Pharmacological Treatment of Schizophrenia Flashcards
Describe the dopamine theory of schizophrenia and the mechanism of action of antipsychotic medication, particularly in relation to dopamine D2 receptor blockade Know how pharmacological treatment of schizophrenia has advanced since the first antipsychotic drug, chlorpromazine, was introduced in the mid-1950s, including the advantages and disadvantages of long-acting injection preparations Know the pharmacological and side effect profiles of the first and second generation antipsychotics Understa
What are the goals of treatment in acute schizophrenia?
Reduce behavioural disturbance and positive symptoms (hallucinations and delusions)
What are the goals of maintenance treatment in schizophrenia?
Prevent relapse, improve negative symptoms, reduce cognitive deficits, aid psychosocial reintegration, encourage adherence
What is chlorpromazine?
A broad-spectrum first-generation antipsychotic which acts as an anti-dopaminergic, anti-cholinergic, and anti-histaminergic
What is haloperidol?
A first-generation antipsychotic and D2 receptor blocker
Name the only drug licensed for treatment resistant schizophrenia
Clozapine
What is the most serious side effect of clozapine?
Agranulocytosis
Name at least 5 second-generation antipsychotics
Risperidone, olanzapine, quetiapine, zotepine, aripiprazole, brexipirazole, sertindole, amisulpride, asenapine, lurasidone
What percentage of individuals respond to second-generation antipsychotics? (Leucht et al, 2012)
41%
Why can antipsychotics cause osteoporosis and sexual side effects?
They tend to increase prolactin
Name the 4 main dopamine pathways in the brain
Nigrostriatal, mesolimbic, mesocortical, tuberoinfundibular
Describe the nigrostriatal pathway
A dopaminergic pathway running from the substantia nigra to the caudate and putamen (striatum), associated with the initiation of motor plans
Describe the mesolimbic pathway
A dopaminergic pathway running from the ventral tegmental area in the midbrain to the limbic region (nucleus accumens, amygdala, hippocampus, medial prefrontal cortex). It is associated with reward, motivation, affect, and memory
Describe the mesocortical pathway
A dopaminergic pathway running from the ventral tegmental area to the frontal cortex and associated with reward and motivation
Describe the tuberoinfundibular pathway
A dopaminergic pathway running from the tuberal region to the median eminence (inferofundibular region at the top of the pituitary stalk). It is associated with prolactin release
Give some evidence for the dopamine theory of schizophrenia
1) Psychostimulant agents that trigger dopamine release are associated with de novo psychosis and worsening of psychosis in patients in remission
2) PD patients given L-DOPA can develop hallucinations
Describe evidence of dopaminergic system abnormalities in schizophrenia from SPECT imaging
Amphetamine-induced dopamine release is higher in schizophrenics than controls
Describe the difference in positive and cognitive symptom pathogenesis in schizophrenia (Silfstein et al, 2015)
Positive symptoms are believed to be due to excess dopamine function in the striatum, whereas cognitive symptoms are believed to be due to insufficient dopamine function in the prefrontal cortex
How does the clinical efficacy of antipsychotics support the dopamine hypothesis of schizophrenia?
The clinical efficacy correlates with their affinity for the D2 receptor
What is the threshold for antipsychotic efficacy?
Above 65% D2 receptor occupancy
What is the threshold for extrapyramidal side effects?
Above 80% D2 receptor occupancy
What is the most significant side effect of antipsychotics?
Weight gain
How much is the relapse risk increased by discontinuing antipsychotics compared to maintenance therapy? (Viguera et al, 1997)
5x
Describe the hypothesis of supersensitivity psychosis
It theorises that antipsychotic medication causes a compensatory state of upregulation of D2 receptors
In what proportion of schizophrenia patients does treatment refractoriness emerge after relapse? (Ohmori et al, 1999)
1 in 6
State some potential consequences of relapse
Risk of harm to self or others, disruption of personal relationships, education, and employment status
Describe the consequences of long-term antipsychotic use
Changes in brain structure (parietal lobe and basal ganglia), metabolic side effects, direct cardiotoxic effects, increased risk of CHD, CVD, and CHF
What percentage of patients are estimated to be poorly or non-adherent? (Kane et al, 2013)
50-75%
Describe the effect of comorbid substance abuse on relapse (Hunt et al, 2002)
It increases the risk of relapse, with a greater negative effect in those who are medication adherent than those who are non-adherent
Kirson et al’s 2013 meta-analysis found no advantage in using long-acting formulations over oral antipsychotics in RCTs. Give some potential reasons why
1) Only selecting adherent patients, removing the advantage of adherence
2) Increased monitoring for both groups
3) Too short-term to see the long-term benefts
State some advantages of long-acting antipsychotics
Avoid covet non-adherence, regular delivery of a known dose, regular scrutiny of mental state and side effects, simplification of medication regime, more predictable and stable serum drug level
State some disadvantages of long-acting antipsychotics
Slow dose titration with a long time needed to achieve a steady state, increased risk of excess dosage, pain and discomfort at injection site
At what point is clozapine trialled?
After no adequate response to 2 trials of antipsychotic medication, confirmation of adequate dosage and correct diagnosis, and trialling high-dose antipsychotic medication
State some clinician-related barriers to initiating clozapine treatment
Need for intense monitoring, risk of serious side effects, lack of adherence by patient
State some system-related barriers to initiating clozapine treatment (Farooq et al, 2018)
Difficulty in identifying suitable patients, service fragmentation, inadequate training in or exposure to use of clozapine
How often must patients on clozapine undergo haematological monitoring in the first 18 weeks?
Weekly
