Antipsychotic Drugs Flashcards
What are the prodromal symptoms of schizophrenia? Why do they matter?
Social isolation/withdrawal, odd behavior / ideas, blunted affect, lack of motivation
-> Associated with poorer prognosis
What brain changes are associated with schizophrenia?
Decreased blood flow in frontal lobe / caudate during working memory tasks, loss of cortical interneurons and reduced hippocampal volume. Ventricles become enlarged due to atrophy
What is the dopamine hypothesis of schizophrenia?
Drugs that augment dopamine can induce / exacerbate psychosis
Drugs that block DA receptors are effective anti-psychotic drugs
DA receptor expression may be linked to schizophrenia
What is the most common dopamine receptor type and where do they exist?
D2
Mesolimbic pathway - motivation / emotional / goal-direct thinking
Mesocortical pathway - cognitive
Nigrostriatal - movement
Hypothalamic - hormones, eating, temp
Area postrema - emesis
What is the original atypical antipsychotic and why is it of interest?
Clozapine - it is not a D2 receptor antagonist, but rather a 5HT2A antagonist which can still help treatment-refractory patients -> pathophys must be more complex
What is an atypical vs typical antipsychotic?
Typical - Primarily D2 receptor antagonists, occupy striatal D2 receptors
Atypical - Primarily 5HT2A antagonist in the cortex, less D2 antagonist action in the striatum (but still some antagonism)
How does LSD function and why has it been illuminating for schizophrenia?
Weak 5HT2A agonist - pure 5HT2A antagonists block its psychotic effects, but these drugs do NOT work as antipsychotics -> more at play here
What types of symptoms are antipsychotic drugs good at treating?
Positive symptoms - i.e. hallucinations
not so good at negative symptoms (may involve different system) - i.e. social isolation / withdrawal
How rapid is the response of schizophrenia to an APD?
Acute psychosis - very rapid
Otherwise - takes full weeks to get response, maintenance treatment will prevent relapse
Why did physicians think second generation antipsychotics would be really good? What is their relative effectiveness?
Less straight D2 receptor activity - there was a thought it would cause fewer extrapyramidal symptoms and be more tolerable
- > turned out not to be statistically true
- > 1st generation antipsychotics thought to be equally effective as second generation
What is the only second generation drug which is better?
Clozapine - good in treatment-refractory cases for unknown reasons
What are the common extrapyramidal side effects of 1st generation APDs? Order of onset?
- Acute dystonia - primarily face / back, curl up like a pretzel
- Akathisia - uncontrollable restlessness
- Parkinsonism
Dystonia will come right before akathisia and parkinsonism, in the first two months
What should be done to treat the acute effects of 1st generation APDs?
Reduce the dose or treat concurrently with antimuscarinics (reduces Ach levels in basal ganglia down to reduced dopamine levels, like benztropine)
What hypothalamic issues can 1st generation APDs cause in the acute phase?
- hyperprolactinemia, due to blockade of dopamine, which is PIH
- neuroleptic malignant syndrome - rarely, dangerous fever + autonomic instability and muscle breakdown
Treat with dantrolene
What are the off-receptor effects of first generation APDs?
Sedation (H1 blockade), orthostatic hypotension (alpha1 blockade), anticholinergic effects (M1 blockade)
What is the chronic adverse effect of all antipsychotics? What makes it better or worse?
Tardive dyskinesia
- > irreversible, in 20-40% of patients
- > induced in accordance with drug D2 affinity, induced by higher doses (try to keep dose low to prevent)
- > masked by increasing the dose of the APD, limiting movement, gets worse upon drug withdrawal
What are the adverse effects of second generation APDs / how do they differ from first gene?
Likely fewer extrapyramidal effects, less tardive dyskinesia
Cause:
QT prolongation
Weight gain, insulin resistance, T2 diabetes, hyperlipidemia (almost like beta blockers)
What are the special added adverse effects of clozapine?
- Seizures
2. Agranulocytosis - potentially fatal, monitor via weekly blood counts for 6 months
What are the two main 1st generation APDs?
- Chlorpromazine
2. Haloperidol
How does haloperidol differ from chlorpromazine in terms of side effects?
Haloperidol - less autonomic effects, but much stronger D2 blockade -> higher risk of EPS in the short term and TD in the long-term
What drug is considered a “borderline atypical” and why?
Risperidone - more DA-related adverse effects than 2nd gen, but less 5HT-related weight gain
What 2nd generation APD has a clozapine-like structure but may have a modest advantage in efficacy / tolerability?
Olanzapine
When is clozapine used and why?
Due to seizure / agranulocytosis added risk, it is only used in treatment-refractory cases. However, it has the highest efficacy of any APD
Give three other uses for APDs outside of schizophrenia?
- Schizoaffective disorders - depression or bipolar with psychotic symptoms, in combination with base therapy (i.e. Papa Miller)
- Gastroprokinetic - unlikely due to TD
- Post-op nausea / vom - short-acting and sedating (remember the D2 receptors in area postrema)
What is the main drug prescribed as an APD for GI issues mentioned previously?
Metoclopramide
How did APDs get such a huge market share?
Used in schizoaffective disorders and refractory bipolar much more
Used in bad indications-
Adults:
GAD, OCD, Alzheimer’s (despite stroke risk)
In children:
Autism, overaggression, ADHD - all bone shit
