9) Psychoactive Compounds Flashcards
Why are brain disorder so detrimental?
- are more disabling than fatal
- are most diabling than all other disease groups
–> high prevalance from childhood
–> typically high degree of impairments/diabilities (= relatively high disability weights in comparison to other disease groups)
–> persistent/relapsing course, many disorders with chronic trajectories
–> underdiagnosed and under-treated
–> future prospects not as promising as healthy population - responsible for more than 42% of all YLDs (= years lost due to disability) in Europe
Mid-20th century breakthroughs in treatment of psychiatric disorder
= introduction of:
- electrconvulsive therapy (ECT)
- tricyclic antidepressants
- antipsychotics (neuroleptics)
- benzodiazepines
- monoamine oxidase inhibitors
- methylphenidate
- mood stabilisers (Lithium)
mid to late 1990s
- reinvention of clozapine and development of selective serotonin reuptake inhibitors
After that a lot of ‘follow-on’ drugs were released
–> still address the same receptors
–> have less side-effects, better tolerated
–> BUT not more efficacious
tragic fact: António Caetano de Abreu Freire Egas Moniz
won Nobel price in Physiology and Medicine 1949 for ‘cure’ of schizophrenia/serious mental illnesses with psychoses
Leucotomy: incision into prefrontal lobe to migitate severe symptoms
- left patient disabled not treated: no more hallucinations, but personality changes and lethargic
Challenges in understanding and treating psychiatric disorders: Etiology/pathogenesis
Etiology/pathogenesis
- CNS is complex
- animal modes are insufficient –> some work well (alcohol, drugs), others don’t (gaming, mobile phone, ADHD, schizophrenia)
–> pathogenetic mechanisms are still poorly understood for most psychiatric disorders
Challenges in understanding and treating psychiatric disorders: Disease classification
Disease classification
- conflicted by diffuse phenotype boundaries/lack of biomarkers
- compromised by interindividual variance and reliance on rater-dependent, questionnaire-based approaches
- large ‘translational gap’ between laboratory findings and clinical practice
Challenges in understanding and treating psychiatric disorders: Treatment/prevention
Treatment/prevention
- unsatisfactory outcomes: based on serendipitous discoveries and post-hoc developed models
- stagnating innovations
- neglect of interindividual variances: choice of treatment guided by individual experience and certifications rather than (neuro)biological facts
- lack of knowledge about ‘environmental embedding’: early signatures of gene-environment interactions (epigenetics) and psychopathology still dubious
What is repurposing and repositioning of drugs?
Idea: drugs developed for one disease could be effective for another illness
Examples:
Menocyclin: developed for severe acne, other infectious diseases (antibiotic)
–> has influence on neuroplasticity, could potentially work as an anti-depressant (not found effective)
Betablockers: calm heart beat and decrease hypotension
–> can be used in certain anxiety disorders, has calming effect, decreases severe stage fright
Advantages of repurposing and repositioning drugs?
- already exist, cut costs of development
- toxicity reports etc available
- already approved for one disease
Too optimistic of repurposing and repositioning drugs?
- drug companies know what they do (probably won’t overlook opportunities to make even more money)
- not all phase I trials can be skipped –> still costs
–> is a complement not an alternative to the industry’s discovery of new molecules
What is ketamine used for?
- used in anaesthesia, anestetic agens
- primarily intravenously
- does not decrease breathing frequency, blood pressure, autonomic brain stem funtion are not too much affected by ketamine use
- used for chronic pain
–> repurposed as antidepressant
Benefits of ketamine in depression?
= N-methyl-D-asparate antagoninst, µ-opioid agonist
- psychotomimetic, dissociative
- µ-opioid agonist/opioid effect might play a role in anti-depressant effect
- might have rapid anti-depressant effect in low dosages
- no loss of conciousness
- effect within hours
- off-label ketamine infusion: ‘miracle effect’ in 35% of patients
- positive effects only last days –> multiple infusions needed
–> addictive even in healthy subjects
Nasal spray:
- approved by FDA in 2019
- possible in Germany as well
–> many rules: not three times a week, needs to be administered in doctor’s office, only eight weeks of administration
Different psychedelics
- psilocybin –> researched for mental disorders, especially PTSD
- ayahuasca (dimethylthryptamine, DMT) –> most data on older people, very unpleasant side-effects
- LSD (lysergic acid diethylamide) –> popular in microdosages, helps focusing
- MDMA (methylendioxymethamphetamine, ‘ecstasy’) –> PTSD, not yet approved
- mescaline (peyote cactus) –> not researched, hallucinations even in small dosages
- 5-MeO-DMT (‘God molecule’) –> from toad, very strong psilocybin
–> LSD different from rest: mostly works on doperminergic system
- lots of research but high recreational use lead to halt –> resumes only slowly
Mystical experiences: Psychedelics
- oceanic boundlessness
- encountering a profound sense of unity
- transcendence of time and space
- deeply felt positive mood
- noetic quality (=relaxing on mental state or intellect)
- ineffability
- transiency
- paradoxicality
- infused with renewed sense of purpose and meaning
Therapeutic potential of psychedelics
- taken for mystcial experiences but might work without experiencing mystical experiences
- psychedelic experience predicts the therapeutic effect
- special setting needed: patient needs to feel safe, have good rapport with therapist, trust
–> ‘living room’ like setting, choose music, therapist is there in a supportive role - context is important –> works by providing patients with a context in which to work with insights gathered from experience
- ‘classic psychedelic’ (=tryptamines like LSD, psilocybin and phenethylamines like MDMA) facilitate or help by occasioning a psychological insight
–> ketamine with psychotherapy not yet clinically proven
Psychedelic-assisted therapy model
- important to set the patient’s emotional/cognitive/behavioural mindset and expectations
- important to set the physical and social environment in which exposure occurs
- preparation seesions (2-3hrs) on several occasions to develop rapport and trust
- psilocybin session(s) (7+hrs): administraions of psilocybin, support through session, self-directed inquiry and experiential processing –> patients often experience sense of connectedness, emotional catharsis and acceptance and gain new perspectives
- integration sessions: reflect and integrate experience on several occasions
How do psychedelics work (brain)?
- decreased integrity between brain regions within the default mode network (DMN)
- increased signal complexity
–> tracks the intensity of the subjective experience - increase in connectivity between usually more independently functioning brain networks
–> connectivity changes are correlated with altered state of consciousness
Effects of psychedelics on psychiatric disorders (anxiety, depression, AUD)
severe anxitey patients:
- anxiety gone, up to 2 months after administration
depression:
- effects between placebo and psilocybin gone after three months
–> individual reactions
–> no diff between anti-depressants and psilocybin
AUD
- possibly positive effect of psilocybin
–> difficult to blind well
Methylenedioxymethamphetamine (MDMA): Effects on brain and therapeutic effects
physiological effects:
- release and reuptake-inhibition of serotonin (+ to a lesser extent dopamine and norepinephrine)
- release of oxytocin and prolactin
- decresed activity in amygdala and hippocamous
- increase in Resting State Functional Connectivity (RSFC) between amygdala and hippocampus
- (possibly) increased activity in medial PFC
- decreased RSFC between ventromedial PFC and posterior cingulate cortex
Therapeutic effects
- up to 60% of PTSD patients do not respond to first line tratment
–> few preliminary studies suggested benefit of MDMA, scarce evidence from phase II/II RCTs
- conducting clinical trials is difficult due to schedule I classification
LSD-assisted therapy in patients with anxiety with/without life-threatening illness
- pilot study
- two high dosages of LSD (200µg LSD) or active placebo (20µg LSD)
results
- trends towards anxiety reduction up to 2 months
- reduction of general psychiatric symptomatology up to 16 weeks
- positive acute experiences, indicated by high oceanic boundlessness ratings
- acute positive subjective effects and mystical-type experience were associated with long-term therapeutic outcome
Critical assessment of psychedelics in therapy
- are neither a cure for mental disorders not a quick fix for an unfulfilled life
- careful of uncritically promoted presumed benefits of psychedelics
–> (mind)set and setting, cultural, societal and individual expectations are (probably) impacting greatly on the outcome of psychedelics-assisted (psycho)therapy - more randomised clinical trials necessary to replicate and extend promising findings
–> better understand contraindications and other potential risks - more studies to better understand the mechanisms, dosing schedules, selecting the most effective compunds and optimal clinical management
–> too much hype, too many expectations, too few (good) RCTs so far
