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
In D2 antagonism, dopamine receptors are ____, causing ____, so we use an ____
blocked
too much excitation
anticholinergic
Tardive dyskinesia (20-40%)
-Occurs ____
late; months to a year
**IRREVERSIBLE
Symptoms of tardive dyskinesia
-Mouth: rhythmic involuntary movements
-Choreiform: irregular purposelessness
-Athetoid: worm-like
-Axial hyperkinesias: “to-and-fro” movements
Treatment for tardive dyskinesia
Prevention! Use the least risky agent at the lowest possible dose and monitor
1. Reduce dose of current agent
2. Change to a different drug; possibly a newer agent
3. Eliminate anticholinergic drugs
4. VMAT inhibitors
MOA of tardive dyskinesia
Unknown; neuroadaptive response-antagonist-induced supersensitivity of receptors to dopamine?
**Cell receptors get blocked and become supersensitive
Monitoring for tardive dyskinesia
Abnormal Involuntary Movement Scale (AIMS) rating skill; check every 6 months
Newer drug therapies for tardive dyskinesia
VMAT2 inhibitors
-Tetrabenazine (Xenazine) for Huntington’s chorea
-Valbenazine (Ingrezza) for TD
-Deutetrabenazine (Austedo) for TD and Huntington’s chorea
**These are adjuncts
Neuroleptic Malignant Syndrome (NMS)
-Immediately upon initiation of med (rapid loss of dopamine receptors)
-Serious and RAPID; 10% fatality
Symptoms of NMS
-EPS symptoms with fever
-Impaired cognition (agitation, delirium, coma)
-Muscle rigidity
Treatment for NMS
Restore dopamine balance
-Discontinue drugs
-DA agonists, diazepam, or dantrolene (skeletal muscle relaxant)
Therapeutic uses of antipsychotic drugs
Treatment of psychosis
-2-3 weeks for effectiveness
-6 weeks to 6 months maximal efficacy
Treatment for other mental disorders
-Anxiety=OVERKILL!
-Mood disorders (mania=secondary to lithium, used in combo; depression=when accompanied by agitation and delusions)
-Tourette’s syndrome-tics, vocalizations (Treat with Pimozide=Orap)
Miscellaneous uses for antipsychotics
-Tetrabenazine (chorea)
-Deutetrabenazine (chorea)
-Chlorpromazine–intractable hiccups
-Haloperidol–alcohol withdrawal
-Metoclopramide and Promethazine–N/V
-Droperidol–potentiation of opiates and sedatives
Pharmacological effects of the antipsychotic drugs
-Behavioral effects: unpleasant in normal subjects or reversal of signs and symptoms of psychosis in affected individuals
-“neuroleptic” syndrome: suppress emotions, reduce initiative and interest, affect; may resemble negative symptoms
-Block conditioned avoidance responses in animal studies
-Decreased spontaneous activity, aggressive, and impulsive behavior.
Precautions and contraindications of antipsychotics
-Cardiovascular (prolong QT interval)
-Parkinson’s disease (from blocking DA receptors)
-Epilepsy (eg: clozapine will lower seizure threshold)
-Diabetes (for newer agents)
***C/I with diabetes because of problems
Which receptors give sedative properties?
Histamine receptors
Which receptors give hypotensive properties?
Alpha receptors
Effects of typical first generation antipsychotics
-More movement problems
-Increased EPS and tardive dyskinesia due to strong D2 block
1st antipsychotic
(contains a phenothiazine nucleus)
Chlorpromazine
-Allowed patients to go home and live a normal life
Phenothiazine nucleus
-Aliphatic phenothiazines
Chlorpromazine (Thorazine): no longer first line therapy
Phenothiazine nucleus
-Aliphatic phenothiazines: used for H1 antagonists properties
Promethazine (Phenergan)
*Used for N/V more than schizophrenia
Phenothiazine nucleus
-Piperidine phenothiazines
Thioridazine (Mellaril)
-Sedation, hypotension; anticholinergic, many SE
**Binds lots of receptors
Phenothiazine nucleus
-Piperazine phenothiazines
-Fluphenazine (Permitil, Prolixin): very strong D2 blocker; EPS
-Prochlorperazine (Compazine): antiemetic
-Perphenazine (Trilafon): CATIE studies: perphenzine and anticholinergic vs several newer agents **Just as effective as newer agents
Antipsychotic
-Thiothixene (Navane)
Modest EPS
*Strong D2 blocker
Antipsychotic
-Bytrophenones
-Haloperidol (Haldol)
EPS
*Strong D2 blocker
Miscellaneous antipsychotic
-Molindone (Moban)
Moderate EPS
-Zyprexa or Risperidal vs. Moban+Benztropine
*Found weight gain/metabolic problems in newer agents; adherence issues
Miscellaneous antipsychotic
-Pimozide (Orap)
Tourette’s disease-tics, vocalizations
Atypical/second generation antipsychotic effects
-Reduced EPS (compared to traditional)
-Efficacy for negative symptoms?
-Similar/enhanced 5HT2A receptor antagonism vs D2
-More metabolic problems (weight gain->adherence issue)
-Linked to diabetes (greater risk in pts < 50 y/o)
**Olanzapine and clozapine
Atypical antipsychotic
-Clozapine (Clozaril)
-1st atypical antipsychotic
-Most effective antipsychotic to date, but has MANY side effects
Why do we monitor patients on Clozapine?
Agranulocytosis risk
-Occurs in 1-2% within 6 months (weekly blood monitoring)
-2nd or 3rd line therapy
Side effects of Clozapine
Anticholinergic and antihistamine
-Reduced D2 potency and acts on serotonin receptor=decreased movement disorders
-Risk of diabetes
Atypical antipsychotic
-Olanzapine (Zyprexa)
-SE of olanzapine
-Similar structure and MOA as clozapine
-Weight gain
-Less likely to cause N/V
-Less likely to cause movement disorders
-Risk of diabetes
Atypical antipsychotic
-Loxapine (Loxitane)
-SE of loxapine
-Similar structure and MOA of clozapine
-Older agent
-Metabolite=Amoxipine (Ascendin)–Inhibits NET–antidepressant
Atypical antipsychotic
-Quetiapine (Seroquel)
-Metabolite with antidepressant activity
-5HT2A and D2 (low antimuscarinic)
-Low EPS
-Hypotension (alpha1)
-Sedation (H1)
-Risk of diabetes
Atypical antipsychotic
-Risperidone (Risperidol)
-SE of risperidone
-Specifically and structurally designed to be both a 5HT2A and D2 receptor antagonist (Rational drug design)
-Relatively low EPS at <8 mg/day b/c it targets serotonin receptor as well
-Weight gain and some sedation
Atypical antipsychotic
-Paliperidone (Invega)
Analog of risperidone
-9-hydroxyrisperidone
Atypical antipsychotic
-Iloperidone (Fanapt)
Analog of risperidone
-Very potent at alpha-1 receptors (0.5 nM vs 5nM at 5HT2A and D2)
Atypical antipsychotic
-Ziprasidone (Geodon/Zeldox)
-5HT2A, D2, alpha-1 affinity
-Prolongs QT interval
-Long acting formulation under study
Atypical antipsychotic
-Asenapine (Saphris)
-5HT2A and D2
-nM affinity at most 5HT, alpha, DA, and histamine receptors (can predict it will have a lot of SE)
Atypical antipsychotic
-Lurasidone (Latuda)
-5HT2A and D2
-Less weight gain and metabolic effects (vs. olanzapine)
-Fast onset (days without titration)
-Low doses have similar effectiveness to high doses
Atypical antipsychotic
-Pimavanserin (Nuplazid)
-Inverse agonist 5HT2A (40x vs 5HT2C)
-Used for Parkinson disease psychosis
Atypical antipsychotic
-Aripiprazole (Abilify)
-High affinity for 5HT2 and D2 (D2 actions are dopaminergic-state dependent and/or it is functionally selective)
-Partial agonist at 5HT1A receptors (being used in depression)
-Moderate affinity for D4, alpha, and histamine receptors
-Prodrug: aripiprazole lauroxil, given q4-8weeks
SE of aripiprazole
-Weight gain
-Low risk for D2 effects
D2/D3 receptor partial agonists use
-“Copy cat” drugs
-Many used as adjuncts in depression
D2/D3 partial agonist
-Brexpiprazole (Rexulti)
-Supposedly less akathisia compared to aripiprazole
-Used in schizophrenia and as an adjunct to antidepressant for major depression
-Partial agonist activity at serotonin 5HT1A and D2 receptors; and antagonist activity at serotonin 5HT2A receptors
D2/D3 partial agonist
-Cariprazine (Vraylar)
-Greater affinity for D3
-Weak, partial agonist activity at 5HT1A.
-Akathisia is high
-Used for schizophrenia, mania, and bipolar disorder.
D2/D3 partial agonist
-Lumateperone (Caplyta)
-Partial D2 agonist presynaptic receptors/antagonist at postsynaptic receptors (5HT2A antagonist)
Drugs in development/under investigation
Dual M1/M4 muscarinic agonist combined with peripheral muscarinic antagonist (KarXT)–blocks peripheral action so you only get muscarinic effect.
