Biology of schizophrenia
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  • ·The rate-limiting step is between L-tyrosine and L-DOPA (tyrosine hydroxylase).
    ·The main break down products are MHPG, HVA and VMA.
    ·MAO acts mainly intraneuronally.
    ·COMT acts at the synaptic cleft.
  • Serotonin (5-HT) is an indolamine neurotransmitter synthesised from tryptophan, an essential amino acid found in the diet that is preferentially taken up by serotonergic neurons. The rate-limiting step in its formation involves tryptophan hydroxylase. 5-HT is catabolised by monoamine oxidase to form 5-hydroxyindolacetic acid.
  • 5-HT1A receptor density is highest in the hippocampus, the septum, the amygdala, and the cortical limbic area and raphe nucleus. Clinically useful drugs that are selective partial agonists at this receptor are buspirone and ipsapirone, both used in the treatment of anxiety. They may owe their activity to an ability to reduce the firing of the raphe nuclei.
  • The “cleaner” the drug, the better the side effect profile. Agents that have greater affinities to multiple receptors will, by definition, run a greater risk of creating unwanted side effects. This slide shows the relationship between neurotransmitter affinity, receptor activity and clinical side effects.
  • Prefrontal cortex
    Dopamine hypoactivity (too little DA – [negative symptoms]), so do not inhibit NA neurons or inhibit axons of VTA neurons
    so if NA not inhibited, and NA ends up with too much DA [positive symptoms]

Transcript

  • 1. Biology of Schizophrenia Supervised By: Hani Hamed Dessoki, M.D. Psychiatry Prof of Psychiatry Acting Head, Psychiatry Department Beni-Suef University 2014
  • 2. Antipsychotics Stahl’s Neuroscience Dr. Radwa Said Abdelazim, M.sc, M.D. (candidate) Psychiatrist and Dance/Movement Therapist Cairo University Hospital- Psychiatry Department EYPTS Representative/secretary in EPA WPA-YPC African and Middle East representative WAYPT- President
  • 3. Hippocampus
  • 4. Dopamine and Serotonin in Pathways
  • 5. Limbic System: Emotions of Fear, Anger, Sorrow, Love Figure 11.19
  • 6. Neurotransmitters and Functioning Vigilance Norepinephrine Drive Euphoria Pleasure Perseveration Impulse Energy Motivation Appetite Sex Aggression Anxiety Irritability Dopamine Serotonin Mood Emotion Cognitive function Adapted from Healy D & McMonagle T. J Psychopharmacol 1997;11(4):S25- 31.
  • 7. Synthesis and degradation of catecholamines Phenylalanine Key COMT = Catechol O-methyltransferase MAO = Monoamine oxidase L-tyrosine Dopamine L-dopa Tyrosine hydroxylase 3-methoxy-tyramine Noradrenaline3,4-dihydroxyphenylacetic acid (DOPAC) Homovalinillic acid (HVA) 3-methoxy-4-hydroxy phenylglycol (MHPG) 3-methoxy-4-hydroxy mandelic acid (VMA)) COMT MAO MAO/COMT Roth et al (1995)
  • 8. Smith et al (1997) Synthesis and degradation of serotonin Tryptophan 5-Hydroxytryptophan (5- HTP) Tryptophan hydroxylase 5-Hydroxytryptamine (5- HT) 5-Hydroxytryptophan decarboxylase 5-Hydroxyindolacetic acid (5-HIAA) Monoamine oxidase (MAO)
  • 9. Pharmacological Targets in Schizophrenia Dopamine Adapted from Kandel et al., eds. Principles of Neural Science. Norwalk, CT: Appleton & Lange; 1991:854. Hypoactivity: Negative and Cognitive Symptoms Hyperactivity: Positive Symptoms Tuberoinfundibular Pathway Mesocortical Pathway Mesolimbic Pathway Nigrostriatal Pathway Dopaminergic Pathways in the Brain
  • 10. Serotonin (5-HT)  In the brain, serotonin is concentrated in the raphe nuclei  Involved in:  mood control  sleep  pain perception  body temperature  blood pressure  neuroendocrine activity  Also involved in gastrointestinal and cardiovascular systems
  • 11. 5-HT1A post-synaptic receptors • May be involved in • anxiety • depression • obsessive-compulsive disorders • sexual behaviour • appetite control • thermoregulation • cardiovascular functions
  • 12. Serotonin in Schizophrenia (1)-5HT 2- A…..decrease release of Da in nigrostriatal area…So, 5HT antagonists counterbalance the decreased Da resulting from antipsychotics. (2)-5HT in mesocortex, area is more than Da…net effect is increase in Da , with 5HT 2 A Antagonists )3(-5HT in tuberoinfundib ular area promotes prolactin release , thus ,counteracting Da. )4(-5HT 1 A agonism may be of help in depression , negative symptoms.. )5(-possible role of 5HT 6 and 7 receptor subtypes? )6(-5HT2c? Sleep ,cognition, weight…. 5HT2c antagonism :increase Da & NE in prefrontal cortex.(NDDI( Of possible help in :depression &negative symptoms Site of action for recent drugs for negative symptoms e.g.Asenapine Site of action for recent drugs for depression e.g.Agomel- atine A new class of drugs acting as NE &Da Disinhibit. Inhibitors (NDDI( Some AD (FLU, MRZ)&AP (CLO,OLA, ZIP,QUET(
  • 13. Serotonin   5HT2a receptors density in PFC leads to  release of dopamine in PFC (-ve and cognitive sx)  5HT1a  (-ve sx, mood sx)* ? Indirect action on DA  5H2c  (+ve ss.)*  ?? 5HT6 and 5HT7 ?? Therapeutic Pharmacological Targets in Schizophrenia Marek G. and Merchant K. (2005): The Journal of the American Society for Experimental NeuroTherapeutics. Vol. 2, 579–589.
  • 14. Subtypes of serotonin receptors Seven major subtypes of serotonin receptor have been cloned so far. They differ in terms of pharmacological property, signal transduction mechanism, and gene sequence. The 5HT1a receptor is both a somatic autoceptor that controls the firing rate of 5HT neurons and a postsynaptic receptor. It thus closely governs mood regulation. The 5HT1b/d receptor is a terminal autoceptor, which controls the release of 5HT; however, its exact role in depression is still unclear. The 5HT2a-c receptor has been implicated in sleep, sex, and appetite regulation. The 5HT3 receptor is involved in the gratification response and drugabuse. The functions of other subtypes of receptors in psychiatric-related disorders remain to be investigated.
  • 15. Muscarinic receptors  Muscarinic receptors may reduce D2 mediated side effects.  Decrease number of M1 receptors and N7* receptors. GABA transmission *  Reduced synthesis and reuptake of GABA in DLPFC  D1. Therapeutic Pharmacological Targets in Schizophrenia Wong A.H.C. and Van Tol H.H.M. (2003): Neuroscience and Biobehavioral Reviews 27, 269–306.
  • 16. Adrenergic receptors  α1 & α2 adrenoreceptor agonists improve cognition.  NE  improve attention, concentration and social function. Therapeutic Pharmacological Targets in Schizophrenia Harvey P.D. and McClure M.M., 2006: Drugs; 66 (11): 1465-1473 Miyamoto S. et al., (2003): Molecular Interventions, Volume 3, Issue 1, 27-39
  • 17. Sexual dysfunction Activating side effects 5HT2 Stimulation Sedation/drowsiness Weight gain H1 block ACh block Blurred vision Dry mouth Constipation Sinus tachycardia Urinary retention Memory dysfunction Nausea5-HT3 Stimulation GI disturbances Activating effects 5-HT reuptake inhibition Dry mouth Urinary retention Activating effects Tremor NE reuptake inhibition Postural hypotension Dizziness Reflex tachycardia Alpha2 blockPriapism Alpha1 block DA reuptake inhibition Psychomotor activation Psychosis Adverse Effects of Neurotransmitter Activity and Receptor Binding Adapted from Richelson E. Current Psychiatric Therapy. 1993;232-239 Antidepressant
  • 18. Potential Clinical implications of receptor activities of antipsychotics D2 antagonism  Positive symptoms efficacy, EPS, endocrine effects 5-HT2A antagonism  Negative symptom efficacy, reduced EPS High 5-HT2A/D2 affinity ration  Antipsychotic efficacy reduced EPS (compared to D2 antagonism alone) 5-HT1A agonism  Antidepressant and anxiolytic activity, improved cognition, reduced EPS 5-HT1D antagonism  Depressive symptom efficacy 5-HT2C antagonism  Positive symptom efficacy, weight gain
  • 19. Potential Clinical implications of receptor activities of antipsychotic Mixed 5-HT/NE neuroal reuptake inhibition  Antidepressant and anxiolytic activity α1 antagonism  Sedation, postural hypotension, sexual dysfunction, weight gain H1 antagonism  Sedation, weight gain M1 antagonism  Memory impairment, Gl symptoms
  • 20. Key DA pathways  A. Nigrostriatal DA pathway: part of Extra  Controls motor function and movement
  • 21. Key DA pathways  B. Mesolimbic DA pathway: part of limbic system  Regulates behaviours, pleasurable sensations, powerful euphoria of drug abuse, delusions and hallucinations seen in psychosis.
  • 22. Key DA pathways  C. Mesocortical DA pathway mediates  Cognitive symptoms = DLPFC  Affective symptoms = VMPFC
  • 23. Key DA pathways  D. DA pathway  Proje Tuberoinfundobular cts from hypothalamus to ant. pituitary gland  Controls Prolactin secretion
  • 24. Key DA pathways  E. fifth DA pathway  Arises from multiple sites  Periaqueductal gray, ventral mesencephalon, hypothalamic nuclei, and lateral parabrachial nucleus and projects into thalamus  Its function is NOT well known
  • 25. Neurobiology of schizophrenia  Dopamine Hypothesis  DA overactive in some brain areas, and underactive in others  Neither “too high” nor “too low” butNeither “too high” nor “too low” but “out of tune”“out of tune”  Serotonin and Glutamate and GABA role  Interplay = negative and positive symptoms  Aid in understanding side effects of different antipsychotics
  • 26. Key Brain regions and their hypothetical functions  Alterations in transmission of NT = Psychiatric disorders  Symptoms depend on which brain area is impaired  DA is dysregulated in schizophrenia = overactive, underactive or out of tune = -ve and +ve symptoms
  • 27. Cognitive symptoms: attention memory executive functions (eg, abstraction) Positive symptoms: delusions hallucinations disorganized speech catatonia IMPACT OF SCHIZOPHRENIC SYMPTOMS ON OVERALL FUNCTIONING Occupational Interpersonal Self- care Social Work Negative symptoms: affective flattening alogia avolition anhedonia Mood symptoms: dysphoria suicidality helplessness QOL 2
  • 28. Schizophrenia Core Symptoms Psychotic Deficit Cognitive Positive Symptoms Mesolimbic pathway Negative Symptoms DLPC &VMPFC Cognitive Dysfunction DLPFC Affective VMPFC
  • 29. Mesocortical / prefrontal cortex Symptoms May Match To Malfunctioning Brain Circuits )Conlry.R, 2007( Positive symptoms Mesolimbic Negative symptoms Nucleus accumbens reward circuits Cognitive symptoms Dorsolateral prefrontal cortex Dopamine Aggressive symptoms AmygdalaOrbitofrontal cortex Affective symptoms Ventromedial Prefrontal cortex
  • 30. Biological basis Brain circuits involved : Brain circuits to , and , from frontal lobes and prefrontal cortex, especially “DLPFC”, regulated by : 1- NE projections ( LC ). 2-Da projections ( VTA ) (D1 more important ) (out of tone ?!). 3-Histaminergic projections ( TMN ). 4-Ach ( connection to hippocampus ). 5-5HT , NMDA , …..
  • 31. How are positive & negative symptoms related? VTA Prefrontal Cortex NA Dopamine Hypoactivity )too little DA( GABA neurons Dopamine hyperactivity )too much DA(
  • 32. Key Glutamate Pathways  Similarly to DA, there are five glutamate pathways in the brain that are of particular relevance to schizophrenia. 1. The cortical brainstem glutamate projection. 2. The cortico-striatal glutamate pathway. 3. Cortico-thalamic glutamate pathway. 4. Thalamo-cortical glutamate pathways. 5. The cortico-cortical glutamatergic pathways.
  • 33. Glutamate acts as accelerator on dopamine in mesocortical area, and act as a brake in mesolimbic area.
  • 34. Glutamenergic function  Glutamate mediated excitatory neurotransmission through the NMDA & AMPA receptor.  Altered glutamate neurotransmission.  NMDA antagonists  (Ketamine & PCP)  psychosis NMDA agonist  improve cognition. N.B.  Excessive Glutamate during development leads to: excitatoxic damage to hippocampus, cortical neurons which result in abnormal pruning of glutametergic innervations during development Therapeutic Pharmacological Targets in Schizophrenia Lara D.R. et al., (2006): Progress in Neuro-Psychopharmacology & Biological Psychiatry 30, 617–629.
  • 35. ٍGlycine Level and Negative Symptoms in Schizophrenia Hani Hamed* Hesham Essa** Amr Zahra*** *Lecturer of Psychiatry and **Clinical Pathology, Beni-Suef University. ***Lecturer of Biochemistry, Al Fayoum University.   Abstract: Objective: Previous studies have suggested that decreased N-methyl-D-aspartate (NMDA)-type glutamate receptor function may contribute to increased negative symptoms in patients with schizophrenia. Selective dysfunction or dysregulation of N-methyl-D-aspartate (NMDA)-type glutamate receptors may play a specific role in the pathophysiology of schizophrenia. Recent studies have investigated the ability of NMDA/glycine-site modulators to ameliorate persistent negative and cognitive symptoms. Method: Plasma levels of glycine, serine, and their ratio, were compared in 30 patientswith schizophrenia, and 30 age- and sex-matchednormal control subjects. All subjects were medication-free. Subjects in both groups were examined using the following tests: Familial Socioeconomic Status Scale, Global assessment of Function, Quality of life Scale, and Positive and Negative Syndrome Scale. Results: Plasma glycine level and glycine-serine ratio were lower in schizophrenic patients than in controlsubjects. Lower glycine level was correlated with a greater numberof negative symptoms. Shizophrenic patients showed lower quality of life. Conclusion: The decrease in plasma glycine level supports the evidence for an abnormality in the glutamatergic system in schizophrenia. The findings of this study support additional evidence that decreased glycine level in schizophrenic patients may be related to the pathophysiology of negative symptoms.
  • 36.  In order to fully understand the properties of antipsychotics, it is imperative to examine the serotonin (5HT) pathways throughout the brain and how they modulate DA and glutamate circuits. Key Serotonin Pathways
  • 37.  5HT1A is dopamine accelerator. However, 5HT2A is dopamine brake (opposite effect is on glutamate).
  • 38.  Signal to noise ratio in schizophrenia could be related to deficit in filtration in information processing, too high, too low (out of tune), and chaotic theory.
  • 39. The behavioral deficit state suggested by negative symptoms certainly implies underactivity or even "burnout" of neuronal systems. This may be related to the consequences of prior excitotoxic overactivity of glutamate systems
  • 40. Basic Conclusion  Glutamate acts as accelerator on dop. in mesocortical area.  Glutamate acts as brake on dop. in mesolimbic area.  5HT 1A acts as accelerator on dop.  5HT2A acts as brake on dop.  5HT 1A acts as brake on glutamate.  5HT2A acts as accelerator on glutamate. So, atypical antipsychotics (mainly serotonergic, can decrease dopamine in mesolimbic area by 2 mechanisms 1st : it’s brake effect on dopamine through 5HT2A, and the 2nd is it’s accelerator effect on glutamate which is brake on dopamine).
  • 41.  Inflammatory changes in schizophrenia  There is a growing body of evidence to suggest a role for inflammatory processes in schizophrenia. Research has shown that there are increased concentrations of pro-inflammatory cytokines, such as interleukin 6 and 8 (IL-6, IL-8) and tumour necrosis factor a (TNFa) in the serum of people with schizophrenia. The presence of a number of other markers of inflammation have also been demonstrated; for example, there is an increase in serum phospholiapse activity. In people with schizophrenia, the blood-cerebrospinal fluid (CSF) barrier is impaired and there is an increase in the concentration of serum intercellular cell adhesion molecule (sICAM) and immunoglobulin G (IgG) in the CSF. The activation of immune cells, such as monocytes and T- lymphocytes, and the production on the free radical NO are also indicators for the presence of an inflammatory process in schizophrenia.
  • 42. Thank You