Dopamine pathways relevant to antipsychotic
pharmacology in the treatment of schizophrenia are:
By blocking these pathways, antipsychotics can produce
both therapeutic and adverse effects.
This is relevant to positive symptoms of
schizophrenia (delusion and hallucination)
Anatomy: it is made up of projections from the
ventral tegmental area (VTA) to the nucleus
Physiology: it is the centre for motivation,
emotions, pleasure, compulsion.
Implication: D2 antagonism reduces positive
symptoms of schizophrenia
Anatomy: This tract is made up of dopaminergic
neurons that projects from the VTA to the pre-frontal
Physiology: it is relevant to the physiology of
cognition, negative symptoms, emotions and affects.
Implications: Hypofunction of this pathway might be
related to cognitive and negative symptoms of
This tract contains about 80% of the brain’s dopamine
Anatomy: It projects from the substantia nigra to basal
Physiology: It plays a key role in regulating movements.
Implication: D2 antagonism of this tract induces
extrapyramidal symptoms (pseudo-parkinsonism, akathisia,
acute dystonia) and Tardive dyskinesia (abnormal writhing
movement of the tongue, face and body).
This pathway influences prolactin release.
Anatomy: This tract projects from the hypothalamus to
the anterior pituitary.
Physiology: Dopamine tonically inhibits prolactin
Implication: D2 antagonism increases prolactin level
Psychosis is a thought disorder characterized by
disturbances of reality and perception, impaired
cognitive functioning, and inappropriate or diminished
Psychosis denotes many mental disorders.
Schizophrenia is a particular kind of psychosis
characterized mainly by a clear sensorium but a marked
Substances that can induce psychotic
• It is a thought disorder.
• The disorder is characterized by a divorcement from
reality in the mind of the person (psychosis).
• Pathogenesis is unknown.
• Onset of schizophrenia is in the late teens early
• Genetic predisposition -- Familial incidence.
• Multiple genes are involved.
• Afflicts 1% of the population worldwide.
• May or may not be present with anatomical changes
Positive Symptoms :
Hallucinations, delusions, paranoia, excited motor
Negative Symptoms :
Slow thought or speech, social withdrawal, emotional
blunting, cognitive deficits, extreme inattentiveness or
lack of motivation to interact with the environment.
Antipsychotic Medications (APMs)
Used to treat manifestations of psychosis and other
Precise mechanism of action is unknown, however
APMs blocks several populations of dopamine (D2,
D4) receptors in the brain.
The newer APMs also block serotonin (5-HT2)
receptors, a property that may be associated with
APMs also variably blocks central and peripheral
cholinergic, histamine and alpha receptors
Division of APMs based on receptor
There are three (3) main groups;
Pure D2 antagonist: Typical APMs (low and high
D2-5HT2 antagonist: Risperidone
a. Clozapine - D2, D4, 5HT2
b. Olanzapine - D2, D4, 5HT2
c. Quetiapine - D2, D4, 5HT2
d. Ziprasidone - D2, D4, 5HT2
e. Aripiprazole - D2, D4, 5HT2
Typical versus Atypical APMs
• Older agents
• Dopamine effects
• Many side effects
• Treatment of positive
• Newer agents
• Dopamine and serotonin
• Fewer side effects
• Treatment of positive
and negative symptoms
Indications for APMs
Other psychotic disorders – delusional, brief
psychotic, schizophreniform, schizoaffective,
substance-induced psychotic disorders
Mood disorders – useful for the treatment of agitation
and psychosis during mood episode.
General Adverse effects of APMs
Weight gain (olanzapine)
Sedation – due to antihistamine activity
Hypotension – effect is due to alpha adrenergic
blockade. It is most common with low potency APMs
Anticholinergic symptoms – dry mouth, blurred
vision, urinary retention, constipation, etc
Endocrine effects – gynecomastia, galactorrhea,
amenorrhea, due to blockade of tuberoinfundibular
Hematological problems such as agranulocytosis
with atypical APMs (clozapine as the most
Pseudoparkinsonism: It is characterized by muscle rigidity,
shuffling gait, masklike facial expression, resting tremor.
Acute dystonia: Prolonged muscle spasm. More common in
men younger than 40yrs. It may mimic seizure
Akathisia: Subjective feeling of motor restlessness.
Tardive dyskinesia: A disorder that involves involuntary,
repetitive movements of the muscles of the tongue, face and
body. You treat with low potency or atypical APMs.
Neuroleptic malignant syndrome: A rare but
potentially life-threatening reaction to APMs. It
causes fever, muscular rigidity, altered mental status,
excessive sweating, salivation, increased BP and
pulse rate. It is treated by stopping the agent and
providing medical support.