Unit 8: Antipsychotics Flashcards
Drugs for schizophrenia: 1st gen (chlorpromazine, haloperidol) 2nd gen (clozapine, olanzapine, risperidone) 3rd gen (aripiprazole)
Schizophrenia
Schizophrenia: a brain disorder characterized by disruptions in thought processes, perceptions, emotional responsiveness and social interactions
Schizophrenia Demographics
Schizophrenia Demographics:
WHO
- affects nearly 1% of global population
- ratio of men to women diagnosed is 1.4 : 1 (estrogen thought to be a protective factor)
WHAT
- a brain disorder affecting thought and perception, obscuring reality
- hallucinations and delusions are most frequent symptoms
- social interactions, motivation, mood and impaired cognitive function are most disabiling and difficult to treat
WHEN
- typical onset in early adulthood
- earlier for men (age 18-25) than women (age 21-30)
- “prodromal period” 2-5 years before diagnosis with subclinical behavioural changes noted by friends and family
WHERE
- globally one of the top 10 causes of disability
- urbanicity is a risk factor — (perhaps due to stress of living amongst many people)
WHY
- cause = unknown
- both genes and environment play a role
- genetic risk factors contribute 80% of the overall risk
- environmental factors (prenatal development, early childhood) make up the remaining 20%
Schizophrenia Positive Symptoms
Positive Symptoms: positive meaning an addition of behaviours/symptoms not normally observed in healthy people
(1) Hallucinations —incorrect processing of sensory information, resulting in false perceptions
- auditory (eg: voices)
- visual
- olfactory and tactile sometime present also
(2) Delusions — implausible beliefs that are resistant to change even in the face of contradictory evidence
- paranoid/percusatory: most common delusion; beliefs of being harrassed, harmed, watched, targeted (eg: conspiracy against self; “they are out to get me”)
- grandiose: exaggerated belief of one’s greatness/feeling superior to other people (eg: having superpowers/related to celebrity)
- referential: external meaning that is personally relevant (eg: communications from the president directly for them)
- somatic: perception of a disturbance in one’s appearance/bodily functions (eg: organs are disintegrating)
- religious: unusual religious beliefs/experiences (eg: having divine powers/ability to see angels/are God)
(3) Illogical Thoughts — disturbances in the flow, order, and content of thought
- disorganized thoughts: loosening of associations and logical thought, manifesting as highly tangential answers or quick shifts between topics
- eg: “what is your name? what does he shut? he shuts his eyes…”
-
neologism: a newly coined term or phrase (making up/parsing words together)
- eg: “bawked”, “flail-wise”
- nonsensical rhymes: eg: “lighting fires and eating wires”
(4) Lack of Goal-Directed Behaviour — abscence of behaviour conducted to achieve a specific goal or outcome
(5) Motor Symptoms and Disorganized/Catatonic Behaviour — deficits in motor functioning, from agitation to immobility
- grossly disorganized behaviour: unpredictable movements/agitation, lack of self care, lack of social inhibition
- catatonia: decrease in reactivity to environment—stupor, rigidity of body
Schizophrenia Negative Symptoms
Negative Symptoms: lack of behaviours normally present in healthy people
(1) Avolition — decreased motiviation
(2) Anhedonia — decreased ability to experience pleasure or identify activities as being pleasurable
(3) Flattened Affect — lack of emotion or expression of emotion; difficulty processing other’s emotions/cues
(4) Poverty of Speech — limited vocabulary
(5) Social Withdrawal — sudden or gradual withdrawal from social activities
(6) Cognitive Impairments — impacted:
- working memory—reduced vocab and word recall ability
- executive functioning—(skill set) low self-control, difficulty regulating emotions, planning ahead, directing attention …
- cognitive flexibility—low critical thinking/problem solving skills
Schizophrenic Brain:
Subtle Neurological Changes
Subtle Neurological Changes
- enlarged lateral ventricles
- reductions in white matter
- reduced cerebral gray matter (reduced synapses, not cell numbers—loss of volume; fewer intraneural connections)
Schizophrenia: Genetic Risk Factors
Genetic Risk: schizophrenia has a high inheritability (0.8)—meaning that 80% of the risk factors are related to genetics
Frequency of schizophrenia among relatives: “concordiance”
(relative; risk/likelihood)
- not a relative: 1%
- aunt/uncle: 3%
- parent: 6%
- sibling: 9%
- child: 13%
- fraternal twin: 18%
- identical twin: 50-70%
Schizophrenia: Environmental Risk Factors
Environmental Risk Factors
In Utero
- maternal infection (eg: influenza) in the 2nd trimester—the brain develops during this period
- maternal malnutrition/starvation
- Plasmodium gondii infection (cat feces)
- obstetric complications (eg: lack of oxygen, bloodloss, premature birth)
Early Childhood
- physical or psychological trauma/abuse
- low SES
- urbanicity
- drug exposure (eg: amphetamine, cannabis, phencyclidine/PCP)
Schizophrenia Treatment:
Before Antipsychotics
Schizophrenia Treatment—before the development of antipsychotics, schizophrenic patients underwent:
- lifetime institutionalization
- fever induction
- hypoglycemic shock induction
- seizure induction
- frontal lobotomy
- sedation (chloral hydrate, other barbiturates)
- Freudian psychotherapy
Schizophrenia Treatment:
Discovery of Antipsychotics
Schizophrenia Treatment—the first antipsychotic was developed in 1950
- French surgeon Henri Laborit — goal: to develop a new anaesthetic void of hypertensive side effects, by combinating sedative, narcotic and hypnotic
- used a compound that lowered body temperature with “reduced antihistamine and enhanced sedative properties
- developed chlorpromazine—given to schizophrenic patients in 1952 after it was reported to generate a “chemical lobotomy”
- after several months, positive symptoms resolved and the patients returned to “normal”
Schizophrenia and Dopamine
Schizophrenia and Dopamine:
- from cases of cocaine/methamphetamine toxicity, we know that too much dopamine results in:
- agitation
- paranoia
- delusions
- hallucinations…
- then schizophrenia (pos symptoms) could be interpretted as having too much dopamine
- all first generation antipsychotics had the shared feature of antagonizing D2 dopamine receptors
Typical Antipsychotics (1st gen):
Chlorpromazine, Haloperidol
Typical Antipsychotics (APS) (1st gen)
- (1) Chlorpromazine
- (2) Haloperidol
- also called neuroleptics (in non-schizophrenia treatments)
Target: D2 dopamine receptors
MOA: antagonists of D2 dopamine receptors
- therapeutic effect observed through by blocking D2R—resulting in modified locomotor activity
- after several weeks, hallucinations and delusions dissipate
Typical Antipsychotics:
(Extrapyrmidal) Adverse Effects
1st Gen APS: (chlorpromazine, haloperidol)
Adverse Effects:
(1) Extrapyramidal Symptoms (EPS)
- severe, drug-induced movement deficits—a result of blocking dopamine:
- deficits similar to those of neurodegenerative disorders
- akinesia—absence of movement
- dystonia—involuntary muscle contractions
- catalepsy—serious motor impairments (slow movement, muscle rigidity) resembling Parkinson’s disease
- tardive dyskinesia (TD)—repetitive, involuntary movements of muscles in the face, neck, arms and legs
(2) Mood Effects
- anhedonia—decreased pleasure as a result of D2R antagonism
(3) Hormonal Effects—increased levels of reproductive hormone prolactin, can cause:
- men: breast development, impotence
- women: prevented menstruation, fertility issues
- both: lactation
(4) Sleep Effects—due to antagonism at H1 histamine receptors
- sedation—calmness/sleep induction
- somnolence—drowsiness; desire to sleep
(5) GI/Metabolic Effects
- anti-emetic properties
- weight gain
Typical antipsychotics do not cause withdrawal symptoms
Atypical Antipsychotics (2nd gen):
Clozapine, Olanzapine, Risperidone
Atypical Antipsychotics (2nd gen): called atypical bc effective at treating psychosis without the impaired motor activity; also bc of serotonin receptor antagonism
(1) Clozapine (1st atypical APS; 1961)
- most effective APS, but prescribed as last resort, due to high risk of agranulocytosis
(2) Olanzapine
- causes severe weight gain
- can cause 20-40lbs gain in just one month
(3) Risperidone
- 1st line treatment
Target:
- D2 dopamine receptors
- 5HT2A/2C serotonin receptors
- also act on muscarinic (acetylcholine) and histamine receptors
MOA: dual D2 and 5HT2 receptor antagonism
Atypical Antipsychotics:
(Metabolic) Adverse Effects
2nd Gen APS: (clozapine, olanzapine, risperidone)
Adverse Effects:
(1) Metabolic Syndrome
- weight gain
- unhealthy plasma lipid levels
- type II diabetes
- increased risk of cardiovascular disease
(2) Weight Gain
- increased appetite, resulting in extreme weight gain (olanzapine can cause 20-40lbs gain in 1 month)
(3) Blood Disorder — clozapine
- agranulocytosis—severe form of neutropenia (loss of white blood cells)
- life-threatening, as the body is highly susceptible to infection (insufficient WBC to fight off pathogens)
APS Adverse Effects: Summary
Summary: APS adverse effects
1st gen:
- EPS (Parkinsonian effects)
- Tardive dyskinesia (TD)
- hyperprolactinemia
2nd gen:
- metabolic syndrome
- cardiovascular disorder
- agranulocytosis (clozapine)
All:
- anhedonia; flattened affect (worsening of neg symptoms)
- sedation/somnolence
- weight gain
Efficacy
- APS are most effective at treating positive symptoms of schizophrenia
- limited ability at treating negative symptoms—oftentimes end up worsening neg symptoms (excluding clozapine)
- benefits are not immediately present, may require between 3-6 weeks to take effect
- 1/3 of schizophrenic patients are “treatment resistant”, meaning APS are ineffective
