PHRM 845-Exam 4 (Watts Lecture) Flashcards
Schizophrenia/Psychotic Disorders
Schizophrenia may be due to …
-Nurturing
-Family orientation
-Interactions growing up
-Environment
-School experience
History and Background of treating schizophrenia:
-Early 1900’s:____
-Before 1950’s, tx included ____
-1950’s tx: ____
-1952 tx:____
-Early 1900’s: Brain disease
-Before 1950: Sedation (if sleeping, don’t have to deal with +/- sx); lobotomy (remove piece of cortex); ECT (depolarizing all of the neurons and ‘restarting’); Rauwolfia alkaloids used in Hindu Medicine
-1950: Riserpine
-1952: Phenothiazines (chlorpromazine): dopamine receptor antagonist **Could manage symptoms and helped empty mental hospitals.
General considerations of schizophrenia: split from reality
Antipsychotic=neuroleptic=anti-schizophrenic
-Severe illness; most debilitating of psychotic disorders.
-Affects 1% of the population (world-wide)
-Onset age: 15-20 y/o
-Not split personality!
Etiology of schizophrenia
**We don’t know what causes schizophrenia, but these increase risk
-Neurodevelopmental/
anatomical (in-utero adolescence-increased ventricle size and changes in gray/white matter)
-Genetics (neuronal growth; migration of neurons)
-Environmental: birth complications, infections
-Gene-environment interaction: COMT-marijuana
-Neurodevelopmental-environment interaction
Genetics of schizophrenia
-If a twin has it, you have a ___ % chance of getting it
-If a family member has it, you have a ___% chance of getting it
50%
10%
Interaction for gene-environment interaction in schizophrenia
Catechol methyltransferase mutation and marijuana (25% increased risk)
Outward expressions of schizophrenia
-Thoughts are loosely connected
-Disturbances in mood
-Global impairment is the biggest psychological function
Positive symptoms in schizophrenia
-Respond well to drug therapy
-Hallucinations (seeing/hearing things that aren’t there)
-Delusions (think they are the most important person/fear of persecution)
-Bizarre behavior (twisting hair)
-Thought disorders (word salad)
Negative symptoms of schizophrenia
-Little response to drug therapy
-Newer agents are better
-Blunted emotion (pulling away from loved ones)
-Poor self care (stop bathing)
-Social withdrawal
-Poverty in speech
-Lack of movement
Cognitive symptoms of schizophrenia
-Decrease in cognitive function
-Involves D1 and glutamate receptors
-Decrease in ability to use executive function/planning
Neurotransmitter hypothesis in schizophrenia
-Dopamine: first to be developed, but incomplete
-Serotonin: based on mechanism of LSD and mescaline (2 hallucinogenic functions)
-Glutamate: based on phencyclidine and ketamine (used for tx-resistant depression)
Serotonin hypothesis for schizophrenia
**14 total serotonin; 13 ion channel and 1 GPCR
- LSD and mescaline were identified as 5HT agonists, inspired search for ‘endogenous’ hallucinogens
- Pharmacological studies with 5HT receptors identified 5HT2A receptor as mediator of hallucinations
- Antagonism and inverse agonism linked to antipsychotic activity
- 5HT2A receptors modulate dopamine release in cortex, limbic region, and striatum
- 5HT2A receptors modulate glutamate release and NMDA receptors.
- 5HT2C agonists may be beneficial in schizophrenia
Glutamate hypothesis of schizophrenia
- Glutamate is a major excitatory neurotransmitter (crank up neuronal activity–allow positive ions in)
- Phencyclidine and ketamine, noncompetitive inhibitors of NMDA receptors, exacerbate psychosis and cognition deficits.
Dopamine hypothesis for schizophrenia
*Most evidence for this
*Influenced by serotonin and glutamate
- D2 receptor antagonists: strong correlation receptor binding affinity vs. clinical effectiveness.
- Dopaminergic agents (L-DOPA, amphetamine, bromocriptine) exacerbate symptoms of schizophrenia.
- Increased D2 receptor density in treated and untreated patients of schizophrenia.
- Imaging studies-increased DA release and receptor occupancy in pts.
- Dopamine metabolites in CSF-D2 receptor antagonists initially increase metabolites in the CNS and later decrease metabolites in CNS.
Determining binding affinity: intermolecular force between ligand and receptor
-Low number=tight binding=high affinity
-Kd/Ki is the estimated concentration at which 1/2 of the receptors are occupied.
-Saturation binding experiments: vary concentration of radio-labeled ligands.
-Competition binding experiments: constant radioligand (hot) concentration competing with unlabeled ligand (cold).
Receptors antagonized by anti-psychotics
Major: Dopamine
Newer agents: Serotonin
Minor: NE, ACh, Histamine
Dopamine receptor breakdown
D1-like (D1 and D5)
D2-like (D2-D4)
Serotonin receptor antagonists
Clozapine
Olanzapine
Risperidone
Older agents: chlorpromazine, haldol, thioridazine
Effects of alpha-1 and alpha-2 receptor blockade from NE receptor antagonism
Alpha-1: hypotension, sedation (SE)
Alpha-2: may be helpful in tx
Acetylcholine receptor antagonism
Muscarinic receptors which will produce anticholinergic effects (clozapine, thioridazine)
Histamine receptor antagonism effects
H1 receptor antagonism: sedation & weight gain
-Ex: taking benadryl when stung by a bee–want to take a nap and eat chips
Which receptor is key for therapeutic effectiveness in tx schizophrenia?
We don’t know (all unique receptor MOA); likely involves multiple receptors; spectrum of schizophrenia which would require different receptors.
-Unable to predict effectiveness of each therapy for individual patient.
-Multiple receptors=many SE=poor adherence
Binding affinity vs clinical dose for dopamine antagonists
-Correlation between binding potency and clinical effectiveness for D2 receptors, therefore more effective drug target.
-Not much of a correlation with D1-like receptors (D1 and D5)
-Almost perfect correlation with D2-like receptors (D2-D4); ability of antipsychotics is predictive based on dose.
-Most antipsychotics are receptor antagonists
Dopamine physiology and function: actions of D2 antagonists in CNS
-Basal ganglia (nigrostriatal pathway): Motor effects (if no dopamine, get extrapyramidal sx)
-Mesolimbic: primary therapeutic effects (the only ones we really want to block)
-Mesocortical: hypofunction in schizophrenia, antagonists may exacerbate cognitive deficits
-Hypothalamus and endocrine systems: D2 receptor blockade in endocrine system (in hypothalamus, there is a change in prolactin secretion–increase in release of prolactin when blocked)
-Medulla: chemoreceptor trigger zone (nausea/vomiting); D2 antagonists are anti-emetics
Importance of receptor occupancy and drug concentration
SE of drugs
Receptor occupancy and PET
We can measure occupancy of dopamine and serotonin receptors
-Radiolabeled ligand gets displaced so there aren’t any bound when we get up to 30 mg of antipsychotic.
Why do we care about receptor occupancy and antipsychotic effect?
To determine therapeutic effects and potential side effects.
**70-80% of dopamine receptors need to die to see symptoms
Drug-induced movement disorders (D2 antagonism)
- Extrapyramidal symptoms (EPS) 30-50%: occurs early, days/weeks, reversible
- Tardive dyskinesia
- Neuroleptic malignant syndrome (NMS)
Symptoms of EPS
-Dystonia: increased muscle tone
-Pseudo parkinsonism: muscle rigidity
-Tremor
-Akathisia: restlessness
**unfortunately most patients will experience EPS (on-target effect, but wrong tissue) as a result of long-term antipsychotic drug therapy; important monitoring parameter
Drug therapy for EPS
-Benztropine (Cogentin), trihexyphenidyl (Artane), or akineton (Biperiden)–anticholinergic agents
-Diphenhydramine (Benadryl)–Antihistamine
-Amantadine (Symmetrel)–Dopamine releasing agent
-Propranolol–used for akathisia
-May use an atypical medication
Neurons involved in EPS
Dopamine: inhibitory
ACh: excitatory
**normally have a good balance of inhibition and excitation
