Causes of Psychosis PDF

**Key - Cannabis & Psychosis (*Luke Sheridan Rains*)** Three main areas covered: 1. Link between cannabis and severe mental illness 2. Different effects of THC vs CBD 3. Treatment/managing cannabis use in severe mental illness Cannabis is the most widely used drug in the UK. Ages 16-24 bein...

**Key - Cannabis & Psychosis (*Luke Sheridan Rains*)** Three main areas covered: 1. Link between cannabis and severe mental illness 2. Different effects of THC vs CBD 3. Treatment/managing cannabis use in severe mental illness Cannabis is the most widely used drug in the UK. Ages 16-24 being significantly more likely to have used cannabis in the last year than across the whole adult population. 1. Use among young people has fallen sharply over the last 30 years - Roughly following the similar trend of young people who have smoked cigarettes in that period. 2. Though high rates of use if still noteworthy with young people as during this period, they are most vulnerable to developing severe mental illness for the first time. 3. This trend is likely to exacerbate the risk of developing psychosis amongst people who may already be vulnerable. Compared to the general population, there is solid evidence collected over decades that use rates are especially high among people with severe mental disorders. 1. Study looked at use in 10,000 people with severe mental illness compared with 10,000 people without 2. Found 3 and half times higher in those with mental illness Others also suggest that as many as 40-50% of people with FEP are current cannabis users. In addition, those with severe mental illness are more likely to use stronger forms of cannabis - such as skunk 1. And to be using them much more often Study found sample of people with FEP from South London were 23x more likely to be using skunk everyday compared to controls (were 3-4x more likely to be using hash frequently). **Cannabis Use and Mental Health** 1. Cannabis = most widely used illicit substance in the general population and psychiatric patients 2. Global prevalence in psychiatric populations: - Varies by country and specific psychiatric disorder - Generally 2-3x higher than general population 3. Specific prevalence rates: - Schizophrenia: Up to 42% lifetime prevalence of cannabis use disorder - Bipolar Disorder: Approx. 20-50% comorbidity with cannabis use - Major Depressive Disorder: Around 17% comorbidity 4. Trends in cannabis potency: - Increasing THC content in available cannabis products - Potential implications for mental health risks 5. Dual diagnosis services: - Often focus more on "harder" drugs like heroin, cocaine, amphetamines - Limited resources lead to less attention on cannabis use - Gap in care for patients with cannabis use issues 6. Impact of cannabis use on mental health: - Can exacerbate symptoms of existing mental illness - Potential trigger for onset of psychotic disorders in vulnerable individuals - Complicates treatment and recovery processes **Neurobiological Mechanisms:** Endocannabinoid system: 1. CB1 and CB2 receptors 2. Role in neurotransmitter regulation, particularly dopamine THC (Tetrahydrocannabinol): 1. Primary psychoactive component of cannabis - Acute effects: Altered perception, impaired memory, increased anxiety - Chronic effects: Potential changes in brain structure and function 2. Skunk is especially high in THC (selectively bred over 30-40 years or longer to increase concentration) 3. Associated with increased risk of psychotic symptoms 4. Can impair cognitive function and memory CBD (Cannabidiol): 1. Non-psychoactive component - Potential neuroprotective properties - Potential therapeutic effects - incl. anti-anxiety and anti-psychotic properties - May counteract some of THC's negative effects Interaction with neurotransmitter systems: 1. Dopamine: Relevance to psychosis and reward pathways 2. Serotonin: Implications for mood regulation 3. GABA and Glutamate: Impact on cognitive function and anxiety Importance of understanding the ratio of THC to CBD in cannabis products. Limited evidence for THC or CBD for treating PTSD, Tourette's, and other disorders (N=10 in some cases). **Synthetic Cannabinoids** 1. THC treated substances increase risk of psychosis - *Fattore, 2016 - the composition of synthetic products varies from package to package, even within the same type.* - *van Amsterdam, 2015 - synthetic cannabinoid receptor agonist (SCRAs) are often more potent than THC* **Cannabis Use and Mental Illness: Detailed Associations** Psychotic Disorders: 1. Dose-dependent relationship between cannabis use and psychosis risk 2. Age of onset: Earlier cannabis use associated with earlier psychosis onset 3. Impact on symptom severity and course of illness Mood Disorders: 1. Bidirectional relationship with depression and anxiety 2. Potential exacerbation of manic episodes in bipolar disorder Cognitive Impairment: 1. Effects on attention, memory, and executive function 2. Potential for cumulative cognitive deficits with long-term use Functional Outcomes: 1. Impact on educational achievement and employment 2. Social functioning and quality of life considerations **Treatment Recommendations** NICE recommends: 4. Brief motivational intervention - Typically 2 sessions, 45 minutes each - Purpose: Explore ambivalence about drug use and treatment options - Goal: Increase motivation to change behaviour - Approach: Provides non-judgmental feedback to patients - Techniques: May include decisional balance exercises, goal setting 5. Self-help or formal interventions such as: - CBT - Specific CBT modules for cannabis use in mental illness - Addressing cognitive distortions related to cannabis use - Focuses on identifying and changing thought patterns and behaviours - Teaches coping skills with cravings and high-risk situations - Mindfulness-Based Relapse Prevention (MBRP) - Integration of mindfulness practices with cognitive-behavioural strategies - Emphasises present-moment awareness and acceptance - May help reduce cravings and manage stress - Motivational Enhancement Therapy (MET) - Principles of motivational interviewing applied to substance use - Typically 2-4 sessions - Focus on building intrinsic motivation to change - Client-centered approach to elicit behaviour change - Explores and resolves ambivalence - Family or Behavioural Therapy - Multi-dimensional family therapy - Involves family members in the treatment process - Addresses family dynamics and communication patterns - Group Therapy - Peer support and shared experiences - Skills training in a group setting Evidence base limitations: *2019 Cochrane* review findings: 1. Included 41 studies on psychosocial interventions 2. Found no evidence supporting any particular treatment over standard care 3. Looked at outcomes such as: - Remaining in treatment - Reduction in substance use - Improving global mental health or physical health **Psychosocial Treatments: Effectiveness and Challenges** Contrast with general population: 1. Strong and increasing evidence for multiple psychosocial therapies in non-psychiatric populations 2. Treatment generally more effective for individuals without severe mental illness Contingency management: 1. Shows most short-term benefits among available interventions 2. Offers financial incentives for reducing cannabis use 3. Recent Randomised Controlled Trial (RCT) findings: - Focus: Cannabis use in early psychosis (first three years) - Results: - No overall benefit found across the entire population - Some benefit observed in those who engaged with treatment - Implications: - Effectiveness may depend on individual engagement and motivation - Highlights complexity of treating this population 4. Interpretation: - Nature of intervention (financial incentive) may explain why engagement is a good indicator of effectiveness - Helped some people in some contexts, but not universally effective 5. Challenges in treating cannabis use in severe mental illness: - Cognitive impairments may affect treatment engagement and efficacy - Symptoms of mental illness can interfere with therapy participation - Higher rates of social and economic challenges in this population - Potential for cannabis use as self-medication for psychiatric symptoms **Effectiveness of Treatments: Nuanced Understanding** 1. Generally less effective in severe mental illness population 2. When treatments work, tend to have smaller benefits 3. Importance of individualised approach: - What works for one person may not work for another - Need to consider patient preferences, severity of use, and mental health symptoms 4. Persistence in offering treatment options: - Despite lack of strong overall evidence, some individuals do benefit - Ethical consideration: Providing access to potential help, even if effects are modest 5. Should not give up offering treatment despite lack of strong evidence for overall effectiveness **Pharmacological Approaches** Limited evidence base for pharmacological treatments specific to cannabis use in mental illness. Potential medications under investigation: 6. N-acetylcysteine (NAC): Glutamate modulator 7. Cannabinoid receptor antagonists/inverse agonists 8. CBD as a potential treatment for both cannabis use and psychosis symptoms **Integrated Treatment Models** Dual Diagnosis Treatment: 1. Simultaneous treatment of both cannabis use and mental illness 2. Challenges in implementation and resource allocation Stages intervention approaches: 9. Engagement and rapport building 10. Motivational enhancement 11. Active treatment 12. Relapse prevention and recovery maintenance **Challenges in Treatment Delivery** 1. Stigma associated with both mental illness and substance use 2. Access to care issues: - Limited availability of specialised dual diagnosis services - Geographical disparities in treatment access 3. Treatment engagement and retention: - Strategies for improving adherence to treatment plans - Use of technologies (e.g. mobile apps) to support treatment 4. Cultural considerations: - Culturally adapted interventions - Addressing disparities in treatment outcomes among different populations **Harm Reduction Approaches** 1. Principles of harm reduction in the context of severe mental illness 2. Strategies: - Education on safer cannabis use practices - Encouraging use of lower THC/higher CBD products - Promoting alternative coping strategies - Regular health monitoring for cannabis users **Policy and Legal Considerations** 1. Impact of cannabis legalisation on mental health services 2. Need for evidence-based policies that consider mental health implications 3. Regulation of cannabis products with mental health considerations in mind **Emerging Research Areas** 1. Genetic factors influencing cannabis use and mental illness comorbidity 2. Neuroimaging studies on the effects of cannabis use in psychiatric populations 3. Development of biomarkers for identifying individuals at high risk for adverse effects 4. Potential therapeutic applications of cannabinoids in mental health treatment **Key Takeaways and Clinical Implications** 1. Limited evidence base for effective treatments specific to this population 2. Importance of managing expectations for treatment outcomes 3. Need for comprehensive assessment of cannabis use and mental health symptoms 4. Consideration of harm reduction approaches alongside abstinence-based treatments 5. Integration of cannabis use treatment with mental health care 6. Regular monitoring and adjustment of treatment plans 7. Need for continued research on effective interventions for this specific population 8. Clinicians should remain open to offering various treatment options, as some individuals may benefit **Future Directions and Research Needs** 1. Development of tailored interventions for individuals with severe mental illness and cannabis use 2. Investigation into neurobiological interactions between cannabis use and mental health symptoms 3. Exploration of potential protective factors and resilience in this population 4. Long-term follow-up studies to assess sustained treatment effects 5. Examination of the role of newer cannabis products (e.g., high-potency strains, edibles) on treatment outcomes 6. Potential for pharmacological interventions to address cannabis use in severe mental illness 7. Collaborative care models involving mental health, addiction, and primary care services Importance of considering the interaction between cannabis use and mental health symptoms in treatment planning. **Conclusion** 1. Complex relationship between cannabis use and severe mental illness 2. Current treatments show limited effectiveness, but can still benefit some individuals 3. Ongoing need for research, innovation, and individualized approaches in clinical practice 4. Importance of addressing cannabis use as part of comprehensive mental health care - **Key - Prep Lecture** 5. Two basic deviancies or abnormalities in Psychosis 6. Companies can check your DNA to see if you carry any genes for any illnesses 7. 108 hits on genome for SCZ - 108 areas of the genome associated with risk of SCZ - You need a lot together to increase your vulnerability to developing SCZ 8. Sample size acquired through collaboration - Blood samples 9. First hard evidence for genetic contribution to SCZ 10. *you either **have** it or you **don't*** 11. But may not come to clinical attention as the symptoms may not present as severely (e.g. may have a few paranoid thoughts / interested in conspiracy theory 12. Signs the individual may be just about to develop psychosis 13. PRS is slightly higher 14. If the individual went psychotic for around 1 week - their PRS would be higher again 15. SCZ is severe psychosis that persists 16. They would have a higher PRS 17. Not good enough for any statistical prediction as it just means around 7% of the population would develop SCZ 18. You wouldn't develop SCZ just from a high PRS 19. But the vulnerability interacts with some environmental factors 20. Too much Dopamine is produced and released → in those that are psychotic 21. Received across the synapse by the D2 receptor - Causes increase in Dopamine signalling - Causing psychotic symptoms 22. Medication prevents the dopamine getting to the receptor 23. it's involved in movement & importance (good and bad) Dopamine normally mediates the attachment of salience to ideas and objects. 24. When individuals are acutely psychotic, they show an excessive release of dopamine *(Laruelle et al 1996)* 25. Dopamine normally mediates the attachment of salience to ideas and objects *(Berridge and Robinson, 1998)* 26. Heightened DA transmission leads to aberrant assignment of salience to external and internal stimuli *(Kapur, 2003)* - Not good at distinguishing true salient events from general experiences - Everything becomes 'important' whether it is or isn't - Try to apply meaning to it (e.g. why is someone looking at me strangely...maybe they can read my mind/are out to get me) 27. Delusions arise from attempts to explain this abnormal salience *(Maher, 1983)* 28. Genes which can impair neurodevelopment 29. Can be compounded by pre/perinatal events (e.g. long labour/starved of oxygen - damage development of babies brain) 30. About 1/3 of children who go on to develop SCZ have some subtle motor difficulties - e.g. later to walk/talk, not very good at sport - some cognitive difficulties too e.g. IQ of 95, and social deficits 31. Into teens, tend to develop anxiety/depression as well as some quasi psychotic ideas - e.g. are these people out to get me or trick me in some way 32. If they persist, you get Dopamine dysregulation - This can trigger psychosis in late teens or early 20s - Average of presentation of psychosis in England = 28/29 33. Famous case: Britney Spears 34. Khat - Africa → we see Khat induced psychosis in people from Yemen and Mali migrants in London - The leaves are chewed for hours (weak amphetamine effects) - Contains 'Cathinone' → Methylmethylcathinone (MMCat) became a popular dance drug 35. The more they smoke, the more at risk they are - particularly the stronger cannabis 36. Cannabis also become potent between McGrath and GAP study 37. OR = 4 38. *Marconi et al., 2016* 39. Tetrahydrocannabinol (THC) - Partial agonist at CB1 receptor - Impairment of attention, memory and learning - Hallucinations and paranoid ideas 40. Cannabidiol (CBD) - inverse agonist at CB1 receptor - Not hallucinogenic - Has anxiety relieving properties - ?Antipsychotic actions - ?Antagonise effects of THC 41. *Older Cannabis (70s) may have had 2-3% THC and 2-3% CBD* - *In 80s/90s, was bred to produce more THC → causing a lower production of CBD* - Skunk = \~16% THC and no CBD 42. Either got THC or Placebo - Those with THC experienced positive symptoms - Particularly Paranoia - If given CBD before - Still got the spike of positive symptoms but CBD aborted the effect 43. Resin = Hash 44. Imported = Marijuana 45. Skunk (15-16% THC) 46. Full agonists - more powerful effects 47. Users are 30x more likely to seek emergency treatment than users of regular cannabis → due to the additional effects of other organs *(Winstock A, Global Drug Survery, 2014)* - Used by homeless - possibly to get through the night 48. Can go psychotic overnight due to its extreme potency 49. These findings point to reductions in cannabis use as a crucial intervention target to improve outcome in patients with psychosis. **Notes:** **Dopamine & Genes** - Two basic deviancies or abnormalities in Psychosis **Genetics** Molecular genetics is revolutionising everything → e.g. IQ, personality etc. - Companies can check your DNA to see if you carry any genes for any illnesses **Striatal Dopamine Synthesis is Elevated in Schizophrenia - PET Scan** - Those who are manic also show and excess of striatal Dopamine - Likely to be hypomanic (requires laying in a PET scanner for \~40 minutes) This is the final common pathway to psychosis. **The Primary Problem in Psychosis is Presynaptic** **The Primary Problem in Schizophrenia is Presynaptic** 'Acute Psychosocial Stress' → (fired, broken up with, attacked) → release more dopamine when stressed - If experienced bad experienced, may have paranoid interpretation in anticipation of a bad event - Causes more stress → more dopamine release → more salience → more likely to develop psychosis The problem in the striatum = synthesis of **too much dopamine** Why do we need Dopamine? - it's involved in movement & importance (good and bad) Dopamine normally mediates the attachment of salience to ideas and objects. - Too much Dopamine is produced and released → in those that are psychotic - Received across the synapse by the D2 receptor - Causes increase in Dopamine signalling - Causing psychotic symptoms - Medication prevents the dopamine getting to the receptor **Dopamine as the "Wind of Psychotic Fire"** - When individuals are acutely psychotic, they show an excessive release of dopamine *(Laruelle et al 1996)* - Dopamine normally mediates the attachment of salience to ideas and objects *(Berridge and Robinson, 1998)* - Heightened DA transmission leads to aberrant assignment of salience to external and internal stimuli *(Kapur, 2003)* - Not good at distinguishing true salient events from general experiences - Everything becomes 'important' whether it is or isn't - Try to apply meaning to it (e.g. why is someone looking at me strangely...maybe they can read my mind/are out to get me) - Delusions arise from attempts to explain this abnormal salience *(Maher, 1983)* **Molecular Genetics is Revolutionising Everything** - E.g. 23andMe Molecular genetics is revolutionising everything → e.g. IQ, personality etc. - Companies can check your DNA to see if you carry any genes for any illnesses **PGC Wave 3, Nature, 2022** - 74,776 Schizophrenic patients and 101,023 controls - Red line = significance - 263 genome wide significant sites - predispose to Schizophrenia - No genes for schizophrenia, just genes that make you more susceptible → some people may have too many of the ones associated with schizophrenia **Association between 37 human tissues and schizophrenia genes** Associations were enriched in genes with high expression in excitatory glutamatergic neurons from cerebral cortex and hippocampus (pyramidal CA1 and CA3 cells, and granule cells of dentate gyrus) and also cortical inhibitory interneurons **Genetic Correlations of Schizophrenia with other Disorders and Traits** - Also an overlap with depression (30%), OCD, Anxiety disorders - But not with BMI (lower BMI), Intelligence (lower) or Subjective wellbeing (lower) Genes for one disorder blend into other disorder. - 75% of genes that predispose to SCZ also predispose to Bipolar - Explains why they both have too much dopamine and respond to the same medication & come on to young adults - can also be difficult to differentiate the two disorders **There is genetic & neurochemical overlap** Implicated: 1. complications of pregnancy 2. abnormal growth and development 3. complications of delivery e.g. asphyxia Effects the development of the brain → may cause subtle damage to the connectivity of the brain. Confirmed large range of factors, with relatively small effects sizes **Copy Number Variants (CNVs)** CNVs = when you lose a chunk of DNA or they're duplicated Showing something developmental may go wrong in people with Schizophrenia. Usually worse to lose genes than have a duplication Copy Number Variants - may account for 10-20% of Autism Also found in learning disability, epilepsy CNVs are found in excess in schizophrenia **Social Factors that Increase the Risk of Psychosis** - Childhood physical, sexual abuse, neglect - Childhood abuse is bad for all psychiatric disorders - Migration/ethnic minority - Potential traumatic reasons for or experiences of migration → fleeing war-torn/severely corrupt countries - Bullying - Intrusive events → e.g. beaten or constantly bullied - leading to feeling less safe - Being brought up in the inner city - Unsure why - though easier to be more socially isolated due to the culture → compared to living in a nice village - Adverse life events/stress **The Final Common Pathway to Psychosis is Dopamine Dysregulation → Social Factors Can Cause This** Increased striatal dopamine synthesis \ 💡 Stress, childhood abuse, migration, drug abuse all impact on striatal DA (Mizrahi et al, 2011, Murray et al, 2014; Egerton et al, 2016) \ Those with psychosis are much more sensitive to stress and a much more active dopamine system. **Schizophrenia has traditionally been considered a discrete category/illness/disease** - *you either **have** it or you **don't*** Though there are lots of personalities that are 'normal' - 'normality' is very broad. Indeed this is the traditional view of psychosis as a separate category or disease, with normality on a normal distribution curve here, and psychosis over there, with no overlap in between Now we know there are hundreds of susceptibility genes - this is not compatible with a discrete illness of schizophrenia: - more compatible with the idea that there is a continuum of liability to psychosis Based on the number of susceptible genes you have, it creates a polygenic risk score (PRS) - towards the right, have a **high risk.** If seen from dimensional view it's not that different from other neurotic disorders, just more extreme. Indeed there's lots of evidence now even from the psychiatric rather than the psychological literature that **psychosis does lie on continuum**, and that looking at symptoms or syndromes is more helpful clinically than diagnoses; and of course symptoms themselves lie on a continuum Minor Psychotic Symptoms If you go over a certain amount of risk, you may display more psychotic symptoms - But may not come to clinical attention as the symptoms may not present as severely (e.g. may have a few paranoid thoughts / interested in conspiracy theory) - Isolated incident with no disruption to function or well-being Prodromal - Signs the individual may be just about to develop psychosis - PRS is slightly higher Psychotic Disorder - If the individual went psychotic for around 1 week - their PRS would be higher again Schizophrenia At the extreme end... - SCZ is severe psychosis that persists - They would have a higher PRS People at the top 10% of PRS vs the bottom end are 7x more likely to develop SCZ - Not good enough for any statistical prediction as it just means around 7% of the population would develop SCZ **Summary** We have learnt that the vulnerability of SCZ is transmitted in a polygenic way through lots of little genes. - You wouldn't develop SCZ just from a high PRS - But the vulnerability interacts with some environmental factors **Developmental Cascade Towards Schizophrenia** - Genes which can impair neurodevelopment - Can be compounded by pre/perinatal events (e.g. long labour/starved of oxygen - damage development of babies brain) - About 1/3 of children who go on to develop SCZ have some subtle motor difficulties - e.g. later to walk/talk, not very good at sport - some cognitive difficulties too e.g. IQ of 95, and social deficits - Into teens, tend to develop anxiety/depression as well as some quasi psychotic ideas - e.g. are these people out to get me or trick me in some way - If they persist, you get Dopamine dysregulation - This can trigger psychosis in late teens or early 20s - Average of presentation of psychosis in England = 28/29 **Drug Use Can Increase Risk of Schizophrenia** Methamphetamine Psychosis → Eastern Countries - Asia, Australia & some cases in US - Famous case: Britney Spears **Cannabis** The majority of people who use Cannabis use it moderatley and come to no harm. - The more they smoke, the more at risk they are - particularly the stronger cannabis **Risk of Psychosis in Relation to Extent of Cannabis Use** OR = 4 Meta-analysis → each line = 1 study Risk is higher the more cannabis is smoked - Cannabis also become potent between McGrath and GAP study (more potent) *Marconi et al Schiz Bull 2016* **Social Factors** Are social factors themselves cause? Obstetric Events (Cannon, 2002) OR 1.9 Childhood adversity (Varese 2012) OR 2.8 Migration (Bourque, 2011) OR 2.1 Urbanicity (Vassos, 2012) OR 2.4 Heavy cannabis use (Marconi 2016) OR 3.9 Recent life events (Beards 2013) OR 3.2 - From meta-analyses by Evangelos Vassos **Can Social Factors Impact on Dopamine?** **Stress and Psychosis** STRESS ---------------------→ Psychosis - Stressful events and onset of psychosis (*Brown and Birley, 1968*) - Vulnerability Stress Model (*Walker and Diforio, 1999; Myin Germeys and Van Os, 2007*) 12 Ultra-high risk subjects (6.9%) and 10 drug- naïve schizophrenic patients (11.44%) showed greater release of dopamine\* in Associative Striatum in response to Montreal Stress Test compared to 12 controls. **Incidence of First Episode Psychosis Across Europe** Support that big cities have more prevalence. *What is the explanation for the low rates in Italy/Spain?* - Mediterranean Diet? - Vitamin D? - Migration → partly as migration there is a more recent thing - Families v Social Isolations? - High Potency Cannabis → is a factor The effect of daily use of high-potency cannabis on the odds for psychotic was particularly visible in London and Amsterdam. **Relationship Between the Frequency of Cannabis Use and the Rate of Psychosis** **Population Attributable Fraction** If nobody smoked high potency cannabis, 12% of all cases of first episode psychosis across Europe would be prevented, rising to 32% in London and 50% in Amsterdam. **What about the Global South** **INTREPID II** - Kancheepuram District of Tamil Nadu, India - Ibadan in Oyo state, Nigeria - 7 municipalities covering northern Trinidad \*\*\*\* **Cannabis and Schizophrenia in Denmark: PAF attributable to Cannabis Dependence** **Summary** Schizophrenia is not a discrete entity. It merges into bipolar disorder. The two are distinguished by developmental cognitive impairment in the former. Schizophrenia is no longer a mystery. We have a clear understanding of the risk factors. These environmental risk factors (or component causes) converge to cause striatal dopamine dysfunction. Now that we know the risk factors, we should be thinking of ways to avoid exposure to them -- a public health approach. Heavy cannabis use is the obvious place to start. Otherwise we may face an epidemic of psychosis.