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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