Biochemistry and Biochemistry and Biological PsychiatryBiological Psychiatry

Department of PsychiatryDepartment of Psychiatry11stst Faculty of Medicine Faculty of Medicine

Charles University, PragueCharles University, PragueHead: 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 large is large

and rapidly reversible and rapidly reversible fluctuation in the fluctuation in the membrane potential, that membrane potential, that propagate along the propagate along the axon.axon.

At the end of axon there At the end of axon there are many are many nerve endingsnerve endings (synaptic terminals, (synaptic terminals, presynaptic parts, presynaptic parts, synaptic buttons, knobs). synaptic buttons, knobs). Nerve ending form an Nerve ending form an integral parts of synapse. integral parts of 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 terminal2. Synthesis by presynaptic neuron3. Releasing on stimulation (membrane

depolarisation)4. Producing rapid-onset and rapidly

reversible responses in the target cell5. Existence of specific receptor

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

Selected Classical Neurotransmitters Selected Classical Neurotransmitters

System TransmitterCholinergic acetylcholineAminoacidergic GABA, aspartic acid, glutamic

acid, glycine, homocysteineMonoaminergic

• 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

peptidesatrial 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 site2.2. Transduction elementTransduction element3.3. 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 proteins3.3. Receptor with intrinsic guanylyl Receptor with intrinsic guanylyl

cyclase activitycyclase activity4.4. 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 receptorsacetylcholine muscarinic receptors

monoaminergic 1-adrenoceptors2-adrenoceptors-adrenoceptorsdopamine receptorsserotonin receptor

aminoacidergic GABA receptorsglutamate ionotropic receptorsglutamate metabotropic receptorsglycine receptorshistamine receptors

peptidergic opioid receptorsother 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 466/71B Gq/11 IP3/DAG 519/71D Gq/11 IP3/DAG 572/7

2-adrenoceptors 2A Gi/o cAMP 450/72B Gi/o cAMP 450/72C Gi/o cAMP 461/72D Gi/o cAMP 450/7

-adrenoceptors 1 Gs cAMP 477/72 Gs cAMP 413/73 Gs, Gi/o cAMP 408/7

Subtypes of Dopamine ReceptorsSubtypes of Dopamine Receptors

RECEPTORS Subtype Transducer Structure (aa/TM)

dopamine D1 Gs cAMP 446/7D2 Gi

Gq/11 cAMPIP3/DAG, K+, Ca2+

443/7

D3 Gi cAMP 400/7D4 Gi cAMP, K+ 386/7D5 Gs cAMP 477/7

Subtypes of Serotonin ReceptorsSubtypes of Serotonin ReceptorsRECEPTORS Subtype Transducer Structure

5-HT(5-hydroxytryptamine)

5-HT1A Gi/o cAMP 421/75-HT1B Gi/o cAMP 390/75-HT1D Gi/o cAMP 377/75-ht1E Gi/o cAMP 365/75-ht1F Gi/o cAMP 366/75-HT2A Gq/11 IP3/DAG 471/75-HT2B Gq/11 IP3/DAG 481/75-HT2C Gq/11 IP3/DAG 458/75-HT3 internal cationic

channel478

5-HT4 Gs cAMP 387/75-ht5A ? 357/75-ht5B ? 370/75-ht6 Gs cAMP 440/75-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

anxiolyticsnegative dysphoric drugs

psychic integrations

positive neuroleptics, atypical antipsychotics

negative hallucinogenic agentsmemory 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 sensitivitychronobiology desynchronisation of

biological rhythmsNEUROCHEMISTRY neurotransmitters availability, metabolism

receptors number, affinity, sensitivitypostreceptor 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 synapsesMAOIs increase availability of monoamine neurotransmitters in synaptic cleftDepressive symptoms are observed after treatment by reserpine, which depletes biogenic amines in synapse

Neurotransmitter Hypothesis of Neurotransmitter Hypothesis of Affective Disorders Affective Disorders

catecholamine hypothesisindolamine hypothesischolinergic-adrenergic balance

hypothesis„permissive“ hypothesisdopamine hypothesishypothesis of biogenic aminemonoamine 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 mellitusblood picture during pharmacotherapydetermination 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 researchcerebrospinal 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