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Pharmacology 3 > L22: Schizophrenia > Flashcards

L22: Schizophrenia Flashcards

1
Q

What is schizophrenia? Who is mostly affected?

A

Dissociation of thought, emotion and mood; inability to interpret feelings and thoughts. Integration disorder. More males are affected.

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2
Q

What other factors is schizophrenia associated with?

A
  • depression (>30% patients)
  • substance abuse (50% patients)
  • suicidal behaviours (10% individuals)
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3
Q

What are the positive symptoms of schizophrenia?

A

Generally associated with uplifting:
- Disorder of thought: incoherent thinking; dissociation of ideas
- Delusions: persecution, grandeur, referential, somatic
- Hallucinations: auditory, visual, olfactory

many positive symptoms respond to therapy

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4
Q

What are the negative symptoms of schizophrenia?

A
  • Blunted emotional response: catatonia (disrupts awareness of the world around); affective flattening; reduced emotional expression
  • Alogia: reduced speech
  • Avolition: Intense apathy

Limited response to therapy

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5
Q

What are the changes in the brain causing schizophrenia?

A
  • cortical thinning (more dense cells in the forebrain, 30% less)
  • reduced synapse number (associated with thinning)
  • reduced inhibitory synapses (soma targeting; that maintain excessive activity)
  • reduced basal ganglia volume (dopamine - reward/movement)
  • impaired blood flow (prefrontal cortex - executive function)
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6
Q

What are the causes of schizophrenia?

A
  • genetic / inherited
  • environmental
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7
Q

What are the genetic causes of schizophrenia?

A
  • All schizophrenia patients: up to 128 single nucletoide polymorphisms (SNPs) at 108 genetic loci
  • Early onset Schizophrenia (<18 years of age): 4 genetic loci
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8
Q

What are the key genes in schizophrenia patients?

A
  • DISC1 (Disrupted in Schizophrenia 1): anchoring molecule in subcellular compartments (incl. synapses)
  • NRG1 (Neuroregulin-ERBB4 signalling pathway): progenitor cell proliferation, neural migration, signalling axon guidance, inhibitory (GABA, to less extent glycine) interneuron maturation
  • NRX1 (Neurexin 1): synaptic protein, scaffold element
  • KCNH2 (hERG K+ channel): potassium channel
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9
Q

What are the environmental factors that cause schizophrenia?

A

Early life stressors:
- prenatal infection
- in utero nutrition
- maternal substance abuse
- obstetric complications

Often associated with underlying genetic predisposition
Hypothalamic-pituitary-adrenal (HPA) axis implicated in onset of symptoms (common to depression)

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10
Q

How is brain development in schizophrenia altered?

A
  • deficient myelination
  • reduced interneuron activity
  • excessive excitatory pruning
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11
Q

When do patients with schizophrenia start to onset?

A

~20 years of age

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12
Q

If early life effects are additive - why do behaviours manifest so late?

A
  • saturation of circuit ability to compensate
  • specific circuits especially prone to dysfunction in late adolscence
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13
Q

What are the theories of schizophrenia?

A
  • dopamine: reward/movement
  • glutamate: excitatory neurotransmission
  • GABA: inhibitory neurotransmission
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14
Q

What are the four dopamine pathways in the brain? How do they relate to schizophrenia?

A
  1. Mesolimbic (SCZ - increase in DA causes positive symptoms)
  2. Mesocortical (SCZ - DA hypoactivity: negative, cognitive and affective symptoms)
  3. Nigrostriatal (Drugs - EPS and TD drug side effects)
  4. Tuberohypophyseal (Drugs - hyperprolactinemia side effects)
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15
Q

How does L-DOPA therapy of Parkinson’s disease affect schizophrenia patients?

A

Increase schizophrenia-like effects (hallucinations)

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16
Q

How does amphetamine (dopamine releaser) affect schizophrenia patients?

A

Increases positive symptoms

17
Q

How does D2 antagonists and reserpine affect schizophrenia patients?

A

Decrease positive symptoms

18
Q

How does D2 receptor agonists affect schizophrenia patients?

A

Boost D2 dependant inhibition, increase positive symptoms

19
Q

What systems are targeted by first generation medications for schizophrenia and how are they affected? What is the mechanism? What are the common side-effects?

A
  • increase mesolimbic dopaminergic function, which results in positive symptoms
  • decrease prefrontal dopaminergic, which results in negative symptoms and cognitive impairment

They usually act as dopamine antagonists

Side effects include: movement problems, extrapyrimidal symptoms; tardive dyskinesia

Example: chlorpromazine

20
Q

What is the mechanism of second/third generation medications for schizophrenia? What are their side effects?

A
  • Mechanism: antagonism of 5-HT2, D1 and D2 receptors - paliperidone, asenapine, clozapine

Alternatively:
- antagonism of D2 and D3 receptors - amisulpride
- partial agonism of D2 (third generation) - aripiprazole

They have fewer side effects compared to first generation:
- low blood pressure
- high risk of weight gain/obesity
Limited effects on negative symptoms

21
Q

What is the glutamate signalling theory in schizophrenia?

A

In schizophrenic patients:
- 30% of excitatory synapses are lost
- NMDA receptors are reduced

Drugs like ketamine and PCP (NMDA receptor antagonists) mimic negative features. Clozapine boosts NMDAr function and signalling

Theory is that glutamatergic signalling is linked to schizophrenia

22
Q

What are the candidate drugs supporting the glutamate theory regarding schizophrenia? What is their mechanism?

A
  • increasing NMDA receptor function (clozapine)
  • boosting endogenous levels of Glycine (NMDA receptor co-agonist)
23
Q

What is the GABA theory regarding schizophrenia?

A

Multiple evidences of GABA signalling deficits in schizophrenic post mortem brains.
- reduced GABA enzymes
- decreased GABA receptor mRNA
- decreased GABA neurochemicals
- decreased GABA transporters

24
Q

What is the endocannabinoids target for schizophrenia therapy?

A
  • cannabis (THC) may increase psychotic events in susceptible individuals
  • cannabis use disorder more likely schizophrenics
  • CBD may improve cognition and psychosis
25
Q

What is the acetyl cholinergic system target for schizophrenia therapy?

A
  • enhancement of dopamine signalling
  • cholinergic dysfunction correlates with congitive disorders
26
Q

What is the serotonin system target for schizophrenia therapy?

A
  • 5-HT modulate dopamine receptors activity
  • 5-HT3 antagonist ondansetron improve cognition
27
Q

What are the side effects of 1st generation schizophrenia medication?

A
  • postural hypotension
  • blurred vision, dry mouth and eyes, constipation, urinary retention
  • drowsiness
28
Q

What are the causes for side-effects of 1st generation schizophrenia medication?

A
  • antagonism of alpha-adrenergic receptors: postural hypotension
  • antagonism of muscarinic acetylcholine receptors: blurred vision, dry mouth and eyes, constipation, urinary retention
  • antagonism of histamine receptors: drowsiness

Pharmacology 3 (21 decks)

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