Psychoactive Compounds in Psychiatry

Question 1

What is drug repurposing?

Answer 1

A strategy for identifying new purposes for an approved drug, other than the scope of the original indication.

Question 2

How is the process of drug repurposing structured? What are his preeminent steps?

Answer 2

1. pathway mapping in the brain: network analysis to repurpose targets
2. genetic association with a disease
3. molecular docking (discover the complementarity between a ligand drug and a target protein)
4. use retrospective clinical analysis
5. novel data sources (compare large amount of genomic and biological data)
6. Phenotypic screening of compounds using disease models
7. Binding assays to identify relevant target interactions

Question 3

What is ketamine and what is it (mainly) used for?

Answer 3

An anesthetic agent used primarily intravenously for chronic pain. It mimics psychosis symptoms (⇒ dissociative state).

Question 4

What has ketamine been repurposed for?

Answer 4

It was repurposed as it has acute antidepressant effects. Ketamine is an NMDA antagonist.

Question 5

Which brain mechanisms are psychedelics supposed to act on?

Answer 5

They increase extracellular glutamate levels in the prefrontal cortex through stimulation of postsynaptic serotonin receptors located in pyramidal neurons of deep layers of the cortex. This activation (and the one of AMPA and NMDA receptors) is thought to ultimately lead to increased expression of brain-derived neurotrophic factor (BDNF).

Question 6

What does the assisted therapy model consist of?

Answer 6

• preparation sessions: to develop trust with the therapist
• Psychedelic sessions: in a non-clinical calming environment, music, eyeshades and the therapist.
• Integration sessions: reflect on the different experiences.

Question 7

How are psychedelics classified?

Answer 7

Psychedelics are stimulants that can have hallucinogenic effects.

Question 8

How is DMN (default mode network) supposed to be affected by psychedelics?

Answer 8

Psychedelics decrease the activity in the default mode network but increase the connectivity between normally separated brain networks (e.g. salience network).

Question 9

Which effects has psilocybin exhibited in the last studies?

Answer 9

1. Psilocybin produces a substantial and sustained decrease in depression and anxiety in patients with cancer.
2. Psilocybin + psychotherapy in patients with treatment-resistant (SSRIs) depression has been shown to have a beneficial effect.
3. psilocybin + psychotherapy ⇒ decrease in the percentage of heavy drinking days above placebo and just psychotherapy in alcoholics.
4. Psilocybin has been shown to have positive effects on smoking addiction.

Question 10

What are the strengths and limitations of these last studies?

Answer 10

Strengths:

• largest psilocybin trial
• active control (SSRIs compared to psilocybin)
• assessment for blinding integrity
• published study protocol

Limitations:

• unblinded with self-reported endpoint
• a large drop in self-reported drinking probably because of screening?

Question 11

what are the most important MDMA effects on the brain?

Answer 11

• release and reuptake-inhibition of serotonin
• release of oxytocin and prolactin
• decreased activity in the amygdala and hippocampus and increased activity in MPFC.
• increase in resting state functional connectivity in amygdala and hippocampus and decrease in VPFC and PCC (posterior cingulate cortex)
• subjective feelings of empathy and bonding.

Question 12

What were the conclusions of phase III trial study on the relation between MDMA and PTSD?

Answer 12

Reduction in CAPS-5 = clinical scale for measuring PTSD disorder (larger in MDMA group)
BUT
- raters blinded but people participating know whether they have taken placebo or drug
- small sample size, lack of diversity, short follow-up

Question 13

What are the conclusions of recent studies on LSD effects?

Answer 13

1. reduction of anxiety disorders in absence of life-threatening illness
2. Reductions of general psychiatric symptomatology (SCL-90-R) up to 16 weeks after the last LSD administration compared with placebo
3. acute positive experiences and mystical experiences associated with long-term therapeutic outcome

Question 14

Which brain regions are part of the DMN?

Answer 14

• posterior cingulate cortex
• dorsomedial PFC
• angular gyrus
• precuneus

Question 15

Which are the main problems with psychedelic research?

Answer 15

• too low rate of randomized trials with control
• often a too-short follow-up
• too small sample sizes
• studies are double-blinded but still based on final self-reports of the participants