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
Neurodegeneration ? [Prgressive Development
Neuroanatomical & Neurochemical
Basis of Shizopherania
Malfunction in different Neuronal Circuits
• Changes in Mesolimbic pathways +ive
• Changes in Mesocortical pathways - ive
• (NMDA Hypofunction Hypothesis [Coyle 2006])
On the basis of indirect
Symptoms of Schizophrenia
Withdrawal from social
Flattening of emotional
Anhedonia (inability to
Reluctance to perform every
Amphetamine release dopamine in brain behavioural
syndrome …. Mimic Schizophrenia “CARLSON 2000”
Dopaminergic activity underlying this
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)
Against Dopamine Hypothesis
Dopminergic activity is suggesteted as cause of
Cognitive Impairment & Negative symptoms of
Dopaminergic Innervation in Medial Temporal
Cortex, Dorsolateral prefrontal cortex,
Hippocampus In decreased levels of DOPAC
Several atypical drugs has much less effect on
D2 receptors & yet are effective
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
5HT2A Also stabilize NMDA receptors
5HT2C currently being studied as antipsychotic
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]”
D1-like receptors group
(Gs coupled …. Stimulate adenylcyclase
( no correlated antipsychotic activity ).
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.
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]
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
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.
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.
According to Receptor Selectivity
( In descending order )
a) On Dopamine
b) On 5-HT2A
Sites of Action of Neuroleptics & Lithium
Dopamine Neurons Receptive Membrane
at D2 & D1- receptors
More antipsychotic activity
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 ( cont.)
metabolites are not so active but mesoridazine,
a metabolite of thioridazine is more potent than
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
Concerning hypothesis for pathophysiological
basis of schizophrenia, which statement is
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
E: The clinical potency of clozapine correlate well
with its dopamine receptor blocking activity
Regarding Classification of antipsychotic drugs
which is highly selective for D2 receptors
a ). CNS
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 &
- In acute cases– a quietening effect in agitated &
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;
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
Tardive Dyskinesia: ( after months ….. Tardive)
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
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
b). Autonomic Nervous System
i). α- Receptors: α – Blockade with initial small
dose (orthostatic hypotension & impaired
but with chronic dose stimulation occurs.
ii). Muscarinic & Nicotinic Receptors:
weak action & blocked
iii). Histaminergic Receptors:
a). Psychiatric Uses
some patients do not respond at all.
2. Schizoaffective Disorders
antipsychotic with antidepressants, lithium or
3. Manic episode in Bipolar Disorders
Olanzapine alone may be useful here
which is withdrawn when mania subsides.
4. Nonmanic Excitated State
Benzodiazepines are combined.
5. Tourette’s Syndrome
6. Alzheimer Senile Dementia
7. Anxiety with Emotional Disorders
with sedative drugs.
b). Non-psychiatric Uses
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
i). Temperature Regulating Center
by depressing it .…Hypothermia ; but in high
environmental temperature hyperthermic
episode may occur due to failure to lose body
ii). Prolactin Release ….
amenorrhea - galactorrhea & infertility,
and in men
loss of libido, impotence & infertility
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.
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.
Cardiac toxicity esp. with thioridazine
Conduction block & sudden death;
Prolongation of QT interval and abnormal ST-
segment & T waves esp. with Sertindol &
but all are reversible.
f). Allergic Reactions
at skin ( eruption rarely ),
liver ( homeostatic jaundice ),
Blood ( agranulocytosis )
esp. with clozapine which is potentially fatal
Drug Deposits in cornea & lens; retinal deposits
with thioridazine associated with browning of
Use in Pregnancy
Neuroleptic Malignant Syndrome
( life threatening disorder in patients
who are extremely sensitive to extra pyramidal
effects of antipsychotic;
Excessive & rapid blockade of postsynaptic
An adverse effect that is common to most
a: A marked increase in blood pressure
b: Rigidity and tremour at rest especially with
c: Suppression of lactation
d: A diminished response to CNSdepressants
The least likely side effect seen in patient taking
chlorpromazine for two months would be
a: Extrapyramidal symptoms
d: weight gain
e: Nausea & Vomiting