Antipsychotics…, where are we ?

Prof. Adel El SheshaiProfessor of Psychiatry , Alexandria university

Member of APA, EAP, WPA, EPAFellow of USC (CA, USA), Emory uni. (GA, USA)

Developments for Medical Treatments for Psychotic Disorders

50s 60s 70s 80s 90s 00s 05s

Reserpine

Chlorpromazine

HaloperidolFluphenazineThioredazineLoxapinePerphenazine

ClozapineRisperidoneOlanzapineQuetiapineziprasidone

Aripiprazolebifeprunox

Typical Typical AP AP

AtypicalAtypicalAPAP

Partial D2 Partial D2 AgonistAgonist

Recent future

Far future

IloperidoneCyamemazineAsenepine

Gly agonistGlyT1 inhibitorsSigma1 ag/antagD3 antagonistAch linked agentPeptide linked agents

Future Future APAP

Sertindole

Key brain regions and their hypothetical functionIn schizophrenia, the neurotransmitter dopamine is theoretically dysregulated, and as a result various brain areas are overactive, underactive, or otherwise “out of tune” resulting in the generation of positive and negative symptoms.

CONVENTIONAL D2 ANTAGONISTS

Conventional antipsychotics

Conventional antipsychotics

Generic name Trade name

ChlorpromazineCymamezineFluphenthixolFluphenazineHaloperidolLoxapine

MesoridazineMolindone

PerphenazinePimozide

PipothiazineSulpiride

ThioridazineThiothixene

Trifluoperazinezuclopenthixol

ThorazineTericanDepixolProlixinHaldol

LoxitaneSerentilMobanTrilafonOrap

PiportilDolmatilMellarilNovane

StelazineClopixol

Atypical antipsychotics

Atypical antipsychotics couple their D2 antagonism with 5HT2A antagonism

The dissociation rate at the D2 receptor sets apart “atypicality” of an antipsychotic (rapid dissociation)

Atypical antipsychotics can also be D2 partial agonists (DPAs). These agents bind in a manner that is neither too antagonizing nor too stimulating, allowing for just the “right” amount of neurotransmission at D2 receptors.

Full or partial agonism at the 5HT1A receptor can also be a characteristic of some atypical antipsychotics.

D2 PARTIAL AGONIST

The agonist spectrum – the theory behind the partial agonist

Source: World Health OrganizationSource: World Health Organization

Schizophrenia ..A Serious Public Health Problem

of people with schizophrenia are not receiving appropriate care

of people with untreated schizophrenia are in developing countries

Etiology:DNA Gene Expression Viruses Toxins Nutrition Birth Injury Psychological Experiences

Pathophysiology: Brain Development

(e.g., neuron formation, migration, pruning, apoptosis)

Neuronal Connectivity and Communication

Impairment in a Fundamental Cognitive Process

Impairment Second-Order Cognitive Processes (e.g., attention, memory, language)

Symptoms of Schizophrenia: (e.g., hallucinations, delusions, negative symptoms, disorganized speech)

WPA Educational Program, Andreassen 2002

Working Model

Schizophrenia – Optimising Treatment Effect and Side Effects

Positive symptoms

Negative symptoms

Cognition

Mood symptoms

Relapse preventionRemissionRecovery

Social functioning QoL

Long-term outcome

Suicidal behaviour

Neurologic side effects

Autonomic side effects

Metabolic syndrome/weight gain

Neuroendocrine

Cardiovascular

Mortality

Unmet needs

Earlier diagnosis of schizophrenia

More effective antipsychotics

Better tolerated antipsychotics

Faster onset-of-action

Improved treatment of comorbid depression and anxiety

Improved treatment of cognition

Atypical Antipsychotics are

not alike

The in vitro receptor-binding affinity profile

Arnt and Skarsfeldt (1997)

SertindoleSertindole ClozapineClozapine ZiprasidoneZiprasidone HaloperidolHaloperidol

RisperidoneRisperidone OlanzapineOlanzapine QuetiapineQuetiapine

D1

D1

D2

D2

5-HT2

5-HT2

α1

α1

MuscarinicMuscarinic

In vitroIn vitro

In Vitro Receptor Profiles – How Much Do They Differ in Terms of Cognition, Sedation and

Weight Gain?

Leysen 2000pKi values (-log to affinity constant, ki)

5 6 7 8 9 105 6 7 8 9 10

Sertindole Risperidone

5HT65HT6

5HT2A 5HT2A

H1 H1

5 6 7 8 9 10

D2

Reference

Olanzapine

5HT65HT6

5HT2A

H1Musc

H1

5HT7

5HT6

5HT3

5HT2C

5HT2A

5HT1A

D4

D3

D2D1

Comparative Side Effect Profiles of Antipsychotics

Clo Ris Ola Que Ser Ari

Sedation ++ + ++ + +/- +/-

EPS - ++ + (+) - (+)

Orthostatic hypotension ++ + (+) + + -

Weight gain/Metabolic Syndrome

+++ + (+) +++ + (+) (+) (+)

Prolactin elevation (+) +++ (+) (+) - -

Salivation/Dry mouth +++ + + + + -

Transaminase elevations + + + (+) + (+) (-)

Haematological effects +++ (+) + (+) (+) (-)

QTC prolongation ++ (+) (+) (+) ++ -

Seizure ++ (+) (+) (+) (+) (-)

+ mild ++ moderate +++ severe Modified after Müller-Spahn 2001

Sertindole’s and Pharmacological Clinical Profile

regionally selective D2 blocker (VTA vs S)

alpha1 antagonist

5-HT2C inverse agonist

5HT6 antagonist

Effective without sedation

Excellent patient acceptability

Enables patients to function

CognitiveCognitivefunctionfunction

CognitiveCognitivefunctionfunction

NoNosedationsedation

NoNosedationsedation

NegativeNegativesymptomssymptoms

NegativeNegativesymptomssymptoms

Functioning

Functioning

Functioning

Functioning

Translates into:Efficacy on Positive & negative symptomsGood cognitive profile No EPS

Sertindole

If positive/negative symptoms are not controlled If sedation, EPS or TD are present If they experience excessive weight gain If they are experiencing anticholinergic side effects If their sexual functioning is impaired If their cognitive function is impaired

Patients are likely to benefit from sertindole:

Antipsychotic Switching Syndrome“ Withdrawal Triad”

1) Cholinergic rebound.

2) Supersensitivity psychosis.

3) Withdrawal dyskinesias ( and other motor syndromes)

Dosage and Efficacy

Sertindole is effective against positive and negative symptoms of Schizophrenia within the dose range 12 – 24 mg daily, with an optimal starting dose of 16 mg daily.

Efficacy is comparable to 10 mg of haloperidol with no difference in the time course of treatment response.

The dose response relationship for efficacy with sertindole seems to plateau at about 16 mg daily with no demonstrable difference in increasing doses above this point.

Hale et al 2000

CATIE Study – reasons for discontinuation

Lieberman et al 2005; Nurnberg 2007

Olanzapine

Quetiapine

Perphenazine Ziprasidone

Risperidone

WeightEPSSedationOther

Weight

EPS

Sedate

Other Other

Weight

EPSSedate

Weight

Other

EPS

Weight

EPS

Sedate

Other

Sedate

Other

Weight

EPS

Reasons for Switching

1-year switch rates: 25–50%1

Lack of efficacy (24%)• Positive and negative symptoms• Outcome (cognitive symptoms)

Adverse events (15%)• EPS• Weight gain• Sedation

Non-compliance

1Weiden 1999

Switching Medications

The reason why the first medication is stopped is an important consideration in choosing the next antipsychotic.

The success of symptom management and the side effects experienced on the first medication may help predict which medication may be more successful next.

Schizophrenia medication should be tailored to the individual patient, maximising benefits and minimising side effects to increase compliance.

Metabolic Syndrome: Definitions

Risk factor US guidelines WHO

Number needed ≥3 ≥2

Obesity Waist circumferenceM >40 inW >35 in

Waist/Hip ratioM >0.90W >0.85

or BMI >30

Triglycerides ≥150 mg/dL Dyslipidemia ≥150 mg/dL

and/or

High density lipoprotein

M <40 mg/dLF <50 mg/dL

M <35 mg/dLF <40 mg/dL

Hypertension ≥130 / ≥85 mmHg >160 / >90 mmHg

Fasting glucose ≥110 mg/dL ≥110 mg/dL

Microalbuminuria AER ≥20 µg/min

Metabolic Syndrome:Metabolic Syndrome:What are the Predisposing Factors?What are the Predisposing Factors?

Metabolic syndrome

Poor diet Lack of exercise

Smoking

Substance abuse

Stress

Medication effectse.g., weight gain

Inadequate self-care

Financial hardship

Limited availability and coordination of medical care

World Federation for Mental Health 2005

% of patients developing diabetes

Casey et al 2001

0

5

10

15

20

25

Ris Que Clz Olz

7-year survival of diabetics without a history of MI is similar to that of non-diabetics who are post-MI

Haffner et al 1998MI=myocardial infarction

2.1

42%42%

0

10

20

30

40

50

No prior MIPrior MI

Non-diabetic Diabetic69 1,304 169 890N

CV mortality (%)

15.415.9

Sertindole :

Hyperglycemia or exacerbation of pre-existing diabetes has been reported in very rare cases during treatment with sertindole

Small increase in mean glucose Potentially clinically significant* glucose values in 4% of

sertindole-treated patients and in 2% of placebo-treated patients

Summary of product characteristics (SPC) 2007* (175 mg/dl)

Sertindole :

No consistent effect on blood lipids

In the placebo-controlled short-term studies and the long-term trials, the mean

cholesterol concentrations at endpoint were similar to those at baseline

Summary of product characteristics (SPC) 2007

Physical health problems – weight gain

Treatment-related weight gain Poor diet Lack of exercise Obesity is a risk factor for type II diabetes,

dyslipidemia, hypertension All can lead to cardiovascular disease and

increased risk of mortality

Casey et al 2004

Weight gain as a function of H1 affinity

Wirshing et al 1999

SertindoleHaloperidol

Risperidone

Olanzapine Clozapine

1 2 3 4 5 63

4

5

6

7

8

9

10

1/H1 Receptor affinity (Ki)

Adjusted maximum weight gain (%)

0

20

40

60

80

No change, or lostweight

<10% weight gain ≥10% weight gain

% Weight change (baseline to maximum weight)

Cloz Olz Ris Sert Hal

Weight gain as a function of antipsychotic

% patients

Wirshing et al 1999

Weight Gain: Short-Term (10 Weeks) Treatment

-2

-1

0

1

2

3

4

5

Place

bo

Molin

done

Zipra

sidon

e

Aripip

razo

le

Fluphe

nazin

e

Haloper

idol

Risper

done

Sertin

dole

Chloro

prom

azin

e

Thiorid

azin

e

Que

tiapin

e

Ola

nzap

ine

Cloza

pine

Cha

nge

from

bas

elin

e w

eigh

t (K

G)

Cha

nge

from

bas

elin

e w

eigh

t (K

G)

Risk factors for heart disease in the general population

BMI = body mass index (kg/m2); TC = total cholesterol (mg/dL); DM = diabetes mellitus; HTN = hypertension

0

2

4

6

8

10

12

14

HTNDMSmokingBMI >27 TC >220

Single risk factors

Od

ds

rati

o

Multiple risk factors

Smoking+ BMI >27

2

Smoking+ BMI >27+ TC >220

3

Smoking+ BMI >27+ TC >220

+ DM

4

Smoking+ BMI >27+ TC >220

+ DM + HTN

5

Wilson et al 1998

QT interval

QT interval = time from beginning of ventricular depolarization through repolarization as seen on the ECG

QT interval shortens as heart rate increases QT interval lengthens as heart rate decreases

QTc interval

QTc interval = QT interval corrected for heart rate

Many different correction formulas are commonly used

Many factors may influence the QTc interval

Athletic trainingAthletic training

Sleeping Sleeping

Obesity Obesity

DrugsDrugs

HypoglycemiaHypoglycemia

Cardiac diseaseCardiac disease

AlcoholismAlcoholism

HypothyroidismHypothyroidism

Electrolyte disturbanceElectrolyte disturbance

Eating & drinkingEating & drinking

QTc QTc

Some drugs are known to prolong the QTc interval

Antiarrythmics Vasodilators/Anti-

ischemics Psychiatric drugs

Antidepressants Antipsychotics

Anti-infective Antimicroial Antimalarial Antimycotic

Antihistamines Other drugs

The QTc interval is variable

The QTc interval is highly variable among healthy individualsMean daily variation has been reported within

healthy individual to be approximately 76 msec. The upper limit of normal is not firmly

established

1Bednar et al 2001; 2EMEA CPMP 1997; 3Gupta et al 2007

QTc interval – key considerations

QTc interval is highly variable1

Within an individual: average 76 msecAmong individuals: up to 80 msecSleeping: mean lengthening is 13 msec Gender: women 10–20 msec longer than

men

No agreed limits for ‘normal’ QTc >450 msec in men, and >470 msec in

women considered prolonged2

1Bednar et al 2001; 2EMEA CPMP 1997; 3Gupta et al 2007

QTc interval – key considerations

Arrhythmic events are generally associated with QTc >500 msec and only in the presence of clinically relevant risk factors1,3

Increase of >30 msec ‘potential concern’; >60 msec ‘concern’ for potential risk of inducing arrhythmias

Sertindole prolong QTc with 20 – 22 msec, with no evidence having a proarrhythmic effect.

All cause & suicide mortalityAll cause & suicide mortality

Parameter Serdolect Olz Ris

Patient-years of exposure (PYE)

1,914 1,122 858

All-cause mortality/100 PYE (Cl)

1.521.52(0.96–2.13)

1.87(1.2–2.9)

1.86(1.1–3.0)

Suicide mortality/100 PYE (Cl)

0.370.37(0.15–0.75)

0.89(0.43–1.64)

1.17(0.56–2.14)

Cl = 95% confidence intervalPerquin & Steinert 2004; Kasper & Toumi 2004;

Moore 2002; H. Lundbeck A/S, data on file

Weightgain

Diabetes

Raisedglucose

Insulinresistance

QTc

CHD

Hyperlipidemia

Present

Shifting perceptions – antipsychotic safety issues

Past

QTc

Weight gain Insulin

resistance

Raisedglucose

CHD

Hyper-lipidemia

LongQT

Torsades de Pointes

Guidelines recommend physical health monitoring

Most include the following parameters (baseline, every 3, 6 or 12 months):EPS, akathisia, and tardive dyskinesiaWeight gain and obesityPhysical activity levels, exercise and

somnolenceGlucose and lipid blood levelsDiabetesECG monitoring

Maudsley Guidelines 8th edition 2005; Marder et al 2004

What are the benefits of monitoring patients?

Monitoring allows patients to identify side effects early, and to respond by dose adjustment, or by switching medication

Monitoring may identify non-compliance with medication before relapse

More frequent consultations increases interaction between patient and physician

Maudsley Guidelines 8th edition 2005; Marder et al 2004

Potential Future Drug Targets

5-HT6

Role in higher cognitive processes

Polymorphisms implicated in schizophrenia and dementia

Several clinically useful second generation antipsychotics do have affinity – although its utility may be masked by e.g., antimuscarinic activity

Mitchell & Neumaier 2007

Other Potential Future Drug Targets

Direct glutamate agonists are not useful drugs

Glutamate modulators are potential antipsychotics

Cholinergic enhancers

Dopamine D1 agonists

Neurokinin (NK3) antagonists

PDE10 inhibitors ( Dual enhancement and inhibition of dopamine signalling –

Phase 1)

A Rational Basis for Choosing an Antipsychotic Drug?

No one atypical antipsychotic is strictly dominant over any other, e.g.,:• olanzapine dominates risperidone on EPS and PRL but…..• risperidone dominates olanzapine on sedation and metabolic

syndrome

Atypical antipsychotics have distinct differences, but on multiple attributes

It could be argued that the most rational policy to adopt is to prescribe each antipsychotic equally, and update that policy by feedback-from-experience

No substantial or consistent superiority of any one antipsychotic over any other in acute phase efficacy

Plausible evidence that atypical antipsychotics outperform typical antipsychotics in long-term efficacy

Atypical antipsychotics have removed some problems, but created others

Atypical antipsychotics have multiple, competing attributes and no one drug is strictly dominant

Serdolect has powerful efficacy on Positive & negative symptomsGood cognitive profile , No EPS

A Rational Basis for Choosing an Antipsychotic Drug?

Drug Pros Cons

Paliperidone dose dependant EPSweight ± PRL

Zotepine Inhibits NE uptake improve in cognitive & mood symptoms

Perospirone interaction with 5HT1A receptors antidepressant and anti-anxiety effect

EPS

Cyamemazine anxiolytic action in low dose, very low EPS & weight

use with caution in cardiac, hepatic or renal patients

Drug Pros Cons

Amisulpiride efficacy against negative symptoms

PRL upto amenorrhea

Bifeprunox no EPS, no PRL, no sedation, very low weight gain

strong GIT (NV), still in testing

Iloperidone first drug with a genetic marker to predict response

Asenapine: Wider receptor variability than clozapine itself.

The ideal antipsychotic

The ideal drug for schizophrenia restoring function