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 dopamineAnatomy: 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;AlcoholCannabis (Marijuana)CocaineAmphetamines 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, 5HT2b. Olanzapine - D2, D4, 5HT2c. Quetiapine - D2, D4, 5HT2d. Ziprasidone - D2, D4, 5HT2e. 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 agitationSchizophreniaOther 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 activityHypotension – 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