BOOK READING

Stahls Essential Psychopharmacology

Neuroscientific Basis and Practical Applications
Third Edition
Chapter 9
Psychosis and Schizophrenia

Disusun oleh
AHMAD MUHAJIRIN,S.Ked
PINIEL FRIMANTAMA,S.Ked
RUCHYYIH DIAN PALUPI,S.Ked

Pembimbing
dr. Yulinar N.S, M.Sc, Sp.KJ

SMF KESEHATAN JIWA

RSJ KALAWA ATEI
FAKULTAS KEDOKTERAN UNIVERSITAS PALANGKARAYA
2017
Symptom dimensions in
schizophrenia
 psychosis

difficult term frequently

misconcept
to define misused

crazy Mental illnes

 Clinical description of psychosis
• Psychosis is a syndrome — a mixture of
symptoms - that can be associated with many
different psychiatric disorders,
• At a minimum, psychosis means delusions and
hallucinations.
• includes symptoms such as disorganized
speech, disorganized behavior, and gross
distortions of reality testing.
 psychosis

disorganized/excited
paranoid psychosis
psychosis

Depressive psychosis
 Schizophrenia is more than a psychosis..

• Schizophrenia affects 1 percent of the

population,
• in the United States there are over 300,000
acute schizophrenic episodes annually.
• Between 25 and 50 percent of schizophrenia
patients attempt suicide, and 10 percent
eventually succeed
 The syndrome of schizophrenia consists of a mixture of
symptoms that are commonly divided into two major categories,
positive and negative.
 syndrome of schizophrenia

Positive symtoms Negative symptoms

• Delusions • Blunted affect
• Hallucinations • Alogia: restrictions in fluency and
• Distortions or exaggerations in language productivity of thought and speech
and communication • Avolition: restrictions in initiation of goal-
• Disorganized speech directed behavior
• Disorganized behavior • Anhedonia: lack of pleasure
• Catatonic behavior • Attentional impairment
• Agitation
Five symtom dimensions of
schizophrenia
Positive symtoms across disorders
Causes of negative symtoms
Cognitive symtoms across disorders
Aggressive symtoms across disorders
Affective symtoms across disorders
Neurotransmitters and
circuits in schizoprenia
 Neurotransmitter dan jalur jalurnya
pada skizofrenia
Dopamin
• Dasar biologis penderita skizofrenia tetap tidak diketahui,
akan tetapi, neurotransmiter dopamin (DA) telah lama
memainkan peran penting dalam hipotesis dari skizofrenia.

Untuk memahami peran potensial dari dopamin di skizofrenia,

pertama-tama penting untuk meninjau bagaimana
• dopamin disintesis, dimetabolisme, dan diatur;
• peran reseptor dopamin;
• lokalisasi jalur dopamin kunci dalam otak.
Neuron Dopamineric
• Neuron dopaminergik menggunakan
neurotransmiter DA, yang disintesis di terminal
saraf dopaminergik dari asam amino tirosin 
diambil menjadi neuron dari ruang ekstraselular
dan aliran darah oleh pompa tirosin, atau
transporter. Tirosin diubah menjadi DA pertama
oleh enzim tirosin hidroksilase (TOH) dan
kemudian oleh enzim dopa dekarboksilase (DDC)
• DA kemudian diangkat ke vesikel sinaptik oleh
monoamine transporter vesikular (VMAT2) dan
disimpan di sana sampai dopamin diperlukan
 Neuron DA neuron memiliki transporter presinaptik
(reuptake pompa)  DAT,
Keunikanya : ia dapat kembali disimpan dalam vesikel
sinaptik untuk reuse berikutnya di neurotransmisi
lain (Gambar 9-19).
Konsentrasinya lebih rendah daripada DA itu sendiri
Misalnya, di korteks prefrontal, DATs relatif jarang.
Kelebihan DA yang di lepaskan akan dihancurkan
dalam neuron oleh enzim monoamine oxidase
(MAO) A atau MAO-B atau di luar neuron oleh enzim
catechol-metil transferase (COMT).
DA yang berdifusi jauh dari sinapsis juga dapat
diangkut oleh transporter norepinefrin (jaring)
sebagai substrat "false“.
• Reseptor untuk dopamin juga mengatur
neurotransmisi dopaminergik  DA transporter
DAT dan transporter vesikular VMAT2 
Kebanyakan reseptor dopamin terdiri dari
sedikitnya lima subtipe farmakologi dan beberapa
isoform lebih molekul.

• Reseptor dopamin yang paling diteliti secara

ekstensif adalah dopamin-2 reseptor, yang
dirangsang oleh dopamin agonis untuk
pengobatan penyakit Parkinson dan diblokir
oleh antipsikotik dopamin antagonis untuk
pengobatan skizofrenia.
JALUR UTAMA DOPAMIN DALAM OTAK
 JALUR DOPAMIN MESOLIMBIC DAN HIPOTESIS
DARI GEJALA POSITIF dan NEGATIF SKIZOFRENIA

• Mesolimbic dari badan sel

dopaminergik di daerah
segmental ventral dari
batang otak ke terminal
akson di salah satu daerah
limbik otak, yaitu nucleus
accumbens di striatum
ventral (Gambar 9-24).

• jalur ini diperkirakan

memiliki peran penting
dalam beberapa perilaku
emosional, termasuk
gejala positif psikosis,
seperti delusi dan
halusinasi (Gambar 9-25).
HIPOTESIS JALUR DOPAMIN MESOCORTICAL DALAM PENGARUHNYA TERHADAP
GEJALA KOGNITIF, NEGATIF, DAN AFEKTIF SKIZOFRENIA

• Jalur dopamin Mesocortical mempengaruhi gejala kognitif, negatif,

dan afektif skizofrenia yang juga timbul dari badan sel di daerah
segmental ventral tapi diproyeksikan ke daerah korteks prefrontal
dikenal sebagai dopamin jalur mesocortical (gambar 9-27)
• Cabang dari jalur menuju korteks prefrontal dorsolateral diduga
untuk mengatur kognisi dan fungsi eksekutif (Gambar 9-27),
sedangkan cabang-cabangnya ke bagian ventromedial prefrontal
cortex yang diduga mengatur emosi (Gambar 9-28).
• Fungsi dopamin pada skizofrenia mungkin "terlalu tinggi" di
daerah mesolimbic dan "terlalu rendah" di daerah
mesocorticai.
• Neuron dopamin "tidak selaras" sehingga menimbulkan
gejala negatif
• Jalur Dopamin mesolimbic tidak hanya untuk
mengendalikan gejala positif psikosis tetapi juga diduga
menjadi pusat kesenangan di otak.
• Ketika seorang pasien dengan skizofrenia kehilangan
motivasi dan minat  anhedonia dan kurangnya
kesenangan,
• gejala mengimplikasikan  adanya kekurangan dopamin
pada jalur mesolimbic bukan hanya kekurangan fungsi di
dopamine jalur mesocortical  pasien yang diobati dengan
antipsikotik, khususnya antipsikotik konvensional, dapat
menyebabkan memburuknya gejala negatif dan keadaan
"neurolepsis" seperti gejala negatif skizofrenia.
 Jalur dopamin Nigrostriatal

•Jalur dopamin nigrostriatal

 bagian dari sistem saraf
pusat jalur ekstrapiramidal
mengontrol gerakan
motorik.

•Kekurangan hormon
dopamine menyebabkan
gangguan pada anggota
gerak, termasuk penyakit
Parkinson yang ditandai
dengan kekakuan, akinesia /
bradykincsia dan tremor
 JALUR DOPAMIN
TUBEROINFUNDIBULAR

• Aktivasi dopamine pada jalur ini akan

menghambat pelepasan prolaktin. Jika fungsi
neuron dopamin tuberoinfundibular terganggu
akibat lesi atau obat-obatan, kadar prolaktin ↑.
• Peningkatan kadar prolaktin dapat menyebabkan
gangguan seperti galaktorea (sekresi payudara),
amenore (hilangnya ovulasi dan menstruasi), dan
masalah disfungsi seksual.
• Pada keadaan postpartum, terjadi penurunan
dopamine  kadar prolaktin ↑
 Jalur dopamin
Tuberoinfundibular

Neuron dopamine
diproyeksikan dari
hipotalamus ke
hipofisis anterior.
 JALUR DOPAMINE PADA multiple site
• Penelitian pada primata mengenai jalur dopamine yang
menginervasi thalamus di dapatkan dopamine muncul
dari beberapa area, termasuk Substansia nigra
periaqueductal, mesencephalon ventral, inti
hipotalamus, dan inti parabrachial lateral.
• Fungsinya  masih dalam tahap penelitian.
• Tetapi fungsi jalur ini diperkirakan berpengaruh
terhadap mekanisme tidur dan informasi yang
melewati thalamus ke korteks dan daerah otak lainnya.
Namun, tidak ada bukti yang mengenai jalur ini dengan
skizofrenia
 GLUTAMAT
• Dalam beberapa tahun terakhir, neurotransmitter
glutamat secara teoritis menjadi sasaran dalam
patofisiologi skizofrenia dan saat ini glutamat menjadi
target utama dari agen psyhopharmacological untuk
perawatan skizofrenia.
• Glutamat  neurotransmitter utama dalam sistem saraf
pusat dan kadang-kadang dianggap sebagai "master
switch" dari otak, karena dapat membangkitkan dan
mengaktifkan hampir semua neuron SSP.
 SINTESIS
GLUTAMAT
• Glutamat atau asam glutamat
adalah neurotransmitter
asam amino untuk sintesis
protein.
• Ketika digunakan sebagai
neurotransmitter, glutamat
disintesis dari glutamin
dalam sel glial
• glutamat pertama kali dirilis
dari vesikel sinaptik
diambil ke dalam sel glial
dengan pompa reuptake
yang dikenal sebagai
transporter asam amino
rangsang (EAAT)
 SINTESIS GLUTAMAT
• Glutamin dilepaskan dari sel-
sel glial melalui transportasi
terbalik dengan pompa atau
transporter
• Transpoter : trasnporter asam
amino netral spesifik (SNAT
glial dan panah 4 pada Gambar
9-33C).
• Ketika SNATs glial dan ASC-
Ts beroperasi di dalam, mereka
mengangkut glutamin dan
asam amino lainnya ke dalam
sel glial.
• glutamin bisa keluar dari sel
glial dan hop naik ke neuron
melalui berbagai jenis neuron
SNAT beroperasi dalam hati
dengan cara reuptake (panah 5
pada Gambar 9-33C).
• Didalam neuron
glutamin diubah 
glutamat oleh enzim
dalam mitokondria
disebut glutaminase
(panah 6 pada Gambar
9-33D).
• Glutamat kemudian
diangkut ke dalam
vesikel sinaptik melalui
glutamat transporter
vesikular (vGluT, panah
7 pada Gambar 9-33D)
di mana disimpan untuk
rilis berikutnya selama
neurotransmisi.
 Sintesis glutamat cotransmitters
glisin dan d-serin
• Sistem glutamat merupakan salah satu reseptor kunci untuk
co-transmitter membuat glutamat agar dapat berfungsi.
• Reseptor  reseptor NMDA
• Co-transmitter  asam amino glisin atau asam amino lain
yang terkait erat dengan glisin, dikenal sebagai d-serin.
• Glycine disintesis oleh neuron glutamat, sehingga neuron
glutamat harus mendapatkan glisin yang mereka butuhkan
untuk reseptor NMDA baik dari neuron glisin atau dari sel-
sel glial.
• Glisin sendiri dapat diambil ke dalam sel glial dari ruang
ekstraselular atau aliran darah dengan tipe 1 glisin
transporter, atau Gly-Tl (Gambar 9-34).
 Neurodegenerative hypothesis of
schizoprenia
&
Neurodevelopmental hypothesis and
genetics of schizoprenia
 Neurodegenerative hypothesis of
schizophrenia
• Both functional and structural abnormalities of
the brain of schizophrenics  neurodegenerative
process with progressive loss of neuronal
function may be ongoing during the course of
schizophrenia
• Hypothesis : genetic programming of abnormal
apoptosis and subsequent degeneration of
critical neurons, prenatal exposure to anoxia,
toxins, infection, or malnutrition and a process of
neuronal loss known as excitotoxicity that initially
can cause positive symptoms
STAGES OF SCHIZOPHRENIA
 Neurodegenerative basis for the
disorder
• Full functioning (100 percent) early in life : virtually asymptomatic
(Stage I)
• During a prodromal phase (Stage II) starting in the teens: odd
behaviors and subtle negative symptoms
• The acute phase in the twenties (Stage III): positive symptoms,
remissions, and relapses but never quite getting back to previous
levels of functioning.
• This is often a chaotic stage of illness with a progressive downhill
course. The final phase of the illness may begin in the forties or
later, with prominent negative and cognitive symptoms and some
waxing and waning, but often more of a "burnout" stage of
continuing disability.
• Continuing and relentless downhill course (-) and the patient may
become progressively resistant to treatment with antipsychotic
medications (Stage IV)
Excitotoxicity and the glutamate system in
neurodegenerative disorders
• Excitotoxicity could be the final common
pathway progressive worsening in any
number of neurologic and psychiatric
disorders
Normal excitatory neurotransmission at NMDA
receptors

• The NMDA receptor : a

ligand-gated ion channel.
This fast transmitting ion
channel is an excitatory
calcium channel
• Occupancy of NMDA
glutamate receptors by
glutamate causes calcium
channels to open and the
neuron to be excited for
neurotransmission
Spectrum of excitation by glutamate at N-methyl-d-
aspartate (NMDA) receptors
 Spectrum of excitation by glutamate at N-methyl-d-
aspartate (NMDA) receptors…

• A major hypothesis : that glutamate may cause

neuronal damage or death by a process of normal
excitatory neurotransmission run amok 
excitotoxicity
• The spectrum of excitation by glutamate:
• Normal glutamate excitation
• Excessive amount of excitatory neurotransmission
• Excitotoxicity that damages dendrites but not
neuronal death;
• Slow progressive excitotoxicity
• Sudden and catastrophic excitotoxicity
Cellular events occurring during
excitotoxicity (1)
• Excitotoxicity : a major current hypothesis for explaining a
neuropathologic mechanism  mediate the final common
pathway of any number of neurologic and psychiatric
disorders characterized by a neurodegenerative course
• The basic idea : normal process of excitatory
neurotransmission runs amok
• Things get out of hand and the neuron is literally excited to
death
• The excitotoxic mechanism thought to begin with a
pathologic process that triggers excessive glutamate activity
• This causes excessive opening of the calcium channel
beginning the process of poisoning of the cell by allowing
too much calcium to enter it
Cellular events occurring during
excitotoxicity (2)
 Cellular events occurring during
excitotoxicity (2)…
• The internal milieu of a neuron is very sensitive to
calcium
• Small increase in calcium concentration  alter the
activities of various enzymes as well as cause
alterations in neuronal membrane excitability
• Calcium levels rise too much begin to activate
enzymes that can be dangerous for the cell owing to
their ability to trigger a destructive chemical cascade
• The beginning of this process may be an underlying
cause of pathologic symptoms of schizophrenia (such
as delusions and hallucinations)
Cellular events occurring during
excitotoxicity (3)
• Excessive glutamate causes too much calcium
to enter the neuron and calcium activates
dangerous enzymes
• The enzymes go on to produce troublesome
free radicals destroying other cellular
components such as organelles and
membranes, by destructive chemical reactions
Cellular events occurring during excitotoxicity (4)
 Cellular events occurring during excitotoxicity (4)…

• As the calcium accumulates in the cell and

the enzymes produce more and more free
radicals, they begin to destroy the dendrites
that serve as postsynaptic targets of
glutamate.
Cellular events occurring during excitotoxicity (5)
 Cellular events occurring during excitotoxicity (5)…

• Too many free radicals lead to indiscriminate

destruction of various parts of the neuron,
especially its neuronal and nuclear membranes
and critical organelles such as energy-producing
mitochondria.
• The damage can be so great that the free radicals
essentially destroy the whole neuron.
• The level of destruction may be related to deficit
states in schizophrenia and be associated with
cognitive, negative, and affective symptoms.
Neurodevelopmental hypothesis of
schizophrenia
 Neurodevelopmental hypothesis of schizophrenia…

• The disorder occurs as a result of abnormalities in brain

development
• Excitotoxicity that occurs early in development, before the
completion of synaptic connections dysconnectivity
between brain regions and consequently symptoms of
mental illness
• Ex: normal development the ventral hippocampus forms
connections with cortical pyramidal neurons to regulate
activity in the prefrontal cortex (left).
• Excitotoxicity in the ventral hippocampus prior to
completion of these connections could impact
development of the prefrontal cortex, causing abnormal
neuronal connections that may lead to symptoms of
schizophrenia (right).
 Neurodevelopmental hypothesis and
genetics of schizophrenia
Inherited or Acquired?
• May start with an acquired neurodegenerative process that
interferes with neurodevelopment.
• Ex: schizophrenia is increased in those with a fetal history of
obstetric complications in the pregnant mother - ranging from viral
infections to starvation to autoimmune processes and other such
problems - suggesting that an insult to the brain early in fetal
development could contribute to the cause of schizophrenia.
• These have the final common pathway of reducing nerve growth
factors and also stimulating certain noxious processes that kill off
critical neurons, such as cytokines, viral infection, hypoxia, trauma,
starvation, or stress.
• This may be mediated by either apoptosis or necrosis
• Also be mediated by excitotoxicity  impact
the development of the prefrontal cortex 
dysconnectivity with the prefrontal cortex
• This abnormal set could be the biological
substrate for symptoms in schizophrenia
• The excitotoxicity could be genetically
programmed or environmentally triggered
 Genes that affect connectivity,
synaptogenesis and NMDA receptors
• The neurodevelopmental processes underlying
schizophrenia are mostly influenced by genes
• Four key genes that regulate neuronal
connectivity and synaptogenesis in schizophrenia
are four key proteins: BDNF (brain-derived
neurotrophic factor), dysbindin (dystrobrevin-
binding protein 1), neuregulin and DISC-1
(disrupted in schizophrenia-1)
• DISC-1 (disrupted in schizophrenia-1) : a protein that is
involved in neurogenesis (A), neuronal migration (B),
and dendritic organization (C)
• Neuregulin is involved in neuronal migration (B),
genesis of glial cells (D), and myelination of neurons by
glial cells (D)
• The abnormalities in the genes for DISC-1 or neuregulin
can disrupt these processes  dysconnectivity among
neurons, abnormal functioning of neuronal circuits
among neurons linked together, increased risk of
schizophrenia, and ultimately the symptoms of
schizophrenia
• Dysbindin, brain-derived neurotrophic factor (BDNF),
DISC-1 (disrupted in schizophrenia-1), and neuregulin
are all involved in synapse formation
• Any subtle molecular abnormalities in these genes
could therefore lead to abnormal synapse formation
(A)
• Specifically, abnormal genetic programming of
dysbindin synaptic cytoarchitecture and scaffolding
• Abnormal genetic programming of DISC-1 and
neuregulin could affect dendritic morphology
• Any of these could contribute to abnormal synapse
formation and increased risk for schizophrenia (B)
• Dysbindin, DISC-1 (disrupted in schizophrenia-1), and
neuregulin are all involved in "strengthening" of
glutamate synapses.
• Under normal circumstances, N-methyl-d-aspartate
(NMDA) receptors in active glutamate synapses trigger
long-term potentiation (LTP), which leads to structural
and functional changes of the synapse to make it more
efficient, or "strengthened."
• This process leads to an increased number of alpha-
amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
(AMPA) receptors, which are important for mediating
glutamatergic neurotransmission
• The genes that regulate strengthening of
glutamate synapses are abnormal
hypofunctioning of NMDA receptors, with a
resultant decrease in LTP and fewer AMPA
receptors
• This would theoretically lead to increased risk
of developing schizophrenia, and these
abnormal synapses could mediate the
symptoms of schizophrenia.
• Strengthened synapses [for glutamate, synapses with
efficient N-methyl-d-aspartate (NMDA)
neurotransmission and multiple alpha-amino-3-
hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
receptors] are more likely to survive than weak
synapses.
• If the genes that regulate strengthening of glutamate
synapses are abnormal, these synapses be weak and
increased risk for elimination, especially during
adolescence, when there is massive restructuring of
the synapses in the brain.
• Affective and negative symptoms of
schizophrenia may involve other areas of the
prefrontal cortex, such as orbital, medial, and
ventral areas
• These brain areas, along with the amygdala,
nucleus accumbens, and other regions,
comprise a "ventral“ system involved in
emotional processing.
Fearful stimuli and schizophrenia
• (A) Normally, exposure to an emotional
stimulus, such as a scary face, causes
hyperactivation in the amygdala.
• (B) Schizophrenic patients often have
impairments in the ability to identify and
interpret emotional stimuli. The underlying
neurobiological explanation for this may be
inefficient information processing within the
ventral system. In this example, the amygdala is
not appropriately engaged during exposure to an
emotional stimulus.
Neutral stimuli and schizophrenia
• (A) Normally, exposure to a neutral stimulus,
such as a neutral face, causes little activation
of the amygdala.
• (B) Schizophrenic patients may mistakenly
judge others as threatening, with associated
inappropriate hyperactivation of the
amygdala.
 SUMMARY
• Dopamine and NMDA receptor hypofunction
hypothesis of schizophrenia: the major
hypotheses for explaining the mechanism
underlying positive, negative, cognitive and
affective symptoms of schizophrenia
• Overactivity of the mesolimbic dopamine system
mediate the positive symptoms of psychosis and
may be linked to hypofunctioning NMDA
glutamate receptors in the descending
corticobrainstem glutamate pathway.
• Underactivity of the mesocortical dopamine
system may mediate the negative, cognitive, and
affective symptoms of schizophrenia and could
also be linked to hypofunctioning NMDA
receptors.
• Dopamine-2 receptors are targets of all known
antipsychotic drugs
• NMDA glutamate receptors require interaction
not only with the neurotransmitter glutamate but
also with the cotransmitters glycine or d-serine.
• Neurodegenerative events such as fetal brain
insults or excitotoxicity may contribute to
schizophrenia
• Neurodevelopmental basis mediated by a whole
host of susceptibility genes that regulate
neuronal connectivity and synapse formation
(abnormal formation of synapses — particularly
those that utilize glutamate as neurotransmitter
and those that function with NMDA receptors) 
central biological flaw in schizophrenia
• Malfunctioning neural circuits can be imaged
in schizophrenic patients, including those in
the dorsolateral prefrontal cortex linked to
cognitive symptoms and those in the
amygdala linked to symptoms of emotional
dysregulation.
THANK YOU