Psychosis and Antipsychotics Flashcards
22q11 deletions
alter expression of genes via decrease of DGCR8 protein expression
Which of these illnessess does not have psychosis??
Brain tumors Dementias Endocrine disorders Depression Seizures Infections Substance intoxication/withdrawal Delirium
Depression
Region hyperactivated in hallucinations
secondary auditory association cortex
located in superior temporal gyrus
Hallucinations result from increased activity from _______ and decreased activity from ________
Increased from emotional regulation/attention,
Decreased from monitoring/volitional functions
Structures involved in delusions
fronto-striatal circuits, parietal cortices, amygdala, cerebellum
Symptoms include: Delusions Hallucinations Disorganized speech Disorganized/catatonic behavior Negative symptoms (flat, alogia, avolition)
Schizophrenia
(at least two symptoms,
at least 1 from the first three
for most of at least 1 month)
Genetics involved in schizophrenia
KCNH2 DTNBP1 NRG1 DISC1 RGS4
Structural abnormalities in schizophrenia include: Enlarged ventricles Reduced total brain volume Enlarged occipital lobes Smaller frontal/temp/par lobes
All but enlarged occipital lobe
Which of these cells are altered in schizophrenia pathology? Pyramidal Chandelier Neurons Oligodendrocytes Astrocytes
All but astrocytes
Which neurotransmitters have dysfunction in schizophrenia?
DA, glut, GABA, 5-HT, ACh
What is the increased risk if a sibling has schizophrenia?
9% if sibling only,
16% if one parent + sibling
What is the heritability estimate of schizophrenia?
80%
What is the increased risk of schizophrenia in offspring?
13% if one parent,
46% if both parents
What are examples of common variants in schizophrenia?
SNPs
Tandem repeats
Account for ~30% of risk variance
8300+ variants
100 different genes
What are examples of rare varients in schizophrenia?
mutations
Unique CNVs (100+ w/ schiz ass’n)
- 22q11 via DGCR8 decrease
- DISC1 translocation (1/11)
Target of antipsychotic drugs
D2 receptor
D2 side effects:
• Extrapyramidal symptoms: Nigrostriatal pathway, parkinsonism, dystonia, akathisia, tardive dyskinesia after chronic use
• Worse negative/cognitive symptoms: mesocortical pathway
• Hyperprolactinemia, galactorrhea, amenorrhea, gynecomastia (esp risperidone)
Increases catecholamine via receptor blockade in the presence of MAO inhibition
Chlopromazine
Classifications of antipsychotics
Chemical
First/Second generation
High/low potency
Included in chemical class of phenothiazines
- Aliphatic: chlorpromazine
- Piperidine: thioridazine
- Piperazine: fluphenazine, perphenazine
First generation antipsychotics
chlorpromazine, haloperidol, fluphenazine, perphenazine, thioridazine, trifluoperazine
Additional effects of second-generation antipsychotics
5-HT2a antagonism, D2 receptor affinity
Low potency antipsychotics have ______ side effects related to D2 blockage, _______ side effects related to non-DA receptors
Decreased
Increased
Non-DA side effects of antipsychotics
Anticholinergic Antihistamine Alpha-1 adrenergic QTc prolongation Increased BP, lipids, blood sugar Neuroleptic malignant syndrome
Side effects include agranulocytosis, seizure (high dose), constipation, sialorrhea, myocarditis, orthostatic hypotension + tachycardia
Clozapine
Shown to be more efficacious than other antipsychotics
Clozapine
Longest time to d/c in CATIE study
olanzapine
FDA approved uses of antipsychotics
schizophrenia schizoaffective disorder bipolar disorder major depressive disorder Tourette's syndrome
Moderate potency antipsychotics
perphenazine, loxapine
High potency antipsychotics
haloperidol, fluphenazine
Low potency antipsychotics
chlorpromazine
Catatonia
decreased reactivity to environment (negativism, rigid posturing, mutism, stupor)
Which major NT systems involved in psychosis?
DA, glut, GABA, 5-HT
Basal magnocellular corticopedal pathway involves…
GABA and ACh pathways
Acute fluctuating disturbance in attention, awareness, cognition
Delirium
Monitoring/volitional structures decreased during auditory hallucinations:
dlPFC, Cerebellum, DACingulate cortex
Emotional regulation and attention structures upregulated during auditory hallucinations:
OFC, VACingulate cortex, subcortical structures
Hyperactive in auditory hallucinations
Secondary auditory association cortex
Delusion of passivity means
someone/somthing external is controlling you
Thought broadcasting means
Others can hear your thoughts
Misinterpreting messages from the external world
Reference
Thought withdrawal means
Thoughts are being taken from your mind
Circuits involved in delusions
Salience/reference
Agency/others
Fear/paranoia
Abberrations in how brain circuits specify hierarchia predictions, how they compute and response
Delusions
the state or quality by which it stands out relative to its neighbors
Saliance
Symptom domains in Schizophrenia include
Delusions Hallucinations Disorganized speech Disorganized or catatonic behavior Negative symptoms (affect, alogia, avolition)
+ Common cognitive deficits
Structures commonly involved in all delusions
prefrontal cortex, midbrain
Other structures: fronto-striatal circuits, parietal cortices, amygdala, cerebellum, anterior cingulate, medial PFC
Alterations in glut affect GABA signalling, increase in glut in PFC, overinhibition of DA.
True –> too little DA results in negative symptoms
Alterations in glut affect GABA signalling, hyperactivity in NAcc and increase in DA.
True –> positive symptoms in schizophrenia
Hereditibility in schizophrenia
up to 80%. Some environmental involvement.
22q11 deletion
alters expression of multiple genes of DGCR8 (microRNA processing complex –> impact other areas of the genome)
DISC1 (disruption of schizophrenia 1)
translocation between 1/11 gene, disrupts gene, produces altered protein, interaction with many pathways (Wint, Dynein, Endopeptidate, Inflammatory, Immune) –> neurodevelopment
Found in Family in Scotland, produces other mental disorders
Schiz with shorter time period
schizophreniform disorder
Schiz with low mood
schizoaffective disorder
Schizophrenia is a chronic illness
True
Potency is inverse to efficacy.
False - potency has NO relationship to efficacy.
Likely to cause hyperprolactinemia, galactorrhea, amenorrhea, gynecomastia
Risperidone
+ other D2 blockades
Antihistamine effects:
Weight gain
EPS clonazapine, olanzapine
Clozapine scary SE
agranulocytosis (+ seizures, constipation, myocarditis, orthostatic hypotension, tachycardia)
Use only for treatment resistant schizophrenia
