Psychotropics in Psychiatric Patient - Psychotic disorders: Pharmacology and Clinical Applications of Antipsychotics

1
Psychotropics in Psychiatric Patient - Psychotic
disordersPharmacology and Clinical
Applications of Antipsychotics

• Pongsatorn Meesawatsom
• B. Pharm., M.Sc. (Pharmacology)
• Faculty of Pharmacy
• Srinakarinwirote University

2
Characteristics of schizophrenia

• Prevalence 0.51.0 of population
• Onset
• Positive features in late adolescence or early
  adulthood
• Aspects of cognitive deficits detectable earlier
  in life
• Comorbidity
• Depression 3050
• Substance abuse 50
• Suicide 510

3
Schizophrenia A Disease with Various Aspects
Negative Symptoms Affective flattening Alogia Avol
ition Anhedonia Social withdrawal
Positive Symptoms Delusions Hallucinations Disorga
nized speech Catatonia
Social/Occupational Dysfunction Work Interpersonal
relationships Self-care
Mood Symptoms Depression Anxiety Aggression Hostil
ity Hopelessness Suicidality
Cognitive Deficits Attention Memory Executive
functions (e.g., abstraction)
4
Inter-relationship between disease factors and
drug-induced adverse factors in the burden of
schizophrenia
Adverse effect of antipsychotic drugs

• Other effects
• Anticholinergic
• Prolactin elevation
• QTc prolongation

Risk of hyperglycemia/ diabetes
Extrapyramidal symptoms
Sedation
Weight gain
Tardive dyskinesia
Dysphoria
Drug-induced factors
Disease factors
Suicidality
Negative symptoms
Cognitive symptoms
Positive symptoms
Depression/Anxiety
Diverse symptoms of schizophrenia
Int Clin Psychopharmacol 2005, 20183198.
5
Treatment Goal of Schizophrenia
Acute Phase Treatment
Stabilization Phase Treatment
Maintenance Phase Treatment

• Rapid symptom control

• Patient relationship
• Insight on medication

• Relapse/recurrence prevention
• Adherence
• Functional recovery

• Initiation of therapeutically effective dose
• No need for initial dose titration for
  tolerability

• Minimal drug-drug interaction
• Proven efficacy and safety

• Increased tolerance to occasional missed doses
• Proven relapse prevention effect
• Improved PSP

6
Factors affecting antipsychotic response
Receptor pharmacology (binding capacity)
Pharmacogenetics (CYP450)
Pharmacokinetics
Patient variables
Comorbid condition/ polypharmacy
7
The Dopamine hypothesis of psychosis

• Overactivity of dopamine neurons in the
  mesolimbic dopamine pathway may mediate the
  positive symptoms
• Dopamine hypocactivity in mesocortical dopamine
  pathway may mediate the negative and cognitive
  symptoms
• Dorsolateral prefrontal cortex negative,
  cognitive symptoms
• Ventromedial prefrontal cortex negative,
  affective symptoms

8
Brain dopaminergic tracts
2
3
1
4
5 CTZ
6 Lateral hypothalamus
9
Simplify Neurocircuitry of Dopamine in
Schizophrenia
Mesolimbic pathway Hyperdopaminergia
Mesocortical pathway Hypodopaminergia
DA
DA
Limbic
PFCx
D2
D1
Negative symptoms Cognitive symptoms Affective
symptoms
Positive symptoms
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Antipsychotic Drugs Development Timeline

• Minimal efficacy with regard to positive symptoms
  in 20-30 of patients
• Much weaker effect on negative symptoms than
  positive symptoms
• Significant parkinsonian symptoms and
  anticholinergic effects (poor compliance and
  potentially disabling)
• Tardive dyskinesia in a minimum of 20 of
  patients who receive chronic neuroleptic
  treatment.

• At least as effective as typical neuroleptics
  with regard to positive symptoms
• More effective than typical agents with regard to
  negative symptoms
• Much lower incidence of parkinsonian symptoms and
  anticholinergic effects than typical agents
• TD does occur but at much lower incidence
• Elevated risk of metabolic side effects

11
Therapeutic effects from D2 receptor blockade

• Amelioration of the positive signs, symptoms of
  psychosis, manic symptoms, aggressive behaviors
• Antiemetic effect

Modified J Clin Psychiatry 199960(suppl 10)514.
12
Adverse effects from D2 receptor blockade

• Extrapyramidal symptom (EPS)
• Acute akathisia, acute dystonia, parkinsonism
• Late tardive dyskinesia
• Endocrine effects prolactin elevation
• Weight gain due to increase feeding

Modified J Clin Psychiatry 199960(suppl 10)514.
13
Binding affinities of chlorpromazine and
haloperidol for various receptor
J Psychiatr Pract 20051125861.
14
Higher potency Higher EPS Lower anticholinergic
effect
Lower potency Low EPS Higher anticholinergic
effect
Haloperidol
Chlorpromazine
Fluphenazine
Thioridazine
Trifluoperazine
Thioxanthine
Mesoridazine
Perphenazine
Pimozide
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Rational explanations for SDA therapeutic effects

• Therapeutic effects
• D2-receptor blockade in the mesolimbic pathway to
  reduce positive symptoms
• Enhanced dopamine release and 5-HT2A receptor
  blockade in the mesocortical pathway to reduce
  negative symptoms
• Side-effect profile
• 5-HT2A antagonism in the nigrostriatal pathway
  reduces EPS and tardive dyskinesia
• 5-HT2A antagonism in the tuberoinfundibular
  pathway reduces hyperprolactinemia

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Role of 5-HT in Nigrostriatal Dopaminergic Synapse
Raphe
Sunstantia nigra pars compacta
Nigrostriatal tract
5-HT
5-HTT
-
5-HT2A
DA
D2
D1
Caudate/putamen
Normal function
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Role of 5-HT in Nigrostriatal Dopaminergic Synapse
Raphe
Sunstantia nigra pars compacta
Nigrostriatal tract
5-HT
5-HTT
-
5-HT2A
DA
Haloperidol
D2
D1
Caudate/putamen
EPS
18
Role of 5-HT in Nigrostriatal Dopaminergic Synapse
Raphe
Sunstantia nigra pars compacta
Nigrostriatal tract
5-HT
5-HTT
-
5-HT2A
DA
SDA
D2
D1
Caudate/putamen
Less EPS
19
Receptor affinities of selected atypical
antipsychotics
All values are reported as Ki (nM).
Modified from Clin Ther 200426649-66
20
Effects of blockade of neuroreceptors
Modified from J Clin Psychiatry
200869suppl426-36.
21
Effects of blockade of neuroreceptors
Modified from J Clin Psychiatry
200869suppl426-36.
22
Effects of blockade of neuroreceptors
Modified from J Clin Psychiatry
200869suppl426-36.
23
Impact of receptor binding affinity on clinical
responses of antipsychotics
24
Receptor affinities of selected atypical
antipsychotics Potential risk
All values are reported as Ki (nM).
Modified from Clin Ther 200426649-66
25
Receptor affinities of selected atypical
antipsychotics Potential Benefit
All values are reported as Ki (nM).
Modified from Clin Ther 200426649-66
26
Aripiprazole Activity at Cloned Human D2 Receptors
100
50
Maximum DA Response ()
0
10-10 10-9 10-8 10-7 10-6 10-5
Drug Concentration
Receptor activity measured as inhibition of
forskolin-induced cAMP accumulation in CHO cells
transfected with human D2L DNA. Adapted from
Burris et al. J Pharmacol Exp Ther. 2002302381.
27
Paliperidone vs Risperidone

• Paliperidone is active metabolite of risperidone
  via metabolism by CYP2D6.
• High affinity for D2, 5-HT2A, ?1 and ?2 receptors
• Very low affinity for M1 as same as as
  risperidone

Expert Opin Drug Saf. 2007 6(6)651-62.
28
Pharmacokinetics differences of risperidone and
paliperidone
29
Adverse Effect Profile of Antipsychotics
30
Shift in Risk Perception of Antipsychotics
Past Areas of Concern
Current Medical Realities
Diabetes
TD
Weight Gain
Prolactin
Tardive Dyskinesia
Hyperlipidemia
Insulin Resistance
Sedation
Weight Gain
Insulin Resistance
Hyper- lipidemia
Coronary Heart Disease
Sedation
CHD
Prolactin
31
D2 Blocking-related Side Effects
32
Spectrum of EPS
Acute onset
Late onset
33
Acute dystonia
34
Relationship between clinical effectiveness, EPS
and D2 receptor occupancy
Threshold for EPS
80
Threshold for antipsychotic efficacy
35
(No Transcript)
36
Medication used to treat EPS
Am J Health-Sys Pharm 1997542461-77.
37
Association of medication, target dose, and
likelihood of treatment-emergent EPS
J Psychiatric Pract 2007131324.
38
Tardive dyskinesia (TD)

• TD is a latent extrapyramidal effect generally
  not occurring for months or years, occur in 20
  patient treated with antipsychotic.
• It is characterized by abnormal movements that
  can occur in any part of the body, including
  faces, tongue, shoulders, hips, extremities,
  fingers, and toes

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Prominent Feature of TD

• Lingual-facial hyperkinesias
• Chewing movements
• Smacking and licking of the lips
• Sucking movements
• Tongue movements within the oral cavity
• Tongue protrusion
• Tongue tremor with mouth open
• Myokemic movements (worm-like movement on the
  surface of the tongue)
• Blinking
• Grotesque grimaces and spastic facial distortions

• Neck and trunk movements
• Spasmodic torticollis
• Retrocollis
• Torsion movements of the trunk
• Axial hyperkinesia (hip-rocking)
• Choreoathetoid movements of the extremities

40
Neuroleptic malignant syndrome

• NMS is an uncommon but serious and potentially
  fatal complication of therapy
• It is a syndrome of EPS, hyperthermia, altered
  consciousness, and autonomic changes
  (tachycardia, unstable BP, incontinence)
• Management
• Discontinuation of the antipsychotic agents
• Supportive therapy
• Bromocriptine may be benificial
• The onset is sudden and recovery may take 5-10
  days after discontinuation of the agent

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Simplified Pathophysiology of Neuroleptic
Malignant Syndrome (NMS)
Am J Psychiatry 2007164870-876.
42
Spectrum-based concept of NMS
J Am Acad Child Adolesc Psychiatry 19923111614.
43
Proposed Treatment Algorithm for NMS
Spectrum-Related Symptoms
Am J Psychiatry 2007164870-876.
44
Hyperprolactinemia possible signs and symptoms
Osteoporosis
J Clin Psychopharmacol 200727639661.
45
Mean Plasma Prolactin Level Changes Over 24 Hours
in 18 Patients After Taking Clozapine,
Olanzapine, or Risperidone and in Five of the
Same Patients After Not Taking the Drugs
Am J Psychiatry 2002 159133135
46
Effects of Antipsychotics on Prolactin Levels
J Clin Psychopharmacol 200727639661.
47
Sedation
48
Receptor blocking properties that affect arousal
and sleep stages

• Blocking of H1 ? sedation
• Blocking of M1 ? sedation, REM sleep
  interference
• Blocking of ?1, ?2, 5-HT2A promote cholinergic
  pedunculopontine (PPT) and laterodorsal tegmental
  nuclei (LDT) firing ? REM sleep improvement

49
Receptor affinities of selected atypical
antipsychotics
All values are reported as Ki (nM).
Clin Ther 200426649-66
50
SGAs and sedation
J Clin Psychiatry 200869 Suppl 118-31.
51
Obesity and metabolic syndromes
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Clinical issues of weight gain and antipsychotics

• Not everyone gains weight
• Difficult to predict who will have weight gain
• Multifactorial etiology
• Not dose related ADR.
• Start in first few weeks
• Reach plateau between 3 months to 1 year

53
Mean weight gain during treatment
withantipsychotic drugs.
CNS Drugs 2005 19 (Suppl. 1) 193.
54
Mechanisms of antipsychotic-induced weight gain
and metabolic abnormalities

• Interfere feeding behavior by blocking many
  neuroreceptor
• Feeding center
• Lateral hypothalamus (DA ? D2)
• Ventromedial hypothalamus (5-HT?? 5-HT2A, 5-HT2C)
• Satiety center
• Paraventricular nuclei (NE ? ?1, ?, Histamine ?
  H1)
• Interfere pancreatic insulin release
• Pancreas (ACh ? M3 )

55
Olanzapine
Clozapine
Atropine
Ziprasidone
Risperidone
Haloperidol
Diabetes 2005 5415521558.
56
Receptor affinities of selected atypical
antipsychotics
All values are reported as Ki (nM).
Clin Ther 200426649-66
57
Olanzapine-Associated Weight Gain Plateaus After
First 39 Weeks of Treatment
LOCF Median 2.5 Years
Weight gain by olanzapine is not dose dependent
(5-20 mg dose range).
Mean Weight Change (kg) up to 3 years
Patients Observed for 39 Weeks or
MoreDouble-blind and open-label olanzapine.
Week
Kinon BJ, et al. J Clin Psychiatry 20016292-100
58
Why Less weight gain in quetiapine, ziprasidone
and aripiprazole?

• Quetiapine
• Norquetiapine inhibit norepinephrine reuptake
  transporter
• Aripiprazole
• Low affinity H1, 5-HT2C
• Partial D2 agonist

• Ziprasidone
• Moderate affinity for a1
• Low affinity H1
• Full 5-HT1A agonist
• Inhibit 5-HT/NA reuptake transporter

59
SGAs and metabolic abnormalities
Clin Psy 200768(Suppl 7)27-33.
60
Monitoring protocol for patients on SDAs
Diabetes Care 2004 27(2) 596-601.
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Other Adverse effects

• QTC interval prolongation
• Thioridazine, ziprasidone
• Agranulocytosis
• Clozapine
• Epileptogenic
• Clozapine
• Retinitis pigmentosa
• Thioridazine gt 800 mg/day

62
Incidence of categorical increases in QTc (Bazett
correction)
There is a consensus that a QTc interval of
gt500ms, or an absolute in-crease of 60ms compared
with drug-free baseline, puts a patient at
significant risk of torsade depointes,
ventricular fibrillation and sudden death
63
Clozapine safety issues

• Clozapine is one of the atypical agents that is
  EPS/TD free, as same as quetiapine
• However, clozapine is still reserved as last-line
  therapy because of its increased incidence of
  agranulocytosis, myocarditis/cardiomyopathy, and
  convulsion and the need for frequent monitoring

64
Clozapine safety issues

• Seizure risk
• 1-2 and increase to 3-5 if dose is greater than
  600 mg/day.

• Agranulocytosis
• ??1 in general
• 95 cases in first 6 m, peak in 4-18 week ? CBC
  weekly

65
Management of clozapine-induced agranulocytosis

• US
• New patients weekly blood counts
• Twice weekly monitoring WBC 3000-3500 and ANC
  gt1500
• Temporary discontinuation WBC 2000-3000 and/or
  ANC 1000-1500
• Permanent discontinuation WBC lt2000 and/or ANC
  lt1000
• gt 6 months monitor once every two weeks

• UK
• New patients weekly blood counts
• Weekly monitoring WBC 3000-3500 and/or
  ANC1500-2000
• Discontinue WBC lt3000 and/or ANC 1500
• Weeks 19-52 at least every 2 weeks
• gt 52 weeks monitor at least monthly thereafter

66
Contribution of CYP450 in atypical antipsychotic
drug metabolism
67
(No Transcript)
68
Dose-response curve for extrapyramidal adverse
effects with risperidone
Dose-response curve for seizure risk with
clozapine
J Psychiatric Pract 200511116-122.
69
Acute treatment of psychoticpatients

• Injectable, conventional agents are typically
  used such as haloperidol 5-10 mg IM or
  zuclopenthixol acetate 50150mg
• It may be given every hour until
• Acute symptoms are controlled
• Side effects occur
• Patient falls asleep
• Once control has been obtained, the patient can
  be converted to oral therapy

70
Selection of antipsychotic agents

• Based on the patients history and safety profile
  of the available agents
• Newly diagnosed patients, the APA suggest
  initiating therapy with atypical agent (SGAs)
  because of these agentsimprove safety profile

71
Monitoring of first episode

• Less disturbed sleep patterns and decreased anger
  and anxiety should be observed within the first
  day or two of treatment, with gradual improvement
  in other symptoms in the first week and
  near-maximal effects in six to eight weeks
• Lack of improvement in the first one to four
  weeks should prompt an increase in the dose,
  followed by a change to another drug, usually
  clozapine or another second-generation drug after
  an additional four to six weeks, if the response
  remains inadequate

N Eng J Med 20033491738-49.
72
Monitoring of early adverse effects

• It appears within days to weeks of starting the
  antipsychotic dose
• It maybe transient and time limited (it will be
  disappear after the first month of treatment)

J Clin Psy 200768(Suppl 7)34-43.
73
Initial dose and titrationschedule for a
firstepisode
J Clin Psy 200768(Suppl 7)3443.
74
Strategies for managing side effects in stable
patients
J Clin Psy 200768(Suppl 7)34-43.
75
Medical Issues in Schizophrenia
Meyer JM and Nasrallah H eds. Medical Illness and
Schizophrenia. APPI 2003 Regenold WT, et al.
Increased prevalence of type 2 diabetes mellitus
among psychiatric inpatients with bipolar I
affective and schizoaffective disorders
independent of psychotropic drug use. Journal of
Affective Disorders. 2002 Jun70(1)19-26
76
Medical conditions that may influence
antipsychotic treatment dicisions
77
Antipsychotics switching

• Avoid if possible
• Consider in
• Not responing patient with adequate trial
• Not able to tolerate
• Non-compliance (switch to depot preparation)
• Significant long term risk with current
  medication
• Obesity, TD, persistent cognitive deficit, CVS
  problems, DDI
• Patient/family member request

78
Switching techniques for antipsychotics
CNS Drugs 2005 19 (1) 27-42
79
Dopaminergic considerations

• Cross switching of 2 high potency D2 antagonist
  may increase EPS risk.

J Clin Psy 200768(Suppl 7)109.
80
Dopaminergic considerations

• Prolong exposure of high potency D2 antagonist
  results in D2 supersensitivity
• Switching D2 antagonist from higher potency to
  lower potency or D2 partial agonist
• May lead to switch-emergent dopamine psychosis.
• Improvement in prolactin-related side effects
  such as galactorrhea, amenorrhea and sexual
  dysfunction and EPS

81
Muscarinic considerations

• There is a potential that patient who have been
  maintained on anticholinergic antipsychotics to
  develop cholinergic supersensitivity.
• Nausea, vomiting and insomnia may occur when
  anticholinergic drugs is withdrawn or switched to
  less potent anticholinergic drugs.

82
Muscarinic considerations

• If patient is being changed because of EPS in
  which an anticholinergic agents was initiated,
  the patient can remain on the anticholinergic
  agent until the cross taper and titrated is
  completed
• Exception in the case of clozapine being added as
  the new therapy, the anticholinergic drugs should
  be discontinued when the cross taper and
  titration begins

83
Estimated side effects after switching
J Clin Psy 200869(Suppl 1)4-17.
84
Conclusions

• Antipsychotics are not uniform drug class which
  different in their pharmacological profile,
  efficacy and ADRs.
• Adherence of treatment should be enhanced by
  various strategies e.g.
• Counseling
• Awareness of DDI
• ADR monitoring and management