List the 4 key dopaminergic pathways targeted by antipsychotics.
Mesocortical, mesolimbic, nigrostriatal and tuberoinfundibular
Which dopaminergic pathway is thought to be responsible for causing the positive symptoms of schizophrenia? List its functional neuroanatomic structures.
Mesolimbic pathway: ventral tegmental area to nucleus accumbens and olfactory tubercle
What symptoms of psychosis is the mesocortical pathway suspected to be responsible for? List its functional neuroanatomic structures.
- Clinical sx: negative symptoms of psychosis, possibly the cause of cognitive deficits
- neuroanatomy: ventral tegmental area to pre-frontal cortex)
Antipsychotics, especially ones with high D2 affinity, can commonly cause hyperprolactinemia. What are the common side effects caused by hyperprolactinemia and which dopaminergic pathway causes this?
- galactorrhea, amenorrhea, gynecomastia
- Tuberoinfundibular pathway (hypothalamus)
Which pharmacokinetic property of an antipsychotic is most predictive of EPS risk?
The duration of time that an antipsychotic drug stays attached to D2 receptor (high affinity) predicts higher risk of EPS. First generation antipsychotics like haldol are more likely to cause EPS because of this.
Describe the different levels of antipsychotic potency and list a first and second-generation example for each.
High potency = need only a “low dose” to get a clinical effect. e.g. haldol and risperdal
Medium potency = intermediate effects in terms of sedation, anticholinegeric side effects, and EPS. e.g. loxapine and olanzapine
Low potency = you need to prescribe a “high dose” to get a clinical effect. e.g chlorpromazine and quetipaine
What is the pharmacological explanation for why low potency antipsychotics are less likely to cause EPS?
Higher anticholinergic activity
What is the pharmacological explanation for why high-potency antipsychotics are less likely to be sedative?
Lower H1 receptor affinity
Which liver enzymes metabolize the majority of antipsychotics?
CYP 2D6 and CYP 3A4
Which 2 antipsychotics are metabolized by CYP 1A2?
clozapine and olanzapine
What is the receptor responsible for Abilify's role in augmentation for mood disorder treatment?
5-HT2A (serotinergic activity)
Which antipsychotic medication is the gold-standard for treatment resistant schizophrenia and has been shown to reduce mortality?
Clozapine
Which investigations will you order before initiation of an antipsychotic? (including physical exam)
CHEM, Cr, LFTs, TSH, fasting BG, A1c, lipid profile, height and weight measurements, blood pressure, EPS exam, prolactin if indicated, EKG if indicated
What is the #1 cause of mortality from clozapine use?
ileus from constipation
1) Put the following antipsychotics in order of least sedating to most: olanzapine, quetiapine, clozapine, risperdal.
i) What is the pharmacological explanation for this order?
1. risperdal -> olanzapine -> quetiapine -> clozapine
2. Increasing H1 affinity
What side effect do you have to worry about when represcribing clozapine if it is unclear whether patient has been compliant with their medication at home?
orthostatic hypotension
Which typical antipsychotic lowers seizure threshold the most? Which atypical antipsychotic does this?
Chlorpromazine and clozapine
Which antipsychotics must be avoided in patients with hepatic impairment?
Paliperidone, asepanine, risperidone and lurasidone
Which antipsychotics are studied to be safe in pregnancy?
clozapine and lurasidone