MPHRM-512 Lec-7 V-3-Date-8-11-14

Antipsychotics
Psychotropic drugs are those having primary effects on Psyche (mental) and are
used for treatment of psychosis.

Psychosis
Severe mental illness with serious
distortion of thoughts, behaviour,
capacity to recognize and of perception
such as delusions and hallucinations.

Psychosis can broadly categorized in to

four groups:
2

Psychosis
1. Acute and Chronic organic brain syndromes
(cognitive disorders) such as delirium, dementia,
confusion, disorientation, defective memory and
disorganized behaviour.
2. Functional disorder: memory and orientation
mostly retained by emotion; thought, reasoning
and behaviour are altered.
3. Schizophrenia (split mind): splitting of
perception and interpretation from realityhallucinations and inability to think coherently.
Described in terms of positive and negative
symptoms.
4. Paranoid state: fixed delusions (false beliefs)
and loss of insight.
3

Psychosis

Environmental factors
Maturational factors
Neuronal connectivity
Neurotransmitters
Receptors/drug targets

Psychosis
Environmental Factors
Exposure to infections

Toxic/Traumatic/nutritional
Insults

( in utero)

ALTERATIONS IN NEURODEVELOPMENT

Autoimmunity

Stress during gestation or

early in childhood/adolescence
5

Maturational Processes

Apoptosis

Synaptic Pruning Myelination (prenatal

to adolescence)

Unmasking Genetic Vulnerability

Neuronal connectivity
Structural changes during development and in
response to environmental factors
Changes in neurotransmitter activity in response to
environmental factors
Neurotrophic factors and changes in gene
transcription
(eg. neuroregulin-1 which regulates neuronal migration)

NEURONAL CONNECTIVITY
Functional activity in
neocortex of psychotic
patients may be
decreased:
Myelination
Hormonal effects of
puberty
Exposure to stressors
Defective connections in
midbrain, thalamus, limbic
and prefrontal cortex

What is SCHIZOPHRENIA?

Schizophrenia is a neurodevelopmental disorder

with complex genetics and incompletely
understood pathophysiology.

Mutations or polymorphisms of many genes

appear to contribute to the risk for
schizophrenia.

STRUCTURAL BRAIN CHANGES IN

SCHIZOPHRENIA

Schizophrenics show deficits in tasks involving

prefrontal cortex or those requiring working
memory
Prefrontal cortical thickness is reduced 5-10%,
neuron size is down, but no change in neuron
number
Synaptic connectivity is reduced
Medial dorsal thalamus shows 30% reduction in
neuron number
Prefrontal cortex receives fewer projections from
the thalamus
10

STRUCTURAL BRAIN CHANGES IN SCHIZOPHRENIA

Schizophrenia patients have increased mesolimbic

DA activity related to positive symptoms.
Schizophrenia patients have decreased DA D1
activity in the dorsolateral and ventromedial
prefrontal cortex (PFC) that is associated with
cognitive deficits and negative symptoms.

11

Schizophrenia - symptoms
Positive Symptoms
Hallucinations
Delusions
Disorganized Thought
Perception disturbances
Inappropriate emotions

Negative Symptom
Blunted emotions
Anhedonia
Lack of feeling

FUNCTION

Cognition
New Learning
Memory

Mood Symptoms
Loss of motivation
Social withdrawal
Insight
Demoralization
Suicide
12

 Positive/active symptoms include thought disturbances,

delusions, hallucinations

Negative/passive symptoms include social withdrawal,

loss of drive, paucity of speech, impaired personal

hygiene.
13

Paranoid-type schizophrenia
characterized by delusions and auditory
hallucinations but relatively normal
intellectual functioning and expression of
affect.
The delusions can often be about being
some other person who is famous.
exhibit anger, aloofness, anxiety, and
argumentativeness.
14

Negative Symptoms - As
Affect Flattening
Found in about 2/3 of schizophrenic patients
Alogia
The failure to respond to questions or comments
Can also take the form of slow or delayed
responses
Avolition
Inactivity or early loss of interest in ongoing activity
Anhedonia
-inability to derive pleasure
15

Prevalence of Schizophrenia

1-2% of U.S. population

2 million diagnosed in U.S.
Median age at diagnosis = mid-20s
Men = Women prevalence

16

Prognosis of Schizophrenia

10% continuous hospitalization

< 30% recovery = symptom-free for
5 years
60% continued problems in
living/episodic periods

17

Schizophrenia Pathophysiology
Schizophrenia
Pathophysiology
Past Excess dopaminergic
activity

Pharmacologic
Profile of APDs
Dopamine D2-receptor
antagonists

Present
Renewed interest in the
role of serotonin (5-HT)

Combined 5-HT2/D2
antagonists

Future
Imbalance in cortical
More selective antagonists
communication and
Mixed agonist/antagonists
cortical-midbrain
Neuropeptide analogs
integration, involving
18
multiple neurotransmitters

DA pathways in the CNS

19
Ref: Goodman and Gilmans Therapeutic Basis of Pharmacology

DA-containing pathways in the CNS

There are three major DA-containing pathways in
the CNS:
The nigrostriatal pathway.
The mesocortical pathway, where neurons in
the ventral tegmental nucleus project to a
variety of midbrain structures and to the
frontal cortex .
The tuberoinfundibular pathway, which
delivers DA to cells in the anterior pituitary
20

Dopaminergic Pathways and Innervations

21

Dopaminergic Pathways and Innervations

The mesolimbic pathway is associated with reward and
learned behaviors.
Dysfunction in this pathway is associated with addiction,
schizophrenia, and psychoses (including bipolar depression),
and learning deficits.
The mesocortical pathway is important for "higher-order"
cognitive functions including motivation, reward, emotion, and
impulse control.
It is also implicated in psychoses, including schizophrenia,
and in attention-deficit hyperactivity disorder.
The mesolimbic and mesocortical pathways are sometimes
grouped together as mesolimbocortical.
22

Dopaminergic Pathways and Innervations

The nigrostriatal pathway is a key regulator of movement.
Impairments in this pathway are evident in Parkinson disease
and underlie detrimental movement side effects associated
with dopaminergic therapy, including tardive dyskinesia.
DA released in the tuberoinfundibular pathway is carried by
the hypophyseal blood supply to the pituitary, where it
regulates prolactin secretion

23

Schizophrenia

Paranoid type is characterized by organized system

of delusions and auditory hallucination.
Individual is often tense, suspicious, and guarded.

24

Schizophrenia: A case study

Tony, age 21, has been diagnosed with paranoid

schizophrenia. He has been socially isolated and
hearing voices telling him to kill his parents. He has
been admitted to the psychiatric unit from the ED.
What would be the INITIAL intervention for Tony?

25

Schizophrenia: A case study

Ensure a safe environment for him and

others
Decrease his anxiety and increase trust
Antipsychotic drugs to decrease psychotic
symptoms

26

DOPAMINE RECEPTORS

Dopamine recognized as a neurotransmitter in the

1950s
Five dopamine receptor subtypes: D-1,-2,-3,-4,-5
Schizophrenics show elevated D2 receptor number
Cortex has much higher amounts of D1 than D2
receptors
chronic antipsychotic drugs downregulate D1s
in the cortex and striatum

27

Schizophrenia - Dopamine Hypothesis

Repeated administration of stimulants like amphetamines and
cocaine cause a psychosis - resembles the positive symptoms
of schizophrenia
Stress can produce a psychotic state in recovered
amphetamine addicts.
Carlsson and Lindqvist (1963) first proposed that drugs such as
chlorpromazine and haloperidol alleviate schizophrenic
symptoms by blocking DA receptors.
These antipsychotic medications have in common their ability to
block dopamine D2 receptors
28

Schizophrenia - Dopamine Hypothesis

A strong correlation between the affinity of antipsychotic
drugs for DA receptors and their clinical potency
But no clear and consistent abnormality in DA function has
been detected in schizophrenic patients.
Some early studies with postmortem tissue revealed
increased numbers of DA receptors (in particular D2-like) in
schizophrenic patients.
Reduced cortical dopamine transmission induced by longterm phencyclidine (PCP) exposure may be associated
with a hyperactivity of subcortical dopamine systems
29

30

Schizophrenia - Serotonin Hypothesis

correlation between DA affinity and antipsychotic efficacy has
become weaker as a result of recently developed atypical
antipsychotic medications that also show substantial affinity
for 5HT2 receptors.
Alteration of 5-HT transmission in the brains of schizophrenics
patients have been reported in post-mortem studies and
serotonin-agonists challenge studies.
There are widespread and complex changes in the 5-HT
system in schizophrenics patients.
These changes suggest that 5-HT dysfunction is involved in the
pathophysiology of the disease.

31

Serotonin-Dopamine Interactions
Dopamine (DA)

Prefrontal Cortex

Serotonin (5-HT)

GABA
Glutamate

Striatum
GABA/ACh
Limbic
System

Motor Outputs
Blockade of D2 receptors
by conventional APDs
causes EPS

Ventral Tegmental Area

Median
Raphe

Substantia Nigra

Dorsal
Raphe

5-HT2A antagonists
release dopamine from
inhibition and decrease
32
EPS

Schizophrenia - Glutamate Hypothesis

Cognitive dysfunction is the greatest predictor of poor
functional outcome in schizophrenia and shows limited
response to antipsychotic treatment.
Glutamate NMDA receptor stimulation is involved in tonic
inhibition of mesolimbic DA release, but facilitates
mesocortical DA release.
The NMDA antagonists phencyclidine and ketamine
indirectly act to stimulate DA availability by decreasing the
glutamate-mediated tonic inhibition of DA release in the
mesolimbic DA pathway.
33

Schizophrenia
Schizophrenia has at least _____
symptoms, each present for a significant
portion of the time during a _________
period and continuous signs of disturbance
for at least _________.

34

Schizophrenia
About half the people with schizophrenia
display significant difficulties with
__________ and other kinds of cognitive
functioning.

35

Schizophrenia
What is the medical term for Poverty of
speech?

36

General Goals of Pharmacotherapy

The immediate goal of antipsychotic
treatment is to decrease in acute symptoms
that induce patient distress, particularly
behavioral symptoms (e.g., hostility, agitation).
The dosing, route of administration, and
choice of antipsychotic depend on the
underlying disease state, clinical acuity, drugdrug interactions with concomitant
medications, and patient sensitivity to short- or
long-term adverse effects.
37

General Goals of Pharmacotherapy

With the exception of clozapine's superior
efficacy in treatment-refractory schizophrenia,
neither the clinical presentation nor
biomarkers predict the likelihood of response
to a specific antipsychotic class or agent.
As a result, avoidance of adverse effects
based upon patient and drug characteristics,
are the principal determinants for choosing
initial antipsychotic therapy.
38

General Goals of Schizophrenia

The immediate goals of acute antipsychotic
treatment are:
reduction of agitated, disorganized, or hostile
behavior
decreasing the impact of hallucinations,
improvement of organization of thought
processes,
reduction of social withdrawal.
39

General Goals of Schizophrenia

Doses used are often higher than those
required for maintenance treatment of stable
patients.
Despite considerable debate, newer atypical
antipsychotic agents are not more effective in
the treatment of positive symptoms than
typical agents although there may be small but
measurable differences in effects on negative
symptoms and cognition.
40

Refractory Schizophrenia
Refractory schizophrenia is defined using the
Kane criteria: failed 6-week trials of two
separate agents and a third trial of a highdose typical antipsychotic agent (e.g.,
haloperidol or fluphenazine 20 mg/day).
In this patient population, response rates to
typical antipsychotic agents, defined as 20%
symptom reduction using standard rating
scales (e.g., Positive and Negative Syndrome
Scale [PANSS].
41

Significance of antipsychotics/neuroleptics
Introduction of chlorpromazine in 1952 led by
the end of the 1950s to emptying psychiatric
hospitals back into community, with mixed
results.
The successful treatment of a psychiatric
disorder with a drug led to a search for
biological mechanisms.

42

ANTIPSYCHOTICS
Pre-90s
Typical, conventional, traditional neuroleptics,
major tranquilizors
Modeled on D2 antagonism
EPS/TD

Post-90s

Atypical, novel, 2nd generation

Modeled on 5-HT2/D2 antagonism
Less EPS, prolactin effects
Weight gain, sedation, diabetes
43

Antipsychotic drugs
Antipsychotic drugs are also known as
neuroleptics, ataractic, major tranquilizer and
anti-schizophrenic drugs.
A first generation antipsychotic known as typical
antipsychotic was discovered in 1950s.
Most of the drugs are in the second generation,
known as atypical antipsychotics, have been
developed more recently.

44

Antipsychotics: site of action

45

Classification

Typical antipsychotics
1. Phenothiazines:
a. aliphatic side chains: Chlorpromazine,
Triflupromazine.
b. Piperidine side chain: Thioridazine
c. Piperazine side chain: Trifluoperazine,
fluphenazine.
2. Butyrophenones: Haloperidol, Trifluperidol.
3. Thioxanthenes: Chlorprothixene,
Flupenthixole
46

Classification of antipsychotic drugs

Atypical antipsychotic
lower affinity for D2 receptors than typical
antipsychotic drugs and high 5-HT2 antagonist
effects.
Olanzipine
Clozapine
Sertindole
Risperidone
47

Goal of antipsychotic treatment

The immediate goal of antipsychotic treatment:
Decrease in acute symptoms that induce patient distress- e.g.
behavioral symptoms that present a danger to the patient or
others.
The dosing, route of administration, and choice of antipsychotic
depend on the underlying disease state, drug-drug interactions
with concomitant medications, and patient sensitivity to short- or
long-term adverse effects.
Neither the clinical presentation nor biomarkers predict the
likelihood of response to a specific antipsychotic class or agent.
Avoidance of adverse effects based upon patient and drug
characteristics, or exploitation of certain medication properties
are the principal determinants for antipsychotic therapy.
48

MECHANISMS OF ACTION
OF TYPICAL NEUROLEPTICS
DOPAMINE-2 receptor blockade in
meso-limbic and meso-cortical systems
for antipsychotic effect.
DOPAMINE-2 receptor blockade in
basal ganglia (nigro-striatal system) for
EPS.
DOPAMINE-2 receptor supersensitivity
in nigrostriatal system for tardive
dyskinesia
49

LONG TERM EFFECTS OF D2

RECEPTOR BLOCKADE:
Dopamine neurons reduce activity.
Postsynaptic D-2 receptor numbers increase
(compensatory response).
When D2 blockade is reduced, DA neurons
resume firing and stimulate increased
number of receptors >> hyper-dopamine
state >> tardive dyskinesia
50

MANAGEMENT OF EPS
Dystonia and parkinsonism: anticholinergic
antiparkinson drugs
Neuroleptic malignant syndrome: muscle
relaxants, DA agonists, supportive
Akathisia: benzodiazepines, propranolol
Tardive dyskinesia: increase neuroleptic dose;
51
switch to clozapine

Typical Antipsychotics: adverse Effects

Sedation initially considerable; tolerance usually

develops after a few weeks of therapy.
Postural hypotension results primarily from
adrenergic blockade; tolerance can develop.
Anticholinergic effects include blurred vision, dry
mouth, constipation, urinary retention; results from
muscarinic cholinergic blockade.
Endocrine effects increased prolactin secretion can
cause galactorhea; results from antidopamine effect
Hypersensitivity reactions jaundice, photosensitivity,
rashes, agranulocytosis can occur.
Idiosyncratic reactions malignant neuroleptic
syndrome (MNS).
Weight gain
Neurological side effects H1 blockade.
52

Antipsychotic Medications
Conventional medications (Typical/ older):

haloperidol (Haldol)

fluphenazine (Prolixin)

pimozide (Orap)

trifluoperazine (Stelazine)

thiothixene (Navane)

perphenazine (Trilafon)

mesoridazine
(Serentil)

loxapine (Loxitane)

molindone (Moban)

thioridazine (Mellaril)

chlorpromazine (Thorazine)
53

Antipsychotic Medications
Atypical medications (newer):
clozapine (Clozaril)
risperidone (Resperidal)
olanzapine
(Zyprexa)
quetiapine (Seroquel)
ziprasodone (Geodon)
aripiprazole (Abilify)
paliperidone (Invega)
iloperidone (Fanapt)
asenapine (Saphris)
lurasidone (Latuda)
54

Neurological Side Effects of antipsychotics

REACTION

FEATURES

TIME OF
MAXIMAL RISK

Acutedystonia

Spasmofmusclesoftongue,
face,neck,back;maymimic
seizures;nothysteria

1to5days

Akathisia

Motorrestlessness;not
anxietyor"agitation"

5to60days

Parkinsonism

Bradykinesia,rigidity,
variabletremor,maskfacies,
shufflinggait

5to30days

Neuroleptic
malignant
syndrome

Catatonia,stupor,fever,
unstablebloodpressure,
myoglobinemia;canbefatal

Weeks;canpersistfor
daysafterstopping
neuroleptic

Perioraltremor
("rabbit"syndrome)
Tardivedyskinesia

PROPOSED
MECHANISM
Unknown

Unknown

TREATMENT
Antiparkinsonianagentsare
diagnosticandcurative
Reducedoseorchangedrug:
antiparkinsonianagents,b
benzodiazepinesor
propranololcmayhelp

Antagonismof
dopamine

Antiparkinsonianagents
helpful

Antagonismof
dopaminemay
contribute

Stopneuroleptic
immediately:dantroleneor
bromocriptinedmayhelp:
antiparkinsonianagentsnot
effective

Perioraltremor(maybealate Aftermonthsoryears
variantofparkinsonism)
oftreatment

Unknown

Antiparkinsonianagents
oftenhelp

Oral-facialdyskinesia;
widespreadchoreoathetosis
ordystonia

Excessfunctionof
dopamine
hypothesized

Aftermonthsoryears
oftreatment(worseon
withdrawal)

Preventioncrucial;treatment
unsatisfactory

a.Manydrugshavebeenclaimedtobehelpfulforacutedystonia.Amongthemostcommonlyemployedtreatmentsarediphenhydraminehydrochloride,25or50mgintramuscularly,or
benztropinemesylate,1or2mgintramuscularlyorslowlyintravenously,followedbyoralmedicationwiththesameagentforaperiodofdaystoperhapsseveralweeksthereafter. b.Fordetails
regardingtheuseoforalantiparkinsonianagents,seetherestofslidesc.Propranololofteniseffectiveinrelativelylowdoses(20-80mgperday).Selectivebeta1-adrenergicreceptorantagonists
arelesseffective.d.Despitetheresponsetodantrolene,thereisnoevidenceofanabnormalityofCa2+transportinskeletalmuscle;withlingeringneurolepticeffects,bromocriptinemaybe
55
toleratedinlargedoses(10-40mgperday).

Adverse Effects - EPS

Details on two main extrapyramidal disturbances (EPS):

Parkinson-like symptoms

tremor, rigidity
direct consequence of block of nigrostriatal DA2 R
reversible upon cessation of antipsychotics
Parkinsonism resembling its idiopathic form occurs when striatal D 2
occupancy exceeds 78%, and often responds to dose reduction or
switching to an antipsychotic with weaker D 2 antagonism

Tardive dyskinesia

involuntary movement of face and limbs

less likely with atypical antipsychotics (AP)
appears months or years after start of AP
result of proliferation of DA R in striatum
treatment is generally unsuccessful
56

Antipsychotic Medications
(Neuroleptics)
Uses:
-reduce hallucinations
-improve organization of thought processes
-reduce preoccupations with improbable
beliefs
-tranquilization
-anti-emesis
57

Common Side effects of

antipsychotics:

sedation
drowsiness
anergy
decreased motivation
slowing of thought processes
depression
dry mouth
constipation
blurred vision
weight gain, diabetes, hyperlipidemia
orthostatic hypotension
amenorrhea
galactorrhea
gynecomastia
58

Common Side effects of

antipsychotics:

rashes
sun sensitivity
sexual dysfunction
restlessness
restless leg syndrome
headache (especially aripiprazole and ziprasidone)
nausea and vomiting (especially risperidone and
ziprasidone)

59

Neurological side effects of

antipsychotics

Parkinsonian Side Effects

Onset generally about 7 days after beginning

antipsychotic medications
Key features:
"pill-rolling" tremor
increased muscle tone
stooped, shuffling gait
bradykinesia
impaired balance
60

Neurological side effects of

antipsychotics

Akathisia

Characterized by extreme motor restlessness

or "nervousness"
People may be observed to pace, jog their
legs, repeatedly sit then stand
When severe, people may not be able to sleep
May be a cause of increased aggression in
people having developmental disabilities
Onset: immediate to a few days
61

Neurological side effects of

antipsychotics

Dystonia

Characterized by a sustained, painful

contraction of one or more muscle groups.
Common presentations:
rigid tongue protrusion
throat "closing up" or tongue drawn
back
upward deviation of the eyes
Onset: frequently within an hour of dosage,
may be recurrent
Can be lethal if airway obstruction occurs
62

Neurological side effects of

antipsychotics

Tardive Dyskinesia

Characterized by involuntary muscle movements

Onset generally after many years of taking
antipsychotic medications, but can occur within weeks
Can be progressive and permanent
Typical movements:

chewing, lip-smacking, lip-licking, puffing

frequent blinking
tongue flickering or protrusion
foot tapping, ankle movements
shrugging, twisting of torso, reflux, vomiting

Progresses to cause respiratory difficulties, aspiration

pneumonia
63

Serious side effects of

antipsychotics

neutropenia
seizures
neuroleptic malignant syndrome
cardiac arrhythmias
hyperthermia
cataracts
precipitation of glaucoma
diabetes
hyperlipidemia
64

Phenothiazines - Side effects

Weight gain 40% - weight gain now attributed to
ratio of binding to D2 and 5-HT2 receptors; also
histamine.
Sexual dysfunction
result from NE blockade
erectile dysfunction in 23-54% of men
loss of libido in men and women
Seizures - <1% for generalized grand mal

65

Phenothiazines - Side effects

Neuroleptic malignant syndrome (1-2% early in trt)
combination of motor rigidity, hyperthermia, and
autonomic dysregulation of blood pressure and heart
rate (both go up)
can be fatal in 5-20% of cases if untreated
treatment discontinue medicines; treatments for
fever and cardiac problems.

66

Sensitivity to sun
some phenothiazines collect in skin (chlorpromazine)
sunlight causes pigmentation changes grayishpurple spot.
can also occur in eye and cause brown in cornea
Agranulocytosis - <1%
reduced white blood cell count
lowered resistance to infection
can be fatal
Jaundice elevated bilirubin in liver - < %
67

Phenothiazines Metabolism and Drug

Interactions
Metabolized by CYP2D6. Over 10 identified human
metabolites, most inactive.
Enzyme interactions with 3A4 inducers barbiturates
(phenobarbital); phenytoin (Dilantin); carbamazepine
(Tegretol) reduce phenothiazine levels
co-administration must be carefully monitored to
prevent toxicity
enzyme competition with SSRIs increases levels
and may increase side effects
68

Haloperidole
entered US market in 1967
more potent than phenothiazines, so doses are lower
also have long half-life
like phenothiazines, they block dopamine and
norepinephrine receptors and show the related side
effects
extrapyramidal effects are worse
but blood pressure effects are less
reduced sedation
no blood abnormalities or jaundice

69

Haloperidole: Metabolism
Multiple CYP pathways, particularly 2D6, 3A4, and
minor pathway 1A2.
One active metabolite, reduced haloperidol (formed
by ketone reductase).
Reduced haloperidol inhibits CYP2D6 and may be
re-oxidized to the parent drug.
Therapeutic serum levels not well defined; 5-20 ng/mL
used as a target for dosing.

70

Limitations Of Conventional Antipsychotics

Approximately one-third of patients with schizophrenia
fail to respond
Limited efficacy against
Negative symptoms
Affective symptoms
Cognitive deficits

High proportion of patients relapse

Side effects and compliance issues
Some safety issues are prominent
71

Antipsychotic Drugs New Generations

atypical
About 40-60% do not respond to phenothiazines or
cannot handle side effects
Questions remain about the efficacy of
phenothiazines and haloperidole for negative
symptoms
Drugs needed that are low in extrapyramidal side
effects and at least equal in efficacy for positive
symptoms, perhaps better for negative
72

Antipsychotic Drugs New Generations

atypical

clozapine
risperidone
olanzapine
sertindole
quetiapine etc.

73

Atypical antipsychotics
MARTA (multi acting receptor targeted agents)
clozapine, olanzapine, quetiapine
SDA (serotonin-dopamine antagonists)
risperidone, ziprasidone, sertindole
Selective D2/D3 antagonists
sulpiride, amisulpiride

74

Clozapine (1989)
Selectively blocks dopamine D2 receptors,
avoiding nigrostriatal pathway
Also blocks NE
More strongly blocks 5-HT2 receptors in cortex
which then acts to modulate some dopamine
activity
Among non-responders to first generation meds or
those who cannot tolerate side effects, about 30%
do respond to Clozapine
75

Clozapine
Extrapyramidal side effects are minimal
May help treat tarditive dyskinesia
shows orthostatic hypotension effects, sedation,
weight gain, increased heart rate
Increased risk for seizures (2-3%)
Agranulocytosis in 1%
Agranulocytosis risks increase when coadministered with carbamazepine
Interactions with SSRIs and valproic acid increase
76
Clozapine levels and risks

Risperidone (1994)
Fewer side effects than Clozapine
Marketed as first line approach to treatment
Blocks selective D2 and 5-HT2
Argued as effective for positive and negative
symptoms (controversial)
Extrapyramidal side effects low (but are shown at
high doses) - controversial
Shares sedation, weight gain, rapid heart beat,
orthostatic hypotension, and elevated prolactin
No agranulocytosis risks
May cause anxiety/agitation (possible OCD)
77

Risperidone (Risperdal)
Research designs clearly stacked in favor of
Risperidone showing better profile for
extrapyramidal side effects and for symptom
reduction
Advantages unclear other than agranulocytosis
issue

78

Olanzipine - Zyprexa 1996

Same poorly supported arguments about improved
negative symptom reduction
Argued to be better than risperidone in
extrapyramidal issues
Does not cause prolactin elevation
Same claim to fame reduced agranulocytosis risks

79

Sertindole Serlect 1995

Some poorly supported arguments about improved
negative symptom reduction
Low risk for extrapyramidal side effects major
advantage
No sedation and very mild prolactin elevation major
advantages
Shares orthostatic hypotension, tachycardia, and
weight gain
Common side effects are rhinitis and reduced
ejaculatory volume (not associated with disturbed
function)
concern about sudden cardiac death or episodes due
80
to cardiac arrhythmia led to its voluntary removal in

Quetiapine Seroquel - 1997

No increased risks for extrapyramidal symptoms
Shares sedation, orthostatic hypotension, weight
gain
Does cause anticholinergic side effects (like older
and Clozapine) dry mouth, constipation
Does not elevate prolactin

Ziprasidone - 2001
Similar to advantages of others, but argued not to
cause weight gain
81

Status
Limited evidence to support arguments about
improved treatment of negative symptoms
clearly do have reduced extrapyramidal side
effects, reduced sedation, and do not cause
prolactin elevation
Weight gain issue is ziprasidone better?
Wetterling 2001 - Evaluation of published data from
varying designs, etc:
Clozapine 1.7 kg/month
kg/month

Risperidone 1

Olanzipine 2.3 kg/month

kg/month

Ziprasidone 0.8
82

Pharmacological effects
A. Effects on dopamine systems
i. Mesolimbic/ mesocortical
ii. Nigrostriatal
iii. Tuberoinfundibular
B. Dopamine receptors and their effects
i. D1/D5
ii. D2/D3/D4 family
83

Dopamine partial agonist

no clinically available effective
antipsychotic is devoid of D2
antagonistic activity.
This reduction in dopaminergic
neurotransmission is presently achieved
through one of two mechanisms: D2
antagonism or partial D2 agonism,
Of which aripiprazole is the only current
example.
84

Antipsychotics
Aripiprazole has an affinity for D2
receptors intrinsic activity is ~25% that
of dopamine.
In the absence of DA, aripiprazole
produces a maximal level of D2 activity
~25% that of DA.

85

Aripiprazole (mechanism of
action)

86

Antipsychotics
Aripiprazole's capacity to stimulate D2
receptors in brain areas where synaptic
DA levels are limited (e.g., PFC
neurons) or decrease dopaminergic
activity when dopamine concentrations
are high (e.g., mesolimbic cortex) is
thought to be the basis for its clinical
effects in schizophrenia.FDA approval.

87

Metabolism
2D6 and 3A4 convert aripiprazole to
active metabolite dehydro-aripiprazole.
Metabolite has longer t1/2 (75 vs. 94
hours).

88

CLOZAPINE: AN EXAMPLE OF AN
ATYPICAL NEUROLEPTIC

Clozapine (sold as Clozaril, Leponex, Fazaclo; Gen-Clozapine in Canada) was the

first of the atypical antipsychotics to be developed. It was approved by the United
States Food and Drug Administration (FDA) in 1989 and is the only FDA-approved
medication indicated for treatment-resistant schizophrenia and for reducing the risk
of suicidal behaviour in patients with schizophrenia. [dubious discuss]
Clozapine has been shown to be superior in efficacy in treating schizophrenia.
Were it not for its side effects it would be first line treatment; however the rare but
potentially lethal side effects of agranulocytosis and myocarditis relegate it to thirdline use. Furthermore it may rarely lower seizure threshold, cause hepatic
dysfunction, weight gain and be associated with type II diabetes. More common side
effects are predominantly anticholinergic in nature, with dry mouth, sedation and
constipation. It is also a strong antagonist at different subtypes of adrenergic,
cholinergic, histaminergic and serotonergic receptors.
Safer use of clozapine requires weekly blood monitoring for around five months
followed by four weekly testing thereafter. Echocardiograms are recommended
every 6 months to exclude cardiac damage.
89

.There is now ample evidence to suggest that neuroleptics (aka. antipsychotics and major tranquillizers) are dangerous drugs, and patients
exposure to them should be minimized wherever possible. This clinical
imperative applies whether neuroleptics are of the traditional type or
atypical variety, albeit for different reasons since the traditional agents are
neurotoxic while atypicals are mainly metabolic poisons. Usage of
traditional neuroleptics seems indeed to be declining progressively, but the
opposite seems to be happening for atypicals, and new indications for
these drugs are being promoted. Yet the atypical neuroleptics are a
category of pharmaceuticals which are close to being un-necessary since
there are safer, cheaper and pleasanter substitutes such as
benzodiazepines and the sedative antihistamines (eg. promethazine).
In terms of therapeutic value, it therefore seems likely that 'atypicals' are merely an
unusually dangerous way of sedating patients. In therapeutic terms these drugs
therefore represent a significant backward step. Rationally, the atypicals should now
be dropped and replaced with safer sedatives. Potential neuroleptic-substitutes
which already exist would include benzodiazepines and sedative antihistamines
such as promethazine [4,8].
90

Clozapine is generally referred to as an "atypical"

neuroleptic. What is the difference between
"atypical" and "typical" neuroleptics (such as
haloperidol)?

There is no rigorous line between typical and

atypical neurolepticsbut
1) Atypicals have less tendency to produce
motor side effects
2) Atypicals produce effects on negative
symptoms of schizophrenia
3) May have effects in therapy-resistant
patients
91

Parkinson's disease
Parkinson's disease (PD also known as idiopathic or primary
parkinsonism) is a degenerative disorder of the central
nervous system. The motor symptoms of Parkinson's
disease result from the death of dopamine-generating cells
in the substantia nigra, a region of the midbrain; the cause
of this cell death is unknown. Early in the course of the
disease, the most obvious symptoms are movementrelated;
these
include shaking, rigidity, slowness
of
movement and difficulty with walking and gait. Later,
thinking and behavioral problems may arise, with dementia
commonly occurring in the advanced stages of the
disease, whereas depression is the most common
psychiatric symptom. Other symptoms include sensory,
sleep and emotional problems. Parkinson's disease is more
common in the elderly, with most cases occurring after the
age of 50
92

Parkinson's disease
The four primary symptoms of PD are tremor, or
trembling in hands, arms, legs, jaw, and face;
rigidity, or stiffness of the limbs and trunk;
bradykinesia, or slowness of movement; and
postural instability, or impaired balance and
coordination. As these symptoms become more
pronounced, patients may have difficulty walking,
talking, or completing other simple tasks. PD usually
affects people over the age of 50. Early symptoms
of PD are subtle and occur gradually.

93

Clinical features of PD
Three cardinal symptoms:
resting tremor
bradykinesia
(generalized
slowness of movements)
muscle rigidity

94

Clinical features of PD
Resting tremor: Most common first symptom, usually
asymmetric and most evident in one hand with the arm at
rest.

Bradykinesia: Difficulty with daily activities such as writing,

shaving, using a knife and fork, and opening buttons;
decreased blinking, masked facies, slowed chewing and
swallowing.

Rigidity: Muscle tone increased in both flexor and extensor

muscles providing a constant resistance to passive movements
of the joints; stooped posture, anteroflexed head, and flexed
knees and elbows.
95

Additional clinical features of PD

Postural instability: Due to loss of postural reflexes.

Dysfunction of the autonomic nervous system:
Impaired
gastrointestinal motility, bladder dysfunction,
sialorrhea, excessive head and neck sweating, and
orthostatic hypotension.
Depression: Mild to moderate depression in 50 % of
patients.
Cognitive impairment: Mild cognitive decline
including impaired visual-spatial perception and
attention, slowness in execution of motor tasks, and
impaired concentration in most patients; at least 1/3
96
become demented during the course of the disease.

Functional neuroanatomy of PD
Substantia nigra: The major origin of the dopaminergic
innervation of the striatum.

Part of extrapyramidal system which processes

information coming from the cortex to the striatum,
returning it back to the cortex through the thalamus.

One major function of the striatum is the regulation of

posture and muscle tonus.

97

Dopamine pathways in human brain

98

Neurochemistry of PD
PD symptoms become manifest when about 50-60 % of
the DA-containing neurons in the substantia nigra and
70-80%ofstriatalDAarelost.
The ventral tegmental area (VTA) cells project to
limbic (mesolimbic projection) and cortical
(mesocortical projection) areas. Neurons of the
substantia nigra project to the striatum (nigrostriatal
projection). In PD, dopaminergic nerve cells in the
substantia nigra develop nerve cell loss, and its
degeneration and the resulting striatal dopamine
depletion are responsible for most of the motor
abnormalities

99

Dopamine synthesis

100

Therapy of PD: levodopa

Late1950s:L-dihydroxyphenylalanine(L-DOPA;levodopa),
aprecursorofDAthatcrossestheblood-brainbarrier,could
restore brain DA levels and motor functions in animals
treatedwithcatecholaminedepletingdrug(reserpine).

First treatment attempts in PD patients with levodopa

resultedindramaticbutshort-termimprovements;tookyears
beforeitbecomeanestablishedandsuccesfulltreatment.

Still today, levodopa cornerstone of PD treatment; virtually

allthepatientsbenefit.

101

TherapyofPD:limitationsoflevodopa
Efficacy tends to decrease as the disease
progresses.
Chronictreatmentassociatedwithadverseevents
(motor
fluctuations,
dyskinesias
and
neuropsychiatricproblems).
Doesnotpreventthecontinuousdegenerationof
nerve cells in the subtantia nigra, the treatment
beingthereforesymptomatic.

102

Inhibition of peripheral COMT by entacapone

increases the amount of L-DOPA and dopamine
in the brain and improves the alleviation of PD
symptoms.

103

TherapyofPD:Othertreatments
DA receptor agonists (bromocriptine,

pergolide, pramipexole, ropinirole,

cabergoline)
Amantadine
Anticholinergics

104

 Alzheimer's disease (AD), also known as Senile

Dementia of the Alzheimer Type (SDAT) or simply
Alzheimers is the most common form of dementia.
This incurable, degenerative, terminal disease was first
described by a German psychiatrist and neuropathologist
Alois Alzheimer in 1906 and was named after him.
Alzheimer's disease (AD) is a slowly progressive disease
of the brain that is characterized by impairment of
memory and eventually by disturbances in reasoning,
planning, language, and perception.
Many scientists believe that Alzheimer's disease results
from an increase in the production or accumulation of a
specific protein (beta-amyloid protein) in the brain that
leads to nerve cell death.

105

 Generally, it is diagnosed in people over

65 years of age, although the lessprevalent early onset of Alzheimers can
occur much earlier.
In 2006, there were 26.6 million sufferers
worldwide.
Alzheimers is predicted to affect 1 in 85
people globally by 2050.
106

107

1) Early Stage
This is considered as a mild/early stage and the
duration period is 2-4 years.
Frequent recent memory loss, particularly of recent
conversations and events.
Repeated questions, some problems expressing
and understanding language.
Writing and using objects become difficult and
depression and apathy can occur.
Need reminders for daily activities and difficulties
with sequencing impact driving early in this stage.
108

2) Second stage
This is considered as a middle/moderate stage and
the duration is 2-10 years.
Pervasive and persistent memory loss impacts life
across settings.
Rambling speech, unusual reasoning, confusion
about current events, time, and place.
Slowness, rigidity, tremors, and gait problems
impact mobility and coordination.
Need structure, reminders, and assistance with
activities of daily living.

109

3) Moderate stage
Increased memory loss and confusion.
Problems recognizing family and friends.
Inability to learn new things.
Difficulty carrying out tasks that involve multiple steps
(such as getting dressed).
Problems coping with new situations.
Delusions and paranoia.
Impulsive behavior.
In moderate AD, damage occurs in areas of the brain
that control language, reasoning,
sensory
processing, and conscious thought
110

4) Last stage
This is considered as the severe stage and the
duration is 1-3 years.
Confused about past and present. Loss of
recognition of familiar people and places
Generally incapacitated with severe to total loss
of verbal skills.
Unable to care for self. Immobility likely.
Patients need total support and care, and often
die from infections or pneumonia
111

 Alzheimer's disease is usually diagnosed clinically from

the patient history, collateral history from relatives, and
clinical observations, based on the presence of
characteristic
neurological
and
neuropsychological
features and the absence of alternative conditions.
Advanced medical imaging with computed tomography
(CT) or magnetic resonance imaging (MRI), and with
single photon emission computer tomography (SPECT) or
positron emission tomography (PET) can be used to help
exclude other cerebral pathology or subtypes of dementia.
The diagnosis can be confirmed with very high accuracy
post-mortem when brain material is available and can be
examined histologically.
112

 Scientists dont yet fully understand what causes AD. It is

likely that the causes include genetic, environmental, and
lifestyle factors.
Some drug therapies propose that AD is caused by
reduced synthesis of the neurotransmitter acetylcholine.
Alzheimer's disease is characterized by a build-up of
proteins in the brain. Though this cannot be measured in a
living person, extensive autopsy studies have revealed this
phenomenon. The build-up manifests in two ways:

Plaques deposits of the protein beta-amyloid that

accumulate in the spaces between nerve cells

Tangles deposits of the protein tau that

accumulate inside of nerve cells

113

 Alzheimer's disease is characterised by loss of neurons

and synapses in the cerebral cortex and certain
subcortical regions. This loss results in gross atrophy of
the affected regions, including degeneration in the
temporal lobe and parietal lobe, and parts of the frontal
cortex and cingulate gyrus.
Both amyloid plaques and neurofibrillary tangles are
clearly visible by microscopy in brains of those afflicted by
AD.
Plaques are dense, mostly insoluble deposits of amyloid
beta peptides and cellular material outside and around
neurons.
Tangles (neurofibrillary tangles) are aggregates of the
microtubule-associated protein tau which has become
hyperphosphorylated and accumulate inside the cells
themselves.
114

 Although there is currently no way to cure Alzheimer's

disease or stop its progression, researchers are
making encouraging advances in Alzheimer's
treatment, including medications and non-drug
approaches to improve symptom management.
Mild/Moderate AD:
Cholinesterase inhibitors increase the levels of
acetylcholine in the brain, which plays a key role in
memory and learning. This kind of drug postpones the
worsening of symptoms for 6 to 12 months in about
half of the people who take it. Cholinesterase inhibitors
most commonly prescribed for mild to moderate
Alzheimer's disease include Aricept (donezepil HCL),
Exelon (rivastigmine), and Razadyne (galantamine).
115

 Moderate/Severe AD:
Namenda (memantine) regulates glutamate
in the brain, which plays a key role in
processing information. This drug is used to
treat moderate to severe Alzheimer's disease
and may delay the worsening of symptoms
in some people. It may allow patients to
maintain certain daily functions a little longer
than they would without the medication.
116

 Exelon is a cholinesterase inhibitor that

prevents the breakdown of acetylcholine and
butyrylcholine in the brain by blocking the
activity of two different enzymes.
Acetylcholine and butyrylcholine play a key
role in memory and learning.
When given orally, bioavailability is about
40% in the 3 mg dose. The compound can
cross the blood-brain barrier.
117

Aricept (Donepizel)
One of the most widely used drugs to
treat the symptoms of Alzheimer's
disease. Aricept is FDA-approved for
mild, moderate, and severe stages of
the disease.

118

 Aricept is available in tablet form or an

orally disintegrating tablet form, and is
commonly started at 5 mg a day.
Can cross the blood-brain barrier.

119

Namenda (Memantine)
Namenda is an N-methyl D-aspartate
(NMDA) antagonist that regulates the
activity of glutamate in the brain.
Glutamate plays a key role in memory
and learning, but excess glutamate can
lead to the disruption of nerve cell
communication or nerve cell death.
120

 Studies involving Namenda have shown that the

drug can slow the rate of decline in thinking and
the ability to perform daily activities in
individuals who have moderate to severe
Alzheimer's disease
A
dysfunction
of
glutamatergic
neurotransmission is thought to be involved in
the etiology of AD.
Namenda is available in generic form
(memantine HCL).
121

Adverse pharmacological effects

a) Behavioural Effects (pseudodepression,
akinesia, confusion)
b) Neurological Effects (parkinsonism,
akathisia, dystonia, tardive dyskinesia)
c) Autonomic Effects (orthostatic hypotension,
impaired ejaculation)
d) Metabolic and Endocrine Effects (weight
gain, hyperprolactinemia, loss of libedo,
impotence)
e) Toxic or allergic effects (agranulocytosis,
choleostatic jaundice, clozapine)
122

Adverse pharmacological effects

f) Ocular complications (thioridazine only)
g) Cardiac toxicity (Thioridazine T wave
abnormality)
h) Neuroleptic Malignant Syndrome (life
threatening, marked muscle rigidity,
sweating, fever, autonomic instability, blood
pressure, heart rate, muscle breakdown,
CV collapse, arrhythmias mortality = 5-12%

123

Pharmacological effects
A. Effects on dopamine systems
i. Mesolimbic/ mesocortical
ii. Nigrostriatal
iii. Tuberoinfundibular
B. Dopamine receptors and their effects
i. D1/D5
ii. D2/D3/D4 family
124

125

Drug Combinations
Combining antipsychotic drugs confounds evaluation of
the efficacy of the drugs being used. Use of
combinations, however, is widespread, with more
emerging experimental data supporting it.
Tricyclic antidepressants or, more often, SSRIs may be
used with antipsychotics for clear symptoms of
depression complicating schizophrenia.
Lithium or valproic acid is sometimes added to
antipsychotic agents with benefit to patients who do
not respond to the latter drugs alone. Clozapine plus
lamotrigine developed here in Psychiatry.
It is
uncertain
whether
such
instances
represent
misdiagnosed cases of mania or schizoaffective
disorder. Sedative drugs may be added for relief of
126
anxiety or insomnia not controlled by antipsychotics.