2. Psychosis
Psychosis is a thought disorder characterized
by disturbances of reality and perception,
impaired cognitive functioning, and
inappropriate or diminished affect (mood).
Psychosis denotes many mental disorders.
Schizophrenia is a particular kind of psychosis
characterized mainly by a clear sensorium but a
marked thinking disturbance.
4. Schizophrenia
• Pathogenesis is unknown.
• Onset of schizophrenia is in the late teens -
early ‘20s.
• Genetic predisposition -- Familial incidence.
• Multiple genes are involved.
• Afflicts 1% of the population worldwide.
• May or may not be present with anatomical
changes.
5. Schizophrenia
• A thought disorder.
• The disorder is characterized by a divorcement
from reality in the mind of the person (psychosis).
• It may involve visual and auditory hallucinations,
delusions, intense suspicion, feelings of
persecution or control by external forces
(paranoia), depersonalization, and there is
attachment of excessive personal significance to
daily events, called “ideas of reference”.
6. Schizophrenia
Positive Symptoms.
Hallucinations, delusions, paranoia, ideas of reference.
Negative Symptoms.
Apathy, social withdrawal, anhedonia, emotional blunting,
cognitive deficits, extreme inattentiveness or lack of
motivation to interact with the environment.
These symptoms are progressive and non-responsive to medication.
8. Etiology of Schizophrenia
Characterized by several structural and
functional abnormalities in the brains of
schizophrenic patients:
1) Enlarge cerebral ventricles.
2) Atrophy of cortical layers.
3) Reduced volume of the basal ganglia.
9. Dopamine Theory of Schizophrenia
Many lines of evidence point to the
aberrant increased activity of the
dopaminergic system as being critical in the
symptomatology of schizophrenia.
There is a greater occupancy of D2
receptors by dopamine => greater
dopaminergic stimulation
10. Dopamine Theory of Schizophrenia
Dopamine Correlates:
• Antipsychotics reduce dopamine synaptic activity.
• These drugs produce Parkinson-like symptoms.
• Drugs that increase DA in the limbic system cause
psychosis.
• Drugs that reduce DA in the limbic system (postsynaptic
D2 antagonists) reduce psychosis.
• Increased DA receptor density (Post-mortem, PET).
• Changes in amount of homovanillic acid (HVA), a DA
metabolite, in plasma, urine, and CSF.
11. Pharmacodynamics
Anatomic Correlates of Schizophrenia...
Areas Associated with Mood and Thought Processes:
Frontal cortex
Amygdala
Hippocampus
Nucleus accumbens
Limbic Cortex
12. Dopamine Theory of Schizophrenia
Evidence against the Theory?
• Antipsychotics are only partially effective in most
(70%) and ineffective for some patients.
• Phencyclidine, an NMDA receptor antagonist,
produces more schizophrenia-like symptoms in non-
schizophrenic subjects than DA agonists.
• Atypical antipsychotics have low affinity for D2
receptors.
• Focus is broader now and research is geared to
produce drugs with less extrapyramidal effects.
13. Dopamine System
There are four major pathways for the
dopaminergic system in the brain:
I. The Nigro-Stiatal Pathway.
II. The Mesolimbic Pathway.
III. The Mesocortical Pathway.
IV. The Tuberoinfundibular Pathway.
17. Dopamine System
• DOPAMINE RECEPTORS
– There are at least 5 subtypes of receptors:
– D1 and D5: mostly involved in postsynaptic inhibition.
– D2, D3, and D4: involved in both pre-and postsynaptic
inhibition.
D2: the predominant subtype in the brain:
regulates mood, emotional stability in the limbic system
and movement control in the basal ganglia.
23. Antipsychotic treatments
Schizophrenia has been around perhaps, since the beginning of
humankind, however, it was not until the last century that
it was established as a separate entity amongst other
mental disorders.
Many treatments have been devised:
Hydrotherapy:
“The pouring of cold water in a stream, from a height of at least
four feet onto the forehead, is one of the most certain means of
subsiding violent, maniacal excitement that we have ever seen
tried”... wrote an anonymous physician in the early 1800’s.
24. Antipsychotic treatments
Lobotomies (Egaz Moniz).
In 1940’s Phenothiazenes were isolated and were
used as pre-anesthetic medication, but quickly
were adopted by psychiatrists to calm down their
mental patients.
In 1955, chlorpromazine was developed as an
antihistaminic agent by Rhône-Pauline Laboratories
in France. In-patients at Mental Hospitals dropped
by 1/3.
25. Antipsychotics treatment
Antipsychotics/Neuroleptics
• Antipsychotics are the drugs currently used in the
prevention of psychosis.
• They have also been termed neuroleptics,
because they suppress motor activity and
emotionality.
** These drugs are not a cure **
• Schizophrenics must be treated with medications
indefinitely, in as much as the disease in lifelong
and it is preferable to prevent the psychotic
episodes than to treat them.
26. Antipsychotics/Neuroleptics
Although the antipsychotic/neuroleptics are drugs
used mainly in the treatment of schizophrenia,
they are also used in the treatment of other
psychoses associated with depression and manic-
depressive illness, and psychosis associated with
Alzheimer’s disease. These conditions are life-
long and disabling.
30. Antipsychotics/Neuroleptics
• It appears that the specific interaction of
antipsychotic drugs with D2 receptors is
important to their therapeutic action.
• The affinities of most older “classical” agents
for the D2 receptors correlate with their
clinical potencies as antipsychotics.
31. Antipsychotic/Neuroleptics
Correlations between therapeutic potency
and affinity for binding D2 receptors.[3H]Haloperidolbinding
IC50(mol/L)
Clinical dose of drug [mg d-1]
haloperidol
clozapine
thiothixene
chlorpromazine
promazine
spiroperidole
32. Antipsychotics/Neuroleptics
• Both D1 and D2 receptors are found in high
concentrations in the striatum and the nucleus
accumbens.
• Clozapine has a higher affinity for the D4 receptors
than for D2.
• Recently it has been found that most antipsychotic
drugs may also bind D3 receptors (therefore, they
are non-selective).
33. Antipsychotics/Neuroleptics
• Antipsychotics produce catalepsy (reduce motor activity).
– BLOCKADE OF DOPAMINE RECPTORS IN BASAL GANGLIA.
• Antipsychotics reverse hyperkinetic behaviors (increased
locomotion and stereotyped behavior).
– BLOCKADE OF DOPAMINE RECPTORS IN LIMBIC AREAS.
• Antipsychotics prevent the dopamine inhibition of prolactin
release from pituitary.
– BLOCKADE OF DOPAMINE RECEPTORS IN PITUITARY.
hyperprolactinemia
34. Pharmacokinetics
Absorption and Distribution
• Most antipsychotics are readily but incompletely
absorbed.
• Significant first-pass metabolism.
• Bioavailability is 25-65%.
• Most are highly lipid soluble.
• Most are highly protein bound (92-98%).
• High volumes of distribution (>7 L/Kg).
• Slow elimination.
**Duration of action longer than expected, metabolites are present and
relapse occurs, weeks after discontinuation of drug.**
35. Pharmacokinetics
Metabolism
• Most antipsychotics are almost completely
metabolized.
• Most have active metabolites, although not
important in therapeutic effect, with one
exception. The metabolite of thioridazine,
mesoridazine, is more potent than the parent
compound and accounts for most of the
therapeutic effect.
42. Antipsychotics/Neuroleptics
• Newer drugs have higher affinities for D1, 5-
HT or α-AR receptors.
• NE, GABA, Glycine and Glutamate have also
been implicated in schizophrenia.
43. Antipsychotics/Neuroleptics
The acute effects of antipsychotics do not explain why their
therapeutic effects are not evident until 4-8 weeks of
treatment.
Blockade of D2 receptors
Short term/Compensatory effects:
⇑ Firing rate and activity of nigrostriatal and mesolimbic
DA neurons.
⇑ DA synthesis, DA metabolism, DA release
44. Antipsychotics/Neuroleptics
Presynaptic Effects
Blockade of D2 receptors
Compensatory Effects
⇑ Firing rate and activity of nigrostriatal and mesolimbic DA neurons.
⇑ DA synthesis, DA metabolism, DA release.
Postsynaptic Effects
Depolarization Blockade
Inactivation of nigrostriatal and mesolimbic DA neurons.
Receptor Supersensitivity
46. Antipsychotic/Neuroleptics
ClinicalEx. Py.
Drug Potency toxicity Sedation Hypote.
Chlorpromaz. Low Medium Medium High
Haloperidol High Very High Very High Low
Thiothixene High Medium Medium Medium
Clozapine Medium Very low Low Medium
Ziprasidone Medium Very Low Low Very low
Risperidone High Low Low Low
Olanzapine High Very Low Medium Very low
Sertindole High Very Low Very low Very Low
50. Antipsychotic/Neuroleptics
Some antipsychotics have effects at muscarinic
acetylcholine receptors:
dry mouth
blurred vision
urinary retention
constipation
Clozapine
Chlorpromazine
Thioridazine
51. Antipsychotic/Neuroleptics
Some antipsychotics have effects at α−adrenergic
receptors:
• orthostatic hypotension
Chlorpromazine
Thioridazine
Some antipsychotics have effects at H1-histaminergic
receptors:
• sedation
Risperidone
Haloperidol
52. Antipsychotic/Neuroleptics
Blockade of D2 receptors in
lactotrophs in breast increase prolactin
concentration and may produce breast
engorgement and galactorrhea.
53. Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
Is a rare but serious side effect of neuroleptic
(antipsychotic) therapy that can be lethal. It
can arise at any time in the course of
treatment and shows no predilection for age,
duration of treatment, antipsychotic
medication, or dose.
54. Antipsychotic/Neuroleptics
Neuroleptic Malignant Syndrome
• Occurs in pts. hypersensitive to the Ex.Py. effects of
antipsychotics.
• Due to excessively rapid blockade of postsynaptic dopamine
receptors.
• The syndrome begins with marked muscle rigidity.
• If sweating is impaired, a fever may ensue. The stress
leukocytosis and high fever associated with this syndrome
may be mistaken for an infection.
• Autonomic instability with altered blood pressure and heart
rate is another midbrain manifestation.
• Creatine kinase isozymes are usually elevated, reflecting
muscle damage.
56. Antipsychotic/Neuroleptics
Drug Interactions
• Additive effects with sedatives.
• Additive effects with anticholinergics.
• Additive effects with antihistaminergics.
• Additive effects with α-AR blocking drugs.
• Additive effects with drugs with quinidine-like
action (thioridazine).
Editor's Notes
The synapse and synaptic neurotransmission
Dopamine and the production of cyclic AMP
Dopamine binding to receptors and uptake pumps in the nucleus accumbens
