NEUROPSYCHIATRY AND ANTIPSYCHOTICS

By

Ekam Emefiele

(Med. Student)

Dopamine pathways relevant to antipsychotic

pharmacology in the treatment of schizophrenia are:

Mesolimbic pathway

Mesocortical pathway

Nigrostriatal pathway

Tuberoinfundibular pathway

By blocking these pathways, antipsychotics can produce

both therapeutic and adverse effects.

Mesolimbic Pathway

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 accumbens.

Physiology: it is the centre for motivation, emotions, pleasure, compulsion.

Implication: D2 antagonism reduces positive symptoms of schizophrenia

Mesocortical Pathway

Anatomy: This tract is made up of dopaminergic neurons that projects from the VTA to the pre-frontal cortex.

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 schizophrenia

Nigrostriatal Pathway

This tract contains about 80% of the brain’s dopamine

Anatomy: It projects from the substantia nigra to basal

ganglia.

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).

Tuberoinfundibular Pathway

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

Antipsychotics

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.

Substances that can induce psychotic

symptom

These includes;

Alcohol

Cannabis (Marijuana)

Cocaine

Amphetamines

L. dopa

Schizophrenia

• 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

twenties.

• Genetic predisposition -- Familial incidence.

• Multiple genes are involved.

• Afflicts 1% of the population worldwide.

• May or may not be present with anatomical changes

Symptoms

Positive Symptoms :

Hallucinations, delusions, paranoia, excited motor

behaviour.

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

psychiatry disorders

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

increased efficacy.

APMs also variably blocks central and peripheral

cholinergic, histamine and alpha receptors

Classification of antipsychotic

drugs • PHARMACOLOGICAL CLASSIFICATION

– FIRST-GENERATION ANTIPSYCHOTIC (low potency)

• Chlorpromazine

• Prochlorperazine

• Thioridazine

– FIRST-GENERATION ANTIPSYCHOTIC (high potency)

• Fluphenazine (Modecate)

• Haloperidol (Haldol)

• Pimozide

• Thiothixene

• Zuclopenthixol (Clopixol)

– SECOND GENERATION ANTIPSYCHOTIC

• Aripiprazole • Asenapine

• Clozapine • Iloperidone

• Lurasidone • Olanzapine

• Quetiapine • Paliperidone

• Risperidone • Ziprasidone

Division of APMs based on receptor

blockade

There are three (3) main groups;

Pure D2 antagonist: Typical APMs (low and high potency).

D2-5HT2 antagonist: Risperidone

Multireceptor antagonist:

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

Typical

• Older agents

• Dopamine effects

• Many side effects

• Treatment of positive

symptoms

Atypical

• Newer agents

• Dopamine and serotonin

effects

• Fewer side effects

• Treatment of positive

and negative symptoms

Indications for APMs

Psychomotor agitation

Schizophrenia

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 APMsWeight 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

tract

Hematological problems such as agranulocytosis

with atypical APMs (clozapine as the most

problematic agent).

Neurologic effects

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.

Thank You