The Science of Schizophrenia

The Science of Schizophrenia
Dr. Stephen M. Stahl LAT November 2016 LAT

Learning Objectives To learn about neuroregulation of schizophrenia symptomatology To understand current hypotheses of schizophrenia and how they influence treatment To become familiar with the focus of current research on treatment and management of schizophrenia LAT

Outline 1. The neuroanatomy and neurotransmitter pathways of schizophrenia 2. Neuromodulation underlying the pathology and treatment of schizophrenia 3. Frontiers in schizophrenia research LAT

Facts and Figures of Schizophrenia
5 per 1000 adults aged 16 to 741 33% had been homeless 13% had been roofless4 Cost of mental illness to the UK economy: £70 to £100 billion per year2 Account for 2% of the prison population, 4x that of the general population5 This slide gives an overview of UK specific data on the prevalence and functional outcomes of individuals with schizophrenia. Rate of employment for people with schizophrenia: 10 – 20%3 Mortality rate 2.5 times greater than the general population6 1Singleton et al. Psychiatric Morbidity Among Adults Living in Private Households. London, UK: Office of National Statistics; 2001. 2Davies, S.C. Annual Report of the Chief Medical Officer 2013, Public Mental Health Priorities: Investing in the Evidence. London: Department of Health September Accessed April 2015. 3Marwaha and Johnson. Soc Psychiatry Psychiatr Epidemiol. 2004;39(5): 4Bebbington et al. Soc Psychiatry Psychiatr Epidemiol. 2005;40(9): 5Singleton et al. Psychiatric Morbidity Among Prisoners: Summary Report. London, UK: Office of National Statistics; 1998. 6Saha et al. Arch Gen Psychiatry. 2007:64(10): LAT

Symptom Domains, Clinical Features and Neuroanatomy of Schizophrenia
Positive Symptoms Hallucinations Delusions Disorganised speech & behaviour Mesocortical circuits Affective Symptoms Depressed mood Anxious mood Guilt Tension Irritability Worry Negative Symptoms Blunted affect Emotional withdrawal Poor rapport Passivity Mesolimbic circuits Frontal cortical circuits Aggressive Symptoms Nucleus accumbens Verbal or physical abuse Self-injurious behaviour Destructive behaviour (arson, property damage) Cognitive Symptoms Difficulties with: Attention Problem solving Working memory Speed of processing This slide reviews the different symptom domains of schizophrenia and the different areas of the brain that are thought to regulate each domain. Amygdala Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

Neurotransmitter Systems Involved in the Pathology and Treatment of Schizophrenia
Dopamine D1 D2 D3 D4 D5 Glutamate NMDA receptor AMPA kainate metabotropic Serotonin 5-HT1A 5-HT2A 5-HT2C 5-HT3 5-HT7 5-HT6 GABA -aminobutyric acid GABAA receptor GABAB GABAC This slide introduces the key neurotransmitter systems involved in both the pathology and treatment of schizophrenia. Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

Dopamine Pathways in the Brain
nigrostriatal Striatum mesolimbic PFC NA T mesocortical HY SN This slide introduces the dopamine pathways in the brain. There are 5 major pathways that are presented here: nigrostriatal, which signals from the substantia nigra to the striatum and is part of the extrapyramidal nervous system controlling motor function and movement; mesolimbic, which signals from the ventral tegmental area to the nucleus accumbens and is part of the reward or pleasure systems and is responsible for the euphoric effects of drugs of abuse; mesocortical, which signals from the ventral tegmental area to the prefrontal cortex and has a role in mediating cognition and affect; tuberoinfundibular, which signals from the hypothalamus to the anterior pituitary and controls prolactin secretion; and thalamic, which signals from a variety of areas to the thalamus. tuberoinfundibular P VTA thalamic Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

The Dopamine Hypothesis of Schizophrenia
Stimulant drugs such as amphetamine or cocaine release dopamine Repeated administration can cause a paranoid psychosis that is indistinguishable from the positive symptoms of schizophrenia1 Striatum PFC NA T All known antipsychotic drugs capable of treating positive symptoms antagonise the dopamine D2 receptor1,2 Chlorpromazine and haloperidol first prescribed in the 1950s and 60s SN HY This slide describes the dopamine hypothesis of schizophrenia , highlighting the data that underlies this hypothesis. P VTA 1Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press 2Bennett MR. J Psychopharmacol. 1998;12(3): LAT

The Dopamine Hypothesis of Schizophrenia
positive symptoms Hyperactivation of both the mesolimbic and nigrostriatal pathway is thought to underlie the positive symptoms of schizophrenia Striatum PFC NA negative symptoms Hypoactivation of the mesocortical pathway is thought to underlie both the negative and cognitive symptoms of schizophrenia SN This slide describes the dopamine hypothesis of schizophrenia, highlighting the different pathways thought to underlie the positive, negative and cognitive symptoms of schizophrenia. cognitive symptoms VTA 1Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press 2Kegeles et al. Arch Gen Psychiatry. 2010;67(3): LAT

Glutamate Pathways in the Brain
cortico-brainstem cortico-striatal Striatum ventral hippocampus to nucleus accumbens PFC NA T thalamo-cortical This slide introduces the glutamate pathways in the brain. The cortico-brainstem, the cortico-striatal, the thalamo-cortical, the cortico-thalamic, and the cortico-cortical pathway. There is a glutamatergic projection from the ventral hippocampus to the nucleus accumbens, as well. In addition, glutamatergic pyramidal neurons can also communicate via GABAergic interneurons, shown here in the cortex. NT cortico-thalamic cortico-cortical Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

The Glutamate Hypothesis of Schizophrenia
Treatment with glutamate receptor (NMDA) antagonists ketamine or phenylcyclidine (PCP) causes symptoms of schizophrenia in healthy volunteers NMDAR antagonists worsen symptoms in schizophrenia patients Striatum PFC NA T Genetic abnormalities of glutamate signalling have been found in patients with schizophrenia Hypofunctional glutamate receptors seen in individuals with schizophrenia This slide describes the glutamate hypothesis of schizophrenia, highlighting the data that underlie this hypothesis. NT Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

positive symptoms Hypoactivation of NMDA receptors on cortical interneurons can lead to hyperactivation of the mesolimbic dopamine pathway Striatum PFC NA This slide describes the glutamate hypothesis of schizophrenia, highlighting the different pathways thought to underlie the positive, negative and cognitive symptoms of schizophrenia. VTA Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

positive symptoms Hypoactivation of NMDA receptors in the ventral hippocampus can lead to hyperactivation of the mesolimbic dopamine pathway Striatum NA GP This slide describes the glutamate hypothesis of schizophrenia, highlighting the different pathways thought to underlie the positive, negative and cognitive symptoms of schizophrenia. VTA Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

Hypoactivation of NMDA receptors on cortical interneurons can lead to hypoactivation of the mesocortical dopamine pathway PFC negative symptoms This slide describes the glutamate hypothesis of schizophrenia , highlighting the different pathways thought to underlie the positive, negative and cognitive symptoms of schizophrenia. cognitive symptoms VTA Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

Summary 1: The neuroanatomy and neurotransmitter pathways of schizophrenia
Positive symptoms of schizophrenia result from the hyperactivation of both the mesolimbic and nigrostriatal dopamine pathways Negative and cognitive symptoms result from the hypoactivation of the mesocortical dopamine pathway Glutamatergic dysregulation of dopamine pathways may underlie the symptoms of schizophrenia LAT

Pyramidal cell + Neuromodulator
Excitatory Cells and Inhibitory Interneurons are Key Mediators of Information Processing Excitatory Glutamatergic Pyramidal Cell Interneurons mediate signals between… Pyramidal cells Pyramidal cell + Neuromodulator Neuromodulators Inhibitory GABAergic Interneurons Chandelier Cells Basket Cells Both pyramidal cells and interneurons express many different neurotransmitter receptors: This slide introduces two major cell types that play a key role in the regulation of information processing. Dopaminergic Noradrenergic Serotonergic Cholinergic Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

Cortical 5-HT2A Receptors Decrease Dopamine Release
Prefrontal Cortex 5-HT2A Striatum PFC NA This slide describes how the action of cortical 5-HT2A receptors in the brain decreases dopamine release in the striatum. NT Brainstem Neurotransmitter Centre Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

Cortical 5-HT1A Receptors Increase Dopamine Release
Prefrontal Cortex Striatum PFC NA 5-HT1A This slide describes how the action of cortical 5-HT1A receptors in the brain increases dopamine release in the striatum. NT Brainstem Neurotransmitter Centre Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

Stimulation of 5-HT7 Receptors in the PFC Reduces Glutamate Release
Prefrontal Cortex 5-HT7 PFC This slide describes how the action of cortical 5-HT7 receptors in the brain decreases glutamate release. NT Brainstem Neurotransmitter Centre Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

Differential Effects of 5-HT Receptors in the Brain
Activation Inhibition 5-HT2A Decreases Dopamine Increases Dopamine 5-HT1A Increases Dopamine Decreases Dopamine This slide summarises the activation and inhibition effects of different serotonergic receptors on either dopamine or glutamate release in the brain. Decreases Glutamate Increases Glutamate 5-HT7 Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

Current Mechanism of Action of Antipsychotics Drugs
Almost all currently approved drugs for the treatment of schizophrenia target only the positive symptoms Amisulpride is currently the only approved drug indicated for the treatment of patients with predominantly negative symptoms (and only in Europe) There are no approved agents that treat cognitive symptoms of schizophrenia Pharmacology Adverse Side Effects Conventional Antipsychotics Dopamine D2 Receptor Antagonists Extrapyramidal symptoms Hyperprolactinemia This slide describes the mechanism of action of currently approved antipsychotics for the treatment of schizophrenia. Atypical Antipsychotics Dopamine D2 Receptor Antagonists Serotonin 5-HT2A Receptor Antagonists Metabolic side effects (weight gain, glucose dysregulation, dyslipidemia) 1Farah A. Prim Care Companion J Clin Psychiatry. 2005:7(6): 2MHRA Public Assessment Report for Amisulpride LAT

Development of Novel Medications for the Treatment of Schizophrenia
Most of the current drug development research in schizophrenia is focused on agents that can improve negative and/or cognitive symptoms Glutamate-based targets mGlu2/3 agonists NMDAR agonists GLTY1 inhibitors Investigated as adjunctive therapies Pomaglumetad methionil for the treatment of negative symptoms Glycine, D-serine, D-cycloserine Sarcosine as a primary antipsychotic agent Glycine and D-serine show promising results as adjunctive therapy Investigation terminated due to lack of efficacy in clinical trials Bitopertin for the treatment of negative and positive symptoms This slide describes the neuropsychopharmacological targets of new agents in development for the treatment of schizophrenia. Cholinergic-based targets Nicotinic 7 agonists Encenicline for the treatment of cognitive symptoms Promising phase 2 results Citrome L J Clin Psychiatry. 75 (Suppl 1):21-26. LAT

Acetylcholine Receptors are Widely Expressed in the Brain and are Important for Cognition
In both animal models and patients with schizophrenia, treatment with 7 agonists resulted in improvements in working memory and attention2 Deficits in sensory gating, a biomarker for cognitive function, are linked to variants in the 7 receptor gene locus3,4 PFC BF T HY This slide describes the cholinergic pathways in the brain and their role in cognition. A H Postmortem studies of patients with schizophrenia show a decreased expression of 7 receptors in the frontal cortex5 NT Cholinergic neurons project from both the brainstem and the basal forebrain1 1Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press 2Martin LF and Freedman R. Int Rev Neurobiol. 2007;78: 4Leonard et al. Arch Gen Psychiatry, 2002;59: 3Freedman et al. Proc Natl Acad Sci USA. 1997;94(2): 5Guan et al. Neuroreport. 1999;10(8): LAT

Summary 2: Neuromodulation underlying the pathology and treatment of schizophrenia
Interaction between excitatory glutamatergic cells and inhibitory GABAergic interneurons plays a key role in the symptomatology of schizophrenia Serotonergic regulation of dopamine is vital to the efficacy of atypical antipsychotics Current drug development efforts are focused on the negative and cognitive symptoms of schizophrenia LAT

Genetics of Schizophrenia
What Has the Research Told Us About the Nature of the Disease? RGS4 DISC1 DTNBP1 STX7 TAAR6 PPP3CC NGR1 DRD2 HTR2A DAOA AKT1 CHRNA7 COMT ARVCF The genetics of schizophrenia is more complicated than once thought and highlights the complexity of the overall disease state Linkage analysis Positional cloning Candidate gene analysis1,2 1960s & 1970s 1980s – 2000s 2014 SZ Gene Database 3 (Schizophrenia Gene) 1727 Studies 1008 Genes 8788 Polymorphisms 287 Meta-analyses Family, twin, and adoption studies showed there was a clear genetic component to the disease1 Schizophrenia Working Group of the Psychiatric Genomics Consortium Multi-stage GWAS4: 36,989 cases/113,075 controls 128 independent associations over 108 different loci This slide summarises the findings of genetic research in schizophrenia over the past 50+ years. 1Kim et al. Schizophr Bull. 2011;37(3): 2Sanders et al. Am J Psychiatry. 2008;165: 3Allen et al. Nat Genet. 2008;40(7): ; 4Schizophrenia Working Group of the Psychiatric Genomics Consortium. Nature. 2014;511(7510):421-7 LAT

Pharmacogenetics of Antipsychotic Drug Response
Using genetics to predict efficacy and susceptibility to adverse drug reactions Individual treatment response to antipsychotic drugs is highly variable Many patients do not achieve a sufficient therapeutic response Many patients experience a high degree of adverse drug reactions that often results in treatment discontinuation Efficacy Genes Pharmacokinetic Genes Adverse Drug Reaction Genes The cytochrome P450 gene CYP2D6 is a major metaboliser of several antipsychotic drugs Functional polymorphisms in the DRD2 promoter shown to significantly influence antipsychotic drug efficacy Candidate genes for antipsychotic-induced weight gain include DRD2, HTR2C, GNB3, and MC4R Many of the over 100 genetic variants found for CYP2D6 result in reduced enzymatic activity This slide introduces the idea of pharmacogenetics and highlights some of the candidate genes used to assay different responses to antipsychotic drugs. Results have yet to achieve both adequate sensitivity and specificity to reliably guide clinical practice Various HLA markers have consistently been shown to be associated with clozapine-induced agranulocytosis (CIA) Diagnostic tests for CYP2D6 variants are commercially available 1Malhotra et al. Mol Psychiatry. 2012;17: DRD2: Dopamine D2 receptor 2Zhang JP and Malhotra AK. Expert Opin Drug Metab Toxicol. 2013:9(2): HTR2C: 5-HT2C receptor; GNB3: Guanine nucleotide binding protein, beta polypeptide 3; MC4R: Melanocortin 4 receptor HLA: Human leukocyte antigen LAT

Pathophysiology of Schizophrenia: Knowledge Gained from Imaging Studies
Parietal Lobe Frontal Lobe Reduced volume Reduced superior parietal gyrus, inferior parietal lobe and supramarginal gyrus Reduced activation during cognitive challenge Reduced grey and white matter volume Reduced DLPFC, OFC, and dorsomedial regions Lower density of dendritic spines of postsynaptic neurons Hypofrontality and hyperfrontality in the DLPFC Reduced activity in VLPFC, RVPMC, and RDACC during cognitive challenge Occipital Lobe Reduced grey matter in visual association area (VAA) Reduced grey matter volume Reduced hippocampus, parahippocampal gyrus, superior temporal gyrus Reduced density of dendritic spines Reduced/abnormal activation of left middle temporal gyrus, bilateral amygdala, parahippocampus, and fusiform gyrus during emotion perception This slide summaries the findings from neuroimaging studies (CT, MRI, MRS, PET, SPECT, fMRI, and DTI) over the past couple of decades of both structural and functional abnormalities seen in patients with schizophrenia. Temporal Lobe Both structural and functional abnormalities are seen throughout the brain in patients with schizophrenia 1Ahmed et al. Curr Psychiatry Rep. 2013;15(3):345. 2Onitsuka et al Schizophr Res. 2007;92: LAT

Current Overarching Mechanism-of-Disease Hypothesis
Environmental Factors1 Prenatal infection/ immune activation Paternal age Malnutrition Hypoxia-related obstetric complications Childhood/adolescence social stress Cannabis abuse Neurochemical Abnormalities3 Dopamine imbalance Glutamate receptor hypofunction Reduced GABA expression Neurodevelopmental Deficiencies2 This slide summarises the current overarching mechanism of disease hypothesis of schizophrenia. Schizophrenia is a complex disorder that results from a combination of environmental factors, genetic factors, neurodevelopmental deficiencies, and neurochemical abnormalities. Reduced grey matter Reduced white matter Deficient myelination Reduced interneuron activity Excessive excitatory pruning Genetic Factors1 Degree of heritability Associated genetic variants 1Jiang et al. Front Behav Neurosci. 2013;7:116. 2Insel TR. Nature. 2010;468: 3Stahl SM. Stahl’s Essential Psychopharmacology, Cambridge, Cambridge University Press LAT

Future Research Directions for the Treatment and Management of Schizophrenia
Cognitive impairment is seen in nearly every patient with schizophrenia Cognitive Impairment in Schizophrenia1 Deficits are significant and broad in nature Deficits appear early in the course of the disease and continue throughout the lifetime of the disease An individual’s level of cognitive function is strongly related to their functional outcome Symptoms present in adolescence and early adulthood Early Detection and Treatment Intervention2 This slide discusses the two major future research directions for the treatment and management of schizophrenia: cognitive impairment and early intervention. The disease course is characterised by recurrent exacerbation and remissions in a chronic state of residual symptoms and functional impairment Meager treatment responses and outcomes are associated with a longer duration from the initial episode of the illness prior to treatment intervention 1Tandon et al. Schizophr Res. 2009;110(1-3):1-23. 2Liberman et al. JAMA. 2013;310(7): LAT

Summary 3: Frontiers in schizophrenia research
The genetics of schizophrenia are much more complicated than once thought A complex interplay of genetics, environmental factors, and defects in both neurodevelopment and in neurotransmitter systems is thought to underlie schizophrenia The future direction of treatment focuses on both cognitive impairment and early detection and intervention LAT

Latuda® ▼(lurasidone) Prescribing Information
Please refer to the full Summary of Product Characteristics (SPC) before prescribing, particularly in relation to adverse reactions, precautions and contraindications. Presentations: Latuda film-coated tablets, containing lurasidone hydrochloride equivalent to 18.6mg, 37.2mg and 74.5mg lurasidone. Indication: Latuda is indicated for the treatment of schizophrenia in adults (≥18 years). Dosage and Administration: For oral administration: Adults: Recommended starting dose: 37mg once daily with a meal. No initial dose titration is required. Effective dose range: 37 to 148mg once daily. Dose increase should be based on physician judgement and observed clinical response. Maximum dose: 148mg per day. Elderly (≥65 years): Caution when treating with higher doses. Children and adolescents (<18 years): Not recommended, safety and efficacy not established. Dose adjustments are required in moderate and severe hepatic and renal impairment, see SPC for further details. Contraindications: Hypersensitivity to the active substance or any excipients. Concomitant administration of strong CYP3A4 inhibitors and inducers. Warnings and Precautions: Clinical improvement may take a few days to some weeks; closely monitor patient during this period. Use with caution in elderly patients with dementia who have risk factors for stroke. Not studied in elderly patients with dementia. Discontinue if patient develops signs or symptoms of neuroleptic malignant syndrome. Consider discontinuation if signs of tardive dyskinesia appear. May exacerbate underlying parkinsonism symptoms. Risk of extrapyramidal symptoms. Caution and clinical monitoring is recommended in patients with a history of seizures or conditions which potentially reduce seizure threshold, cardiovascular disorders, orthostatic hypotension, diabetes or risk factors for diabetes and weight gain. May elevate prolactin levels. All risk factors for venous thromboembolism (VTE) should be identified before and during treatment and preventative measures taken. Caution in patients with a family history of QT prolongation, hypokalaemia and concomitant medication known to prolong the QT interval. Closely supervise high risk patients for risk of suicide. Avoid grapefruit juice. Pregnancy and lactation: Do not use during pregnancy unless potential benefit clearly outweighs potential risk to the foetus. Breast feeding should be considered only if the potential benefit of treatment justifies the potential risk to the child. LAT

Latuda® (lurasidone) Prescribing Information
Interactions: Caution is advised when combining with alcohol or CNS active medications, and medicines known to cause QT prolongation; P-gp and BCRP inhibitors may increase exposure to lurasidone, lurasidone is an inhibitor of P-gp and BCRP, see SPC for details. Dose adjustment is recommended in combination with CYP3A4 inhibitors and inducers, see SPC for details. Monitoring recommended when lurasidone and CYP3A4 substrates known to have a narrow therapeutic index are coadministered. Undesirable effects: In clinical trials, the following adverse drug reactions were reported: very common (≥10%): akathisia, somnolence; common (≥1% to <10%): weight increased, insomnia, agitation, anxiety, restlessness, parkinsonism, dizziness, dystonia, dyskinesia, nausea, vomiting, dyspepsia, salivary hypersecretion, dry mouth, upper abdominal pain, stomach discomfort, musculoskeletal stiffness, blood creatinine phosphokinase increase, serum creatinine increase, fatigue; uncommon (≥0.1% to <1%): decreased appetite, blood glucose increased, catatonia, tardive dyskinesia, tachycardia, hypertension, hypotension, alanine aminotransferase increase, blood prolactin increased; rare(≥0.01% to <0.1%): eosinophilia, rhabdomyolysis, neuroleptic malignant syndrome (NMS). This is not a complete list of adverse reactions. Prescribers should consult the SPC in relation to all adverse reactions. Special precautions for storage: Store in the original package in order to protect from light. Special precautions for disposal and other handling: Any unused medicinal product or waste material should be disposed of in accordance with local requirements. Legal classification: Prescription Only Medicine (POM). Package Quantities and Basic NHS Costs: Latuda 18.5mg, 37mg and 74mg £90.72 per pack of 28 tablets. Marketing Authorisation Holder: Sunovion Pharmaceuticals Europe Ltd, Southside, 97 – 105 Victoria Street, London, SW1E 6QT. Latuda is a registered trade mark. Marketing Authorisation Number(s): EU/1/14/913/ Date of Preparation: February 2016 (MI-LAT ). This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions Adverse reactions should be reported. Reporting forms and information can be found at Adverse events should also be reported to Sunovion Pharmaceuticals Europe Ltd. on LAT

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