LECTURE 18 - schizophrenia

Question 1

What is schizophrenia?

Answer 1

• ‘divided mind’
• severe psychiatric disorder
• distortion of thoughts and perception as well as mood
• cognitive impairment
• affects ~1% of population

Question 2

What are the clinical features of schizophrenia?

Answer 2

• onset in adolescence of early adulthood
• males = females percentage wise
• repeated episodes
• or chronic –> progressive decline
• chronic schizophrenics account for most of the patients in long-stay psychiatric hospitals

Question 3

What are the positive symptoms of schizophrenia?

Answer 3

Type I - presence of abnormal thoughts and behaviours

• delusions (often paranoid)
• hallucinations (auditory e.g. hearing voices)
• disorganised speech
• grossly disorgasned catatonic behaviour
• [thought disorder (inserted thoughts)] - no longer diagnostic

This is according to DSM 5= diagnostic and statistical manual of mental disorders

Question 4

What are the negative symptoms of schizophrenia?

Answer 4

Type II - absence of normal responses/ behaviours

• reduced expression of emotion
• social withdrawal (avolition)
• cognitive impairment - not currently diagnostic

Type I and type II are not just one disease each, more of a spectrum with subtypes e.g. paranoid schizophrenia; catatonic

Question 5

What is the aetiology of schizophrenia?

Answer 5

• strong but not invariable hereditary component - suggest environment has an impact (identical twin has 48% chance of development if other twin gets it)

possible factors include

• slow viral infection
• associated autoimmune process
• poor maternal nutrient
• developmental abnormality
• genetic predisposition with environmental trigger

Question 6

What is the dopamine hypothesis of schizophrenia?

Answer 6

• states that dopaminergic hyperactivity underlies schizophrenia
• evidence in support comes from the effects of a number of dopaminergic agents

Question 7

How is amphetamine abuse evidence for the dopamine hypothesis of schizophrenia?

Answer 7

(dopamine releasing drug)

• can lead to toxic psychosis manifesting:
• -> paranoid delusions
• -> either visual or auditory hallucinations
• -> compulsive behaviours
  i. e. Type I-like symptoms in non-schizophrenic
• exacerbates symptoms of Type I schizophrenic

Question 8

What other evidence is there for the dopamine hypothesis of schizophrenia?

Answer 8

Dopamine D2 receptor agonists (used to treat Parkinson’s)

• -> Type I-like symptoms e.g. apmorphine, bromocriptine
• also exacerbates Type 1 patient symptoms

Too much L-DOPA –> Type 1 symptoms, disappear when dose reduced

Question 9

What was the first antipsychotic drug to be used?

Answer 9

Chlorpromazine

• originally developed as an antihistamine (Thorazine)
• attenuates positive symptoms without excessive sedation
• part of a group of related drugs termed typical or first generation neuroleptics

Question 10

What are the types typical neuroleptics?

Answer 10

neuroleptic = antischizophrenic = antipsychotic = major tranquilliser

3 main classes of neuroleptics

1. Phenothiazines e.g. chlorpromazine, fluphenazine
2. Butyrophenones e.g. haloperidol, droperidol
3. Thioxanthines e.g. flupenthixol, clopenthixol

Question 11

What are typical neuroleptics?

Answer 11

• receptor antagonists
• ‘dirty drugs’ especially phenothiazines

Block a variety of receptor sites
- dopamine (D1 and D2)
- ACh (muscarinic)
- histamine (H1)
- noradrenaline (alpha)
- 5-HT 
antipsychotic activity through dopamine receptor block (specifically D2)

Question 12

What are atypical neuroleptics?

Answer 12

(second generation)
Distinction from typical on the basis of:
- different pharmacological profile e.g. higher dopamine receptor selectivity
- fewer motor (extrapyramidal) side effects (EPS)
- more effective against -ve symptoms
- more effective against treatment-resistant schizophrenia (TRS) (~30%)

Question 13

What are some atypical neuroleptics?

Answer 13

• Selective dopamine receptor antagonists (D2/D3)
  <> sulpiride
  <> amisulpride *

Multi Acting Receptor Targeted Agents (MARTAs)
<> clozapine **
<> olanzapine *

Serotonin-Dopamine antagonists
<> risperidone *
<> zotepine *
<> sertindole

Novel type
<> quetiapine *

• = first-line for newly diagnosed
  ** = first-line for TRS
  NICE guidelines 2002

Question 14

Describe the therapy with antipsychotic drugs

Answer 14

• effective treatment for ~7-&

Typical:

• control +ve symptoms Bettie than -ve
• side effects problematic

Atypical:

• better for -ve symptoms
• side effects less marked
• some efficacy in TRS e.g. clozapine

Question 15

How is the dopamine pathway affected by schizophrenia?

Answer 15

• cell bodies in SN releasing dopamine in striatum and cortex
• +ve symptoms caused by hyperfucntion of the mesolimbic pathway, +ve symptoms respond best to neuroleptics
• -ve symptoms caused by hypofunction of mesocortical pathway

Question 16

What are the side effects of neuroleptic drugs?

Answer 16

• anti-emetic
• increased prolactin release
• extrapyramidal motor symptoms (EPS)

Question 17

What are the anti-emetic effects of neuroleptic drugs?

Answer 17

• due to dopamine receptor block in the chemoreceptor trigger zone (CTZ)
• H1 receptor block also important
• this is beneficial

Question 18

What are the endocrine effects of neuroleptic drugs?

Answer 18

• prolactin (hormone) released by pituitary gland
• release normally inhibited by dopamine
• D2 receptor-mediated
• neuroleptics block inhibition
  => breast swelling, pain, lactation

Question 19

What are the motor disturbances effects of neuroleptic drugs?

Answer 19

Acute: dystonias
Chronic: Tardive dyskinesia

• due to blockade of dopamine receptor in the striatum

Question 20

What are the dystonias?

Answer 20

• involuntary movements (face, tongue, neck)
• parkinsonian: tremor at rest, muscle rigidity, decreased mobility
• developed relatively rapidly
• reversible

Question 21

What is tardive dyskinesia?

Answer 21

• severely disabling motor disturbance
• involuntary movements on face/tongue, limbs, trunk
• slow developing (tardive), chronic treatment
• generally irreversible

Question 22

What are the non-dopaminergic side effects of neuroleptic drugs?

Answer 22

• related to blockade of other receptor sites
• anti muscarinic effects: dry mouth, constipation, visual disturbances
• postural hypotension due to alpha adrenoceptor block
• sedation due to histamine H1 receptors block

Question 23

What are the side effects of atypical neuroleptics?

Answer 23

• better side effect profiles
• mainly due to greater selectivity
• lower incidence of motor disturbances
• increased likelihood of compliance i.e. will continue to take the drugs

Question 24

What other receptors are blocked by neuroleptics?

Answer 24

• 5-HT(2A) blocked with similar affinities as D2
• MARTAs block D2, D4, 5-HT(2A), ACh muscarinic
• more effective for treatment of -ve symptoms
• risk of serious side effects with clozapine: agranulocytosis, myocarditis)

Question 25

What are the problems with the dopamine hypothesis?

Answer 25

• neuroleptics take weeks to work therefore secondary effects important
• less effective on -ve symptoms therefore too simplistic
• dysfunction of dopaminergic systems may not be the primary cause