Exam 4 Schizophrenia Flashcards
The creation of which schizophrenia drug in the 1950’s lead to the emptying out of mental hospitals?
Phenothiazines (chlorpromazine)
What is the most debilitating psychotic disorder?
Schizophrenia
What is the onset age of schizophrenia?
15-20 years old
(onset late adolescence to early adulthood)
Men: late teens, early 20’s
Women: late 20’s, early 30’s
Why do women have a later onset of schizophrenia than men?
Estrogen is protective against schizophrenia onset
What are the 5 etiologies of schizophrenia?
Neurodevelopmental/anatomical
Genetics
Environmental
Gene-Environment Interaction
Neurodevelopment-Environment Interaction
What are the neurodevelopmental/anatomical differences seen with schizophrenia?
In utero/adolescence:
-Increased ventricle size
-Changes in gray and white matter
What are the environmental etiologies that can result in schizophrenia?
-Birth complications
-Infections
Mutations in what gene may cause schizophrenia with the use of marijuana?
COMT
What is the cause of schizophrenia?
UNKNOWN
-just know some risks
What are positive schizophrenia symptoms?
Hallucinations, Delusions, Bizarre Behavior, Thought Disorders
What are negative schizophrenia symptoms?
Blunted Emotion, Poor Self Care, Social Withdrawal, Poverty in Speech
What are cognitive symptoms of schizophrenia?
*Decrease in cognitive function
-Involves D1 receptors and glutamate receptors
*Newly acknowledged
(Decreased ability to use executive functioning, ex: planning)
What type of schizophrenia symptoms respond well to drug therapy?
Positive symptoms
*note: newer agents work better on negative symptoms
What are the 3 types of neurotransmitter hypotheses for schizophrenia?
-Dopamine
-Serotonin
-Glutamate
What two hallucinogens is the serotonin hypothesis based on?
LSD and Mescaline
What is the serotonin hypothesis?
-LSD and Mescaline are 5HT agonists which inspired a search for endogenous hallucinogens
-Studies identified the 5HT2A receptor as a mediator of hallucinations
*Antagonism and inverse agonism are linked to antipsychotic activity
-5HT2A receptors modulate dopamine release, glutamate release, and NMDA receptors
*5HT2C receptors may be beneficial in schizophrenia
What two drugs is the glutamate hypothesis based on?
Phencyclidine and Ketamine
**EXACERBATE PSYCHOSIS*
What is the glutamate hypothesis?
*Glutamate is a major excitatory neurotransmitter
-Phencyclidine and Ketamine are noncompetitive inhibitors of NMDA receptors. THEY EXACERBATE PSYCHOSIS AND COGNITIVE DEFECTS
What is the dopamine hypothesis?
D2 receptor antagonists have a strong correlation between binding affinity and effectiveness
**Dopaminergic agents (L-DOPA, amphetamine) EXACERBATE schizophrenia symptoms
Schizophrenia patients have increased D2 receptor density and increased dopamine release
What does Kd/Ki represent?
Estimated concentration at which 1/2 of the receptors are occupied
(used in binding affinity)
When determining a binding affinity, does a high or low number represent tight affinity (good)?
LOW
*we want low numbers for binding affinity
What are the dopamine receptors?
D1-like: D1 and D5
D2-like: D2, D3, D4
What is the serotonin receptor?
5HT
What are the 2 norepinephrine receptors and what effect does blocking them have?
a1: Hypotension, Sedation
a2: May be helpful in therapy
(adrenergic receptors)
What are the acetylcholine receptors and what effect does blocking them have?
Muscarinic receptors: anticholinergic effects (dry mouth, constipation, tachycardia)
What is the histamine receptor and what affect does blocking it have?
H1 Receptor: sedation, weight gain
Which receptor is the key for therapeutic effectiveness in schizophrenia?
UNKNOWN
-multiple receptors involved
-different types of schizophrenia may rely on different receptors more
Most antipsychotic drugs function as what towards receptors?
Antagonists
Which dopamine receptor (D1 or D2) shows a correlation between binding potency and clinical effectiveness?
(ability to bind to receptor is predicted by the dose and determines effectiveness)
D2 receptors
**more effective drug target
*dose does not predict ability to bind to D1
When presynaptic receptors for dopamine are BLOCKED, what affect does it have on dopamine release?
When blocked: increased dopamine release + synthesis
-these receptors regulate synthesis and release of dopamine
-when dopamine comes back, it tells the receptors there is too much dopamine in the synapse and the receptors work to decrease synthesis and release
-blocking these keeps dopamine in the system
D2 receptor antagonists block which receptors in the synapse?
BOTH pre-and post- synaptic
*even though more dopamine is being released into the synapse, there is not an exacerbation of symptoms because the post-synaptic receptors are blocked not signaling
*not ideal situation but how it works
What affect do antipsychotics have on dopamine metabolites?
There is an increase in synthesis and release of dopamine which increases dopamine metabolite levels (note that postsynaptic receptors are blocked)
-overtime, there is an adaptive response that makes metabolite levels go back down
-the eventual normalization of metabolites is associated with increased therapeutic efficacy over time
What part of the CNS is responsible for the primary therapeutic effects in schizophrenia (what we want to target)?
Mesolimbic
**only receptors we want to block
If we block dopamine receptors in the Basal Ganglia what happens?
Motor effects
(this is where Parkinson’s motor tremors comes from, blocking these receptors cause these tremors)
If we block dopamine receptors in the Mesocortical area what happens?
Exacerbation of cognitive defects
*note: this area is already hypo-functioning in schizophrenia
If we block dopamine receptors in the Hypothalamus/ Endocrine System what happens?
Increased prolactin release
(normally inhibited by dopamine)
If we block dopamine receptors in the Medulla what happens?
DECREASED nausea + vomiting
*ok to block these
-Where anti-emetics work (D2 antagonists)
What percent of dopamine receptors must be lost for symptoms of Parkinson’s to appear?
70-80%
How quickly do extrapyramidal symptoms (movement disorders) begin after starting antipsychotic treatment?
EARLY (days/weeks)
What are the extrapyramidal symptoms (motor symptoms) that can occur with antipsychotic use?
Dystonia
Pseudoparkinsonism (muscle rigidity)
Tremor
Akathisia
What is dystonia?
Increased muscle tone
What is akathisia?
Restlessness
What do we use to treat drug-induced extrapyramidal symptoms?
Anticholinergics:
-Benztropine -Trihexyphenidyl -Akineton
Antihistamines:
-Diphenhydramine
Amantadine (dopamine releasing)
Propranolol (akathisia)
Why do we give anticholinergics to decrease drug-induced extrapyramidal symptoms?
Dopamine acts as an inhibitory signal in the neuron to counteract the excitatory signals of acetylcholine
-When dopamine receptors are blocked, there is an increase in excitatory signaling by acetylcholine
-This is why we give anticholinergics
How quickly does the side effect Tardive Dyskinesia occur after starting antipsychotics?
LATE (months to a year)
What important fact about Tardive Dyskinesia makes it more severe than some other antipsychotic side effects?
IRREVERSIBLE
(want to prevent it)
What are the symptoms of Tardive Dyskinesia?
Mouth: rhythmic, involuntary movements
Choreiform: jerking movements
Athetoid: involuntary writhing movements of face or hands
Axial hyperkinesias: “To-and Fro” movements
What is the MOA of Tardive Dyskinesia?
Unknown
-possible antagonist-induced hypersensitivity of dopamine receptors
What treatment is available for Tardive Dyskinesia?
PREVENTION
- Reduce dose of current agent
- Change to a different drug, possibly newer agent
- Eliminate anticholinergic drugs
- VMAT inhibitors (“zine’s”) ***
(use the least risk agent at the lowest dose possible and monitor with the AIMS scale)
How do VMAT2 inhibitors help treat Tardive Dyskinesias?
-Prevent dopamine from being packaged into synaptic vesicles
-Allows dopamine to be out in the cell and metabolized (deletes dopamine)
-Super sensitive receptors cannot be activated if there is no dopamine
Drugs: Tetrabenazine, Valbenazine, Deutetrabenazine
“azine”
How quickly after starting antipsychotics does the side effect Neuroleptic Malignant Syndrome (NMS) occur?
RAPID***
Note: serious and has high fatality
What are the symptoms of Neuroleptic Malignant Syndrome (NMS)?
-Extrapyramidal symptoms with fever
-Impaired cognition (agitation, delirium, coma)
-Muscle rigidity
What is the treatment for Neuroleptic Malignant Syndrome (NMS)?
-Discontinue drug
-Dopamine agonists
-Diazepam
-Dantrolene (skeletal muscle relaxant)
How long to antipsychotics take to work?
2-3 weeks for effectiveness
6 weeks - 6 months for maximal efficacy
One pharmacological effect of antipsychotics is “Neuroleptic” Syndrome. What is this?
-Suppression of emotions
-Reduced initiative and interest
*May resemble negative symptoms
What are the two autonomic side effect mechanisms?
How do these manifest?
Muscarinic Cholinoceptor Blockade:
-Loss of accommodation (vision loss)
-Dry mouth
-Difficulty urinating
-Constipation
Alpha Adrenoceptor Blockade:
-Orthostatic hypotension
-Impotence/ Failure to ejaculate
What are the four CNS side effect mechanisms?
How do these manifest?
Dopamine receptor blockade:
-Parkinson’s syndrome
-Akathisia
-Dystonias
Supersensitivity of Dopamine Receptors:
-Tardive Dyskinesia
Muscarinic blockade:
-Toxic-confusional state
Histamine (H1) receptor blockade:
-Sedation
-Weight gain
What is the endocrine system side effect mechanism?
How does it manifest?
Dopamine receptor blockade
Results in hyperprolactinemia
-Amenorrhea-galactorrhea
-Infertility
-Impotence
What mechanisms cause weight gain?
Combined H1 (histamine) and 5HT blockade
Blocking muscarinic receptors causes what?
Toxic confusional state
For cholinoceptors (autonomic):
-Loss of accommodation (vision loss)
-Dry mouth
-Difficulty urinating
-Constipation
Blocking dopamine receptors causes what?
-Parkinson’s syndrome
-Akathisia
-Dystonias
Endocrine blockade resulting in hyperprolactinemia:
-Amenorrhea-galactorrhea
-Infertility
-Impotence
New antipsychotics are CONTRAINDICATED with which disease state?
Diabetes
What was the first antipsychotic?
Chlorpromazine
What drugs are the aliphatic phenothiazines?
(first gen antipsychotics)
Chlorpromazine
Promethazine (used for H1 antagonist property)
What property is Promethazine used for and what other indications does it have?
H1 antagonism
-Used for nausea/vomiting
What is the Piperidine Phenothiazine?
-Thioridazine
What are the Piperazine Phenothiazines?
-Fluphenazine
-Prochlorperazine
-Perphenazine
What did the CATIE studies show?
Perphenazine is just as effective as newer agents when used in combination with anticholinergics
*this drug is much cheaper as well
What is the Thioxanthine drug?
Thiothixene
What is the Butyrophenone drug?
Haloperidol
What are the benefits of using Atypical/Second Generation (new) antipsychotics?
-Reduced EPS (dual 5HT and D2 blockers)
-Better efficacy for negative symptoms
What is the downside of using Atypical/Second Generation (new) antipsychotics?
More metabolic problems
-Weight gain
-Linked to diabetes
*can cause compliance issues
What affect do presynaptic serotonin receptors have on dopamine?
-Control the dopaminergic neuron (which is in charge of making dopamine)
-Activated serotonin receptors lead to decreased dopamine synthesis and release
*Antagonizing these receptors leads to increased dopamine synthesis and release
*D2 receptor agonists compete with dopamine for the receptor which lessens movement disorders
What are the Atypical/ 2nd Generation Antipsychotics?
-Clozapine
-Olanzapine
-Loxapine
What was the first Atypical Antipsychotic?
Clozapine
What is the most effective Antipsychotic?
Clozapine
What is a downside to using clozapine?
Many side effects!
What are the side effects of clozapine?
-Agranulocytosis (*requires weekly blood tests)
Anticholinergic
-Antihistamine
*Risk of diabetes
What are the side effects of Olanzapine?
**Weight gain
-Diabetes
(Causes less N/V and EPS)
What atypical antipsychotics have metabolites?
Loxapine -> Amoxipine (inhibits NET, antidepressant)
Quetiapine (antidepressant)
What are the side effects of Quetiapine?
-Hypotension (a1)
-Sedation (H1)
-Diabetes
*low antimuscarinic (blocks both 5HT and D2)
*Low EPS
Which antipsychotic is specifically designed to have 5HT and D2 antagonist properties?
Risperidone
What are the side effects of Risperidone?
Weight gain
Some sedation
(low EPS)
What makes D2 receptors different than D3 or D4?
D2 has very long binding pockets that drugs must be able to enter
What atypical antipsychotic has a fast onset?
Lurasidone
When dosing Lurasidone, what is an important note to make?
Low doses have similar efficacy to high doses
Which atypical antipsychotic is used to treat Parkinson’s Disease Psychosis?
Pimavanserin
Which atypical antipsychotic prolongs the QT interval?
Ziprasidone
What are the 3 D2/D3 partial agonists?
-Brexipiprazole
-Cariprazine
-Lumateperone
What are the key features that define psychotic disorders?
-Delusions
-Hallucinations
-Disorganized thinking and speech
-Disorganized or abnormal motor behavior
-Negative symptoms
What are delusions?
Fixed false beliefs that are not amenable to change even with conflicting evidence
What are positive symptoms?
Outward symptoms
What are negative symptoms?
Symptoms relating to long-term functioning
*impact long-term outcomes and how well a person is able to live alone
What substances are associated with schizophrenia?
-Smoking
-Marijuana
-Cocaine, Amphetamine
How does smoking induce schizophrenia?
-Induces 1A2
*not due to nicotine, caused by hydrocarbons produced and inhaled
-Decreases the serum concentration of 1A2 substrate antipsychotics
What are the 1A2 substrate antipsychotics?
Olanzapine
Asenapine
Clozapine
Loxapine
How do marijuana, cocaine, and amphetamine affect schizophrenia?
-Hasten the onset of schizophrenia
-Exacerbate symptoms
-Reduce time to relapse
*note: only people with specific genetics are at risk for schizophrenia with marijuana use
What is the only substance that can cause schizophrenia?
P2P methamphetamine
What must be considered when choosing a drug therapy for a patient?
-Doses per day
-Side effects
-Previous drug therapy (including family members)
-Cost
-Concomitant therapy
-Need for monitoring
What dosage form is considered first-line schizophrenia treatment?
Oral therapy
*unless there are reasons why IM would be better
Older agents (Typical Antipsychotics) primarily have what function?
D2 receptor antagonist
True or False: Typical Antipsychotics worsen negative schizophrenia symptoms
True
What are the partial agonists?
-Aripiprazole
-Brexpiprazole
-Cariprazine
What function do partial agonists have on dopamine transmission?
“Stabilize” dopamine transmission
Partial agonists are associated with what side effects overall?
*More akathisia than other antipsychotics
*Boxed warning for suicidal thoughts/behavior (depression use)
The partial agonists are substrates of what?
Aripiprazole + Brexpiprazole: 2D6 and 3A4
Cariprazine: 3A4
What is a good antipsychotic to use to avoid weight gain?
Aripiprazole
Which group of antipsychotics causes the most weight gain?
The “pines”
What are the “pines”?
Asenapine
Clozapine
Olanzapine
Quetiapine
The “pines” are substrates of what?
Asenapine, Clozapine, + Olanzapine: 1A2
Quetiapine: 3A4
Which antipsychotic has a sublingual and patch form?
Asenapine
Which “pines” are associated with QTc prolongation?
Asenapine
Clozapine
Quetiapine
Which antipsychotics have a DRESS warning?
Olanzapine
Ziprasidone
Which antipsychotic causes the most weight gain?
Clozapine
Which antipsychotic is also a UGT substrate?
Asenapine
What are the directions for applying an Asenapine patch?
Apply one patch every 24 hours
-rotate patch site to minimize application site reactions
Clozapine is associated with agranulocytosis which requires blood monitoring while taking this medication. What is the monitoring regimen?
Weekly x 6 months
then Biweekly x 6 months
then Every 4 weeks
What is the available combination antipsychotic?
Lybalivi
(Olanzapine/Samidorphan)
When is the combination product Olanzapine/Samidorphan (Lybalvi) contraindicated?
*Samidorphan is an opioid antagonist preferring the mu opioid receptor
*Contraindicated in patients currently taking opioids or in opioid withdrawal
What 2 antipsychotic meds need to be taken with food to increase absorption and bioavailability?
-Lurasidone
-Ziprasidone
Which antipsychotic has a CONTRAINDICATION for QTc prolongation?
Ziprasidone
Which antipsychotic causes hyperprolactinemia?
Risperidone
(pseudopregnancy, gynecomastia)
Which antipsychotic is renally eliminated?
Paliperidone
*requires dose adjustment
Which new agent is associated with few side effects?
Lumateperone (Caplyta)
Which antipsychotic can be used to treat hallucinations/delusions in Parkinson’s Disease?
Pimavanserin
Which agent is an inverse agonist and antagonist at the 5HT 2A receptor?
Pimavanserin
What boxed warning do all antipsychotics have?
Increased risk of death in ELDERLY patients treated for dementia related behaviors
Which antipsychotic is available as a long-acting injection?
Haloperidol
Why might the long-acting injection of haloperidol not be a great medication choice?
Oil-based
*requires a Z-track method of injection to increase area of injection into the deep IM muscle
NOT FIRST-LINE
What is the most commonly used immediate release antipsychotic?
Haloperidol
What is the treatment for acute dystonias?
IM anticholinergic NOW
-Benztropine 2mg
-Diphenhydramine 50mg
What is the treatment for Drug-Induced Parkinson’s?
-Oral anticholinergic
-Benztropine
-Trihexyphenidyl
-Diphenhydramine
What is the treatment for Akathisia?
Beta-blocker (*propranolol)
Benzodiazepine (*lorazepam)
What is the treatment for Tardive Dyskinesia?
VMAT inhibitors
What are the VMAT inhibitors?
Valbenazine (Ingressa)
Deutetrabenazine (Austedo)
What are the VMAT inhibitors substrates of?
Valbenazine: 2D6/3A4
Deuetrabenazine (2D6)
What is a common side effect of the VMAT inhibitors?
QTc prolongation
True or False:
Future antipsychotic use after development of Neuroleptic Malignant Syndrome is contraindicated
False
-still need treatment
Which antipsychotics have the highest risk of causing Neuroleptic Malignant Syndrome?
Clozapine
Olanzapine
Which antipsychotics have the lowest risk of causing Neuroleptic Malignant Syndrome?
Ziprasidone
Lurasidone
Aripiprazole
