olanzapine (n=93) P<0.05 0200.20 0.5 P<0. 05 * 0.15 0.4 * * * 0.3 0.10 0.2 0.05 010.1

0 0 Week 8 Week 26 Week 8 Week 26 *Significant improvement from baseline (P<0.05).LOCF analysis, based on the California Verbal Learning Test and the Continuous Performance Test - Identical Pairs version. Cornblatt et al. Int J Neuropsychopharmacol. 2002;5(suppl 1):S185. Anticholinergic Side‐Effects • Adverse Effect Medical Complications

• Decreased Secretions Drying of membranes – Mouth Dental caries, ulcers – Lungs Mucous plugs – Skin Hyperthermia, dry skin • Increased Pupil Size Acute narrow‐angle glaucoma Photophobia • In hibite d AdtiAccomodation Blurre d viiision, especiillally near viiision • Tachycardia Angina, Myocardial infarction • Urinary retention Bladder distention, aggravates UTIs • Decreased GI Motility Constipation, toxic adynamic ileus

Mostly Phenothiazines [PTZ’s] (aliphatic and piperidine, lesser frequency and severity with piperazine), mild with atypicals CNS Effects

• Cognitive Effects – Drowsiness – Weakness, lethargy, fatigue – Nightmares, agitation, restlessness, insomnia – Confusion, disturbed concentration, disorientation • Neurological Effects (mostly traditional antipsychotics) – Fine tremor – DtDyston ia – Akathisia (rare) – Parkinsonian‐like movements – Tardive Dyskinesia • Seizures (abrupt withdrawal, rapid dose increases) • Tinnitus • Myoclonus Cardiovascular Effects

• ’s – Orthostatic Hypotension (anti‐adrenergic); avoid use of adrenergic blockers • Prazocin – Tachycardia and/or cardiac arrhythmias – Prolonged conduction time (QTc interval) • contraindicated in heart block or post‐ myocardial infarction – Congestive heart failure – ECG Abnormalities • Non‐specific ST‐T changes • Flattening of T‐waves – Quinidine‐like effect – Do not administer epinephrine in asthmatic attacks • Atypical Antipsychotic’s – Rare cardiodynamic effects other than mild Orthostatic Hypotension – Prolongation of the ECG QTc interval Aripiprazole Short-Term Clinical Trials: MChiQTItlMean Change in QTc Interval*

6 • QTc interval (>450 msec) 4 occurred in 1 patient om c) treated with placebo, 2 rr ee 2 patients treated with † 0 haloperidol, and in 2 hange f line (ms

cc patients treated with -0.62 -2 aripiprazole base Mean -4 -3.56 • No patient had a QTc -4.16 interval of >500 msec -6 Placebo All Haloperidol aripiprazole

*QTc interval determined by Fractional Exponent Correction Method (FDA). †P≤0.05, significantly different from placebo. * Endocrine and Sexual Side‐Effects

• Gynecomastia, Galactorrhea, Breast tenderness ‐ males and females – mostly Typical antipsychotic’s, rare with Risperidone • Testicular swelling, Decreased libido • Anorgasmia – (helped by bethanecol, pseudoephedrine or cyproheptadine • Weight gain – (mostly olanzapine, clozapine or quetiapine, also chlorpromazine) • Increased blood sugar levels – (clozapine > olanzapine > chlorpromazine) • Increased blood triglyceride, cholesterol (LDL) – (clozapine > olanzapine > chlorpromazine) Mean Change in Weight With Antipsychotics Estimated Weight Change at 10 Weeks on “Standard” Dose 6 13.2

5 * 11.0 Wei 4 8.8 (kg) g

3 6.6 ht chan 2 4.4 1 2.2 g t change 0 0 e (lb) -1 -2.2 Weigh -2 -4.4 -3 -666.6

*Extrapolated from 6-week data. Little weight gain seen Allison et al. Am J Psychiatry. 1999;156:1686. with Aripiprazole Differential Incidence of Type 2 Diabetes Mellitus Retrospective Assessment of 396 Patients With S chi zoph reni a b y Ch art R evi ew121,2 20 M

DD Few Di abet es Pr obl em s 15 seen with Aripiprazole f type 2 oo 10

5 centage rr Pe 0 Clozapine Olanzapine Risperidone Haloperidol Fluphenazine

McIntyre et al. Can J Psychiatry. 2001;46:273. Zoler. Clin Psychiatr News. 1999;27;20. Aripiprazole Long‐Term Trial 1: Effects on LDL, HDL, and TiTrig lycer ide LlLevels

ee 4 2 0 baselin -2 -4 Placebo g/dL) ge from from ge -6 Aripiprazole mm ( -8 -10 an chan ii -12

Med -14 LDL HDL Triglycerides n = 119/116 120/116 120/116

Data obtained from fasted plasma samples. Consensus Panel’ s Conclusions

Drug Drugmaker Weight Diabetes Worsening Gain Risk Cholesterol

Clozaril Novartis Strong effect Clear risk Clear effect Zyprexa Eli Lilly Strong effect Clear risk Clear effect Risperdal J & J Some effect Conflicting data Conflicting data Seroquel AstraZeneca Some effect Conflicting data Conflicting data Abilify** BMS/Otsuka Little/no effect No effect No effect Geodon** Pfizer Little/no effect No effect No effect

*Consensus Panel Members represent: American Diabetic Association, American Psychiatric Association, American Association of Clinical Endocrinologist, North American Association for the Study of Obesity. **New medicine; less data is available. Diabetes Care, Volume 27, No. 2, February 2004. Allergic and Miscellaneous Reactions • Allergic Reactions (more with PTZ’s) – Pigment ddiieposition in lens and cornea (may cause vilisual ch)hanges) – Pigment deposition in retina can lead to irreversible blindness – Allergic maculopapular skin rashes, urticaria, pruritis are common – Photosensitivity – Serum sickness (all) • Miscellaneous Reactions – Effects on Hepatic Function – Increased AST/ALT levels: ? Problem – Increased GGTP and bilirubin levels: obstructive disease – Hematological Effects (mostly Clozapine) – Transient leukopenia or leukocytosis – Agranulocytosis – Poikilothermia Serum Prolactin Levels: Pooled Data From Aripiprazole Short‐Term Clinical Stu dies Median Serum Prolactin Levels at Baseline and End Point 25 ↑ 120%* Baseline 20 LOCF ng/mL) (( 15 ↑ 0% ↓ 57%*

rolactin 10 pp

5 Serum 0 Placebo Haloperidol Aripiprazole n = 339 185 729

*P<0.01 vs change with placebo. All patients but one remained within normal limits. Stock et al. Int J Neuropsychopharmacol. 2002;5(suppl 1):S185. Comparison of Atypical Antipsychotic Drugsa

Drug EPS Weight Metabolic ↑Prolactin ↑QT Sedation Comments Gain Changesb Secretion Interval

Clozapine - +++ +++ -++++ Can cause agranulocytosis, seizures, ↑salivaon Risperidone ++ ++ + +++ ++ +/-

Olanzapine + +++ +++ ++++

Quetiapine ++++ - ++++

Ziprasidone + -- -+++ + May improve cognitive function

Aripiprazole +- - - - +/-Partial agonist at D2 receptors and 5‐

HT1A receptors a Important distinguishing features are highlighted. b ↑Risk for diabetes; worsening lipid profile. Reading

• Harrison’s Medicine –chapter on schizop hren ic disor ders • Goodman and Gilman –chapter on psychiatric disorders, psychosis and mania • UK Medicines Information, Issue No. 04//,07, June 2004 • Roth et al., Nature Rev. Drug Discovery, 3, 353, (2004) • Domino, Psychosom. Med. 61, 591, (1999) Organizational Behavior

Careful Clinical Observation – clorpromazine (Thorazine) to aripiprazole (Abilify) 8 Aripiprazole – Process Issues • Large number of atypical antipsychotics on market – too much competition for aripiprazole – Market is highly striated and typically each compound will find a niche – Market will be large if aripiprazole is superior as anticipated • Partial agonist strategy unproven and risky – Value of partial agonist antipsychotics need to be proven clinically – Can run small clin ica l program as proof of concept Aripiprazole – Process Issues – cont. • Antipsychotic efficacy depends on a panel of ppproperties? ‐ partial agonism will not make a difference – Value of partial agonist antippysychotics need to be proven clinically – Can run small clinical program as proof of concept • Otsuka small company – how will we market outside of Japan to amortize development costs? – Need to find a partner, but need clinical data to attract partner