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Psychology & Neuroscience of Psychosis > Novel pharmacotherapies > Flashcards

Novel pharmacotherapies Flashcards

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1
Q

How do psychiatric drugs act on neurons?

A

They impact how neurons in a network communicate with each other

  • memory
  • movement
  • thinking
  • personality
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2
Q

What is the evolution of our knowledge on neurons?

A

Before 1900s: neuronal communication unknown

After 1900s: direct electrical transmission, chemical transmission
-> neuronal doctrine

1970: possible to visualise receptors
1990: neurons isolated, cloned sequence, and their 3D structure modelled
2000s: antipsychotics act by targeting specific receptors on the surface of neurons

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3
Q

What is the work of Ramon y Cajal?

A

Observed the synapse and predicted that the strength of synapses might be altered by experience

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4
Q

Why makes the power of nervous tissue?

A

The connectivity between neurons

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5
Q

Were antipsychotics discovered by chance?

A

No, they were discovered by design:

  • Paul Janssen observed effects of amphetamine in professional cyclists (used to combat fatigue)
  • many developed acute psychosis, identical to paranoid schizophrenia
  • He wanted to find a drug that could block the effects of the psychosis-inducing compound
  • > Haloperidol: highly effective for schizophrenic psychoses
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6
Q

What characterises dopamine components?

A

They are highly interconnected dynamic adaptive systems

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7
Q

What is the effect of stimulants in the brain?

A

They cause massive release of dopamine:

  • initial experiences of confidence and pleasure
  • repeated exposure causes decrease in dopamine release (desensitisation)
  • it carries psychiatric risk
  • encompassing biochemical and structural changes in the network
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8
Q

Does drug-induced psychosis occur after a single exposure?

A

No, it takes repeated use of very potent forms of amphetamines and cocaine before psychosis emerges

  • plastic adaptations in multiple components of neural network are necessary for psychotic reactions and addiction
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9
Q

How is dopamine synthesised?

A

Tyrosine (TYR) + Tyrosine hydroxylase -> DOPA

DOPA + Aromatic L-amino acid decarboxylase -> Dopamine

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10
Q

What are the dopamine receptors?

A
  • D1: cortical neurons, basal ganglia neurons

- D2: basal ganglia neurons, auto-receptors on dopamine neurons (negative feedback)

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11
Q

How is dopamine recycled?

A
  • DAT: transports dopamine back into varicosity (target of cocaine)
  • VMAT: transports dopamine back into vesicle (target of amphetamine)
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12
Q

Which psychosis-inducing drugs were discovered following the success of haloperidol?

A
  • LSD (acid)

- Mescaline and psilocybin (2 natural hallucinogenic compounds)

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13
Q

What is the effect of LSD (acid) associated to?

A

Specific actions on serotonin signals in the brain

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14
Q

How was risperidone discovered?

A

Need to discover a compound to block LSD

-> trial in people with schizophrenia

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15
Q

Which antipsychotics were developed after the discovery of risperidone?

A

Olanzapine, sertindole, quetiapine

  • first-line treatment in many countries: much less propensity to cause extrapyramidal side-effects
  • careful attention to problems of weight gain and high cholesterol
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16
Q

On which systems do second generation anti-psychotics act on?

A

Dopamine and serotonin

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17
Q

What does the anti-psychotic ketamine act on?

A

Glutamate signalling system
- blocks NDMA channel

(when open: Ca2+ and NA+ flow in)

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18
Q

What characterises ketamine?

A
  • Championed as most convincing drug model of schizophrenia
  • Acute ketamine also produces marked detrimental effects on cognition
  • > essential for normal integration of consciousness into an understandable whole
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19
Q

How is ketamine related to ibogaine?

A

Both molecules can produce bizarre trance-like and mystical states

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20
Q

What are the glutamate receptors?

A
  • NDMA

- AMPA

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21
Q

What is the role of NMDA channels?

A

Essential component of learning and memory

  • the higher the traffic of Ca2+ and Na+, the stronger the synapse
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22
Q

What is long-term potentiation (LTP)?

A

Process of strengthening of synapses

  • models trillions of synapses
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23
Q

Why is there an interest in altering the NMDA receptor by influencing the glycine site rather than the glutamate site?

A

Glutamate is the main excitatory neurotransmitter

-> direct drug action at Glu receptor site can be very toxic

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24
Q

What is the principle of glutamate drugs?

A

Reversal of the effects of ketamine

  • boost glycine site on NMDA channel
  • > bitopertin blocks glycine transporter -> more available binding to NMDAr
  • autoreceptor on the glutamate terminal
  • > LY-023 blocks effects of ketamine
25
Q

What did a bitopertin trial suggest?

A

Benefits against the negative symptoms of schizophrenia

26
Q

What did the first trial on LY-023 suggest?

A

LY-023 as effective as the powerful antipsychotic olanzapine, without its side-effects
BUT these results were found incorrect

27
Q

What is the impact of the current efforts in research on glutamate signalling using bitopertin and LY-023?

A

No therapeutic benefits in schizophrenia

28
Q

What is the problem with the ketamine model of psychosis?

A

Effect of ketamine on consciousness:

- catatonic state: NOT resembling paranoid schizophrenia

29
Q

What is sodium nitroprusside?

A

Nitric oxide donor
- shown to prevent the effects of ketamine in animals

  • used in cardiovascular medicine (for severe hypertension)
  • natural signalling system in the body
  • > neurotransmitter in the brain
30
Q

What is the natural effect of sodium nitroprusside?

A

Potent vasodilator:

- relaxing blood vessels and keeping the open

31
Q

What did the Brazilian trial of sodium nitroprusside show?

A
  • Administration of nitroprusside -> marked and very quick reduction in psychotic symptoms over several hours
  • Large difference between the active and placebo group
  • Single injection could lead to maintained improvements over following month
32
Q

What did the 2015-2016 London study on the effects of sodium nitroprusside on psychosis show?

A
  • No clear effect soon schizophrenic psychosis

- Discrepancy could be due to patients’ longer period of illness

33
Q

What is nitric oxide?

A
  • Gaseous neurotransmitter
  • First retrograde signal discovered (1990s)
  • > some nitric oxide will end up at nearby blood vessel and cause its dilation
  • > BOLD response in fMRI
  • Produced at glutamate synapses
  • > enzymes that synthesise nitric oxide and NMDA channel are attached to each other
  • > these enzymes sense an active Glu synapse
  • Nitric oxide also signals to other neurons in the vicinity and nerve terminal
33
Q

What is nitric oxide?

A
  • Gaseous neurotransmitter
  • > some nitric oxide will end up at nearby blood vessel and cause its dilation
  • > BOLD response in fMRI
  • produced at glutamate synapses
  • > enzymes that synthesise nitric oxide and NMDA channel are attached to each other
  • > these enzymes sense an active Glu synapse
34
Q

What is retrograde transmission?

A

Direction of information flow from post to pre-synaptic side

35
Q

How can cannabis cause major mental illness?

A

THC as active ingredient

- presence of numerous other molecules

36
Q

What characterises the new form of cannabis ‘skunk’?

A

Very high in THC, but absent or low in other ingredients

  • THC is far more psychotogenic than amphetamine or cocaine
37
Q

Which cannabis ingredient is a promising antipsychotic drug?

A

CBD

38
Q

Which receptors on neurons are associated to cannabis?

A

CB1 cannabis receptors

39
Q

What is the endocannabinoid system?

A

Natural inbuilt cannabinoid system in the brain, involved in neural communication

40
Q

What did community surveys in South London show on cannabis and psychosis?

A

1 in 4 new cases of psychotic illness in South London were caused by skunk

  • people who use skunk cannabis are more likely to experience a psychotic illness
41
Q

What makes CBD a promising antipsychotic drug?

A

Laboratory experiments suggested that CBD could soften the effects of THC

  • adding CBD was able to protect against the effects of THC
42
Q

What did researchers in Brazil find on CBD?

A

CBD could be effective in schizophrenia

43
Q

What did the trial by the German group show on CBD compared to the antipsychotic amisulpride?

A

After 4 weeks, group randomised to CBD showed as much improvement as those randomised to receive amisulpride

44
Q

What did King’s research group find about the effect of CBD in schizophrenic patients?

A

Patients under treatment with existing antipsychotic drugs had partial improvement

  • those who were given CBD showed improvement in their psychosis and overall mental health (compared to placebo)
  • CBD carries few if any side-effects, and may translate into practice in the next few years
45
Q

What do we currently know about CBD working mechanisms?

A

Impacts on transition of CB1 signals into neurons

  • > molecular effects of THC could be halted
  • CBD known to bind to other components and receptors in nervous tissue
46
Q

How is natural endocannabinoid synthesised?

A

Post-synaptically, in dendritic spines

47
Q

How are endocannabinoids related to nitric oxide?

A

Similar to nitric oxide, endocannabinoids are also retrograde transmitters
- in which information flow is from post to pre-synaptic side

48
Q

What is 2-AG?

A

One of the main cannabinoids that binds to CB1 receptor on Glu terminal
- believed to be critically important for synaptic plasticity

  • weakens Glu transmission
  • > long-term depression (LTD)
49
Q

What explains the marked effect of THC on memory?

A

Endocannabinoid-mediated LTD in the cortex, including hippocampus

  • THC disrupts fine-grained, precise endocannabinoid physiology
  • > major mental illness probably stems from disordered neuronal networks
50
Q

What is the role of the striatum?

A
  • Receives input from whole of cortical mantle
  • Crucial for organising psychomotor programmes
  • Main neurons in striatum: medium spiny neurons
  • Believed to be responsible for the effortless and automatic selection of particular stream of content
  • > emotional or motor programmes
  • Learns from experience: connections between cortex and striatum: corticostriatal synapse
  • same programmes repeatedly selected
  • > repertoire of thought patterns are ‘engrained’ in the circuits
51
Q

What are medium spiny neurons?

A
  • Main neurons in the striatum

- they use excitatory glutamate neurotransmission: make synapses at dendritic spines

52
Q

How does learning occur in the striatum?

A

From experience
- connections between cortex and striatum: corticostriatal synapse

  • same programmes repeatedly selected
  • > repertoire of thought patterns are ‘engrained’ in the circuits
53
Q

What is required for endocannabinoid production?

A

3 conditions have to be fulfilled, one of which is dopamine D2 receptor activation

  • endocannabinoid, dopamine, adenosine, glutamate function in harmony under natural physiological conditions
54
Q

How can individual neuroconnections be strengthened or weakened?

A
  • Strengthen neuroconnections by LTP through Glu NMDAr

- Weaken neuroconnections by endocannabinoid-mediated LTD

55
Q

What is the effect of antipsychotic drugs such as amisulpride?

A

They block LTD at corticostriatal synapses and enlarge striatum after some time

-> impact upon structural plasticity in the network

56
Q

What are the key characteristics of synapses?

A
  • Highly interconnected and highly dynamic systems
  • Network health is vital for mental health
  • Some components span the gap between nerve terminals and dendritic spines
  • Some signalling pathways control the dynamic, flexible actin scaffold
  • There is ready-to-hand, protein-synthesis machinery for making additional spines as learning proceeds
  • There are mechanisms for ‘clearing up’ the debris when connections are no longer required
57
Q

Which synaptic enzyme clears debris in the synapse and redundant synaptic elements?

A

Phagocytic microglia

58
Q

What are the neuroconnection phenomenon associated to autism?

A

Increased dendritic spines and increased connectivity

Psychology & Neuroscience of Psychosis (16 decks)

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