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Depression and anxiety disorders are caused primarily by two closely interrelated problems; low effective levels of the mood -regulating neurotransmitter serotonin, and overproduction of the anxiety, or fight-flight, neurotransmitters and hormones epinephrine and norepinephrine. Another central neurotransmitter dopamine, seems to be very involved in depression and anxiety disorders too as well as with schizophrenia and tourette's syndrome, but the reasons why are only beginning to be understood. Because of how the brain's neurochemistry interacts, imbalances of other neurotransmitters can also result in depression and anxiety disorders. Further, levels of neurotransmitters are closely tied to levels of endocrine hormones and to metabolic health such that disruptions to these things appear to also cause mood and anxiety disorders. One must start with an understanding of how these neurotransmit- ters operate. Nerves are not directly connected with each other. They communicate, or send signals, by firing chemical molecules into the space between nerve cells. Those molecules are picked up by receptors specifically structured to receive that chemical on neighboring nerve cells. There are a great many chemicals taht can serve as neurotransmitters; they range from simple electri- cally charged ions like calcium, magnesium and potassium, to large proteins like serotonin. There are often more than one kind of transmitter for any given neurotransmitter. For instance there are five kinds of receptors for serotonin, and atleast four for dopamine. Those transmitters have specific functions, too. The chemical that is fired into the space between nerve cells and the kind of receptor that picks up the chemical determines what the message is. Some neurotransmitters function chiefly to moderate the effects of other neurotransmitters, or the amount of neurotransmitters released. The most important neurotransmitters in the regulation of the nervous system are serotonin, epinephrine or adrenaline, norepinephrine or noradrenaline, dopamine, and GABA. One effect of that is that imbalances of these chemicals have more than "merely" emotional or mental symptoms. For instance, someone pulse and may have heart palpitations, high blood pressure, sweats, etc. Someone with too little serotonin or too much serotonin may move sluggishly, lack energy, have trouble digesting food, and is likely to have an impaired immune system and have trouble fighting off disease. Depression more than doubles one's risk of heart and other cardiovascular disease, often many years later, and also affects how blood clots. Recent research has found that levels of serotonin and its receptors on blood cells actually affect the tendency of blood to act in the ways that cause cardiovascular disease. These effects of depression make it a leading killer of the elderly. Other key elements of the cycle are enzymes that break down, or metabolize, neurotransmitters, which remove them from further action, like MAO, which breaks down the neurotransmitters serotonin, dopamine, and norepinephrine, enzymes that help make or control the rate of production of neurotransmitters, like the enzyme tryptophan pryrollase which, by metabolizing hte amino acid from which serotonin is made, controls how much sero- tonin is made, and so-called transporters. Transporter chemicals affect the release or uptake of neurotransmitters by the receptors they land in, and help determine the availability of that neurotransmitter to carry the chemical message to more nerve cells. ONe needs to understand the full significance of this complexity of the chemistry of the nervous system; the levels of neuro- chemical receptors, metabolic enzymes and transporter chemicals are as important to the chemical balance of the nervous system as one's levels of the neurotransmitters themselves. If any of this goes wrong, you can have a problem. The brain is the most complex and delicate organ in the body; small wonder that it is the organ of the body that most often has things go wrong with it; that one is far more likely to develop mental illness in one's lifetime than either diabetes or liver disease. And the problem is treatable in the same way as any other problem that goes chemically wrong in the body. Serotonin is the central mood regulating neurotransmitter. It is a "feel good" chemical; high levels help one feel cheerful, calm, "on top" and assertive. Serotonin also acts to calm by turning off the neurochemistry of anxiety. A key feature in both anxiety management and clinical obsessive compulsive disorder is that certain knds of deliberate mental and physical activity momentarily cause the brain to produce serotonin and switches off anxiety. A brain with too little serotonin "can't calm itself properly" as a recent USA Today article on the neurochemistry of anxiety put it. Adrenaline or epinephrine, and noradrenaline and norepinephrine, are the "fight flight chemicals" or the chemicals of anxiety. They prepare the brain and the body to meet some threat. The brain and body act on the assumption that the threat is immediate and physical. The entire function of the body changes to, for instance, survive the imminent attack by a saber-toothed tiger, from normal function. Blood shifts from the digestive system and other functions not immediately needed to the muscles. The heart speeds up. The immune system gets in gear. The body's hormone production prepares to survive possible serious injury, and at the same time shuts down non-critical functions like a woman's estrous cycle. The term fight-flight is based on if the saber toothed tiger is attacking, too responses may be appropriate; fight or run. Both require immediate great physical strength and effort. This dual effect of the chemistry of anxiety leads to a dualism of emotion; anger and anxiety are flip sides of the same emotion, and someone with an anxiety disorder is likely to also be impatient, irritable, short tempered, volatile, easily angered, and anxiety attacks not infrequently take the form of violent rage. But clinical depression, when the brain doesn't have enough serotonin or can't utilize it properly, secondarily causes symptoms of anxiety and anger. In fact, current research shows that most of the genes that cause depression are about equally likely to actually cause clinical depression and clinical anxiety disorders. Researchers think THAT may be a function of experience and environment. Dopamine is another "feel good" chemical that is important in anxiety disorders and depression. REsearchers have almost established that by establishing the fact that genes that r regulate dopamine and its receptors are among the most important causes of clinical depression and anxiety disorders. Dopamine is known to be important in the regulation of the entire nervous system, and has particularly many receptors in certain regions of the emotional brain, for instance, in the caudate nucleus of the basal ganglia, which is important in obsessive compulsive disorder. Problems with the basal ganglia cause obsessive compulsive disorder in standard lightening hit the telephone wire, the phone is ringing, noone is really calling format. In addition to the major transmitters, there is evidence that the entire balannce between sex hormones, the adrenal cortex, other metabolic activity esp thyroid and blood sugar, a basic neurotransmitter called choline, interact with the major mood controlling chemicals and with the metabolic activity of key parts of the emotional brain in mood disorders and a number of minor physical problems that go with mood disorders. I will put something on this in the section on research on bipolar disorder. If any genes have been found, they are among the "suspect regions" found in research on the genetics of bipolar disorder! It is fairly clear that bipolar disorder, and depression, share some common underpinnings. Here are the genes currently believed to cause or contribute to anxiety disorders and depression. 5HTT gene - serotonin transporter gene. Length due to number of repetitions of a key sequence of code that results in quantity of a protein made correlated with "neuroticism", a scale of anxiety and depression; with harm avoidance, and with worry and pessimism - particularly ruminating worry. A gene for temperament, probably contributes 5 to 20% of a clinical anxiety disorder. Also common, only l/3 of people have the two long genes of the calmer and happier people. But 9 (STin2.9), 10 (STin2.10), and 12 (STin2.12) alleles of same gene raise ones odds of major depression and manic depression 3 or 4 times. Catechol-O-methyltransferase (COMT) metabolizes the catecholamines dopamine, noradrenaline and adrenaline. exists as common high and low activity alleles in the population. G256 allele and val 158 allele associated with schizophrenia, schizoaffective disorder, and functional psychoses. COMT alleles also associated with obsessive compulsive disorder and rapid cycling bipolar disorder (manic depression) A common COMT allele that results in a 3 to 4-fold reduction in enzyme activity associated in a recessive manner with obsissive compulsive disorder partic in men. G fwdarw A tansition at codon 158 of the COMT gene. Also associated with mood disorders and alcoholism and substance abuse. DRD2, dopamine D-2 receptor, D-beta-H, dopamine beta-hydroxylase, and DAT1, dopamine transporter, additively contribute to Tourette's syndrome. Tourette's syndrome is a whole clinical syndrome consisting of tics, clinical OCD, attention deficit disorder, and symptoms of anxiety disorder. Also tendency to alcohol abuse, stuttering, oppositional-defiant (personality disorder), mania. DRD2 NcoI allele increases one's chance of migraine with aura, major depression, generalized anxiety disorder, panic attacks, and phobia 3 times over chances of people with NcoI T/T allele. DRD2 alleles homozygous E8 A/A geneotype associated with increased neuroticism scores in alcoholics following clinical detoxification. People with this allele have a harder time getting over alcoholism. DRD4 dopamine D4 receptor gene contributes to OCD with tics. DRD4 gene signif assc with mood disorders, particularly major depression. Dopamine D3 receptor gene (DRD3) assocated with tourette's but not with OCD. Wolfram syndrome. Causes psychiatric illness in people homozygous for the gene. But heterozygous relatives far more likelyt han spousal control relatives to have been hospitalized for psychiatric illness or to commit suicide. Alpha 2-adrenoreceptors work differently in people with panic disorder. It results in higher levels at some times of norepinephrine. MTHFR (methylenetetrahydrofolate reductase) T677 allele associated with both schizophrenia and depression - doubles or triples odds. GABRA5 (GABA-A receptor alpha-5 subunit gene associated with major depression. Polymorphisms in serotonin receptor 2c (5-HTR2c) and 5-HTT genes cause minor increase in women's susceptibility to bipolar depression. Findings on a role of 5-HT-2A serotonin receptor genes are com- pletely contradictory. Serotonin (5-HT) receptors 5-HT-1A, 1B, 1D, 1E, 1F 5-HT-2A, 2B, 2C linked to multifunctional phosphinositide (PI) signalling system 5-HT-3 ion-gated receptors and linked to PI signalling system 5-HT-4 5-HT-5 5-HT-6 5-HT-7 5-HT-2A most studied of 5-HT receptors in psychiatric disorders (suicide, depression, schizophrenia) 5-HT-2C and 5-HT-3 play less clear roles in psychiatric illness All three play important role in alcoholism. Evidence suggests that serotonin production may have more to do with depression than serotonin receptors. The reader will notice that these genes vary greatly in the strength of their effect. Some of them cause mental illness in an almost mendelian dominant, or sometimes mendelian recessive, fashion. Others raise one's odds of developing clinical mental illness so much, from a little, to quite dramatically as in the case of the D2DR gene. Some of these genes are genes for temperament. By themselves they stand little chance of causing clinical mental illness. The most common alleles of the 5HTT gene are an example. They cause a calm and laid back or an anxious and dour temperament. Interestingly, the short forms of this gene are correlated with "neuroticism"; defined basically as compulsive worrying, repetitive scary thoughts, a glum outlook; all symptoms of mood and anxiety disorders. But a number of these genes together can cause clinical mental illness, and they also of course affect one's odds by affecting how one handles stressful situations. In fact, researchers found that given that one has clinical depression, having the short 5HTT gene makes one more likely to commit suicide! One is not highly unlikely to have a number of these genes. Some of them, like the short 5HTT gene, are common. And my genealogy illustrates how genes of this nature are likely to accumulate in a line. People usually marry people of similar temperament and background. Researchers think that genes for an anxious or dour temperament became common in the human population because they are functional. People who have a glum or anxious outlook perceive danger more realistically than do calm and happy people, and also react to it more realistically - whatever else they do. People have often experienced long periods of deadly danger; anxious and glum people disproportionately survived! My genealo- gy illustrates this theory perfectly; my temperament and mental health clearly are the product of selective forces that acted during the Protestant Reformation. Researchers think the variation in the number of repitions in the 5HTT gene that makes it long or short got its start when we evolved from the apes. All apes have longer 5HTT genes than nearly any human. That is part of why they tend to be calmer and more placid than we are. Researchers think that the complexity of human socialization, like, one had to become capable of worrying about doing the right thing, resulted in the shorter 5HTT gene! Even genes that dramatically raise one's probability of clinical mental illness can be functional if they affect only a proportion of people that drastically. REmember the sickle cell anemia gene; it protects half of the population that carries it from death from malaria. Though it also kills a quarter of them, it allows the group as a whole to survive in that environment. Evolution is not logical; it proceeds on the basis of literally what produces a statistical advantage. ONe implication of the new understanding of the neurochemistry of mental illness is that there isn't a sharp dividing line between mental illness and mental health. There is a whole gray area of emotional problems, personality disorders, which are proving through high correlation with clinical illness, common neuro- chemistry and common genes, to be subclinical or borderlined mental illness, and extremes of "normal" temerament "within the normal range" whatever that means. Many people, like the author of a recent Newsweek article blasting the new neuroscience, see what they see as the patent absurdity of this implication of knew knowledge as disproving it. Actually, this notion is not absurd, it is reality. It bothers alot of people who are scared of mental illness and like their frightening issues stereotyped and clear cut. When one applies common sense to the matter, one quickly sees that mental illness and its borderlined states are the only human health matter one thinks like this about. On all other health matters, whether colds, headaches, stomach problems, toothache, arthritis, heart trouble, we think in terms of, well, I know I have a health problem, but how badly is it bothering me, will it clear up by itself, what are the relative costs and benefits of treating it vs leaving it alone, and what is the least radical intervention that will work. For arthritis, for instance, peoples' doctors don't prescribe surgery or drugs when a few months of (physical) therapy will work - at least mine doesn't! Tracing genetic mental illness poses special problems. It needs to be done, just like any other genetic medical problem that tends not to be recognized and properly treated has to be traced and documented, and the people at risk for it informed and educated about it. Now, how to trace it. Mental illness doesn't OFTEN show on peoples' death certificates, but it may. I have two great grandparents died in state psychiatric hospitals, one fairly young from breast cancer; both had been ill for much or all of their adult lives. My first cousin on my father's side died from combining alcohol and sleeping pills. It turns out he was an alcoholic. THe father of one of the great grandmothers who died in the state psychiatric hospital died directly from alcoholism. Allied health problems and certain sorts of causes of death might make one suspicious, like the apparent strong Dehaven genetic tendency to alcoholism. Untreated mental illness is the leading cause of alcoholism, and some of the genes found to influence the clinical course of alcoholism are the same genes that cause depression and anxiety disorders! Usually mental illness in one's ancestors wasn't correctly diagnosed or labelled, and even if people describe an ancestor as "a REAL nutcase", they don't actually mean, NUTCASE. They mean very peculiar. Never mind if the specific ways that person was peculiar are classic symptoms of a serious mental illness. Usually, TODAY mental illness is not correctly diagnosed and labelled. Someone is just "moody" or "that way". If people in the past did realize something was wrong, their diagnosis and labelling are likely to be Freudian. That person wasn't clinically ill, he had an overbearing mother! Never mind that the overbearing mother was clearly as seriously clinically ill as he was. I had five ancestors condemned as witches at Salem, and on investigation three probably had mood disorders that ran in their family, and two had bouts of serious mental illness. In the past, mentally ill people were often thought to be witches or possessed; and people who were anti-social, moody or given to acting out were very selectively likely to become victims in witch hunts. Current advice on how to trace possibly genetic mental illness in one's lines specifically states to look both for peculiar behavior and for legal trouble. People who aren't doing very well emotionally or who have tendencies to be anti-social in any respect often have legal troubles. What one in fact is likely to see when one traces mental illness is the visible signs and effects of it; extreme behavior, a pattern of under- achievement in well-educated and prosperous families, like mine, family breakdown, alcoholism. One often sees patterns of extremes of temperament and behavior. When genealogists, who as a group never notice anything but names and dates, note in published genealogies that every other member of an entire, highly inbred, clan, is extremely intense, dogmatic, and so quiet that they never get called up for discipline, never get a parking ticket or bounce a check, and never have ANYTHING outside of their public and religious duties to do with other people, which happened with my father's Quaker line, something is going on. My father's great-great grandfather, in a small, close-knit community half to all of which turned out for any wedding and everyone present signed the marriage certificate, ever signed teh wedding certificate of just one of four brothers. His son married a cousin from a family as abnormally quiet and asocial, and when she died in childbirth, instead of going off for a few months like people do, he dropped out of sight for several years and the birth of the child, unlike that of his other children, was never recorded at his meeting. He didn't leave town, understand. He developed clinical depression and withdrew even more extremely than he already had! The Dehavens as a family group characteristically act in ways consistent with an extremely intense temperament, and for hundreds of years have been given to doing extreme and peculiar things that anxiety would explain, such that Dehavens give the appearance of having an instinctive inborn fear and distrust of the world and everyone in it! My father took this to new heights. We children literally were not allowed out of the house except for school, church, and work at age l6, even to go to the movies with friends at age l8, because something, often something strange, improbable or vaguely defined, was going to happen, and it was his responsibility! One day, when I was 18 and attending community college because my parents didn't want me to go away to school, I wanted to go out with a group of kids from school for the evening. I wasn't yet allowed to date. My father said, "I trust you, but I know something will happen." I pointed out that I was legally of age to do anything I wanted including move out (which I ended up doing, and for which my father never forgave me); clearly, then, my actions and their consequences are my own responsibility. My father said, "It is my responsibility." I couldn't get reality through to him. When my brother and I were children, my parents felt that every child in all of our collective grades at aschool, or his/ her parents, had something wrong with them, that made them from unsuitable to dangerous as playmates. "If you ride with Mr. Quigan, and he gets in an accident, he will sue me." There was noone my father didn't think was likely to do something to him. When the quiet, well-behaved daughter and niece of the Baptist minister and their mothers tried to rescue me by having the mothers call my mother to invite me to their houses after school, my mother repeatedly turned them down! My mother both pulled out of the long bout of depression she spent my childhood having, and stood up to my father on behalf of my sister, and as a result my sister, who was only twelve when I left home at 18, had a more normal social life. But she was seriously affected both by my father's continual put-downs and his efforts to control her, and by the fact that she had to be home before dark unless someone took her to the school activities, such as sports teams, that she participated in, "and you know it gets dark at 3:00 in the afternoon in the winter", and neither of my parents could seem to muster the ambition and meet the challenge of taking her to these activities and picking her up. What my father really had was one of the more subtle and difficult forms of obsessive compulsive disorder; a deep obsessive fear of something happening to himself and his family, accompanied by a greatly exaggerated sense of responsibility born of the depression that more often than not goes with obessive compulsive disorder. Like me, he combined this with general anxiety disorder, and his doctor treated the physical symptoms of this quite inappropriately with valium, for twelve years. Sedatives alone like this often exacerbate the problem because they aggravate depression. Further, my father had acquired ways of thinking and of dealing with things, with people, and of relating to his family that exacerbated his problems. The family physician never told my father he had a mental disorder called general anxiety disorder. He told him he had "stress". Just take valium, and you can go on taking it. Forever. It won't hurt you. Most people with mental disorders need counselling whatever else is done to treat it. That still happens all to often when people with symptoms of mental illness turn to their primary care physician. A pattern of extreme behavior in one's ancestors may mean several things. It may mean they were clinically mentally ill. Sometimes one really can't tell or can't be sure. One knows something wsn't right but doesn't know how badly. It may mean they had one of the genes that increase one's probability of developing clinical mental illness, and shape the temperaments of everyone else in the family who inherits the gene. Or it can mean that the people with this temperament carried one or more of the genes for temperament, that fed together with other lines that carried similar genes into my family that developed clinical mental illness. All of the evidence is not in; I now know, for instance, that the family of my father's brother was as badly hit by the mental health problems as my family; I already knew that both of his parents appeared to have problems. His father almost certainly had a mood/anxiety disorder. He was intense and volatile; noone seems to have known him well, and his employees were afraid of him. His sons had cause to be afraid of him, but one son seems to have been tough, rebellious, and fearless as well as possibly even more intense and moody and even more violent tempered than his father, and my father too completely withdrawn to notice! Except that, as children in such situations usually do, he accepted his parents' word that his six years older brother was a bad seed. There was extreme trouble of some sort in his mother's family such that the family seem to have actually moved to another city under scandalous cir- cumstances and then concealed their wherabouts; and I as yet know nothing about her father's family. But I suspect that the pattern in my father's genealogy is atleast in part the result from genes for extremes of temperament accumulating in our lines as people repeatedly married people very similar to themselves in temperament and in background. I think one or more genes came from the Thompson line, one or more genes came from the Dehaven line, and one or more genes came from his Doors/ possibly Op den Graeff line that I've newly found. Before that, my Dehaven line picked up genes from the temperamentally similar Leverings, and Cramers, and from apparently clone of my mother Mary Pluck. IN the mean time, the Thompson genealogy is in its own way as remarkable. Where did the ancestors of this family group FIND all of the Quaker founders and leaders they ever only married? Then my father's father married his somber, withdrawn mother, whose story I don't know yet, I just have vague tales of something wrong in her family, and then my father married my mother, "a very remarkable woman" the daughter of a "very remarkable woman" in my father's words. Both women are/ were indeed remarkable, in temperament. INdications are taht the genes my mother carries are more vicious. But suppose that eaach of these lines had one or more genes for a dour, anxious temperament within the bounds of "normalcy" that contribute maybe 5 to 20% of a clinical anxiety disorder, according to the thinking of the author of a recent study of the serotonin transporter gene. Over time, one can end up with people who carry five to twenty of these genes! In my mother's family, the situation is much simpler; a Noyes line that was seriously unstable and left a trail of serious mental illness everywhere they married crossed with my Rice line that had manic depression. The probably moody descendants of the Raymond-Bishop marriage in Salem (she was a daughter of the family who had three members condemned as witches) MERGED by marriage of the sons of thje Raymond family with teh daughters of the Balch family, with the Balch family which carried a serious mood/ anxiety disorder. A generation later, for reasons not very hard to figure out, one of the children of one of those marriages married a recent Rice descendant whose family still had the manic depression. Then first cousins married each other for the next two generations; a result of the second marriage was my great grandmother. Next, my grandmother married my grandfather, whose mother greatly resembled my intense, at times irrational and phobia- ridden grandmother; she had a mood disorder and an extremely violent, unpredictable, irrational temper, and she eventually was hospitalized when she became psychotic.
Email me at dorasmith24@hotmail.com
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