Final: Antipsychotics Flashcards
Features of bipolar disorder
1% incidence in all populations
life-long, managed with treatment
Cyclic episodes of mania/depression
2x episodes of severe mania= need for treatment
Treatable, but only ~1/3 seek treatment
Bipolar 1
severe mania/severe depression
Bipolar 2
Low mania/severe depression
Cyclothymia
low mania/low depression
Treatment for bipolar disorder: Lithium
lithium- also helps kidneys
first in lethargic guinea pigs
Effect, poor patient compliance (50%)
Narrow Therapeutic range/index, need to be monitored, varies with Na+ levels.
Exerts synaptic effects via GABA, dopamine, glutamate, signal transduction mechanisms.
Treatment for bipolar: Anticonvulsants
Valproate
Lamotrigine
Treatment for bipolar: antipsychotics
quetiapine, Olanzepine
Treatment for bipolar: Antidepression and more
SSRIs
Psychotherapy
Lithium reduces ____ of manic and depressive episodes
FREQUENCY
Lithium and carbamazepine reduce ______ of manic episodes
SEVERITY
Side-effects of lithium
Nausea, Thirst, Polyuria, Tremor, Weakness, Confusion, Seizures, Arrhythmias, Coma, Death
Schizophrenia: gen info
1-1.5% world population
similar rates female/males, age onset varies
Onset peak 16-25, later onset possible
complex patterns of symptoms vary across patients
Schizo: Thought disorder
Incoherent, delusional, inappropriate associations
Schizo: perceptual disorders
Hallucinations in all modalities, most often auditory
Schizo: emotional disorder
Inappropriate affect, can be agitated or flat
Schizo: motor disorders
○ Repeated purposeless movements (stereotypies)
Schizophrenia diagnosis
2 symptoms for 1 month: • Delusions • Hallucinations • Disorganized Speech • Disorganized or Catatonic Behavior • Affective Flattening, Alogia, Avolition
Additional Criteria: Dysfunction at Work, Home, or Self-care, Continuous Signs for 6 Months, Not an Affective Disorder, Not Substance Induced
4 types of schizophrenia
1) Paranoid: delusions, persecution
2) hebephrenic: immature emotionality
3) catatonic: immobility and agitation
4) undifferentiated: mix of symptoms
Type 1 schizophrenia
Positive symptoms
hallucinations
thought disorders
Delusions (persecutions, grandeur, control)
Type 2 schizophrenia
Negative symptoms
flattened affect, poverty of speech, lack of initiative, lack of persistence, anhedonia, social withdrawal
Biological correlates:
Genetics
mono: 48%, di: 17%
increase risk with relatedness
risk predicted by bio > adoptive parent.
128 gene variants
epigenetics control what genes expressed
Dreadful gene quadruplets
identical genes
varied degrees of illness
severity correlated with low birth weight, degree of hypofrontality, and level of stress exposure
Eye tracking (schizo): impaired smooth pursuit tracking
control: smooth
Schizo: saccadic
Energy usage (schizo)
reduced activity frontal cortex
hypo frontality, low energy use in frontal lobe
Brain Structure in schizophrenia
less cortical complexity, enlarged ventricles, small brain volumes, grey matter loss, greater loss in childhood onset.
Disorganized structure: abnormal cytoarchitecture. Prenatal virus: altered development, abnormal cell pattern in hippocampus and cortex.
Brain development in schiophrenia
Ventricular Enlargement
Underdeveloped hippocampus
Underdeveloped amygdala
Underdeveloped Cerebral Cortex
Abnormal Cytoarchitecture
Neurochemical imbalance
Neurotransmitter theory of schizophrenia
Glutamate interacts with dopamine leading to symptomology consequences
Role of Dopamine in schizophrenia
Traditional Antipsychotic Medications Block Dopamine Receptors with High Affinity
Reserpine Depletes Monoamine Levels and Reduces Symptoms of Schizophrenia
Antipsychotics Induce Motor Side-effects Similar to Parkinson’s Disease
Amphetamine-induced Release of Dopamine Exacerbates Symptoms of Schizophrenia
The potencies of traditional antipsychotics are predicted by D2 receptor affinities
Imaging studies in humans demonstrate binding of antipsychotics to D2 receptors
Symptoms of Schizophrenia related to major dopaminergic pathways
D2 receptor affinity predicts…
clinical potency \
(higher dose = higher Ki)
correlation not seen for 5HT, H1, or alpha-2
Antipsychotics compete for _______ labelled by [11C] Raclopride
d2 receptors
Haloperiodol, clozapine, risperidone
Therapeutic potency graph by…
DOSE-RESPONSE CURVE
x-axis: Ki
y-axis: avg. daily clinical dose
How do you get Ki?
[drug] displaces 50%- COMPETITION
Mesocortical pathway
Thought/perceptual schizophrenia symptoms
VTA–> Cortex via thalamus
Mesolimbic pathway
Mediates EMOTIONAL disorders and RESPONSE TO REWARD
VTA–> NA
Nigrostriatal Pathway
Mediates SENSORY-MOTOR dysfunction
Substantia nigra –> Striatum
Schizo: Kraepelin vs. Crow
Crow: +/- type 1 and 2 symptoms
Kraepelin: paranoid, catatonic, etc.
History of antipsychotics
LaBorit first used promethazine as pre-anesthetic in 1950
notes promethazine/chlorpromazine calmed paients. First admin to sedate schizo.
Actions beyond sedation
History of antipsychotics:
___ > ____ = ____
major tranquilizers > neuroleptics = antipsychotics
Rule of thrids in treatment
1/3- recover
1/3- chronically ill
1/3- recover by relapse
Individual therapy
Psychotherapy may help to normalize thought patterns. Also, learning to cope with stress and identify early warning signs of relapse can help people with schizophrenia manage their illness.
Social skills training
Focuses on improving communication and social interactions and improving the ability to participate in daily activities.
Family Therapy
Provides support and education to families dealing with schizophrenia.
Vocational rehab and supported employment
Assists people with schizophrenia to prepare for, maintain jobs.
Typical antipsychotics
1st gen, traditional
Atypical antipsychotics
2nd gen
Name the Atypical antipsychotics
Clozapine (Clozaril) aripiprazole (Abilify) risperidone (Risperdal) quetiapine (Seroquel) olanzapine (Zyprexa)
Atypical: CARSZ
CARQO
Name the typical antipsychotics
Chlorpromazine (Thorazine)
Haloperidol (Haldol)
Reserpine
Thioxanthines (Navane)
What are the effects of typical antipsychotics?
Block D2 receptors
Require several weeks of treatment
effective on + symptoms
Not effective on negative symptoms
many serious side effects
Typical antipsychotics: Extrapyramidal (early developing) motor effects
Parkinsonianisms (tremor, rigid, bradykinesia)
Akathisia (restless)
Dystonia (involuntary contraction)
**CAUSED BY D2 RECEPTOR BLOCKING
Typical antipsychotics: Tardive Dyskinesia (late developing)
abnormal movements of upper body, head (jaw clench, eye blink, jerk torso, twitching)
longterm use in 30-70% patients
can sometimes persist after discontinuation
**POSSIBLY DUE TO SUPERSENSITIVITY OF D2 RECEPTORS
incidence increase w/treatment duration
Antipsychotics at D2 receptors causes
Block Dopamine receptors
motor: Extrapyramidal/tardive dyskinesia
endocrine: prolactinemeia, glactorrhea
(increase prolactin)
antipsychotics at H1 receptors
Block histamine receptors
sedation (antihistamine)
antipsychotics at M receptors
Block muscarinic receptor
Sympathomimetic (Antimuscarinic)
Sympathetic
antipsychotics at Alpha 1 receptors
block adrenergic alpha-1 receptors
Postural (orthostatic) hypotension
antipsychotics at 5HT2 receptors
block serotonin receptor
Weight gain
Tuberoinfundibular pathways
hypothalamic DA inhibits prolactin release
antispychotics block D2 and induce hypersecretion of prolactin
Gynecomastia/galactorrhea, not good
A12 –> Median Eminence –> Anterior pituitary
Antipsychotics Block [m] receptors, list of sympathetic side effects
Tachycardia, blurred vision (dilate pupils), constipation, urinary retention, dry mouth, erectile dysfunction.
Postural (orthostatic) hypotension antipsychotics block alpha-1 receptors
What does this mean
alpha 1 receptors constrict vessels
increase blood flow to brain on standing
Antipsychotics block alpha 1 receptors, light headed standing up
Difference between 1st and 2nd generation antipsychotics
Both: H1, Ach, Alpha-1, D2
Only atypical: 5HT2, 3, 2c, alpha-2, D1, D4
Overall: Atypical compared to typical has weaker affinity for ____ and stronger affinity for _____
weaker: D2
Stronger: D4 and 5-HT2A
Atypical have ___ affinity for D2 and ___ affinity for 5HT
lower D2
higher 5HT
Are atypical psychotics as effective as typical?
Yes! and in patients resisting traditional treatment
fewer extrapyramidal/tardive dyskinesia side effects
Side effects of atypical antipsychotics
weight gain, diabetes, hyperlipidemia, cardio, urinary, sexual, sedation, agranulocytosis
Atypical: Agranulocytosis
loss of infection fighting white blood cells (leukocytes)
more infect/death
Clozapine (Clozaril) = highest risk, need to monitor cells regularly
Atypical: diabetes
alterations in carbo/fat metabolisms
weight gain
diabetes mellitus can develop
FDA approved use of antipsychotics
Schizophrenia (adult/adolescent) Bipolar affective disorder (mania) MDD agitation ASD Tourette Psychosis
Off label use of antipsychotics
dementia, substance abuse, anorexia, OCD, PTSD, GAD, ADHD, hiccups, nausea, ICU delirium
Block box warnings
death with atypical in elderly with dementia
15% increase risk mortality
