Novel pharmacotherapies Flashcards
How do psychiatric drugs act on neurons?
They impact how neurons in a network communicate with each other
- memory
- movement
- thinking
- personality
What is the evolution of our knowledge on neurons?
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
What is the work of Ramon y Cajal?
Observed the synapse and predicted that the strength of synapses might be altered by experience
Why makes the power of nervous tissue?
The connectivity between neurons
Were antipsychotics discovered by chance?
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
What characterises dopamine components?
They are highly interconnected dynamic adaptive systems
What is the effect of stimulants in the brain?
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
Does drug-induced psychosis occur after a single exposure?
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
How is dopamine synthesised?
Tyrosine (TYR) + Tyrosine hydroxylase -> DOPA
DOPA + Aromatic L-amino acid decarboxylase -> Dopamine
What are the dopamine receptors?
- D1: cortical neurons, basal ganglia neurons
- D2: basal ganglia neurons, auto-receptors on dopamine neurons (negative feedback)
How is dopamine recycled?
- DAT: transports dopamine back into varicosity (target of cocaine)
- VMAT: transports dopamine back into vesicle (target of amphetamine)
Which psychosis-inducing drugs were discovered following the success of haloperidol?
- LSD (acid)
- Mescaline and psilocybin (2 natural hallucinogenic compounds)
What is the effect of LSD (acid) associated to?
Specific actions on serotonin signals in the brain
How was risperidone discovered?
Need to discover a compound to block LSD
-> trial in people with schizophrenia
Which antipsychotics were developed after the discovery of risperidone?
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
On which systems do second generation anti-psychotics act on?
Dopamine and serotonin
What does the anti-psychotic ketamine act on?
Glutamate signalling system
- blocks NDMA channel
(when open: Ca2+ and NA+ flow in)
What characterises ketamine?
- 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
How is ketamine related to ibogaine?
Both molecules can produce bizarre trance-like and mystical states
What are the glutamate receptors?
- NDMA
- AMPA
What is the role of NMDA channels?
Essential component of learning and memory
- the higher the traffic of Ca2+ and Na+, the stronger the synapse
What is long-term potentiation (LTP)?
Process of strengthening of synapses
- models trillions of synapses
Why is there an interest in altering the NMDA receptor by influencing the glycine site rather than the glutamate site?
Glutamate is the main excitatory neurotransmitter
-> direct drug action at Glu receptor site can be very toxic
What is the principle of glutamate drugs?
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
What did a bitopertin trial suggest?
Benefits against the negative symptoms of schizophrenia
What did the first trial on LY-023 suggest?
LY-023 as effective as the powerful antipsychotic olanzapine, without its side-effects
BUT these results were found incorrect
What is the impact of the current efforts in research on glutamate signalling using bitopertin and LY-023?
No therapeutic benefits in schizophrenia
What is the problem with the ketamine model of psychosis?
Effect of ketamine on consciousness:
- catatonic state: NOT resembling paranoid schizophrenia
What is sodium nitroprusside?
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
What is the natural effect of sodium nitroprusside?
Potent vasodilator:
- relaxing blood vessels and keeping the open
What did the Brazilian trial of sodium nitroprusside show?
- 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
What did the 2015-2016 London study on the effects of sodium nitroprusside on psychosis show?
- No clear effect soon schizophrenic psychosis
- Discrepancy could be due to patients’ longer period of illness
What is nitric oxide?
- 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
What is nitric oxide?
- 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
What is retrograde transmission?
Direction of information flow from post to pre-synaptic side
How can cannabis cause major mental illness?
THC as active ingredient
- presence of numerous other molecules
What characterises the new form of cannabis ‘skunk’?
Very high in THC, but absent or low in other ingredients
- THC is far more psychotogenic than amphetamine or cocaine
Which cannabis ingredient is a promising antipsychotic drug?
CBD
Which receptors on neurons are associated to cannabis?
CB1 cannabis receptors
What is the endocannabinoid system?
Natural inbuilt cannabinoid system in the brain, involved in neural communication
What did community surveys in South London show on cannabis and psychosis?
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
What makes CBD a promising antipsychotic drug?
Laboratory experiments suggested that CBD could soften the effects of THC
- adding CBD was able to protect against the effects of THC
What did researchers in Brazil find on CBD?
CBD could be effective in schizophrenia
What did the trial by the German group show on CBD compared to the antipsychotic amisulpride?
After 4 weeks, group randomised to CBD showed as much improvement as those randomised to receive amisulpride
What did King’s research group find about the effect of CBD in schizophrenic patients?
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
What do we currently know about CBD working mechanisms?
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
How is natural endocannabinoid synthesised?
Post-synaptically, in dendritic spines
How are endocannabinoids related to nitric oxide?
Similar to nitric oxide, endocannabinoids are also retrograde transmitters
- in which information flow is from post to pre-synaptic side
What is 2-AG?
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)
What explains the marked effect of THC on memory?
Endocannabinoid-mediated LTD in the cortex, including hippocampus
- THC disrupts fine-grained, precise endocannabinoid physiology
- > major mental illness probably stems from disordered neuronal networks
What is the role of the striatum?
- 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
What are medium spiny neurons?
- Main neurons in the striatum
- they use excitatory glutamate neurotransmission: make synapses at dendritic spines
How does learning occur in the striatum?
From experience
- connections between cortex and striatum: corticostriatal synapse
- same programmes repeatedly selected
- > repertoire of thought patterns are ‘engrained’ in the circuits
What is required for endocannabinoid production?
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
How can individual neuroconnections be strengthened or weakened?
- Strengthen neuroconnections by LTP through Glu NMDAr
- Weaken neuroconnections by endocannabinoid-mediated LTD
What is the effect of antipsychotic drugs such as amisulpride?
They block LTD at corticostriatal synapses and enlarge striatum after some time
-> impact upon structural plasticity in the network
What are the key characteristics of synapses?
- 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
Which synaptic enzyme clears debris in the synapse and redundant synaptic elements?
Phagocytic microglia
What are the neuroconnection phenomenon associated to autism?
Increased dendritic spines and increased connectivity
