INTRODUCTION TO BIOLOGICAL PSYCHIATRY (http://www1.lf1.cuni.cz/~zfisar/bpen/default.htm) RNDr. Zdeněk Fišar, CSc. Department of Psychiatry 1 st Faculty of Medicine, Charles University, Prague E-mail: [email protected]This work was supported by FRVŠ 2448/2002 grant.
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INTRODUCTION TO BIOLOGICAL PSYCHIATRYzfisar/bpen/BPEN1.pdf3 Introduction Biological psychiatry occupies itself by mental disorders from biological, chemical and physical point of view.
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Integral and peripheral proteins (ion channels, receptors, enzymes, transporters)
Main properties of lipid bilayer are included in model of fluid mosaic:
1. Heterogeneity in the plane horizontal and vertical
2. Fluid state of most lipids at physiological conditions
3. Translation and rotation movement of membrane molecules
Dynamic properties of biological membranes enable movement and mutual interactions
of membrane proteins (Figure 1.5), so membrane lipids can participate on signal
transduction.
1. NEUROBIOLOGY
9
Figure 1.4. Model of plasma membrane
peripheral glycoproteins glycolipids proteins
cholesterol integral proteins ion α-helix phospholipids channels
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Figure 1.5. Lipid bilayer and function of membrane proteins
(See: Shinitzky M.: Membrane fluidity and receptor function. In: Membrane Fluidity, M. Kates, L.A. Manson, eds., Plenum Publ. Corp. 1984, pp. 585-601.)
movement movement perpendicular in the plane to membrane of membrane
lipid bilayer in fluid state
lipid bilayer in gel state
1. NEUROBIOLOGY
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1.4. Action potential All living cell, including neurons, exhibit a voltage difference across plasma membrane
known as membrane potential. In neurons the resting potential is usually in the range
-40 to -90 mV. Information is carried from one part of the neuron to another in the form
of active response of membrane termed as action potential. Action potential is a large
and rapidly reversible fluctuation in the membrane potential, that propagate along the
axon. Generation and propagation of action potentials are enabled by membrane ion
channels.
Specific properties of axonal membranes allowing signal transmission in the form of
action potentials:
1. There is a threshold for generation of action potential; i.e. small random
fluctuations in the membrane potential are not interpreted as useful information.
2. The all-or-none law ensures full size of action potential.
3. There is frequency coding of the strength and latency of the initial stimulus.
4. Properties of the axonal membrane allow passive spread of the action potential
depolarization along the axon, which is essential in propagation of active
response. Saltatory conduction, i.e. jumping of action potentials along
myelinated axons, is enabled by passive spread of depolarizing stimulus and by
accumulation of ion channels in the nodes of Ranvier.
When the depolarization exceeds threshold the active response of the membrane
occurs and a large change in membrane potential is observed several milliseconds in
duration (Figure 1.6). The amplitude of the action potential is independent on stimulus
intensity. The membrane potential depolarises very rapidly, and then there is a slightly
less rapid return to the resting level. It is impossible to evoke another action potential
immediately after firing of an action potential; this absolute refractory period is followed
by relative refractory period, during which initial depolarization must be larger to evoke
action potential.
Amplitude of action potential carries little information about stimulus that triggered them;
in fact information about stimulus strength and latency can be coded in the frequency of
action potential firing (Figure 1.7).
Zdeněk Fišar: Introduction to Biological Psychiatry
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Figure 1.6. Action potential
Figure 1.7. Frequency coding
(See: Levitan I.B. a Kaczmarek L.K.: The Neuron. Oxford Univ. Press, New York, Oxford, 1997; Ganong W.F.: Přehled lékařské fyziologie. Nakl. a vyd. H&H, 1995.)
equilibrium potential for Na+
40
∆ψ (mV) 20
0
- 20
- 40 threshold
- 60 resting potential
- 80 equilibrium potential for K+
1 2 4 8 16 32 depolarizing time (ms) stimulus
following following latency depolarization hyperpolarization
depolarizing stimulus
small short longer long large+long depolarization stimulus (mV)
+20
0
response ∆ψ (mV) +30
threshold resting potential
time (ms)
1. NEUROBIOLOGY
13
1.5. Ion channels Ion channels underlie electrical signalling in neurons. It is the sum of the various
currents flowing at any point that determines the neuron's membrane potential (Figure
1.8). The activities of the sodium and potassium channels responsible for axonal action
potentials are dependent on voltage.
Sequence of events during the nerve impulse in a large unmyelinated axon (Figure 1.9):
second messengers activate protein kinases A, G, C or CaM-II.
Receptors are able to adapt their properties to increased or decreased activation (Table
2.5, Figure 2.5). Changes in the number of receptors are known mechanism of their
adaptation. But response to receptor activation can be altered at unchanged density of
receptors too. Regulation of properties of receptors consists of decreased or increased
activity of post receptor events, which results in decreased or increased final
physiological response to receptor stimulation (Table 2.6).
Table 2.5. Regulation of receptors
Number of receptors (down-regulation, up-regulation)
Properties of receptors (desensitisation, hypersensitivity)
Table 2.6. Mechanisms of receptor desensitisation
Interactions of subunits of active molecules (by phosphorylation, ribosylation, changes in membrane lipid composition, etc.) Production of messengers - inhibitors of receptors
Production of receptor clusters (by cytoskeleton)
Internalisation of receptors (by endocytosis)
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Figure 2.5. Adaptation of receptors
reactive hyperfunction (upregulation)
balance
secondary hyperfunction
adaptive hypofunction (desensitization)
secondary hypofunction
RECEPTOR
NEUROTRANSMITTER
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2.7. Receptor classification There are many types of receptors and they can be classified by different criteria, for
example according to their pharmacological properties (it is according to activating
neurotransmitter or other agonist) or according to effectors system, which is connected
with their function (Table 2.7).
Table 2.7. Classification of receptors by their effector system
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
2.8. Receptors coupled to ion channels Direct coupling of the neurotransmitter receptor to the ion channel whose activity it
regulates is the simplest and the most rapid way of signal transduction. An example of
receptor with internal ion channel is GABAA receptor, nicotinic acetylcholine receptors,
or ionotropic glutamate receptors.
Nicotinic acetylcholine receptor complex is one of ligand-gated ion channels; it
contains both the acetylcholine binding site and the ion channel that is activated by
acetylcholine binding. Following receptor activation, nicotinic acetylcholine receptors as
well as ionotropic glutamate receptors increase membrane permeability for cations
Na+, K+ or Ca2+; they are excitatory receptors.
Receptor for γ-amino butyric acid includes chlorine (Cl-) channel, which is opened in
response to binding of GABA (Figure 2.6). Chlorine inputs into cell and
hyperpolarization of membrane occurs; so it is inhibitory receptor. There are many
modulation sites on GABAA receptor, for example benzodiazepines positively modulate
activity of this receptor.
Zdeněk Fišar: Introduction to Biological Psychiatry
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Figure 2.6. GABAA receptor
Pi
Cl-
barbiturates GABA, bicuculine neurotransmitter binding site neurosteroids benzodiazepines
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Figure 2.9. Signal transduction: Phosphoinositide system
PI-PLC - phospholipase C specific for phosphoinositides, PIP2 - phosphatidylinositol-4,5-biphosphate, IP3 - inositol-1,4,5-triphosphate; DG - diacylglycerol; PKC – protein kinase C
γ γ Pi Pi β β
Gq αq PKC Gi/o PI-PLCγ αi/o
IP3 protein phosphorylation
Ca2+-dependent Ca2+
processes IP3 receptor
endoplasmic reticulum
receptor receptor receptor Ca2+- with intrinsic associated with s Gq associated with Gi/o channel tyrosin kinase PI-PLCβ1 DG PI-PLCβ2
PIP2 PIP2
2. NEUROCHEMISTRY
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Figure 2.10. Signal transduction: Guanylyl cyclase system
Figure 2.12. 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
PKC
AC
5-HT2 β-AR α2-AR
Ca2+
Ca2+/CaM
IP3 + DAG
PIP2
Gq/11 Gs Gi/o
PI-PLC
-
+
+
-
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normal
Pi
++ -
+
+
excitation inhibition
GαGTP GαGTP
IP3, DG, Ca2+, cAMP, FFA
PLC, PLD, PLA2, AC
gene expression
PKC, PKA, PKCaM
PP
neurotransmitters membrane receptors G proteins effector enzymes second messengers protein kinases and gene expression phosphoprotein phosphatases
+-+-
Pi Pi Pi
Figure 2.13. Scheme of signal transduction (implying feedback)
G – G protein, GTP – guanosine triphosphate, PLC - phospholipase C, PLD - phospholipase D, PLA2 - phospholipase A2, AC – adenylyl cyclase, IP3 – inositoltriphosphate, DG – diacylglycerol, cAMP – cyclic adenosine monophosphate, FFA – free fatty acids, PKC – protein kinase C, PKA – protein kinase A, PKCaM – Ca2+ and calmodulin dependent protein kinase, PP – phosphoprotein phosphatase
3. PSYCHOPHARMACOLOGY
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3. Psychopharmacology Psychopharmacology is very extensive branch of medicine. This chapter will emphasize
basic pharmacological concepts of action of antipsychotics and antidepressants only.
The reader should consult standard reference sources for more information from
psychopharmacology.
Psychotropic drugs are amphiphilic molecules frequently; i.e. they are soluble both in
the water phase and in the lipid bilayer. Amphiphilic drugs rapidly permeate through
plasma membrane and/or accumulate in hydrophobic interior of lipid bilayer (Figure
3.1), so, interactions are possible both with membrane macromolecules and with
cytoplasmatic or nuclear molecules.
Central nervous system drugs act primary as agonists or antagonists of
neurotransmitter receptors, inhibitors of regulatory enzymes or blockers of stimulators of
G proteins, adenylyl cyclase (AC), phospholipase (PL),
protein kinase (PK), phosphatase, ATPase, phospholipid
dependent proteins, transcription factors, 2nd a 3rd
messengers
Therapeutic response is observed after a few weeks of antidepressant treatment; so,
many adaptive changes in cellular functions occur. The neurotransmitter receptor
hypothesis of antidepressant action explains the ultimate mechanism of their
therapeutic action by receptor sensitivity changes. Currently, there is focus on the gene
expression that is activated by antidepressants (see Chapter 5).
Zdeněk Fišar: Introduction to Biological Psychiatry
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Figure 3.2. Potential mechanisms of antidepressants action
transporter COMT
transmitter synthesis metabolic degradation transport to vesicles releasing to synaptic cleft reuptake interaction with receptors interaction with transducers
interaction with presynaptic autoreceptors and heteroreceptors metabolic degradation of neurotransmitter
Schizophrenia is specific human disease. It is group of diseases characterized by
delusions, hallucinations, disorganized speech, grossly disorganized or catatonic
behaviour, of negative symptoms (Table 4.1). Symptoms of schizophrenia can be
subcategorized into:
1. Positive symptoms
2. Negative symptoms
3. Cognitive symptoms
4. Aggressive/hostile symptoms
5. Depressive/anxious symptoms
In this chapter, environmental, genetic, neurodevelopmental and biochemical
hypotheses of schizophrenia are presented. Classification, clinical description and
criteria for diagnosis of schizophrenia are not described.
For practical purposes the descriptive psychopathology of schizophrenia can be treated
in three sections:
1. Purely positive symptoms (hallucinations and other abnormal experiences,
delusions and catatonia)
2. What used to be referred to as psychological deficit, purely negative symptoms –
impaired attention, intelligence, memory, perception and will.
3. Traditional psychopathological groupings containing positive and negative
symptoms (mixed) – thought disorder and disturbances of emotions.
Table 4.1. Positive and negative symptoms of schizophrenia
negative positive
alogia hallucination
affective flattening delusions
avolition – apathy bizarre behaviour
anhedonia – asociality positive formal thought disorder
attentional impairment
Biological models of schizophrenia can be divided into three related classes:
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Environmental models
Genetic models
Neurodevelopmental models
4.1. Environmental models Environmental models suppose that either stress or physical factors are the main
evoking phenomenon in schizophrenia (Table 4.2).
Table 4.2. Environmental models of schizophrenia
Model of “evocative influence of complex social demands”:
There are four criteria for schizophrenia-evoking stress:
1. A situation demanding action or decision
2. Complexity or ambiguity of the information supplied to deal with the task
3. Unless resolved, the situation demanding action or decision persist
4. The subject has no “escape route” available
Most stresses of this nature will be non-pathogenic; a schizophrenia-evoking effect
occurs only in conjunction with a specific genetic liability.
Non-psychosocial environmental model:
An unspecified number of varieties of physical factors will be sufficient to produce the
specific cerebral lesions and dysfunction thought to be characteristic of schizophrenia,
regardless of the presence or absence of a genetic susceptibility (see
“Neurodevelopmental models” below). (See: Jablensky A.: Schizophrenia: the epidemiological horizon. In: Schizophrenia, Hirsch S.R. and Weinberger D.R., eds., Blackwell Science, pp. 206-252, 1995.)
4. SCHIZOPHRENIA
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4.2. Genetic models Evidence for a genetic contribution to schizophrenia comes from twin and familiar
studies. The genetic factors in schizophrenia have specificity as they do not increase
the risk for major affective disorders or delusional disorder. Clearly, schizophrenia is
clinically or phenotypically heterogeneous, but whether this variety is paralleled by
etiological heterogeneity or to what extent is problematic. Genetic models are
summarized in Table 4.3. Published data indicates that monogenic models could be
rejected and multifactorial threshold model or mixed models are favoured.
Table 4.3 Genetic models
Distinct heterogeneity model:
Schizophrenia is a collection of several separate diseases, each associated with single
major locus (SML) that may be inherited either dominantly or recessively. In addition,
there are sporadic, environmentally caused cases.
Monogenic models (single major locus models):
Schizophrenia might be a single-gene dominant disorder with highly variable
expression or reduced penetrance of the trait; i.e. all cases of schizophrenia share the
same single major locus (SML).
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.
A mixed or combined model:
The model includes the elements of some, or all, of the above three. (See: Jablensky A.: Schizophrenia: the epidemiological horizon. In: Schizophrenia, Hirsch S.R. and Weinberger D.R., eds., Blackwell Science, pp. 206-252, 1995; Asherson P., Mant R., McGuffin P.: Genetics and schizophrenia. In: Schizophrenia, Hirsch S.R. and Weinberger D.R., eds., Blackwell Science, pp. 253-274, 1995.)
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4.3. Neurodevelopmental models The leading hypothesis for the aetiology of schizophrenia is related to disturbance in
normal brain development. The principal assumption is that normal brain development
is disrupted in specific ways at critical periods and the resulting lesion produces the
symptoms of schizophrenia only through interaction with the normal maturation
processes in the brain, which occur in late adolescence or early adulthood.
Neurodevelopmental hypothesis states that:
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.
The neurodevelopmental model therefore directs attention to both genetic and no
genetic risk factors that may have impacted on the developing brain during prenatal
and perinatal life; pregnancy and birth complications (PBCs) are considered in
psychiatry:
viral infections in utero
gluten sensitivity
brain malformations
obstetric complications
Genetic contribution to schizophrenia development consists in wrong genetic program
for the normal formation of synapses and migration of neurons in the developing brain.
These risk factors may have the final common effect on nerve growth factors reduction
resulting in structural abnormalities, selection of wrong neurons to survive in the fetal
brain, neuron migration to the wrong places, neuron inervation of wrong targets or mix-
up of the nurturing signals.
4. SCHIZOPHRENIA
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4.4. Delayed onset of symptoms We can propound the question, why is the illness manifestation delayed typically for
about two decades after birth? Delayed onset of symptoms of schizophrenia (in early
adult) can be explained by different mechanisms:
1. There is an additional pathological process occurring around the time of onset of
the clinical symptoms
2. An interaction between a static developmental defect and normal developmental
events that occur in early adulthood is necessary
It is supposed that onset of schizophrenia can be initiated by wrong organization,
elimination and restructuring of synapses during adolescence, which may be or not
secondary to the maldevelopment in utero.
4.5. Neurodegenerative hypothesis Recent post mortem studies on schizophrenics described a multitude of morphological
changes in different brain structures. The most often reported structural alterations are
in the limbic system, mainly in hippocampal formation and parahippocampal and
cingulate gyri. However, other structures such as the thalamus, frontal and temporal
cortex and basal ganglia seem to be affected too.
Neurodegenerative hypothesis of schizophrenia suggest an ongoing
neurodegenerative processes with loss of neuronal function during the course of the
disease. Excitotoxic hypothesis proposes that neurons degenerate as a consequence of
excessive glutamatergic neurotransmission.
Combined neurodevelopmental/neurodegenerative hypothesis suggest that
schizophrenia may be a neurodegenerative process superimposed on a
neurodevelopmental abnormality.
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4.6. Biochemical basis of schizophrenia The biochemical hypotheses of schizophrenia are orientated towards the role of
neurotransmitters and their receptors; dopamine, serotonin, glutamate, GABA,
norepinephrine and so on are considered (Table 4.4). Dopamine plays a key role in
biochemical hypotheses of schizophrenia. Dopamine hypothesis of schizophrenia was
formulated almost 40 years ago by Randrup and Munkvad (1965) and plays a
prominent role in schizophrenia research hitherto. Basis or motives for dopamine
hypothesis are summarized in Table 4.5.
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.
Table 4.4. Biochemical hypotheses of schizophrenia
classical dopamine GABAergic
norepinephrine glutamatergic
serotonin peptidergic
monoaminoxidase membrane
revisited dopamine transmethylation
Table 4.5. 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 neuroleptic drugs, 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.
4. SCHIZOPHRENIA
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Revised dopamine hypothesis of schizophrenia postulate that a reduced striatal
inhibition on the thalamus, caused by either an increased dopaminergic or a reduced
glutamatergic tone, should lead to an increase in arousal and psychomotor activity and
to an increased sensory input transmitted to the cortex. If a certain threshold is
exceeded the integrative capacity of the cortex will become insufficient and this will lead
to positive symptoms of schizophrenia. An excessive dopaminergic function may also
lead to a disintegration of motor functions. This inhibitory function of the striatum
appears to be exerted via the indirect pathways (Figure 4.1 A). The direct pathways
(Figure 4.1 B) should be able to mediate the excitatory glutamatergic input from the
cortex to the thalamus; the dopamine input in the direct pathways appears to be
excitatory, and dopamine should thus be behaviourally stimulating also via the direct
pathways.
Hypothetical scheme of interactions, leading to psychotogenic responses, is shown in
Figure 4.2.
Zdeněk Fišar: Introduction to Biological Psychiatry
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Figure 4.1. Excitatory and inhibitory influence of dopamine on the direct and
indirect pathways
Glu – glutamate, DA – dopamine, GABA - γ-amino butyric acid (See: Carlsson A.: The dopamine theory revisited. In: Schizophrenia, Hirsch S.R. and Weinberger D.R., eds., Blackwell Science, pp. 379-400, 1995.)
+ excitatory action - inhibitory action
cerebral cortex
striatum
substantia nigra, area ventralis tegmenti
thalamus sensory input
behaviour
Glu + Glu +
DA -
3 GABA
-
cerebral cortex
striatum
substantia nigra, area ventralis tegmenti
thalamus sensory input
behaviour
Glu + Glu +
DA +
2 GABA
+
A) „indirect“ pathways (negative feedback)
B) „direct“ pathways (positive feedback)
4. SCHIZOPHRENIA
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cortex
GluGlu
substantia nigra, area ventralis tegmenti
DA
striatum
ACh
GABA
nucleus raphe
5-HT
locus coeruleus
NE
GABA
LSD (5-HT2 agonist) muscimol (GABAA agonist)
PCP (NMDA antagonist)
atropine (M1 antagonist)
PCP (NMDA antag.)
LSD
(5-HT2 agon.)
amphetamine (DA releaser)
Figure 4.2. Potential psychogenic pathways and sites of action of psychotogenic
and antipsychotic agents
LSD – diethyl amid of lysergic acid, PCP – phencyclidine, 5-HT – serotonin, Glu – glutamate, DA – dopamine, GABA – γ-amino butyric acid, ACh – acetylcholine, NE – norepinephrine, NMDA – N-methyl-D-aspartate (See: Carlsson A.: The dopamine theory revisited. In: Schizophrenia, Hirsch S.R. and Weinberger D.R., eds., Blackwell Science, pp. 379-400, 1995.)
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5. Affective disorders
Mood disorders are characterized by depression, mania, or both. In this chapter,
biochemical hypothesis of affective disorders are presented. Classification, clinical
description and criteria for diagnosis of disorders of mood are not described.
Depression and mania are thought to be heterogeneous illnesses that can result from
dysfunction of several neurotransmitter or metabolic systems. Approaches of biological
psychiatry to the affective disorders are summarized in Table 5.1.
Table 5.1 Biological psychiatry and affective disorders
genetics vulnerability to mental disorders stress increased sensitivity
BIOLOGY
chronobiology desynchronisation of biological rhythms
creatinine hepatic tests: GGT, AST, ALT, AF hepatic tests: GGT, AST, ALT, AF total protein, S-albumin glycaemia prothrombine time nephric function (N-urea, S-creatinine) serum Ca, P serum Ca, P lithic acid thyroidal tests toxicological survey of urine cortisolemia alcoholemia screening on syphilis (RRR, BWR) and Lyme
Borreliosis screening on syphilis (RRR, BWR) think on hypovitaminosis B12 ECG HIV test at risk person thorax Rtg urine + deposit urine + deposit toxicological survey of urine ordure uropophyrine and porphobilinogene in urine S-ammonia thorax Rtg cranium Rtg or CT ECG HIV survey EEG or CT
creatinine hepatic tests hepatic tests: GGT, AST, ALT, AF thorax Rtg thyroidal tests ECG screening on syphilis (RRR, BWR) serum minerals and electrolytes think on hypovitaminosis B12 total protein urine + deposit urine + deposit HIV tests special survey: cortisolemia, thyroid tests, serum prolactin, nephric function, EEG, cranium Rtg or CT, special test on laxative
cranium Rtg
Bulimia ECG glycaemia EEG or CT serum Ca, P Malign neuroleptic syndrome ECG all basic blood and urine tests toxicological survey of urine S-creatine kinase special test on laxative myoglobin in urine lumbal puncture to rule out CNS infection ECG thorax Rtg
Zdeněk Fišar: Introduction to Biological Psychiatry
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Table 6.3. Immunological tests
Test Indication
venereal disease research laboratories
(VDRL) Test
syphilis
rapid reagine reaction (RRR) syphilis
antibodies against Borrelia Burgdorferi Lyme Borreliosis