L05 Antipsychotics Flashcards
Describe briefly what ‘schizophrenia’ is.
Chronic disease that is highly disabling to social & vocational functioning
- Onset in late adolescence / early adulthood
- Lifetime incidence of schizophrenia = ~ 1%
- Prevalence = ~0.3%
What are the five classical symptom domains of schizophrenia?
1) Positive symptoms
2) Negative symptoms
3) Cognitive symptoms
4) Aggressive symptoms
5) Anxiety / Depression
Explain what the positive symptoms of schizophrenia are.
Abnormal behaviours are added & are often interspersed with periods during which negative symptoms predominate.
- Usually the presentation of positive symptoms that is most disturbing to others leads to first referral for detection of schizophrenia
- Patients usually lack insight on these +ve symptoms
E.g.:
- Delusions (often paranoia)
- Hallucinations (e.g. exhortatory voices)
- Thought disorders (i.e. feeling that thoughts are controlled by an outside agency)
- Stereotypical or aggressive behaviours
Explain what the negative symptoms of schizophrenia are.
Normal behaviours are subtracted & are often interspersed with periods during which positive symptoms predominate.
- For the individual, the presentation of negative symptoms are often most distressing to themselves & are cognizant of (in contrast to lack of insight of +ve symptoms).
- Generally become more dominant with disease progression
- Frequently associated with depression consequently
- Results in suicide in 10% of cases
E.g.:
- Withdrawal from social contacts
- Flattening of emotional responses
Patients who present with positive symptoms of schizophrenia are often aware of their display and are subsequently distressed about them. True or false?
False!
Pt w/ schizophrenia are generally aware & distressed by negative symptoms, BUT lack insight on positive symptoms displayed.
- Others are more disturbed by positive symptoms.
Explain what causes the manifestation of negative symptoms of schizophrenia.
Primary deficit of the illness (schizophrenia) Secondary causes include: - Depression - Extrapyramidal symptoms (EPS) - Environmental deprivation - Positive symptoms
Explain what the cognitive symptoms of schizophrenia are.
Cognitive dysfunction resulting in:
- Impairment of selective attention
- Impairment of working memory
Recently recognised to be a persistent core feature of disease, NOT iatrogenic
- Impt as it predicts level of social & vocational functioning & thus Tx outcome, rather than via positive symptoms (less prominent over time)
Cognitive symptoms of schizophrenia are manifested as a result of long-term use of antipsychotics. True or false?
False
Recently recognised to be a persistent core feature of schizophrenia, NOT via iatrogenic (i.e. by physician or medications) causes!
Explain the etiology of schizophrenia.
1) Genetic factors:
- Incomplete hereditary tendency, in which there is a 50% risk of being symptomatic for schizophrenia in monozygotic twin of affected individual
- Genetic studies established linkage to various chromosomal regions
- Genes for susceptibility have been elusive, but some candidate genes identified are e.g. DISC1, neuregulin, dysbindin 1, COMT
- Not all schizophrenics share the same mutations of susceptibility genes.
2) Environmental factors:
- Various theories relating to possible neurodevelopmental abnormalities e.g. maternal viral infections during pregnancy or obstetric complications
3) Neurodevelopmental disorder:
- Onset in late adulthood / early adulthood is consistent with neurodevelopment abnormality involving myelination of corticocortical pathways.
- Evidence of enlarged ventricles and abnormalities in laminar organisation of cortical cells
What was the proposal of neurochemical theories primarily for in the pathophysiology of schizophrenia?
To account for the manifestation of positive symptoms of schizophrenia.
Briefly describe the neurochemical theories proposed to explain how the various symptoms of schizophrenia are manifested.
1) Dopamine theory:
- Amphetamine (dopaminergic compound) produce symptoms similar to acute schizophrenia
- Most important basis for pharmacotherapy: ALL antipsychotics are D2 receptor antagonists that correlate with clinical efficacy.
2) Serotonin theory:
- Lysergic acid diethylamide (LSD; 5-HT2 agonist) produces symptoms similar to acute schizophrenia
- Many newer atypical antipsychotics have 5-HT2 antagonism
3) Glutamate theory:
- Drugs that block NMDA receptor channels (e.g. phencyclidine, ketamine) produces symptoms similar to acute schizophrenia
- Gaining popularity in research, but yet to produce clinically useful drugs via NMDA agonist activity.
Explain what the dopamine pathways of the brain are.
1) Nigrostriatal pathway (D1 > D2»_space; D3 = D4)
- From substantia nigra to dorsal striatum
- Involved in voluntary movement
- Antipsychotics may affect this pathway as off-target effects due to presence of D2 receptors, resulting in extrapyramidal symptoms (EPS)
2) Mesocortical pathway (primarily D4)
- From ventral tegmental area (VTA) to prefrontal cortex
- Involved in cognition & attention
- Dopamine is increased in acute schizophrenia
3) Mesolimbic pathways (primarily D4)
- From ventral tegmental area (VTA) to limbic brain
- Involved in reward & emotion
- Dopamine is increased in acute schizophrenia
4) Tuberinfundibular pathway (D3 > D2)
- From hypothalamus to anterior pituitary gland
- Regulates prolactin secretion into blood circulation
- Antipsychotics may affect this pathway as off-target effects due to presence of D2 receptors, resulting in gynaecomastia in males OR breast swelling, pain & lactation in females
Explain what ‘extrapyramidal side effects’ refer to.
Acute dystonias, tardive dyskinesia & akathisia
- i.e. motor symptoms
Extrapyramidal pathway involves the basal ganglia, including the dorsal striatum & substantial nigra
- Thus, D2 antagonism of nigrostriatal pathway result in Parkinsonian-like syndrome.
- However, pyramidal motor pathway is the output from primary motor cortex via pyramids of medulla oblongata to spinal cord.
- Thus, motor side-effects are due to the actions on extrapyramidal motor pathways, rather on pyramidal motor pathway!
Explain what ‘acute dystonia’ refers to.
Parkinsonian-like syndrome:
- Displayed as cogwheel rigidity & tremor at rest
- Occur w/in first few weeks of Tx
- Reversible when drug is stopped
- Appeared to be caused by D2 antagonism of nigrostriatal pathway
Explain what ‘tardive dyskinesia’ refers to.
Tardive: Slow development over months / years of Tx
Dyskinesia: Repetitive & stereotypical involuntary movements of face, tongue & limbs
- Occurs in 20-40% of patients on typical antipsychotics
- Often irreversible
- Most likely due to upregulation or hypersensitivity of dopamine receptors in the nigrostriatal pathway
- Blockade of receptors in nigrostriatal dopaminergic pathway possibly led to upregulation of dopamine receptors -> tardive dyskinesia
Explain what ‘akathisia’ refers to.
Involuntary movements & compulsion to act, in association with restlessness, anxiety & agitation.
- Akathisia correlates directly w/ duration of medication.
- Occurs in 20-40% of patients on typical antipsychotics
- Often irreversible
- Most likely due to upregulation of dopamine receptors in the nigrostriatal pathway
There is a general positive correlation between the duration in which a patient is on typical antipsychotics with the development of tardive dyskinesia. True or false?
False.
Akathisia correlates directly with duration of antipsychotics, NOT tardive dyskinesia.
Many schizophrenics are able to come off their antipsychotics & retain near pre-illness levels of function. True or false?
False
- Schizophrenia is a chronic illness that requires patients to be on almost lifelong antipsychotics.
- There is still an unmet need for improved antipsychotics!
