Therapeutic Uses of Drugs of Abuse

Question 1

Historically, theories of depression have focussed on…

Answer 1

… noradrenaline and serotonin.

Question 2

______ dose administration of ketamine can result in ______ onset of antidepressant action in treatment of ______ individuals

Answer 2

Low
rapid
resistant

Question 3

Why is it so important to explore ketamine as a potential therapy for depression?

Answer 3

Because it has been shown to lead to alleviation of depression symptoms in individuals resistant to more traditional drugs, such as SSRIs

Question 4

Why might ketamine be a better alternative to SSRIs (and other traditional antidepressants)?

Answer 4

Because SSRIs have a 2-week lag period, whereas ketamine exerts its effects rapidly

Question 5

How is ketamine usually used?

Answer 5

It’s used as a drug of abuse for it’s effects as a dissociative anaesthetic, whereby an individual under the influence is dissociated from the sensations of pain

Question 6

Are any studies planned to look into the effects of ketamine on a greater scale?

Answer 6

Yes- larger clinical trials are scheduled to take place to look at the efficacy of ketamine in a larger population e.g. in Australia

Question 7

What does a temporal association mean between psychotogenic and antidepressant effects of ketamine at low doses?

Answer 7

Berman et al. (2000):
Psychotogenic effects (such as psychosis and euphoria symptoms) appear rapidly and subside within 2 hours, whereas the desired therapeutic antidepressant effects remain for much longer for up to 72 hours.

The psychotogenic effects occur even at low doses.

Question 8

How did the Berman et al (2000) study measure the different variants indicating a temporal dissociation between between psychotogenic and antidepressant effects?

Answer 8

• Significant decrease in the HDRS (Hamilton Depression Rating Scale) scores over 72 hours
• Rapid increase (within 30 minutes) of euphoria (as measured by a Visual Analog Scale- VAS), followed by a decrease back to basal levels within 2 hours
• Rapid increase (within 30 minutes) in positive symptoms of a psychosis-like state (as measured by the Brief Psychiatric Rating Scale- BPRS), followed by a decrease back to basal levels within 2 hours

Question 9

In light of the Berman et al. (2000) study, how can ketamine administration be optimised in terms of depression treatment?

Answer 9

The “unwanted” effects of ketamine, such as euphoria and positive symptoms of a psychosis-like state occur even at low doses of ketamine administration, so finding a way to minimise these effects or finding a dosage that permits the antidepressant effects without producing the “unwanted” effects would be a good line of research to explore

Question 10

Why has ketamine been used as an experimental model of schizophrenia?

Answer 10

By administering ketamine, you can induce a psychotic-like state, even through using a low dose

Question 11

Why is ketamine preferred to amphetamine for experimental models of schizophrenia?

Answer 11

Ketamine induces both positive AND negative symptoms, whereas amphetamine tends to only induce positive symptoms

Question 12

In terms of the neurobiology of depression, alongside the catecholamine theory, there is also believed to be some … changes, such as … in certain brain regions, which might be playing a role in depression

Answer 12

neuronal and non-neuronal

glial cell loss

Question 13

Why has glial cell loss been highlighted as a potential way in which depression develops or is a consequence of?

Answer 13

Glial cell loss is a consistent finding in post-mortem studies of depressed patients’ brains

Although it is not possible to attribute this solely to depression, or label it is as the sole underlying cause of depression, the role of glial cell density and function in depression cannot be ignored

Question 14

What is the function of a glial cell?

Answer 14

Many functions but one of them is to be involved in the reuptake mechanisms for glutamate

Question 15

What does loss of glial cells lead to and why?

Answer 15

Increased extrasynaptic glutamate, because the reuptake mechanisms are reduced/disrupted.

Question 16

What does increased extrasynaptic glutamate (as a result of loss of glial cells) lead to?

Answer 16

• activation of extrasynaptic NMDA-R

Question 17

What does activation of extrasynaptic NMDA-R as a result of extrasynaptic ______, lead to? Which pathway is being activated?

Answer 17

glutamate

leads to the control/regulation of dendritic spine growth by activating the “stop pathway”

Question 18

How does activation of the stop pathway via activation of NMDA-R by extrasynaptic glutamate lead to reduced dendritic spine growth?

Answer 18

• Extrasynaptic glutamate activates NMDA-R postsynaptically
• Leads to decrease in BDNF expression/action (?)
• Which leads to decreased dendritic spine growth

Question 19

Summarise the effect of glial cell loss on BDNF and resulting changes to dendritic spine growth.

Answer 19

• Glial cells are involved in glutamate reuptake
• Loss of glial cells leads to excessive increase of extrasynaptic glutamate
• This glutamate activates postsynaptic/extrasynaptic NMDA-R
• The activation of NMDA-R = less BDNF
• Less BDNF = reduced dendritic spine growth
• Reduced dendritic spine is associated with depression

Question 20

Ketamine increases synaptic transmission of ______

Answer 20

glutamate

Question 21

Despite increasing synaptic transmission of glutamate, excess NMDA-R activation isn’t occurring postsynaptically in the presence of ketamine. How so?

Answer 21

Because ketamine is a direct antagonist of NMDA-R.

It is effectively blocking the NMDA-R, such that the glutamate cannot bind them.

Question 22

If ketamine is working to antagonise glutamate at the postsynaptic NMDA-R, where is the excess glutamate going?

Answer 22

The excess glutamate is now only binds other glutamate receptors on the postsynaptic cell e.g. AMPA-R

Question 23

If glutamate can’t bind the postsynaptic NMDA-Rs in the presence of ketamine, why can it bind the postsynaptic AMPA-R?

Answer 23

Because ketamine is an antagonist of NMDA-R but not of AMPA-R

Question 24

What happens when the increased levels of glutamate transmission as a result of ketamine lead to the activation of postsynaptic AMPA-R?

Answer 24

They lead to the activation of the “go pathway”

Question 25

What is the “go pathway” (start with ketamine administration)

Answer 25

• Ketamine is administered and leads to increased synaptic transmission of glutamate
• Ketamine also binds NMDA-R on the postsynaptic cell, such that the excess glutamate cannot bind them
• Instead, the glutamate binds to postsynaptic AMPA-R
• This activates Akt-mTOR signalling pathways within the postsynaptic cell
• This will lead to an increase in dendritic spine growth

Question 26

The dual effect of ketamine leads to the resulting …

Which dual effect?

Answer 26

increased dendritic spine growth

1. Increased synaptic transmission of ketamine (more AMPA-R activation = more “go pathway” activation)
2. Antagonism of NMDA-R (less NMDA-R activation = less “stop pathway” activation)

Question 27

How else has the role of BDNF in dendritic spine growth regulation been proven?

Answer 27

When comparing WT BDNF expression to Met/Met (low activity polymorphism) BDNF expression, it was found that:

• Upon saline administration, there is no difference in dendritic spine growth between the WT and Met/Met homoygote
• Upon ketamine administration, there is an increase in dendritic spine growth of the WT individuals, but no increase in dendritic spine growth of the low activity BDNF polymorphic individuals

Question 28

What do the results comparing WT BDNF to Met/Met (low activity polymorphism) BDNF show?

Answer 28

They show that ketamine increases dendritic spine growth through its effects on BDNF since the mutant mice with low activity BDNF showed no difference in dendritic spine growth upon ketamine administration

Question 29

How does the dendritic spine growth data (of WT and Met/Met mice) correlate with HDRS scores?

Answer 29

Upon ketamine administration:

• Met carriers (i.e. low activity BDNF polymorphism) mice have a smaller decrease in depression score
• WT mice have a larger decrease in depression score

This correlates with the observed dendritic spine growth data, since WT mice had increased dendritic spine growth, whereas the mice with low activity BDNF polymorphism showed no change in dendritic spine growth in response to ketamine.

Question 30

Concisely summarise the mice study that looked at the effect of BDNF polymorphisms on dendritic spine growth upon administration of ketamine.

Answer 30

Ketamine given:

• WT mice showed increase of dendritic spine growth, which correlated with a larger decrease in HDRS score
• Met/Met low activity polymorphism of BDNF in mice led to no change in dendritic spine growth, which correlated with a smaller decrease in HDRS score

Question 31

Although the data of the mice study looking at WT vs Met/Met polymorphism of BDNF wasn’t perfect (e.g. large error bars), it provides some indication that the low activity BDNF gene polymorphisms result in…

Answer 31

…reduced ability for dendritic spine growth when given ketamine, compared to WT mice which show a large increase in dendritic spine growth. This correlates with a reduced antidepressant effect in these mice, compared to the WT mice.

Question 32

What is the Forced Swim Test and what is used to measure?

Answer 32

They put mice in beakers full of water, from which the mice are unable to escape.

Normal mice will keep swimming to try and escape.

Immobility or time spent immobile is used as a readout for “depression symptoms” since it shows a lack of motivation.

Question 33

When given antidepressants, mice in a Forced Swim Test will…

Answer 33

…swim for longer before they give up and become immobile.

Question 34

How did scientists study whether the effects of ketamine are AMPA-R- or NMDA-R-mediated?

Answer 34

They conducted a Forced Swim Test on mice and administered “ketamine alone” vs. “ketamine with NMBQ” (AMPA-R antagonist).

Question 35

What did the study looking at how ketamine exerts its effects show?

What did these results suggest?

Answer 35

• Ketamine only administration led to an antidepressant effect once a certain dosage was reached
• Ketamine combined with NBQX led to a recovery of the basal immobility time i.e. NBQX is effectively reversing the antidepressant effect of ketamine

The results suggest that some of ketamine’s antidepressant effects are definitely AMPA-R-mediated, since blocking of AMPA-R using NBQX led to a reversal of ketamine’s antidepressant effects.

Question 36

What is NBQX?

Answer 36

An AMPA-R antagonist

Question 37

How are traditional depression drugs and ketamine similar (in terms of end result)?

Answer 37

Conventional antidepressants e.g. SSRIs work by increasing levels of NE and 5-HT = increased BDNF = increased survival and growth of dendritic spines

Ketamine blocks NMDA-R postsynaptically, whilst increasing synaptic transmission of glutamate via postsynaptic AMPA-R, such that there is an activation of the “go pathway” (which results in increased BDNF = increased dendritic spine growth) and a inhibition of the “stop pathway” (which would have resulted in decreased BDNF = decreased dendritic spine growth)

This means that BOTH types of drugs lead to the same end result: increased growth/survival of dendritic spines

Question 38

How does the Zanos et al. (2016) study contradict previous science regarding ketamine’s mode of action?

Answer 38

It was previously thought that ketamine exerted its effects by binding as an antagonist to NMDA-R to inhibit the “stop pathway” and by increasing activation of the “go pathway” via AMPA-R, however, this study found that ketamine’s mechanism of action may not be NMDA-R-mediated after all

Question 39

Zanos et al. (2016) also conducted a Forced Swim Test on mice. What did they find regarding how ketamine exerts its antidepressant effects?

Answer 39

They compared:
Racemic mixture of ketamine, ((R, S)-Ket) vs. standard antidepressants (e.g. DSP)

They found that along with the standard antidepressants, some (R, S)-Ket mixtures had significant antidepressant effects
- They found that although the S-enantiomer of ketamine is the antagonist of NMDA-R, the R-entantiomer also led to antidepressant effects

This suggests that perhaps the effects of ketamine are not through antagonising NMDA-R

Question 40

What else (besides ketamine’s mode of action) did the Zanos et al. (2016) study address?

Answer 40

They investigated whether the antidepressant effect of ketamine is due to ketamine itself or due to one of its metabolites, hydroxynorketamine.

Question 41

What did the Zanos et al. (2016) study find with regards to whether ketamine itself or ketamine’s metabolites are leading to antidepressant effects?

Answer 41

They found that only the R-enantiomer of hydroxynorketamine has an effect on mice by antagonising NMDA-R, whereas both the S-enantiomer and R-enantiomer of ketamine itself had effects on immobility time in the Forced Swim Test

Question 42

Although there appears to be conflicting evidence in terms of whether it’s ketamine or ketamine’s metabolites that have an effect on immobility time in mice (and therefore on depression), the Zanos et al. (2016) study clearly demonstrates that…

Answer 42

… a certain drug may not be exerting its effects solely through one mode/mechanism of action.

Question 43

Is ketamine or its metabolites having the antidepressant effect?

Answer 43

It’s not possible to say (just yet) which is having the greatest effect, but it is entirely possible that both ketamine AND its metabolites are having some antidepressant effects (through different mechanisms of action).

Question 44

What are some drawbacks of ketamine as a potential antidepressant?

Answer 44

• Long-term effects have not yet been studied
• Studies can carefully control dosages, how it’s used etc. but how will this be controlled if given to patients? It might be difficult to ensure that it doesn’t become used a drug of abuse
• Likelihood of rebound suicidal ideation hasn’t been thoroughly researched. If a patient stops taking the drug, will the symptoms of previous depression come back and be worse?
• Small studies have shown that in some cases, ketamine use has led to the acceleration of transition to mania in bipolar patients
• Given the psychotogenic effects of ketamine, could long-term use lead to unwanted cognitive effects?
• Ketamine has been shown to lead to bladder damage

Question 45

What other alternatives are there for the treatment of depression, in terms of glutamatergic transmission (as opposed to NE/5-HT transmission)

Answer 45

• Selective GluN2B (glutamate receptor) antagonists
• Glycine site partial agonists (e.g. NMDA-R needs glycine as a co-agonist)
• mGluR2 and mGluR5 antagonists (glutamate receptors)

Question 46

Why is glutamate a particularly important neurotransmitter in terms of psychiatric disease?

Answer 46

It is involved in BOTH depression AND schizophrenia.

Question 47

Is ketamine a psychedelic?

Answer 47

According to some sources it is (due to hallucinogenic effects) but not, according to other sources

Question 48

Many psychedelics studied have activity at ______ receptors, specifically in ______ receptors

Answer 48

5-HT

5-HT2A

Question 49

Why are studies on psychedelic drugs so controversial?

Answer 49

Because they are drugs of abuse- difficult to get funding!

Question 50

What did the Sakashita et al. (2014) study show in terms of neurotransmitter levels in presence of psilocybin (psychedelic compound)?

Answer 50

It was shown that psilocin, the active metabolite of psilocybin, rapidly increases 5-HT in the medial prefrontal cortex, but does not increase dopamine.

The increased 5-HT last for ~70/80 minutes.

Question 51

What does the Sakashita et al. (2014) study suggest?

Answer 51

It suggests that the potential antidepressant effects of psilocin might be 5-HT-mediated.

Question 52

Does the Sakashita et al. (2014) study contradict the role of glutamatergic synaptic transmission when looking at alternative drugs to treat depression?

Answer 52

Not necessarily. Although psilocin (active metabolite of the psychedelic compound psilocybin) is shown to increase 5-HT levels in the medial prefrontal cortex, there are also 5-HT receptors in the deep cortical laters, which are found on glutamatergic neurons! These could be “interneurons”

Question 53

How do we know that glutamatergic transmission is really important in psychedelic drugs exerting their effects, even though they lead to increased levels of 5-HT (not glutamate)?

Answer 53

Because when scientists looked at behavioural responses to a couple of hallucinogens (DOI and LSD) they found that mice with a knocked out mGluR2 glutamate receptor didn’t have an increase in “hand-twitch behaviour” compared to WT mice with functioning mGluR2 glutamate receptors (who had a dramatic increase in hand-twich behaviour)

Suggests the involvement of a glutamatergic interneuron in the effects of drugs which have a mainly serotonergic effect e.g. psilocybin (and its metabolite psilocin) which increase levels of 5-HT

Question 54

What are the observed effects of psilocybin in humans?

Answer 54

One study has shown that psilocybin has effects on the amygdala (important brain region involved in information processing including fear responses).

They found that psilocybin led to a decrease in amygdala reactivity with increased positive mood in healthy volunteers

Question 55

How did they measure changes in amygdala of volunteers in the study looking at the effects of psilocybin on humans?

Answer 55

They administered psilocybin to volunteers and presented them with negative stimuli.

They then observed the reactivity of the amygdala (via MR scans) to show that reactivity had reduced, pointing towards an antidepressant effect exerted by the psilocybin.