Biochemistry and Biological Psychiatry
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Transcript of Biochemistry and Biological Psychiatry
Biochemistry and Biochemistry and Biological PsychiatryBiological Psychiatry
Department of PsychiatryDepartment of Psychiatry
11stst Faculty of Medicine Faculty of Medicine
Charles University, PragueCharles University, Prague
Head: Prof. MUDr. Jiří Raboch, DrSc.Head: Prof. MUDr. Jiří Raboch, DrSc.
IntroductionIntroduction
Biological psychiatry studies Biological psychiatry studies disorders in human mind from the disorders in human mind from the neurochemical, neuroendocrine and neurochemical, neuroendocrine and genetic point of view mainly. It is genetic point of view mainly. It is postulated that changes in brain postulated that changes in brain signal transmission are essential in signal transmission are essential in development of mental disorders.development of mental disorders.
NEURONNEURON The The neuronsneurons are the are the
brain cells that are brain cells that are responsible for responsible for intracellular and intracellular and intercellular signalling.intercellular signalling.
Action potentialAction potential is is
large and rapidly large and rapidly reversible fluctuation in reversible fluctuation in the membrane potential, the membrane potential, that propagate along the that propagate along the axon.axon.
At the end of axon there At the end of axon there are many are many nerve nerve endingsendings (synaptic (synaptic terminals, presynaptic terminals, presynaptic parts, synaptic buttons, parts, synaptic buttons, knobs). Nerve ending knobs). Nerve ending form an integral parts of form an integral parts of synapse. synapse.
SynapseSynapse mediates the mediates the signal transmission from signal transmission from one neuron to another.one neuron to another.
Model of Plasma Membrane Model of Plasma Membrane
SynapseSynapse
Neurons communicate with one Neurons communicate with one another by another by direct electrical couplingdirect electrical coupling or or by the by the secretion of neurotransmitterssecretion of neurotransmitters
SynapsesSynapses are specialized structures are specialized structures for signal transduction from one for signal transduction from one neuron to other. Chemical synapses neuron to other. Chemical synapses are studied in the biological are studied in the biological psychiatry.psychiatry.
Morphology of Chemical Synapse Morphology of Chemical Synapse
SynapsesSynapses
Chemical Chemical Synapse - Synapse -
Signal Signal Transduction Transduction
Criteria to Identify Neurotransmitters 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 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
aahistamine, taurine
Purinergic adenosine, ADP, AMP, ATP
Catecholamine Biosynthesis Catecholamine Biosynthesis
Serotonin Biosynthesis Serotonin Biosynthesis
Selected Bioactive Peptides 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)
adrenocorticotropic hormone (ACTH)pituitary hormonesgrowth hormone (GH), prolactin (PRL), lutenizing
hormone (LH), thyrotropin (TSH)
oxytocin, vasopressin neurohypophyseal peptides
atrial natriuretic peptide (ANF), vasoactive intestinal peptide (VIP)
neuronal and endocrine
enkephalines (met-, leu-), dynorphin, -endorphin opiate peptides
Membrane Membrane Transporters Transporters
Growth Factors in the Nervous System 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-1FGF-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 Membrane Receptors
ReceptorReceptor is macromolecule specialized is macromolecule specialized on transmission of information.on transmission of information.
Receptor complex includes:Receptor complex includes:1.1. Specific binding siteSpecific binding site
2.2. Transduction elementTransduction element
3.3. Effector system (2Effector system (2ndnd messengers) messengers)
Regulation of receptorsRegulation of receptors::1.1. Number of receptors (down-regulation, up-Number of receptors (down-regulation, up-
regulation)regulation)
2.2. Properties of receptors (desensitisation, Properties of receptors (desensitisation, hypersensitivity)hypersensitivity)
Receptor Classification Receptor Classification
1.1. Receptor coupled directly to the ion Receptor coupled directly to the ion channelchannel
2.2. Receptor associated with G proteinsReceptor associated with G proteins
3.3. Receptor with intrinsic guanylyl Receptor with intrinsic guanylyl cyclase activitycyclase activity
4.4. Receptor with intrinsic tyrosine Receptor with intrinsic tyrosine kinase activitykinase activity
GABAGABAAA Receptor Receptor
Receptors Receptors Associated with Associated with
G ProteinsG Proteins
• adenylyl cyclase system
• phosphoinositide system
TypeTypess of Receptors of Receptors System Type
acetylcholinergic 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 Subtypes of Norepinephrine Receptors Receptors
RECEPTORS Subtype Transducer Structure (aa/TM)
1-adrenoceptors 1A Gq/11 IP3/DAG 466/7
1B Gq/11 IP3/DAG 519/7
1D Gq/11 IP3/DAG 572/7
2-adrenoceptors 2A Gi/o cAMP 450/7
2B Gi/o cAMP 450/7
2C Gi/o cAMP 461/7
2D Gi/o cAMP 450/7
-adrenoceptors 1 Gs cAMP 477/7
2 Gs cAMP 413/7
3 Gs, Gi/o cAMP 408/7
Subtypes of Dopamine ReceptorsSubtypes of Dopamine Receptors
RECEPTORS Subtype Transducer Structure (aa/TM)
dopamine D1 Gs cAMP 446/7
D2 Gi
Gq/11 cAMPIP3/DAG, K+, Ca2+
443/7
D3 Gi cAMP 400/7
D4 Gi cAMP, K+ 386/7
D5 Gs cAMP 477/7
Subtypes of Serotonin ReceptorsSubtypes of Serotonin ReceptorsRECEPTORS Subtype Transducer Structure
5-HT(5-hydroxytryptamine)
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 cAMP 387/7
5-ht5A ? 357/7
5-ht5B ? 370/7
5-ht6 Gs cAMP 440/7
5-HT7 Gs cAMP 445/7
Feedback to Transmitter-Releasing Feedback to Transmitter-Releasing
Crossconnection of Transducing Crossconnection of Transducing Systems on Postreceptor Level Systems on Postreceptor Level
AR – adrenoceptorG – G proteinPI-PLC – phosphoinositide
specific phospholipase CIP3 – inositoltriphosphateDG – diacylglycerolCaM – calmodulinAC – adenylyl cyclasePKC – protein kinase C
Interaction of Amphiphilic Drugs Interaction of Amphiphilic Drugs with Membrane with Membrane
Potential Action of Psychotropics Potential Action of Psychotropics
1. Synthesis and storage of neurotransmitter
2. Releasing of neurotransmitter3. Receptor-neurotransmitter
interactions (blockade of receptors)4. Catabolism of neurotransmitter5. Reuptake of neurotransmitter6. Transduction element (G protein)7. Effector's system
Classification of Psychotropics Classification of Psychotropics parameter effect group
watchfulnes (vigility)
positive psychostimulant drugs
negative hypnotic drugs
affectivity positive antidepressants
anxiolytics
negative dysphoric drugs
psychic integrations
positive neuroleptics, atypical antipsychotics
negative hallucinogenic agents
memory positive nootropics
negative amnestic drugs
Classification of Antipsychotics Classification of Antipsychotics group examples
conventional antipsychotics(classical neuroleptics)
basal (sedative) antipsychotics
chlorpromazine, chlorprotixene, clopenthixole, levopromazine, periciazine, thioridazine
incisive antipsychotics
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
Mechanisms of Action of Mechanisms of Action of Antipsychotics 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
Receptor Systems Affected by Receptor Systems Affected by Atypical Antipsychotics 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
Classification of AntidepressantsClassification of Antidepressants (based on acute pharmacological actions)(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
Action of Action of SSRISSRI
SchizophreniaSchizophrenia
Biological modelsBiological models of schizophrenia of schizophrenia can be divided into three related can be divided into three related classes:classes:
Environmental modelsEnvironmental models Genetic modelsGenetic models Neurodevelopmental modelsNeurodevelopmental models
Schizophrenia - Genetic Models Schizophrenia - Genetic Models
Multifactorial-polygenic threshold Multifactorial-polygenic threshold modelmodel::
Schizophrenia is the result of a combined Schizophrenia is the result of a combined effect of multiple genes interacting with effect of multiple genes interacting with variety of environmental factors; i.e. several variety of environmental factors; i.e. several or many genes, each of small effect, or many genes, each of small effect, combine additively with the effects of non-combine additively with the effects of non-inherited factors. The liability to inherited factors. The liability to schizophrenia is linked to one end of the schizophrenia is linked to one end of the distribution of a continuous trait, and there distribution of a continuous trait, and there may be a threshold for the clinical may be a threshold for the clinical expression of the disease.expression of the disease.
Schizophrenia - Schizophrenia - Neurodevelopmental Models Neurodevelopmental Models
A substantial group of patients, who receive A substantial group of patients, who receive diagnosis of schizophrenia in adult life, have diagnosis of schizophrenia in adult life, have experienced a disturbance of the orderly experienced a disturbance of the orderly development of the brain decades before development of the brain decades before the symptomatic phase of the illness.the symptomatic phase of the illness.
GGenetic and no genetic risk factorsenetic and no genetic risk factors that may that may have impacted on the developing brain have impacted on the developing brain during prenatal and perinatal lifeduring prenatal and perinatal life - - pregnancy and birth complications (PBCs):pregnancy and birth complications (PBCs):
• viral infections viral infections in uteroin utero• gluten sensitivitygluten sensitivity• brain malformationsbrain malformations• obstetric complicationsobstetric complications
Basis of Classical Dopamine Basis of Classical Dopamine Hypothesis of Schizophrenia Hypothesis of Schizophrenia
Dopamine-releasing drugs (amphetamine, Dopamine-releasing drugs (amphetamine, mescaline, diethyl amide of lysergic acid - mescaline, diethyl amide of lysergic acid - LSD) can induce state closely resembling LSD) can induce state closely resembling paranoid schizophrenia.paranoid schizophrenia.
Conventional neuroleptics, that are Conventional neuroleptics, that are effective in the treatment of effective in the treatment of schizophrenia, have in common the ability schizophrenia, have in common the ability to inhibit the dopaminergic system by to inhibit the dopaminergic system by blocking action of dopamine in the brain.blocking action of dopamine in the brain.
Neuroleptics raise dopamine turnover as a Neuroleptics raise dopamine turnover as a result of blockade of postsynaptic result of blockade of postsynaptic dopamine receptors or as a result of dopamine receptors or as a result of desensitisation of inhibitory dopamine desensitisation of inhibitory dopamine autoreceptors localized on cell bodies.autoreceptors localized on cell bodies.
Biochemical Basis of Schizophrenia Biochemical Basis of Schizophrenia
According to the According to the classical dopamine classical dopamine hypothesishypothesis of schizophrenia, of schizophrenia, psychotic symptoms are related to psychotic symptoms are related to dopaminergic hyperactivity in the dopaminergic hyperactivity in the brain. Hyperactivity of dopaminergic brain. Hyperactivity of dopaminergic systems during schizophrenia is result systems during schizophrenia is result of increased sensitivity and density of of increased sensitivity and density of dopamine D2 receptors. This increased dopamine D2 receptors. This increased activity can be localized in specific activity can be localized in specific brain regions.brain regions.
Biological Psychiatry and Biological Psychiatry and Affective Disorders Affective Disorders
BIOLOGY genetics vulnerability to mental disorders
stress increased sensitivity
chronobiology desynchronisation of biological rhythms
NEUROCHEMISTRY neurotransmitters availability, metabolism
receptors number, affinity, sensitivity
postreceptor processes
G proteins, 2nd messengers, phosphorylation, transcription
IMMUNONEURO-ENDOCRINOLOGY
HPA (hypothalamic-pituitary-adrenocortical) system
increased activity during depression
immune function different changes during depression
Data for Neurotransmitter Data for Neurotransmitter Hypothesis 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 Neurotransmitter Hypothesis of Affective Disorders Affective Disorders
catecholamine hypothesis
indolamine hypothesis
cholinergic-adrenergic balance hypothesis
„permissive“ hypothesis
dopamine hypothesis
hypothesis of biogenic amine
monoamine hypothesis
Monoamine Hypothesis Monoamine Hypothesis
Depression was due to a deficiency of Depression was due to a deficiency of monoamine neurotransmitters, monoamine neurotransmitters, norepinephrine and serotonin. MAOI act as norepinephrine and serotonin. MAOI act as antidepressants by blocking of enzyme MAO, antidepressants by blocking of enzyme MAO, thus allowing presynaptic accumulation of thus allowing presynaptic accumulation of monoamine neurotransmitters. Tricyclic monoamine neurotransmitters. Tricyclic antidepressants act as antidepressants by antidepressants act as antidepressants by blocking membrane transporters ensuring blocking membrane transporters ensuring reuptake of 5-HT or NE, thus causing reuptake of 5-HT or NE, thus causing increased extracellular neurotransmitter increased extracellular neurotransmitter concentrations.concentrations.
Permissive Biogenic Amine Permissive Biogenic Amine Hypothesis Hypothesis
A deficit in central indolaminergic A deficit in central indolaminergic transmission permits affective disorder, but transmission permits affective disorder, but is insufficient for its cause; changes in is insufficient for its cause; changes in central catecholaminergic transmission, central catecholaminergic transmission, when they occur in the context of a deficit in when they occur in the context of a deficit in indoleaminergic transmission, act as a indoleaminergic transmission, act as a proximate cause for affective disorders and proximate cause for affective disorders and determine their quality, catecholaminergic determine their quality, catecholaminergic transmission being elevated in mania and transmission being elevated in mania and diminished in depression.diminished in depression.
Receptor Hypotheses Receptor Hypotheses
The common final result of chronic The common final result of chronic treatment by majority of treatment by majority of antidepressants is the down-regulation antidepressants is the down-regulation or up-regulation of postsynaptic or or up-regulation of postsynaptic or presynaptic receptors. The delay of presynaptic receptors. The delay of clinical response corresponds with clinical response corresponds with these receptor alterations, hence many these receptor alterations, hence many receptor hypotheses of affective receptor hypotheses of affective disorders were formulated and tested.disorders were formulated and tested.
Receptor HypothesesReceptor HypothesesRReceptor catecholamine hypothesiseceptor catecholamine hypothesis:: Supersensitivity of catecholamine receptors in the Supersensitivity of catecholamine receptors in the
presence of low levels of serotonin is the presence of low levels of serotonin is the biochemical basis of depression.biochemical basis of depression.
Classical norepinephrine receptor hypothesisClassical norepinephrine receptor hypothesis:: There is increased density of postsynaptic There is increased density of postsynaptic -AR in -AR in
depression (due to decreased NE release, disturbed depression (due to decreased NE release, disturbed interactions of noradrenergic, serotonergic and interactions of noradrenergic, serotonergic and dopaminergic systems, etc.). Long-term dopaminergic systems, etc.). Long-term antidepressant treatment causes down regulation of antidepressant treatment causes down regulation of 11-AR (by inhibition of NE reuptake, stimulation or -AR (by inhibition of NE reuptake, stimulation or blockade of receptors, regulation through blockade of receptors, regulation through serotonergic or dopaminergic systems, etc.). serotonergic or dopaminergic systems, etc.). Transient increase of neurotransmitter availability Transient increase of neurotransmitter availability can cause fault to mania.can cause fault to mania.
Postreceptor Hypotheses Postreceptor Hypotheses
Molecular and cellular theory of depressionMolecular and cellular theory of depression:: Transcription factor, Transcription factor, cAMP response element-cAMP response element-
binding proteinbinding protein (CREB), is one intracellular target (CREB), is one intracellular target of long-term antidepressant treatment and of long-term antidepressant treatment and brain-brain-derived neurotrophic factorderived neurotrophic factor (BDNF) is one (BDNF) is one target gene of CREB. Chronic stress leads to target gene of CREB. Chronic stress leads to decrease in expression of BDNF in hippocampus. decrease in expression of BDNF in hippocampus. Long-term increase in levels of glucocorticoids, Long-term increase in levels of glucocorticoids, ischemia, neurotoxins, hypoglycaemia etc. ischemia, neurotoxins, hypoglycaemia etc. decreases neuron survival. Long-term decreases neuron survival. Long-term antidepressant treatment leads to increase in antidepressant treatment leads to increase in expression of BDNF and his receptor trkB through expression of BDNF and his receptor trkB through elevated function of serotonin and norepinephrine elevated function of serotonin and norepinephrine systems.systems.
Antidepressant TreatmentsAntidepressant Treatments
Laboratory Survey in Psychiatry Laboratory Survey in Psychiatry
Laboratory survey methods in psychiatry Laboratory survey methods in psychiatry coincide with internal and neurological coincide with internal and neurological methods:methods:
Classic and special biochemical and Classic and special biochemical and neuroendocrine testsneuroendocrine tests
Immunological testsImmunological tests Electrocardiography (ECG)Electrocardiography (ECG) Electroencephalography (EEG)Electroencephalography (EEG) Computed tomography (CT)Computed tomography (CT) Nuclear magnetic resonance (NMR)Nuclear magnetic resonance (NMR) PhallopletysmographyPhallopletysmography
Classic and Special Biochemical Tests 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 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 determinationincreased during treatment with neuroleptics