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Biology of Schizophrenia
Supervised By:Hani Hamed Dessoki ,
M.D. PsychiatryProf of Psychiatry
Acting Head, Psychiatry DepartmentBeni-Suef University
2014
AntipsychoticsStahl’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
Hippocampus
Dopamine and Serotonin in Pathways
Limbic System: Emotions of Fear, Anger, Sorrow, Love
Figure 11.19
Neurotransmitters and Functioning
Vigilance
Norepinephrine
DriveEuphoria
PleasurePerseveration
Impulse
EnergyMotivatio
n
AppetiteSex
Aggression
AnxietyIrritability
Dopamine
Serotonin
MoodEmotionCognitiv
efunction
Adapted from Healy D & McMonagle T. J Psychopharmacol 1997;11(4):S25-31.
Synthesis and degradation of catecholamines
PhenylalanineKey
COMT = Catechol O-methyltransferase
MAO = Monoamineoxidase
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)
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)
Pharmacological Targets in Schizophrenia
Dopamine
Adapted from Kandel et al., eds. Principles of Neural Science. Norwalk, CT: Appleton & Lange; 1991:854.
Hypoactivity: Negativeand Cognitive Symptoms
Hyperactivity:Positive Symptoms
Tuberoinfundibular Pathway
MesocorticalPathway
MesolimbicPathway
NigrostriatalPathway
Dopaminergic Pathways in the Brain
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
5-HT1A post-synaptic receptors
May be involved in anxiety depression obsessive-compulsive disorders sexual behaviour appetite control thermoregulation cardiovascular functions
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,weig
ht.…
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)
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.
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.
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.
Adrenergic receptors 1 & 2 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): 1465-1473Miyamoto S. et al., (2003): Molecular Interventions, Volume 3, Issue 1, 27-39
Sexual dysfunctionActivating side effects
5HT2
Stimulation
Sedation/drowsinessWeight gain
H1 block
ACh block
Blurred visionDry mouth
ConstipationSinus tachycardiaUrinary retention
Memory dysfunction
Nausea5-HT3 Stimulation
GI disturbancesActivating effects
5-HT reuptakeinhibition
Dry mouthUrinary retentionActivating effects
Tremor
NE reuptakeinhibition
Postural hypotensionDizziness
Reflex tachycardia
Alpha2 block
Priapism
Alpha1 block
DA reuptakeinhibition
Psychomotor activationPsychosis
Adverse Effects of NeurotransmitterActivity and Receptor Binding
Adapted from Richelson E. Current Psychiatric Therapy. 1993;232-239
Antidepressant
Potential Clinical implications of receptor activities of antipsychoticsD2 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
Potential Clinical implications of receptor activities of
antipsychoticMixed 5-HT/NE neuroal reuptake inhibition
Antidepressant and anxiolytic activity
1 antagonism Sedation, postural hypotension, sexual dysfunction, weight gain
H1 antagonism Sedation, weight gain
M1 antagonism Memory impairment, Gl symptoms
Key DA pathways
A. Nigrostriatal DA pathway: part of Extra
Controls motor function and movement
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.
Key DA pathways C. Mesocortical DA pathway
mediates Cognitive symptoms = DLPFC Affective symptoms = VMPFC
Key DA pathways D. DA pathway Proje Tuberoinfundobular cts from
hypothalamus to ant. pituitary gland Controls Prolactin secretion
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
Neurobiology of schizophrenia
Dopamine Hypothesis DA overactive in some brain areas, and
underactive in others Neither “too high” nor “too low” Neither “too high” nor “too low”
but 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
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
Cognitive symptoms:attentionmemoryexecutive functions
(eg, abstraction)
Positive symptoms:delusionshallucinationsdisorganized speechcatatonia
IMPACT OF SCHIZOPHRENIC SYMPTOMS
ON OVERALL FUNCTIONING
Occupational
Interpersonal
Self-care
Social
Work
Negativesymptoms:affective flatteningalogiaavolitionanhedonia
Mood symptoms:dysphoriasuicidalityhelplessness
QOL 2
Schizophrenia Core Symptoms
Psychotic Deficit Cognitive
PositiveSymptoms
Mesolimbic pathway
NegativeSymptoms
DLPC &VMPFC
CognitiveDysfunction
DLPFC
AffectiveVMPFC
Mesocortical /prefrontal cortex
Symptoms May Match To Malfunctioning Brain Circuits
(Conlry.R, 2007)
Positivesymptoms
Mesolimbic
Negativesymptoms
Nucleus accumbens reward circuits
Cognitivesymptoms Dorsolateral
prefrontal cortex
Dopamine
Aggressivesymptoms
AmygdalaOrbitofrontalcortex
Affectivesymptoms Ventromedial
Prefrontalcortex
Biological basisBrain 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 , …..
How are positive & negative symptoms related?
VTA
PrefrontalCortex
NA
DopamineHypoactivity
)too little DA(
GABA neurons
Dopamine hyperactivity)too much DA(
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.
Glutamate acts as accelerator on dopamine in mesocortical area, and act as a brake in mesolimbic area.
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.
�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 patients with schizophrenia, and 30 age- and sex-matched normal 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 control subjects. Lower glycine level was correlated with a greater number of 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.
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
5HT1A is dopamine accelerator. However, 5HT2A is dopamine brake (opposite effect is on glutamate).
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.
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
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).
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.
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