Psycho-pharmacology
76-806-01
Thanks to Ayala Klimek
Structural methods:
Skull X-rays: Using radioactive rays and projecting them onto area and placing a photo board on the other side. The more dense the material the whiter the parts on the picture. Bones come out white. Problems - exposure to radioactive rays can be damaging to healthy. It is also difficult to see the brain itself because we only see the skull. Therefore this is rare to use x-rays for brains. Cerebral angiography: Inject into a persons blood "homer nugudi" which has a different density to blood and to use an x-ray to see blood vessels in the brain. E.g. strokes etc. Used when there is indication of problem with blood vessels. EEG - ElectroEncephalon Graph -Electric Impulses of the brain: Allows us to get a graphic sketch of brain activity without actually looking at the brain. It gives us functional aspect of brain. Hans Berger found that if he connects electrodes to outside of skull allow person to see electrical activity in brain. Electrical activity is connections between neutrons in brain which communicate with one another. Each electrode picks up different activities but is still limited because be have billions of neurons in the brain. Fairly good resolutions can be received and rather quickly. Each electrode has a graph line and shows activity. There are 4 types - frequency of waves per second. All waves appear simultaneously. Beta (13-30 Hz) - is most dominant in person who is fully awake. Alpha (8-13 Hz) - is slower and is dominant in a person who is sitting quietly and in a relaxed state but awake. Theta (4-8 Hz) - meditative, trance state, day dreaming state. Delta (<4 Hz) - predominant in sleep stage. When we dream Beta wave are dominant because the brain in very active. The waves change and transfer from one to the other in transactional stages. We use this test to determine if there is problem in certain part of brain as a diagnostic tool. Abnormal activity indicates a problem. EEG can also be used to observe the progression of a disability. Mild ischemic - like a stroke and when there is severe ischemia then there is a flat line and death. Epilepsy: Epileptic fit - presence of brain activity under no external stimulus. There are two types epileptic fits: Generalized Tonic Clonic seizure (the entire brain, Tonic-tension of muscles, clonic- relaxed muscles. This releases neurotransmitters in the brain and physical fatigue like after extreme exercise. Petimal fit (children in age 4-6) the child does a repetitive act and disappears from the world for a while, switches off for a few minutes. Localized Seizure (the fit is only in a certain location depending on areas that is attacked. Can be visual, sensual etc). EEG has other uses in the criminal field: When a person is exposed to something surprising AAAAGAA - the G will produce a wave P300 because it is surprising. Mental Prosthesis - a person looks at a board and wants to say a word he looks at a letter and forms a word and the P300 affect takes place, this way he can communicate if he lost natural way of communicating. This is similar to the polygraph. Hyperactivity- ADHD - EEG can be therapeutic tool to define the patient's position. Neurofeedback treatment to treat ADHD. Attention Deficit Hyperactivity Disorder - The DSM speak of 3 modules which are present over time: Lack of attention: Less girls are diagnosed because they are dreamers. Boys are naturally hyperactive. Lack of attention is selective. Does not seem to hear what others are saying. Does not finish homework. In adults there is better concentration or especially when things are written. Coming on time, managing time. Not able to consider alternatives. Forgetfulness. If medication works then the diagnose is correct and if not then not (this, unfortunately is how it works in reality). Many emotional problems produce similar symptoms to ADHD. A diagnoses needs to be whole (כוללני) relating to all aspects. The symptoms of ADHA prevent a person from doing things due to fear of failure. Hyperactivity: Action in ones life, adventurous sports, keeping busy, talkative, addictive behaviours, impulsive behaviour, sees only the present. These symptoms need to appear in all aspects of life. There are 3 types of ADHD people: More attention deficit, more hyperactivity and impulsivity, the integration of both. Chronological development of attention at the frontal lobe matures. Infants first have over stimulation, then autistic attention, then moving focus of attention from target to target, sharing attention. ADHD has other pathologies with may exist (not causal relationship but correlations or high risk). Treatment - Ritalin, works for 3-4 hours and effect stops. It increases the level of dopamine in the synapses in certain part of brain. A normal person, with normal levels of dopamine will lead to high, sharpness similar to cocaine and fight or flight reaction. A person with ADHD, his levels of dopamine are lower than normal therefore they act hyperactively to compensate for the lack of energy. If he takes the Ritalin there is more dopamine in synapses and is more balanced and therefore he does not have to be hyperactive to compensate. There are side effects to this medication (like all other matters). There can be long term changes with people who take Ritalin on a daily basis. But what are the effects of not taking Ritalin and the child dealing with frustration, low self-esteem etc. Its all cost-benefit ratio. The brain of ADHD is lack of activity in areas of brain connected to attention and motoric areas. Therefore by means of behaviour the person tries to compensate for lack of activity in brain. EEG - we can see in pre-frontal lobe (attention, delay, planning) there is prominence of theta waves, meaning he is in a meditative state and not concentrated. There are few beta waves. As we grow up the alpha waves develop and the brain activity is more focused. The theta waves of dreaming and imagining are more common when we are younger and then the alpha waves develop. But with people with ADHD they are mainly in theta and not in beta. Biofeedback - feedback form biological info form body. Tells us what happens in body here and now. We can control what is happening in our body. People who are more nervous or active have more sweat from fingers and then he hears the sound of level of excitement/nervousness. A person learns to control his emotions and reactions and is aware of them. This person is helped to cope with stress. ADHA - nerofeedback treatment - feedback comes from neural cells. ADHA - increasing beta waves through operant conditioning. There are pleasant or unpleasant sound as enforcement and punishment.Functional Methods:
PET - Positron emission tomography: Measures cerebral glucose metabolism using radioactive tracker à marker of neuron activity (usually radioactive glucose or even oxygen). Neurons with are more active acquire more oxygen and glucose, just like a muscle which is used. Glucose which is radioactive is injected into the body and then tracked so see where it moves to in the brain. We ask person to think of something like a trauma or a situation and we see how he reacts mentally and where glucose is directed to. This gives us the place that is active in processing trauma for example. Or areas in brain responsible for good and bad is faulty (psychopaths). Cannot self-regulate fear for example. Use PET for diagnoses of disease like cancer for example. Activity in neuron needs energy = glucose, therefore there will be more blood in that location of the brain. Method: Person is asked consent then inserted into the scanner and head is secured. Radioactive glucose is injected. Person is asked questions. Not to be exposed to PET scan more than 4 times a year. Radioactive material disintegrates. PET cameras are constructed such that opposing detectors are connected. When separate events in paired detectors coincide an annihilation even is presumed to have occurred at some point along imagery. When the ray coincides some energy is released. Disadvantages: radioactive material. Limited to 4 times a year. The moment a person is exposed to trigger there is delay before the machine picks it up. There may be a delay of a second, a few seconds or even a minute. Therefore this is not so accurate and the resolutions are not exact. Looks like colourful pictures showing activity. The red area shows brain activity. Visual area is at back of brain, audio near ears, thinking in frontal cortex etc. Also people who dream and have eyes closed see with their brain like some blind people. The impairment can be in the organ (eye or ear) or in the brain itself. In people with Parkinson's there is less activity but once he gets eldopa treatment it is more similar to normal brain. PET scans of infant children - we can see the increase of brain activity. There is very little brain activity in depressed people. With schizophrenia (lack of activity in frontal lobe). PET also detects tumors - too much blood flow of glucose sugar. PET is less accurate but gives dynamic picture. CT is more accurate but static. Brain scan of a Cocaine drug addict is functional and is of normal active activity only with use of the drug. There can be a predisposition to drug use through lower default brain activity and then a person does self medication to compensate.Telencephalon: Left and right brain
Cerebral cortex: The external part of the brain which is divided into two hemispheres and the central fissure divides it. They are symmetric but certain sides have preferences. For example some are ambidextrous, some have preferred leg to walk up stairs. The two hemispheres are different preferences. Left brain (steps and details): Analysis, words, logic, linearity, lists, numbers, sequence. Broca and Vernica (understanding language). Processes negative feeling. Reading maps with details. Right brain (the big picture): Rhythm, spatial, wholeness, daydreaming, imagination, synthesize. Processes positive feeling. Spatial understanding of directions. Parallel to understanding language a person has musical ability.Occipital Lobe:
Back part or brain - אורפית. Area of vision and associative areas that connect the primary visual area and those that interpret what was registered. Area number 17 - vision area, area 18, 19 are associative areas. There areas 17 and 18,19 communicate in this occipital area. Info from the area is (then connected other emotional and cognitive associative areas), talmus (does integration between 18, 19 but is in different area of brain, using all the other associative areas), associates with the temporal (smelling) and others. Many schemes and memories are activates. There is no place for memory in brain because memory is multi- dimensional using numerous neural networks. What happens when there is an injury to 17 - there is loss of vision in a specific are on the opposite side. If larger areas of area 17 are injured thee is larger blind spots. This is brain blindness because here is nothing wrong with the רשתית. This blind stops can be compensated for since the eyes and head moves to complete picture. Therefore often people will not know that they have this handicap - ליקוי. We complete through bottom up and top down processes. Visual Agnosia: picture of pipe and it says this is not a pipe. This is people we see but do not know what they see. They cannot interpret what they see if they have an injury in areas 18,19. They see but do not know what it is. They can describe everything to detail about object/person but cannot say "this is my wife". There is no confabulations (completing info and inventing details). Examples of this can be seen in optical illusions.Parietal Lobe: קודקודית
On top of brain. Does sensory mapping of every organ in body connected to touch. Somato-tropism of touch sensor from body. This is proportional to sensitivity of touch of organ. The more sensitive an organ is (ie. More touch receptions on the skin per square centimeter) then area is parietal area is larger. The back is a large area but is not as sensitive as lips of fingers. A small area for the back and more area of קליפת מוח is given to sensitive areas like lips, fingers. There is a proportional picture of body "homunculus". The primary location is responsible for feeling touch (from where pain or touch comes, when it comes, hard or gentile). The secondary associative areas are connected to consciousness of body and how one experience the body. What is meaning of this area and associative area. If there is pathology then there are clumsy children. They see perfectly but do not know the gap between their body and objects. These are also cultural differences. Physical distance between people when speaking (or this area or cultural). If there is pathology then there is also a symbolic problems to connected to special orientation, then I can also have problem to perceive the other and what the other feels and sees in his experience. We need to change out visual perspective of objects. To try to see the picture from another place. This is not connected to vision. They will need to see the world for other point of view and symbolically to the picture/world from another point of view. This is connected empathy. Another function of the associative area of the parietal area. Responsible for spatial coordination that build the world. Is able to do a mental rotation of objects/letters. Some objects are identical and one needs to be rotated so that we see the two objects are the same. If there is pathology it will be difficult to read an analogical watch with hands. This abilities develop with age and maturity. Dislexia - jumping lines, skipping letters. Using a ruler helps. Letters are similar because cannot be mentally rotates. Cannot differentiated between right and left. Acalculia, Agraphia This does not necessary connected to dyslexia but can be connected to this area. Is there is serious injury is when certain areas of body are not felt. Aprexia - תנועות גסות של ידיים - knowing how to make movements more delicate. Injury in right parietal area - problem with special perception. Can get lost. Neglect - neglecting the consciousness of the area in body connected to the opposite side of body. They see things but do not pay attention or notice things.Temporal Lobe -צדית, רכתית
Auditory primary lobe - connected to hearing. Language area on right side Auditory Emotional - left hand side Left side Broka - to say language, using muscles and speaking. Will understand language but will not be able to speak physically. Right side - Vernika - to understand language. Injury in this areas - speaking works and sounds but will not be connected to any spoken language will language rules. Hippocampus inside the brain under the cortex, deeper behind the temporal. Responsible for memory from short term to long term and organizing memories.Frontal lobe:
The largest part of brain. Takes more the 2/3 or cortex. In the primary area is the motor ability because there is mapping of all organs and limbs and the control of the motor of these organs and limbs. The representation is proportional to the motor control that we have over the area. There is very much control over the muscles of limps that can express numerous feelings. Fingers - there is a lot of control. If one mentally practice playing musical instrument then area in the brain in charge of control of these fingers gets bigger. Motor-homunculus. Another part of frontal lobe is the pre-frontal lobe. It matures latest. It is the מושב האינטלקט האנושי. The prefrontal lobe plans for the future, judges, moral or not. Playing chess, planning marriage and children. Ability to imagine and delay impulses because its not worth it, עלות-תועלת. Problems in super ego - morals OCD, addictions, - impulses Changing thought schemes - mental and emotional disorders like depression.Semester
2:
20/5/08
Schizophrenia
"A Beautiful Mind"
There are a number of schizophrenias (catatonic, paranoid)
Psychoses is very common - Passage from Samuel 1 21: 11- ?. A description of a mad man in the bible. Exorcisms were sometimes performed to rid possessed individuals of the psychology disorder caused by evil spirits.
Throughout history schizophrenics was perceived in various ways:
Mystic - evil spirit- different brain - difficult childhood (schizophrenogenic mother which is not consistent behaviour) - social rebellion = madness
Schizophrenia is a heterogenic
group of other diseases.
Consists of a number of behavious like psychoses - loss of permanent
connection to reality.
Psychoses had delusions הרהורי -שווא which cannot be disproved
by logical claimor the mind on the person cannot be changed. Thinking
that neighbors are transmitting radio waves to ones head.
Hallucinations - הזיות: The world is perceived in another way (sensual perceptions). Hearing voices and seeing visions.
Sever psychoses - can be an
emergency, can have life risking for person and others. He can try to
fly, cut himself, be violent etc. Emergency from psychiatric or physical
perspective (like a LCD pill). Psychoses indicated that a person may
have a physical problem like temperature and inflammation of part of
brain, or a person has been poisoned (LCD or other drug) etc.
Psychoses and delirium
Delirium : a person has . הכרה מעורפל. Does not know what day it is
בעות המצאות, מעורפל, חוסר תפקוד מוחי מוחטת
Psychoses: a person will know
what his name is, will know he needs to be dressed
DSM: Diagnostic Manual
No person will ever have all criteria, but the manual helps us to organize a chaotic world. But there is a problem with stigma
Axis I: Major disorder (psychotic, anxiety, mood)
Axis II: Personality (borderline, OCD)
Axis III: Psychical disorder (diabetic, thyroid, obese etc )
Axis IV: Psychosocial and environment, family.
Axis V: Overall functioning
on a scale form 0-100.
Other Psychotic types
Delusional Disorder - הפרעת הרהור שווא
Brief Psychotic Disorder - הפרעת פסיכוטית חולפת
Substance Induced Psychotic Disorder - can induce schizophrenia in the future.
Schizophrenia:
Prominence of 1% of population.
A 1/3 of sever schizophrenics are in psychiatric wards, develops in
second decade of life, 20-50% attempt suicide, 10% succeed (6X more
than in population)
There are 2 stages:
Active: psychotic episode
Stable: and remission, light hallucination may be present.
Schizophrenia is a multi-dimensional disorder influencing various parts of life and high intensity:
Perception, cognition. Emotion, volition
Objective and subjective behavioural signs of schizophrenia:
Perception - hallucination, paranoid thoughts
Subjective behavioural signs of schizophrenia:
Change in thought process - racing thoughts, retardation, delusions, ideas of reference (ייחוס), lack or decrease and minimal speech, lack of selective attention
Change is conscious - confusion, non coherent speech
Change is affect - dull, fat, overactive, ambivalence
Objective behavioural signs of schizophrenia:
Change in interpersonal relations - lacking fine tuning to social situations, physical appearance, avoiding social relations, lack of communication or not active
Change in activity - psychomotor activity, rigidity, agitation, echopraxia (repetitive movements), stereotypical (repetitive words and behaviour).
Types of schizophrenia:
Type I: Positive symptoms - symptoms that appear - hallucination, delusions, over activity
Type II: Negative symptoms - all that decreases - dull and flat affects, decrease is thought, attention, motivation etc. Affect flattening, alogia (logic and words decrease), avolition, anhedonia (decreased emotion and joy), attentional impairment, ambivalence, associations.
One month positive, 6 months of negatives to diagnoses schizophrenia
Louis Wain (artist who painted
cats). Became schizophrenia and continued painting.
The schizophrenogenic mother:
The mother and her style of
mothering which is not constant leads to alck of basic security in child,
disability to creat a logial world and cuase and affect and the child
ability to decide. But this does not explain why these types of mothers
have normal children.
Biological influence and genetic influences:
Monozygotic twins - 48% risks of developing schizophrenia
First degree relatives - 9-13% risks
Second degree relatives - 2-6% risks
Population - 1% risk
28/5/08
We can conclude that chances of becoming schizophrenic is much higher if once genetic family member is schizophrenic. And max ability to predict schizophrenia is 48% in identical twins. Therefore more than 50% is environment (including family, school, therapists, caregivers etc.). It is a complex disease which is probably due to a number of genes. WE do not yet know the genetic basis of schizophrenia. We cannot do preventive treatment because we do not yet know the genetic makeup of the disease.
There are a number of structural data which are common to all schizophrenics:
Change in 3 areas of brain: Prefrontal lobe, temporal lobes (hearing hallucination), limbic system (connected to feeling, emotional lack, paranoia, violence and aggressing connected to over emotional activation not connected to stimuli), both negative and positive symptoms. Agitation, motor activity (גרעיני הבסיס)- basells.
We have these constant findings, are statistically proven, but are also common in other disorders and therefore these are not necessary indicators of schizophrenia. The change is not large enough not ייחודי מדי to indicate schizophrenia. But why are all these brain areas connected.
Loss of brain volume in monozygotic schizophrenic twins. Butterfly shaped, fluid . large butterfly in a affected twin because there is less brain matter and more fluid.
Pet scan -in unaffected scan there is brain activity in all areas, looks normal.
The affected twin we see orange and red colours meaning more active (temporal) and blue in prefrontal (less active) comparing to the unaffected twin.
FMRI - a picture of entire brain 3D, we see decrease in activity of prefrontal. May be connected to positive and negative symptoms. There is motor change yet new invented language , or emotional overactivity and same time dull affect. It seems like contradictions. Hilgard - Look much dopamine. Parkinson - lack of dopamine. But today we see a more complex picture (in some areas there is lack, in others overactivity, surplus).
Temporal lobes left ( the more he hallucinates, voices, etc, then the activity connected to brain , veronica, broke are more active. Broke is also active when we talk to ourselves , or talking but in the heart or mind. We do not use lips but Broke is active and reads these words. When schizophrenics report of auditory hallucinations their broke is very active. Brian looks the same in hallucination as when they head speaking. Each cell that hears sound in primary area is active without the external stimuli.
There is connecting of hearing
voices in the temporal lobes and also in the broke language area. Therefore
they really hear voices and this is their reality.
Environmatla causes:
Schizophrenia breakes out in the second decade in life. The trigger is stress. The stress enable the schizophrenia to be expressed. If we had a predisposition and had stress then it will be expressed, but we cannt ever know.
In Israel with recursions to the army ther is a liot of stress and caos - everything is determined to the person. Using drugs can also increase schizophrenia because it makes changes in the brain and emotional regulation. This is a trigger.
Etiology:
Dopamine theory:
The first theory is most common and most easy to prove and logical . In last 20 years theory it changed/modified.
20 years ago. Continuum between schizophrenia and Parkinson.
Today - over dopamine in synapses on brain of schizophrenia. To treat schizophrenia there must be treatment which decrease dopamine. The first generations of pharmacology make a revolution because many patients were released to community. The symptoms were decreases (hallucinations) but negative symptoms became much worse, deteriorated (alienation, cannot concentrate, cannot regulate emotions etc) and the sick persons abilities were deceased and cannot function in a day to day basis and are hopeless due to the medication. The most common thing is schizophrenia is compliance and the sliding doors.
What is dopamine - a neurotransmitter - moves info from one nerve cell to another. Nerve cell produces at end axon the molecular or neurotransmitters. Nerve cell is connected of 3 parts. The nucleus of the cell (center ball), dendrites are the hairs coming for the body of cell, the soma. These dendrites can be split or less but changes when we learn, then there are more dendrites and more splits are formed. On the axon (the tail of the cell), it knows how to transfer info, process info or to loose info. A cell which gets info it gets it through receptions on the dendrites on the body of the cell. The body cell and dendrites receive info - there fore the bigger it is and the more there are the more it received. When neurotransmitters on head are chemical paths. On Axon (Hillock), there are calculations of which info may come in and which may not and whether they pass criteria. This occurs in the stem of the axon. If the calculation concludes send info, then the electric impulse moves message through the entire axon and then reaches the next cell. There is synapse (spaces) between each cell and info moves through the synapse. All feeling of joy and sorrow comes from the synapse. We have 100 billion of these cells in the brain. At each second in time each cell getting 1000 till 100 thousands of messages simultaneously.
How does message more through synapse?
At end of axon thee is a mechanism
responsible to transmit info. It releases neurotransmitters in packages
which are collected on end of axon and wait for release when electric
pulse is sent. Then they release their contents into the synapse.
Once they are released into synapse they are close to the receptor and
stick to the receptors and it released its contents. Neurotransmitter
dos not enter the cell. The dendrites absorb the neurotransmitters contents.
The synapse dilutes the neurotransmitter so that they wont travel to
other cells where they were not intended to go.
85% of the molecules are released return to the end of the axon and are absorbed before they were even used. This is called reuptake. 14,5% of the remaining 15% are diluted by an enzyme called COMT (once it gets to dopamine or noradrenalin it dilutes them).
Presynapse - Post synapse. The COMP diluted mefarek so that there will be clean space for the new neurotransmitter to be absorbed. The COMP acts automatically without thinking if that’s the right thing to do. Therefore only half a percent gets to his target. There are many mental diseases that are connected to over neurotransmitters, therefore the COMP acts as a double break system. When a person has the synapse with more that the 14,5% percent or less we have a problem. Medications and drugs change the number of available neurotransmitters that are in the synapses. This is a chemical process. This deterined everything, metal illness, if I am in love or hate, or angry etc.
The original dopamine hypotheses
says there is continuum of schizophrenia and Parkinson. We need to check
what produces the dopamine. Begine will ingredients of matter form which
dopamine is produces. This matter, Tirozin is an amino acid with protein.
Amino acids are in blood after digestion. Tirozin is a חיוני positive
amino acid which is not produced by body, only through nutrition. If
I don’t eat then everything connected to dopamine will be limited.
Tirozin is caught by enzym TH becomes "dopa". Another enzyme
called LAAAD catches this dopa and turns it into dopamine. This neurotransmitter
is critical for mood. In nerve cells of dopamine there are 2 enzymes.
In other nerve cell there is also a third enzyme called DpH. In nerve
cells of Nuroadrenaline … the DpH turns the dopamine into the neuroadrenaline.
This all depends on whether there are 2 or 3 enzymes there are at end
of axon. Both dopamine and neroadrenaline are produced by tironzin.
DNA determines whether the cell will have 2 or 3 enzymes. Only in one
place in body
(adrenal) we have all the enzymes TH, LAAAD, DpH. In the cell in can
produce the hormone adrenaline because it has all the enzymes. The brain
does not have the ability to produce adrenaline. PNMT - enzyme.
3/6/08
We eat protein which is digested
and becomes amino acid (Tirozin). TH turns Tiroznin to Dopa. LAAAD
takes dopa and turns it into dopamine. If I only have these 2 then the
there will be pnly dopamine. Dopaminargic cell. If there is a 3rd
amino acid it will become neroadrenaline. There is only one place
where they have all 4 amino acid it will turn everything into adrenaline
which is in the blood which will get into each and every cell (unlike
a neuro-transmitter which is only in brain in synapse.
Dopamine - schizophrenia have a problem with their dopamine.
There are 4 pathways on dopamine in the rain, seeds of nerve cell which are pathways.
The first pathway begins in
the brain stem in an area called substantia nigra (the area is black
due to the dopamine). (There are cells with axons of millimeters while
others are hundreds on centimeters.) There are nerve pathways which
lead to Basal Ganglia. The body of cell of dopamine is in the substantia
nigra and the pathway moves all the way to the Basal Ganglia. This is
the "nigro
striatal path"
and its function is motor functioning. There is no feeling and thought
in this area only motor activity because it is an areas low in the brain.
With
Parkinson patient we see the dysfunction of the motor activity in this
pathway. The major symptoms in dysfunctional motor activity. Begins
at age of late 30's and 40's. Begins with tremor of muscles, has less
control over fingers. Less control over tongue and speak seems swallowed.
Later there is ridged posture and walk. So it begins with too much action
and then becomes ridged. This is a progressive disease for which there
is no treatment. Later patient cannot become physically disabled, cannot
dress, cannot control urinal needs. Degenerative disease. Fewer dopamine
cells there mean less motor activity and less brain activity in that
area. There is no problem with muscles but in the brain which sends
the messages.
How do we treat?
Give dopamine in the form of oral pill or vein, but this does not increase the dopamine in brain BBB (blood brain barrier) which is a wall which prevents mater to enter brain. This serves survival. Dopamine molecule is so large that is has not way of entering the brain. But "dopa" is more refined and smaller and therefore has a chance of entering the brain. Parkinson so not have problem with tirozin, dopa and dopamine but the problem is in the enzyme TH. Ldopa treatment works for mild and medium but not for severe Parkinson. Works as long as the system works weakly. What about the dose? How do we know exactly which dose to give? The dose increase as the disease progresses. But still cells continue dying so medication only aids with cells that are still functioning. Sometimes side affects of treatment are light psychoses, then dose should be decreased.
If there is noo much dopamine
in this path - there will be over motor- hyperkinetic, restlessness,
movements, ticks or in extreme cases there is catatonia (over used of
all the muscles and motor.
Second path: mesolymbic path
Source in the brain stem and reaches the limbic system responsible for regulation of feelings. If there is over activity there will be presence positive symptoms (intense emotions, and fears). All the anti-psychotic medications put barriers on receptors.
This comes from brain stem from an areas called the tegmentum which send paths to the nucleus accumbens, responsible for pleasure (anhedonia and dull feelings together).This is the mesolymbic path connected to positive symptoms.
Theory: all anti-psychotic medication barrier hosem- receptors of dopamine and therefore is best theory we have at the moment. Carlson won Nobel prize in 2000.
Empirical lab research: If Amphetamines like speed, cocaine are given to normal people then I can induce psychoses. These amphetamines increase activity and discharge of dopamine in synapses.
Experiment: Materials which cancel/decrease amphetamines decrease psychoses.
These two studies support the
dopamine theory that psychoses is connected to dopamine.
Semester 2:
20/5/08
Schizophrenia
"A Beautiful Mind"
There are a number of schizophrenias (catatonic, paranoid, hebephrenic etc.)
Psychoses is a common symptom - Passage from Samuel 1 21: 11- There is a description of a mad man in the bible. Exorcisms were sometimes performed to rid possessed individuals of the psychology disorder caused by evil spirits.
Throughout history schizophrenics was perceived in various ways:
Mystic - evil spirit - different brain - difficult childhood (schizophrenogenic mother which is not consistent behaviour) - social rebellion = madness
Schizophrenia is a heterogenic group of other diseases. Consists of a number of symptoms like psychoses - loss of permanent connection to reality.
There are two types of psychoses:
Delusions הרהורי -שווא : which cannot be disproved by
logical persuasion and the mind on the person cannot be changed. Thinking
that neighbors are transmitting radio waves to ones head.
Hallucinations - הזיות: The world is perceived in another way (sensual perceptions). Hearing voices and seeing visions.
Sever psychoses - can be an
emergency, can be life threatening for person and others. He can try
to fly, cut himself, be violent etc. In other cases there may also be
urgency with psychoses induced through substance use (like a LCD pill).
Psychoses may also be an indicator that a person may have a physical
problem like temperature and inflammation in part of brain, or a person
has been poisoned (LCD or other drug) etc.
Psychoses and delirium
Delirium: a person has הכרה מעורפל. Does not know what day it is
בעות המצאות, מעורפל, חוסר תפקוד מוחי מוחטת
Psychoses: a person
will know what his name is, will know he needs to be dressed etc.
DSM: Diagnostic Manual
No person will ever have all criteria, but the manual helps us to organize a chaotic world. But there is a problem with stigma
Axis I: Major disorder (psychotic, anxiety, mood)
Axis II: Personality (borderline, OCD)
Axis III: Psychical disorder (diabetic, thyroid, obese etc )
Axis IV: Psychosocial and environment, family.
Axis V: Overall functioning
on a scale form 0-100.
Other Psychotic types
Delusional Disorder - הפרעת הרהור שווא
Brief Psychotic Disorder - הפרעת פסיכוטית חולפת
Substance Induced Psychotic
Disorder - can induce schizophrenia in the future.
Schizophrenia:
Prevalence of 1% of population.
A 1/3 of sever schizophrenics are in psychiatric wards. Schizophrenia
develops in second decade of life; 20-50% attempt suicide; 10% succeed
- 6X more than in population.
There are 2 stages:
Active: psychotic episode
Stable: and remission, light hallucination may be present.
Schizophrenia is a multi-dimensional disorder influencing various parts of life. Perception, cognition, emotion, volition
Objective and subjective behavioural signs of schizophrenia:
Perception - hallucination, paranoid thoughts
Subjective behavioural signs of schizophrenia:
Change in thought process - racing thoughts, retardation, delusions, ideas of reference (ייחוס), lack or decrease and minimal speech, lack of selective attention
Change is conscious - confusion, non coherent speech
Change is affect - dull, flat, overactive, ambivalence
Objective behavioural signs of schizophrenia:
Change in interpersonal relations - lacking fine tuning to social situations, physical appearance, avoiding social relations, lack of communication and initiation.
Change in activity - psychomotor activity, rigidity, agitation, echopraxia (repetitive movements), stereotypical (repetitive words and behaviour).
Types of schizophrenia:
Type I: Positive symptoms - symptoms that appear - hallucination, delusions, over activity.
Type II: Negative symptoms - lack or decreases - dull and flat affect, decrease is thought, attention, motivation etc. Affect flattening, alogia (logic and words decrease), avolition, anhedonia (decreased emotion and joy), attentional impairment, ambivalence, associations.
Diagnosis: To diagnose schizophrenia - one month positive and 6 months of negative symptoms.
Louis Wain (artist who painted
cats). Became schizophrenia and continued painting.
The schizophrenogenic mother:
The mother and her style of
mothering which is not constant leads to lack of basic security in child,
disability to create a logical world of cause and effect, and effect
child's ability to decide. But this does not explain why these types
of mothers also have normal children.
Biological influence and genetic influences:
Monozygotic twins - 48% risks of developing schizophrenia
First degree relatives - 9-13% risks
Second degree relatives - 2-6% risks
Population - 1% risk
27/5/08
We can conclude that the probability of becoming schizophrenic is much higher if one genetic family member is schizophrenic. And max ability to predict schizophrenia is 48% in identical twins. Therefore more than 50% is due to environment (including family, school, therapists, caregivers etc). It is a complex disease which is probably due to a number of genes. We do not yet know the genetic basis of schizophrenia. We cannot use preventive treatment because we do not yet know the genetic makeup of the disease.
There are a number of structural data which are common to all schizophrenics:
Change in 3 areas of brain: Prefrontal lobe, temporal lobes (hearing hallucination), limbic system (connected to feeling, emotional lack, paranoia, violence and aggressing connected to over emotional activation not connected to stimuli), and both negative and positive symptoms. Agitation, motor activity (גרעיני הבסיס)- basils.
These dysfunctions have been statistically proven, however, are also common in other disorders hence are not necessary indicators of schizophrenia. The change is not large enough not unique or exclusive to indicate schizophrenia. But why are all these brain areas connected.
Brain volume: Loss of brain volume in monozygotic schizophrenic twins. There is a large butterfly shape in affected twins because there is less brain matter and a lot of fluid.
Pet scan -in unaffected people the scan shown normal brain activity in all areas.
In affected twin we see orange and red colours meaning more active (temporal) and blue in prefrontal (less active) comparing to the unaffected twin.
FMRI - a picture of entire brain 3D, we see decrease in activity of prefrontal. Maybe connected to positive and negative symptoms. There is motor change yet new invented language, or emotional overactivity and simultaneously dull affect. There seem to be contradictions. Hilgard book refers to too much dopamine, while in Parkinson there is lack of dopamine. Today we know the picture is more complex (in some areas there is lack, in others over activity/surplus).
Temporal lobes left (More activity
in the Vernika and Broke areas, therefore more hallucinates and hearing
voices). Broke is also active when we talk to ourselves or thinking
to ourselves. We do not use lips but Broke is active and reads these
words. When schizophrenics report auditory hallucinations their Broke
is very active. The brain looks the same in hallucination and when hearing
speaking. In hallucination, each cell that hears a sound in the primary
area is active without the external stimuli. There is a connection between
hearing voices in the temporal lobes and also in the Broke language
area. Therefore they really hear voices and this is their reality.
Environmental causes:
Schizophrenia breaks out in the second decade in life. The trigger is stress. The stress enables the schizophrenia to be expressed. If we have a predisposition and were exposed to stress then it will be expressed, but we cannot ever know.
In Israel with recruitment
to the army there is increased stress and chaos. Each person reacts
differently. Using drugs can also increase schizophrenia because it
makes changes in the brain and emotional regulation. This is a trigger.
Etiology - we will discuss 4 theories:
1) Dopamine Theory
2) Neurodevelopment Hypothesis
3) Serotonergic Theory (change is serotonin)
4) Glutamatergic
Theory (connected to glutamate neurotransmitter in brain).
1) Dopamine theory:
The first theory is most common, logical and easiest to prove. In last 20 years this theory has been changed and modified.
20 years ago it was believed that schizophrenia and Parkinson are on a continuum.
Today we know in schizophrenia there is too much dopamine in the synapses of the brain. Treating schizophrenia includes decreasing dopamine levels. The first generation of pharmacology was revolutionary because many patients were released to community. Positive symptoms (hallucinations) were decreases but negative symptoms deteriorated (alienation, lack of concentration, cannot regulate emotions etc) and the schizophrenics abilities deteriorated, couldn’t function on a day to day basis and were hopeless due to the medication. The most common thing in schizophrenia is compliance and the sliding doors effect.
Dopamine is a neurotransmitter which transfers information from one nerve cell to another. Neurotransmitters are produced at the end of the nerve cells at the axon.
The nerve cell is divided into three parts:
The nucleus of the cell (center ball).
Dendrites are the hairs coming for the body/soma of cell. These dendrites can differ in number and form and are modified through learning by splitting up and increasing in number.
Axon (the tail of the cell), transfer information and is responsible for processing information or loosing information. A cell receives information through receptors on the dendrites on the body of the cell. The soma and dendrites receive information - the bigger the soma the dendrites there are to receive information.
Neurotransmitters in the brain are chemical paths. The Axon (Hillock), regulates by calculating which information may pass and which is blocked - checks whether it passes criteria. This process occurs in the stem of the axon. If the axon orders that information be sent then an electric impulse transfers the message through the entire axon to the next cell. There is synapse (spaces) between each cell and information is transferred through the synapse. All feeling of joy and sorrow comes from the synapse. We have 100 billion of these cells in the brain. Each and every second every cell receives 1000 to 100 000 of these messages simultaneously.
How does message more through synapse?
At end of the axon there is a mechanism responsible for transmitting information. It releases neurotransmitters in packages which are collected at the end of the axon and wait to be released. When electric pulses are sent they release their contents into the synapse. Once released into the synapse these neurotransmitters attach themselves to the receptors/dendrites of the next cell and release their contents. Neurotransmitters do not enter the cell. The dendrites absorb the neurotransmitters contents. The synapse dilutes the rest of the neurotransmitter so that it won't travel to other cells where they were not intended to go.
85% of the molecules which are released return to the end of the axon and are absorbed before they were even used. This is called reuptake. 14,5% of the remaining 15% are diluted by an enzyme called COMT (dilutes any dopamine or noradrenalin on contact).
Pre synapse - Post synapse.
The COMP dismantles and dilutes the neurotransmitter creating a clean space for new neurotransmitters to be absorbed. The COMP acts automatically without logical thinking. Therefore only half a percent of neurotransmitters get to their target. Many mental diseases are connected to excess of neurotransmitters therefore the COMP acts as a double break system. There is a disorder when there is more or less than the 14,5% of neurotransmitter is a synapse. Medications and drugs change the number of available neurotransmitters that are in the synapses. This is a chemical process which determines whether on is mentally ill, in love, feels hate, anger etc.
The original dopamine hypothesis claims that schizophrenia and Parkinson are on a continuum. We need to determine what produces dopamine.
Dopamine is produced by and consists of:
Tirozin is an amino acid with protein. Amino acids are in blood after digestion. Tirozin is an essential amino acid gained only through nutrition. We need to eat to form Tirozin (and later dopamine). Tirozin is caught by enzyme TH and becomes "dopa". Another enzyme called LAAAD catches this dopa and turns it into dopamine. This neurotransmitter is critical in mood. There are two enzymes in nerve cells of dopamine. In other nerve cell there is also a third enzyme called DpH.
In Noradrenalin nerve cells DpH turns the dopamine into the noradrenalin. This all depends on whether there are 2 or 3 enzymes are at end of axon. Both dopamine and noradrenalin are produced by Tirozin. DNA determines whether the cell will have 2 or 3 enzymes.
Only in one place in body (adrenal gland) we have all the amino acids or enzymes TH, LAAAD, DpH. This cell can produce the hormone adrenaline because it has all the enzymes and it is in the blood therefore will reach every cell. But the brain does not have the ability to produce adrenaline. The brain has neurotransmitter which is only in the synapse.
PNMT - enzyme.
Some cells have axons the length
of just a few millimeters while others are hundreds on centimeters.
3/6/08
We eat protein which is digested and becomes amino acid (Tirozin).
Tirozin àTH turns Tirozin into Dopa à LAAAD turns dopa into dopamine = Dopaminargic cell.
If there is a 3rd
amino acid DpH à turns dopamine into noradrenalin.
Dopamine - Excess of dopamine in the schizophrenic brain
There are 4 pathways on dopamine in the rain, seeds of nerve cell which are pathways.
1) The Nigro Striatal Path (connected to motor functioning)
The first pathway begins in the brain stem in an area called substantia nigra (the area is black due to the dopamine). There are nerve pathways which lead to Basal Ganglia. The body of cell of dopamine is in the substantia nigra and the pathway moves all the way to the Basal Ganglia. This is the "nigro striatal path" and its function is motor functioning. There is no feeling or thought in this area only motor activity because it is an area low in the brain. With Parkinson patient we see the dysfunction of the motor activity in this pathway. The major symptom is dysfunctional motor activity. Begins when a person is in his late 30's and 40's. Begins with tremor of muscles, has less control over fingers. Less control over tongue and speech seems swallowed. Later there is ridged posture and walk. At first there is over activity and then rigidity. This is a progressive, degenerative disease for which there is no treatment. Later patient become physically disabled, cannot dress, cannot control urinal needs. Fewer dopamine cells there mean less motor activity and less brain activity in that area. There is no problem with muscles but in the brain which sends the messages.
How do we treat this medical condition?
Give dopamine in the form of oral pill or intravenously, but this does not increase the dopamine in the brain due to the BBB (blood brain barrier) which is a wall which prevents matter entering the brain, as a survival mechanism. The dopamine molecule is so large that is has no way of entering the brain. But "dopa" is more refined and smaller and therefore has a chance of entering the brain. Patients with Parkinsons do not have problem with tirozin, dopa and dopamine but the problem is in the enzyme TH. Ldopa treatment works for mild and medium but not for severe Parkinson. It is efficient as long as the system works even though weakly. What about the dose? How do we know exactly which dose to give? The dose increase as the disease progresses. However since the disease is progressive cells continue dying so medication only aids with still functioning cells. Sometimes side affects of treatment are light psychoses, on which dose should be decreased.
If there is too much dopamine
in this path - there will be over motor activity - hyperkinetic, restlessness,
movements, ticks or in extreme cases there is catatonia (over used of
all the muscles and motor ability).
2) The Mesolimbic Path (connected to affect)
Source in the brain stem and reaches the limbic system responsible for regulation of feelings. If there is over activity there will be a presence of positive symptoms (intense emotions, and fears). All the anti-psychotic medications put barriers on receptors.
The path leads from the brain stem, from an area called the tegmentum, through to the nucleus accumbens, responsible for pleasure (lack of hedonism and dull feelings together).
Theory: All anti-psychotic medication block and obstruct dopamine receptors and therefore this is the best theory we have at the moment. Carlson won Nobel Prize in 2000.
Empirical lab research: Amphetamines like speed and cocaine given to a normal person can induce psychoses. These amphetamines increase activity and discharge dopamine into synapses.
Experiment: Material which cancel/decrease amphetamines will decrease psychoses.
These two studies support the
dopamine theory that psychosis is connected to dopamine.
10/6/08
Cerebral spinal fluid (CSF) is the fluid in which the brain floats. This fluid teaches us a lot about the brain. We can take fluid from spine to learn about the brain since the same fluid is in the spine and brain. When we examine CSF we will expect to find an excess of dopamine. In post mortem of schizophrenics we see that the level of dopamine is normal.
Medication - should barricade receptors of dopamine of the type D2. These medications can treat only the positive symptoms of schizophrenia. Decreasing dopamine helps only positive symptoms but not negative symptoms and therefore the original dopamine theory is incorrect. We need a more complex theory.
Conclusion: The simple
dopamine theory is incorrect. Positive symptoms are a result of too
much dopamine in the mesolimbic path. When we block dopamine with medication
positive symptoms decrease; when we bombard with dopamine there are
psychotic symptoms, like with drug intake (speed, cocaine etc). But
how do we treat negative symptoms. Maybe negative symptoms are cause
by lack of activity in another path. We need to now how much dopamine
we have in each of the different paths and not overall dopamine in the
brain. Medication was responsible for making negative symptoms more
sever. This is first generation medication.
3) The Mesocortical Path (connected to negative symptoms)
Also starts in the tegmentum
and reaches the frontal and prefrontal cortex connected to abstract
thought, judgment, high mental activity, perseverance, initiation. Therefore
schizophrenics lack these abilities, they are apathetic. Schizophrenics
have over activity in the temporal lobes and lack of activity in frontal
lobes. We can conclude that there is a defect in the second and third
path but not in the first motor path which is normal. Motor defects
are due to medication.
4) Tuberoinfundibular Path
The forth dopamine path is
in tact in schizophrenics. In normal people the path connects hypothalamus
and the hypofisa. The hypothalamus sends axons to the hypofisa
and dopamine is constantly discharged and it sends a message to decrease
prolactine which leads to increased breast activity and prolatical (milk)
activity. Medications of the first generation of schizophrenia decreases
dopamine (by blocking receptors) in all paths therefore this path was
also affected even though initially there were not problems with this
path. Too much prolactine leads to lack of sexual desire and has negative
affects on the male erection.
Summery - The four paths:
1) Nigro Striatal - functions. Decreased dopamine will lead to EPS extra pyramidal symptoms like Parkinsonism
2) Mesolimbic - dysfunctional - excess dopamine leads to positive symptoms
3) Mesocortical - dysfunctional - deficiency of dopamine leads to negative symptoms
4) Tuberoinfundibular - functions. Decreased dopamine leads to prolactine production.
In schizophrenics the first
and forth are functioning; in the second there is over activity and
in the third there is under activity.
The dopamine theory is problematic. Apart from the 4 pathways there are other hypotheses.
Maybe serotonin is also involved. Taking the drug LSD increases serotonin levels and induces psychosis. So maybe schizophrenia is connected to serotonin. Some matter imitates the serotonin.
Other hypotheses include membrane
problems, cell problems etc. but none of these explanations are satisfactory.
2) Neurodevelopment Hypotheses: Viral virus - זיהום ויראלי
Schizophrenia is caused by a lack or dysfunction in the brain of the embryo in the second trimester connected to stress. During this stage nerve cells develop. Something in the incubator is not right. There could have been a trauma to mother and the embryo draws from the mother's mechanisms. Example: Mother has flue and this can affect the embryo; Or mother's stress and improper breathing. When we are under stress, fight or flight, growth hormones are affected which can harm the embryo - one affected cell in the embryo will not be able to produce the millions to come. The embryo has cells which need to be created but also other neurons or cells which need to be destroyed.
Apoptosis: Pre-determined death of cells (the web-like sheath between the fingers; the tail).
Our brain works with use it or loose it - what we do not use in our brain is forgotten or withers. The drug Ecstasy leads to some kind of apoptosis - cells which should die in later age. Mothers stress or lack of eating also leads to apoptosis in the second trimester.
Necrosis: Cells discharge inflammation or poison that kills nerve cells.
Epidemiology - statistically whoever was born in a certain months and was exposed to some viruses in the second trimester. But a child is not born schizophrenic - it develops in the second decade of life. In teenage years the brain functions differently and there is more pressure on it to function. Schizophrenia may break out but the foundations were always there and waiting for the trigger.
Why is this explanation incorrect?
We see healthy children but do not often see signs of the disease before. We see brain chambers that are larger in these children but we do not see symptoms. Many synapses are created in the first years or life while others are destroyed.
Epidemiological study
(2008) emotional stress of mother in the first or second trimester.
Stress is connected to death of someone is close circle. They found
that there is a correlation between the two.
Neurodegenerative Hypotheses:
The natural course of the disease from the moment it begins. What is the neurodegenerative stage?
Pre-morbid stage: age 0-10
Pro-dromal stage: age 10-20. There are slight symptoms. Social alienation, lack of regulation of emotions. There are changes but one cannot stigmatise them.
Onset stage: age 20-30 Drastic decrease in function and then there are relapses and episodes and remission and gradually the person does not return to his prior functioning. Disease is progressive.
Stable relapse: age 30-50: Even though he is in remission he person cannot function well. There is a total decrease of overall functioning. Medication can help maintain some sort of stability. Without medication the relapse remission will be more frequent.
After age 60
Treatment:
Today there are 2 types of medication (first and second generation) which different in how they work, which symptoms they treat, and which side-effects they cause.
First generation: Conventional (typical; neurolectical; ant-psychotic) medications
Relieve positive symptoms and worsen negative symptoms and have many side effects.
Haloperidol (Haldol), Mellaril. Thorazine
The first anti-psychotic drug
(chlorpromazine) was given to rats to decrease their motor activity.
They were more relaxed when they moved slowly. It was given to schizophrenics
to decrease emotional activity (dull emotions) and motor activity. It
was revolutionary. A third of the patients were discharged. Today 3
out or 4 are sent home. The drug revolution in psychiatry 1946-1947;1967
17/6/08
Halidol blocks dopamine receptors called D2. It works in the form of "antagonism" - it is similar to dopamine and imitates it. The molecule can fall on receptor because it is similar but not identical and therefore allows some dopamine to enter and decreases the potential stations that would absorb all the dopamine. This molecular (medication) is similar to the dopamine. This therefore decrease dopamine ability to fall on each dopamine receptor because now there are partial medication molecules that fall in these receptors. The strength of this action depends on the type of medication and the affinity they have with the receptor. Strong affinity medication molecules lock all receptors; low affinity medication molecules lock receptors particularly, allowing more natural dopamine to fall on receptors. (Sketch on board of molecule on receptor and how teeth match on both sides).
The areas that are lit up are the basal ganglia, the caudate and the putaman.
Sketch: Haloperidol in the brain has occupancy in the therapeutic levels of between 80-95%.
Affect of chronic haloperidol
treatment on activity of dopaminergic neurons in the brain.
Side effects of first generation/neuroleptics
Side effects are severe since we cannot just improve mesolimbic paths of dopamine. If pills are taken orally other paths are influenced such as the mesocortical path (negative symptoms) which is severely affected and worsens existing negative symptoms. Affects the motor path (EPS - extra pyramidal symptoms), takes a healthy path and induces Parkinsons symptom in patients.
List of side effects
Acute Dystonia: Appears within 5 days of taking medication. Affects motor activity and is expressed in the form of ticks in body; deformed tongue, muscles of throat and face. Can lead to strangulation.
It person suffers from dystonia medications to relaxes muscles are given. Acute dystonia can become Parkinsonism.
Parkinsonism: Appears within one month and is expressed in cog wheeling, shuffling gait, rigidity, salivary drool, shaking, hunchback, and mask-face. It may improve symptologically or medication and be given against the side-effects.
Akathisia: Appears in the first two months of treatment and is expressed in restlessness, jumpy behavior and being in constant movement. There are medications against these side-effects. It is best to see whether the side effects disappears but themselves because brain may get used to medication.
Tardivedyskinesia: Appears a months to a year after taking medication and is expressed in large circular movements of the tongue and deformed facial expressions. About 5% of patients treated by this medication suffer from this side effect. If medication is stopped in time side-effect may cease but often may remain for ever.
Neuroleptic Malignant Syndrome: Sudden increase in blood pressure, temperature, increased heart beat to high risk level. Immediate hospitalization and stabilization is crucial. Stop treatment immediately.
There are so many side effects because medication affects all 4 paths.
Dry mouth, changes heart beat,
retention of urine, blurred vision, retention of fluid in body, constipation,
confusion, weight gain, endocrine hormonal - prolactine, decrease seizure
threshold, sexual dysfunction. There are also emotional side effects.
There is a problem with compliance because medication relieves symptoms
and people feel better and therefore take lower doses or stop. In a
month there may be relapse of 10% in the first month and 50% in the
first half a year.
Second generation: Unconventional (atypical) medications
Relieve positive and negative symptoms and also have fewer side effects.
Leponex, Ziprexa, Respiridal, Geodon. There are fewer EPS symptoms. Blocks D2 and 5-HT2A.
Cause weaker immune system and fewer red blood corpuscles, therefore needing blood tests.
Causes- agranulocytosis. Monitor blood counts and early symptoms on infection.
How do atypical medications work?
SDA (serotonin, dopamine, antagonism of both). There is antagonism of both serotonin and dopamine receptors. Both these neurotransmitters cooperate. Serotonin delays dopamine release. Therefore in a normal brain the more serotonin these is the less dopamine there is. And visa versa, decreasing serotonin will increase dopamine.
Taking a SDA medication affects each path differently:
1) Nigro striatal path (motor):
SDA delays dopamine but also delays serotonin. We have a similar number of dopamine and serotonin receptors and therefore they balance each other out. Block serotonin then dopamine increases. Block dopamine then dopamine also decrease. A balance is maintained in this path.
2) Mesolimbic path (positive symptoms):
Many dopamine receptors and few serotonin receptors. So opposite affect to mesocortical occurs. Block serotonin then increase dopamine a little; block dopamine block dopamine a lot. Therefore there is a significant decrease in positive symptoms.
3) Mesocortical path (frontal lobe - negative symptoms):
Many receptors of serotonin and few of dopamine. Block serotonin then dopamine increases a lot.
Block dopamine then dopamine decreases since I have few dopamine receptors. Overall I have an increase of dopamine therefore there is more activity. Negative symptoms have been relieved.
4) Tuberoinfundibular path (prolacine):
Same number of serotonin and
dopamine receptors in this path, but there are patients who have a bit
more dopamine receptors and therefore there may be some prolactine.
There is less relief of dopamine symptoms with medication which leads
to these hormonal problems and libido problems.
We use atypical medication for other disorders like
Bi-polar and mood disorders, drug induced psychoses, manic episodes, increase cognitive function of Alzheimer, improve impulses and aggression and violent behaviour. Borderline PD.
After 12 weeks of medication we see change in physical structure of brain tissue. Brain rehabilitates.
The new generation of medication
is very expensive because they are protected by a patent. Many years
of experiments have to be conducted on animals, very sick patients,
less sick patients which cost a fortune. Medications are so expensive
because companies have to return there expenses.
We prefer first generation medication when someone has a psychotic episode because they act immediately or when there is problem with compliance an injection can be given.
Side-effects of second generation atypical medication
Metabolic syndrome - Health
problems like the elderly; gaining weight, diabetes, over eating, heart
problems, cholesterol, high insulin, high blood pressure, CVA - brain
stroke, stop breathing, calcium release. EPS but not as severe.
24/6/08
Affective Disorders:
What do we know about emotions? Encyclopedia Britannica - An enlightened-high mood (mania)
Lower levels of these moods (depression);
Changing moods (bi-polar).
Different expressions of this disorder - dysthemia, cyelothmia.
Lifetime 10-20%.
Extreme behaviour which is
appropriate. We need to ask whether the feeling is appropriate, for
how long it lasts, what intensity is it.
Female-male ratios in population.
Dysthemia 8:5%, Major Depression 22:12%, Bipolar 2:2% ratio of women and men.
Men complain less and somatize
their mental pain and use self medication (alcohol, and drugs or medication
to deal with depression and anxiety).
Graphs of types of affect disorders;
Normal - a normal graph ^^^^^^^^^^^
Major Depression - graph below normal line with hard falls
Dysthemia - normal looking constant graph below normal level.
Bipolar Disorder - graph of high peaks and low falls around the normal line graph
Cyelothymia - less severe version
of bipolar
DSM - IV affective disorders:
Adjustment disorder with depressed mood: passes within half a year. Is connected to situations and changes is situations. Is not connected to mourning. Is connected to stress.
Dysthemia: a person is depressed but the symptoms are fewer and less intense than major depression.
Major depression: Sever symptoms that affect all levels of life. Without hypomania or mania.
First case of depression רוח רעה is of King Saul who got music therapy - David played the violin.
What is depression?
We are all sad but in depression the intensity and time of these affects is more severe. This is connected to the physical structure of the brain. What is the connection between biology and psychology and functioning? Is it a result of thought processes or structure of brain?
Author, William Styron - "Sophie's
Choice" wrote a book about depression.
Depression: a group of Symptoms
Mood disorders, vegetative (sleep, eating, weight, frustration), cognitive (lack of hope and interest, attention, memory, pessimism), impulses (suicide), behavioural (motivation, fatigue), physical (head ache, digestion, stress).
These symptoms must occur most of the day, everyday for at least two weeks.
Children and elderly (irritation - עצבני). In children - no drive to develop and grow and succeed.
Endogenous Depression (major depression) - symptoms are most severed in the morning.
Reactive Depression (situational depression) - symptoms are more sever in the evening.
Weight - loss or gaining weight of more than 5% of body weight without dieting.
Sleep - insomnia or over sleeping
It is easy to identify these symptoms. Two weeks of symptoms to be diagnosed. Why? Treatment is successful. There is not such a stigma. Medication is cheaper and efficient. Medications to not induce disease like medication for schizophrenia. It is worth while to make a false positive mistake (diagnosing someone with depression who has no depression) than false negative (dealing with side-effects of depression) or than false negative with schizophrenia which can be harmful.
Questionnaire to determine
intensity of depression: Refers to all diagnostic criteria of DSM.
Depression - the physical presentation
69% of diagnosed depression report unexplained physical symptoms as chief complain - there is no physical basic for this.
Statistics of depression is varies over countries.
Taiwan - less than 1%;
USA -9.5%; Israel - 11%
Causes of major depression:
One who had a depressive episode has 50% probability of having another depressive episode. If you had 2 - 70% you'll have third. If you had 3 - 90% you'll have forth.
Gender: women have twice as much chance than men.
Age: 20-40. In Israel it usually occurs at age 50-60.
Family history: Increases probability 1.5-3 X. Genetic factors
Family status: Increased chances for single men > married men.
Married women with children > than single women.
Depression can also be co-morbidity to:
Organic disorders like Parkinson; Alcoholism and other substance disorders; Schizophrenia; Eating Disorders; Mental Retardation; Anxiety Disorder; Vegetarianism - lack of B12; Thyroid problems.
Mental health professionals
need to cooperate with doctors to eliminate other biological physical
causes of depression. Depression is also a side-effect of medications
and nutritional changes. Part of anamnesis must include all nutritional
additions (lowering blood pressure medication etc).
Cost of treatment: On a continuum form the most expensive to cheapest.
Cardiovascular, Cancer, Alzheimer, schizophrenia, Depression, Aids…
170 000 work days were lost
due to depression. Billion -
8/7/08
Depression kills due to high suicide rates, which differ among countries. Some suicide attempts are to get help and not to die. In addition, depressed people are less healthy, neglect themselves; don’t take routine checkups; lack of compliance to heath medications, unhealthy life styles; overall they have shorter life spans.
Study of 3007 people.
There are 3/4 X more death (not related to suicide) in depressed population in comparison to normal population. Death is a result of other diseases connected to physical health.
Causes of death: 63% cardiovascular, 22% cancer, 15% other. They have weak immune systems. They seek help less frequently and if they do there is no compliance to treatment. Mortality and post-stroke depression - it is difficult to deal emotionally with the effects of stroke. CVT patients have disease related depression and not major depression. Out of those who received anti-depressive medication and placebo we see a larger mortality rate among the control group who received placebo over a 10 year study.
The natural cycle of
the depressive episode is a year, after which patients report relief
of symptoms. There is spontaneous recovery and remission within a year.
Following two years the person recovers and there is complete remission
according to research. But what happened during these two years. Aren't
their emotional wounds? Could medication decrease the damage and ease
the emotional pain?
There are 4 stages or depressive states when a person is pharmacological treated (The 4 R's):
Response: At least 50% reduction of symptoms but residual symptoms exist.
Remission: 100% reduction of symptoms.
Recovery: 6-12 months in a state of 100% reduction of symptoms.
Relapse/ Reoccurrence:
Symptoms return.
ECT - Electro convulsive therapy
Treats severe depression but we do not understand why this treatment works. It is a very stigmatic treatment. This technique was used since 1895 part of great and desperate cures. When all other treatment fails ECT is given. It is usually not the first treatment to be given. It is most effective because the effect is rather rapid for patients who to do respond to other treatment and patient who are in danger of dying.
Electrodes are attached to
the brain and an electric shock is given, inducing electrical activity
in the brain. It is done under full anesthetic and muscles are very
relaxed and therefore physical injury is not cause like in the past
early treatment. There is EEG seizure activity followed by seizure termination
while body and brain relax from over activity. ECT treatment has a negative
effect on memory, in particular short-term memory and new information
coming in especially during the 2-3 days prior to treatment since memories
have not yet been formed by hippocampus. There is a black hole in the
personality and 2-3 days are missing from the conscious memory. A monitor
reads brain activity; an anesthetist is present. The electric source
is placed on the temples or on one temple (on the right hemisphere where
there are more pessimistic feelings). Therefore one side of the brain
and the hippocampus is not injured. ECT memory may be largely tied to
technique. ECT is used under severe depression, and anorexia. When medication
cannot be given or when there is no response to medication.
A number of theories explain depression:
1) Freud's Dynamic explanation and treatment is least effective of all treatments. Freud: mourning and melancholy - depression is a result of loss of something (person, limb, dream, and fantasy). There is ambivalence in depression (one hates who left me and there is sorrow and love. Love-hate relationship because feelings are not fulfilled). I cannot be angry at mother who left me because it is dangerous and therefore I internalize the anger and project it onto myself. 2) Cognitive explanation and treatment (Beck): Depression is a result of a dysfunctional schemes and negative and incorrect thought processes which are reflexive and automatic and determine my beliefs about the world. These schemas destroy the way I experience the world. They refer to 3 levels: Incorrect perceptions about myself (I'm a failure/ugly). Negative thoughts about the world (nothing is good) and negative thoughts about the future (nothing will change). Part of treatment is writing a journal of their thoughts. Thoughts are dichotomy (good and bad; I'm a success or failure) 3) Learned Helplessness (Seligman): Depression is due to lack of control. What you do and think do not have an implication on you life and fate. A 2 stages study: Two groups of dogs in a cage with two areas - an electric floor and a non electric floor while dogs can choose to jump from one to the other. They learn very quickly to be on the non electric side. The second group of dogs was in the same cage but were yoked and could not decide when to jump - they could only jump when the dogs in the other change jumped and were dependent on them. They got the same amount of shocks but they could not decide how long they want to suffer the shocks. During the second stage of research the dogs had their yolks removed. When they got shocks they did not jump to the other side. They showed signs of stress. Over time they became depressed - ate less, libido decreased. If a person has learned hopelessness and lack of control they can develop depression. 4) Physiological- biological theory : Depression is a lack of a neurotransmitter in certain parts of brain.Monoamine Hypotheses - lack of serotonin, dopamine, noradrenalin.
Noradrenaline/Norepinephrine are neurotransmitters. Adrenaline is a hormone. Noradrenalin is responsible for concentration, interests, motivation. Serotonin is connected to sexual desire, appetitive, and aggression. Both of these acting together are connected to depressed mood, anxiety, pain irritability, thought processes. Electric pulse moves on axon. Neurotransmitter are released into synapses and picked up. We have an enzyme COMT which destroy the matter in the synapse. There is reuptake 85% which returns the neurotransmitter back the cell. In the end of the anon there is an enzyme called MAO - mono anim oxidaz (takes monoamines and makes oxidation meaning breaks them). As soon as the brain creates noradrenalin it packs them into safe packages so that MAO cannot destroy them. They are collected at end of axon and then release into the synapse Depression is a result of too little monoamines in the synapse and therefore the MAO must be delayed. The first generation of anti-depression are MAO-I (inhibitors) which prevent MAO from functioning. They treat depression but have many side affects. They treat motivation but only later mood (therefore there was more chance of suicide). Depressed patients are suicidal but not motivated to kill themselves. Therefore MAO-I was given only under supervision. There is also MAO- I in liver and destroys other matter in body. Certain materials need to be removed from the body though urine and discharge because they are poisonous to the body. Today MAO-I can only be taken while on a special diet. This poisoning is called cheese effect.Depression treatments:
ECT - Electro Convulsive Therapy MAOI - First generation medication SSRI - Second generation medicationSecond Generation Medications:
Tricyclic anti-depressants: describes 3 chemical cycles: Imipramine, clomipramine, etc… They work by partially inhibiting the reuptake and therefore the number of active molecules in the synapses are increased. Disadvantage - Second generation medications inhibit reuptake of the 3 monoamines but also inhibit reuptake of another 6-7 other neurotransmitters therefore other functional processes are tampered with. These medications are given for depression, OCD, panic disorders, anorexia and bulimia, obesity, chronic pain. Side effects: Dry mouth, confusion, drowsiness, heat beat problems, low blood pressure, over eating and obesity. Very dangerous on overdosed. Interaction with alcohol is fatal and psychoses and heart attacks can be induced. But these medications are effective and have fewer side-effects than the medications of the first generation. Must be taken for 2-4 weeks until it starts working. The side-effects appear before the positive affect of the medication. These medications will not be given to people who have atypical depression (less classic symptoms like oversleeping, over-eating, feeling better in the evening). Whoever has classical depression will react well to these medications in comparison to someone who has atypical depression. Classical depression (irregular sleep, loss of appetite, negative feeling in the morning, lack of pleasure etc.Third Generation medications:
SSRI (selective, serotonin, reuptake inhibitors) Only inhibit or partially block serotonin reuptake. Drugs such as cocaine completely block reuptake. There is a significant decrease in side effects and this is the main advantage of the 3rd generation of medications and therefore is less harmful physically and mentally. Usually we do not have to find the correct dose because they are more specific. Side-effects: Decrease in Libido (impotence and lack of sexual desire); flat affect, lack of excitement and enjoyment in comparison to past. The diversity of feelings is deceased. This is a high price to pay although the person does no fall to the pits of despair. Prozac, faboxil, seroxat, tsipromil. Prozac - has fewer side effects. Effective for eating disorders, anxiety, PTSD. Some medications of the 3rd generation are also safer during breast feeding.Psychobiology: Abuse and Neglect
Study on rats. A few rats in experimental group were removed from mother for an hour a day for a week while getting all they needed nutritionally and environmentally. They were then returned to mother and all rats (experimental and controlled) were attached to a cocaine pipe and could choose when to use or not. The rats that had been separated became "junkies" because they used higher doses of cocaine more frequently in comparison to the control rats. Therefore early life and connection to mother is critical and maternal care in important in early life.Processes of develop of brain.
Neurogenesis: Creation of nerve cells in the first trimester till birth. Some researchers claim that new nerve cells can develop in the frontal lobe and hippocampus but this is controversial. Migration: How does the nerve cell know how to migrate from place to place, from brain to part of body. Process of localization of nerve cells to places where they will need to function. Drugs and viruses can disrupt the migration process. Takes place in womb till age three. The first 3 years are also crucial for object relations. Differentiation: Nerve cells get there differentiation. Once is motor and another is a sensor, one is in heart and helps pumping while other does something else. Each nerve cell has a different role in body and brain. Develops mainly in the womb but continues till age three. Therefore if there is injury then there can be rehabilitation in the first 2-3 years. The later the abuse the better prognoses for the child because most nerve cell are developed by age three. Apoptosis/Pruning: Process of planned death for nerve cells. Pruning is the cutting of axons which are not relevant (e.g. reflexes are stopped which are no longer needed - the infant will no longer cling but will need to develop the skill of differential controlled use of fingers). These processes take place till the first year and later in adolescence. There are many nerve cells, which are pruned as the brain gets older and therefore there are fewer connections between them. We have cognitive schemas which are more accessible, meaning they have more connections. "Neurons that fire together wire together" and this creates schemas. If a person takes drugs during adolescence he will not be able to prune properly (deal with frustration, need immediate gratification, emotional processing, processes of inhibition, finding an alternative path to the impulsive path, lack morals). Traumas affect the brain and interfere with pruning. In later life we will need pruning of associations and knowing how to be selective with associations in conversation with others. Primarily we need those associations which are essential for survival, then the secondary ones. Synaptogenesis: New synapses develop till death but mainly till 8 months till age 10 and the second wave in adolescence especially in the cortex and frontal cortex. Myelination: The formation of a covering of fat on axons, which makes them more efficient. This occurs between age 1-4 and 10 and the second wave near the end of adolescence. This is good news since we understand that brain is plastic and flexible and rehabilitation is possible even at adolescence. But also, injury in first 20 years of life is more severe. Over stimulus is also negative for development of infant mind.Completing the processes of neuro-development
Plasticity: The potential for change in nerve cells and new neural connections associated with change in environment. There are more critical/sensitive periods for certain types of learning. (e.g. Learning language at the critical age of 4-7; learning to play an instrument at a younger age). Critical period: Something must occur in order for normal development to take place. At a certain age the body needs to be visually stimulated in order to see. If during this critical period the eyes are covered then person can remain blind forever. The synapse expects the stimulus to be given at a certain time. And what about a critical period of emotional develop? Stimulus needs to be gradual for an infant to enjoy stimulus. This is a window of opportunity that needs to be taken advantage of because if the moment is missed then possibly later no change can be achieved. Injury: When did the injury take place? What king of injury? Lack of X or over stimulation. Is abuse a one time occurrence (rape) or continuous abuse (incest)? Is it consistent, forming a clear pattern or is it chaotic and unexpected, when flight or flight is dominant. The latter is the worst case scenario.Schematic view of functions:
Neocortex - concrete thoughts and abstract thoughts - adulthood Limbic - emotional, sex, attachment - adolescence Diencephalons - sleeping, agility - childhood Brainstem - pulse, temperature, heart - childhood If I use alcohol/drugs during adolescence then I can harm functioning of emotional aspects but not functions connected to the physical brainstem.Pre-frontal cortex
Dorsolateral - Cold non-emotional rational intelligence, management. Info procession, inhibition. Organizing info to achieve goal. Orbitofrontal (above the eyes) - Warm prefrontal intelligence, connected to emotion, stimulus, separation-distance-nearness. e.g. The Iowa gambling task: 4 decks of cards. Gradually the subject realizes that the gains and losses in two decks are very high while in the other two there are small gains and small losses. Usually people chose the safer decks. This way we can discover who has injury in the frontal cortex (gamblers, drug addicts, children). There is more emotional involvement which clouds decision making. This area is also responsible for Social cognition - with who to talk and what to say. How much to hug or not. Ability to attribute certain emotions to others; to be able to read others emotions correctly. This is important in social situations. Like reading another's mind - is the basis of empathy. This is the key to being a social human being and is the result of orbitofrontal functioning. We catch facial expressions in a blink of a second, almost unconsciously, automatic and survival. Fonogin research - borderline and narcissistic personality, PTSD. The more severe the physical abuse the more damaged the ability to recognize facial expression. On a scale of 0 à good. The more severe the abuse the less ability to be empathetic. Also we see same scale in victims of sexual abuse. The ability to mentalize, recognize facial expressions and feel empathy is damaged. Point of pain: For many years researches of pain and brain thought that pain comes from sensory cortex, but this is not entirely true. Many people have physical problem but do not feel any pain. Therefore, there is also an emotional aspect of pain. People often don’t feel pain until they are aware of themselves. There are 2 active areas involved in pain - emotional pain (my heart is broken; I'm in pain when I'm hurt emotionally). Physical pain has sensory and emotional pain. Study - hypnotized people and placed hand in ice or heat. Stage 1: When pain was activated the somato-sensory area lit up proportional to the part of the body that was harmed. ACC- anterocimulate cortex Stage 2: Hypnoses and decreases unpleasantness. Subject was told that he would feel pain but that it would not be unpleasant nor would bother him (i.e. changes emotional factor; i.e. affects ACC - there was no response. Stage 3: Hypnoses decrease the intensity of the physical pain (somato sensory) without talking about emotional pain. They proved that in hypnoses physical sensory and emotional areas can be separated. People don’t feel pain in the same way.