6. Psychosis
a variety of mental disorders e.g.,
Schizophrenia:
characterized by a “ clear sensorium ”
but a “ marked-disturbed thinking ”
- Hallucination
- Delusions ( False beliefs)
7. Not curatives
Decrease intensity of symptoms
i.e.
• Hallucination,
Auditory, Visual, Tactile, Olfactory
• Delusions (False Beliefs)
Patient can function/move in supportive
enviornament
9. Genetic & Environmental Factors
Single gene predisposes
Environmental factors required for
Schizophrenia to develop.(appear with age)
Identical twins one has schizophrenia….
Probability 50% … points towards
Environmental factors
Neurodegeneration ? [Prgressive Development
10. Neuroanatomical & Neurochemical
Basis of Shizopherania
Malfunction in different Neuronal Circuits
• Changes in Mesolimbic pathways +ive
• Changes in Mesocortical pathways - ive
Dopamine Hypothesis
Serotonin Hypothesis
Glutamate Hypothesis
• (NMDA Hypofunction Hypothesis [Coyle 2006])
On the basis of indirect
pharmacological evidence
11. Symptoms of Schizophrenia
Positive Symptoms
Delusions
Hallucinations
Thought Disorders
Abnormal disorganized
behaviour
Catatonia (purposeless
motor activity)
Negative Symptoms
Withdrawal from social
contact
Flattening of emotional
responses
Anhedonia (inability to
express pleasure)
Reluctance to perform every
day tasks
12. Amphetamine release dopamine in brain behavioural
syndrome …. Mimic Schizophrenia “CARLSON 2000”
I. Dopamine-Hypothesis:
Evidence of
Dopaminergic activity underlying this
disorder.
a). D - agonists leads to Schizophrenic symptoms.
b). Increased Dopamine-Density in brains of
Schizophrenic patients ( post mortalm reports ).
c). Typical Antipsychotic are D2 blockers……
d). Positron Emission Tomography (haloperidol binding)
“excessive”
13. Against Dopamine Hypothesis
Dopminergic activity is suggesteted as cause of
Cognitive Impairment & Negative symptoms of
Scizopherania
Dopaminergic Innervation in Medial Temporal
Cortex, Dorsolateral prefrontal cortex,
Hippocampus In decreased levels of DOPAC
(dihydroxyphenylacetic acid)
Several atypical drugs has much less effect on
D2 receptors & yet are effective
14. Serotonin Hypothesis
5HT2A receptor blockade is key factor In M.O.A.
of ATYPICAL drugs (Inverse agonists)
5HT2A receptors modulate the releases of
Dopamine (Cortex, Limbic Region)
5HT2A stimulation leads to depolarization of
Glutamate Neurons
5HT2A Also stabilize NMDA receptors
5HT2C currently being studied as antipsychotic
15. Glutamate/NMDA Hypofuntion
Hypothesis
NMDA receptor antagonists (ketamine,
Phencyclidine,dizocilpine) can produce
+ive & -ive symptoms
• Amphetamine produce only +ive symptoms
It has been postulated
“ schizophrenia may result from disruption of
Glutamatergic neurotransmission [Moghaddam,
2003]… Evident as reduction in function of
NMDA receptors [ Coyle, 2006]”
17. D2-like receptor group
(correlated with antipsychotic activity )
(Gi/G0 coupled … inhibitadeny cyclase …activate K+
channels, inhibit Ca++, may also activate Phosphlipase C)
i. D-2 receptor ( found pre- & postsynaptically in the
caudate-putamen, nucleus accumbens and olfactory
tubercle ):decreases cAMP and inhibits Ca++ channels
but opens K+ channels.
ii. D-3 receptors ( located in the frontal cortex,
medulla and midbrain ): decreases cAMP.
iii. D-4 receptors also decreases cAMP.
18. Dopaminergic Pathways
Five important pathways / systems in the brain.
1. Mesolimbic-mesocortical Pathways:
more closely related to behavior;
( it projects from cell bodies near to substantia nigra to the limbic
system and neocortex ) …+ive & -ive Symptoms
2. Nigrostriatal Pathways:
involved in coordination of voluntary movement;
( it projects from substantia nigra to the caudate and putamen.)
[ Extrapyramydal Effects …. Dystonias, Tardive dyskinasias]
19. 3. Tuberoinfundibular System:
inhibits prolactin secretion;
( connects arcuate nuclei and periventricular neurons to the
thalamus and posterior pituitary.)
4. Medullary-periventricular Pathways:
involved in eating behavior;
( consists of neurons in the nucleus of the vagus whose
projections are not well defined.)
5. Incertohypothalamic Pathways:
It regulates the anticipatory motivational phase
of copulatory behavior in rats;
( connections from the medial zone incerta to the hypotalamus
and amygdala.)
20. II. Role of Other Neurotransmitters:
excessive Serotonin / GABA etc. Activity.
a). Decreased 5-HT2 activity
by Risperidone, Olanzapine.
b). Decreased GABA, Glutamatergic &
Cholinergic activity, or some α1-blockers.
21. 5-HT Receptors
i. 5-HT1A receptors
ii. 5-HT2A receptors:
LSD – Lysergic acid Diethylamide - is an agonist here
produces transient hallucinations and other mental
aberrations including insomnia.
Similarly Psilocin ( found in mushrooms ),
DMT- Dimethyltryptamine - are also hallucinogens.
Ectasy produces euphoria followed by depression etc.
24. According to Receptor Selectivity
( In descending order )
a) On Dopamine
Receptors
Thiothixene,
Chlorpromazine,
Fluphenazine,
Haloperidol,
Aripiprazole,
Clozapine,
Risperidone,
Olanzapine,
Quetiapine,
Ziprasidone.
b) On 5-HT2A
Receptors
Clozapine,
Risperidone,
Olanzapine,
Quetiapine,
Ziprasidone,
Aripiprazole,
Haloperidol,
Chlorpromazine,
Fluphenazine,
Thiothixene.
33. Rapid but incomplete absorption;
Significant first pass metabolism
( oral bioavailability of chlorpromazine &
thioridazine is 25% to 35% while of haloperidol
is about 65%.)
Highly lipid soluble & protein-bounded ( 92-99%);
Vd > 7 L/kg.
Prolonged D2 & other receptors occupancy, so
longer duration of action than their half lives.
Pharmacokinetics
34. Pharmacokinetics ( cont.)
metabolites are not so active but mesoridazine,
a metabolite of thioridazine is more potent than
parent drug.
Excretion
Almost all are completely metabolized into
more water soluble substances. Metabolites of
chlorpromazine may be excreted in the urine
after weeks of the last dose of chronically given
drugs.
35. Concerning hypothesis for pathophysiological
basis of schizophrenia, which statement is
accurate?
a: All clinically effective antipschotic drugs have
high affinity for D2 receptors
b: Dopamine receptor blocking drugs are used to
alleviate psychotic symptoms in parkinsonism
c: Drug induced psychosis can occur without
activation of brain dopamine receptors
d: Serotonin receptors are present at lower than
normal levels in the brains of untreated
schizophrenics
E: The clinical potency of clozapine correlate well
with its dopamine receptor blocking activity
C
36. Regarding Classification of antipsychotic drugs
which is highly selective for D2 receptors
a: Sulpride
b: Clozapine
c: Olanzapine
d: Quetiapine
e: Risperidone
a
40. a ). CNS
1.
i). Behavioral Effects dopaminergic site at
limbic system & reticulating activating system:
- Depressing- anesthesia like state;
- Open Chain are more sedating & less Antipsychotic;
but chlorpromazine after longer use is antipsychotic
( pt. is less disturbed & having fewer hallucinations &
delusions );
- In acute cases– a quietening effect in agitated &
disturbed patients.
41. Tolerance develops only to sedative effects
ii). Extra pyramidal Effects(acute dystonias & Tardive dyskinesias)
Dystonia …involunry movements, retlessness, Muscle spasm, Protuding
tounge, fixed upward gaze, Torticolis (Involuntry spasm of neck muscles)
Dopaminergic Sites: at Nigrostriatal Sites:
rarely in acute cases;
Parkinsonism like:
due to increased cholinergic activity in CNS
( to counter act the decreased dopaminergic activity )
so Antipsychotic with high anticholinergic activity like
Thioridazin will have lowest incidence of parkinsonism
like symptoms but has high esdative & hypotensive
effects.
42. Tardive Dyskinesia: ( after months ….. Tardive)
Disabeling. Irreversible,
involuntry movements of face & tongue, also trunk & limbs
perhaps due to imbalance of Ach. & Dopamine activity
( esp. decreased cholinergic activity leads to up
regulation of dopaminergic receptors – super
sensitivity which may occur after prolong therapye.g.,
by thioridazine like drugs which intensify this
syndrome )
Treatment is to discontinue all drugs with
anticholinergic activity or reduce the dose.
If it fails give Diazepam in larger doses.
2. Medulla at CTZ( therapeutic doses ) &
Vomiting Center( larger doses ): Anti- Emetic effect
43. b). Autonomic Nervous System
i). α- Receptors: α – Blockade with initial small
dose (orthostatic hypotension & impaired
ejaculation)
but with chronic dose stimulation occurs.
ii). Muscarinic & Nicotinic Receptors:
weak action & blocked
iii). Histaminergic Receptors:
Antihistaminic Effect
44. Uses
a). Psychiatric Uses
1. Schizophrenia
some patients do not respond at all.
2. Schizoaffective Disorders
antipsychotic with antidepressants, lithium or
valproic acid.
3. Manic episode in Bipolar Disorders
Olanzapine alone may be useful here
which is withdrawn when mania subsides.
45. 4. Nonmanic Excitated State
Benzodiazepines are combined.
5. Tourette’s Syndrome
6. Alzheimer Senile Dementia
7. Anxiety with Emotional Disorders
with sedative drugs.
46. b). Non-psychiatric Uses
1. Anti-emetic
due to dopamine receptors blockade at CTZ & Stomach
e.g., Prochlorperazine, Benzquinamide.
2. Anti-histaminic for pruritus.
3. Preoperative Sedative Promethazine.
4. As neuroleptanalgesia Droperidol with
Fentanyl.
48. c). Hypothalamus
i). Temperature Regulating Center
by depressing it .…Hypothermia ; but in high
environmental temperature hyperthermic
episode may occur due to failure to lose body
temperature.
ii). Prolactin Release ….
Hyperprolactinemia results:
in women
amenorrhea - galactorrhea & infertility,
and in men
loss of libido, impotence & infertility
49. d). Pituitary
i). Increased Melanocyte Hormone Activity
– Hyper pigmentation esp. with those drugs which
have high antipsychotic activity.
ii). Increased Gonadotropin Activity –
Delayed Ovulation & Menstruation ;
with high doses amenorrhea.
iii) . False positive pregnancy test
iv). Hyperglycemia in non-diabetic patients.
v). Weight gain occurs esp. with
clozapine and olanzapine.
50. e). CVS
Orthostatic hypotension and
High resting pulse rates due to large doses of low potency drugs.
Decreased mean arterial pressure, peripheral resistance
and stroke volume but increased heart rate.
ECG
Cardiac toxicity esp. with thioridazine
Ventricular arrhythmias,
Conduction block & sudden death;
Prolongation of QT interval and abnormal ST-
segment & T waves esp. with Sertindol &
Ziprasidone ;
but all are reversible.
51. f). Allergic Reactions
at skin ( eruption rarely ),
liver ( homeostatic jaundice ),
Blood ( agranulocytosis )
esp. with clozapine which is potentially fatal
but reversible.
g). Miscellaneous
Ocular Complications
Drug Deposits in cornea & lens; retinal deposits
with thioridazine associated with browning of
vision.
Use in Pregnancy
Dysmorphogenesis: teratogenesis
52. Neuroleptic Malignant Syndrome
( life threatening disorder in patients
who are extremely sensitive to extra pyramidal
effects of antipsychotic;
there is
Excessive & rapid blockade of postsynaptic
dopamine receptors.
54. An adverse effect that is common to most
phenothiazines is
a: A marked increase in blood pressure
b: Rigidity and tremour at rest especially with
prolong use
c: Suppression of lactation
d: A diminished response to CNSdepressants
e: Nausea
b
55. The least likely side effect seen in patient taking
chlorpromazine for two months would be
a: Extrapyramidal symptoms
b: Hypotension
c: Lethargy
d: weight gain
e: Nausea & Vomiting
e