Pharmacological Treatments for Schizophrenia

Question 1

Goals of pharmacological treatment of schizophrenia?

Answer 1

Acute

• behavioural disturbance
• positive symptoms
• initiating therapeutic alliance

Maintenance/relapse prevention

• Preventing relapse
• Maintaining antipsychotic efficacy and adheance
• improving negative symptos
• therapeutic relationship
• psychosocical reintegration

Question 2

Notable first generation antipsychotics and moa?

Answer 2

1950s: chlorpromazine (“dirty drug” w/ lots of receptor blockage)

haloperidol (D2 receptor antagonist

flupentixol: depo medication

Question 3

Notable second generation antipsychotics?

Answer 3

clozapine]- larger efficacy than other antipsychs

NB: risk of neutropenia so must monitor bloods

Question 4

Efficacy of first and second gen antipsycotics?

Answer 4

Second gen: more responders, less symptoms and relapses

Clozapine had a larger efficacy in general w/ minimal differences between others

Question 5

DA related pathways involved in schizophrenia?

Answer 5

• Nigrostriatal pathway: SNpc -> caudate/putamen
• Mesocorticolimbic pathway:
  mesolimb: VTA -> limbic regions -> [reward]
  mesocort: VTA -> frontal cortex
• Tuberoinfundibular pathway: hypothal -> med eminence -> role in prolactin release

Question 6

DA theory in schizophrenia?

Answer 6

• increased DA in striatum -> positive symptoms

- decreased DA in prefrontal cortex -> cogn + negative symptoms

Question 7

Experimental evidence of DA in striatum and schizophrenia?

Answer 7

Amphetamine -> increased DA -> de novo psychosis and worsens psychostic symptoms of schiz pts in remission

L-DOPA -> increased DA -> worsened symptoms (may cause halluc)

Neuroimaging shows: increased DA synthesis in SCZ when psychotic

Question 8

Experimental evidence of DA in prefronal fortex and schizophrenia?

Answer 8

Neuroimaging shows decreased DA in SCZ (and role in working memory deficits)

Clinical efficacy of DA antag antipsychotics corelates w/ D2 receptor affinity

Clinical threshold for antipsychotics~ 65% blockade of D2-R produces antipsych effect BUT >65% -> extrapyramidal S/E

Question 9

DA hypothesis of psychotics and antipsychotics

Answer 9

DA has role in reward and learning

Increased DA in ventral midbraine associated w/ motivational salience of enviromental stimuli]- this is dysregulated and fired abnerrantly e.g. w/ no stimuli

Cognitive schema to explain aberrant experience -> delusional mood

Antipsychs block motivational salience]- if this is stopped, delusions can start again

Question 10

Supersensitivity hypothesis of psychosis

Answer 10

Antipsychotics block D2 receptor -> increased numbers of receptors -> “breakthrough psychosis”

Abrupt withdrawal of meds -> endogenous DA acts of highly sensitive receptors -> hugely increased psychosis (“rebound psychosis”)

Question 11

Side effects of first gen antipsychotics vs second gen

Answer 11

First gen: movement disorders

Second gen: metabolic effects (e.g. weight gain)

Question 12

Onset of antipsychotic efficacy?

Answer 12

Bulk of improvement over first year occurs in first month

Early response is an indicator for continued response (if you dont respond at the start, you probs wont later)

80% respond at start, 10% don’t respond

Question 13

Effects of staying on antispsychotics vs discontinuation?

Answer 13

Staying on: decreased relapses, decreased hospitalisation risk

Discontinuation: 5x relapse risk

NB: abrupt withdrawal has a MUCH higher relapse than a gradual withdrawal

Question 14

Depot/long acting injection antipsychotics: ADV and DISADV

Answer 14

NB: depot has a slightly higher efficacy than oral antipsychotics

ADV

• avoids covert non-adherance
• followups are useful to assess S/E
• simple treatment regimen

DISADV

• slower dose titration
• longer time required to achieve steady state
• pain

NB: validity of RCTs hindered since people who sign up are more compliant; studies may be too short; trials have more clinical attention

Observational studies have no blinding

Question 15

Rationale of continuing long term anti-psychotics?

Answer 15

Risks of NOT treating

• more relapses
• risk of harm to self and others
• disrupted personal relationships
• possible loss of med efficacy

Risk of treating/adverse effects

• metabolic S/Es
• brain structure changes (parietal lobe and basgang)
• cardiotoxic effects (increased CVD,stroke,CHF risk)

Question 16

Clinical risk factors relevant for relapse prevention?

Answer 16

• loss of medication efficacy
• changes in brain structures on meds
• increased DUP is associated with worse outcomes
• 50% of schizos are poorly/non adherent
• substance abuse in any form wipes out any benefit of antipsychotics (non-compliant w/ NO subst is same as compliant with subst)

Question 17

Risk-benefit considerations for clozapine (second gen) for treatment refractory schiz

Answer 17

If no adequate response to 2 trials of antipsych:
check correct diagnosis, if treatment reluctant, correct dose/, duration, adherance, a/e masking response, comorbid, substance misuse

If excluded above, consider high dose antipsychotic medication or switch antipsychotic

If no benefit -> clozapine

If no benefit -> combo or aug therapies OR target specific symptoms

Question 18

Experimental evidence for risk-benefit considerations of clozapine?

Answer 18

CUTLASS 2: schiz with poor treatment response to 2 or more antipsychs should start clozapine

Yokimura: if treat-resist-schiz diagnosed -> after 3 yrs -> clozapine is less effective

Question 19

Overview of Clozapine history with schizophrenia?

Answer 19

1960: confirmed antipsychotic w/ few extrapyramidal S.Es
1975: 7 deaths due to agranulocytosis -> withdrawn

Kane, 1988: Cloz shown to be more effective than other antipsychotics (blocks multiple receptors e.g. DA, adrenerg, histam, 5-HT, musc)

Less symptoms overall than other antipsychs

Question 20

Prognosis of clozapine in schizophrenia?

Answer 20

1/3 rule:

1/3 good long term outcome
1/3 intermediate outcome
1/3 poor outcome