Lecture 2: Schizophrenia and Psychosis

• 1-1.5 % of the Australian population suffers from schizophrenia. But 7% of indigenous population with mental health issues report schizophrenia
• Schizophrenia

  • Onset in adolescence (males earlier than females)
  • often precipitated by major changes in life (uni, army)
• Schizophrenia

  • 7% Indigenous have more males (70%) impacted than females (30%)
  • 60% of sufferers improve or recover with age
  • Not necessarily a chronic condition
• Schizophrenia

  • Huge cost to society
  • Early onset
  • Severe
  • Chronic (relapses)/hospitalisation
• Perceptual change over time of progressing illness (schizophrenia)

  
• Schizophrenia Symptoms

  1. Psychotic ‘positive’ symptoms (episodic)
  2. Delusions, hallucinations, thought disorders
  3. Deficit ‘negative’ symptoms (chronic)
  4. disturbances in: motivation, experience of pleasure social interactions, spontaneous speech, mood expression
  5. Cognitive impairment (chronic)
  6. intellectual, memory, executive function, attention
• Psychotic ‘Positive’ Symptoms

  • Hallucinations - usually auditory (single or multiple)
  • These are the obvious symptoms which is why people with positive symptoms are often treated most
  • Delusions (paranoid) - persecution, grandiosity, external control, thoughts inserted or removed, mind read
  • Thought disorder - tangential, loosening associations, garbage; Disorganised thinking and behaviour - trouble with simple tasks
• Schizophrenia Core Symptoms (all lead to social/occupational dysfunction in interpersonal relationships; self-care; work)

  1. Positive” Psychotic Symptoms
  2. Delusions; Hallucinations; Catatonia; Agitation
  3. Disorganised Symptoms
  4. Confused thinking; Disorganised Speech; Disorganised Behaviour; Disorganised Perceptions
  5. Negative-Deficit Symptoms
  6. Emotional Flattening; Alogia - limited speech; Avolition - lack of motivation; Anhedonia - lack of pleasure
  7. Cognitive Symptoms
  8. Decreased attention; Decreased memory; Decreased executive functions (preoccupation)
  9. Mood Symptoms
  10. Dysphoria; Suicidality; Hopelessness
• Cognitive Impairment Symptoms

  • Greater cognitive deficits correlate with severe negative symptoms, antisocial behaviour and neurological abnormalities (subtle: dyskinesia)
  • Dyskinesia = maladaptive movements
• Cognitive Impairment Symptoms

  • consistent with frontal lobe impairment
  • The frontal lobe is involved in sequencing, planning and producing complex behaviours
  • Schizophrenics have deficits in sensorimotor gating
  • Unable to respond appropriately to environmental stimuli
  • Sensorimotor gating
  • Being able to respond appropriately to stimuli in your environment
  • If someone comes to talk to you, you talk to them, not freak out and walk away.
• Example of evidence for good sensorimotor gating

  • Prepulse Inhibition (PPI)
• Deficits in sensorimotor gating are observed using the prepulse inhibition (PPI) test

  1. Warning tone (prepulse)
  2. Loud tone
  3. Measure the startle response
  4. The warning prepulse inhibits startle to the next loud tone

  Schizophrenics do not show inhibited startle response to the prepulse warning - similar to amphetamine treated subjects!
• • Prepulse inhibition (PPI)
  • If given a warning sign that something will happen, you should adapt.
  • People with schizophrenia don't have that ability.
  • They can't recognise that something is warning them that a loud sound is coming so they startle a lot more.
• Reduced ‘Theory of Mind’

  • Deficits in sensorimotor gating may also be responsible for the lack of ‘theory of mind’ in schizophrenics
  • Schizophrenics are unable to gauge the mental state of others
  • inappropriate social interaction
  • encourages belief of persecution or grandiosity
• IMPORTANT SUMMARY 1

  1. Schizophrenia occurs in 1-1.5% of population
  2. characterised by several symptom types
  3. psychotic (positive), deficits (negative) and cognitive impairment
  4. Schizophrenics have abnormal sensorimotor gating (PPI test)
  5. Schizophrenics have altered ‘theory of mind’
• Too much dopamine reduces ‘filtering capacity’: too much information!

  • The prefrontal cortex and basal ganglia can’t focus on relevant info for those with schizophrenia

  
• • Dopamine gets released in all of these areas.
  • People with schizophrenia = too much dopamine in basal ganglia and in nucleus accumbens (mainly)= can't focus
  • Too much dopamine in striatal areas and too little in prefrontal cortex area = schizophrenia

  
• • Example
  • Touch = stimuli
  • Sensory input comes up though brain stem
  • Goes into parietal cortex to be interpreted
  • Goes through thalamus
  • Goes into PFC and basal ganglia at same time
  • These make decisions about how to respond to stimuli
  • Dopamine helps you recognise stimuli - what do I need to pay attention to?
  • Too much dopamine in nucleus accumbens = pay attention to everything (reduced filtering capacity)

  
• Neurochemistry of Schizophrenia - The main neurotransmitters

  1. Dopamine (main)
  2. Serotonin
  3. Glutamate
  4. GABA
• Dopamine Hypothesis of Schizophrenia

  • Drugs that increase dopamine levels in the nucleus accumbens exacerbate or produce positive psychotic symptoms
  • Amphetamine, cocaine, dopamine receptor agonists
  • Drugs that block dopamine transmission alleviate some of the symptoms of schizophrenia
  • dopamine antagonists
  • 1950’s Chlorpromazine (developed as an antihistamine) reduced the positive symptoms of schizophrenia - blocks dopamine receptors
  • So... Dopamine neurotransmission is involved in psychosis
• Schizophrenics have increased dopamine (DA) in the nucleus accumbens and decreased dopamine in the prefrontal cortex (hypofrontality)

  • Nucleus accumbens = ventral stratum
  • Dorsal stratum = cordate putamen

  
• Dopamine Hypothesis: Hypofrontality

  • Prefrontal cortex
  • Hypofrontality = Decreased Dopamine:
  • Cognitive deficits
  • Negative symptoms
  • Nucleus Accumbens
  • Increased dopamine:
  • Positive symptoms (psychoses)
  • Euphoria at beginning

  
• Mesocorticolimbic Dopamine System

  • The positive psychotic symptoms are produced by increased dopamine in the nucleus accumbens (mesolimbic dopamine)
  • The negative and cognitive symptoms are produced by decreased dopamine in the prefrontal cortex (mesocortical dopamine)
  • Mesocorticolimbic dopamine system is abnormal in schizophrenia
• Mesolimbic Dopamine System

  • The positive psychotic symptoms are produced by increased dopamine in the nucleus accumbens (mesolimbic dopamine)
  • Increased numbers of dopamine D2 receptors in mesolimbic system
  • *D2 receptors are located pre and post-synaptically. Difficult to determine levels of neurotransmitter by receptor number
  • Generally considered that enhanced dopamine neurotransmission at D2 receptors produces positive symptoms of schizophrenia
• First Generation Typical Antipsychotics ‘neuroleptics’

  • BAD!! Many side effects as it blocks D1 receptors too unnecessarily instead of just D2.
  • Early stage drugs blocked both D1 and D2 receptors. They were not good and had many bad side effects
• First Generation Typical Antipsychotics ‘neuroleptics'

  1. Phenothiazines
  2. Thioxanthines (similar to phenothiazines)
  3. Butyrophenones & Diphenylbutylpiperidines
• First Generation Typical Antipsychotics ‘neuroleptics’

  • Phenothiazines TYPES
  • Chlorpromazine (Largactil), Promazine, Perphenazine, Triflupromazine, Trifluoperazine (Stelazine), Periciazine (Neulactil) Fluphenazine (Anatensol/Modecate), Thioridazine (Aldazine/Melleril)
  • Prochlorperazine (Stemetil & Stemzine) - antiemetics (prevent vomiting)
• First Generation Typical Antipsychotics ‘neuroleptics’

  • Phenothiazines:
  • Main action is to antagonise dopamine receptors
  • All have antihistaminic (sedative), anticholinergic & adrenaline-like effects (ie ‘sympathetic’ effects)
  • Cholinergic = important for parasympathetic nervous system --> anticholinergic = antiparasympathetic
  • Adrenaline-like effects = important for sympathetic effects
  • So… side effects of these drugs will make you feel like your sympathetic system is overridden (hyper-aroused) i.e. 'sympathetic effects'
  • *Anticholinergic similar to antimuscarinic (blocks acetylcholine)
• First Generation Typical Antipsychotics ‘neuroleptics’

  • Thioxanthines TYPES
  • Zuclopenthixol (Clopixol) Chlorprothixene, Clopenthixol, Flupentixol (Fluanxol), Triperoxine
• First Generation Typical Antipsychotics ‘neuroleptics’

  • Thioxanthines (work similar to phenothiazines):
  • Main action is to antagonise dopamine receptors
  • All have antihistaminic (sedative), anticholinergic & adrenaline-like effects (ie ‘sympathetic’ effects)
• First Generation Typical Antipsychotics ‘neuroleptics’

  • Butyrophenones & Diphenylbutylpiperidines TYPES
  • Haloperidol (Haldol/Serenace) - most widely used neuroleptic Azaperone, Fluanisone, Benperidol, Spiperone, Bromperidol, Trifluperidol, Pimozide (Orap), Droperidol (Droleptan)
• First Generation Typical Antipsychotics ‘neuroleptics’

  • Butyrophenones & Diphenylbutylpiperidines: how they work
  • Main action is to antagonise dopamine receptors
  • Mostly lack antihistaminic (sedative), anticholinergic & adrenaline-like effects (ie ‘sympathetic’ effects)
  • A bit better because it doesn't have as many side effects
• First Generation Typical Antipsychotics ‘neuroleptics’

  • They worked on both D1 and D2 receptors. But they had high affinity to D2 receptors
  • The ability for these drugs to bind to dopamine D2 receptors made them more effective at reducing psychotic symptoms
  • Better binding (high affinity) to D2 receptors = better clinical potency (reduction of psychotic symptoms)
• Correlation between the clinical potency and affinity for dopamine D2 receptors among antipsychotic drugs

  • X-axis = how well it works
  • Y axis = how well it inhibits
  • Spiroperidol = good at inhibiting = lower dose needed
  • Higher up = less well it binds to D2 receptor.

  
• Bad News About First Generation Typical Antipsychotics

  • The first generation typical neuroleptics antagonised both Dopamine D1 and D2 receptors (and many other receptors!!)
  • We only want to block D2!!
  • We want to be as selective as we can with the target receptor. By hitting D1 receptors, we're causing many more side effects!
  • no effect on negative or cognitive symptoms
  • ineffective in 30% patients
  • exacerbate symptoms in some
  • 20% relapse rate
  • 5-10% have intolerable side effects (due to many receptors involved)
  • cardiotoxicity
  • Extrapyramidal Side Effects (EPS)
• First Generation Typical Antipsychotics

  • Typical neuroleptics block the D1 and D2 family of receptors
  • D1 receptor family: D1 & D5
  • D2 receptor family: D2, D3, & D4
  • D2 receptors in the nucleus accumbens produce positive psychotic symptoms
  • D1 receptors are very important for normal movement
  • Ventral tegmental area (VTA) dopamine is involved in reward, psychosis AND movement
• Substantia Nigra dopamine involved in movement: Caudate Nucleus

  • Dorsal Striatum = Caudate Nucleus + Putamen
  • Major component of the BASAL GANGLIA
  • Nigrostriatal DA system
  • Important for movement
  • D1 receptors are concentrated in nigrostriatal DA system
  • Decreased DA in nigrostriatal causes Parkinson’s Symptoms
  • Blocking D1 and D2 receptors interrupts our ability to move

  
• Pyramidal vs Extrapyramidal Movement

  • Pyramidal
  • Primary Motor Cortex M1 --> Premotor area --> Supplementary motor area --> Spinal cord and muscle
  • VOLUNTARY movement
  • Extrapyramidal
  • Nigrostriatal dopamine (A9) --> Substantia Nigra --> Caudate/Basal Ganglia
  • If you have D1 receptors in the nigrostriatal area and you're blocking them, you'll have issues moving!
  • This is the problem with first generation typical antipsychotics/neuroleptics
  • Rhythmic/phasic movement
  • Subconscious e.g. walking
  • you're not thinking consciously about moving one leg after the other.

  
• Extrapyramidal Side Effects

  • 80% of D2 receptors need to be blocked for antipsychotic to work and reduce psychosis (huge dose!)
  • This will then also block and effect D1 receptors
  • Parkinson’s like symptoms
  • reduced dopamine transmission in Caudate nucleus
  • Acute dystonias (involuntary movements), muscle spasms, protruding tongue
  • May cause development of Tardive Dyskinesia (20-40% over years)
  • Debilitating movement disorder - involuntary movements: jaw/lips/limbs
• After seeing issues with first generation typical antipsychotics we realised we

  • Needed to develop antipsychotics that were specific for D2 subtype
  • Needed to discover other neurotransmitter involvement (not just dopamine)
  • Reduce EPS & reduce negative and cognitive symptoms