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!
Name the classes of medications available for the treatment of schizophrenia. Name some examples of each class of drugs.
1) Typical antipsychotics (-azine):
- In increasing order of D2 receptor affinity: Chlorpromazine, trifluoperazine, haloperidol, fluphenazine
2) Atypical antipsychotics:
- Serotonin-dopamine antagonism is the core of most atypical antipsychotics MOA
- E.g. [CORAA] Clozapine, olanzapine, risperidone, amisulpride & aripiprazole
Both typical & atypical antipsychotics can control both positive & negative symptoms of schizophrenia. True or false?
False!
Typical antipsychotics can control ONLY positive symptoms of schizophrenia AND effects of atypical antipsychotics on negative symptoms, cognition & mood stability are weak!
Which class of antipsychotics will result in stronger extrapyramidal side effects being experienced as potential side effects?
Typical antipsychotics
- Due to less selectivity for D4 receptors
- Result in off-target effects on nigrostriatal pathway by antagonising D2 receptors found on this pathway
Which typical antipsychotic was the first drug used for the Tx of schizophrenia?
Chlorpromazine
- Derived from antihistamines like TCAs
Which typical antipsychotic remains as one of the most widely used antipsychotic drugs for Tx of schizophrenia?
Haloperidol
Which typical antipsychotic lacks M1 & H1 receptor antagonism activity?
Haloperidol
What are some side effects experienced from the use of typical antipsychotics?
Chlorpromazine, trifluoperazine, haloperidol, fluphenazine:
- Extrapyramidal SE: acute dystonias, tardive dyskinesia & akathisia
- Antiadrenergic (alpha-1) SE: postural hypotension, dizziness
Chlorpromazine, trifluoperazine, fluphenazine:
(i. e. exclude haloperidol)
- Anticholinergic SE: blurred vision, dry mouth & constipation
- Antihistaminic SE: sedation, weight gain
What makes an antipsychotic atypical?
Production of less extrapyramidal side effects.
Many atypical antipsychotics have:
- Greater affinity for 5-HT2 receptor antagonism
- Greater affinity for D4 receptor antagonism -> less EPS
- Mixed antagonism at M1, H1, 5-HT2 & alpha-1 receptor
- Thus, serotonin-dopamine antagonism forms the ‘core’ MOA for most atypical antipsychotics, BUT these properties do NOT define atypicality!!
Which atypical antipsychotic is a selective D2/D3 antagonist?
Amisulpride
Which atypical antipsychotic is a partial agonist that serves as a functional antagonist in the presence of dopamine?
Aripiprazole
- Full 5-HT2 & 5-HT7 antagonism BUT partial agonist of D2 & D3
- Has ONLY H1 & alpha-1 antagonism
- NO M1 antagonism
Which atypical antipsychotics are more effective against negative symptoms of severe schizophrenia?
Clozapine, olanzapine & risperidone
Which atypical antipsychotics are more effective in ameliorating the cognitive dysfunction of severe schizophrenia, as compared to typical antipsychotics?
Clozapine & risperidone
- Due to additional 5-HT7 antagonism activities
Which atypical antipsychotics are more effective at mood stabilisation of severe schizophrenia, as compared to typical antipsychotics?
Clozapine, olanzapine & risperidone
What are some side effects experienced from the use of clozapine?
1) Extrapyramidal SE (less): acute dystonias, tardive dyskinesia & akathisia
2) Antiadrenergic (alpha-1) SE: postural hypotension, dizziness, reflex tachycardia
3) Anticholinergic SE (significant): blurred vision, dry mouth & constipation
4) Antihistaminic SE (significant): sedation
5) Clozapine-induced agranulocytosis (fatal: 1%)
- Regular blood counts are required to monitor pt
- Potentially fatal due to bone marrow supression
6) Drug-induced weight gain:
- Besides H1 antagonism, alpha-1 antagonism & 5-HT2 antagonism results in suppression of satiation -> hunger -> weight gain
7) Onset/exacerbation of diabetes:
- May not reverse even when drug is stopped
- Possible involvement of 5-HT antagonism in hypothalamus and/or pancreatic beta cells (unknown)
Which particular fatal side effect led to the development of compounds related to clozapine w/o this adverse effect?
Clozapine-induced agranulocytosis
- Led to development of olanzapine
What are some side effects experienced from the use of olanzapine?
1) Extrapyramidal SE (less): acute dystonias, tardive dyskinesia & akathisia
2) Antiadrenergic (alpha-1) SE: postural hypotension, dizziness, reflex tachycardia
3) Anticholinergic SE (significant): blurred vision, dry mouth & constipation
4) Antihistaminic SE (significant): sedation
5) Drug-induced weight gain:
- Besides H1 antagonism, alpha-1 antagonism & 5-HT2 antagonism results in suppression of satiation -> hunger -> weight gain
6) Onset/exacerbation of diabetes:
- May not reverse even when drug is stopped
- Possible involvement of 5-HT antagonism in hypothalamus and/or pancreatic beta cells (unknown)
What condition is olanzapine experimentally used for currently?
Anorexia nervosa
What are some side effects experienced from the use of risperidone?
1) Extrapyramidal SE (less): acute dystonias, tardive dyskinesia & akathisia
2) Antiadrenergic (alpha-1) SE (significant): postural hypotension, dizziness, reflex tachycardia
3) Anticholinergic SE: blurred vision, dry mouth & constipation
4) Antihistaminic SE: sedation
5) Drug-induced weight gain:
- Besides H1 antagonism, alpha-1 antagonism & 5-HT2 antagonism results in suppression of satiation -> hunger -> weight gain
6) Onset/exacerbation of diabetes:
- Higher chance with risperidone»_space; olanzapine = clozapine
- May not reverse even when drug is stopped esp. risperidone
- Possible involvement of 5-HT antagonism in hypothalamus and/or pancreatic beta cells (unknown)
Which atypical antipsychotics can result in significant dry mouth, blurred vision & constipation?
Clozapine & olanzapine
Which atypical antipsychotics can result in significant sedation?
Clozapine & olanzapine
Which atypical antipsychotic can result in significant reflex tachycardia & postural hypotension?
Risperidone
Which atypical antipsychotics can result in a greater risk of the irreversibility of onset/exacerbation of diabetes?
Risperidone»_space; clozapine & olanzapine
- Amisulpride may be an exception.
Which atypical antipsychotic lack M1, H1, 5-Ht2 & alpha-1 receptor antagonism?
Amisulpride
What are some side effects experienced from the use of amisulpride?
1) Extrapyramidal SE (less): acute dystonias, tardive dyskinesia & akathisia
2) Gynaecomastia in males / Breast swelling, pain & lactation in females:
- Increased prolactin secretion due to block of dopamine receptors in anterior pituitary glands along the tuberoinfundibular pathway.
Which atypical antipsychotic has an atypical pattern of receptor affinities, as compared to the others within the class?
Amisulpride
What are some side effects experienced from the use of aripiprazole?
1) Extrapyramidal SE (less): acute dystonias, tardive dyskinesia & akathisia
2) Antiadrenergic (alpha-1) SE (significant): postural hypotension, dizziness, reflex tachycardia
3) Antihistaminic SE: sedation
4) Drug-induced weight gain (possible):
- Besides H1 antagonism, alpha-1 antagonism & 5-HT2 antagonism results in suppression of satiation -> hunger -> weight gain
5) Onset/exacerbation of diabetes:
- May not reverse even when drug is stopped esp. risperidone
- Possible involvement of 5-HT antagonism in hypothalamus and/or pancreatic beta cells (unknown)
What warning does FDA require to be placed on all atypical antipsychotics?
Risk of hyperglycaemia & onset/exacerbation of diabetes
H1 & alpha-1 adrenoreceptor hypotheses do explain why chlorpromazine does not cause so much weight gain. True or false?
False!
Why do atypical antipsychotics produce less extrapyramidal symptoms, as compared to typical antipsychotics?
1) Potent 5-HT2A receptor antagonism vs weaker D2 antagonism -> lower EPS and higher efficacy against negative symptoms (clozapine and olanzapine)
2) Higher D3 > D2 antagonism ratio favours actions on nucleus accumbens over striatum (mainly D1 and D2) (amisulpride)
3) Higher D4 > D2 antagonism ratio favours actions in prefrontal cortex over striatum (clozapine)
4) Higher D2 > D1 antagonism ratio blocks negative feedback of presynaptic D2 autoreceptor -> allows dopamine to continue being released i.e. less complete blockade of dopaminergic function conferred -> reduces the impact of antagonism in the striatum (amisulpride and risperidone)
