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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
CONVENTIONAL D2 ANTAGONISTS
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
D2 PARTIAL AGONIST
of people with schizophrenia are not receiving appropriate care of people with untreated schizophrenia are in developing countries
Working Model
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
QoL
Long-term outcome
Unmet needs
Faster onset-of-action
Improved treatment of comorbid depression and anxiety Improved treatment of cognition
Sertindole
Clozapine
Ziprasidone
Haloperidol
Risperidone
Olanzapine
Quetiapine
In Vitro Receptor Profiles How Much Do They Differ in Terms of Cognition, Sedation and Weight Gain?
Olanzapine
Musc H1
a2 a1 5HT7 5HT6 5HT3 5HT2C 5HT2A 5HT1A D4 D3 D2 D1
5 6 7
Sertindole
H1
H1
Risperidone
H1
5HT6
5HT6
5HT2A
5HT2A
5HT2A
D2 Reference
8 9 10 5
10
10
Leysen 2000
Ser
+/+ (+) + (+) (+) ++
Seizure
+ mild ++ moderate +++ severe
++
(+)
(+)
(+)
(+)
(-)
Cognitive function
No sedation
Translates into:
Efficacy on Positive & negative symptoms Good cognitive profile No EPS
Sertindole
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
1) 2) 3)
Cholinergic rebound. Supersensitivity psychosis. Withdrawal dyskinesias ( and other motor syndromes)
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
Perphenazine
Weight
Ziprasidone
Weight
Other Weight
Sedate EPS
Other
EPS
Sedate
EPS
Quetiapine
Weight
Risperidone
EPS Other Weight EPS Sedation Other
Other
EPS Sedate
Weight
Sedate
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
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.
Triglycerides
150 mg/dL
Smoking
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
Ris
Que
Clz
Olz
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
42%
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)
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
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
Olanzapine
Clozapine
Risperidone
Cloz
Olz
Ris
Sert
Hal
Wirshing et al 1999
Pl
-2 0 1 2 3 4 5 -1
Odds ratio
8 6 4
2
0
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
Sleeping QTc
Hypothyroidism
Obesity
Alcoholism
Drugs Hypoglycemia
Cardiac disease
Anti-infective
Antidepressants Antipsychotics
Mean daily variation has been reported within healthy individual to be approximately 76 msec.
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
No
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.
1Bednar
Parameter Patient-years of exposure (PYE) All-cause mortality/ 100 PYE (Cl) Suicide mortality/ 100 PYE (Cl)
Perquin & Steinert 2004; Kasper & Toumi 2004; Moore 2002; H. Lundbeck A/S, data on file
Present
Diabetes
QTc
Long QT
Weight gain
Raised glucose
CHD
Weight gain
QTc
Raised glucose
Hyperlipidemia
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
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
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)
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
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
Pros
Zotepine
Perospirone
EPS
Cyamemazine
Drug
Pros
Cons
Amisulpiride
Bifeprunox
Iloperidone
Asenapine: