Thursday, April 26, 2007

Over Her Knee In Her Paties

medicine and drugs

depression and antidepressants

Introduction

Depression is a very common disease. It is estimated that approximately 12-17% of people at least once in their lives like this. Of the elderly over 65 years should be 15 - 25% experience at least one depressive episode. This depression is the most common psychiatric illness in old age.


Vincent Van Gogh (1880), Wikipedia

Sufferers experience depression often much worse than physical illnesses. Tormenting the different symptoms are experienced: uncertainty about themselves through the experience and behavior changes, loss of self-esteem, drive, motivation and loss of will, comprehensive hopelessness, and physical weakness. Fortunately
go past depressive episodes, but they occur at 70 -80% for the first time it ill patients again. Only 20 -30% of patients, they will never return.
antidepressants contribute to depression mood enhancing, anxiolytic and drive-enhancing, but they have substantial side effects. The success of antidepressant therapy can be difficult to assess for several reasons: which helps agents in individual patients is best, one can not clearly predict the disease. Also help with depression and placebo effects, and intensive care of patients. Due to their versatile effects antidepressants are used for other diseases, for example in the treatment of anxiety disorders, panic disorder, social phobia, obsessive compulsive disorder, in pain therapy and palliative medicine.




diagnosis of Depressive episode

diagnosed depression is now an internationally recognized classification system, known as ICD-10 - criteria. An assessment is the presence of typical symptoms and other common symptoms.

are the typical symptoms:

- have increased fatigue due to reduction of the drive


Other common symptoms of depressed mood
- - Loss of interest or pleasure :

- reduced concentration and attention
- reduced self-esteem and confidence
- guilt, feelings of worthlessness
- negative and pessimistic Future prospects
- suicidal thoughts, self harm or Suizdhandlungen
- Sleep
- decreased appetite


The severity will be assessed as follows:

Mild: at least two typical and two of the other symptoms
Moderate: at least two typical and three of the other symptoms
Expert: three typical and at least four of the other symptoms.

Furthermore we distinguish subtypes of depression:
Washed depression, psychotic depression, inhibited depression, atypical depression, depression in the elderly, anankastic depression (where compulsive symptoms in the foreground), recurrent brief depressive disorder, seasonal affective disorder, postpartum depression and dysthymia.


causes and pathophysiological mechanisms of depression

Despite intensive research, the pathogenic causes and mechanisms of depression is not clearly understood. It is certain that heredity may be involved in emotional stress in childhood and acute mental and physical stress on the development of depression.





disturbances in the hormonal

The hormones from the brain by means of controlled stress regulation is disturbed in depressed people. We speak of the hormonal stress axis is disturbed, and thus thinks the interaction of hypothalamus, pituitary and adrenal gland (HPA axis), which leads to the release of the stress hormone cortisol.
forms Normally, the hypothalamus, when a threat is detected, increases the corticotropin-releasing factor (CRF). On the pituitary secretion of adrenocorticotropic hormone reacts with short ACTH. This hormone stimulates the adrenal gland to pour out the stress hormone cortisol. The whole process makes the body ready to face stress. At the same time are not currently required or disruptive activities inhibited. Cortisol increased as energy supply to the muscles, CRF suppresses appetite and sex drive, but promotes vigilance.

The axis of hormonal control from the brain to the thyroid gland seems to be disturbed. Again, the steering is done with a hypothalamic hormone, TRH, and then a pituitary hormone TSH. TSH on the thyroid response to the release of thyroid hormones that stimulate the metabolism. Depressed patients respond to the stimulation of this system differently than healthy and are found deviating from the normal hormone levels in the body. Other than that it is possible that hypothyroidism presenting as depression, antidepressants do not help then, but thyroid hormones.



imbalance of several neurotransmitter systems

It is thought that disturbances of various neurotransmitter systems of the central nervous system are involved in depression. In particular, the activities of the serotonin and noradrenaline of the system are reduced. Will be found in the brain and spinal fluid of depressed patients significantly less degradation products of these two neurotransmitters in healthy subjects. Additionally, the concentration of serotonin and norepinephrine receptors in the brain of depression increased. A receptor propagation will always occur if too little messenger is available. Antidepressants increase the activity of norepinephrine and serotonin system in the brain. The slow onset of action of antidepressants, however, says that the lack of the two neurotransmitters only part of the depressive state says.


changes in the brain during a depression

changed in different regions of the brain, the activity: It rises in the limbic system and brain stem, and decreases in the frontal lobe.
in the left frontal lobe, both negative emotions and desire and drive controls. Melancholic mood or little desire to go back there, let the activity. This makes it difficult to get grief, fear or anxiety about the future under control. Depression is not only a sequence of dark Feelings, but also from too little content.
The forebrain also serves as a working memory for temporary storage of information. Matching the mood is they regulate the perception. For negative mood, the brain is mainly for negative stimuli open. It thus tries to get the negative mood upright.

For people who have repeatedly suffered in life from a severe depression, take certain neurons in the frontal lobe one-third less space than normal. Previously it was only for depression, a chemical disorder of the transmitter, today it is thought likely that a growth fault of the neurons, which mainly is caused by stress.

Because in a state of depression the patient is under continuous stress from negative thoughts. We speak of uncontrollable stress, if the person does not have for them cognitively and emotionally meaningful strategy to deal with the situation.
In this situation, stress hormones such as cortisol permanent. A permanently increased cortisol release damages nerve connections in the brain and its re-growth is inhibited. A state of paralysis occurs. The brain seems to rest as the vegetation in the winter. The capacity for feeling fades, even mind and concentration to make. Depressed people can not handle even simple everyday tasks as well as healthy people.


The stress axis plays a crucial role
in depressive disorders


whole brain regions may shrink, such as the hippocampus, which is very important for the Gedächnisbildung.
flow in this part of the brain together information from different sensory systems, processed and returned from there to the cortex
. The hippocampus causes Consolidation of memory, ie the transfer of Gedächnisinhalten from the short-term in the Langzeitgedächnis . People whose hippocampus (there are, strictly speaking, two, one for each side of the brain) is removed or destroyed, can not form new memories and thus have an anterograde amnesia on . Old memories will remain. The hippocampus is thus seen as a structure that generates the memories, while the actual memory contents at various other locations in the cerebral cortex are stored .
It has now been evidence that can be formed even in the adult brain in the hippocampus new connections between existing neurons (synaptic plasticity
) and that this formation is related to the acquisition of new Gedächnisinhalte.
dimensional view of the brain

The hippocampus is also important for spatial orientation. Pyramidal cells in a certain section of the hippocampus, each representing a location in space. People with damaged hippocampus can indeed focus on everyday life, but are unable to give directions.
The hippocampus is ultimately responsible for the coordination of the various memories. That is, for example, again important for spatial orientation. Thus, there is the inner mental "map" of a city visited several times from many impressions were gained at different times. In the hippocampus, these together and you can orient themselves.


early traumatic experiences

Stressful experiences in childhood such as neglect or abuse, favor the later onset of depression. Because there is not just an activation of the Stress axis instead, which goes over again, but it increases the activity of CRF neurons in the hypothalamus permanently. These are precisely the nerve cells that respond repeatedly to stress and its activity is elevated in depressed patients always. The sensitivity of the stress axis is then permanently increased by a childhood trauma. How much stress can permanently shape the brain in childhood, shows the following example:
Charles B. Nemeroff and his colleagues at Emory University in Atlanta (Georgia, USA) tested the effect of social deprivation on rat babies. The animals were born during the first three weeks of life to about 10 days each briefly taken away from the mother. After they were weaned, then they grew up without disturbing other operations in a standard colony rats.


Standard - rat colony

When these animals were adults then left to their CRF neurons changes in a similar manner as in sick people are depressed. Your CRF secretion was significantly increased and thus the hormonal stress response greatly above normal.
By administering an antidepressant, which of course only increases the activity of the neurotransmitters norepinephrine and serotonin, could be the stress response in these animals again ! Normalize


The neurotransmitters

antidepressants not only affect the norepinephrine and serotonin system, but it will also affect other transmitter systems. This explains the numerous side effects of this drug class.
acetylcholine is one of the most important neurotransmitters. It is found in the CNS, but also peripherally: in the neuromuscular synapse and in large parts of the autonomic nervous system. It is an antagonist of dopamine. Anticholinergic drug effects include dry mouth, accommodation disturbances, urinary retention, sweating, tachycardia, memory impairment, confusion.


histamine, serotonin, dopamine, norepinephrine and epinephrine have some chemical similarity to each other and are known as monoamines.

dopamine is found in the CNS as a transmitter in the synapses of the basal ganglia, the limbic system and the pituitary gland. Basal ganglia have a share in the control of voluntary movement, the limbic system controls mental processes and the pituitary gland has, among other neuroendocrine functions. Dopamine controls wakefulness and draws attention, it raises curiosity, learning ability, creativity and desire for sex. Dopamine is the hormone of anticipation and desire. It makes us ready to turn words into action to leave. Transmitter can either own or act as a signal modulating the strength of a signal. Dopamine acts as a door opener for other neurotransmitters: it works to modulate the signal transmission.


noradrenaline is found in almost all postganglionic fibers of the sympathetic nervous system and has in the CNS functions in the thalamus, hypothalamus, cerebral cortex and the anterior and posterior horns of the spinal cord. It has significance in the control of alertness, attention and brain excitability. Norepinephrine exerts its effect as a neurotransmitter and as a stress hormone. As the latter is given together with adrenaline from the adrenal medulla in the blood and acts from there on adrenergic receptors, alpha and beta receptors.


adrenaline found in the CNS as a transmitter in the medulla oblongata. Blood pressure, breathing and eating are also controlled by it. In addition, adrenaline acts as a hormone such as norepinephrine on adrenergic receptors. Adrenaline and noradrenaline stimulate sensory perception and metabolism.

serotonin as a neurotransmitter found in the thalamus, hypothalamus and the cerebral cortex. It is about mood control, pain relief, blood pressure control, sleep-wake cycle, body temperature and nutrition. In the spinal cord to inhibit flexor reflexes. When serotonin is released in the brain a lot, it pays out less stress hormones such as cortisol and nerve cells can grow better, because stress hormones in the brain inhibit the growth of nerve cells. Between the noradrenergic system and the serotonergic system, there are many interactions, and both systems can alter dopaminergic systems.


serotonin in the intestinal nervous system as a neurotransmitter important. There increases intestinal motility. The largest amount of serotonin in the body is in enterochromaffin cells of the intestine and stored in blood platelets.
Serotonin has complex effects on the cardiovascular system. It causes at different serotonin receptors partly contradictory effects. About 5-HT2 receptors in blood vessels it affects pressor, via 5-HT1 receptors in the CNS reduce the Sympathotonus thus expanding blood vessels and blood pressure. It is also involved in blood clotting For serotonin, there are at least 13 different receptors.

histamine occurs mainly in mast cells. It acts as a mediator of allergic reactions and substance to the release of stomach acid. Histaminergic neurons within the CNS modulator function. example, they are involved in the regulation of the sleep-wake cycle.


In the group of Amino acids glutamic acid, aspartic acid, GABA and glycine are important.

glutamic acid is the major excitatory transmitter in the CNS. It is important for learning, memory, voluntary motor and transmission of afferent impulses.

aspartic acid, like glutamic acid, an excitatory neurotransmitter.

GABA is the main central inhibitory transmitter. Ca. 30% of all synapses of the brain GABA-erg. GABA occurs practically everywhere in the CNS, especially abundant in the basal ganglia.

glycine is an inhibitory transmitter. It has significance in the control of voluntary movement.

Other neurotransmitters such as endorphins are neuropeptides and tachykinins, as well as ATP and adenosine.



mode of action of antidepressants

in a variety of antidepressants increase the amount of transmitters in the synaptic gap. As a result, there is increased drive, anxiety and mood brightening solution. However, the antidepressant effect usually starts after one to three weeks. The rather non-specific mode of action brings extensive side effects. This set within a short time after ingestion.
Typical side effects by inhibiting serotonin reuptake are nausea, vomiting, headache, sweating, insomnia, restlessness, sexual dysfunction, decreased appetite, Weight loss.
Typical side effects by inhibiting the reuptake Nordrenalin are tremor, tachycardia, restlessness, headache, urinary retention, micturition disorders. Tricyclic antidepressants, and some others also block receptors for neurotransmitters and thus have more serious side effects such as sedation and impaired cardiac work. Are typical of vegetative disturbances.

It is shown that by antidepressants during continuous administration, the activity of different receptors is changed in the brain: serotonin 5-HT 2 receptors and beta receptors are less active alpha-receptors and GABA receptors are more active. Antidepressants act accordingly as an indirect fertilizer for the growth of neurons; antidepressants increase concentrations of transmitters, which act in turn stimulates the communication of neurons to existing synapses and the formation of new synapses.
antidepressants also weaken the influence of stress on the brain.

To date, we can not for the individual patient based on the clinical picture previously say for sure which medicine will help him. First, needs to be clarified what kind of depression and whether it makes sense to use antidepressants. Then must be tested and maintained. Intensive psychological care proven to promote healing. For moderate depression is estimated that one-third each of the Therapeutic success by placebo effect, Antidepressants and psychological care is achieved.


classification of antidepressants
Tricyclic antidepressants

you have been about fifty years, most available and side effects. Your name points to the chemical structure: A lipophilic three-ring system with a hydrophilic chain. So that they can lodge themselves well in cellular membranes and structures. They block different receptors for neurotransmitters, leading to the acute side effects and acute increased drive. In addition, they also inhibit the reuptake of serotonin and norepinephrine from the synaptic cleft.
particular note is the cardiodepressant effect. This leads to characteristic changes in the ECG. Therefore, tricyclic antidepressants are contraindicated in pre-existing conduction abnormalities. For therapy, an ECG examination is routine before treatment and at intervals. Beware of very high doses and overdose.

side effects of tricyclics by receptor blockade:

receptor in the central nervous system side effects
----------------------------------- -------------------------------------------------- ----------------------------
histamine H1-receptor sedation, weight gain, confusion

muscarinic receptor (transmitter: acetylcholine) dry mouth , accommodation disturbances
tachycardia, constipation, Miktionsstörun-
gene, memory problems, confusion

alpha-1 receptor (norepinephrine, epinephrine), orthostatic hypotension, reflex tachycardia,
dizziness, fatigue
5-HT-2 receptor (serotonin) and decreased appetite and weight gain

dopamine receptor Prolactinanstieg, sexual disorders, disorders of voluntary motor


A very rare but life-threatening side effect is the cholinergic syndrome. This can occur if the patient has Metabolisierungsdefekte or by interaction with anticholinergic agents or overdose. Tricyclic antidepressants should not be combined with other antidepressants, especially not with MAO inhibitors.

Application: Due to the sometimes severe side effects mainly take tricyclic antidepressants in severe depression if better tolerated agents help according to experience worse. In addition, the tricyclic antidepressants different applications in treatment of anxiety, pain management and palliative care.

The effect is in three stages: First week sedation, increased drive second week, third week in sentiment.

examples with classification by 3 types:

amitriptyline-type: strongly absorbing, dissolving depression, anxiolytic. These include:

amitriptyline often called orthostatic Dysregulation forth. Beneficial for sleep disturbances and suicidality. Beware of circulation problems.

Doxepin acts-like amitriptyline, but also antiadrenergic. Frequently used in alcohol withdrawal. It is part of amitriptyline-type.

-Imipramintyp The effect loosening depression, marked mood-enhancing, balanced psychomotor. This includes:

imipramine does not sedating, anticholinergic, antiadrenergic. Use also in pain syndromes.
-Desipramintyp The psychomotor activating effect. This includes Nortriptylen. It causes the least circulatory ailments.

Selective serotonin reuptake inhibitors (SSRIs)

They represented a revolution when it was introduced, because they are relatively well tolerated and effective very effective. Therefore, they are very often used nowadays.

These include substances (called by its trade name): citalopram (escitalopram), fluoxetine (Prozac), fluvoxamine (Fevarin), paroxetine (Seroxat, Tagonis) and sertraline (Zoloft, Glade).
you are in the spectrum is very similar, have no sedation, but seem more exciting. The difference is their inhibitory effect on cytochrome P450 isoenzymes, thus on the metabolism of other substances in the liver. At least this blocking effect citalopram.
because of their favorable therapeutic properties they are used frequently.
Typical side effects include nausea, vomiting, headache, sweating, insomnia, restlessness, weight loss, sexual dysfunction, decreased appetite.
The SSRIs should not be administered concomitantly with moclobemide and other MAO inhibitors, because this can lead to a toxic concentration of serotonin in the brain.


selective norepinephrine reuptake inhibitor (NRI)

This includes the agent reboxetine (Edronax). It works well on drive, motivation and interest. Side effects from all sympathetic autonomic effects: tachycardia, tremor, sweating, urination and bladder emptying disorders.


selective serotonin norepinephrine reuptake inhibitors (SSNRI)

They influence the reuptake of serotonin and norepinephrine, the effect and the side effects are similar to the SSRI.
the only of its kind in Germany antidepressant venlafaxine (Effexor) is. Among the group of substances including duloxetine (Yentreve), which is approved in Germany for the treatment of stress urinary incontinence.


monoamine oxidase inhibitors

monoamine oxidase inhibitors, block the oxidative degradation of monoamines in the synapse, which are here adrenaline, noradrenaline and dopamine and serotonin and histamine. Thus, their availability in the synaptic gap increased. The group consists of only two active ingredients. Moclobemide (Aurorix) is a selective reversible MAO-A inhibitor and is used eg for ineffectiveness of tricyclic antidepressants. Also like the elderly, because it is better tolerated in the gastrointestinal area as SSRIs.
tranylcypromine inhibits irreversible nonselective monoamine oxidase and is therefore difficult to handle. It only has meaning as the reserve.
side effects of moclobemide are dry mouth, insomnia, nausea and headache.


lithium salts for prevention of mania

Lithium is an alkali metal such as sodium and potassium. It is with many water-soluble acids Salts. In therapy are common Lithiumacetet (Quilonum), lithium sulfate (Li-Duriles) Lithiumaspartat (Lithium-Aspartate), and lithium carbonate (Hypnorex). Lithium changes the properties of the cell membrane and alters the neurotransmitter transport. A final idea about the mechanism of action does not exist yet. Lithium is in the broad sense of the psychotropic drugs. In a narrower sense it is one to neuroleptics, antidepressants and Tranquilantien. Lithium seems to slow down the manic phase of manic-depressive psychosis and Preventive measures against the recurrence of manic and depressive phases


Its effect begins only after several weeks. normalized in the manic phase, the excited or euphoric mood, and reduces the excess power. In healthy people Lithium sedative effect. Lithium has a narrow therapeutic index. Symptoms of poisoning are fine tremor, impaired concentration, fatigue, nausea, vomiting, renal disorders, convulsions and coma. Even a change of the daily salt intake may alter the renal excretion and thus the blood levels significantly. The patient's cooperation and intensive medical care are therefore a prerequisite for the lithium therapy. The main reason for non-compliance of the patient is weight gain. In addition, connect to various other side effects.


St. John's St. John's wort extract has

in daily doses of at least 300 mg to 900 mg demonstrated mild to moderate depression. Therefore, it is also paid by the statutory health insurance, although it is not because of its good tolerability prescription in pharmacies, but is. In lower doses could not be demonstrated antidepressant activity. One of the ingredients, hyperforin acts as a non-selective reuptake inhibitors. The extract is apparently in many places simultaneously on the metabolism of monoamines (serotonin, histamine, dopamine, epinephrine, norepinephrine). In contrast
to synthetic antidepressants, it has few side effects. Its effect is, however, were rather weak. It has
interactions by enzyme induction by various means.
Rarely, it causes a photo-allergy.


final consideration

fit antidepressants for the treatment of depression may be as good as automotive tool to repair a clock, because the impact is strong, but not always perfect. Nevertheless, they are an important pillar in the treatment of depression dar. They should not use it as the sole means of healing, because behind depression in general, personal problems, which demand a solution. An antidepressant is better currently researching. For example, with several companies inhibitors of CRF, corticotropin-releasing factor in the testing, but also more selective SSRI is working.

Hedda Heuer

Sources: Scientific American DIGEST, riddles brain
Color Atlas of Pharmacology, Heinz Lüllmann and Klaus Mohr
drug reactions, Ernst Mutschler including
Intensive General and Special Pharmacology, Edward Burgis
depression - symptoms and treatment, Norbert Müller and Dorothea Strobach
The Science of Happiness, Stefan Klein
Brain Modelling, Internet lecture,
http://brain.exp.univie.ac.at/