Biochemistry and Biological Psychiatry

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Biochemistry and Biological Psychiatry

• ass. prof. Zdenek Fišar, CSc.
• Department of Psychiatry
• 1st Faculty of Medicine
• Charles University, Prague
• Head prof. MUDr. Jirí Raboch, DrSc.

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Biochemistry and Biological Psychiatry

• cellular neurochemistry (neurons, action
  potentials, synapses)
• intercellular signalling (neurotransmitters,
  receptors, growth factors)
• intracellular signalling (G proteins, effectors,
  2nd messengers, proteinkinases, transcription
  factors)
• psychotropic drugs (antipsychotics,
  antidepressants)
• biological hypotheses of mental disorders
  (schizophrenia, affective disorders)

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Biological Psychiatry Web Pages

• 1. Educational portal of our faculty
• http//connect.lf1.cuni.cz
• http//portal.lf1.cuni.cz/
• (section Psychiatry, Psychology, Sexuology)
• 2. Direct links
• http//www.lf1.cuni.cz/zfisar/psychiatry/
• (presentation of lectures from psychiatry)
• http//psych.lf1.cuni.cz/bpen/default.htm
• (teaching material from biological psychiatry)

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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 (at the level of chemical synapse)
  are essential in the development of mental
  disorders.

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Cellular Neurochemistry

• Neurons
• Action potentials
• Synapses

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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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Synapse

• Neurons communicate with one another by
• direct electrical coupling
• 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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Chemical Synapse - Signal Transduction
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Model of Plasma Membrane
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Membrane Transporters
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Intercellular and Intracellular Signalling

• Neurotransmitters
• Growth factors
• Receptors
• G proteins
• Effector systems (2nd messengers, proteinkinases,
  transcription factors)

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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
nitric oxide
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Catecholamine Biosynthesis
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Serotonin Biosynthesis
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Reuptake and Metabolism of Monoamine
Neurotransmitters

• Reuptake
• Monoamine oxidase (MAO)
• Catechol-O-methyltransferase (COMT)

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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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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
• Internal ion channel or transduction element
• Effector system (ion channels or system of 2nd
  messengers)

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Regulation of receptors

1. Density of receptors (down-regulation,
   up-regulation)
2. 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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1. Receptors with Internal Ion Channel
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1. Receptors with Internal Ion Channel
Nicotinic acetylcholine receptor is made of 5
subunits, 2 of which (shown in orange) bind
acetylcholine (red).
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1. Receptors with internal ion channel
GABAA receptor, nicotonic acetylcholine
receptors, ionotropic glutamate receptors, etc.
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2. Receptors Associated with G Proteins

1. adenylyl cyclase system
2. phosphoinositide system
3. arachidonic acid system

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Receptors Associated with G Proteins
SYSTEM Adenylyl cyclase system Phosphoinositide system Arachidonic acid system
NEURO-TRANSMITTER NE, 5-HT, DA, Ach NE, 5-HT, DA, Ach Histamine
TRANSDUCER Gs, Gi Gp Unknown G-protein
PRIMARY EFFECTOR Adenylyl cyclase Phospholipase C Phospholipase A
SECONDARY MESSENGER cAMP IP3, DAG, Ca Arachidonic acid
SECONDARY EFFECTOR Protein kinase A Calcium and calmoduline dependent protein kinases Protein kinase C 5-Lipoxygenase 12-Lipoxygenase Cycloxygenase
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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-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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Psychotropic Drugs

• Biochemical hypotheses of mental disorders are
  based on the study of mechanisms of action of
  psychotropic drugs at the level of
• chemical synapse
• intracellular processes connected with signal
  transduction

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Classification of Psychotropics
parameter effect group
watchfulness (vigility) positive psychostimulant drugs
watchfulness (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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Main Psychotropic Drugs

• Antipsychotics
• Antidepressants
• Anxiolytics
• Hypnotics
• Cognitives
• Psychostimulants
• Hallucinogens

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Potential Action of Psychotropics
1. Synthesis and storage of neurotransmitters
2. Releasing of neurotransmitters
3. Receptor-neurotransmitter interactions (agonists, antagonists)
4. Catabolism of neurotransmitters
5. Reuptake of neurotransmitters
6. Transduction element (G protein)
7. Effector's system
8. Transcription factor activity and gene expression
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Classification of Antipsychotics
Group Examples
Conventional antipsychotics (classical neuroleptics) chlorpromazine, chlorprotixene, clopenthixole, levopromazine, periciazine, thioridazine
Conventional antipsychotics (classical neuroleptics) droperidole, flupentixol, fluphenazine, fluspirilene, haloperidol, melperone, oxyprothepine, penfluridol, perphenazine, pimozide, prochlorperazine, trifluoperazine
Atypical antipsychotics (antipsychotics of 2nd generation) amisulpiride, clozapine, olanzapine, quetiapine, risperidone, sertindole, sulpiride, aripiprazole
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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
aripiprazole D2, 5-HT2A, 5-HT1A, ?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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Biological Hypotheses of Mental Disorders

• Schizophrenia
• Affective disorders

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Schizophrenia

• Biological models of schizophrenia can be divided
  into four related classes
• Environmental models
• Genetic models
• Neurodevelopmental models
• Dopamine hypothesis

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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.
• 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.

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Basis of Classical Dopamine Hypothesis of
Schizophrenia

1. Dopamine-releasing drugs (amphetamine, mescaline,
   LSD) can induce state closely resembling paranoid
   schizophrenia.
2. Antipsychotics, 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.
3. Antipsychotics raise dopamine turnover.

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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 and serotonergic 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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Monoamine Hypothesis

• Depression was due to a deficiency of monoamine
  neurotransmitters, norepinephrine and serotonin.
• Advanced monoamine theory serotonin or
  norepinephrine levels in the brain are regulated
  by MAO-A activity mainly. However, specific
  symptoms of depression or mania are related to
  changes in the activity of monoamine transporters
  in specific brain regions. So, both MAO-A
  activity and density of transporters are included
  in the pathophysiology of affective disorders.

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Permissive Biogenic Amine Hypothesis

• A deficit in central serotonergic 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 serotonergic
  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.

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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. Long-term antidepressant treatment
  causes down regulation of ?1-AR. Transient
  increase of neurotransmitter availability can
  cause fault to mania.

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Neurotransmitter Regulation of Mood and Behavior
Motivation Pleasure Reward
Alertness Energy
Dopamine
Norepinephrine
Attention Interest
Obsession Compulsion
Mood
Anxiety
Serotonin
Nutt 2008
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Postreceptor Hypotheses

• Neurotrophic hypothesis (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.

Duman et al. 1997
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Neurotrophic Effects of Antidepressants
Nestler et al. 2002
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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
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