Schizophrenia Lecture Notes PDF

Human brain nutrition facts… Hungry?????? DHA, an important omega-3 fatty acid, is found concentrated in HUMAN brains The makeup of the brain is about 29% fat and 20% protein Good source of vitamin C and iron  Confusion...

Human brain nutrition facts… Hungry?????? DHA, an important omega-3 fatty acid, is found concentrated in HUMAN brains The makeup of the brain is about 29% fat and 20% protein Good source of vitamin C and iron  Confusion Inside disrupted Trapped by it all The voice inside Paranoid Paranoid with visual Shadowy menace Auditory hallucinations hallucinations 2 Schizophrenia National Institute of Health (NIH) considers Schizophrenia as a chronic and severe mental disorder that affects how a person thinks, feels, and behaves - people can be withdrawn, completely preoccupied with own thoughts and delusions Typically occurs in early 20’s - disrupts most productive years - 30% of people with this disorder are institutionalized at some point (may re-occur) At Rest - better therapies have helped MRI demonstrates smaller brain with larger ventricles - more empty space Prefrontal cortex function depressed = “hypofrontality” - issues with executive function, response inhibition, problem solving… 3 4 Answer E – excessive adolescent exercise All of the other factors have studies linking to increased incidence of schizophrenia (adolescence cannabis, urban birth, prenatal malnutrition, c-sections, children of dry cleaners). 5 Schizophrenia Genetic and environmental factors play a role 1 = no risk - if parent with disease, 10% chance for child to develop the disease (may increase susceptibility) - environment linked but not worked out - born late winter/early spring - infections - vitamin D deficiency - pollution (urban birth) - prenatal malnutrition - smoking - C-sections 6 Schizophrenia Symptoms can be divided into 3 categories: 1. Positive symptoms: hallucinations, delusions, irrational thinking, disorganized speech 2. Negative symptoms: blunted affect, social withdrawal, speech/communication impairment, loss of normal pleasures 3. Cognitive impairment: poor attention, learning and memory issues, difficulty with abstract thinking and problem solving (other affective and aggressive symptoms also manifest) - no two people are alike in their symptoms: hard to diagnose - symptoms can increase/decrease over time 7 Range of Symptoms and Sites Associated with Schizophrenia Except for positive symptoms (mesolimbic), most symptoms are cortical associated (mesocortical) - emotions can be absent or inappropriate 8 Biochemistry of Schizophrenia Dysfunction of dopamine, serotonin (5-HT), glutamate, nicotinic acetylcholine (nACh), and other neurotransmitters Role of dopamine really demonstrated by early pharmacology - amphetamine Augmenting dopamine induces positive symptoms of schizophrenia, including - levodopa hallucinations (amphetamine, cocaine “psychosis”) - chloropromazine - non-selective dopamine antagonist (“dirty drug” also effects 5-HT, NA, H1, mACh) Strong side effects (motor, drowsy, insomnia, dry mouth, - reduced positive symptoms anxiety…) 9 Dopamine and Schizophrenia 10 Dopamine and Schizophrenia: Imbalance Theory Dopamine dysfunction goes in 2 directions depending on symptom and pathway - hyperfunction (positive symptoms) - hypofunction (negative symptoms) Positive symptoms related to mesolimbic dopamine hyperfunction - high levels of dopamine release in NAc - high numbers of postsynaptic D2 (inhibitory) receptors in NAc - D2 on a variety of neurons in NAc (ACh, GABA, Glutamate) - relates to “psychotic” episodes 11 Dopamine and Schizophrenia: Imbalance Theory Dopamine dysfunction goes in 2 directions depending on symptom and pathway - hyperfunction (positive symptoms) - hypofunction (negative symptoms) Negative and cognitive symptoms related to mesocortical dopamine hypofunction - low levels of dopamine release in PFC - reduced postsynaptic D1 (excitatory) receptor activation in PFC - low activity in this region may also contribute to the increased activity within the mesolimbic pathway (PFC is a negative control on NAc) 12 Glutamate and Schizophrenia Role of glutamate also demonstrated by early pharmacology - ketamine NMDA antagonists induce negative and positive symptoms in healthy people, make symptoms worse in schizophrenic - phenylcyclidine (PCP: aka, Angel Dust) patients Hyperactivation in mesolimbic dopamine system (positive symptoms) due to less glutamate/NMDA activity on inhibitory GABAergic neurons in VTA - less activation of “the brake” on dopamine X X VTA Hypoactivation in mesocortical dopamine system (negative symptoms) due to low local glutamate/NMDA activity - less glutamate-induced excitation in prefrontal cortex 13 Biochemistry of Schizophrenia: Serotonin Serotonin modulates both dopamine and glutamate - receptor subtype dependent - mainly regulation of negative symptoms - dorsal raphe (to PFC) is primary origin of 5-HT input 14 Biochemistry of Schizophrenia: Serotonin Serotonin - overactivity of 5-HT may contribute to hypofrontality through activation of 5-HT2A (excitatory) receptors - activates GABA interneurons - consequence: reduces dopamine release in PFC - also may reduce glutamate - LSD activates this receptor - 5-HT1A (inhibitory) is a receptor activated by different anti-psychotic medications - these meds increase dopamine release in PFC - 5-HT1a is an autoreceptor inhibiting 5-HT release (prevents 5-HT overactivity: see above) - unclear if 5-HT1a has a role in disease pathophysiology - activation of 5-HT7 (excitatory) receptors decreases glutamate release in PFC Need a 5-HT7 antagonist - via activation of GABA to help improve - thus, activation decreases PFC excitability hypofrontality ( = hypofrontality) 15  Biochemistry of Schizophrenia: Acetylcholine nACh (nicotinic acetylcholine receptors) - α7 nACh receptors found in areas involved with cognition (e.g., prefrontal cortex and hippocampus) - reduced in schizophrenic patients - α7 agonists improve focus and memory - a very high proportion (~ 75%) of schizophrenic individuals smoke cigarettes - 50% are heavy smokers - self medication (claim it helps with negative symptoms) - often have a nicotine dependence - morbidity associated with smoking related health issues 16 17 B “Ya, I know that” Quiz... A drug that works on which mechanism will induce symptoms similar to the positive symptoms of schizophrenia? Answer C: DA reuptake inhibitor Positive symptoms related to mesolimbic dopamine hyperfunction 18  Classical treatments of schizophrenia 19  Treatments for Schizophrenia 1st generation (anti-psychotics or neuroleptics) - Dopamine D2 antagonists (“D2 receptor family”) - post-synaptic D2 receptors (this family can also be presynaptic, but not the focus here) - these are effective vs. positive symptoms - Chlorpromazine and subsequent related “Neuroleptic” drugs - e.g., haloperidol, thorazine - 30% of patients do not respond to D2 receptor antagonists -Tardive dyskinesia and other side effects Hypothesis: Prolonged block of D2 receptors leads to DA receptor supersensitivity in Nigrostriatal pathway 20  Treatments for Schizophrenia 3rd generation (also atypical antipsychotics) - D2 partial agonists - aripiprazole, cariprazine Reduces hyperactivity 1. With high levels of mesolimbic DA, it can act as an antagonist to compete with dopamine for the receptor - not a total block, sometimes DA will win out in the competition, but it diminishes it effects Counters the hypoactivity 2. With low levels of mesocortical DA, it can act as an agonist to partially activate the receptors Dopamine stabilizer Other recent trends - combination drugs - low doses D2 antagonist (decrease DA in mesolimbic) with NMDA agonists (increase activity in PFC) - muscarinic Ach receptor agonists 21  Treatments for Schizophrenia 3rd generation (also atypical antipsychotics) - D2 partial agonists - also may be partial agonists at 5-HT1A, and antagonists at 5-HT2A - aripiprazole, cariprazine Reduces hyperactivity 1. With high levels of mesolimbic DA, it can act as an antagonist to compete with dopamine for the receptor - not a total block, sometimes DA will win out in the competition, but it diminishes it effects Counters the hypoactivity 2. With low levels of mesocortical DA, it can act as an agonist to partially activate the receptors + modulates 5-HT activity Dopamine stabilizer Other recent trends - combination drugs - low doses D2 antagonist (decrease DA in mesolimbic) with NMDA agonists (increase activity in PFC) - muscarinic ACh receptor agonists 22  Take Home… Schizophrenia is a neurological disease that is heterogeneous in its manifestation across patients - symptoms (and degree of) can be individualistic - cause remains unknown First drugs focused on positive symptoms, and the next waves added in side effect control and action on negative symptoms (including cognitive) - dopamine remains at the center of symptom control 23 24  Pharmacokinetics Pharmacokinetics: from Greek - pharmakon (drug) and kinetikos (movement) - how the drug is: - absorbed - biodistributed “ADME” properties - metabolized - excreted HOW THE BODY EFFECTS YOUR DRUG (Pharmacodynamics - how the drug effects your body) 25  Biodistribution First-pass metabolism - metabolism of oral drug before enters systemic circulation - mouth → GI → portal vein → liver - amount leaving liver into circulation varies by drug - enzymatic degradation of drug in liver and GI tract - cytochrome (CYP) P-450 enzymes (>50 enzymes) are the most common drug metabolizers (e.g., Xanax, haloperidol, hydrocodone…) - grapefruit juice can inhibit these enzymes - low levels of drug leaving liver = low bioavailability 26  Biodistribution Factors that affect distribution of drug, including into tissue: - protein binding - many circulating proteins in the blood that can non- selectively bind different drugs (making them inert) (proteins = albumin (major), α1 acid glycoprotein, lipoprotein, globulin) - if bound, drug tends to stay in blood (does not goes to desired tissue/target) - the amount of “free” unbound drug is important to efficacy (the more free the better) - can determine clinical response - varies between people - level of protein binding varies across drugs - bad if a drug is bound too much - many drugs are greater than 99% bound (= 1% free) 27  Biodistribution Some (not all) factors that affect distribution of drug, including into tissue: - lipophilicity - ease at which it can move across lipid membranes (GI tract) - if lipid soluble, can move across membranes with passive diffusion -blood flow in desired tissue - brain has good blood flow - poor circulation can affect drug distribution - molecular size - larger molecules may have more difficulty getting across barriers - movement across barriers - BBB - placental 28  Biodistribution: Blood Brain Barrier Blood-Brain Barrier (BBB) Blood supplies the brain with oxygen, glucose, and amino acids. It carries away CO2 and waste products Blood-Brain Barrier (BBB) - blood–brain barrier protects against circulating toxins or pathogens that may cause brain infections, while permitting entry of vital nutrients - specialized capillary: microvessel lining (endothelium, Brain/spinal cord signaling needs a highly negatively charged) surrounded by astrocytes and controlled/protected microenvironment pericytes (cells that wrap the endothelium) is a major site for blood–CNS exchange of molecules BBB is a physical barrier - larger sized molecules (antibody drugs) cannot pass - specialized transporters to bring across molecules - has enzymes that degrade molecules (e.g., acetylcholinesterase) - repels negatively charged (anions) molecules (though there are that would not normally pass and the brain needs some ion transporters) (glucose) - selective transporters (e.g., glucose) - transporters go in both directions - lipid soluble drugs can pass - ∼100% of large-molecule & more than 98% of all small- molecule drugs cannot cross the BBB 29  Metabolism Metabolized - the “parent” drug is broken down in the body before being excreted - often by liver enzymes, but other processes as well - metabolites can be formed - both inactive and active metabolites - active metabolites can have an action of their own - active metabolites can have similar (contribute to therapeutic effect) or different (side effect) effects than the parent drug 30  Excretion Excretion (or drug “clearance”) - elimination of “parent” drug and it’s metabolites from the body - another factor that determines how frequently you have take a drug (elimination rate of the drug) - the faster elimination rate, the more you need to take the drug - most common route is via kidney/urine - also feces, sweat, saliva, breast milk 31  Steady State Steady state: period of time when the blood concentration Curves represent drug levels in blood of a drug remains relatively constant (intake is balanced by drug that remains in body, and elimination) Need to reach steady state before determining “right” efficacious dose for a patient - what is the efficacy at a consistent level of drug Next dose Factors that contribute to steady state: - frequency of dosing - drug’s T1/2 - metabolism/elimination 32  Cariprazine (Vraylar) Cariprazine, partial agonist of D2, D3, and antagonist of 5-HT2A, 5-HT2B (and more) for treatment of schizophrenia and bipolar disorders - high oral bioavailability - crosses the blood brain barrier - T1/2 of 2-4 days - Active metabolite with T1/2 of 1-3 weeks What are the implications of this PK profile? - high drug levels get into blood circulation and into the brain (to get to target) - take the drug less frequent (long T1/2) - may take awhile to find the right dose - can take longer to reach steady state with long T1/2 - need to measure both parent and metabolite to determine appropriate dosing (metabolite is active) - upon stopping drug may have residual left in blood for weeks - may be an advantage with schizophrenia patients who can miss doses (less of an impact) 33 “Ya, I know that” Quiz... 34 C “Ya, I know that” Quiz... Which is an incorrect association? Answer D: first pass metabolism: protein binding - Enzymatic breakdown in liver (Protein binding in blood) 35  Take home… Potency is not enough to make a drug work, its pharmacokinetic profile is integral to a drug’s efficacy and degree of side effects 36 Brain Awareness Week Lectures Robert B. Glassman Memorial Brain, Mind, and Behavior Symposium  To do… Read text LO 4.5 (placebo section) and LO 17.7-17.12 (Affective Disorders) Treat a Neurological Disease Monique + Janitza: TBD Ryan + Anna: TBD 39 40