Biochemistry%20and%20Biological%20Psychiatry

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Biochemistry and Biological Psychiatry

• Department of Psychiatry
• 1st Faculty of Medicine
• Charles University, Prague
• Head Prof. MUDr. Jirí Raboch, DrSc.

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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.

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• NEURON
• 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.

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Model of Plasma Membrane
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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.

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Morphology of Chemical Synapse
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Synapses
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Chemical Synapse - Signal Transduction
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Criteria to Identify Neurotransmitters
Presence in presynaptic nerve terminal
Synthesis by presynaptic neuron
Releasing on stimulation (membrane depolarisation)
Producing rapid-onset and rapidly reversible responses in the target cell
Existence of specific receptor

• There are two main groups of neurotransmitters
• classical neurotransmitters
• neuropeptides

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Selected Classical Neurotransmitters
System Transmitter
Cholinergic acetylcholine
Aminoacidergic GABA, aspartic acid, glutamic acid, glycine, homocysteine
Monoaminergic
Catecholamines dopamine, norepinephrine, epinephrine
Indolamines tryptamine, serotonin
Others, related to aa histamine, taurine
Purinergic adenosine, ADP, AMP, ATP
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Catecholamine Biosynthesis
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Serotonin Biosynthesis
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Selected Bioactive Peptides
Peptide Group
substance P, substance K (tachykinins), neurotensin, cholecystokinin (CCK), gastrin, bombesin brain and gastrointestinal peptides
galanin, neuromedin K, neuropeptideY (NPY), peptide YY (PYY), neuronal
cortikotropin releasing hormone (CRH) hypothalamic releasing factors
growth hormone releasing hormone (GHRH), gonadotropin releasing hormone (GnRH), somatostatin, thyrotropin releasing hormone (TRH) hypothalamic releasing factors
adrenocorticotropic hormone (ACTH) pituitary hormones
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
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Membrane Transporters
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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)
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Membrane Receptors

• Receptor is macromolecule specialized on
  transmission of information.
• Receptor complex includes
• Specific binding site
• Transduction element
• Effector system (2nd messengers)
• Regulation of receptors
• Number of receptors (down-regulation,
  up-regulation)
• Properties of receptors (desensitisation,
  hypersensitivity)

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Receptor Classification

• Receptor coupled directly to the ion channel
• Receptor associated with G proteins
• Receptor with intrinsic guanylyl cyclase activity
• Receptor with intrinsic tyrosine kinase activity

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GABAA Receptor
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Receptors Associated with G Proteins

• adenylyl cyclase system
• phosphoinositide system

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Types of Receptors
System Type
acetylcholinergic acetylcholine nicotinic receptors
acetylcholinergic acetylcholine muscarinic receptors
monoaminergic ?1-adrenoceptors
monoaminergic ?2-adrenoceptors
monoaminergic ?-adrenoceptors
monoaminergic dopamine receptors
monoaminergic serotonin receptor
aminoacidergic GABA receptors
aminoacidergic glutamate ionotropic receptors
aminoacidergic glutamate metabotropic receptors
aminoacidergic glycine receptors
aminoacidergic histamine receptors
peptidergic opioid receptors
peptidergic other peptide receptors
purinergic adenosine receptors (P1 purinoceptors)
purinergic P2 purinoceptors
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Subtypes of Norepinephrine Receptors
RECEPTORS Subtype Transducer Transducer Structure (aa/TM)
?1-adrenoceptors ?1A Gq/11 ?IP3/DAG 466/7
?1-adrenoceptors ?1B Gq/11 ?IP3/DAG 519/7
?1-adrenoceptors ?1D Gq/11 ?IP3/DAG 572/7
?2-adrenoceptors ?2A Gi/o cAMP 450/7
?2-adrenoceptors ?2B Gi/o cAMP 450/7
?2-adrenoceptors ?2C Gi/o cAMP 461/7
?2-adrenoceptors ?2D Gi/o cAMP 450/7
?-adrenoceptors ?1 Gs ?cAMP 477/7
?-adrenoceptors ?2 Gs ?cAMP 413/7
?-adrenoceptors ?3 Gs, Gi/o ?cAMP 408/7
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Subtypes of Dopamine Receptors
RECEPTORS Subtype Transducer Transducer Structure (aa/TM)
dopamine D1 Gs ?cAMP 446/7
dopamine D2 Gi Gq/11 cAMP ?IP3/DAG, ?K, ?Ca2 443/7
dopamine D3 Gi cAMP 400/7
dopamine D4 Gi cAMP, ?K 386/7
dopamine D5 Gs ?cAMP 477/7
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Subtypes of Serotonin Receptors
RECEPTORS Subtype Transducer Transducer Structure
5-HT (5-hydroxytryptamine) 5-HT1A Gi/o cAMP 421/7
5-HT (5-hydroxytryptamine) 5-HT1B Gi/o cAMP 390/7
5-HT (5-hydroxytryptamine) 5-HT1D Gi/o cAMP 377/7
5-HT (5-hydroxytryptamine) 5-ht1E Gi/o cAMP 365/7
5-HT (5-hydroxytryptamine) 5-ht1F Gi/o cAMP 366/7
5-HT (5-hydroxytryptamine) 5-HT2A Gq/11 ?IP3/DAG 471/7
5-HT (5-hydroxytryptamine) 5-HT2B Gq/11 ?IP3/DAG 481/7
5-HT (5-hydroxytryptamine) 5-HT2C Gq/11 ?IP3/DAG 458/7
5-HT (5-hydroxytryptamine) 5-HT3 internal cationic channel internal cationic channel 478
5-HT (5-hydroxytryptamine) 5-HT4 Gs ?cAMP 387/7
5-HT (5-hydroxytryptamine) 5-ht5A ? 357/7
5-HT (5-hydroxytryptamine) 5-ht5B ? 370/7
5-HT (5-hydroxytryptamine) 5-ht6 Gs ?cAMP 440/7
5-HT (5-hydroxytryptamine) 5-HT7 Gs ?cAMP 445/7
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Feedback to Transmitter-Releasing
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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
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Interaction of Amphiphilic Drugs with Membrane
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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
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Classification of Psychotropics
parameter effect group
watchfulnes (vigility) positive psychostimulant drugs
watchfulnes (vigility) negative hypnotic drugs
affectivity positive antidepressants
affectivity positive anxiolytics
affectivity negative dysphoric drugs
psychic integrations positive neuroleptics, atypical antipsychotics
psychic integrations negative hallucinogenic agents
memory positive nootropics
memory negative amnestic drugs
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Classification of Antipsychotics
group group examples
conventional antipsychotics (classical neuroleptics) basal (sedative) antipsychotics chlorpromazine, chlorprotixene, clopenthixole, levopromazine, periciazine, thioridazine
conventional antipsychotics (classical neuroleptics) incisive antipsychotics droperidole, flupentixol, fluphenazine, fluspirilene, haloperidol, melperone, oxyprothepine, penfluridol, perphenazine, pimozide, prochlorperazine, trifluoperazine
atypical antipsychotics (antipsychotics of 2nd generation) atypical antipsychotics (antipsychotics of 2nd generation) amisulpiride, clozapine, olanzapine, quetiapine, risperidone, sertindole, sulpiride
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Mechanisms of Action of Antipsychotics
conventional antipsychotics D2 receptor blockade of postsynaptic in the mesolimbic pathway
atypical antipsychotics D2 receptor blockade of postsynaptic in the mesolimbic pathway to reduce positive symptoms enhanced dopamine release and 5-HT2A receptor blockade in the mesocortical pathway to reduce negative symptoms other receptor-binding properties may contribute to efficacy in treating cognitive symptoms, aggressive symptoms and depression in schizophrenia
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Receptor Systems Affected by Atypical
Antipsychotics
risperidone D2, 5-HT2A, 5-HT7, ?1, ?2
sertindole D2, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, D3, ?1
ziprasidone D2, 5-HT2A, 5-HT1A, 5-HT1D, 5-HT2C, 5-HT7, D3, ?1, NRI, SRI
loxapine D2, 5-HT2A, 5-HT6, 5-HT7, D1, D4, ?1, 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, 5-HT6, 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
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Classification of Antidepressants (based on
acute pharmacological actions)
inhibitors of neurotransmitter catabolism monoamine oxidase inhibitors (IMAO)
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 inhibitors or stimulators of other components of signal transduction
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Action of SSRI
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Schizophrenia

• Biological models of schizophrenia can be divided
  into three related classes
• Environmental models
• Genetic models
• Neurodevelopmental models

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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 non-inherited 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.

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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

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Basis of Classical Dopamine Hypothesis of
Schizophrenia

• 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.

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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.

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Biological Psychiatry and Affective Disorders
BIOLOGY genetics vulnerability to mental disorders
BIOLOGY stress increased sensitivity
BIOLOGY chronobiology desynchronisation of biological rhythms
NEUROCHEMISTRY neurotransmitters availability, metabolism
NEUROCHEMISTRY receptors number, affinity, sensitivity
NEUROCHEMISTRY postreceptor processes G proteins, 2nd messengers, phosphorylation, transcription
IMMUNONEURO- ENDOCRINOLOGY HPA (hypothalamic-pituitary-adrenocortical) system increased activity during depression
IMMUNONEURO- ENDOCRINOLOGY immune function different changes during depression
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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
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Neurotransmitter Hypothesis of Affective
Disorders
catecholamine hypothesis
indolamine hypothesis
cholinergic-adrenergic balance hypothesis
permissive hypothesis
dopamine hypothesis
hypothesis of biogenic amine
monoamine hypothesis
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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.

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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.

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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.

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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.

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Postreceptor Hypotheses

• Molecular and cellular theory of depression
• Transcription factor, cAMP response
  element-binding 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.

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Antidepressant Treatments
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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

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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 lt 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
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Classic and Special Biochemical Tests
Test Indication
determination of neurotransmitter metabolites, e.g. homovanilic acid (HVA, DA metabolite), hydroxyindolacetic acid (HIAA, 5-HT metabolite), methoxyhydroxyphenylglycole (MHPG, NE metabolite) research
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), TRH test, fenfluramine test depressive disorders
prolactin determination increased during treatment with neuroleptics