P&B Lecture 2 - Psychopharmacology PDF

Week 2 - 11th Oct Created @August 10, 2024 10:00 AM Tags Psychopharmacology in Psychosis - Pathways and Therapies: Reading list: PSBS0005: Current Research in Psychosis and Bipolar | University College London (talis.co...

Week 2 - 11th Oct Created @August 10, 2024 10:00 AM Tags Psychopharmacology in Psychosis - Pathways and Therapies: Reading list: PSBS0005: Current Research in Psychosis and Bipolar | University College London (talis.com) Location: Birkbeck Mallet St Room B36 Derek Tracy (SLAM NHS Trust) Class Prep: Additional: Read: Antipsychotics Read: Dopamine and Glutamate in Schizophrenia: Biology, Symptoms and Treatment Read: Glutamate in Schizophrenia: Neurodevelopmental Perspectives and Drug Development Read: Treatment with Medication: Side Effects, Adherence, and Risk Read: A Systematic Review of Factors Influencing Adherence to Antipsychotic Medication in Schizophrenia-Spectrum Disorders Optional - Read: Realising Stratified Psychiatry Using Multidimensional Signatures and Trajectories Optional - Read: Dementia Praecox Redux: A Systematic Review of the Nicotinic Receptor as a Target for Cognitive Symptoms of Schizophrenia Optional - Read: Glutamate Modulators for Treatment of Schizophrenia Week 2 - 11th Oct 1  Optional - Read: Treatment-Refractory Schizophrenia: Definition and Assessment Optional - Read: Hominin Evolution II Sapiens, Masters of the Known Universe Optional - Read: Hominin Evolution I The Origins of Homo Sapiens KEY Prep intro lecture: Pharmacological Interventions in Mental Health Challenges We Our Approach What We Will Achieve Face Build a framework of a Confidence about Introduction plausible model of brain neurobiology to new functions/dysfunction in the Build a plausible names/medication brain. model of brain Biochemistry Evolution of the brain regulation Biological Basic Neuroanatomy Understanding of how medication Preconceptions How the brain is impact brain about the role regulated and controlled regulation of How dysfunction of medications regulation can lead to in mental signs of mental illness health How medication impacts on the brain (re-regulate the brain) How effective are these? Side effects A Brief History of Time Week 2 - 11th Oct 2  Building a Brain 1. Overview of brain anatomy: Neuroanatomy - Orientate ourselves with major structures 2. Primal Activity: Evolutionary perspective of the nervous system 3. Evolutionary Psychology: Prefontal cortex - how it evolved The Brain: A Staggering Communication Device The most complicated machine in the known universe 1mm3 of cortex have 1,000 million synapses 1 neuron can be 1m long 1,000 trillion connections 100 billion neurons 1 neuron can receive 150 million pieces of information in 3 milliseconds 1 neuron = 30,000 inputs 1 input can transmit 5,000 quanta of neurotransmitter in 3-5 milliseconds Week 2 - 11th Oct 3  Video: … Brain Divisions and Terminology Brainstem Basic functions Automate heart & lung functions Contains the basis of important neurotransmitters: Serotonin Adrenaline Dopamine The Forebrain The Diencephalon - the bit of the brain The Cerebrum - the vast bulk of the that isn’t the cerebrum (lobes), brain above and surrounding the cerebellum or brainstem. diencephalon (Cortical lobes). Thalamus Occipital lobe Motivational drive Vision (receiving and Libido interpreting information) Hypothalamus Frontal lobe Week 2 - 11th Oct 4  Sleep Temporal lobe Appetite Auditory cortex (perception of speech) Thirst Memory Very important, basic, critical functions. Declarative memories Episodic ‘autobiographical memories’ Semantic ‘factual memories’ Parietal lobe Primary sensory cortex Making sense of sensory information Grey Matter: Top 0.5 - 1cm containing the cell bodies. Cell bodies project their axons ‘wiring’ underneath communicating down to… White matter: Surrounded by fat. Convolved for increased surface area. The Frontal Lobe Prefrontal (PFC) Lobe “Everything else” all of the frontal lobe apart from the section that controls movement. Higher functions that make us human: Personality/expression Social awareness Week 2 - 11th Oct 5  Goal setting Attentive & Task Switching Executive Functioning Primary Motor Cortex Control motion. Gross Behaviour Evolution of the nervous system The Hypothalamus The size of an almond Regulates a large number of primal/basic behaviours: Appetite Motivation Reproduction Inputs Functions Sensory: Taste, smell, genitals Sexual Behaviour: Eyes: Light input acts a Hypothalamic Pituitary Axis ‘zeitgeber’. Is it day or night? Hunt (HPA): menstruation, or hide? spermatogenesis. Week 2 - 11th Oct 6  Neurotransmitters: Serotonin, Basic sexual functions: Male Noradrenaline which are key for mounting, female hip appetite, libido and motivation elevation. Hippocampal: memory input Interpretation of pheromones: Role in humans is debated. Amygalae: emotional input Motivational Behaviour: Basic primal: food, water, reproduction Known as appetitive or consummatory motivation Food/Fluid Intake: Tells us when we’re hungry so we seek out food. Not the only input - others incl. signals from fat tissue - but it coordinates and drives this behaviour. Limbic System & Hippocampal System Brain Stem —> Hypothalamus —> Limbic System & Hippocampal System Phylogenetically Ancient System - it has been with us for 100+ million years Limbic System Hippocampal System Controls the function of memory. Hippocampi —> Memory formation Three neuronal layers of cells (usually 6) Tells us it’s an ancient part of the brain Connects with various regions of One of the brain’s ancient systems the brain Week 2 - 11th Oct 7  Confusing, ill-defined set of ‘Circuit of papez’, long-term structures potentiation (LTP) whihc is necessary for encoding, storage and Involved in emotional processing retrieval of memory. Sits in the ‘deep’ subcortical part of Amydalae —> Fearful (aversive) the brain memory (assists survival) Important part of the memory system that connects to the hippocampi Unwanted thought keeps recurring Thought is linked with a stimulus (e.g. bus) This important evolutionary process isn’t immune to defects. In extreme examples it can become a pathological problem — e.g. PTSD Evolutionary Psychology Hominin & Hominids Spinal cord & Brain stem (organ control) —> Hypothalamus (basic functions - eat, drink, sex) —> Limbic system & hippocampal system (emotions & memory) —> Cortical growth (higher cognitive processing - “makes us human”) Week 2 - 11th Oct 8  The Origins of our Species Sexual dimorphism: Distinct differences in size or appearance between the sexes of an animal. Australopithecus: Our Grandfather - “southern stone man” - Grandfather of Homosapiens Lifespan: 4.2 - 1.2 mya Cranial Capacity: 3-600 cm3 (chimpanzee) Evolution Significance: Settled a great anthropological debate. We walked before we got smarter. Evolutionary (bipedalism) Advantages: Evolutionary (bipedalism) Disadvantages: Walk longer distances Week 2 - 11th Oct 9  Moved from tress to the plains Locked hips Posture > Cooler > More hours Difficult child-birth active Hands free to make and carry tools and eventually master fire Able to get more food than it needed just to survive — resulting in enough energy being available to allow brains to grow and develop The Birth of Genus Homo Children of Homo Heidelbergensis 200,000 years ago, 3 species derived from the same ancestor, were living side by side. Homo Heidelbergensis —> Neanderthal -x-> Homo Sapiens Homo Neanderthalensis Vs Homo Sapiens What’s the differentiates? Week 2 - 11th Oct 10  Differences between these two species helps us understand the final evolution of the prefrontal cortex in the human brain. Homo Neanderthalensis Homo Sapiens Cultural Characteristics: Physical Attributes: Complex culture Nuchal ligament (connects skull to the spine) Tool making A strong Achilles tendon Language Could run over long distances Physical Attributes: - Neanderthals could not Stocky (stronger than homo Hunting Style: sapiens) Persistence hunters - chase Large cranial volume (greater than down/follow prey over long homo sapiens) distances Hunting Style: Cognitive Makeup: Ambush larger prey Smaller occipital cortex Cognitive Makeup: Larger orbital frontal cortex (key to Large occipital cortex (very good social behaviour and mentalisation) vision, good night vision) — this ultimately differentiated us. ?Videos on Mentalisation 1st to 5th and 6th and above … A Genetic History 200,000 years ago - 50,000 years ago - 12,000 years ago - 70,000 years ago 12,000 years ago modern day 7bn people on the planet Behavioural The Neolithic but we are all incredibly explosion revolution connected. We buried our Animal Event time dead domestication and farming Week 2 - 11th Oct 11  ~70,000 years Huge increase in The rise of great ago artwork and cities: Ur, Babylon, jewellery Jericho Location We spread from The first empires: Lake Toba - our African home Persian, Assyrian, Current day through the Egyptian Indonesia Levant and across The Bronze age Supervolcano the world The Iron age The largest Wiped out the known Neanderthalensis The Industrial explosion on revolution Earth for the The Scientific past 25 million revolution years The computer and mDNA Findings - information population dropped revoultion. to: 2,000 — 3,000 breeding females A population of 10,000 or less remained All humans follow this lineage Summary What have we asked Nervous system recap What will be asking ourselves? next? A ‘reactive’ spinal To think about the cord How do we control human brain is this on a day-to-day Week 2 - 11th Oct 12  rational and logical A brain stem that basis? sense. controls our How could breathing and Why do we have the dysfunctions of this heart rate functions we have? lead to signs and Hypothalamus symptoms of mental Why are they located controlling basic ill health? where they are? behaviours How could (eating, drinking, medication help reproducing) ameliorate Limbic system symptoms? driving powerful emotions Hippocampi and Amydalae that helps us remember Growth of our Prefrontal Cortex Short Article on Antipsychotics https://www-sciencedirect- com.libproxy.ucl.ac.uk/science/article/pii/S1357303920302243?via=ihub Definitions: Extrapyramidal adverse effects: Involuntary movement that a person cannot control, caused by medication effects on the extrapyramidal system in the brain. Key Points: Response and tolerability of antipsychotic drugs varies greatly between individual patients. Antipsychotic choice should involve the patient and consider patient characteristics as well as past experience of pharmacological treatment. Week 2 - 11th Oct 13  Physical health should be assessed before starting medication and monitored regularly during antipsychotic treatment. Antipsychotic drugs reduce the severity of psychotic symptoms and prevent relapse in Schizophrenia and other psychotic disorders. Used in mania, depression and delirium etc. Classified in 2 groups: Conventional or First-Generation Antipsychotics (FGAs) More likely to cause extrapyramidal side effects at typical doses. ‘Atypical’ or Second-Generation Antipsychotics (SGAs) Some can lead to extrapyramidal effects - incl. tardive dyskinesia Neuroscience-based nomenclature approach - suggests referring to each drug according to its pharmacological function. Basic principles of prescribing antipsychotics for psychosis and Schizophrenia Initiate treatment in primary care only after consulting a psychiatrist for first psychotic episodes. Provide information on benefits and side effects, involving the patient in medication choice. Offer CBT and family intervention when possible. Start with lower doses for first-episode patients, adjusting carefully based on response and tolerability. Assess response over 2-3 weeks at an effective dose. Avoid 'as-required' prescribing due to increased risks of adverse effects and drug interactions. Avoid antipsychotic combinations except during short switching periods and only with psychiatric consultation. Monitor physical health regularly throughout treatment. Week 2 - 11th Oct 14  Continue treatment for 1-2 years after a first episode to reduce relapse risk. If discontinuing, taper the dose slowly. FGAs SGAs Cause more extrapyramidal Lower incidence of extrapyramidal adverse effects and adverse effects at usual clinical hyperprolactinaemia than SGAs. doses Option when metabolic adverse And a lack of sustained effects are a problem with SGAs. increase in plasma prolactin concentration (e.g. Some cause weight gain (e.g. hyperprolactinaemia). common with Chlorpromazine) Commonly prescribed SGAs in Currently licensed FGAs in UK: UK: Chlorpromazine Risperidone Trifluoperazine Olanzapine Haloperidol Quetiapine Flupentixol Aripiprazole Zuclopenthixol Amisulpride Sulpiride Clozapine Paliperidone Asenapine Lusidone Capiprazine FGAs and SGAs are available as long-acting injections (LAIs) to improve adherence to treatment. FGA LAIs were less favoured initially due to adverse effects and complex pharmacokinetics. The introduction of SGA LAIs (risperidone, olanzapine, paliperidone, aripiprazole) offers better options for adherence. Week 2 - 11th Oct 15  Mechanism of Action Most antipsychotics act as antagonists at D2 receptors in the mesolimbic pathway to reduce positive symptoms. D2 receptor blockade in two different brain areas leads to two distinct side effects of antipsychotic medications: In the striatum: D2 receptor blockade causes extrapyramidal side effects These are movement-related problems like muscle stiffness, tremors, or restlessness In the tuberoinfundibular pathway: D2 receptor blockade leads to hyperprolactinaemia This means increased levels of the hormone prolactin in the blood It can cause symptoms like irregular menstrual cycles, breast enlargement, or sexual dysfunction Blocking D2 receptors in one brain area (striatum) affects movement, while blocking them in another area (tuberoinfundibular pathway) affects hormone levels. Both of these are common side effects of antipsychotic medications. FGAs and SGAs affect multiple receptor types beyond dopamine D2 receptors: 1. Both can block serotonergic 5HT2, α1-adrenoceptor, H1-histamine, and muscarinic receptors. 2. SGAs generally have lower D2 affinity and higher 5HT2A affinity, which may explain their reduced extrapyramidal side effects and improved affective/cognitive effects. 3. Optimal D2 occupancy for antipsychotic effect is 65-70%, with adverse effects emerging above 72%. 4. Aripiprazole, brexpiprazole, and cariprazine are partial D2/D3 agonists, resulting in: Low risk of extrapyramidal side effects Week 2 - 11th Oct 16  Prolactin-sparing effects Dose-related akathisia This diverse receptor activity profile contributes to the varying efficacy and side effect profiles of different antipsychotics. Notes: Neurobiology & Treatment of Psychosis What is ‘psychosis’; what is ‘normal’? Why does psychosis persists? Psychosis - spectrum disorder / comes on early - early 20s (potentially limits individuals ability to reproduce). If it’s debilitating, why does it persist? Unlike later onset disorders. Is there something enriching to society? Admiring what is different Throughout history - acting or thinking differently has been okay. E.g. the pythia’s were renowned across the world for their prophecies: ‘oracle of Delphi’ / inhaled and consumed sources with psychotic elements. And Shaman in South America will consume psychotics to ‘transcend’ Epidemiology: Genes and Environment Confounder: life challenges - Psychosis can make challenges harder and possibly a deterrent. Association with mental health and creativity - might be helpful to us as a species. Looking beyond high-profile individuals Study: Study: Power et al. 2015 Srinivasan et al. 2016 86,292 individuals in Iceland Analysis Week 2 - 11th Oct 17  Analysis Compared humans and Neanderthals and primates and looked at how genes Looked at polygenic risk factors for change over time in humans and how it schizophrenia and bipolar affective differs from Neanderthal and other disorder primates Findings Findings The polygenic risk for these two Genes associated with schizophrenia disorders was significantly associated were strongly associated with language with creativity parts in our brain Associated not found for other non- creative professions Association not found for other mental health conditions Genetic risks for schizophrenia MZ twins have a 50% chance of having psychosis. Risk Strong heritability Polygenetic risk Finding Having an identical twin with psychosis given 50% chance of also developing it Kahn et al. 2015 Psychosis 50% Genes 50% Environment Psychosis risk factors Childhood traumas are cumulative - the more you have, the more likely it will affect you - the more severe, the earlier it will present. Week 2 - 11th Oct 18  Immigration - can vary dependant on other demographics. Meyer-Lindenberg & Tost 2012; Tandon, Keshavan & Nasrallah 2008; Tsuang, Faraone & Glatt 2011 Other reported factors: Urbanicity 1st/2nd trimester infections or Maternal stress malnutrition Maternal influenza Late winter/early spring birth Obstetric complications Paternal age >35 Poorer socioeconomic status Male gender Childhood CNS infections Neurodevelopmental Trajectories Week 2 - 11th Oct 19  Insel 2010 Percentage of maximum - neuronal changes. 80-85% of the neurons in the brain are excitatory - major communication in the brain Over time the amount of glutamate neurons decrease - Neurons stay where used, prune when not GABA 5-10% - inhibitory neurons increase with time. Myelination (fat insulating neurons) - increases over time. The network on neurons has a chronic connectivity problem. EIS - first presentation to services (blue box) - what you begin to see are people dropping out of college, losing friends, not keeping in touch - though not noticeable until later stages of psychosis. The best predictor of outcomes is how early you treat → the longer DUP, the worse the outcome. Epigenetics - your body changing to what happens around it. Dopamine: what is does, why it’s important Incomplete hypothesis, aware it’s not the primary issue. Week 2 - 11th Oct 20  The glutamate impacts the dopamine in the brain that can be modified. Most communication in the brain ‘glutamate’ is go, ‘gaba’ is stop. Some elements in the brain have more regulation via neurotransmitters. — if they don’t get the input, they don’t work properly. Dopamine release neurotransmitters into the body of the cell - it sets off a chain reaction to the nucleus - keeps it regulated. Only 0.25 million brain neurons are dopaminergic Only four dopaminergic pathways and each projects to a specific area Those parts of the brain, expect and need dopamine to work Pathways can be categorised according to where they originate and terminate Dopaminergic Pathways Dopamine actives all of D1-5 but they all cause a different reaction. Mesolimbic System (1) Week 2 - 11th Oct 21  Limbic system = emotions → good because they guide and control behaviour/actions. Supports survival - avoid threats due to fear. Mesolimbic system helps to drive this process through fear and pleasure - needs dopamine to function. Spectrum of the threat system but works fast. Others may perceive threat differently. Pleasure system is also regulated by dopamine. In psychosis - this pathway doesn’t work properly: This pathway is hyperactive Phasic dopamine release - doesn’t respond to the overactive dopamine. Neurons and threat system starts to dysfunction. The pathology of things going wrong - overestimates threat perception (paranoia). Receives dopamine to active this system. Pleasure system - same response. No Pleasure system - if taking drugs of abuse, response to the dopamine firing at the such as stimulants, it starts to over-activate neuron. the firing of dopamine. Mesocortical System (2) Week 2 - 11th Oct 22  PFC = cognition, thinking, motivation, social enagement (bit that makes you you) - around 100,000 neurons. Mesocortical dopamine neuron (D1-5) - when fired, protein expression, keeps it healthy. In psychosis - this dopamine pathway is hypoactive / underactive: Harder for the PFC to work Cognitive impairment Social withdrawal Though still affects people on a spectrum Nigrostriatal System (3) 3 & 4 Not involved in psychosis but require dopamine to function properly. Nigrostriatal neuron - involved with the basal ganglia - involved in the initiation of movement. Start the movement Requires dopamine input In psychosis - nothing changes — unsure why. Tuberoinfundibular System (4) Week 2 - 11th Oct 23  Tuberoinfundibular neuron - HPA — part of the hormonal feedback system in the brain and body. Particularly neurons involved in menstruation/menstrual cycle (regulate the cycle), breast milk production, libido (sexual drive). Neurons get the fire of dopamine to work In psychosis - nothing changes. ‘Antipsychotics’: How they help, how they harm Positive symptoms seem to be the focus to society as more noticeable and bring you to the attention of others in an unwelcome way. And often the target of therapeutic therapies - not as easy to treat negative symptoms. Negatives symptoms have more of an affect on the individual with psychosis. Week 2 - 11th Oct 24  Pharmacological Terms Can you shut down a neuron firing/overfiring? - not commonly, really difficult to do in practice but would be good to do. Glutamate - if you mess with it (it’s 90% of brain activity) - it may/would kill you. Only a quarter of a million dopamine neurons so not impacting a lot of the brain. Can’t turn off the neuron firing but can block the receptors to stop/minimise the effect. Medications plug into the receptors and block the compound - enough gets through to keep it healthy. Though will bind to any receptor - doesn’t go to the problem causing area. Agonist: A compound that binds to a receptor and causes a biological response (not all medications are agonists). Antagonist: A compound that binds to a receptor and blocks a biological response (many medications are antagonists). Antipsychotics and Dopamine All modulate the dopaminergic system Are all postsynaptic dopamine antagonists Circulate widely, but (should) only affect dopamine receptors The D2 receptor seem to be particularly important - seems to matter more to block D2. Antipsychotics and the mesolimbic system Must block 60-70% of dopamine in the mesolimbic system - will treat most people with psychosis. Threat system re-regulates Though blocks 60-70% of the pleasure neurons (previously normal in psychosis) — begins to dysfunction with time Can cause dysphoria (a loss of pleasure in life) not depression This can lead to people abandoning their medication - not enjoying life Week 2 - 11th Oct 25  Antipsychotics and the mesocortical system Suppress system even further - through blocking 60-70% of receptors Worsen negative symptoms (called secondary or iatrogenic (caused by medication) symptoms) Anti-cognitive Good for positive (mesolimbic) symptoms, but bad for negative (mesocortical) Newer atypical antipsychotics suppress the mesolimbic while stimulating the mesocortical. First and Second generation antipsychotics: how they differ Mesocortical system: underactive in psychosis, leading to some of its cognitive and negative symptoms. First generation: Can make this worse - medication induced side-effects Second generation: Seemed to improve cognitive and negative symptoms. Cognitive functioning in Psychosis Improvement in cognition can be seen when switching from first generation antipsychotics to second generation one. Nigrostriatal and Tuberoinfundibular pathway - movement and hormonal functioning Week 2 - 11th Oct 26  2nd generation antipsychotics - seem to improve this functioning (due to fast off- time & disinhibition). Attach and release much more quickly Due to blocking 60-70% of receptors… With time - medication makes the 💡 ‘New atypical second generation have faster off-time’ movement pathway dysfunctions (previously normal function in psychosis) - visible movement When 2nd generation antipsychotics first problems came out (1980s-90s) they were seen as revolutionary - treating delusions and Hormonal pathway - medication causes hallucinations and improving cognitive and dysfunction (normal in psychosis), over negative symptoms without causing any time causes menstruation to stop, movement and hormonal problems. lactating when not required, shut down libido - can increase risk of breast New type of side effect - Cardio metabolic cancer. symptoms (early onset diabetes, weight gain, CVD). Landmark studies: CATIE and CUtLASS ( elevated people taking these medications and found that they dislike both classes. How Antipsychotics Vary Disinhibition Week 2 - 11th Oct 27  5HT2A: Presynaptic auto-receptor - (off switch) - if the neuron gets too active, they ‘cool themselves down’ - they start to defuse around the synapse and some will get reabsorbed into the presynapse and shuts the neurone down. Will release after a while, allowing the neurone to fire again. First Generation: Second generation antipsychotics still block 60-70%, but are more dynamic with off- Helpful in the mesolimbic system but time and this seems to help reduce side causes problems on other pathways effects. causing further problems. Neurons typically have a self-regulating Second Generation: function - ‘homeostasis’ Still want to block 60—70% of Primary function is to release receptors in the threat system to reduce neurotransmitters positive symptoms. Has a function to shut itself down if it’s But wants to compensate the other getting too active areas by allowing more dopamine to release. Binds to the presynaptic auto- receptor (antagonists at the ‘off switch’) - blocks the reuptake and prevents the neuron from shutting down and allows the release of more dopamine. Reducing side-effects - seems to help therapeutically (particularly with leading to less dysphoria in the pleasure system) - fewer cognition, movement and hormonal problems. Week 2 - 11th Oct 28  More likely to give first generation to individuals who may already have difficulties (e.g. CVD/diabetes/obesity) that second generation antipsychotics would exacerbate/increase risk of. Also individual variation to response of medication. Comparative efficacy and tolerability of antipsychotic drugs (1) Most classes of medication have a similar class size effect. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple- treatments meta-analysis. Review: 212 RCTs of antipsychotics. Findings: Drugs are approx. equivalent but there are differences Leucht et al. 2013 💡 We need drugs that do different things Predictive of the drug that works with the individual to help guide prescribing (2) Variation with side effects of medications. These data can be helpful when prescribing medication to patients. Week 2 - 11th Oct 29  Clozapine Characteristics: Clearly more effective than other psychotics Has particular side-effects Reserved for “treatment-resistant illness” (try 2 other antipsychotics and fail on them before being prescribed clozapine - e.g. therapeutic trial - 6 weeks each) Due to the poor side effect: Routine: sedating, drooling/dribbling, HTN - falling Less common/severe: death (reduce white cell count - unable to fight infections) - can be prevented through regular blood tests - though can deter individuals - if it happens then stop taking it Key prognostic factor in psychosis: DUP - the longer one goes without adequate treatment, the worst one’s life will be Why do psychiatrists do not prescribe clozapine earlier?: Average time to prescribe following diagnosis = 5 years More complex to prescribe Longer-term Outcomes in Psychosis Week 2 - 11th Oct 30  Trajectories in psychosis A ‘classic but simplistic’ model of psychosis Premorbid: Things may be happening but we can’t see it - not sophisticated imaging. Though aware of potential risk factors but can’t necessarily change it all. Prodromal: EIS focus on this area - soft deterioration. Unaware until ‘progression’ Nearly 20 years ago, Harrison et al. and experiencing psychosis. 2001 wrote of ‘striking heterogeneity’ Progression: Symptoms typically get worse in outcomes in psychosis. with more prevalence of negative symptoms later in life - as well as societal influence. Pattern of relapse and remission → varies across the population — around 1/8 will have one episode though 7/8 relapse. Long-term effects (1) This is scientifically difficult to evaluate. A possible solution would be to evaluate naturalistic data sets. The long-term effects of One-year symptom Should psychiatrists be antipsychotic medication on trajectories in patients more cautious about the clinical could in with stable schizophrenia long-term prophylactic use schizophrenia. Goss et al. maintained on of antipsychotics? Murray 2017 antipsychotics vs placebo: et al. 2016 Week 2 - 11th Oct 31  meta-analysis. Takeuchi et al. 2017 Key findings: 1. The effectiveness in 3. Some people can 5. There is not good evidence treating positive recover without to causally link symptoms is really well medication. antipsychotic use with established. brain changes. 4. The effectiveness 2. There is not good of maintenance 6. Sensitisation: if dopamine evidence for long-term on antipsychotics receptors keep being harmful effects from is well blocked, sometimes cells medication use. established. respond by increasing the number of receptors (seen in some animal and human studies). Meta-analysis of 11 studies of long-term outcomes in patients with psychosis who were stable and were then switched to placebo (N=1208) or maintained on an antipsychotic (N=1618). Findings: Outcomes are considerably worse on those switched to placebo. Polypharmacy (1) - being on more than one medication at once All guidelines against: Polypharmacy ‘above maximum dose’ prescribing Though some metabolise medication quickly and seem to respond to a higher dose Though this is common in clinical practice as: we’re faced with the burden of treatment- resistant psychosis. About half of patients on Clozapine fail to show significant improvement Week 2 - 11th Oct 32  Frequency varies with setting (more common on inpatient wards than outpatient ones) and geography POMH-UK Study: About 40% inpatients and 13-60% of outpatients were on more than one medication Practice seems to be increasing with time, despite guidelines specifically recommending against it Sometimes reducing Drug A, and slowly inducing Drub B (cross-titration) - individual feels well and decides to remain on low dose of both regardless of guidelines. Why do we persist? There’s data to support the fact that there are older psychiatrists who are more experienced and more sceptical of guidelines and therefore more likely to co-prescribe. There can be pressure from staff, patients and carers to do something when treatments don’t seem to be working. A common reason for co-prescribing is terminated cross-titration, especially if it coincides with a well patient. Week 2 - 11th Oct 33  Side effects Direct: Side effect caused by what you want to do Cardiac: Cause problems with the heart ‘Other’: Cardiometabolic Side effects and mortality on antipsychotic medication (1) Direct: Side effects from the intended action of medication Dopamine blocking is good in the mesolimbic pathway - first generation and bad everywhere else. The nigrostriatal pathway is vulnerable to disruption (when blocked it causes extrapyramidal side-effects (EPSE)). These include (in how quickly they occur following taking antipsychotics): Acute dystonia: sharp muscle spasms in the face and neck (often distressing but typically not dangerous unless impacting breathing) Akathisia: sense of inner restlessness - feel unable to sit still (can last for days and weeks) Parkinsonism: stiffness of movement - (come on from months-years) - e.g. shuffling gate and ‘pill rolling tremor pinching and rubbing of fingers’, flat and emotionless expression Tardive dyskinesia: long-term abnormal movements of mouth and lips - (comes on years of treatment) - around eyes and mouth e.g. lip smacking and grimacing - incredibly stigmatised and unable to control or override Cardiometabolic/endocrine Symptoms - ‘Other’ side-effects, incl. anticholinergic, second generation antiadrenergic, antihistaminergic ones Different hypothesis on 2nd generation There is a direct impact on the functioning antipsychotic cardiometabolic side effects: of the heart - affecting its rhythmicity and Week 2 - 11th Oct 34  1. Impact on the hypothalamus (primal contractility. drives: reproduction, eating, drinking) It affects the QTc interval - individuals on a. Result: the satiety part seem to be antipsychotics can be prone to cardiac impacted (unable to feel full) and arrest. patients commonly overeat and This is a significant problem that requires snack often. an ECG prior to antipsychotic prescription i. Need to work on portion and that needs monitoring over time. control and work with a dietitian ii. Will lead to putting on weight and adding strain to CVS 2. Lead to after blood lipid and cholesterol profiles. a. Result: Long-term, it causes CVD and in worse case scenario - death i. Even if overeating is controlled 3. Affect glucose tolerance and impacts on insulin production. a. Result: Individual prone to develop type II diabetes. All leads to metabolic syndrome: stroke (CVA), myocardial infarction (Heart Attack) There is a complex interplay with other confounders - social disadvantage and exclusion, non-engagement with services, bad eating habits, lack of exercise, drugs, stigma, etc. Mortality Week 2 - 11th Oct 35  There is a loss of 15 to 20 years of life from psychosis, usually from CVD. Psychosis: Health problems from medications Health problems from social problems Being on mediations has better outcomes long term than not being on medication - incl. mortality. And being engaged with a therapeutic service - incl. societal engagement. Mortality and cumulative exposure to antipsychotics, antidepressants, and benzodiazepine in patients with schizophrenia: and observational follow-up study. Participants: 21,492 Looked at: Cumulative exposure to medications - antipsychotics, benzodiazepines and antidepressants Question: Does the amount of medication you’re on impact your mortality? Answer: Compared with no exposure, moderate and high antipsychotic dose were associated with lower mortality. The same was true for antidepressants, but not for benzodiazepines. Possible reasoning: The medication can directly cause harm but can also improve people’s mental state. Treatment → possible harm from medications but improved mental state, making patients more likely to : Visit GP Engage in exercise Take physical Get a job health medication The future’s social - Optimising our Current Medication Week 2 - 11th Oct 36  Green et al. (2014); Heide et al. (2015) New Treatments There is a need to get new medications instead of developing the current ones. Steps for the future - rationalise our current drugs Two main areas of research Sendt et al. 2012 Week 2 - 11th Oct 37