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Their struc- ture depends on diverse discount female viagra online visa, often weak purchase generic female viagra, interactions between their amino-acid building blocks order 50 mg female viagra. These interactions are optimally coordinated only within a very narrow range of ambient condi- tions that correspond precisely to those in which the organism from which the protein is derived best thrives discount female viagra 100mg fast delivery. Because of this, even relatively small changes in the temperature, salt content or pH of the ambient solution can damage the structure. This, in turn, can neutralise the function of the protein, since this de- pends on the precise natural shape of the molecule. Most of these mole- cules act as vital chemical Detecting signals: interferon gamma and its receptor messengers in the body. The target cells that receive and translate the signals bear special receptors on their surface into which the cor- responding chemical mes- senger precisely fits. If the three-dimensional shape of The signal protein interferon gamma (blue) is recognised by a the chemical messenger is specific receptor (left and right) located on the surface of its even slightly altered, the target cells. Interferon gamma as a biopharmaceutical is used to treat certain forms of immunodeficiency. The situation is similar for another group of therapeutic proteins, the antibodies. Their function is to recognise foreign structures, for which purpose they have a special recognition region whose shape pre- cisely matches that of the target molecule. Changing just one of the several hundred amino acids that make up the recognition region can render the antibody inactive. It is possible to produce antibodies to target any desired foreign or endogenous sub- stance. Modern biotechnology makes use of the technique to block metabolic pathways in the body involved in disease pro- cesses. Like other therapeutic proteins, antibodies must there- fore assume the correct molecular arrangement to be effective. Biopharmaceuticals: This structural sensitivity also causes problems biological instead of because proteins do not always automatically as- chemical production sume the required structure during the produc- tion process. Long chains of amino acids in solu- tion spontaneously form so-called secondary structures, arranging themselves into helical or sheetlike structures, for ex- ample. However, this process rarely results in the correct overall shape (tertiary structure) especially in the case of large pro- teins where the final structure depends on the interactions of several, often different, amino acid chains. During natural biosynthesis of proteins in the bodys cells, a se- ries of enzymes ensure that such protein folding proceeds cor- rectly. The enzymes prevent unsuitable structures from being Drugs from the fermenter 29 Diverse and changeable: the structure of proteins primary structure } A chain of up to twenty different amino acids (primary struc- ture the variable regions are indicated by the squares of dif- ferent colours) arranges itself into three-dimensional struc- secondary tures. The position of these secondary structures in rela- tion to one another determines the shape of the protein, i. Often, a number of proteins form func- tional complexes with quaternary structures; only when arranged in this way can they perform their intended func- tions. When purifying proteins, it is extremely difficult to retain such protein complexes in their original form. These strictly controlled processes make protein production a highly complex process that has so far proved impossible to replicate by chemical means. Instead, proteins are produced in and isolated from laboratory animals, microorganisms or special cultures of animal or plant cells. Natural sources limited Biological production methods do, however, have several disadvantages. The straightforward ap- proach, isolating natural proteins from animals, was practised for decades to obtain insulin (see article Beer for Babylon). But the limits of this approach soon became apparent in the second half of the 20th century. Not only are there not nearly enough slaughtered animals to meet global demands for insulin, but the animal protein thus obtained differs from its human counter- part. The situation is similar for virtually every other biophar- maceutical, particularly since these molecules occur in animals in vanishingly small amounts or,as in the case of therapeutic an- tibodies, do not occur naturally in animals at all. Most biopharmaceuticals are therefore produced in cultures of microorganisms or mammalian cells. Simple proteins can be 30 Little helpers: the biological production of drugs The bacterium Escherichia coli is relatively easy to cultivate. For complicated substances consisting of several proteins or for substances that have to be modified by the addition of non-protein groups such as sugar chains, mam- malian cells are used. To obtain products that are identical to their human equivalents, the appropriate human genes must be inserted into the cultured cells. These genetically manipulated cells then contain the enzymes needed to ensure correct folding and processing of the proteins (especially in the case of mam- malian cells) as well as the genetic instructions for synthesising the desired product. In this way a genetically modified cell is obtained which produces large quan- tities of the desired product in its active form. Biotech production: each But multiplying these cells poses a technological facility is unique challenge, particularly when mammalian cells are used to produce a therapeutic protein. Cells are living organisms, and they react sensitively to even tiny changes in their environment. From the nutrient solution to the equip- ment, virtually every object and substance the cells touch on their way from, say, the refrigerator to the centrifuge can affect them. Drugs from the fermenter 31 High-tech cell cultivation: biotechnological production facility in Penzberg Large-scale industrial production facilities for biopharma- smallest impurity can render a batch useless. These factors determine not only the yield of useful product but also the quantity of interfering or undesired byproducts and the structure of the product itself. As a result, each biopharmaceu- tical production plant is essentially unique: Changing just one of hundreds of components can affect the result. Focus on Chinese Laboratories and manufacturers around the hamster cells world work with standard cell lines to produce biopharmaceuticals, enzymes and antibodies. These cell lines are used because they are well researched and, as far as is possible with living organisms, are amenable to stan- dardisation. Biotech researchers insert structural and control genes into the cells of these and similar lines to produce the desired pharma- ceutical. This establishes a new cell line, which is usually treated as a closely guarded company secret. After all, these cells are the actual factories of the biopharmaceutical concerned. They are allowed to reproduce and are then safely stored at low tempera- tures in what is known as a master cell bank. If the cells need to 32 be stored for long periods, they can be kept almost indefinitely in liquid nitrogen at 196C. Cells are then drawn from the cell banks and used in biophar- maceutical production. Broadly speaking, the production pro- cess is divided into the following steps: Cultivation: The cells are transferred from the cryogenic cell bank to a liquid nutrient medium, where they are allowed to reproduce. The cells secrete the desired product, ent solution is inoculated with cells from a cell bank. These which is then isolated from the solution, purified and trans- are allowed to reproduce in stages up to a scale of several ferred to containers. During the growth phase the cell culture is transferred to progressively larger culture vessels. Fermentation: The actual production of the biopharmaceutical occurs during this phase. The culture medium contains sub- stances needed for the synthesis of the desired therapeutic protein. In total, the medium contains around 80 different constituents at this stage, although manufacturers never dis- close the exact composition. The industrial-scale steel vessels in which fermentation takes place have capacities of 10,000 liters or more. There are not only technological but also bio- logical constraints on the size of the reactor vessel: The big- ger a fermenter is, the more difficult it becomes to create uni- form conditions around all the cells within it. Purification: In technical terms, the production of biopharma- ceuticals in cells is a one-step process and the product can be purified immediately after fermentation. In the simplest case the cultured cells will have secreted the product into the am- bient solution. If, on the other hand, the product remains in the cells follow- ing biosynthesis, the cells are first isolated and digested (i.

In addition to the classical order female viagra mastercard, mostly agricultural purchase female viagra 50mg without prescription, products buy 100mg female viagra, more and more new products entered the market- place buy generic female viagra 100 mg online. Enzymes were isolated in highly purified form and made available for a wide variety of tasks, from producing washing powder to measuring blood glucose. Standardised biochemical test methods made their entrance into medical diagnostics and for the first time provided physicians with molecular measuring instruments. The structures and actions of many biomolecules were elucidated and the biochemical foundations of life thereby made more transparent. Gene technology spurs However,it was only with the advent of gene tech- innovation nology that biology and biotechnology really took off. Desired changes in the genetic makeup of a species that previously would have required decades of system- atic breeding and selection could now be induced within a few months. For example, newly developed techniques made it possible to in- sert foreign genes into an organism. This opened up the revolu- tionary possibility of industrial-scale production of medically important biomolecules of whatever origin from bacterial cells. The first medicine to be produced in this way was the hormone insulin: in the late 1970s Genentech, an American company, de- veloped a technique for producing human insulin in bacterial cells and licensed the technique to the pharmaceutical company Eli Lilly. Gene technology: human insulin from bacteria In 1982 human insulin became the worlds first biotechnolog- In 1978 the biotech company Genentech developed a method ically manufactured medicine. These were then separately isolated, combined and betes and most people with type 2 diabetes require regular finally converted enzymatically into active insulin. In its day, this classical biotechnological method it- Some 200 million diabetics worldwide now benefit from the self represented a major medical breakthrough: until 1922, production of human insulin. Without gene technology and when medical scientists discovered the effect of pancreatic biotechnology this would be impossible: in order to meet cur- extracts, a diagnosis of type 1 diabetes was tantamount to a rent demands using pancreatic extract, around 20 billion pigs death sentence. A new economic This technology laid the foundation for a new in- sector arises dustry. The early start-up biotech companies joined forces with large, established pharmaceu- tical companies; these in turn used biotechnology to develop high-molecular-weight medicines. Rapid expansion In the early 1980s very few companies recognised and stock market boom the medical potential of the rapidly expanding field of biotechnology. This was true both in relation to sales and number of companies and also in relation to public profile. The situation changed abruptly, however, when biotech prod- ucts achieved their first commercial successes. In the 1990s pro- gress in gene technological and biotechnological research and development led to a veritable boom in the biotech sector. Within a few years thousands of new biotech companies sprang up all over the world. Fuelled by expectations of enormous future profits, the burgeoning biotechnology indus- try became, together with information technology, one of the driving forces behind the stock market boom of the final years of the 20th century. Measured on the basis of their stock market value alone, many young biotech companies with a couple of dozen em- ployees were worth more at that time than some estab- lished drug companies with annual sales running into hundred of millions of dollars. While this investor exuberance was no doubt excessive, it was also essen- tial for most of the start-ups that benefited from it. For This life-size bronze sculpture of Genentechs founders the development of a new is on display at the companys research centre in South drug up to the regulatory San Francisco. The main reason for this is the high proportion of failures: only one in every 100,000 to 200,000 chemically synthesised molecules makes it all the way from the test tube to the pharmacy. Biotechnological production permits the manufacture of com- plex molecules that have a better chance of making it to the mar- ket. On the other hand, biotechnological production of drugs is more technically demanding and consequently more expensive than simple chemical synthesis. Without the money generated by this stock market success, scarcely any young biotech com- pany could have shouldered these financial risks. The first modern biotechnology company: Genentech It took courage to found a biotechnology company in 1976. Yet their conversation lasted three hours and by the the search for financial rewards might endanger basic re- time it ended the idea of Genentech had been born. Itwas scarcelysurprising,therefore,that the respected developments followed rapidly: 1976 On 7th April Robert Swanson and Herbert Boyer found- ed Genentech. If these too are taken into account, the 17 Pfizer 481 following picture emerges: 18 Abbott Laboratories 397 19 Akzo Nobel 375 20 Kirin 355 Source: Evaluate Service companies or the services of contract manufacturers. As a result of the changed stock market conditions after 2000 some of these alliances evolved into takeovers: the market value of most biotech companies collapsed as abruptly as it had risen, and access to additional capital via the stock market was mostly impossible. The modern biotechnology sector is therefore now in the middle of its first wave of consolidation. Europe: Pharma enters This development did not, however, occur in the biotech sector exactly the same way all over the world. However the motors driving development in the worlds second most important biotech region are derived almost exclusively from the classical industrial sectors. As a supplier of laboratory equipment for use in biochem- ical research and medical diagnostics, this German company had possessed an abundance of expertise in developmental and manufacturing processes for the biotechnology sector since its very inception. It made the transition to modern bio- technology during the 1980s with the introduction of a number of recombinant (i. In a more recently developed form, this drug still plays an important role in the treatment of anemia and in oncology. This makes it one of the worlds top-selling genetically engineered medicines and an important source of income for the company, which was integrated into the Roche Group in 1998. It be- gan large-scale production of recombinant enzymes as long ago as the early 1980s. In 1986 it introduced its first genetically en- Beer for Babylon 17 1997 1998 2001 For the first time a eukaryotic genome, The first human embryonic cell lines The first draft of the human genome is that of bakers yeast, is unravelled. This product for use against hairy cell leukemia was manufactured under li- cence from Genentech. After its takeover of Boehringer Mannheim, Roche devel- oped the Penzberg site into one of Europes biggest bio- technology centres. Finally, its ac- quisition of a majority stake in the Japanese pharmaceu- ticalandbiotechnology com- pany Chugai in 2002 put the Roche Group close behind the world market leader Amgen in terms of biotech sales. Its competitors have fol- lowed a similar course, though in some cases later or with different focuses. Boehringer & Shne, under- first recombinant drug to be discovered, developed and pro- takes biochemical work in the former Hotel Simson in Tutzing. The resulting expertise has paid off: The Roche Group Syntex and in 1995 converts it into Roche Biosciences. Roches returns 42% of the companys shares to the stock market; the Diagnostics Division supplies over 1700 biotechnology-based monoclonal antibody Herceptin is approved for use in breast products. Key milestones on the way to this success 2000 The Basel Institute for Immunology is transformed in- are listed below: to the Roche Center for 1896 Fritz Hoffmann-La Roche founds the pharmaceutical Medical Genomics. Japan: potential in Compared to their counterparts in Europe, the biotechnology pharmaceutical companies of the various Asian countries which are otherwise so enthusiastic about new technology were slow to recognise the potential of this new industrial sector. This despite the fact that the Japanese pharmaceutical market is the worlds second largest, after that of 20 Number one in Japanese biotechnology: Chugai Pharma 1925 Juzo Uyeno founds a small pharmaceutical company in Tokyo that becomes increasingly impor- tant nationally over the coming decades. A few years ago the Japanese phar- in Japan and later also in Europe, Australia and China. Roche, Chugai has become not only the fifth largest pharma- 1997 Chugai Diagnostics Science is formed. Moreover, two Japanese companies, Takeda and Sankyo, rank among the 20 largest pharmaceutical companies in the world. In the 1990s Japan set out on the road to catch up, in particular via large-scale support programmes and targeted alliances. The result is that Japanese pharmaceutical companies are now at least on a par with their counterparts in most European coun- tries in terms of sales of biopharmaceutical products. However, the country still lags behind in terms of the number of biotech companies based there, the period of rapid expansion in the 1990s having largely passed Japan by. As yet,Japanese companies devoted exclusively to modern biotechnology have an even smaller slice of the world market than their European competi- tors. Japanese biotechnology is largely in the hands of representatives of classical branches of industry such as the brewery Kirin, the food manufacturer Takara, the chemical manufacturer Kyowa Hakko and variouspharmaceutical companies.

Twenty-four hour mean plasma testos- terone concentration declines with age in normal premenopausal women generic 50mg female viagra with amex. Evidence for diminished mid cycle ovarian androgen production in older reproductive aged women order 100 mg female viagra free shipping. Changes in reproductive hor- mones in sex hormone binding globulin in a group of postmenopausal women measured over 10 years purchase female viagra 100 mg on-line. A prospective longitudinal study of serum testosterone purchase generic female viagra on line, dehydroepiandrosterone sulphate and sex hormone binding globulin levels through the menopause transition. Psychological reactions and sexual life after hysterectomy with and without oophorectomy. Vaginal atrophy in the postmenopausal woman: the importance of sexual activity and hormones. Transdermal testosterone therapy improves well-being, mood and sexual function in pre-menopausal women. Replacement of dehydroepiandrosterone in adrenal failure: no benet for subjective health status and sexuality in a 9-month randomized parallel group clinical trial. Improvement in mood and fatigue after dehydroepian- drosterone replacement in Addisons disease in a randomized, double blind trial. The effect of dehydroepiandrosterone supplementation to symptomatic perimenopausal women on serum endocrine proles, lipid parameters, and health-related quality of life. Female androgen insufciency: the Princeton consensus statement on denition, classication, and assessment. Physiological changes in dehydroepiandro- sterone are not reected by serum levels of active androgens and estrogens but of their metabolites: Intracrinology. A prospective study of the effects of oral contraceptives on sexuality and well being and their relationship to discontinu- ation. Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: potential clinical implications. Risks and benets of estrogen plus progestin in healthy postmenopausal women: principal results from the Womens Health Initiative randomized controlled trial. Using a different model for female sexual response to address womens problematic low sexual desire. The effect of a cog- nitive behavioral group treatment program on hypoactive sexual desire in women. Evaluation of a cognitive behaviour therapy program for people with sexual dysfunction. A comparative study using orgasm consistency training in the treatment of women reporting hypoactive sexual desire. A eld trial of the effectiveness of behavioral treatment for sexual dysfunctions. Factors related to successful outcome in the treatment of sexually unresponsive women. Therapy for sexual and relationship problems: the effects on outcome of attending as an individual or as a couple. Prevention of postmenopausal bone loss at lumbar spine and upper femur with tibolone: a 2-year randomized controlled trial. Two-year prospective and comparative study of the effects of tibolone on lipid pattern, behaviour of apolopoproteins A1 and B. The comparison of effects of tibolone and conjugated estrogen medroxy progesterone acetate therapy on sexual performance in postmenopausal women. Effects on sexual lifea comparison between tibolone and a continuous estradiolnorethisterone acetate regimen. Comparative effects of estrogens plus andro- gens and tibolone on bone, lipid pattern and sexuality in postmenopausal women. Buproprion sustained release for the treatment of hypoactive sexual desire disorder in premenopausal women. This viewpoint about men and sex is held not only by women, but by most men too (including Robin Williams). The idea that a man may be much less interested in sex compared with other men may not make sense to many. In the argot of the times, such an idea represents a disconnect; it does not compute. Likewise, partners nd the experience of being with a perpetually sexually disinterested man to be not only confusing, but agonizing. In tears, she told the doctor of her longing to have children and hearing the ticking of the biological clock. In the course of asking detailed fertility-related questions, the doctor discovered that intercourse was taking place only about once in 2 months. In retrospect, Rebecca had always been more sexually interested than Jim prior to their marriage, and in the early days, sexual frequency seemed not to be a problem. In accord with the psychiatrists usual pattern of practice to see part- ners separately as part of an assessment, and in an effort to understand Jims point of view, he saw Jim alone. The psychiatrist discovered in the process that Jim was in fact just as disinterested in sexual matters as his wife described. He had few thoughts about sexual issues, denied having sexual fantasies or dreams, masturbated rarely, and had never had any sexual experiences with other women (or men). Although Jim understood his wifes distress, he also thought that her sexual interest was excessive. With reluctance, Jim accepted the idea of referral to another psychiatrist who had a special interest in the care of people with sexual problems. The idea of including separate chapters on sexual desire problems in men and women in this book is unusual. The editors evidently considered that such problems in the two gender groups were not identical. However, apart from dis- orders, is sexual desire itself different for men and women? In what appears to have been an effort to redress an attitudinal imbalance in much of human history in which men were perceived to be much more sexual than women, Masters and Johnson (1) attempted to make the two genders sexu- ally symmetrical. However, in the early part of the 21st century, attitudes towards sexuality in men and women seem to have evolved (at least in some parts of the world) so as to permit the idea that they may be sexually different without at the same time implying that one is superior to the other. Male Hypoactive Sexual Desire Disorder 71 health professionals who care for people with sexual difculties suggest that there may be major differences in sexual desire for men and women. Levine (2) has written extensively on the subject of sexual desire generally and although recognizing differences between men and women, has focussed particularly on underpinnings that are common to both. This focus on women has resulted in, paradoxically, clarication of how men are different from women, particularly in the area of sexual desire. For example, a study of couples found that lesbian pairs engaged in sexual activity considerably less often than those who were either heterosexual or gay men (3). Explanations might include the notion that sexual events in heterosexual couples often seem to occur on the initiative of men and that men are obviously omitted from consideration in a lesbian twosome. One might therefore reason that a lower level of sexual activity in lesbian couples suggests that sexual desire in women is, from a quantitative viewpoint, less than that in men. Nichols (4) also looked at lesbian couples and not only observed that they exhibit stereo- typical female sexual behavior but also speculated about women being wired differently. Examining the issue of womens sexual desire from a different perspective, Basson (7) comes to a similar conclusion. They summarized their ndings by saying: we did not nd a single study, on any of near a dozen different measures, that found women had a stronger sex drive than men. Male Hypoactive Sexual Desire Disorder 73 comment here, as sexual desire is a subjective phenomenon (which, indeed, might have behavioral consequences but far from always). Results of the survey indicated a consistent and signicant decline with age in feeling desire, in sexual thoughts and dreams, and in the desired level of sexual activity. Since the data were cross-sectional, it was not possible to answer the question about which came rst. First, as discussed earlier, some see it as much more useful when con- sidering the sexual sequence experienced by men compared with women (5). For example, desire is not simply at the beginning of a sexual event, but under ordinary circumstances, continues the whole way through (11). The assumption is evidently made that sexual desire and desire problems are the same in both gender groupsa concept that is debatable.

Mechanisms include so-called survivor guilt exist and by and large has similar symptoms as in (that others died or were severely injured) purchase female viagra australia, complicated bereavement generic female viagra 100mg visa, problems in adults purchase female viagra 50mg fast delivery. While depressed carrying out tasks of daily living owing to impaired concentration or intrusive children may initially memories purchase female viagra overnight delivery, and distress arising from chronic anxiety symptoms. New Zealands Dunedin Health and Development Study followed a cohort of 1,037 children from 3 to 26 years of age carefully tracking the development of psychiatric disorders, serious life events and other factors such as childhood mistreatment. That is, individuals with the short allele of this gene were more likely to develop depression in response to severe stressors or maltreatment during childhood, compared to those with the long allele exposed to the same experiences (Caspi et al, 2003). This fnding caused much excitement because it seemed to fnally prove a plausible gene-environment interaction in the causation of depression. However, a subsequent meta-analysis concluded that alterations in the serotonin transporter gene alone or in combination with stressful life events were not associated with an elevated risk of depression (Risch et al, 2009). Another meta-analysis published not long after (Karg et al, 2011) reached the opposite conclusion, while an additional prospective studyalso from New Zealandfailed to confrm such an association (Fergusson et al, 2011). Clearly more research is needed to resolve this tantalizing issue, which highlights the importance of replication before fndings are accepted, let alone used in clinical practice (e. Risk factors and their implications for prevention, detection or treatment Implications for prevention, detection or Risk Factor treatment Family history of depression Increase suspicion of depression when there is a positive family history of depression or suicide. Female gender Female adolescents who attend family doctors should be screened for depression. Puberty Depression is much more common in post-pubertal adolescents, particularly females. Chronic medical illness Exclude depression in patient with chronic physical illness or disability. Previous history of depression Relapse-prevention strategies integral part of treatment. Comorbid psychiatric disorder, Detection and treatment of comorbid psychiatric disorders. Negative cognitive styles, low Detection of individuals at risk and targeted preventive self-esteem interventions. Bereavement and losses Detection of individuals at risk and targeted preventive interventions. Abuse, neglect Targeted preventive interventions such as parenting and abuse prevention programs. Negative parenting styles: Targeted preventive interventions such as parenting programs. Child and adolescent Detection of individuals at risk and targeted preventive offenders interventions. Institutionalised or fostered Detection of individuals at risk and targeted preventive children, refugees, homeless, interventions. She complained of having felt sad most of the time over the past 6 months and thinking about death a lot. Her decision to drink the poison had come after learning that she would have to repeat a year at school. She felt guilty because her poor school performance was causing a drain in her fathers fnances. Her family interpreted this as laziness and she often got scolded or beaten for leaving her chores unfnished. She also felt isolated from her classmates because of her poor school performance. Adolescents underlying personality features are amplifed when they are depressed. For example, those who are anxious tend to show higher levels of anxiety, avoidance and somatic symptoms when depressed (anxious depression), those who are externalizers are likely to show more hostility and irritability. Teir fears of abandonment can be accompanied by intense but usually brief episodes of sadness, anger, or irritability, which sometimes culminate in incidents of self-harm. Both a depressive disorder and borderline personality traits or disorder can coexist. On the other hand, a depressive episode can exaggerate personality characteristics suggesting that a personality disorder may exist when that is not the case. In the latter situation, the symptoms of personality disorder would remit once the individual has recovered from the depressive episode. Diagnosis of personality disorder should be provisional in a depressed adolescent and made on the bases of symptoms and functioning outside of the depressive episode. Depression and suicidal behavior Suicide is one of the leading causes of death in adolescents worldwide. For each completed suicide in adolescents, there are about 100 reported suicide attempts. Suicidal thoughts are common among the young; about one in six girls aged 12 to 16 reports having them in the previous six months (one in ten for boys) but rates in clinic samples are much higher. While suicide is the result of complex interactions in which individual and psychosocial factors as well as mental health problems play a role, there is considerable evidence that depression is the strongest individual risk factor (although there are exceptions; in some countries such as China, impulsivity seems to be the strongest risk factor). About 60% of depressed young people report having thought about suicide and 30% actually attempt suicide. The risk increases if: Tere have been suicides in the family The young person has attempted suicide previously Tere are other comorbid psychiatric disorders (e. Suicidal behaviors and risk need to be carefully evaluated in every depressed young person (see chapter E. Young people tend to present initially with behavioral or physical complaints which may obscure the typical depressive Symptoms of symptoms seen in adults. For example, depression Diffculty concentrating, should be considered in the diferential diagnosis in a 14-year-old boy with a six- Appetite disturbance month history of oppositional and conduct symptoms but no previous behavior (decrease or increase) problems. Similarly, depression may account for the recent academic failure of a Sleep problems 15-year-old girl who had previously topped her class. To make a diagnosis of depression in practice requires the presence of: Core symptoms Some associated symptoms (usually four should be present) Pervasiveness (symptoms must be present every day, most of the day) Duration (for at least two weeks) Symptoms must cause impairment in functioning or signifcant subjective distress, and Symptoms are not the manifestation of the efects of a substance or another medical condition. Irritability is the most ambiguous because it can be present in a wide range of psychiatric conditions (e. The outcome of the risk assessment will have an important bearing on management, for example in deciding the best setting (e. Informant To make a diagnosis of depression in practice Parents and teachers tend to under-estimate depressive feelings in requires: children while young persons may overestimate them. Additionally, reports the presence of core and questionnaire data from diferent informants often disagree. This does not symptoms necessarily imply untruthfulnessit often refects observers difculty interpreting some associated childrens emotions and behavior, and their limited knowledge of the child (e. Integrating information from several sources, a key clinical skill, is often most of the day) difcult in this context. Severity Evaluating the severity of a depressive episode is important because treatment guidelines use severity as one of the yardsticks to indicate what treatment should Table E. However, current defnitions of severity are inadequate; assessment of severity is largely based on clinical consensus and largely relies on the skills and experience of the clinician. For example, an adolescent with high suicide risk may require hospitalization while another with an otherwise similarly severe depression but with low risk of suicide may not. Sometimes, however, these feelings are so intense and persistent that individuals are unable to function at the level to which they are accustomed. Adolescent with clinical Normal adolescent depression In spite of some angst*, There is a change from previous moodiness and other diffculties, behavior (e. They take longer to complete homework and class work than before and it takes more effort; school performance may decline. Withdraw into themselves, their room or the Internet at the expense of previously enjoyed friendships and other social activities. People in everyday life speak about being depressed, meaning that they feel unhappy, down or sad. The issue therefore is how to distinguish clinical depression on the one hand, from the normal ups and downs of adolescents lives and, on the other hand, from conditions that may mimic depression.