This document discusses the neurobiology of schizophrenia. It covers the dopamine, serotonin, glutamate, and other neurotransmitter pathways involved in the disorder. The dopamine hypothesis proposes that dopamine is dysregulated in schizophrenia, being either overactive, underactive, or "out of tune" in different brain areas. This leads to both positive and negative symptoms. The document outlines key brain regions and circuits impacted, including the prefrontal cortex, mesolimbic pathway, and others. It also discusses various pharmacological targets for antipsychotic drugs that aim to modulate these neurotransmitter systems.

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

5. Dopamine and Serotonin in Pathways

6. Limbic System: Emotions of Fear, Anger,
Sorrow, Love
Figure 11.19

7. 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.

8. 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)

9. 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)

10. 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

11. 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

12. 5-HT1A post-synaptic receptors
• May be involved in
• anxiety
• depression
• obsessive-compulsive disorders
• sexual behaviour
• appetite control
• thermoregulation
• cardiovascular functions

13. 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(

14. 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.

15. 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.

16. 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.

17. 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

18. 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

19. 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

20. 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

21. Key DA pathways
 A. Nigrostriatal DA pathway: part of Extra
 Controls motor function and movement

22. 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.

23. Key DA pathways
 C. Mesocortical DA pathway mediates
 Cognitive symptoms = DLPFC
 Affective symptoms = VMPFC

24. Key DA pathways
 D. DA pathway
 Proje Tuberoinfundobular cts from
hypothalamus to ant. pituitary gland
 Controls Prolactin secretion

25. 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

27. 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

28. 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

29. 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

30. Schizophrenia Core Symptoms
Psychotic Deficit Cognitive
Positive
Symptoms
Mesolimbic pathway
Negative
Symptoms
DLPC &VMPFC
Cognitive
Dysfunction
DLPFC
Affective
VMPFC

31. 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

32. 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 , …..

33. How are positive & negative
symptoms related?
VTA
Prefrontal
Cortex
NA
Dopamine
Hypoactivity
)too little DA(
GABA neurons
Dopamine hyperactivity
)too much DA(

35. 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.

36. Glutamate acts as accelerator on dopamine
in mesocortical area, and act as a brake in
mesolimbic area.

37. 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.

38. ٍ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.

39.  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

40.  5HT1A is dopamine accelerator. However, 5HT2A
is dopamine brake (opposite effect is on glutamate).

42.  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.

43. 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

44. 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).

46.  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.

47. Thank You