Antipsychotics
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Transcript of Antipsychotics
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