![Page 1: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/1.jpg)
Schizophrenia BlockAdapted from the American Society for
Clinical Psychopharmacology
Model Curriculum
![Page 2: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/2.jpg)
Learning Objectives
• Identify major target symptoms of schizophrenia treatment
• Become familiar with conventional & atypical antipsychotic medications
• Recognize major side effects of antipsychotic medications
• Recognize unique features of clozapine & depot antipsychotics
*
![Page 3: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/3.jpg)
Outline• Background about Schizophrenia
• Dopamine Hypothesis• Dopamine Pathways
• Efficacy of Anti-psychotics• Treats agitation• Prevents relapse• Compliance, Medication dose & relapse
• Overview of an Antipsychotic Medication Trial• Different Anti-psychotic medications• Side effects of the Anti-psychotics
• Common-EPS, TD, anti-cholinergic, metabolic syndrome, • Rare but serious-NMS
• Antipsychotic selection and treatment strategies algorithm
![Page 4: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/4.jpg)
Dopamine Hypothesis of Schizophrenia
![Page 5: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/5.jpg)
Dopamine Hypothesis
• Psychotic symptoms can be induced by dopamine agonists*• cocaine, amphetamines cause psychosis
• All anti-psychotics are dopamine antagonists• Normal subjects-10% dopamine receptors occupied at
baseline**• Schizophrenic subjects-20% dopamine receptors
occupied at baseline**
**Laruelle M, Quart J Nuc Med 1998;42:211
![Page 6: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/6.jpg)
Major Dopamine Pathways
1. Nigrostriatal tract- (extrapyramidal pathway) substantia nigra to caudate nucleus & putamen of the basal ganglia
2. Mesolimbic tract - midbrain tegmentum to nucleus accumbens & adjacent limbic structures
3. Mesocortical tract - midbrain tegmentum to anterior cortical areas
4. Tuberoinfundibular tract - arcuate & periventricular nuclei of the hypothalamus to the pituitary
*
![Page 7: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/7.jpg)
Dopamine Receptor Subtypes
D1 Family• D1 and D5 receptors
• Poor correlation with antipsychotic activity
• D1 family may modulate effects of D2 family
D2 Family• D2, D3, D4 receptors
• High correlation with antipsychotic activity
• D4 is prominent in limbic structures, but absent from extrapyramidal pathways
• Atypical antipsychotics have high D4 affinity
![Page 8: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/8.jpg)
Clinical Efficacy and Dopamine D2 Blockade
Seeman P, Synapse 1987:1:133
IC50(M)
Average Clinical Dose (mg/d)
10-8
10-9
10-10
1 10 100 1000
Spiroperidol
Benperidol
Trifluperidol Pimozide
Fluphenazine Droperidol
Haloperidol Thiothixene
MoperoneMolindone
ProchlorperazineThioridazine
Clozapine ChlorpromazineTrazodone
Promazine
0.1
Trifluperazine
*
![Page 9: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/9.jpg)
1st Generation Antipsychotic: FGA’s (Conventional/Neuroleptics)
High Potency• Haloperidol (Haldol)• Fluphenazine (Prolixin)• Perphazine (Trilafon)• Thiothixine (Navane)
Low Potency• Chlorpromazine
(Thorazine)• Thioridazine (Mellaril)• Mesoridazine (Serentil)
*
![Page 10: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/10.jpg)
Dopamine and Antipsychotics
• 65% D2 receptor occupancy is required for efficacy
• 80% D2 receptor occupancy is correlated with EPS
• How can anti-psychotics hit this therapeutic window?• Typical vs. Atypical
Kapur S & Remington G, Biol Psychiatry 2001;50:873
*
![Page 11: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/11.jpg)
General Treatment CourseOnset of effect of Anti-psychotics
• IM: peak plasma level, ~ 30 min
• PO: peak plasma level, ~ 1-4 hrs
• bioavailability IM > PO• PO, incomplete GI absorption, 1st pass effect
• 90% protein bound; unbound passes through blood brain barrier
![Page 12: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/12.jpg)
Elimination Half-Times
Olanzapine
Quetiapine
Clozapine
Risperidone/Paliperidone
Ziprasidone
25 50 750Hours
Aripiprazole
![Page 13: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/13.jpg)
Dopamine Hypothesis
• Psychotic symptoms can be induced by DA agonists*• cocaine, amphetamines cause psychosis
• All anti-psychotics are DA antagonists• Antipsychotic’s clinical efficacy correlates w/ D2 blockade*• Normal subjects-10% DA receptors occupied at baseline**• Schizophrenic subjects-20% DA receptors occupied at baseline**
• ~30% pts no sig. response to anti-psychotic treatment• Glutamate system dysfunction also linked to schizophrenia
*Carlsson A, Am J Psychiatry 1978;135:164; Seeman P, Synapse 1987:1:133
**Laruelle M, Quart J Nuc Med 1998;42:211
![Page 14: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/14.jpg)
Dopamine D2 EffectsDopamine pathway
1. Nigrostriatal tract
2. Mesolimbic tract3. Mesocortical tract4. Tuberoinfundibular tract
Effects
1.EPS: Dystonia, parkinsonism, akathisia,Tardive dyskinesia
2. Antipsychotic effect3. Negative type symptoms?4. Endocrine changes:
Prolactin elevation, galactorrhea, gynecomastia, menstrual changes, sexual dysfunction
![Page 15: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/15.jpg)
Dopamine and Antipsychotics
• % of D2 receptors occupied by anti-psychotic effects efficacy alone or efficacy & EPS
• Shorter time of D2 receptor occupancy is correlated with lower EPS
Kapur S & Remington G, Biol Psychiatry 2001;50:873
*
![Page 16: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/16.jpg)
Efficacy of Antipsychotics
![Page 17: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/17.jpg)
FDA Approved Indications forAntipsychotic Medications
Adults• Schizophrenia (acute and maintenance)• Bipolar disorder (acute mania, maintenance,
bipolar depression)• Agitation associated with schizophrenia or bipolar
disorder
Children and Adolescents• Schizophrenia• Autism
*
![Page 18: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/18.jpg)
Risperidone for Short-term Treatment
0
20
40
60
80
100
0 2 4 6 8
Placebo
Risperidone 6 mg
Haloperidol 20 mg
Percent ofPatientsRemainingIn Study
Weeks
Marder SR & Meiback RC, Am J Psychiatry 1994;151:825
*
*p<0.002 vs Placebo**p<0.05 vs Risperidone
**
*
![Page 19: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/19.jpg)
Olanzapine for Prevention of Relapse
Days
*
0
20
40
60
80
100
0 20 40 60 80
Haloperidol
Olanzapine
% ofPatientsRemainingin Study
*p=0.06
Lieberman JA, et al. Am J Psychiatry 2003; 160:1396
*
![Page 20: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/20.jpg)
Haloperidol for Long-term Prevention of Relapse
0
20
40
60
80
100
0 5 10 15 20 25
PlaceboHaloperidol
Months
Percent ofPatientsRelapsed
Hogarty GE & Goldberg, SC, Arch Gen Psychiatry 1973;28:54
*
![Page 21: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/21.jpg)
Relationship between Medication Dose and Relapse
0
10
20
30
40
50
60
70
200 mg 50 mg 25 mg IntermittentDosing
% of Patients Relapsed
Dose Every 4 Weeks
1 Year of Haloperidol Decanoate Treatment
Davis JM, et al., J Clin Psychiatry 1993;54(Suppl):24
*
![Page 22: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/22.jpg)
Risperidone for Long-term Prevention of Relapse
0.0
0.2
0.4
0.6
0.8
1.0
0 200 400 600 800
RisperidoneHaloperidol
Days
Probability of RemainingRelapse Free
Csernansky JG, et al., NEJM 2002;346:16
*
![Page 23: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/23.jpg)
Neurocognitive Deficits
• Atypical antipsychotics have better cognitive profiles than conventional agents
• Atypical antipsychotics do not return cognitive functions to normal
• Neurocognitive benefits of atypical antipsychotics are of minor clinical significance
*
![Page 24: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/24.jpg)
Injectable Olanzapine for Acute Agitation
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
0 30 60 90 120
Placebo
Haloperidol 7.5 mg
Olanzapine 5 mg
Olanzapine 10 mg
Minutes
ChangeIn PANSSAgitationSubscale
Breier A, et al., Arch Gen Psychiatry 2002;59:441
**
*
*p<0.001 vs Placebo
Olanzapine vs Haloperidol not significant
*
![Page 25: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/25.jpg)
Oral Risperidone vs IM Haloperidol for Acute Agitation
-25
-20
-15
-10
-5
0
0 30 60
Haloperidol +LorazepamRisperidone +Lorazepam
Minutes
ChangeIn PANSSAgitationSubscale
Currier GW & Simpson GM, J Clin Psychiatry 2001;62:153
*
*
*p<0.0001 vs InitialPANSS scoreHaloperidol vs Risperidonenot significant
*
![Page 26: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/26.jpg)
Target Symptoms
• Active psychosis • most common reason for hospitalization
• most responsive to medications
• Negative symptoms • poor response to medication
• progress most rapidly during early acute phases of illness
*
![Page 27: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/27.jpg)
Target Symptoms
• Cognitive impairment• may be improved or worsened by medications
• Functional deterioration• Highly correlated with cognitive symptoms
• Moderately correlated with negative symptoms
• Occurs mostly during acute episodes, which can be prevented by medications
*
![Page 28: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/28.jpg)
Overview of Pharmacologic Treatment of Schizophrenia
Initial Medication Trial
![Page 29: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/29.jpg)
Pharmacologic Treatment of Schizophrenia
• Psychopharmacology algorithms help structure the knowledge base that pertains to decision making
• Dosing strategies should be informed by the pertinent evidence base
• Anti-psychotic choice should be influenced by the patient’s likely susceptibility to the common side effects
![Page 30: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/30.jpg)
Anti-psychotic Algorithm
• Stage 1: SGA (2nd generation antipsychotic)• Partial or non-response?
• Stage 2: different SGA or FGA• Partial or non-response?
• Stage 3: Clozapine trial• Stage 4: Clozapine + SGA or FGA• Stage 5: New FGA or SGA• Stage 6: 2 FGA’s, 2 SGA’s or FGA+SGA
*
![Page 31: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/31.jpg)
Anti-psychotic Algorithm
• Stage 1: SGA (2nd generation antipsychotic)• Partial or non-response?
• Stage 2: different SGA or FGA• Partial or non-response?
• Stage 3: Clozapine trial• Stage 4: Clozapine + SGA or FGA• Stage 5: New FGA or SGA• Stage 6: 2 FGA’s, 2 SGA’s or FGA+SGA
*
![Page 32: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/32.jpg)
Adequate Anti-psychotic Trial
• FGA or SGA generation antipsychotic• At least 4 weeks of therapeutic dose
• Full response? Continue dose• Partial response? Continue or → ↑ dose• No response → next step
• 4 more weeks (8 weeks) - repeat• 4 more weeks (12 weeks) - may repeat, but
should be able to decide
*
![Page 33: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/33.jpg)
Speed of Response
• Speed of response• Not well understood• Clinical effects begin in the first week
• half life about 20 hours, steady state 4-7 days
• If patient does not achieve a 25% reduction in symptoms in the first 2 weeks, outcome is likely to be poor at 4 weeks (Leucht S: J Clin Psychiatry 2007)
• More improvement occurs in the first two weeks than the second two weeks (Leucht S: Biol Psychiatry 2007)
![Page 34: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/34.jpg)
Adequate Anti-psychotic Trial
• First episode patients• Require lower antipsychotic dosing
• Tend to have greater sensitivity to side effects
*
![Page 35: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/35.jpg)
Anti-psychotic Algorithm
• Stage 1: SGA (2nd generation antipsychotic)• Partial or non-response?
• Stage 2: different SGA or FGA• Partial or non-response?
• Stage 3: Clozapine trial• Stage 4: Clozapine + SGA or FGA• Stage 5: New FGA or SGA• Stage 6: 2 FGA’s, 2 SGA’s or FGA+SGA
*
![Page 36: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/36.jpg)
Clozapine
• Requires more time• 1st 4 weeks-initial titration of clozapine• At least 12 weeks of therapeutic dose (16 weeks)
• Full response? Continue dose• Partial response → Assess serum level and adjust dose accordingly• No response → Assess serum level and adjust dose accordingly
• 12 more weeks (28 weeks) -• Full response? Continue dose• Partial response → Assess serum level and adjust dose accordingly or
consider next stage• No response → consider next stage
• Effective for 30-50% of treatment-refractory patients
![Page 37: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/37.jpg)
Clozapine for Long-term Treatment
Months
Conley RR, et al., Am J Psychiatry 1999;156:863
Percent ofPatientsRemainingDischarged
50
60
70
80
90
100
0 4 8 12 16 20 24
RisperidoneClozapine
95% CI:Clozapine 77-97Risperidone 52-80
*
![Page 38: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/38.jpg)
Prevention of Suicide
0
0.1
0.2
0.3
0.4
0 200 400 600 800
ClozapineOlanzapine
Days
Probabilityof SuicidalIdeation orAttempt
P=0.02
Meltzer HY, et al., Arch Gen Psychiatry 2003;60:82
*
![Page 39: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/39.jpg)
Clozapine
• Other considerations-when to use clozapine• Pts with recurrent suicidality or violence
• Pts with substance abuse
• Persistence of positive symptoms • if > 2 years-consider trial
• if > 5 years-almost have to justify not doing a trial
![Page 40: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/40.jpg)
Antipsychotic Medications
![Page 41: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/41.jpg)
The Evolution of Antipsychotic Medications
Adapted from Lieberman J, et al., APA Annual Meeting, May 2001
1900 '40s
Reserpine ChlorpromazineFGA
Low Potency
HaloperidolFGA
High PotencyFluphenzaineTrifluperazineThioridazinePerphenazine
Molindone LoxapineClozapine“Atypical”
RisperidoneOlanzapineQuetiapine
SGA
ZiprasidoneAripiprazolePaliperidone
SGA
Conventional, TypicalNeuroleptics, or
First Generation Antipsychotics“FGA’s”
AtypicalAntipsychotics
“AtypicalAtypicals”
2000'50s '60s '70s '80s '90s
Second Generation Antipsychotics“SGA’s”
![Page 42: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/42.jpg)
Conventional or 1st Generation (FGA’s) Antipsychotic Medications (Neuroleptics)
• Chlorpromazine (Thorazine) introduced in 1952; Several classes introduced in 1950s & 1960s
• Principal pharmacological activity: D2 blockade• Variable activity (side effects) at:
• H1 (histamine), M1 (muscarinic), & α1 (adrenergic) receptors
• High risk of Dopamine system side effects• EPS & Tardive Dyskinesia
*
![Page 43: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/43.jpg)
Conventional or 1st Generation (FGA’s) Antipsychotic Medications (Neuroleptics)
Low Potency
• Lower EPS risk-(dopamine system side effects)
• Stronger anticholinergic (muscarinic) effects
• Most common agents• Chlorpromazine (Thorazine)• Thioridazine (Mellaril)• Mesoridazine (Serentil)
*
![Page 44: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/44.jpg)
Conventional or 1st Generation (FGA’s) Antipsychotic Medications (Neuroleptics)
High Potency
• High EPS risk-(dopamine system side effects)
• Weaker anticholinergic effects
• Most common agents• Haloperidol (Haldol)• Fluphenazine (Prolixin)• Perphazine (Trilafon)• Thiothixine (Navane)
*
![Page 45: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/45.jpg)
Extrapyramidal Symptoms (EPS)
• Bradykinesia (slow movements)• Tremor• Stiff, rigid muscles
• Dystonia (muscle spasms)• Akathisia (subjective sense of restlessness)
*
![Page 46: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/46.jpg)
Extrapyramidal Symptoms (EPS)
• Akathisia (subjective sense of restlessness)• Common
• Prevalence ~20-30%• Most data obtained with FGA’s
• Occurs early in treatment course• Reversible, often treatment responsive
*
![Page 47: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/47.jpg)
Extrapyramidal Symptoms (EPS)
Treatment Options
• Reduce medication dose
• Slow down the rate of titration
• Consider alternative medication
• Adjunctive medication
*
![Page 48: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/48.jpg)
Extrapyramidal Symptoms (EPS)
Treatment – Adjunctive Medication• Anticholinergic
• Benztropine 1-2 mg bid-qid• Trihexyphenidyl 2-5 mg bid-qid
• Antihistamine• Diphenhydramine 25-50 mg bid-qid
• Dopaminergic• Amantadine 100 mg bid-tid
*
![Page 49: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/49.jpg)
Tardive Dyskinesia
• Adverse reaction to antipsychotic medications
• Irregular, choreoathetotic movements
• Chorea - irregular, spasmodic movements
• Athetosis - slow writhing movements
• May occur in any muscle group
• Most common in facial, oral, and truncal muscles
*
![Page 50: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/50.jpg)
Cumulative Incidence of TD with Conventional Antipsychotics
Kane JM, et al., J Clin Psychopharmacol 1988;8(4 Suppl):52SJeste D, et al., Am J Geriatric Psychiatry, 1999;7:70
6350
2915105
0
20
40
60
80
100
0 12 24 36Months
Perc
ent w
ith T
D
Older Adults
Young Adults
![Page 51: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/51.jpg)
Tardive Dyskinesia
Natural History
• May spontaneously improve, remain static, or worsen
• Static symptoms are most common
• Spontaneous improvement is least common
• About half of patients experience relief of symptoms within 3 months of antipsychotic discontinuation
*
![Page 52: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/52.jpg)
Tardive Dyskinesia
Acute Treatment
• Increase antipsychotic dose temporarily suppresses symptoms
• Benzodiazepine my bring about a modest reduction in symptoms
*
![Page 53: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/53.jpg)
Tardive Dyskinesia
Maintenance Treatment
• Reduce antipsychotic dose and time of exposure
• Clozapine (standard dose)
• 50% of patients show 50% reduction in movements
• Other treatments have not consistently been effective• Vitamin E Benzodiazepine
• Dopaminergic agents Branched-chain amino acids
*
![Page 54: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/54.jpg)
Extrapyramidal Symptoms (EPS)
Risk by class of medication
• High-potency conventional neuroleptic (20-40%)
• Low-potency conventional neuroleptic
• Paliperidone/Risperidone
• Aripiprazole/Olanzapine/Ziprasidone
• Quetiapine/Clozapine
Ris
k
*
![Page 55: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/55.jpg)
Tardive Dyskinesia
Risk by class of medication:
• High potency conventional neuroleptic (7%/yr)
• Low potency conventional neuroleptic (5%/yr)
• Paliperidone/Olanzapine/Risperidone/Ziprasidone (0.5%/yr)
• Quetiapine/Aripiprazole (uncertain)
• Clozapine (none reported)
Ris
k
*
![Page 56: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/56.jpg)
TD Incidence in Older Patients:Haloperidol versus Risperidone (1mg/d)
0
20
40
60
80
100
1 3 6 9
Haloperidol(n = 61)
Risperidone(n = 61)
Perc
ent w
ith T
D
* p < .05
Jeste DV, et al., J Am Geriatrics Soc 1999;47:716
Months
*
![Page 57: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/57.jpg)
Cumulative Incidence of Persistent TD With Quetiapine in Elderly Psychosis Patients
Jeste DV, et al., Am Assoc Geriatric Psychiatry poster, 2000
Quetiapinen=85
0
10
20
30
40
50
0 100 150 200 250 300 350 400
Days
% T
D In
cide
nce
![Page 58: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/58.jpg)
Tardive Dyskinesia
Age 20 Age 70Conventional Neuroleptic 5% 30%
Atypical Antipsychotic 0.5% 2.5-5%
Cumulative Annual Risk of Tardive Dyskinesia
Kane JM, et al., J Clin Psychopharmacol 1988;8:52S. Chakos MH, et al., Arch Gen Psychiatry 1996;53:313. Woerner MG, et al., Am J Psychiatry 1998;155:1521. Correll CU, et al., Am J Psychiatry 2004; 161:414. Glazer WM, J Clin Psychiatry 2000; 61 suppl 4:21.
*
![Page 59: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/59.jpg)
Conventional or 1st Generation (FGA’s) Antipsychotic Medications: High Potency
• Advantages• Injectable formulations (including IV)
• Depot formulations (Haldol & Prolixin)
• Inexpensive
• Disadvantages• High risk of Dopamine system side effects
• EPS & Tardive Dyskinesia
*
![Page 60: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/60.jpg)
Conventional or 1st Generation (FGA’s) Antipsychotic Medications: Low Potency
• Advantages• Highly sedating• Injectable formulations• Inexpensive
• Disadvantages• Highly sedating• Risk of qTc prolongation• Risk of tardive dyskinesia
*
![Page 61: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/61.jpg)
The Evolution of Antipsychotic Medications
Adapted from Lieberman J, et al., APA Annual Meeting, May 2001
1900 '40s
Reserpine ChlorpromazineFGA
Low Potency
HaloperidolFGA
High PotencyFluphenzaineTrifluperazineThioridazinePerphenazine
Molindone LoxapineClozapine“Atypical”
RisperidoneOlanzapineQuetiapine
SGA
ZiprasidoneAripiprazolePaliperidone
SGA
Conventional, TypicalNeuroleptics, or
First Generation Antipsychotics“FGA’s”
AtypicalAntipsychotics
“AtypicalAtypicals”
2000'50s '60s '70s '80s '90s
Second Generation Antipsychotics“SGA’s”
![Page 62: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/62.jpg)
Atypical Antipsychotics(Second Generation Antipsychotics-SGA’s)
• Developed on the basis of receptor activity in addition to D2 blockade
• Less Dopamine system side effects•Less EPS and Tardive Dyskinesia
• Broader spectrum of activity• Some benefit for negative & cognitive symptoms
• Beneficial for treatment-refractory patients (clozapine only)
*
![Page 63: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/63.jpg)
Atypical Antipsychotics-SGA‘s
• Aripiprazole (Abilify)• Risperidone (Risperdal)• Paliperidone (Invega)• Ziprasidone (Geodon)• Asenapine (Saphris)
• Quetiapine (Seroquel)• Olanzapine (Zyprexa)
• Clozapine (Clozaril) – Second-line use only
*
![Page 64: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/64.jpg)
Aripiprazole (Abilify)
• Advantages• Unique pharmacology (partial agonist)• Disintegrating tablet & injectable formulations• Long half-life• 15 mg superior to 30 mg; no advantage to ↑ dose• Minimal risk of metabolic syndrome
• Disadvantages• Unpredictable response when combined with dopamine
antagonists (what would you predict?)• Moderate-high cost• Akathesia
*
![Page 65: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/65.jpg)
Risperidone (Risperdal)
• Advantages• Extensive clinical experience• Liquid, disintegrating tablet, & depot preparations• Relatively low cost
• Disadvantages• Dopamine system side effects
• Dose-dependent EPS & Prolactin elevation
• Moderate risk of weight gain
*
![Page 66: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/66.jpg)
Paliperidone (Invega)
• Advantages• Does not require hepatic metabolism• Extended-release formulation: Invega Sustenna, monthly• 80% renally excreted; use in pts with liver disease
• Disadvantages• Dopamine system side effects
• Dose-dependent EPS & Prolactin elevation
• Moderate risk of weight gain• Avoid if pt has impaired renal clearance capacity• Limited clinical experience
*
![Page 67: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/67.jpg)
Ziprasidone (Geodon)
• Advantages• Low risk of weight gain or sexual dysfunction• Relatively low cost• Injectable formulation
• Disadvantages• Twice-daily dosing with meals• qTc prolongation
• Avoid if EKG shows qTc >500 milliseconds• Is pt on meds that may prolong qTc (TCA, quetiapine, thioridazine, foxacins)—
re-check EKG• Check pulse. Low pulse risks Torsades. Is pt on a drug that lowers pulse?
(Beta-blocker?)
*
![Page 68: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/68.jpg)
Quetiapine (Seroquel)
• Advantages• Lowest EPS risk• Sustained Release formulation-take once daily• Rapid onset of action• Sedating, but may cause insomnia
• Disadvantages• Longer dose titration (9 days to max dose?)• Moderate risk of weight gain• Moderate-high cost
*
![Page 69: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/69.jpg)
Olanzapine (Zyprexa)
• Advantages• Extensive clinical experience• Superior retention in maintenance treatment (CATIE)• Disintegrating tablet and injectable forms
• Disadvantages• High risk of weight gain and metabolic syndrome
• 30% pt ↑ >7% body weight• ↑ triglycerides, ↑ lipids, ↑ HgbA1C; ↑ risk diabetes
• Sedation• Liver irritation-be cautious in hepatitis pt or of pt on other meds
that irritate liver (statins, depakote, carbamazepine, naltrexone)• High cost
*
![Page 70: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/70.jpg)
Asenapine (Saphris)
• Advantages• New-will become clearer over time the benefits vs problems
with this medication• Disadvantages
• New!! Yet to learn from non-drug company studies.• Risk of dopamine system side effects
• EPS & TD• ↑ Prolactin• NMS
• Orthostasis, hypotension, syncope, QTc prolongation, • Weight gain
*
![Page 71: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/71.jpg)
Clozapine (Clozaril)
• Advantages• Effective for 30-50% of treatment-refractory patients
• Suicidal risks, substance problems
• Most effective for negative symptoms• Only proven treatment for TD
• Disadvantages• Risk of agranulocytosis• Weekly x 6 months, biweekly x 6 months, then monthly blood
draws• Unfavorable side effect profile
*
![Page 72: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/72.jpg)
Depot Antipsychotics
• FGA’s• Haloperidol (Haldol) decanoate
• Fluphenazine (Prolixin) decanoate
• SGA’s• Risperidone depot (Risperdal Consta)
• paliperidone palmitate (Invega Sustenna)
• So far no evidence of better efficacy or safety than the FGA depot antipsychotics
*
![Page 73: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/73.jpg)
Depot Antipsychotics
• Advantages• Ensured compliance
• Underutilized in the US. Many pts are not as compliant as we think and do better with Depot
• Lower total doses compared with oral medication may reduce side effects
• Disadvantages• Poor patient acceptance
• Minimal flexibility in dosing
*
![Page 74: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/74.jpg)
Side Effects
Common: EPS, Tardive Dyskinesia; Metabolic Syndrome
Uncommon but Serious: qTc; Increased Mortality in Elderly; NMS
![Page 75: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/75.jpg)
Metabolic Syndrome
• Weight gain• Type 2 diabetes• Elevated LDL
cholesterol
• Elevated triglycerides• Decreased HDL
cholesterol• Diabetic ketoacidosis
Use of atypical antipsychotics is associated with metabolic dysregulation
*
![Page 76: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/76.jpg)
Metabolic Syndrome
• Prevalence of obesity and diabetes in patients with schizophrenia is 1.5-2.0 times higher than the general population
• No studies on obesity and diabetes in drug-naïve schizophrenia patients are available
*
![Page 77: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/77.jpg)
Risk of Metabolic Complications
Relative risk of medications
• Clozapine/Olanzapine/Low Potency FGA Neuroleptics
• Paliperidone/Quetiapine/Risperidone/High Potency FGA Neuroleptics
• Aripiprazole/Ziprasidone
Ris
k
*
![Page 78: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/78.jpg)
76543210
-1-2-395
% C
onfid
ence
Inte
rval
for W
eigh
t Cha
nge
Meta-analysis of Antipsychotic-related Weight GainEstimate at 10 Weeksa
Allison DB, et al., Am J Psychiatry 1999;156:1686
Weight (kg)
a Quetiapine weight gain estimated at 6 weeks
15
10
5
0
-5
Weight (lb)
*
![Page 79: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/79.jpg)
Metabolic Syndrome
ADA et al., Diabetes Care 2004; 27:596
Baseline 4 wks 8 wks 12 wks Quarterly Annual 5 yrs
Personal/family history X
X
Weight (BMI) X X X X X
Waist Circumference X X
Blood pressure X X X
Fasting plasma glucose X X X
Fasting lipid profile X X
X
Recommended monitoring for patients on atypical antipsychotics
*
![Page 80: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/80.jpg)
Cardiovascular Adverse Events
• FGA low potency drugs thioridazine (Mellaril) & mesoridazine (Stelazine) are associated with qTc prolongation & increased risk of cardiac death
• Ziprasidone carries a “bold” warning regarding qTc prolongation & associated cardiac risk, but no increased incidence of cardiac mortality or morbidity has been detected with ziprasidone
*
![Page 81: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/81.jpg)
Increased Mortality
• All atypical antipsychotics carry a “black box” warning of increased mortality in elderly patients with dementia-related psychosis
• Risk is comparable among all conventional and atypical antipsychotics
*
![Page 82: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/82.jpg)
Increased Mortality
Mortality Odds Ratio
Controls 2.3%
SGA’s 3.5% 1.54
FGA-Haldol 3.9% 1.68
Schneider LS, et al., JAMA 2005; 294:1934
Meta-analysis of 15 studies of risk of FGA & SGA in elderly patients
*
![Page 83: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/83.jpg)
Increased Mortality
Retrospective study of mortality in 22,890 elderly patients receiving antipsychotics
• Higher risk with FGA antipsychotics OR = 1.37
• Higher risk with recent initiation of medicine
• Higher risk with higher doses
Wang PS, et al., N Engl J Med 2005; 353:2335
*
![Page 84: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/84.jpg)
Side Effects - Overview
EPS Prolactin Elevation
Anticholinergic Symptoms
(Muscarinic)
Orthostatic Hypotension(Adrenergic)
Aripiprazole +/- +/- +/- +/-
Clozapine 0 +/- +++ +++High-potencyFGA +++ ++ +/- +
Low-potency FGA ++ ++ +++ +++
Olanzapine +/- +/- + +/-
Quetiapine +/- +/- ++ ++
Risperidone + ++ +/- +
Paliperidone + ++ +/- +
Ziprasidone +/- +/- +/- +/-
*
![Page 85: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/85.jpg)
Side Effects - Overview
qTc ProlongationSedation
(Histamine) Weight Gain*Aripiprazole +/- +/- +/-Clozapine + +++ +++High-potency FGA +/- + +
Low-potency FGA ++ +++ +++
Olanzapine +/- ++ +++
Quetiapine +/- +++ ++
Risperidone +/- + ++
Paliperidone +/- + ++
Ziprasidone + +/- +/-
*ADA et al., Diabetes Care 2004;27:596
*
![Page 86: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/86.jpg)
Neuroleptic Malignant Syndrome
• Incidence 0.2%• Estimated by combining data from published studies
• Dx criteria• D2-blockers use in past 30 days
• 1 of 6 develop NMS within 24 hours of D2 exposure
• 4 of 6 within 1 week
• Nearly all within 30 days
![Page 87: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/87.jpg)
D2-blockers
• Typical anti-psychotics
• Atypical anti-psychotics
• Anti-emetics:
• Pro-peristaltic agents:
• Anesthetics:
• Sedatives:
Prochlorperazine (Compazine)
Metocloperamide (Reglan)
Droperidol (Innovar)
Promethizine (Phenergan)
![Page 88: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/88.jpg)
NMS Dx Criteria
1. D2-blockers
2. Hyperthermia
3. Muscle rigidity
4. 5 of the 9 following symptoms
5. R/O other hyperthermia causes
No use in past 30 days
> 38 C
↑HR, ↑ & ↓ BP, ↑RR/hypoxia,
↑CPK, metabolic acidosis, tremor,
incontinence, ↑ WBC,
diaphoresis/sialorrhea,
![Page 89: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/89.jpg)
Neuroleptic Malignant Syndrome
• Treatment• Stop d2-blocker
• Supportive treatment-iv fluids, anti-pyretic, monitoring
• No consensus on other treatment options• Lorazepam (Ativan)-useful in reversing catatonia
• Amantadine (Symmetrel)-may release dopamine from terminals
• Bromocriptine (Parlodel)- d2-agonist
• Dantrolene (Dantrium)-causes direct muscle relaxation
• ECT
![Page 90: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/90.jpg)
NMS Dx Criteria
• Mortality rate• Once 20-30%, now estimated at 5-12%
• Good prognosis, especially if • No rhabdomyolysis, renal failure, or aspiration pneumonia
• Post NMS• 30% risk of recurrent NMS with restarting d2-blocker,
but most patients can be safely restarted with precautions
![Page 91: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/91.jpg)
Antipsychotic Treatment SelectionSummary
![Page 92: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/92.jpg)
Treatment Selection with SGA’s
• All first-line SGA’s are effective against psychotic symptoms
• All first-line SGA’s are equally well tolerated in large studies
• Each medication has unique side effects• Each medication has unique pharmacokinetics• Individual patients may respond preferentially to the
medications
*
![Page 93: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/93.jpg)
Treatment Recommendations
• Continuous, full-dose antipsychotic treatment is the key to good outcome in schizophrenia
• “Lowest effective dose” strategies are associated with higher relapse rates and poorer outcomes
*
![Page 94: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/94.jpg)
Antipsychotic Augmentation Strategies
• Augmentation strategies have generally shown modest results
• No one strategy is generally accepted• Mood stabilizers• Benzodiazepines• Antidepressants• Antipsychotic combinations• ECT
APA Practice Guideline, Am J Psychiatry 2004;161 (2:suppl):1
![Page 95: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/95.jpg)
Antipsychotic Combinations
• 20-25% of patients receive more than one antipsychotic• Few data are available on efficacy & safety of
antipsychotic combinations• Anecdotal accounts of specific combinations have not
been supported by formal studies• Pharmacologic justification is weak• Side effects tend to be additive• Costs are always additive
![Page 96: Current Biological Treatments of Schizophrenia• Background about Schizophrenia • Dopamine Hypothesis • Dopamine Pathways • Efficacy of Anti -psychotics • Treats agitation](https://reader030.vdocuments.us/reader030/viewer/2022040718/5e258d4fde2aeb6fcf48e898/html5/thumbnails/96.jpg)
Relative Costs of Atypical Antipsychotic Medications
Annual Cost at Midrange Doses$2000 $4000 $6000 $8000 $10000
Risperidone
Aripiprazole
Ziprasidone
Quetiapine
RisperidoneDepot
Clozapine
Olanzapine