Neurobiology and aetiology

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Neurobiology and aetiology

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Neurobiology and aetiology

Index
  1. Neurobiology and aetiology
  2. Introduction to neuroanatomy
  3. Organisation of the nervous system
  4. Neurones
  5. Anatomical regions of the brain
  6. Cerebrum
  7. Lobes of the brain
  8. Neurosynaptic transmission
  9. Neurotransmission
  10. The synapse
  11. Process of chemical neurotransmission
  12. Neurotransmitters
  13. Neurotransmitters and receptors
  14. Dopamine
  15. Serotonin
  16. The dopamine D1, D2, and serotonin 5-HT2A and 5-HT6 receptors are distributed across a variety of locations in the brain
  17. The dopamine D1, D2, and serotonin 5-HT2A and 5-HT6 receptors are distributed across a variety of locations in the brain
  18. The dopamine D1, D2, and serotonin 5-HT2A and 5-HT6 receptors are distributed across a variety of locations in the brain
  19. The dopamine D1, D2, and serotonin 5-HT2A and 5-HT6 receptors are distributed across a variety of locations in the brain
  20. Glutamate
  21. GABA – gamma-aminobutyric acid
  22. Noradrenaline
  23. The pathophysiology of schizophrenia
  24. The positive symptoms of schizophrenia
  25. The negative and cognitive symptoms of schizophrenia
  26. Major dopamine pathways and the symptoms of schizophrenia
  27. The conundrum of treating schizophrenia – i
  28. The conundrum of treating schizophrenia – ii
  29. The conundrum of treating schizophrenia – iii
  30. The conundrum of treating schizophrenia – iv
  31. Antipsychotic drugs and the dopamine pathways of the brain
  32. The role of glutamate in the pathology of schizophrenia
  33. The pathophysiology of treatment-resistant schizophrenia
  34. Hypotheses for the underlying causes of schizophrenia
  35. The neurodevelopmental model of schizophrenia
  36. Socio–developmental–cognitive models of schizophrenia
  37. Neurotransmitters and schizophrenia
  38. Inflammation and schizophrenia
  39. The microbiome and schizophrenia
  40. Environmental factors
  41. The environment and schizophrenia
  42. Environmental factors and schizophrenia
  43. Cannabis as a risk factor for developing psychosis
  44. Genetic factors
  45. The heritability of schizophrenia – twin and adoption studies
  46. The genetics of schizophrenia
  47. Results from a large-scale twin study
  48. The future of genetic research in schizophrenia
  49. Quote
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Neurobiology and aetiology
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Introduction to neuroanatomy
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Organisation of the nervous system
Slide information
References

To understand psychiatric disorders, it is important to have a working understanding of the normal structure and function of the nervous system. The central nervous system (CNS; brain, spinal cord) and peripheral nervous system (PNS) are made up of neurones and glial cells (sometimes called neuroglia) as explained on the slide.[Tortora & Derrickson, 2009; Martin, 2003]

Martin JH. Neuroanatomy Text and Atlas. 3rd edition. McGraw-Hill, 2003.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.

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Neurones
Slide information
References

The neurone constitutes the functional unit of the nervous system; there are over 100 billion neurones in the brain.[Purves et al., 2008; Martin, 2003; Kandel et al., 2000] Each neurone has the ability to interact with and influence many other cells, which creates a system of intricate complexity.[Purves et al., 2008] There are several different classes of neurones – a simplified neurone is shown on the slide, along with explanations of its various component parts.[Martin, 2003]

Although there are different types of nerve cells, the complexities of human behaviour stem not from the specialism of different types of neurones, but rather from the association of a great many neurones into coherent, and precise, anatomical circuits.[Kandel et al., 2000] In this way, nerve cells with similar properties can effect a variety of different functions, depending on how they are interconnected.[Kandel et al., 2000]

Neurotransmitters – chemicals in the nervous system that transmit nerve impulses between neurones.Action potential – in neurophysiology, an electrical charge that moves through an axon.
 

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.

Martin JH. Neuroanatomy Text and Atlas. 3rd edition. McGraw-Hill, 2003.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008.

Oxford Concise Medical Dictionary. 2nd edition. © Oxford University Press, 1998.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.

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Anatomical regions of the brain
Slide information
References

The brain is divided into four anatomical regions: the diencephalon, brainstem, cerebrum, and cerebellum, as described on the slide.[Kandel et al., 2000; Tortora & Derrickson, 2009]

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.

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Cerebrum
Slide information
References

The cerebral cortex is the main functional unit of the cerebrum.[Tortora & Derrickson, 2009] The three main functional areas of the cerebral cortex are:[Tortora & Derrickson, 2009; Prise & Wilson, 2003]

  • motor areas that control voluntary movement (primary, secondary, and association motor areas)
  • sensory areas that allow for visual, auditory, gustatory, olfactory, and sensory perception (primary, secondary, and association sensory areas)
  • areas associated with higher mental functions.

The surface of the brain is highly convoluted, with folds and grooves.[Martin, 2003] These convolutions are an evolutionary adaptation that allows a greater surface area to fit within the confined, and limited, space of the skull.[Martin, 2003] The elevated convolutions are called ‘gyri’, and the grooves are called ‘sulci’, as shown on the slide.[Martin, 2003]

Gustatory – relating to the sense of taste.
Olfactory – relating to the sense of smell.
Nuclei – in neuroanatomy, localised masses of grey matter in the CNS.

Martin JH. Neuroanatomy Text and Atlas. 3rd edition. McGraw-Hill, 2003. 

Price SA, Wilson LM. Pathophysiology: Clinical Concepts of Disease Processes. 6th edition. Mosby, 2003. 

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.

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Lobes of the brain
Slide information
References

The brain can be thought of as comprising five ‘lobes’ – the four lobes of the cerebral cortex and a fifth lobe, the insula, deep within the brain, as shown on the slide.[Martin, 2003; Tortora & Derrickson, 2009; Price & Wilson, 2003] The lobes of the cerebral cortex are named after the cranial bones that overlie them (frontal, parietal, occipital, and temporal).[Martin, 2003]
The lobes have distinct functions. The frontal lobe has a diverse range of behavioural functions, including movement, speech, cognition, and emotion.[Martin, 2003] The parietal lobe mediates perceptions of touch, pain, and proprioception.[Martin, 2003] The occipital lobe can be thought of as the visual processing centre, containing the primary visual cortex.[Martin, 2003] Finally, the temporal lobe controls a range of sensory functions, and is important in memory and emotion.[Martin, 2003]

Martin JH. Neuroanatomy Text and Atlas. 3rd edition. McGraw-Hill, 2003.

Price SA, Wilson LM. Pathophysiology: Clinical Concepts of Disease Processes. 6th edition. Mosby, 2003.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.

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Neurosynaptic transmission
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Neurotransmission
Slide information
References

Information moves through the nervous system via two integrated forms of communication – electrical neurotransmission and chemical neurotransmission, as shown on the slide.[Kandel et al., 2000]
An action potential is generated at the origin of the axon following sufficient excitatory stimulation of the neurone. The action potential is created by movement of electrically charged particles (ions) in and out of the neurone through pores (ion channels) in the cell membrane in a particular pattern, travelling along the length of the axon.[Kandel et al., 2000] When the action potential reaches the axon terminal it stimulates the release of chemical neurotransmitters.[Kandel et al., 2000] After the action potential has induced the release of chemical neurotransmitters, the neurotransmitters pass information to the next neurone.[Kandel et al., 2000]
 

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.

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The synapse
Slide information
References

Neurones do not physically touch one another; two neurones are separated by a gap, known as a synaptic cleft.[Kandel et al., 2000] Because neurones do not touch, and an action potential cannot ‘jump’ across a synaptic cleft, the signal must be converted to a chemical signal to enable communication between neurones to occur.[Kandel et al., 2000] The presynaptic neurone uses chemical signals (neurotransmitters) to increase (excite) or decrease (inhibit) the generation of action potentials in the postsynaptic neurone. It is also possible to effect other biochemical processes, such as cell signalling pathways, in the postsynaptic neurone. This complex interconnectivity gives rise to the rich functional communication network that is the central nervous system.[Kandel et al., 2000]

Presynaptic neurone – a neurone from which an electrical impulse is transmitted across a synaptic cleft to a postsynaptic neurone by the release of a chemical neurotransmitter.
Postsynaptic neurone – a neurone to which an electrical impulse is transmitted across a synaptic cleft by the release of a chemical neurotransmitter from the axon terminal of a presynaptic neurone.

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.

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Process of chemical neurotransmission
Slide information
References

The idea that neurotransmission occurs at synapses and is mediated by chemicals was, at first, a contentious issue.[Purves et al., 2008] It was in the first half of the 1900s that experiments proved chemical neurotransmission occurred.[Purves et al., 2008]
The process is outlined in brief on the slide.[Purves et al., 2008; Kandel et al., 2000; Tortora & Derrickson, 2009; Sadock et al., 2009] Briefly, an action potential arrives at the terminal end of the presynaptic neurone, which means that the membrane potential at the terminal is altered.[Purves et al., 2008] This altered potential causes voltage-gated ion channels to open, leading to a rapid influx of calcium (detail not shown on slide).[Purves et al., 2008] The increased calcium within the neurone terminal (which is just a transient effect) causes vesicles to fuse with the membrane, and release their contents into the synaptic cleft.[Purves et al., 2008] Among the released contents are neurotransmitters, which bind to specific receptors on the postsynaptic neurone.[Purves et al., 2008] The effect of this binding varies, but usually leads to altered conductance of the postsynaptic neurone, and the propagation of the action potential.[Purves et al., 2008]

Vesicle – a membrane-enclosed sac that stores or transports substances.
Receptor – a protein molecule on a cell membrane that binds to a specific chemical, such as a neurotransmitter or drug, and produces a specific physiological effect.
Reuptake – a mechanism by which a neurotransmitter is taken back into the axon terminal that released it; the most common mechanism for removal and inactivation of neurotransmitters.
Astrocyte – a class of glial cells; functions include maintenance of extracellular ionic environment, and structural and metabolic support of neurones.
Diffusion – in regard to neurotransmission, a mechanism by which neurotransmitters drift out of the synaptic cleft.

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008.

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Tortora GJ, Derrickson B. Principles of Anatomy and Physiology. 12th edition. John Wiley & Sons, 2009.

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Neurotransmitters
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Neurotransmitters and receptors
Slide information
References

There are many different neurotransmitters in the CNS, each binding to a specific receptor type which has a distinct distribution and role within the CNS.[Purves, Augustine & Fitzpatrick et al., 2008; Kandel, Schwartz & Jessell, 2000; Stahl, 2013] Some common neurotransmitters are listed in the table on this slide. Defects in many neurotransmitter pathways have been implicated in psychiatric disorders.

The variety of neurotransmitters that operate within the CNS adds to the functional complexity of the brain.[Purves, Augustine, Fitzpatrick et al., 2008] Different neurotransmitters can produce different responses on the same neurone; e.g., a neurone might be excited by serotonin but inhibited by the binding of GABA.[Purves, Augustine, Fitzpatrick et al., 2008]

Exactly what constitutes a neurotransmitter has been the subject of some disagreement but, generally, a neurotransmitter must:[Purves, Augustine, Fitzpatrick et al., 2008]

  • be present within the presynaptic neurone
  • be released in response to presynaptic depolarisation, and the release must be calcium-dependent
  • have specific receptors on the postsynaptic neurone.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th Edition. Sinauer Associates, 2008.

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th Edition. McGraw-Hill, 2000.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th Edition. © Cambridge University Press, 2013.

Grieg NH, Reale M, Tata AM. New advances in pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors. Recent Pat CNS Drug Discov 2013; 8 (2): 123–141.

Sadek B, Stark H. Cherry-picked ligands at histamine receptor subtypes. Neuropharmacology 2016; 106: 56–73.

Wierońska JM, Zorn SH, Doller D, Pilc A. Metabotropic glutamate receptors as targets for new antipsychotic drugs: Historical perspective and critical comparative assessment. Pharmacol Ther 2016; 157: 10–27.

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Dopamine
Slide information
References

Dopamine is believed to be involved in motivation, reward, and reinforcement.[Purves et al., 2008] Dopamine also plays an essential role in the control and coordination of movement.[Purves et al., 2008]
Dopamine receptors all influence the activity of the second messenger, cyclic AMP, which is involved in many biochemical processes within a neurone.[Kandel et al., 2000] Dopamine receptor subtypes D1 and D5 increase the levels of cyclic AMP, whereas D2, D3, and D4 subtypes decrease the levels of cyclic AMP.[Kandel et al., 2000] Thus, depending on which receptor subtype the neurotransmitter binds with on the postsynaptic neurone, dopamine can increase or decrease cellular activity.[Kandel et al., 2000]
Dopamine, and its actions within the CNS, is critical to the underlying disease state of many conditions, including Parkinson’s disease, which is characterised by a dearth of dopamine, and schizophrenia, which appears to be caused by an overactivity of dopamine within certain brain regions.[Stahl, 2013] Furthermore, many addictive substances work by altering the effect of dopamine within the brain.[Purves et al., 2008] For instance, the drug cocaine appears to act by inhibiting the reuptake of dopamine, which leads to an increased concentration of dopamine in the synapse, prolonging its action.[Purves et al., 2008]

Delusion – a disturbance in thought leading to false beliefs.Hallucination – a false sensory perception, such as hearing voices or seeing things that are not there.Prolactin – a hormone, produced and released into the bloodstream by the pituitary gland, that is involved in the secretion of milk and breast growth; unusually high amounts are responsible for impotence and loss of libido in both men and women.
 

Kandel ER, Schwartz JH, Jessell TM (eds). Principles of Neural Science. 4th edition. McGraw-Hill, 2000.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008. 

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.

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Serotonin
Slide information
References

Serotonin (also known as 5-HT) is a neurotransmitter that is found throughout the body.[Brunton et al., 2006; Stahl, 2013; Purves et al., 2008] The wide dispersal of serotonergic neurones throughout the brain enables serotonin to be involved in modulating diverse body functions. Body functions modulated by serotonin include:[Brunton et al., 2006]

  • mood
  • sleep
  • cognition
  • sensory perception
  • pain perception
  • movement
  • regulation of internal temperature 
  • appetite 
  • sexual behaviour 
  • hormone secretion.
     

Brunton LL, Lazo JS, Parker KL (eds). Goodman & Gilman’s the Pharmacological Basis of Therapeutics. 11th edition. McGraw-Hill, 2006.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.

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The dopamine D1, D2, and serotonin 5-HT2A and 5-HT6 receptors are distributed across a variety of locations in the brain
Slide information
References

As shown on the slide, dopamine and serotonin receptors are distributed across a variety of locations in the brain.
 

Ayano. Dopamine: receptors, functions, synthesis, pathways, locations and mental disorders: review of literatures. J Ment Disord Treat 2016; 2: 1–4.

Cadet JL, Jayanthi S, McCoy MT, et al. Dopamine D1 receptors, regulation of gene expression in the brain, and neurodegeneration. CNS Neurol Disord Drug Targets 2010; 9 (5): 526-538.

Jaber M, Robinson SW, Missale C, Caron MG. Dopamine receptors and brain function. Neuropharmacology 1996; 35 (11): 1503–1519.

Charnay Y, Léger L. Brain serotonergic circuitries. Dialogues Clin Neurosci 2010; 12 (4): 471–487.

Zhang G, Stackman RW Jr. The role of serotonin 5-HT2A receptors in memory and cognition. Front Pharmacol 2015; 6: 225.

Mansour A, Watson SJ. Dopamine receptor expression in the central nervous system. In: Bloom FE, Kupfer DJ (eds).

Psychopharmacology: The Fourth Generation of Progress. Raven Press. 1995.

Ramírez MJ. 5-HT6 receptors and Alzheimer’s disease. Alzheimers Res Ther 2013; 5 (2): 15.

Upton N, Chuang TT, Hunter AJ, Virley DJ. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease. Neurotherapeutics 2008; 5 (3): 458–469.

López-Giménez JF , Mengod G, Palacios JM, Vilaró MT. Human striosomes are enriched in 5-HT2A receptors: autoradiographical visualization with [3H]MDL100,907,[125I](+/-)DOI and [3H]ketanserin. Eur J Neurosci 1999; 11 (10): 3761–3765.

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The dopamine D1, D2, and serotonin 5-HT2A and 5-HT6 receptors are distributed across a variety of locations in the brain
Slide information
References

As shown on the slide, dopamine and serotonin receptors are distributed across a variety of locations in the brain.

Ayano. Dopamine: receptors, functions, synthesis, pathways, locations and mental disorders: review of literatures. J Ment Disord Treat 2016; 2: 1–4.

Cadet JL, Jayanthi S, McCoy MT, et al. Dopamine D1 receptors, regulation of gene expression in the brain, and neurodegeneration. CNS Neurol Disord Drug Targets 2010; 9 (5): 526-538.

Jaber M, Robinson SW, Missale C, Caron MG. Dopamine receptors and brain function. Neuropharmacology 1996; 35 (11): 1503–1519.

Charnay Y, Léger L. Brain serotonergic circuitries. Dialogues Clin Neurosci 2010; 12 (4): 471–487.

Zhang G, Stackman RW Jr. The role of serotonin 5-HT2A receptors in memory and cognition. Front Pharmacol 2015; 6: 225.

Mansour A, Watson SJ. Dopamine receptor expression in the central nervous system. In: Bloom FE, Kupfer DJ (eds). Psychopharmacology: The Fourth Generation of Progress. Raven Press. 1995.

Ramírez MJ. 5-HT6 receptors and Alzheimer’s disease. Alzheimers Res Ther 2013; 5 (2): 15.

Upton N, Chuang TT, Hunter AJ, Virley DJ. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease. Neurotherapeutics 2008; 5 (3): 458–469.

López-Giménez JF , Mengod G, Palacios JM, Vilaró MT. Human striosomes are enriched in 5-HT2A receptors: autoradiographical visualization with [3H]MDL100,907,[125I](+/-)DOI and [3H]ketanserin. Eur J Neurosci 1999; 11 (10): 3761–3765.

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The dopamine D1, D2, and serotonin 5-HT2A and 5-HT6 receptors are distributed across a variety of locations in the brain
Slide information
References

As shown on the slide, dopamine and serotonin receptors are distributed across a variety of locations in the brain.

Ayano. Dopamine: receptors, functions, synthesis, pathways, locations and mental disorders: review of literatures. J Ment Disord Treat 2016; 2: 1–4.

Cadet JL, Jayanthi S, McCoy MT, et al. Dopamine D1 receptors, regulation of gene expression in the brain, and neurodegeneration. CNS Neurol Disord Drug Targets 2010; 9 (5): 526-538.

Jaber M, Robinson SW, Missale C, Caron MG. Dopamine receptors and brain function. Neuropharmacology 1996; 35 (11): 1503–1519.

Charnay Y, Léger L. Brain serotonergic circuitries. Dialogues Clin Neurosci 2010; 12 (4): 471–487.

Zhang G, Stackman RW Jr. The role of serotonin 5-HT2A receptors in memory and cognition. Front Pharmacol 2015; 6: 225.

Mansour A, Watson SJ. Dopamine receptor expression in the central nervous system. In: Bloom FE, Kupfer DJ (eds). Psychopharmacology: The Fourth Generation of Progress. Raven Press. 1995.

Ramírez MJ. 5-HT6 receptors and Alzheimer’s disease. Alzheimers Res Ther 2013; 5 (2): 15.

Upton N, Chuang TT, Hunter AJ, Virley DJ. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease. Neurotherapeutics 2008; 5 (3): 458–469.

López-Giménez JF , Mengod G, Palacios JM, Vilaró MT. Human striosomes are enriched in 5-HT2A receptors: autoradiographical visualization with [3H]MDL100,907,[125I](+/-)DOI and [3H]ketanserin. Eur J Neurosci 1999; 11 (10): 3761–3765.

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The dopamine D1, D2, and serotonin 5-HT2A and 5-HT6 receptors are distributed across a variety of locations in the brain
Slide information
References

As shown on the slide, dopamine and serotonin receptors are distributed across a variety of locations in the brain.

Ayano. Dopamine: receptors, functions, synthesis, pathways, locations and mental disorders: review of literatures. J Ment Disord Treat 2016; 2: 1–4.

Cadet JL, Jayanthi S, McCoy MT, et al. Dopamine D1 receptors, regulation of gene expression in the brain, and neurodegeneration. CNS Neurol Disord Drug Targets 2010; 9 (5): 526-538.

Jaber M, Robinson SW, Missale C, Caron MG. Dopamine receptors and brain function. Neuropharmacology 1996; 35 (11): 1503–1519.

Charnay Y, Léger L. Brain serotonergic circuitries. Dialogues Clin Neurosci 2010; 12 (4): 471–487.

Zhang G, Stackman RW Jr. The role of serotonin 5-HT2A receptors in memory and cognition. Front Pharmacol 2015; 6: 225.

Mansour A, Watson SJ. Dopamine receptor expression in the central nervous system. In: Bloom FE, Kupfer DJ (eds). Psychopharmacology: The Fourth Generation of Progress. Raven Press. 1995.

Ramírez MJ. 5-HT6 receptors and Alzheimer’s disease. Alzheimers Res Ther 2013; 5 (2): 15.

Upton N, Chuang TT, Hunter AJ, Virley DJ. 5-HT6 receptor antagonists as novel cognitive enhancing agents for Alzheimer’s disease. Neurotherapeutics 2008; 5 (3): 458–469.

López-Giménez JF , Mengod G, Palacios JM, Vilaró MT. Human striosomes are enriched in 5-HT2A receptors: autoradiographical visualization with [3H]MDL100,907,[125I](+/-)DOI and [3H]ketanserin. Eur J Neurosci 1999; 11 (10): 3761–3765.

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Glutamate
Slide information
References

Control of the CNS can be thought of in terms of a balance between ‘go’ (excitatory) and ‘stop’ (inhibitory) signals.[Purves et al., 2008; Stahl, 2013] If the sum of the ‘go’ signals that a neurone receives outweighs the sum of the ‘stop’ signals, then that neurone will exist in an active state, and will continue to signal to the downstream neurone.[Purves et al., 2008; Stahl, 2013] The main excitatory neurotransmitter in the CNS is glutamate; the main inhibitory neurotransmitter is gamma-aminobutyric acid (GABA).[Purves et al., 2008]

Glutamate is arguably the most important neurochemical for normal brain function.[Purves et al., 2008] Nearly all excitatory neurones in the CNS are glutamatergic – more than half of the neurones in the brain.[Purves et al., 2008] It is noteworthy, though, that high concentrations of glutamate are neurotoxic.[Purves et al., 2008] There are three types of receptor to which glutamate can bind (named after the agonists that activate them), each of which has slightly different properties:[Purves et al., 2008]

  • NMDA (N-methyl-d-aspartate)
  • AMPA (α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate)
  • kainate (kainic acid).
     

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008. 

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.

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GABA – gamma-aminobutyric acid
Slide information
References

GABA is the main inhibitory neurotransmitter found in the brain.[Purves et al., 2008] GABA is synthesised predominantly from glutamate, by the enzyme glutamic acid decarboxylase that is found almost exclusively in GABAergic neurones.[Purves et al., 2008] The ionotropic GABA receptors are usually inhibitory, because when activated they allow the flow of negative chlorine ions across the membrane – reducing the potential for neuronal signalling.[Purves et al., 2008]

Chemicals that function as GABA agonists have been used to treat various conditions, and include anticonvulsants, anxiolytics, benzodiazepines, and hypnotics.[Stahl, 2013]
 

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013.

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Noradrenaline
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References

Noradrenaline acts on two classes of adrenergic receptor, α and β.[Purves et al., 2008] Noradrenergic neurones project widely throughout the brain, and there are many brain areas where serotonin, noradrenaline and dopamine projections overlap, allowing interactions.[Stahl, 2013]

Noradrenaline and the locus coeruleus are thought to have important input into the control the CNS exerts over mood, cognition, stress, arousal, pain, and other functions.[Stahl, 2013; Dunn & Swiergiel, 2008] Malfunction of the locus coeruleus is thought to underlie disorders such as depression, anxiety, and disorders of attention and information processing.[Stahl, 2013]

Low or abnormal noradrenaline activity is, theoretically, characterised by impaired attention; concentration, working memory and information processing difficulties; as well as psychomotor retardation, fatigue, and apathy.[Stahl, 2000] In addition, abnormalities in the noradrenergic projection to the hypothalamus, which mediates stress response, are indicated in depressive and anxiety disorders.[Dunn & Swiergiel, 2008]

Dunn AJ, Swiergiel AH. The role of corticotropin-releasing factor and noradrenaline in stress-related responses, and the inter-relationships between the two systems. Eur J Pharmacol 2008; 583 (2–3): 186–193.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th edition. Sinauer Associates, 2008.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 2nd edition. © Cambridge University Press, 2000.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. 4th edition. © Cambridge University Press, 2013. 

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The pathophysiology of schizophrenia
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The positive symptoms of schizophrenia
Slide information
References

The positive symptoms of schizophrenia are thought to be caused by an excess of dopamine within the pathway of the brain that projects from the ventral tegmental area in the brainstem to the nucleus accumbens in the ventral striatum.[Owen et al., 2016; Stahl, 2013] This dopamine pathway of the brain is known as the ‘mesolimbic’ dopamine pathway.[Stahl, 2013] Hence, the ‘dopamine hypothesis’ of schizophrenia can perhaps more accurately be described as ‘the mesolimbic dopamine hypothesis of positive symptoms of schizophrenia’.[Stahl, 2013]

Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet 2016; 388 (10039): 86–97.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. Fourth Edition. © Cambridge University Press, 2013.

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The negative and cognitive symptoms of schizophrenia
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References

Schizophrenia is more than simply positive symptoms; the syndrome includes cognitive and negative symptoms as well.[Owen et al., 2016; Stahl, 2013] The negative symptoms of schizophrenia include dysfunction of:[Stahl, 2013]

  • communication (alogia)
  • affect (affective blunting)
  • socialisation (asociality)
  • capacity for pleasure (anhedonia)
  • motivation (avolition).

It is hypothesised that the cognitive, and some of the negative, symptoms of schizophrenia arise due to a deficit of dopamine activity in mesocortical projections to areas of the dorsolateral prefrontal cortex, whereas affective and other negative symptoms of schizophrenia may be due to a deficit in projections to areas of the ventromedial prefrontal cortex.[Stahl, 2013] One of the conundrums of treating patients with schizophrenia, therefore, has been that to treat both positive and negative symptoms, dopamine levels need to be simultaneously decreased (in the mesolimbic pathway) and increased (in the mesocortical pathway).[Stahl, 2013] Additionally, it is beoming increasingly clear that the symptoms of schizophrenia stem from disruptions in multiple neurotransmitter systems, rather than simply involving dopaminergic signalling.[Aleman et al., 2017; Tripathi et al., 2018]

Aleman A, Lincoln TM, Bruggeman R, et al. Treatment of negative symptoms: where do we stand, and where do we go? Schizophr Res 2017; 186: 55–62.

Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet 2016; 388 (10039): 86–97.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. Fourth Edition. © Cambridge University Press, 2013.

Tripathi A, Kar SK, Shukla R. Cognitive deficits in schizophrenia: understanding the biological correlates and remediation strategies. Clin Psychopharm Neurosci 2018; 16 (1): 7–17.

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Major dopamine pathways and the symptoms of schizophrenia
Slide information
References

Dopamine signalling in the brain is complex, and is key to several emotional, motivational, and cognitive processes.[Laviolette, 2007; Owen et al., 2016; Stahl, 2013] Some of this complexity is simplified on the slide.

Laviolette SR. Dopamine modulation of emotional processing in cortical and subcortical neural circuits: evidence for a final common pathway in schizophrenia? Schizophr Bull 2007; 33 (4): 971–981. 

Owen MJ, Sawa A, Mortensen PB. Schizophrenia. Lancet 2016; 388 (10039): 86–97.

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. Fourth Edition. © Cambridge University Press, 2013.

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The conundrum of treating schizophrenia – i
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References

These slides outline the conundrum of treating schizophrenia – in the ‘normal’ brain the levels of dopamine in the mesolimbic and mesocortical pathways are in balance.[Stahl, 2013] However, in the brain of a patient with schizophrenia, the levels are out of balance, with levels in the mesolimbic pathway too high and levels in the mesocortical pathway too low.[Stahl, 2013] 

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. Fourth Edition. © Cambridge University Press, 2013.

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The conundrum of treating schizophrenia – ii
Slide information
References

These slides outline the conundrum of treating schizophrenia – in the ‘normal’ brain the levels of dopamine in the mesolimbic and mesocortical pathways are in balance.[Stahl, 2013] However, in the brain of a patient with schizophrenia, the levels are out of balance, with levels in the mesolimbic pathway too high and levels in the mesocortical pathway too low.[Stahl, 2013] 

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. Fourth Edition. © Cambridge University Press, 2013.

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The conundrum of treating schizophrenia – iii
Slide information
References

These slides outline the conundrum of treating schizophrenia – in the ‘normal’ brain the levels of dopamine in the mesolimbic and mesocortical pathways are in balance.[Stahl, 2013] However, in the brain of a patient with schizophrenia, the levels are out of balance, with levels in the mesolimbic pathway too high and levels in the mesocortical pathway too low.[Stahl, 2013] 

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. Fourth Edition. © Cambridge University Press, 2013.

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The conundrum of treating schizophrenia – iv
Slide information
References

These slides outline the conundrum of treating schizophrenia – in the ‘normal’ brain the levels of dopamine in the mesolimbic and mesocortical pathways are in balance.[Stahl, 2013] However, in the brain of a patient with schizophrenia, the levels are out of balance, with levels in the mesolimbic pathway too high and levels in the mesocortical pathway too low.[Stahl, 2013] 

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. Fourth Edition. © Cambridge University Press, 2013.

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Antipsychotic drugs and the dopamine pathways of the brain
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References

Evidence for the dopamine hypothesis of schizophrenia comes, in part, from the mechanism of action of known antipsychotic drugs. The therapeutic actions of typical antipsychotic drugs are due to blockade (antagonism) of D2 receptors, specifically in the mesolimbic dopamine pathway.[Stahl, 2013] This has the effect of reducing the excess release of dopamine in this pathway that is thought to cause the positive symptoms of psychosis.[Stahl, 2013] However, typical antipsychotics block D2 receptors throughout the brain and not just those in the mesolimbic dopamine pathway; this extensive blockade of D2 receptors is responsible for many undesirable adverse effects because it further reduces the already reduced dopamine levels in the mesocortical pathway.[Stahl, 2013]

Atypical antipsychotics, or second-generation antipsychotics, are more discriminating. Partial agonism of dopamine receptors results in stabilisation of dopamine neurotransmission in a state between fully on and fully off.[Stahl, 2013; Lieberman, 2004] Partial agonism is a neat answer to the conundrum of treating both a deficit of dopamine and dopamine overactivity in different areas of the brain.[Stahl, 2013; Lieberman, 2004]
 

Stahl SM. Stahl’s Essential Psychopharmacology. Neuroscientific Basis and Practical Applications. Fourth Edition. © Cambridge University Press, 2013.

Lieberman JA. Dopamine partial agonists a new class of antipsychotic. CNS Drugs 2004; 18 (4): 251–267.

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The role of glutamate in the pathology of schizophrenia
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There has been a suggested link between glutamate and schizophrenia for many decades.[Howes et al., 2015] Originally, the hypothesis was that, in schizophrenia, there was simply a lack of glutamatergic neurotransmission, but this has been refined to specifically focus on NMDA receptor dysfunction.[Howes et al., 2015; Stone et al., 2007] The involvement of NMDA receptors in schizophrenia is supported by NMDA-receptor antagonist evidence, as well as evidence obtained using neuroimaging techniques.[Howes et al., 2015; Stone et al., 2007] Integrating the dopamine and glutamate hypotheses of schizophrenia has been a challenge. However, glutamate signalling can be integrated upstream of dopamine signalling in certain regions of the brain, as shown on the slide.[Howes et al., 2015]
 

Howes O, McCutcheon R, Stone J. Glutamate and dopamine in schizophrenia: an update for the 21st century. J Psychopharmacol 2015; 29 (2): 97–115.

Stone JM, Morrison PD, Pilowsky LS. Glutamate and dopamine dysregulation in schizophrenia – a synthesis and selective review. J Psychopharmacol 2007; 21 (4): 440–452.

Purves D, Augustine GJ, Fitzpatrick D, et al. (eds). Neuroscience. 4th Edition. Sinauer Associates, 2008.

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The pathophysiology of treatment-resistant schizophrenia
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References

Treatment-resistant schizophrenia (TRS) is defined in several different guidelines in different ways, but can broadly be described as schizophrenia that has no significant improvement in target symptoms after treatment with at least two different antipsychotics (at an adequate dose and duration).[Hasan et al., 2012; Lehman et al., 2010]

That many patients with schizophrenia fail to respond to antipsychotic drugs – known to bind to dopamine receptors in the brain – poses a challenge to the dominance of the dopamine hypothesis.[Gillespie et al., 2017] This has led some to consider whether treatment-resistant schizophrenia (TRS) is a separate pathophysiological entity to what is classically termed schizophrenia.[Gillespie et al., 2017] 

There are some indications that TRS may be characterised by a dysregulated glutamate system, however much more research is needed.[Gillespie et al., 2017] One of the problems that plagues researchers in this field is the lack of a universal definition of ‘treatment resistance’.[Gillespie et al., 2017] A consensus definition, were it to be adopted, would allow for easier comparison of different studies and pooling of samples.[Gillespie et al., 2017]

Gillespie AL, Samanaite R, Mill J, et al. Is treatment-resistant schizophrenia categorically distinct from treatment-responsive schizophrenia? A systematic review. BMC Psychiatry 2017; 17 (1): 12.

Hasan A, Falkai P, Wobrock T, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry 2012; 13 (5): 318–378.

Lehman AF, Lieberman JA, Dixon LB, et al. APA. Practice guideline for the treatment of patients with schizophrenia. 2nd ed. 2010; 1–184.

Anderson VM, Goldstein ME, Kydd RR, Russell BR. Extensive gray matter volume reduction in treatment-resistant schizophrenia. Int J Neuropsychopharmacol 2015; 18 (7): pyv016.

Roberts RC, Roche JK, Conley RR, Lahti AC. Dopaminergic synapses in the caudate of subjects with schizophrenia: relationship to treatment response. Synapse 2009; 63 (6): 520–530.

White TP, Wigton R, Joyce DW, et al. Dysfunctional striatal systems in treatment-resistant schizophrenia. Neuropsychopharmacology 2016; 41 (5): 1274–1285.

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Hypotheses for the underlying causes of schizophrenia
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The neurodevelopmental model of schizophrenia
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References

There is increasing recognition that schizophrenia is a neurodevelopmental disorder that involves alterations in brain circuits.[Insel, 2010]

Normal cortical development involves proliferation, migration of cells, dendritic arborisation (circuit formation), and myelination, with the first two processes occurring mostly during prenatal life and the latter two continuing through the first two post-natal decades.[Insel, 2010] A progressive reduction of grey-matter volume with age is observed with longitudinal neuroimaging.[Insel, 2010; Paus, Keshavan & Giedd, 2008] The combined effects of pruning of the neuronal arbor and myelin deposition are thought to account for this.[Insel, 2010] Local changes are far more complex.[Insel, 2010] Data from human and nonhuman primate brains indicate increasing inhibitory synaptic strength and decreasing excitatory synaptic strength in the prefrontal cortex throughout adolescence and early adulthood – the period of prodrome and emergence of psychosis.[Insel, 2010]

Psychosis nearly always emerges in late adolescence or early adulthood, with a peak between the ages of 18 and 25, when the prefrontal cortex is still developing.[Insel, 2010] The neurodevelopmental trajectory in children developing schizophrenia could include reduced elaboration of inhibitory pathways, and excessive pruning of excitatory pathways, leading to altered excitatory–inhibitory balance in the prefrontal cortex.[Insel, 2010] Reduced myelination would alter connectivity.[Insel, 2010] Although data support these possible neurodevelopmental mechanisms for schizophrenia, none has been proven to cause the syndrome.[Insel, 2010]

Insel TR. Rethinking schizophrenia. Nature 2010; 468 (7321): 187–193.

Paus T, Keshavan M, Giedd JN. Why do many psychiatric disorders emerge during adolescence? Nat Rev Neurosci 2008; 9 (12): 947–957.

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Socio–developmental–cognitive models of schizophrenia
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One of the important implications of socio–developmental–cognitive models of schizophrenia, is that attempts to reduce stress, and application of psychological and social therapies, may interrupt the vicious cycle that leads to paranoia and psychosis.[Howes & Murray, 2014] Because the models postulate that dopaminergic dysregulation is a result of the altered cognitive schema, these interventions would be best administered early in the disease process, before psychotic patterns of interpreting events have been hardwired by changes in dopamine circuitry in the brain.[Howes & Murray, 2014]

Howes OD, Murray RM. Schizophrenia: an integrated sociodevelopmental-cognitive model. Lancet 2014; 383 (9929): 1677–1687.

Bentall RP, Rowse G, Shryane N, et al. The cognitive and affective structure of paranoid delusions. A transdiagnostic investigation of patients with schizophrenia spectrum disorders and depression. Arch Gen Psychiatry 2009; 66 (3): 236–247.

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Neurotransmitters and schizophrenia
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References

As mentioned, the dysregulation of dopamine systems is key to the pathology of schizophrenia. Several other neurotransmitter systems are also linked, as is outlined on the slide.

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s comprehensive textbook of psychiatry. 9th Edition. Vol 1–2. © Lippincott Williams & Wilkins, 2009.

Santini MA, Ratner C, Aznar S, et al. Enhanced prefrontal serotonin 2A receptor signaling in the subchronic phencyclidine mouse model of schizophrenia. J Neurosci Res 2013; 91 (5): 634–641.

Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Bäbler A, et al. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 1998; 9 (17): 3897–3902.

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Inflammation and schizophrenia
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References

Inflammation and inflammatory processes within the body have been linked to the pathology of schizophrenia, particularly the activity of microglia cells, which are the primary immune cells of the central nervous system.[Howes & McCutcheon, 2017; Melborne et al., 2017]

In one study, the role of microglia in schizophrenia was interrogated using PET to image microglial activity in the brains of individuals identified as being at ‘ultra high risk’ of developing psychosis, as assessed on the Comprehensive Assessment of the At-Risk Mental States (CAARMS), as well as in patients with schizophrenia.[Bloomfield et al., 2016] The study found a correlation between microglial activity and being at ultra high risk of developing psychosis (Cohen’s d effect size of 1.2).[Bloomfield et al., 2016] This effect was specific to schizophrenia and was not seen in patients with depressive symptoms.[Bloomfield et al., 2016] Studies of this nature can struggle to separate the potential effect of antipsychotic treatment on the brain from the underlying pathology of schizophrenia, which is why it is powerful to include patients who have developed schizophrenia, as well as patients who are deemed to be at ultra high risk of developing psychosis, as determined on the CAARMS scale.[Bloomfield et al., 2016]
 

Bloomfield PS, Selvaraj S, Veronese M, et al. Microglial activity in people at ultra high risk of psychosis and in schizophrenia: an [11C]PBR28 PET brain imaging study. Am J Psychiatry 2016; 173 (1): 44–52.

Howes O, McCutcheon R. Inflammation and the neural diathesis-stress hypothesis of schizophrenia: a reconceptualization. Transl Psychiatry 2017; 7: e1024.

Melborne JK, Feiner B, Rosen C, Sharma RP. Targeting the immune system with pharmacotherapy in schizophrenia. Curr Treat Options Psychiatry 2017; 4 (2): 139–151.

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The microbiome and schizophrenia
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Several psychiatric and neurological disorders have been linked with the function of the gut microflora, including schizophrenia.[Nguyen et al., 2018; Chrobak et al., 2016; Dickerson et al., 2017] There are several pathways in the body that link the gut and the brain, as shown on the slide.[Rodrigues-Amorim et al., 2018]

Researchers have compared the oropharynx microbiome of patients with schizophrenia to that of healthy controls, in an attempt to isolate differences between them and potentially demonstrate the importance of inflammatory pathways in the pathology of schizophrenia.[Castro-Nallar et al., 2015] Many striking differences were seen in the analysis, including in the variety and in the types of microbiome species seen.[Castro-Nallar et al., 2015] It is at least conceivable that a greater understanding of the composition of the microbiome and its affect on the cognitive functioning and neurobiology of humans could lead to new approaches for diagnosing, typing, and treating schizophrenia.[Castro-Nallar et al., 2015]
 

Castro-Nallar E, Bendall ML, Pérez-Losada M, et al. Composition, taxonomy and functional diversity of the oropharynx microbiome in individuals with schizophrenia and controls. PeerJ 2015; 3: e1140.

Chrobak AA, Nowakowski J, Dudek D. Interactions between the gut microbiome and the central nervous system and their role in schizophrenia, bipolar disorder and depression. Arch Psychiatr Psychother 2016; 2: 5–11.

Dickerson F, Severance E, Yolken R. The microbiome, immunity, and schizophrenia and bipolar disorder. Brain Behav Immun 2017; 62: 46–52.

Nguyen TT, Kosciolek T, Eyler LT, et al. Overview and systematic review of studies of microbiome in schizophrenia and bipolar disorder. J Psychiatr Res 2018; 99: 50–61.

Rodrigues-Amorim D, Rivera-Baltanás T, Regueiro B, et al. The role of the gut microbiota in schizophrenia: current and future perspectives. World J Biol Psychiatry 2018; 19 (8): 571–585.

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Environmental factors
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The environment and schizophrenia
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The risk of developing schizophrenia can be thought of as a mix of genetic vulnerability and environmental factors; an individual’s genes set the stage for them to become prone to the assaults of the environment.[Dean & Murray, 2005] Some of the environmental risks are shown on the slide, and include pre- and post-natal factors, and cannabis use.[Sadock et al., 2009; Lakhan & Vieira, 2009]

Indeed, it is now accepted that most common diseases involve discrete genetic and environmental risk factors, and that these two elements interact to form complex genetic–environmental joint risk.[Hunter, 2005] If the genetic, or the environmental, risk factors of a condition are studied in isolation, this element of joint effect can be overlooked.[Hunter, 2005] A simple example of gene–environment interaction is the interplay between skin colour and sun exposure when considering the risk of skin cancer.[Hunter, 2005] Although unarguably more complex, schizophrenia can be conceptualised in this manner.[Hunter, 2005; Dean & Murray, 2005]

Dean K, Murray RM. Environmental risk factors for psychosis. Dialogues Clin Neurosci 2005; 7 (1): 69–80.

Hunter DJ. Gene–environment interactions in human diseases. Nat Rev Genet 2005; 6 (4): 287–298.

Lakhan SE, Vieira KF. Schizophrenia pathophysiology: are we any closer to a complete model? Ann Gen Psychiatry 2009; 8: 12.

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1. Lippincott Williams & Wilkins, 2009.

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Environmental factors and schizophrenia
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References

There are many environmental factors that have been linked to schizophrenia, pre- and post-natal, including exposure to rubella, bereavement during pregnancy, and obstetric CNS damage.[Sullivan, 2005; Dean & Murray, 2005] It is unclear what the general impact of some of these factors is, and indeed how the risk factors may combine. 

Whilst the factors outlined in the graph on the slide focus on pre- and post-natal risks for schizophrenia,[Sullivan, 2005] there are some risks of later life that have been identified as well.[Dean & Murray, 2005] These factors include drug use, migration, urbanicity, life events, and social adversity (e.g., social class, unemployment, and being single).[Dean & Murray, 2005]

For a person with a positive family history of schizophrenia, the odds ratio of developing schizophrenia is approximately 10 – greater than any of the individual risk factors outlined on the slide.[Sullivan, 2005] Schizophrenia should be conceptualised as a complex condition arising both from genetic and environmental influences.[Sullivan, 2005; Dean & Murray, 2005; Lakhan & Vieira, 2009] The role of genetics in schizophrenia will be explored in some detail later in this slide deck.
 

Dean K, Murray RM. Environmental risk factors for psychosis. Dialogues Clin Neurosci 2005; 7 (1): 69–80.

Lakhan SE, Vieira KF. Schizophrenia pathophysiology: are we any closer to a complete model? Ann Gen Psychiatry 2009; 8: 12.

Sullivan PF. The genetics of schizophrenia. PLoS Med 2005; 2 (7): e212.

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Cannabis as a risk factor for developing psychosis
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References

Several large-scale analyses have associated cannabis use with a risk of developing psychosis or schizophrenia.[Semple et al., 2005; Vaucher et al., 2017] The association is still somewhat controversial, and it is hard to be certain of an association that can only be demonstrated using observational or epidemiological studies.[Vaucher et al., 2017] A recent analysis found little support for an association between cannabis use and the development of schizophrenia after adjusting for certain appropriate covariates.[Ryan et al., 2019] A randomised-controlled trial (RCT) is often considered the ‘gold standard’ to demonstrate an association, however, in the case of cannabis and schizophrenia, an RCT would be highly unethical![Vaucher et al., 2017] 

Questions remain over the salience of the association between cannabis use and schizophrenia; in Australia, for example, the use of cannabis is much higher than elsewhere, but the incidence of schizophrenia is not.[Semple et al., 2005] What is the reason for this discrepancy? There are also questions surrounding the importance of early exposure to cannabis – is exposure in adolescence necessary for cannabis to exert its effect as a risk factor for psychosis?[Semple et al., 2005] More research is needed to answer these questions.[Semple et al., 2005]
 

Ryan JE, Veliz P, McCabe SE, et al. Association of early onset of cannabis, cigarette, other drug use and schizophrenia or psychosis. Schizophr Res 2019 [Epub].

Semple DM, McIntosh AM, Lawrie SM. Cannabis as a risk factor for psychosis: systematic review. J Psychopharmacol 2005; 19 (2): 187–194.

Vaucher J, Keating BJ, Lasserre AM, et al. Cannabis use and risk of schizophrenia: a mendelian randomization study. Mol Psychiatry 2018; 23 (5): 1287–1292.

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Genetic factors
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The heritability of schizophrenia – twin and adoption studies
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References

It has long been known that there is a genetic component to the risk of developing schizophrenia.[Gejman et al., 2010] 
Twin studies and adoption studies have produced some of the most compelling evidence for this.[Gejman et al., 2010] Any differences between identical twins are ascribed to the environment, whilst differences between non-identical twins can be ascribed to either genetics or the environment.[Gejman et al., 2010] Twin studies often calculate the concordance rate, which is the probability that one twin will develop a condition that their twin has developed.[Gejman et al., 2010] When comparing the concordance rates between identical and non-identical twins, a percentage heritability can be calculated.[Gejman et al., 2010] Adoption studies can further interrogate the influence of genetics, for example by studying children adopted by parents who have schizophrenia.[Gejman et al., 2010] In schizophrenia, twin studies and adoption studies support a significant role for genetic factors.[Gejman et al., 2010; Sadock et al., 2009]
 

Gejman PV, Sanders AR, Duan J. The role of genetics in the etiology of schizophrenia. Psychiatr Clin North Am 2010; 33 (1): 35–66.

Sadock BJ, Sadock VA, Ruiz P (eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th Edition. Vol 1. Lippincott Williams & Wilkins, 2009.

Keshavan MS, Nasrallah HA, Tandon R. Schizophrenia, “Just the Facts” 6. Moving ahead with the schizophrenia concept: from the elephant to the mouse. Schizophr Res 2011; 127 (1–3): 3–13. 

Lakhan SE, Vieira KF. Schizophrenia pathophysiology: are we any closer to a complete model? Ann Gen Psychiatry 2009; 8: 12. 

McGue M, Gottesman II. Genetic linkage in schizophrenia: perspectives from genetic epidemiology. Schizophr Bull 1989; 15 (3): 453–464.

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The genetics of schizophrenia
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References

When the study was published, in 2014, this was, to the authors knowledge, the largest molecular genetic study into any neurological disorder ever undertaken.[PGC, 2014] The size of the sample was of paramount concern from the outset, because it was postulated that sample size was the most important limiting factor when applying genome-wide association study (GWAS) techniques to schizophrenia.[PGC, 2014] In order to achieve this, all the available schizophrenia samples (whether published or not) were combined into a single sample.[PGC, 2014] This sample included case–control samples of European and Asian ancestry.[PGC, 2014] 

Many of the novel genes identified by the GWAS are not randomly distributed across genes of all classes and function, but rather converged on genes expressed in certain tissues and cell types.[PGC, 2014] Potentially, many of these novel findings provide a foundation for mechanistic studies into the pathology of schizophrenia, and the possibility of new treatments that stem from this new understanding.[PGC, 2014]

 

Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511 (7510): 421–427.

Ma C, Gu C, Huo Y, et al. The integrated landscape of causal genes and pathways in schizophrenia. Transl Psychiatry 2018; 8 (1): 67.

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Results from a large-scale twin study
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References

The large-scale twin study described on this slide used data from two Danish databases: the Danish Twin Register and the Danish Psychiatric Research Register.[Hilker et al., 2017; Hilker et al., 2018] From these sources, a sample was constructed comprising twin pairs born between 1951–2000.[Hilker et al., 2017; Hilker et al., 2018]

Interestingly, when the concordance rates of the incidence of schizophrenia were compared between monozygotic and dizygotic twins (i.e., identical and non-identical twins) a distinct difference emerged, from which the authors were able to estimate the hereditability of schizophrenia to be approximately 79%.[Hilker et al., 2018] There are problems with the approach that was taken, however, and the authors are clear that, ideally, twins would be followed over the course of their whole lives.[Hilker et al., 2018] In reality, this approach would be impractical, and very costly. As a compromise position, in this analysis of Danish twin data, a supplementary dataset was constructed, ensuring a minimum follow-up time of 30 years by including only twin pairs born between 1951–1981.[Hilker et al., 2018] The results of the main and the supplementary datasets were almost identical.[Hilker et al., 2018] Furthermore, the result seems closely aligned with a previous attempt to estimate the heritability of schizophrenia, using a collection of twin studies, which reported a genetic heritability value of 81%.[Sullivan et al., 2003; Hilker et al., 2018]
 

Hilker R, Helenius D, Fagerlund B, et al. Is an early age at illness onset in schizophrenia associated with increased genetic susceptibility? Analysis of data from the nationwide Danish twin register. EBioMedicine 2017; 18: 320–326.

Hilker R, Helenius D, Fagerlund B, et al. Heritability of schizophrenia and schizophrenia spectrum based on the nationwide

Danish twin register. Biol Psychiatry 2018; 83 (6): 492–498.

Sullivan PF, Kendler KS, Neadle MC. Schizophrenia as a complex trait: evidence from a meta-analysis of twin studies. Arch Gen Psychiatry 2003; 60 (12): 1187–1192.

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The future of genetic research in schizophrenia
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References

Much has been uncovered about the genetics of schizophrenia but, as with so much of science, this has led to more questions.[Corvin & Sullivan, 2016] The field of schizophrenia genetics still faces challenges:[Corvin & Sullivan, 2016]

  • There are now many known susceptibility loci for schizophrenia. Elucidating how these genes interact and potentially form molecular pathways in the aetiology of schizophrenia is the next step.
  • Much of the illness susceptibility of schizophrenia is still unexplained. Are there rare risk variants that are still to be uncovered? 
  • Most of the known susceptibility loci for schizophrenia are likely to have subtle effects. There are likely to be much rarer (not yet discovered) mutations that have a large impact on protein function. These highly penetrant mutations are likely to be much easier to place within hypothetical models of disease pathology, and so will complement ongoing efforts to understand the underlying causes of schizophrenia.
     

Corvin A, Sullivan PF. What next in schizophrenia genetics for the Psychiatric Genomics Consortium? Schizophr Bull 2016; 42 (3): 538–541.

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Quote
References

Corvin A, Sullivan PF. What next in schizophrenia genetics for the Psychiatric Genomics Consortium? Schizophr Bull 2016; 42 (3): 538–541.

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