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Antipsychotics, where are we ?

Prof. Adel El Sheshai

Professor of Psychiatry , Alexandria university Member of APA, EAP, WPA, EPA Fellow of USC (CA, USA), Emory uni. (GA, USA)

Developments for Medical Treatments for Psychotic Disorders

50s 60s 70s 80s 90s 00s 05s
Recent future Far future

Clozapine Haloperidol Fluphenazine Risperidone Thioredazine Olanzapine Quetiapine Loxapine Perphenazine ziprasidone Reserpine Chlorpromazine

Iloperidone Cyamemazine Aripiprazole Asenepine bifeprunox Gly agonist GlyT1 inhibitors Sigma1 ag/antag Sertindole D3 antagonist Ach linked agent Peptide linked agents

Typical AP

Atypical AP

Partial D2 Agonist

Future AP

Key brain regions and their hypothetical function

In 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 antipsychotics
Conventional antipsychotics Generic name Chlorpromazine Cymamezine Fluphenthixol Fluphenazine Haloperidol Loxapine Mesoridazine Molindone Perphenazine Pimozide Pipothiazine Sulpiride Thioridazine Thiothixene Trifluoperazine zuclopenthixol Trade name Thorazine Terican Depixol Prolixin Haldol Loxitane Serentil Moban Trilafon Orap Piportil Dolmatil Mellaril Novane Stelazine Clopixol

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


The agonist spectrum the theory behind the partial agonist

Schizophrenia ..A Serious Public Health Problem

of people with schizophrenia are not receiving appropriate care of people with untreated schizophrenia are in developing countries

Source: World Health Organization

Working Model
DNA Gene Expression Viruses Toxins Nutrition Birth Injury Psychological Experiences

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

Schizophrenia Optimising Treatment Effect and Side Effects

Positive symptoms Negative symptoms Cognition Mood symptoms Suicidal behaviour Metabolic syndrome/ weight gain Cardiovascular Relapse prevention Remission Recovery Social functioning Mortality

Neurologic side effects

Autonomic side effects Neuroendocrine

Long-term outcome

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








In vitro D1 D2 5-HT2 1 Muscarinic

Arnt and Skarsfeldt (1997)

In Vitro Receptor Profiles How Much Do They Differ in Terms of Cognition, Sedation and Weight Gain?
Musc H1
a2 a1 5HT7 5HT6 5HT3 5HT2C 5HT2A 5HT1A D4 D3 D2 D1
5 6 7








D2 Reference
8 9 10 5



pKi values (-log to affinity constant, ki)

Leysen 2000

Comparative Side Effect Profiles of Antipsychotics

Clo Sedation EPS Orthostatic hypotension Weight gain/Metabolic Syndrome Prolactin elevation Salivation/Dry mouth Transaminase elevations Haematological effects QTC prolongation ++ ++ +++ (+) +++ + +++ ++ Ris + ++ + + (+) +++ + + (+) (+) Ola ++ + (+) +++ (+) + + (+) + (+) Que + (+) + + (+) (+) + + (+) (+)

+/+ (+) + (+) (+) ++

Ari +/(+) (+) (-) (-) -

+ mild ++ moderate +++ severe







Modified after Mller-Spahn 2001

Sertindoles and Pharmacological Clinical Profile

regionally selective D2 blocker (VTA vs S) alpha1 antagonist 5-HT2C inverse agonist Negative 5HT6 antagonist symptoms Effective without sedation Excellent patient acceptability Enables patients to function

Cognitive function

No sedation

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

Patients are likely to benefit from 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

Antipsychotic Switching Syndrome Withdrawal Triad

1) 2) 3)

Cholinergic rebound. Supersensitivity psychosis. 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




Other Weight
Sedate EPS




EPS Other Weight EPS Sedation Other


EPS Sedate



Lieberman et al 2005; Nurnberg 2007

Reasons for Switching

1-year switch rates: 2550%1 Lack of efficacy (24%) Positive and negative symptoms Outcome (cognitive symptoms) Adverse events (15%) EPS Weight gain Sedation Non-compliance


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 Number needed Obesity US guidelines 3 Waist circumference M >40 in W >35 in WHO 2 Waist/Hip ratio M >0.90 W >0.85 or BMI >30 Dyslipidemia 150 mg/dL and/or M <35 mg/dL F <40 mg/dL >160 / >90 mmHg 110 mg/dL AER 20 g/min


150 mg/dL

High density lipoprotein Hypertension Fasting glucose Microalbuminuria

M <40 mg/dL F <50 mg/dL 130 / 85 mmHg 110 mg/dL

Metabolic Syndrome: What are the Predisposing Factors?

Poor diet Stress Lack of exercise


Metabolic syndrome
Inadequate self-care Medication effects e.g., weight gain
Substance abuse Limited availability and coordination of medical care
World Federation for Mental Health 2005

Financial hardship

% of patients developing diabetes

25 20 15 10 5 0





Casey et al 2001

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

CV mortality (%) 50 40 30 20 10 0 N 2.1 69 1,304 Non-diabetic 169 890 Diabetic 15.9 15.4 No prior MI Prior MI


MI=myocardial infarction

Haffner et al 1998

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

* (175 mg/dl)

Summary of product characteristics (SPC) 2007

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

Adjusted maximum weight gain (%) 10 9 8 7 6 5 4 3 1 Haloperidol Sertindole 4 3 5 2 1/H1 Receptor affinity (Ki) 6
Wirshing et al 1999




Weight gain as a function of antipsychotic

% patients
80 60 40 20 0
No change, or lost weight < 1 0 % weight gain 1 0 % weight gain






% Weight change ( baseline t o maximum weight )

Wirshing et al 1999

-2 0 1 2 3 4 5 -1

Change from baseline weight (KG)

ac eb o

Weight Gain: Short-Term (10 Weeks) Treatment

M do Zi ne pr as id A rip on e ip r Fl up azo le he na zi H n al op e er id R is pe ol rd Se on C e hl rt or in do op le ro m az Th in io rid e az Q i ue ne tia pi O ne la nz ap in C e lo za pi ne ol in

Risk factors for heart disease in the general population

14 12 10 5

Multiple risk factors


Odds ratio

8 6 4

Single risk factors


BMI >27 Smoking TC >220 DM HTN Smoking Smoking Smoking Smoking + BMI >27 + BMI >27 + BMI >27 + BMI >27 + TC >220 + TC >220 + TC >220 + DM + DM + HTN

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

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

Eating & drinking Athletic training Electrolyte disturbance

Sleeping QTc




Drugs Hypoglycemia

Cardiac disease

Some drugs are known to prolong the QTc interval

Antiarrythmics Vasodilators/Antiischemics Psychiatric drugs


Antimicroial Antimalarial Antimycotic

Antidepressants Antipsychotics

Antihistamines Other drugs

The QTc interval is variable

The QTc interval is highly variable among healthy individuals

Mean daily variation has been reported within healthy individual to be approximately 76 msec.

The upper limit of normal is not firmly established

QTc interval key considerations


interval is highly variable1

Within an individual: average 76 msec Among individuals: up to 80 msec Sleeping: mean lengthening is 13 msec Gender: women 1020 msec longer than men


agreed limits for normal QTc

>450 msec in men, and >470 msec in women considered prolonged2


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.


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

All cause & suicide mortality

Parameter Patient-years of exposure (PYE) All-cause mortality/ 100 PYE (Cl) Suicide mortality/ 100 PYE (Cl)

Serdolect 1,914 1.52 (0.962.13) 0.37 (0.150.75)

Olz 1,122 1.87 (1.22.9) 0.89 (0.431.64)

Ris 858 1.86 (1.13.0) 1.17 (0.562.14)

Cl = 95% confidence interval

Perquin & Steinert 2004; Kasper & Toumi 2004; Moore 2002; H. Lundbeck A/S, data on file

Shifting perceptions antipsychotic safety issues

Torsades de Pointes




Long QT

Weight gain

Raised glucose


Weight gain

Insulin resistance CHD

Insulin resistance Hyperlipidemia


Raised glucose


Guidelines recommend physical health monitoring

Most include the following parameters (baseline, every 3, 6 or 12 months): EPS, akathisia, and tardive dyskinesia Weight gain and obesity Physical activity levels, exercise and somnolence Glucose and lipid blood levels Diabetes ECG 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


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

A Rational Basis for Choosing an Antipsychotic Drug?

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 symptoms Good cognitive profile , No EPS

Drug Paliperidone


Cons dose dependant EPS weight PRL


Inhibits NE uptake improve in cognitive & mood symptoms


interaction with 5HT1A receptors antidepressant and anti-anxiety effect



anxiolytic action in low dose, very low EPS & weight

use with caution in cardiac, hepatic or renal patients





efficacy against negative symptoms

PRL upto amenorrhea


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

strong GIT (NV), still in testing


first drug with a genetic marker to predict response


Wider receptor variability than clozapine itself.

The ideal antipsychotic

The ideal drug for schizophrenia restoring function