psychosis and schizophrenia

Question 1

how to you describe what psychosis is

Answer 1

an acute or severe episode of being out of touch with reality and lack of insight

Question 2

what are various diagnoses associated with psychosis

Answer 2

organic disorders
- epilepsy
- cerebral lesions
- CNS illness (infections, genetic, congenital)
- endocrine disorders
- metabolic disorders
- iatrogenic causes
- relating to alcohol and psychoactive substances misuse
- dementia
- parkinson’s

affective disorders
- mania
- psychotic depression
- postpartum psychosis

schizophrenia

Question 3

what is the pathophysiology of schizophrenia

Answer 3

dysregulation in one of the neurotransmitter functions: DA, 5HT and glutamatergic

DA – D2 receptors and four tracts (nigrostriatal involved with involuntary movements, mesolimbic and mesocortical involved with attention, cognition, emotion, tuberoinfundibular involved with prolactin secretion)

Question 4

what is the etiology of schizophrenia

Answer 4

predisposing factors
- genetic
- environment in utero
- neurodevelopmental effects
- social, physical, psychosocial factors in infancy and early childhood
- personality

precipitating factors
- brain tumor/ injury
- substance/ drug-induced
- personal misfortune
- environment of high expressed emotion

perpetuating factors
- lack of social support/ poor socio-economic status
- social withdrawal
- secondary demoralisation
- poor adherence with antipsychotic medications

Question 5

what are the five symptom domains of schizophrenia and how does the course of the disease affect the domain presented

Answer 5

• positive symptoms
• negative symptoms
• cognitive symptoms
• aggressive symptoms
• anxiety/ depression

periods of acute presentation with positive symptoms interspersed with negative symptoms that predominate but as disease progresses, negative symptoms become more dominant

Question 6

list examples of positive and negative symptoms

Answer 6

positive symptoms
- delusions
- hallucinations
- thought disorders
- abnormal behaviors

negative symptoms
- withdrawal
- flattening of emotional responses

Question 7

what is the diagnostic criteria for schizophrenia (DSM-5)

Answer 7

at least 2 of the following each lasting for at least 1m with a total duration for at least 6m (which may include prodromal or residual sx) and there is social or occupational dysfunction
- delusions
- hallucination
- grossly disorganized/ catatonic behavior
- disorganized speech
- negative symptoms

Question 8

what is the general assessments for schizophrenia

Answer 8

1. HPI
2. psychiatric hx
3. substance use hx
4. complete medical and medication history
5. family, social, developmental, occupational history
6. physical and neurological exam
7. mental state exam
8. labs and other investigations

Question 9

what are the non-pharmacological management of schizophrenia

Answer 9

• individual CBT
• neurostimulation (ECT for treatment resistent schizophrenia, rTMS may reduce auditory hallucinations)
• psychosocial rehabilitation programmes

Question 10

what are the goals of therapy for schizophrenia

Answer 10

for acute phase
- minimise threat to self and others
- minimise acute sx
- improve role functioning
- identify appropriate intervention strategies
- collab with family and caregivers, support for carers

for stabilisation phase
- prevent or minimise relapse
- optimise dose and manage ADRs
- promote adherence

for maintenance phase
- improve functioning and QoL
- maintain baseline functioning
- optimise dose and monitor and manage ADR if any
- monitor for prodromal sx of relapse

Question 11

what is the treatment algorithm for managing schizophrenia

Answer 11

after confirming diagnosis of schizophrenia –> start with a single FGA/SGA except clozapine –> if inadequate response, use another single FGA/SGA not previously tried except clozapine –> if inadequate or no response, use clozapine –> (i) if inadequate or no response, clozapine + FGA/SGA/ECT (ii) if intolerable, use combination therapy of FGA+FGA or FGA+SGA or antipsychotic + ECT or antipsychotic + mood stabiliser –> if (i) still inadequate or no response, go to combination therapy of FGA+FGA or FGA+SGA or antipsychotic + ECT or antipsychotic + mood stabiliser

• an adequate trial is of at least 2-6w at optimal therapeutic dose before considered a non-responder
• for clozapine, requires 3m to show therapeutic response, trial would be for up to 8-10w

Question 12

what are some long acting injections

Answer 12

• IM risperidone microsphere
• IM paliperidone prolonged-release suspension
• IM aripiprazole
• IM haloperidol decanoate
• IM flupenthixol decanoate
• IM zuclopenthixol decanoate

Question 13

what is the structural significance of the decanoate compound

Answer 13

has an OH group that binds to a long aliphatic chain to create an ester bond, resulting in a very big molecule that easily dissolves in fat f/b breaking down into fatty acids, as ester bond breaks to release parent molecule

Question 14

how would you explain what an antipsychotic is

Answer 14

an antipsychotic is a medication that tranquilises without impairing consciousness and without causing paradoxical excitement to relieve symptoms of psychosis and prevent relapse

Question 15

what does the blockade of each dopamine tract result it

Answer 15

mesolimbic
- overactivity is responsible for positive symptoms thus blockade is common MOA of antipsychotics

mesocortical
- blockade of this tract leads to negative symptoms

nigrostriatal
- blockade of this tract can lead to EPSE

tuberoinfundibular
- blockade of this tract can lead to hyperprolactinemia

Question 16

what are the precautions for use of antipsychotics

Answer 16

• CVD (c/i for QTc prolongation, monitoring of ECG required)
• parkinson’s disease (worsen EPSE)
• epilepsy
• elderly with dementia (increased risk of stroke and mortality)
• severe respiratory disease
• myasthenia gravis
• hx of jaundice
• depression
• prostate hypertrophy
• blood dyscrasias (esp clozapine)
• close angle glaucoma

Question 17

what is the advantage of SGA (atypical antipsychotics) over FGA and why

Answer 17

SGA has fewer EPSE than FGA due to
- greater affinity to 5HT2
- greater affinity to D4
- mixed antagonism to alpha, H1, muscarinic acetylcholine, 5HT2

Question 18

what are the clinical implications of various receptor affinities

Answer 18

D2 antagonism = improves positive symptoms, but also EPSE and hyperprolactinemia

5HT1A agonism = anxiolytic

5HT2A antagonism = antidepressant and antipsychotic effects

5HT2C antagonism = weight gain

H1 antagonism = sedation, weight gain

alpha 1 antagonism = orthostasis, sedation

M1 antagonism = memory dysfunction and peripheral anticholinergic s/e (dry mouth, urinary retention, blurred vision)

Ikr antagonism = QTc prolongation (pro-arryhthmic)

Question 19

key receptor affinities for various antipsychotics

Answer 19

• clozapine and olanzapine have potent 5HT2 antagonism compared to weak D2 antagonism thus reduces EPSE and more effective against negative symptoms
• amisulpride has selectivity for D3 and D2 thus reducing EPSE and increases prolactin secretion (DA binds to D2 to inhibit prolactin secretion but amisulpride now interferes with this)
• clozapine has high D4 to D2 antagonism ratio thus favors action in prefrontal cortex which regulates emotion and higher cognition
• amisulpride and risperidone has high D2 to D1 antagonism ratio (D1 receptors primarily on direct pathway while D2 on indirect; direct pathway stimulates motor activity while indirect inhibits motor activity; the selectivity allows for more balanced in motor regulation thus reducing risk of EPSE)

Question 20

what are the key PK characteristics of oral antipsychotics

Answer 20

• most have Tmax of 1-3hrs, ie. rapidly absorbed and fast onset, except olanzapine, brexipiprazole and aripiprazole
• most have long half life and thus can be consolidated as OD dosing but consider risk of hypotension and seizures, except chlorpromazine, amisulpride, clozapine, quetiapine and zuprasidone requires divided dosing

Question 21

what are the agents for pharmacological management of schizophrenia

Answer 21

FGA
- haloperidol
- chlorpromazine

SGA
- amisulpride
- olanzapine
- clozapine
- risperidone
- brexipiprazole
- aripiprazole
- quetiapine
- lurasidone
- paliperidone

avail LAI
- IM haloperidol decanoate
- IM flupenthixol decanoate
- IM zuclopenthixol decanoate
- IM risperidone microspheres
- IM aripiprazole
- IM paliperidone prolonged release suspension

Question 22

what are the types of adverse effects of antipsychotics and management strategies

Answer 22

EPSE
- tardive dyskinesia (orofacial, hand movements)
[higher risk if FGA]
- akathisia (restlessness) [higher risk if high potency]
- pseudo-parkinsonism (tremor, rigidity, bradykinesia, salivation) [higher risk if elderly, previous neurological damage, manage with anticholinergics like brenhexol, brenztropine]
- dystonia (muscle spasm) [higher risk if high potency, manage with anticholinergic like benztropine, diphenhydramine]

metabolic
- weight gain
- increase DM and lipid

CNS
- sedation
- serizures

CV
- orthostatic hypotension
- QTc prolongation

hyperprolactinemia
- decreased libido
- gynacomastia
- amenorrhea

dermatological
- pigmentation, photosensitivity, maculopapular rash [risk with CPZ]

ophthalmic
- cornea or lens changes, pigmentation retinopathy [risk with CPZ]

hepatic
- elevated TFTs
- jaundice with CPZ [CPZ, O, Q]

blood dyscrasias
- decreased WBC, agranulocytosis [risk with clozapine]

Question 23

what are the monitoring parameters for antipsychotics, in view of their side effect profiles

Answer 23

general
- BMI every visit x6m f/b q3m
- waist circumference every visit x6m f/b q12m
- FBG q12m for low risk, at 4m after initiation f/b q12m for high risk (at 3m for SGA)
- lipid q2-5yrs for low risk, q6m (also at 3m for SGA)
- plasma prolactin (baseline)
- BP q12m (at 3m for SGA)
- EPSE exam weekly x2w f/b q6m FGA/ q12m SGA for low risk, q3m FGA/ q12m SGA for high risk

drug specific
- WBC and ANC for clozapine weekly x18w f/b q1m
- ECG for ziprasidone repeated if symptomatic

Question 24

what are the significant ddis for antispychotics

Answer 24

• CNS depressants
• 5HT augmenting agents
• DA augmenting agents
• Lithium
• CBZ with clozapine = agranulocytosis
• TCA
• antihypertensives/ trazodone = increased hypotensive
• alpha/H/M blocker
• CYP1A2 inducers/ inhibitors
• CYP2D6 inducers/ inhibitors
• CYP3A4 inducers/ inhibitors

Question 25

how might therapeutic outcomes be evaluated

Answer 25

monitoring for effectiveness
- mental state exam
- psychiatric rating scales
- time course

monitoring for adverse effects
- metabolic parameters
- EPSE

patient’s self-assessment

Question 26

what is the time course for improvements upon initiation of antipsychotics

Answer 26

week 1
- reduced agitation, aggression, hostility

week 2-4
- reduced paranoia, hallucinations, bizarre behaviors, improved organization in thinking

late improvements
week 6-12
- reduced delusions, may improve negative sx

month 3-6
- cognitive symptoms may improve with SGA

Question 27

what are the adjunctive treatments

Answer 27

acute agitation and cooperative
- PO lorazepam 1-2mg
- PO antipsychotic (haloperidol 2-5mg with pretx ECG, risperidone 1-2mg, quetiapine 50-100mg, olanzapine 5-10mg)

acute agitation and uncooperative
- IM lorazepam 1-2mg
- IM aripiprazole 9.75mg

catatonia
- PO/IM lorazepam

depressive or negative sx for chronic schizophrenia
- antidepressants

Question 28

how to manage schizophrenia in special populations

Answer 28

pregnancy
- olanzapine, clozapine
(monitor for gestational DM)

renal impairment
- aripiprazole (avoid amisulpride)

hepatic impairment
- amisulpride

elderly
- avoid drugs with high propensity for alpha 1 blockade due to risk of OH, or of anticholinergics
- start low go slow
- simplify regimen
- avoid adverse interactions
- avoid drugs with long half life
- FGAs and SGAs reported to increase mortality and stroke in elderly with dementia