Biochemistry and
Biological Psychiatry
Department of Psychiatry
1st Faculty of Medicine
Charles University, Prague
Head: Prof. MUDr. Jiří Raboch, DrSc.
Introduction

Biological psychiatry studies
disorders in human mind from the
neurochemical, neuroendocrine and
genetic point of view mainly. It is
postulated that changes in brain
signal transmission are essential in
development of mental disorders.
NEURON
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The neurons are the
brain cells that are
responsible for
intracellular and
intercellular signalling.
Action potential is
large and rapidly
reversible fluctuation in
the membrane potential,
that propagate along the
axon.
At the end of axon there
are many nerve
endings (synaptic
terminals, presynaptic
parts, synaptic buttons,
knobs). Nerve ending
form an integral parts of
synapse.
Synapse mediates the
signal transmission from
one neuron to another.
Model of Plasma Membrane
Synapse


Neurons communicate with one
another by direct electrical coupling or
by the secretion of neurotransmitters
Synapses are specialized structures
for signal transduction from one
neuron to other. Chemical synapses
are studied in the biological
psychiatry.
Morphology of Chemical Synapse
Synapses
Chemical
Synapse Signal
Transduction
Criteria to Identify Neurotransmitters
1. Presence in presynaptic nerve terminal
2. Synthesis by presynaptic neuron
3. Releasing on stimulation (membrane
depolarisation)
4. Producing rapid-onset and rapidly
reversible responses in the target cell
5. Existence of specific receptor
There are two main groups of neurotransmitters:
• classical neurotransmitters
• neuropeptides
Selected Classical Neurotransmitters
System
Cholinergic
Aminoacidergic
Monoaminergic
• Catecholamines
• Indolamines
• Others, related to
aa
Purinergic
Transmitter
acetylcholine
GABA, aspartic acid, glutamic
acid, glycine, homocysteine
dopamine, norepinephrine,
epinephrine
tryptamine, serotonin
histamine, taurine
adenosine, ADP, AMP, ATP
Catecholamine Biosynthesis
Serotonin Biosynthesis
Selected Bioactive Peptides
Peptide
Group
substance P, substance K (tachykinins), neurotensin, brain and
cholecystokinin (CCK), gastrin, bombesin
gastrointestinal
peptides
galanin, neuromedin K, neuropeptideY (NPY),
peptide YY (PYY),
neuronal
cortikotropin releasing hormone (CRH)
growth hormone releasing hormone (GHRH),
gonadotropin releasing hormone (GnRH),
somatostatin, thyrotropin releasing hormone (TRH)
hypothalamic
releasing factors
adrenocorticotropic hormone (ACTH)
growth hormone (GH), prolactin (PRL), lutenizing
hormone (LH), thyrotropin (TSH)
pituitary hormones
oxytocin, vasopressin
neurohypophyseal
peptides
atrial natriuretic peptide (ANF), vasoactive intestinal
peptide (VIP)
neuronal and
endocrine
enkephalines (met-, leu-), dynorphin, -endorphin
opiate peptides
Membrane
Transporters
Growth Factors in the Nervous System
Neurotrophins
Nerve growth factor (NGF)
Brain-derived neurotrophic factor (BDNF)
Neurotrophin 3 (NT3)
Neurotrophin 4/5 (NT4/5)
Neurokines
Ciliary neurotrophic factor (CNTF)
Leukemia inhibitory factor (LIF)
Interleukin 6 (IL-6)
Cardiotrophin 1 (CT-1)
Fibroblast growth
factors
FGF-1
FGF-2
Transforming growth
factor 
superfamily
Transforming growth factors  (TGF)
Bone morphogenetic factors (BMPs)
Glial-derived neurotrophic factor (GDNF)
Neurturin
Epidermal growth
factor
superfamily
Epidermal growth factor (EGF)
Transforming growth factor  (TGF)
Neuregilins
Other growth factors
Platelet-derived growth factor (PDGF)
Insulin-like growth factor I (IGF-I)
Membrane Receptors
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
Receptor is macromolecule specialized
on transmission of information.
Receptor complex includes:
1. Specific binding site
2. Transduction element
3. Effector system (2nd messengers)

Regulation of receptors:
1. Number of receptors (down-regulation, upregulation)
2. Properties of receptors (desensitisation,
hypersensitivity)
Receptor Classification
1. Receptor coupled directly to the ion
channel
2. Receptor associated with G proteins
3. Receptor with intrinsic guanylyl
cyclase activity
4. Receptor with intrinsic tyrosine
kinase activity
GABAA Receptor
Receptors
Associated with
G Proteins
• adenylyl cyclase system
• phosphoinositide system
Types of Receptors
System
acetylcholinergic
Type
acetylcholine nicotinic receptors
acetylcholine muscarinic receptors
monoaminergic 1-adrenoceptors
2-adrenoceptors
-adrenoceptors
dopamine receptors
serotonin receptor
aminoacidergic
GABA receptors
glutamate ionotropic receptors
glutamate metabotropic receptors
glycine receptors
histamine receptors
peptidergic
opioid receptors
other peptide receptors
purinergic
adenosine receptors (P1 purinoceptors)
P2 purinoceptors
Subtypes of Norepinephrine
Receptors
RECEPTORS
1-adrenoceptors
2-adrenoceptors
-adrenoceptors
Subtype
Transducer
Structure
(aa/TM)
1A
Gq/11
IP3/DAG
466/7
1B
Gq/11
IP3/DAG
519/7
1D
Gq/11
IP3/DAG
572/7
2A
Gi/o
cAMP
450/7
2B
Gi/o
cAMP
450/7
2C
Gi/o
cAMP
461/7
2D
Gi/o
cAMP
450/7
1
Gs
cAMP
477/7
2
Gs
cAMP
413/7
3
Gs, Gi/o cAMP
408/7
Subtypes of Dopamine Receptors
RECEPTORS
dopamine
Subtype
Transducer
Structure
(aa/TM)
D1
Gs
cAMP
446/7
D2
Gi
Gq/11
cAMP
IP3/DAG, K+,
Ca2+
443/7
D3
Gi
cAMP
400/7
D4
Gi
cAMP, K+
386/7
D5
Gs
cAMP
477/7
Subtypes of Serotonin Receptors
RECEPTORS
5-HT
(5-hydroxytryptamine)
Subtype
Transducer
Structure
5-HT1A
Gi/o
cAMP
421/7
5-HT1B
Gi/o
cAMP
390/7
5-HT1D
Gi/o
cAMP
377/7
5-ht1E
Gi/o
cAMP
365/7
5-ht1F
Gi/o
cAMP
366/7
5-HT2A
Gq/11
IP3/DAG
471/7
5-HT2B
Gq/11
IP3/DAG
481/7
5-HT2C
Gq/11
IP3/DAG
458/7
5-HT3
internal cationic channel 478
5-HT4
Gs
5-ht5A
?
357/7
5-ht5B
?
370/7
5-ht6
Gs
cAMP
440/7
5-HT7
Gs
cAMP
445/7
cAMP
387/7
Feedback to Transmitter-Releasing
Crossconnection of Transducing
Systems on Postreceptor Level
AR – adrenoceptor
G – G protein
PI-PLC – phosphoinositide
specific phospholipase C
IP3 – inositoltriphosphate
DG – diacylglycerol
CaM – calmodulin
AC – adenylyl cyclase
PKC – protein kinase C
Interaction of Amphiphilic Drugs
with Membrane
Potential Action of Psychotropics
1. Synthesis and storage of
neurotransmitter
2. Releasing of neurotransmitter
3. Receptor-neurotransmitter
interactions (blockade of receptors)
4. Catabolism of neurotransmitter
5. Reuptake of neurotransmitter
6. Transduction element (G protein)
7. Effector's system
Classification of Psychotropics
parameter
effect
group
watchfulnes
(vigility)
positive
psychostimulant drugs
negative
hypnotic drugs
affectivity
positive
antidepressants
anxiolytics
psychic
integrations
memory
negative
dysphoric drugs
positive
neuroleptics, atypical
antipsychotics
negative
hallucinogenic agents
positive
nootropics
negative
amnestic drugs
Classification of Antipsychotics
group
examples
chlorpromazine,
basal
chlorprotixene,
clopenthixole,
(sedative)
antipsychotics levopromazine, periciazine,
thioridazine
conventional
antipsychotics
(classical
neuroleptics)
incisive
antipsychotics
atypical antipsychotics
(antipsychotics of 2nd
generation)
droperidole, flupentixol,
fluphenazine, fluspirilene,
haloperidol, melperone,
oxyprothepine, penfluridol,
perphenazine, pimozide,
prochlorperazine,
trifluoperazine
amisulpiride, clozapine,
olanzapine, quetiapine,
risperidone, sertindole,
sulpiride
Mechanisms of Action of
Antipsychotics
 D2 receptor blockade of postsynaptic in
conventional
the mesolimbic pathway
antipsychotics
 D2 receptor blockade of postsynaptic in the
mesolimbic pathway to reduce positive
symptoms;
 enhanced dopamine release and 5-HT2A
atypical
receptor blockade in the mesocortical
pathway to reduce negative symptoms;
antipsychotics
 other receptor-binding properties may
contribute to efficacy in treating cognitive
symptoms, aggressive symptoms and
depression in schizophrenia
Receptor Systems Affected by
Atypical Antipsychotics
risperidone D2, 5-HT2A, 5-HT7, 1, 2
D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D3, 1
sertindole
ziprasidone D2, 5-HT2A, 5-HT1A, 5-HT1D, 5-HT2C, 5HT7, D3, 1, NRI, SRI
D2, 5-HT2A, 5-HT6, 5-HT7, D1, D4, 1,
loxapine
M1, H1, NRI
zotepine
D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D1,
D3, D4, 1, H1, NRI
clozapine
D2, 5-HT2A, 5-HT1A, 5-HT2C, 5-HT3, 5HT6, 5-HT7, D1, D3, D4, 1, 2, M1, H1
olanzapine D2, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, D1,
D3, D4, D5, 1, M1-5, H1
quetiapine D2, 5-HT2A, 5-HT6, 5-HT7, 1, 2, H1
Classification of Antidepressants
(based on acute pharmacological actions)
inhibitors of
monoamine oxidase inhibitors (IMAO)
neurotransmitter
catabolism
reuptake
inhibitors
serotonin reuptake inhibitors (SRI)
norepinephrine reuptake inhibitors (NRI)
selective SRI (SSRI)
selective NRI (SNRI)
serotonin/norepinephrine inhibitors (SNRI)
norepinephrine and dopamine reuptake
inhibitors (NDRI)
5-HT2A antagonist/reuptake inhibitors (SARI)
agonists of
receptors
5-HT1A
antagonists of
receptors
2-AR, 5-HT2
inhibitors or stimulators of other components of signal transduction
Action of
SSRI
Schizophrenia
Biological models of schizophrenia
can be divided into three related
classes:
 Environmental models
 Genetic models
 Neurodevelopmental models
Schizophrenia - Genetic Models
Multifactorial-polygenic threshold
model:
Schizophrenia is the result of a combined
effect of multiple genes interacting with
variety of environmental factors; i.e. several
or many genes, each of small effect,
combine additively with the effects of noninherited factors. The liability to
schizophrenia is linked to one end of the
distribution of a continuous trait, and there
may be a threshold for the clinical
expression of the disease.
Schizophrenia Neurodevelopmental Models
A substantial group of patients, who receive
diagnosis of schizophrenia in adult life, have
experienced a disturbance of the orderly
development of the brain decades before
the symptomatic phase of the illness.
Genetic and no genetic risk factors that may
have impacted on the developing brain
during prenatal and perinatal life pregnancy and birth complications (PBCs):
•
•
•
•
viral infections in utero
gluten sensitivity
brain malformations
obstetric complications
Basis of Classical Dopamine
Hypothesis of Schizophrenia
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Dopamine-releasing drugs (amphetamine,
mescaline, diethyl amide of lysergic acid LSD) can induce state closely resembling
paranoid schizophrenia.
Conventional neuroleptics, that are
effective in the treatment of
schizophrenia, have in common the ability
to inhibit the dopaminergic system by
blocking action of dopamine in the brain.
Neuroleptics raise dopamine turnover as a
result of blockade of postsynaptic
dopamine receptors or as a result of
desensitisation of inhibitory dopamine
autoreceptors localized on cell bodies.
Biochemical Basis of Schizophrenia
According to the classical dopamine
hypothesis of schizophrenia,
psychotic symptoms are related to
dopaminergic hyperactivity in the
brain. Hyperactivity of dopaminergic
systems during schizophrenia is result
of increased sensitivity and density of
dopamine D2 receptors. This increased
activity can be localized in specific
brain regions.
Biological Psychiatry and
Affective Disorders
BIOLOGY
genetics
vulnerability to mental
disorders
stress
increased sensitivity
chronobiology
desynchronisation of
biological rhythms
NEUROCHEMISTRY neurotransmitters availability, metabolism
IMMUNONEUROENDOCRINOLOGY
receptors
number, affinity, sensitivity
postreceptor
processes
G proteins, 2nd messengers,
phosphorylation,
transcription
HPA
increased activity during
depression
(hypothalamicpituitaryadrenocortical)
system
immune function
different changes during
depression
Data for Neurotransmitter
Hypothesis
Tricyclic antidepressants through blockade
of neurotransmitter reuptake increase
neurotransmission at noradrenergic
synapses
MAOIs increase availability of monoamine
neurotransmitters in synaptic cleft
Depressive symptoms are observed after
treatment by reserpine, which depletes
biogenic amines in synapse
Neurotransmitter Hypothesis of
Affective Disorders
catecholamine hypothesis
indolamine hypothesis
cholinergic-adrenergic balance
hypothesis
„permissive“ hypothesis
dopamine hypothesis
hypothesis of biogenic amine
monoamine hypothesis
Monoamine Hypothesis
Depression was due to a deficiency of
monoamine neurotransmitters,
norepinephrine and serotonin. MAOI act as
antidepressants by blocking of enzyme MAO,
thus allowing presynaptic accumulation of
monoamine neurotransmitters. Tricyclic
antidepressants act as antidepressants by
blocking membrane transporters ensuring
reuptake of 5-HT or NE, thus causing
increased extracellular neurotransmitter
concentrations.
Permissive Biogenic Amine
Hypothesis
A deficit in central indolaminergic
transmission permits affective disorder, but
is insufficient for its cause; changes in
central catecholaminergic transmission,
when they occur in the context of a deficit in
indoleaminergic transmission, act as a
proximate cause for affective disorders and
determine their quality, catecholaminergic
transmission being elevated in mania and
diminished in depression.
Receptor Hypotheses
The common final result of chronic
treatment by majority of
antidepressants is the down-regulation
or up-regulation of postsynaptic or
presynaptic receptors. The delay of
clinical response corresponds with
these receptor alterations, hence many
receptor hypotheses of affective
disorders were formulated and tested.
Receptor Hypotheses
Receptor catecholamine hypothesis:
 Supersensitivity of catecholamine receptors in the
presence of low levels of serotonin is the
biochemical basis of depression.
Classical norepinephrine receptor hypothesis:
 There is increased density of postsynaptic -AR in
depression (due to decreased NE release, disturbed
interactions of noradrenergic, serotonergic and
dopaminergic systems, etc.). Long-term
antidepressant treatment causes down regulation of
1-AR (by inhibition of NE reuptake, stimulation or
blockade of receptors, regulation through
serotonergic or dopaminergic systems, etc.).
Transient increase of neurotransmitter availability
can cause fault to mania.
Postreceptor Hypotheses
Molecular and cellular theory of depression:
 Transcription factor, cAMP response elementbinding protein (CREB), is one intracellular
target of long-term antidepressant treatment and
brain-derived neurotrophic factor (BDNF) is
one target gene of CREB. Chronic stress leads to
decrease in expression of BDNF in hippocampus.
Long-term increase in levels of glucocorticoids,
ischemia, neurotoxins, hypoglycaemia etc.
decreases neuron survival. Long-term
antidepressant treatment leads to increase in
expression of BDNF and his receptor trkB through
elevated function of serotonin and norepinephrine
systems.
Antidepressant Treatments
Laboratory Survey in Psychiatry
Laboratory survey methods in psychiatry
coincide with internal and neurological
methods:
 Classic and special biochemical and
neuroendocrine tests
 Immunological tests
 Electrocardiography (ECG)
 Electroencephalography (EEG)
 Computed tomography (CT)
 Nuclear magnetic resonance (NMR)
 Phallopletysmography
Classic and Special Biochemical Tests
Test
Indication
serum cholesterol (3,7-6,5 mmol/l) and
lipemia (5-8 g/l)
brain disease at
atherosclerosis
cholesterolemia, TSH, T3, T4, blood pressure,
mineralogram (calcemia, phosphatemia)
thyroid disorder,
hyperparathyreosis or
hypothyroidism can be an
undesirable side effect of
Li-therapy
hepatic tests: bilirubin (total < 17mmol/l),
cholesterol, aminotranspherase (AST, ALT,
TZR, TVR), alkaline phosphatase
before pharmacotherapy
and in alcoholics
glycaemia
diabetes mellitus
blood picture
during pharmacotherapy
determination of metabolites of psychotropics
in urine or in blood
control or toxicology
lithemia (0,4-1,2 mmol/l), function of thyroid
and kidney (serum creatinine, urea), pH of
urine, molality, clearance, serum
mineralogram (Na, K)
during lithiotherapy
Classic and Special Biochemical Tests
Test
Indication
determination of neurotransmitter
metabolites, e.g. homovanilic acid (HVA, DA
metabolite), hydroxyindolacetic acid (HIAA, 5research
HT metabolite),
methoxyhydroxyphenylglycole (MHPG, NE
metabolite)
neurotransmitter receptors and transporters
research
cerebrospinal fluid: pH, tension, elements,
abundance of globulins (by electrophoresis)
diagnosis of progressive
paralysis, …
neuroendocrinne stimulative or suppressive
tests: dexamethasone suppressive test (DST), depressive disorders
TRH test, fenfluramine test
prolactin determination
increased during treatment
with neuroleptics