Schizophrenia pharmacotherapy semina.ppt

Clinical

1. SCHIZOPHRENIASCHIZOPHRENIA

2. Schizophrenia
◦Is a chronic heterogeneous syndrome of
disorganized and bizarre thoughts,
delusions,
hallucinations,
inappropriate affect,
cognitive deficits, and
impaired psychosocial functioning

3. Epidemiology Epidemiology
Lifetime prevalence of schizophrenia ranges from 0.6% to
1.9%, with an average of approximately 1%.
The worldwide prevalence of schizophrenia is remarkably
similar among all cultures.
Although the prevalence of schizophrenia is equal in males
and females, the onset of illness tends to be earlier in males
◦Males most frequently have their first episode during their
early twenties,
◦Females it is usually during their late twenties to early
thirties

4. schizophrenia
positive
symptoms
negative
symptoms
anx/dep
aggressive
symptoms
cognitive
symptoms

5. Positive Symptoms of SchizophreniaPositive Symptoms of Schizophrenia
Delusions
Hallucinations
Disorganized Speech
Disorganized or catatonic or agitated
behavior

6. –Delusions:
•Persecutory: False belief that one’s self or others are
being persecuted, watched or conspired against by
others.
•Delusion of control: False belief that ones thoughts,
feelings or behaviors are controlled by an outside
force.
•Delusions of guilt or sin: False belief that one has
committed a terrible act.
•Somatic delusions: False belief that ones appearance
or part of one’s body is diseased or altered.
•Grandiose delusions : False belief that one has
“special” power or that “supernatural knowledge”
etc.

7. Hallucinations:Hallucinations:
▪Auditory hallucinations:Auditory hallucinations: the patient the patient
experiences hearing voices from outside experiences hearing voices from outside
which will tell him to “do certain things” which will tell him to “do certain things”
or two or more voices talking among each or two or more voices talking among each
other commenting about the patient.other commenting about the patient.
▪Visual hallucinations: It is rare in functional
psychoses like schizophrenia, however
some schizophrenics do experience
“seeing things” which are not there.

8. ◦Thought disorder:
Looseness of association
Incoherence ( word salad )
Neologisms
Lack of abstraction
Echolalia

9. positive
symptoms
psychotic
depression
bipolar
childhood
psychotic
illnesses
schizo-
affective
Alzheimer’s

10. Cognitive symptomsCognitive symptoms
Impaired attention & impaired information
processing
Impaired verbal fluency(finding words to express
your thoughts and feelings- Semantic memory)
Problems with serial learning
Impairment in vigilance for executive functioning (
decision making; mental flexibility)
Impaired working and secondary (storage)
memory

11. schizophrenia
Alzheimer’s
autism
post
stroke
cognitive symptoms

12. Negative SymptomsNegative Symptoms
Affective flattening
Alogia (Inability to use or understand
language)
Avolition (restrictions in initiation of goal-
directed behavior)
Anhedonia (inability to experience
pleasure)
Attentional impairment

13. negative
symptoms
1 deficit
2 to
environmental
deprivation
2 to positive
symptoms
2 to EPS
2 to
depression

14. Aggressive SymptomsAggressive Symptoms
Overt hostility
Self-injurious behavior
Sexual acting out
Suicide
Arson or other property damage

15. bipolar
ADHD/
conduct
disorder
borderline
personality
disorder
childhood
psychosisschizophrenia
Alzheimer &
dementias
aggressive
symptoms

16. Depressive & Anxious SymptomsDepressive & Anxious Symptoms
Depressed mood
Anxious mood
Guilty feeling
Tension
Irritability
Worry

17. bipolar
treatment
resistant
psychotic
depression
organic
major
depression
child
schizophrenia/
schizoaffective
Depression

18. The stages of SchizophreniaThe stages of Schizophrenia
The patient has full functioning (100%) early in life and is
virtually asymptomatic (stage I).
During a prodromal phase (stage II) starting in the teens,
there may be odd behaviors and subtle negative
symptoms
The acute phase of the illness usually announces itself
fairly dramatically in the twenties (stage III) with positive
symptoms, remissions, and relapses
The final phase of the illness (stage IV) may begin in the
forties or later, with prominent negative and cognitive
symptoms and some waxing & waning during its course,
but more of a burnout stage of continuing disability.

19. 100%
50%
0
15 20 40 60
AGE

20. Pathophysiology Pathophysiology
Dopaminergic hypothesis
◦Psychosis may result from hyper- or hypoactivity of
dopaminergic processes in specific brain regions
Glutamatergic dysfunction.
◦A deficiency of glutamatergic activity produces symptoms
similar to those of dopaminergic hyperactivity and
possibly symptoms seen in schizophrenia.
Serotonin (5-HT) abnormalities
◦Schizophrenic patients with abnormal brain scans have
higher whole blood 5-HT concentrations

21. poorly innervated
poor neuronal migration
inadequate synapse
selection, especially
before the age of 6
toxic or genetic insult
dysfunction
death
Neurodevelopmental Hypothesis of Schizophrenia

22. normal DNA
normal DNA
10-15
Stahl S M, Essential
Psychopharmacology (2000)

23. abnormal
DNA
abnormal
DNA
Stahl S M, Essential
Psychopharmacology (2000)
An abnormality in the
DNA of a
schizophrenia
Patient may cause
the Wrong synaptic
Connections.

24. Dopamine Pathways and the Dopamine Pathways and the
biological basis of Schizophreniabiological basis of Schizophrenia
The Mesolimbic Pathway
The Mesocortical pathway
The Nigrostriatal Pathway
The Tubero infundibular Pathway

25. hypothalamus
d
c
Nucleus
accumbens
Tegmentum
b
Substantia
nigra
Basal
Ganglia
a
DOPAMINE PATHWAYS
10-7

26. The Mesolimbic Dopamine PathwayThe Mesolimbic Dopamine Pathway
It projects from dopaminergic cell bodies in the ventral
tegmental area of the brainstem to axon terminals in
limbic areas of the brain, such as the nucleus accumbens.
It is thought to have an important role in emotional
behaviors.
Hyperactivity of the mesolimbic dopamine pathway
hypothetically accounts for positive symptoms of
schizophrenia.

27. mesolimbic pathway

28. mesolimbic overactivity =
positive symptoms of psychosis
10-9

29. Mesocortical Dopamine PathwayMesocortical Dopamine Pathway
It also projects from the midbrain ventral
tegmental area to axons of the frontal cortex
especially to dorsolateral prefrontal cortex.
It mediates the negative and cognitive
symptoms in schizophrenia.
It has been implicated in aspects of learning &
memory.
Dopamine Antagonists worsen negative
symptoms of schizophrenia.

30. Meso-cortical pathway
10-10
Stahl S M, Essential
Psychopharmacology (2000)

31. primary
dopamine
deficiency
D2
receptor
blockade
secondary
dopamine
deficiency
mesocortical pathway
increase in
negative
symptoms
10-11

32. Nigrostriatal PathwayNigrostriatal Pathway
It projects from dopaminergic cell bodies in the
substantia nigra of the brainstem via axons terminating
in the basal ganglia or striatum.
Deficiencies in dopamine In this pathway cause
movement disorders, including Parkinson's disease,
which is characterized by rigidity, akinesia, or
bradykinesia, and tremor.
Dopamine deficiency in the basal ganglia also can
produce akathisia or dystonia.
Hyperactivity of dopamine in the nigrostriatal pathway
is thought to underlie various hyperkinetic movement
disorders, such as chorea, dyskinesias, and tics

33. Nigrostriatal pathway
10-12
Stahl S M, Essential
Psychopharmacology (2000)

34. Tuberoinfundibular Dopamine Tuberoinfundibular Dopamine
PathwayPathway
It projects from the hypothalamus to the anterior pituitary
It regulates prolactin secretion into the circulation.
Dopamine inhibits prolactin secretion.
Post-synaptic D2 receptor blockade by antipsychotic drugs
increase prolactin secretion which produces galactorrhea,
amenorrhea, sexual dysfunction, depression and
osteoporosis.

35. Tubero infundibular pathway
10-13
Stahl S M, Essential
Psychopharmacology (2000)

36. Diagnosis criteria: DSM-IV-TRDiagnosis criteria: DSM-IV-TR

37. Treatment

38. DESIRED OUTCOME
•Alleviation of target symptoms,
•Avoidance of side effects,
•Improvement in psychosocial functioning and
productivity,
•Compliance with the prescribed regimen,
•Involvement of the patient in treatment
planning

39. Psychotherapeutic ApproachesPsychotherapeutic Approaches

40. Pharmacologic Pharmacologic
D2
pure D2 blocker

41. pure D2
blocker
Mesolimbic

42. Increase in
negative
symptoms
11-3
Mesocortical pathway

43. EPSs
Nigrostriatal pathway

44. = acetylcholine
= dopamine
Dopamine & Acetylcholine have a
reciprocal relationship in the nigro-
Striatal dopamine pathway. Dopamine
Suppresses acetylcholine activity

45. = D2 blocker
11-10
Increase in acetylcholine
Activity which is associated
With the production of EPS

46. = anticholinergic
11-11
One compensation for the over-
activity of acetylcholine that occurs
When dopamine receptors are blocked
is to block the acetylcholine receptors
With an anticholinergic agent.

47. Blockade of
receptors in the
nigrostriatal
dopamine pathway
causes them to up-
regulate
This up-regulation
may lead to tardive
dyskinesia
11-5

48. Prolactin levels
rise
Tuberoinfundibular pathway

49. H1
M1
D2
1
Conventional
antipsychotic
drug

50. Conventional antipsychoticsConventional antipsychotics
Chlorpromazine (Thorazine)
Fluphenazine (Prolixin)
Haloperidol (Haldol)
Loxapine (Loxitane)
Mesoridazine (Serentil)
Molindone (Moban)
Perphenazine (Trilafon)
Thiorizadine (Mellaril)
Thiothixene (Navane)
Trifluoperazine (Stelazine)

51. constipation
LAXATIVE
blurred vision
dry mouth drowsiness
SIDE EFFECTS
M1 INSERTED

52. H1 INSERTED
drowsiness
weight gain

53. drowsiness
decreased
blood pressure
dizziness
1 INSERTED

54. 5HT2A
D2
SDA
Atypical Antipsychotic DrugsAtypical Antipsychotic Drugs

55. Serotonin-Dopamine AntagonismSerotonin-Dopamine Antagonism
Atypical antipsychotic is defined in part by the clinical
properties that distinguish such drugs from conventional
antipsychotics, namely, low EPS and efficacy for negative
symptoms.
Atypical antipsychotics
◦(1) have stronger antagonism of 5-HT2 receptors than D2-dopamine
receptors
◦(2) atypical antipsychotics cause fewer EPS than conventional
antipsychotics
◦(3) atypical antipsychotics improve positive symptoms as well as do
conventional antipsychotics.

56. 5HT-DA Interactions: Serotonin inhibits dopamine release, thus
the release of serotonin acts as a “brake” on dopamine release.
Substantia
nigra
raphe nucleus
brake
brake

57. serotonin neuron
dopamine neuron
Substantia
nigra
Raphe nuclei
dopamine
5HT2A
receptor
serotonin
5HT2A
receptor
Serotonin regulation of dopamine release from nigrostriatal neurons part I

58. serotonin neuron
dopamine neuron
Substantia
nigra
Raphe
dopamine
5HT2A
receptor
serotonin
5HT2A
receptor
Part II

59. serotonin neuron
dopamine neuron
Substantia
nigra
Raphe nuclei
5HT2A
receptor
Part III

60. DA neuron
5HT neuron
postsynaptic
neuron
dopamine
D2 receptor
5HT2A
receptor
Nigrostriatal pathway

61. serotonin
Nigrostriatal pathway
no dopamine release
Dopamine
release is
being
inhibited by
5HT

62. SDA
D2 receptor
Nigrostriatal pathway

63. 5HT2A
receptor
Nigrostriatal pathway
11-24
Blocking 5HT2A reverse D2
blockers in the striatum, causing
little EPS.

64. mesocortical pathway
primary dopamine deficiency
secondary dopamine deficiency
dopamine release
serotonin
SDA
11-27
Blockade of 5HT2A receptors with
An atypical antipsychotic leads to
dopamine release, which
compensates for dopamine
Deficiency.

65. pituitary lactotroph
5HT2A
receptor
D2 receptor
dopamine
serotonin
prolactin
Dopamine inhibits prolactin
release.

66. pituitary lactotroph
5HT2A
receptor
serotonin
prolactin
Serotonin
stimulates
prolactin
release

67. D2
receptor prolactin
D2
antagonist
pituitary lactotroph
Conventional
antipsychotic
being D2
antagonist
increase
prolactin
release

68. D2
receptor prolactin
5HT2A
receptor
SDA
pituitary lactotroph
5HT2A
antagonism
reverses the
ability of D2
antagonism
to increase
prolactin
secretion

69. 5HT7
5HT6
5HT3
5HT2C
5HT1D
5HT1A
M1
H1
1
2
SRI
NRI
D1
D3D4
5HT2A
D2
atypical
antipsychotic

70. 5HT7
5HT6
5HT3
5HT2C
5HT1A
M1
H1
1
2
D1
D3D4
5HT2A
D2
Clozapine

71. Clozapine Clozapine
Is considered the prototype of the atypical antipsychotic.
It is a weak antagonist of the D2 receptor but appears to be a potent
antagonist of the D4 receptor and 5HT2 receptors. Thus there is a
hypothesis that a non-D2 dopamine receptor may be the most
effective target for antipsychotic drugs.
Is indicated for treatment resistant schizophrenia and for patients
who have tardive dyskinesia.
It is also associated with the risk of a life-threatening called
agranulocytosis which occurs in 0.5 to 2% of patients.
It also entails an increased risk of seizures, especially at high dose.

72. Clozapine…..Clozapine…..
The most common other adverse effects associated with
clozapine treatment are sedation, fatigue, weight gain, and
at times fever.
Lab monitoring: weekly WBCs for the first 6 months and
then every 2 weeks.
Clozapine should be discontinued if the granulocyte
count is less than 1000/mm3.

73. 5HT7
1
2
5HT2A
D2
Risperidone

74. RisperidoneRisperidone
It has the simplest pharmacologic profiles and
comes closest to an SDA
It is atypical at lower doses but can become more
“conventional” at high doses in that EPS can occur.
The major adverse events are somnolence, fatigue,
orthostatic dizziness, tachycardia, weight gain,
sexual dysfunction, rhinitis and nausea.

75. 5HT6
5HT3
5HT2C
M1
H1
1
D1
D3D4
5HT2A
D2
olanzapine

76. OlanzapineOlanzapine
It is atypical because it lacks EPS not only in
smaller dosage but also at higher dosage.
It is associated with weight gain because of its
antihistaminic and serotonin 2C antagonist
properties.
It is the first antipsychotic medication which has
been approved for the treatment of acute mania
and maintenance of bipolar disorder in USA.

77. 5HT7
5HT6
H1
1
2
5HT2A
D2
Quetiapine
11-41

78. QuetiapineQuetiapine
No EPS
Implicated in the development of new-onset
type-2 diabetes.
No report of tardive dyskinesia or prolactin
elevation

79. Selection of an antipsychotic should be
based on:
◦The need to avoid certain side effects
◦Concurrent medical or psychiatric disorders
◦Patient or family history of response.

80. multiple
mechanisms =
side effects
chlorpromazine
single selective
mechanisms = loss of
side effects
Haloperidol
multiple
therapeutic
mechanisms =
improved
efficacy
Clozapine
SDA
Risperidone
Quetiapine
Olanzapine
Typical vs atypical

83. Phases of therapy Phases of therapy
Initial therapy
◦For 7 days
◦Goal- decrease agitation, hostility, anxiety, and aggression and normalization
of sleep and eating patterns
Stabilization therapy
◦During weeks 2 and 3
◦Goal-improve socialization, self-care habits, and mood.
◦Improvement in formal thought disorder may require an additional 6 to 8
weeks.
Maintenance therapy
◦At least 12 months after remission of the first psychotic episode

84. Summary of adverse effectsSummary of adverse effects
Autonomic Nervous System
◦Anticholinergic (ACh) side effects
◦Low potency FGAs, clozapine, and olanzapine
are most likely
◦Elderly patients are especially sensitive

85. Central Nervous System
◦Extrapyramidal System
Dystonia
Akathisia
Pseudoparkinsonism
Tardive Dyskinesia
◦Sedation and Cognition
◦Seizures
◦Thermoregulation
◦Neuroleptic Malignant Syndrome

86. Neuroleptic Malignant SyndromeNeuroleptic Malignant Syndrome
It is a life-threatening complication of antipsychotic
treatment.
The symptoms include severe muscle rigidity, akinesia,
mutism, obtundation, agitation, high fever, sweating,
increased blood pressure, and tachycardia.
Abnormal lab findings include: leukocytosis, elevated CPK
(usually > 1000)
Treatment is supportive but medications like Dantrolene (
a muscle relaxant) and bromocriptine (dopamine agonist)
are very useful.

87. ◦

88. Endocrine System
◦Elevations in prolactin levels with associated
galactorrhea and menstrual irregularities
Mgt-use SGA
◦Weight gain

89. Cardiovascular System
◦Orthostatic hypotension
Reduce the dose or change to an antipsychotic with less -adrenergic blockade
α
◦ECG changes
Psychiatric Side Effects
◦Apathy and withdrawal
Ophthalmologic Effects
◦Impairment in visual accommodation and photophobia
Pilocarpine-if severe
◦Opaque deposits in the cornea and lens with phenothiazines
◦Retinitis pigmentosa can result from thioridazine

90. Hepatic System
◦Liver function test abnormalities
◦Cholestatic hepatocanalicular jaundice
◦Cholestatic hepatitis
Genitourinary System
◦Urinary hesitancy and retention
◦Urinary incontinence is especially problematic with clozapine
Hematologic System
◦Transient leukopenia
◦Agranulocytosis
Dermatologic System
◦Contact dermatitis
◦Photosensitivity
◦Blue-gray or purplish discoloration of skin

91. Use in pregnancy and lactationUse in pregnancy and lactation
No relationship between haloperidol use and
teratogenicity
Weight gain and potential risk for gestational diabetes
Use of clozapine during breast-feeding is not
recommended

92. Management of treatment-resistant schizophreniaManagement of treatment-resistant schizophrenia
Only clozapine has shown superiority
Augmentation with non-antipsychotic drug
◦Mood stabilizers-For labile affect and agitated behavior
◦Selective serotonin reuptake inhibitors-For –ve symptoms
◦Propranolol, pindolol, and nadolol- For antiaggressive
effects

93. POSITIVE SYMPTOM PHARMACY
3rd line
treatment
2nd line
treatment
noncompliant
(depot)
1st line
treatment
In case of
emergency
polypharmacy combos
D2
clozapine
D2
SDA
D2
BZ

94. AFFECTIVE SYMPTOM
PHARMACY
2nd line
treatment
clozapine
SDA
SSRI
+
1st line
treatment
schizophrenia
and others
suicide
1st line
treatment
bipolar
disorder
SDA
SDA
SDAlithium
mood
stabilizer

95. COGNITIVE SYMPTOM
PHARMACY
2nd line
treatment
1st line
treatment
SDA
ChEl
ACH

96. NEGATIVE SYMPTOM
PHARMACY
2nd line
treatment
1st line
treatment
SDA
ZiQu
R O
avoid those caused by
conventional
antipsychotics
reduce those caused
by schizophrenia

97. AGGRESSIVE SYMPTOM
PHARMACY
2nd line
treatment
1st line
treatment
SDA
in case of
emergency
clozapine D2
BZ
D2
BZ

98. FIRST LINE ANTIPSYCHOTIC USE
DOSE
TIME
atypical #1 atypical #2
acceptable polypharmacy
atypical #3
Polypharmacy protocols

99. GETTING TRAPPED IN CROSS-TITRATION
TIME
atypical #1
DOSE
atypical #2
unacceptable polypharmacy

100. USE OF CONVENTIONAL ANTIPSYCHOTICS TO “LEAD IN”
OR “TOP UP” ATYPICAL ANTISPYCHOTICS
TIME
DOSE
conventional
antipsychotic
“lead in”
atypical antipsychotic
conventional antipsychotic “top up”

101. WHEN ALL ELSE FAILS
TIME
DOSE
high
dose
cost
effective
and
atypical
properties
atypical
antipsychotic
conventional
antipsychotic
option 2 -
conventional
add-on
atypical
antipsychotic
option 1 - high
dose atypical