Lecture 1 & 2: Pathophysiology and Pharmacology of Schizophrenia And Case Study

Question 1

What is Psychosis?

Answer 1

• Mental health condition characterised by a disconnection from reality. (Ability to distinguish what is real or not)
• Can occur in a variety of psychiatric disorders: Schizo

Question 2

What are the symptoms of Psychosis?

Answer 2

• Hallucinations
• Delusions
• Disorganised Thinking
• Affecting behaviour, emotional regulation and social functioning

Question 3

What is Schizophrenia?

Answer 3

• A chronic severe mental disorder.
• Affects how a person thinks, feels, losing touch of reality
• No cure
• Suggest genetic association
• Starts early on (20s and 30s)

Question 4

What are positive symptoms associated with Schizophrenia?

Answer 4

• Delusions - False held belief (not true)
• Hallucinations - perception of something in absence of stimuli (smell, sight, visual)
• Disorganised Speech
• Unusual behaviour and agitation

Question 5

What can Schizophrenia cause?

Answer 5

• Bio: Genetic load, Dopamine and Glutamate dysregulation
• Psycho: Concrete thinking, difficulties with abstract thought, Issues with sensory filtering
• Social: Increased incident in urban environment

Question 6

What are the differences between Psychosis and Schizophrenia?

Answer 6

• Psychosis is broad and schizo is a specific diagnosis. Psychosis is a primary symptom
• Psychosis is temp and triggered by factors. Schizo is long term and chronic

Question 7

What are amphetamines and what do they do to Schizo?

Answer 7

• Type of stimulant drug that affects CNS by increasing levels of dopamine and norepinephrine.
• Dopamine agonists - can give psychotic symptoms. This can cause dysregulation of neurotransmitter leading to it worsening

Question 8

What is the mechanism of action of amphetamines?

Answer 8

• Stimulate release of dopamine and norepinephrine
• Block reuptake of dopamine and norepinephrine - remains in presynpatic cleft
• Inhibition of monoamine oxidase - enzyme responsible for breaking down neurotransmitters

Question 9

What is Chlorpromazine and its mechanism of action and some side effects?

Answer 9

• First gen antipsychotic drug
• Blocks D2 receptors in the brain
• Tardive Dyskinesia: Involuntary movement in face and mouth, Anticholinergic effects: Urinary retention and dry mouth

Question 10

How do dopamine, its receptors and the negative feedback?

Answer 10

• Dopamine is stored into synaptic vesicles via VMAT2 (Vesicular monoamine transporter)
• Dopamine released acts on 5 types of post synaptic receptors (D1-5)
• Presynaptic D2 autoreceptor acts as a negative feedback mechanism- regulates the release of dopamine from Presynaptic neuron

Question 11

What are the types of dopamine receptors?

Answer 11

• Type 1 & 5 - similar in structure and drug sensitivity (D1 like) don’t have clinically relevant antipsychotic effects
• Types 2, 3, 4 are similar in structure (D2 like). Only D2 receptor is blocked by antipsychotic drugs

Question 12

What are the different dopamine pathways?

Answer 12

• Mesocortical:
• Nigrostriatal:
• Mesolimbic:
• Tuberoinfundibular:

Question 13

What symptoms are associated with the mesolimbic pathway dysfunction and what does it control?

Answer 13

• Depression, reduced motivation, and pleasure.
• Links the ventral tegmental area (VTA) to the Limbic system
• It regulates emotion, reward and motivation

Question 14

What is the function of the mesocortical dopamine pathway?

Answer 14

• Connects the VTA to the prefrontal cortex
• regulating cognition, attention, and executive function.
• Difficulty with planning and decision-making

Question 15

What is the role of the nigrostriatal pathway?

Answer 15

• Transmits dopamine from the substantia nigra to the striatum, crucial for voluntary movements.
• Typical symptoms
• Chronic blocking can produce tardive dyskinesia (movement disorder) facial & tongue movements such as constant chewing, grimace
• Limb movements are quick and jerky

Question 16

What happens to the tuberoinfundibular pathway when dopamine levels are reduced?

Answer 16

• This pathway connects dopamine neurons to the arcuate nucleus of the hypothalamus to the pituitary gland
• Prolactin secretion increases, leading to hyperprolactinemia and galactorrhea (milk production not associated with/ breastfeeding) and sexual dysfunction

Question 17

What are the side effects of cholinergic M1 antagonism?

Answer 17

• Dry mouth
• Blurred Vision
• Constipation
• Cognitive blunting

Question 18

What is the ideal antipsychotic drug? What will it target/not?

Answer 18

• Ideal drug will decrease dopamine in the mesolimbic to treat positive symptoms (hallucinations)
• Increase dopamine in mesocortical to treat negative and cognitive symptoms (depressive)
• Leaving nigrostatial and tuberoinfundibular pathways to avoid side effects

Question 19

What are the types of atypical (newer) antipsychotics?

Answer 19

• Pines - Olanzapine, Quetiapine
• Dones -Risperidone
• 2 Pips: Aripiprazole (partial agonist)
• Rip: Cariprazine (partial agonist)

Question 20

What are some first gen low potency and higher potency antipsychotics?

Answer 20

• First gen low potency: Chlorpromazine
• First gen high potency: Haloperidol

Question 21

What are some 2nd generation antipsychotics? and what are the differences between the generations?

Answer 21

• Aripiprazole
• Quetiapine
• Risperidone
• Olanzapine
• First gen have high incidence of extra pyrimidal side effects. They have varying affinity for D2 receptor and target serotonin receptor
• 2nd gen can have metabolic side effects
• Theory proposes that 1st gen bind more tightly than dopamine to D2 receptor. 2nd gen bind more loosely

Question 22

What type of receptors do resperidone and paliperidone work on?

Answer 22

• Resp: strong binding for serotonin and dopamine d2, a1/2 adrenergic receptors. Low affinity for H1.
• Pali: a major active metabolite of resp. centrally active D2 and serotonin antagonist. Antagonist for a1/2. Better w/ cognition

Question 23

What receptors do Olanzapine and Quetiapine work on?

Answer 23

• Olan: high affinity to serotonin and medium dopamine receptors. Highest for H1 - causes weight gain
• Quet: Dirty drug but has low EPS side effects but causes sedation

Question 24

What are the some receptors that second generation antipsychotics work on?

Answer 24

• Risperidone: D2, serotonin, a1
• Olanzapine: works on all (mostly serotonin, D2, M1)
• Aripiprazole: D2 mostly and some others
• Quetiapine: serotonin, a1

Question 25

What are the types of delusion?

Answer 25

- Delusion of reference: Read into somethinmg/overthink/ normal things have special meaning - Delusion of grandeur: Think you are God/more important - Paranoid delusion: People trying to get you

Question 26

What are the types of disorganised speech?

Answer 26

- Derailment : talk about something then about something else not relevant - Tangentiality: Talk about subject but not answer question - Incoherence: Say words and words dont make sense

Question 27

What are some negative symptoms of Schizophrenia?

Answer 27

- Alogia (Poverty of speech, talk slowly) - Lack of socialization - Avolition (Not able to engage in goal sustaining activities) - Loss of emotional connectedness - Loss of executive functions

Question 28

What are som e first generation (typical) antipsychotics and what receptor do they all work on?

Answer 28

* Haolperidol * Chlorpromazine - also works on M1 (more sedative) * All work on dopamine receptor. D2 receptor antagonist

Question 29

What are the 3 main stages of treating someone with schizophrenia?

Answer 29

* Acute stage: Aim to calm patient and prevent harm * Stabilisation stage: patient becoming stable. Symptoms under control * Stable phase: Treatment plan long term, no exacerbation of symptoms. No positive but can negative symptoms

Question 30

What is the main problem with first generation antipsychotics?

Answer 30

* Extrapyrimidal symptoms: dystonia (bad, painful muscle spasms, stiff neck early sign), reversible * Tardive dyskinesia: Has involuntary movement of jaw (irreversible) * Akathisia: Restlessness of hands and legs. Reversible

Question 31

What is a main side effect of Risperidone (2nd gen)?

Answer 31

* Hyperprolactanemia (high level of prolactin in blood) * High levels of prolactin but not pregnant (false belief)

Question 33

What is a main side effect of olanzapine (2nd gen) and why should ciprofloxacin not be used with it?

Answer 33

* Pain in her lower back and foul smelling urine (signs of UTI), it also causes weight gain * Cipro - quinolone antibiotic (narrow spectrum) * Cipro inhibits CYP1A2 which is meant to metabolise Olanzapine - leads to elevated levels (more side effects: drowsiness and tremor)

Question 34

What are some things that should be monitored when taking 2nd gen antipsychotics?

Answer 34

* Weight (BMI) * Waist circumference * Blood pressure * Blood glucose and lipids * Long term can lead to diabetes, heart attack and stroke

Question 35

Why is Clozapine good and not good?

Answer 35

* 2nd gen antipsychotic and most effective. Used in treatment resistant schizo * Associated w/ neutopaenia and agranulocytosis. Less neutrophils (cant fight infections)

Question 36

What are some considerations when taking clozapine?

Answer 36

* Reduces peristalsis (constipation) * Might get seizures * Myocarditis (inflammation of the heart) * Drooling * Smoking: induces metabolic enzymes. If stopped wont be induced. High dose will be toxic