The core symptoms of psychosis—delusions, hallucinations, and thought disorders—are not unique to the disorder traditionally called schizophrenia. They occur at the early stages of various brain diseases, too. Psychosis seems to be a preformed pattern of response of the human brain. Most schizophrenia onsets are marked by a prodromal stage extending over several years and producing the maximum of social consequences. Schizophrenia incidence shows a steep increase culminating at age 15 to 25 years in males. In females it reaches a first peak at age 15 to 30 years and a second, flatter peak at menopausal age (44-49 years). Thereafter, incidence declines to a plateau at later ages. Unlike what the findings of most large-scale epidemiological studies applying an upper age limit of 45 to 55 years suggest, schizophrenia is a disorder of all ages. The lifetime risk seems to be the same for both sexes. The lower incidence in premenopausal women is accounted for by the downregulating effect of oestrogen on dopamine receptors. This hormonal protective effect is antagonised by the genetic effect of a high familial load. In the long-term illness course, right-censored to 11.2 years following first admission, the number of psychotic relapse episodes ranges from 0 to 29 with a mean of 3. The positive symptom dimension produces the highest number of relapses and the shortest duration of exacerbations with a mean length of two months. The depressive and negative symptom dimensions show exacerbations extending over nearly six months on average. Following the first illness episode symptom scores decline sharply, reaching a plateau five years after first admission. Negative symptoms come to a plateau after 2 to 3 years in females and after 5 years in males. Depression is the most frequent type of symptom in the long-term course. In the light of these results urgent treatment issues will be discussed. Schizophrenia, defined as a disorder, is characterised by symptoms that distort or in part block some basic functions of the human mind, such as outer and inner perception and memory. In that respect schizophrenia is a disorder that hampers or distorts reality control during episodes of acute symptomatology and in a few cases also permanently.Mental disorders involving loss of reality control can have serious consequences for both the affected individual and the community. For this reason, elucidating their causes has long been one of the main issues in psychiatric research. Since Emil Kraepelin's  first atDefining the diagnosis Emil Kraepelin proceeded both from the main age of onset (praecox) and from the outcome (dementia) of the disease construct he called dementia praecox. The diagnostic features of a young age of onset, up to 45 years, and an unfavourable outcome frequently resembling dementia were eagerly accepted in those days and continued to be used in clinical practice. This changed partially after Eugen Bleuler's  concept However, both of these criteria are wrong: a majority of patients suffering from so-called dementia praecox never develop genuine dementia even after long histories of illness, and illness onsets are fairly common beyond 60 years of age, too. These were the reasons why Eugen Bleuler , a SwissGiving the disorder a new name Eugen Bleuler also introduced ancillary concepts intended to explain the pathology involved, such as autism, ambivalence, associative disturbances, none of which are specific for schizophrenia and hence have not qualified as proper descriptions. The same is true of the disease concepts and their underlying causes proposed after Bleuler. All this just reflects the fact that we simply do not know yet what schizophrenia really is.As we set out to throw some light on this murky chapter of schizophrenia research, we first looked for findings and issues that, when replicated and resolved, were promising of providing insights into the fundamental nature of the disorder.A fairly fundamental finding seemed to us to be what Kraepelin  and someOur first social hypothesis ran that incipient schizophrenia and its prodromal stage are perceived later in nonemployed women in their home environment than in employed men. At the time of our investigation, conducted in Denmark and the Mannheim area in Germany, women of childbearing age in paid work were clearly a minority in both places. We compared first-admission age between employed and nonemployed men and women on data from the national Danish and the Mannheim psychiatric case registers in cooperation with P. Munk-Jørgensen's team . We founGiven this result, we then had to find a way of accurately determining age of schizophrenia onset. For this purpose we developed the “Interview for the Retrospective Assessment of the Onset and Course of Schizophrenia and Other Psychoses”, IRAOS , 7. The Astonishing about this result was that the sex difference did not emerge after the manifestation of the first psychotic episode, for example, as a corollary of the unfolding biological disease process, but was already there to a considerable extent when the very first signs of disorder appeared. This meant that looking for factors explaining the sex difference we had to focus on causes active at earlier stages and probably biological in nature.Since the IRAOS is a culture-neutral instrument, we were able to compare data on the sex difference in age of onset between different geographical areas, e.g., countries, political systems, and ethnicities. We started by analysing first-admission data on schizophrenia from the Danish national case register 1976) and data on first-episode cases from the German A (age) B (beginning) C (course) Schizophrenia Study (1987-1989). The two data sets were compiled using comparable criteria. The analysis was conducted in cooperation with our Danish colleagues , 9. The 76 and da right) than the German data ( left). A difference of one year and a few months would have been reasonable, because the German data were based on age at the onset of the first psychotic symptom and the Danish data on age at first admission, but that did not explain the bulk (2-3 years) of the difference we found.The age distributions for males and females depicted on the left differ from those on the right in two respects: first, in the ABC Schizophrenia Study data on schizophrenia onset were collected for probands in age range 12 to 59 years from a population of about 1.5 million living in the area of the cities of Mannheim and Heidelberg, Rhine-Neckar District and eastern Palatinate, whereas the Danish case-register data stemmed from the whole of the Danish population of about 5.2 million without any age limit. The second difference was that, as we had expected, the age distributions for both sites showed a high first peak at early adult age—higher for males than females—and a second peak for females in menopausal age, but that second peak of onsets turned up some 5 years later, on average, in the Danish , right tman data , left. ATo explain the unexpected rest of that age difference in the pattern of schizophrenia onsets between the Danish and German females, we drew a randomized, stratified sample of 116 first-admission patients with a diagnosis of schizophrenia or related disorder from the Danish case register and obtained their case records from the hospitals where they had been treated. We did this in cooperation with our Danish colleagues and with the permission of the regional authorities , 11. Usi, left).We did not expect to achieve the result we did: while 51% of the Danish males clearly meeting the diagnostic criteria for schizophrenia had received that diagnosis at discharge from hospital, the corresponding figure for females was only 32%. No such sex difference in age either at the appearance of the first psychotic symptom or at fulfilling the diagnostic criteria for schizophrenia emerged in the Mannheim data . Hence, Figure 2We then proceeded to test the transnational and transcultural stability of the sex difference in age of onset on a wider range of countries, because until then we had focused on two culturally fairly uniform European countries. A global comparison would have been unfeasible for lack of detailed enough data from a sufficiently large number of international epidemiological schizophrenia studies.For this reason we chose the then best possible access to international data for addressing this question : in coopVenturing a conclusion from these results, it is reasonable to expect that a sex difference consisting in women's being a few years older than men at schizophrenia onset is bound to emerge anywhere in the world provided that sound study methods are being applied.A British meta-analysis of 46 selected epidemiological studies yielded a significant, but only small sex difference of about a year in age of onset of schizophrenia . The sexA few other reviews focusing on the sex difference in age of onset of schizophrenia in various smaller national populations , 18–21 hThe strategy we had thus far adopted in our research activities, i.e., consistent hypothesis testing and formulating new questions and new hypotheses on the basis of the results achieved, had turned out successful. Sticking with this strategy we started a long-term research project, the afore mentioned ABC Schizophrenia Study , 23, whiSo far we have discussed age at illness onset in males and females on the basis of various consecutive definitions of that event  over the course of incipient disorder. Since schizophrenia is a disorder of all ages, we should take a look at the sex-specific age distributions at illness onset across the life-cycle. In the ABC Schizophrenia Study we analysed the age distribution at illness onset for males and females up to age 60 years and obtained an intriguing overall picture :As In contrast, female onsets are somewhat slower to increase in youth. They reach a first, slightly flatter peak compared to males at age 15 to 30 years, as already demonstrated in Since our ABC study sample was limited to age 60 years and younger, we studied another sample of 1109 consecutive first admissions different from the ABC sample and not limited by age. Included in that sample were first admissions for a diagnosis of schizophrenia spectrum disorder (ICD-9) to the Central Institute of Mental Health, a mental-health care facility located in Mannheim, Germany, and serving the city and its surrounding region . We founsee below). The reason is that all these studies have used 45 to 55 years as an upper age limit, thus partly or completely excluding the higher incidence rates of postmenopausal women. The most pronounced male-female differences in incidence fall in certain phases of life: a higher male incidence in the first half of life and a higher female incidence in menopausal age in the second half of life. The second peak of female onsets means that women finally catch up on incidence in the second half of life. As a result, both sexes end up with nearly the same lifetime risk of currently 13.21/100,000 for men and 13.14/100,000 for women at age 60 years [A look at the incidence of schizophrenia spectrum disorders over the entire life-cycle shows that the lifetime risk seems to be approximately the same for both men and women. In contrast, most of the large international epidemiological studies report a higher lifetime risk for males than females  depend on age. However, there were two symptom dimensions that ran counter to this pattern: systematised delusions and delusions of persecution, i.e., paranoid and delusional phenomena . The freThe symptoms that showed markedly different frequencies in old age—systematised delusions in particular, but also paranoid delusions—are complex in nature and contain a cognitive component of processing primary symptoms such as severe anxiety. They are complex, because they have multiple functional components. Usually, they also have a cognitive component, which means that through these symptoms persons experiencing them try to cope for example with severe anxiety arising from a delusional belief of being harmed by external causes (paranoid), or the symptoms are embedded in a comprehensive delusional system constructed as an explanation for fearful events or experiences. A further characteristic of such cognitive coping by way of systematised delusions is externalisation, i.e., attributing unpleasant experiences, personal failures and mishaps or feelings of guilt to external causes. This type of behaviour is quite common in elderly persons not diagnosed with schizophrenia, too. Obviously, age seems to have a considerable impact on the core symptoms of schizophrenia.In contrast, the clinical picture of childhood-onset schizophrenia is characterised by hardly any or no symptoms possessing a clear-cut cognitive component. Typical of the disorder at this age are primary or elementary symptoms, such as diffuse, at times very severe states of anxiety, fluctuating attention disorders, profoundly altered perception of self and others, elementary distortions of self-experience, such as believing that thoughts are being inserted from outside into one's mind, and symptoms of mental confusion , 35. TheAs a consequence of these factors, the onset of schizophrenia in childhood—very rare—and in youth seems to be associated with particularly severe socioeconomic consequences in the further course of the disorder –40.At a higher age, when personality has matured and attained a more stable structure of the self and the cognitive functions have fully developed, the pathological process of schizophrenia can no longer upset the core structures and central functions of personality to any greater extent. As a consequence, there will be less mental disorganisation and social impairment and more symptoms of cognitive and projective coping, i.e., by attributing unpleasant or fearful experiences to outer causes. In addition, due to decreasing emotional intensity in old age, late-onset schizophrenia tends to produce symptoms characterised less by emotional dynamism.Let us return to the sex difference in age of onset. Since it seems reasonable to assume that women are a few years older than men at any stage of incipient schizophrenia, except at a higher age, we are faced with the question of what causes this fundamental difference in disease development.The graphs illustrating the age distributions of men and women at schizophrenia onset in Figures Underlying women's distribution of schizophrenia onsets could be an oestrogen effect. The secretion of this sex hormone increases steeply in puberty and declines rapidly as soon as women reach menopause. The effect of the male sex hormone testosterone on the organism, too, increases sharply at young age, but it shows no rapid decline comparable to that of oestrogen at menopausal age.This could mean that the flatter increase in female incidence at young age and the second peak at menopausal age point to a kind of protective effect capable of warding off illness onset in some women for a certain period of time. As soon as these women reach menopause, the protective effect comes to an end and the illnesses warded off until then manifest. A conceivable alternative explanation for men's lower age of onset and more severe symptoms in the first half of life might be that testosterone is capable of speeding up schizophrenia manifestation, in other words: it exerts an effect opposite to that of oestrogen. We tested both hypotheses in animal experiments.2-receptors [We tested how the two sex hormones influence dopaminergic behaviour. The effect of four-week oestrogen applications was compared with testosterone applications in three groups of animals (rats): (1) Group 1 received dopaminergic stimulation through apomorphine, (2) Group 2 comprised sham-stimulated, and (3) Group 3 nonstimulated, but placebo-treated animals. It was exclusively in the oestrogen-treated group that a neuroleptic-like blockade of dopaminergic behaviours could be observed. A histochemical analysis showed that oestrogen down-regulates Deceptors , 42, whiThe conclusion to draw from these results is that oestrogen essentially accounts for the sex difference in age of schizophrenia onset. The oestrogen hypothesis has since been confirmed experimentally in a direct way, too. Treatment trials have demonstrated that medium to high doses of estradiol as an adjunct to classic, treatment-guideline-conform antipsychotic therapy has an additional antipsychotic effect in women of childbearing age diagnosed with schizophrenia or schizoaffective disorder –47.Conclusive as this result may seem there is still the question of whether the oestrogen effect is the only conceivable, neurophysiologically effective mechanism capable of bringing about the sex difference in age of schizophrenia onset. There are good reasons for asking this question, for, according to the studies published by DeLisi et al.  and AlbuAt 4.9 years the difference in age of onset between women with familial load and women free of such load was slightly greater than the age difference between the corresponding male groups, on whose age of onset familial load exerted no significant effect. We concluded from this result that the schizophrenia-boosting impact of genetic load must be more powerful than the schizophrenia-reducing hormonal effect.Having explained the sex difference in age of schizophrenia onset until menopausal age we were intrigued to find out how age and other major risk factors might influence age at onset in men and women in the second half of life. We examined our ABC sample of first illness episodes and found that with increasing age the impact of both familial load for schizophrenia spectrum disorder and that of pre-, peri-, and postnatal brain damage declines steadily in both men and women . The dimRational cognitive coping with the disorder by means of systematised and paranoid delusions and a tendency to externalisation, as already stated, probably represent types of reaction typical of old and very old age. They are triggered by secondary risk factors such as hearing loss and a subjective feeling of loneliness , 53).An important age-related factor is the socially negative behaviour of young males. Compared with men aged 40 years and older and women of any age younger men diagnosed with schizophrenia show a significantly higher frequency of aggressive behaviour, self-neglect and some other types of socially adverse behaviour . This saWhile focusing on age- and sex-related aspects of illness onset and symptomatology we have thus far considered aspects of illness course only fleetingly. Let us now explore how the prodromal, short-, medium-, and long-term course of schizophrenia spectrum disorder depend on inherent (disease-related) and external  factors. We will also take a look at the social course, governed by patients' illness-related social impairment on the one hand and by the type and amount of social consequences, i.e., changes in socioeconomic, occupational and familial conditions, patients suffer over the course of their illness, on the other hand.In the ABC study we analysed how age and social status at illness onset influence patients' further social course. In terms of the frequency patients experience social decline during illness course, early-onset patients, who develop the disorder before finishing school and/or occupational training, suffer only modest social decline in the further illness course. Instead, since an early illness onset impedes social development and becomes reflected in lack of attainment of common steps of socioeconomic ascent, they rather suffer social stagnation. In contrast, individuals who have already run through the usual stages of social attainment before falling ill at middle or a higher age are at risk of suffering pronounced social decline. Young adults who have finished school and occupational training and have a promising occupational career occupy an intermediate position in terms of social decline , 55 see.In old age, when people have reached retirement and ceased to work and the changes in socioeconomic conditions typical of this age have already taken place, the risk of experiencing social decline as a consequence of schizophrenia onset is fairly small. The situation looks different and shows a lot of variation as far as the other concomitant social characteristics of illness course, such as number and quality of social contacts and range and availability of leisure activities, are concerned. A precondition for not suffering socioeconomic loss due to illness in old age is that there are pension schemes and/or a health-care system in place that guarantee an adequate living, treatment and care—as in Western societies—through state provision and/or private insurance. Under such conditions there is hardly any risk of suffering objective social decline in old age. The situation is different in countries without adequate provision for old age: there the proportions of poor social courses of schizophrenia tend to be the largest among people falling ill in old age after working life has ended –59.In As mentioned, a maximum of onsets of schizophrenia and schizophrenia-like disorders occurs between 15 and 25 years of age for men and between 15 und 30 years of age for women. In the Western culture these are the periods of life characterised by the most pronounced individual socioeconomic development. As a consequence, the earlier illness onset in males tends to be associated with more pronounced social consequences, whereas the later onset in females leads to less severe social consequences. This sex difference is reflected in patients' level of social competence and even influences medium-term (5-year) social course and outcome in male patients. Another factor with an unfavourable impact on young men's social competence in the early and medium-term illness course is the fact mentioned above that schizophrenia clearly compounds normal socially negative male behaviour.To give an example for a social course from the prodromal stage of schizophrenia extending from onset to first admission we have depicted in As the figure shows, larger proportions of healthy women than women with schizophrenia or healthy men marry or enter a stable partnership at early adult age. Part of this finding is attributable to the fact that at the time of our study, on average, women in Germany were some years younger than their male counterparts when getting married. With increasing age, the proportion of healthy men married or living in a stable partnership, too, increases markedly, but clearly falls short of the percentage of healthy women. In contrast, the corresponding proportions of both men and women with schizophrenia show a steady decline resulting in significant differences to their healthy peers at first admission .In the further course of illness, not depicted in the Figure, divorce rates for both male and female patients are on the rise. But larger proportions of female than male patients are capable of finding new partners and remarrying, while growing proportions of their male counterparts are living alone. Underlying this sex difference are normal sex-related behaviours, and this also applies to young male patients' socially negative behavioural traits. Women, on average, have better communication skills and more sex appeal than men have. But schizophrenia permanently reduces their bonding abilities, too, with a result of high divorce rates among female patients.As far as the long-term social course is concerned, we reexamined probands from our ABC first-episode sample an average of 12.3 years after first admission where ever we could reach them, at home, hospital, or residential home. The results on the social course of schizophrenia we obtained were encouraging. Just under a third of the probands (32.7%) had a regular job, as was the case at first admission . HoweverFor a detailed analysis of long-term illness course we right-censored the probands' histories of illness at 11.2 years (= 134 months), the shortest span between first admission and follow-up (range: 11.2-14.6 years). In this way we obtained identical durations of illness for all probands .The frequency of psychotic relapse episodes (a psychotic relapse was defined as a two-week period of deteriorating psychotic symptoms preceded and followed respectively by four weeks in which symptoms were either absent or reduced) showed a mean of three per patient over the total course of 11.2 years. With a minimum of 0 and a maximum of 29 relapses there was a lot of variation indicating a high degree of heterogeneity in the illness courses  and no pBesides the course of schizophrenia as such we also analysed how the individual symptom dimensions—positive, negative, depressive, and manic—evolved. Based on means, symptoms declined continuously on these dimensions; however, the numbers for the manic dimension were too small to be included in this analysis. The decline started at first admission and extended over up to five years at the most and differed in speed. Thereafter, all the symptom dimensions showed a plateau-like course without any further decline or increase in symptoms. No significant sex differences could be found either on the positive or the depressive symptom dimension. On the negative symptom dimension women reached a plateau sooner than males did, i.e., in two to three years after first admission compared to four to five years for men. From that point on not only did all the symptom dimensions, but also the course of schizophrenia as such show no essential variation in the sense of either deterioration or further recovery . This imBesides tracing the course of the overall symptom dimensions mentioned and counting the individual illness episodes on the basis of a defined duration we also took a detailed look at the exacerbations irrespective of their duration. At a median of two months positive symptoms showed the shortest exacerbations and negative and depressive symptoms the longest at a median duration of almost five months respectively .To sum up, characteristic of the long-term symptom-related course of schizophrenia is an initially high degree of heterogeneity and, after several years of illness, considerably less heterogeneity both in the overall clinical presentation and on the core symptom dimensions. All the pathological dimensions have in common a course that first shows a sharp decline in the core symptoms, which is followed, after a five-year history of illness, by more or less stable mean symptom frequencies. The only exception to this pattern is displayed by positive symptoms in that they decline more rapidly after illness onset and settle on a plateau as soon as two to three years after that event. A further exception is that on the negative symptom dimension female patients start displaying a plateau one to two years earlier than male patients do. The only other sex differences observable in the long-term course of schizophrenia are limited to age at illness onset up until menopausal age and the consequences that sex difference produces in the medium-term illness course and the social course until old age.Since an early age of onset is to a great extent genetically determined while a very late onset of schizophrenia spectrum disorder shows no clear-cut genetic component, the question arises again whether age of onset and severity of first-episode schizophrenia might generally be associated with a more or less pronounced familial load.Asarnow  reviewedThe enormous advances achieved in molecular-genetic research in the last few years have considerably improved our understanding of the genetic transmission of schizophrenia risk, despite the failure to settle the question conclusively. A long time ago it had become clear that only a tiny fraction of schizophrenias are transmitted by the Mendelian laws of inheritance. In such cases the risk for schizophrenia is usually associated with further neurobiological deficits such as mental retardation, peripheral malformations etc. These findings, however, do not provide pointers to the modes of transmission in the overwhelming majority of genetically determined cases of schizophrenia spectrum disorder.The complex mode of transmission of schizophrenia risk is governed by susceptibility or risk genes, each of which accounts only for a tiny fraction, less than 2%, of the total morbid risk , 64. TheSystematic genome-wide analysis have recently yielded quantitative information on the number of risk genes and thus made it possible to validate the mathematical hereditary estimates proposed on the basis of epidemiological twin and family studies. These analyses have revealed a considerably lower heredity, but we do not yet know how to explain this difference.Gene editing, a newly developed method of isolating and removing single genes by means of restriction enzymes, has enabled researchers to conduct selective, targeted operations on DNA chains. Using this method it has been possible to remove pathogenic amino acid sequences resulting from mutations. First the pathogenic genes are cut out using the technique of gene surgery and then a piece of the organism's own normal DNA is inserted in the gap as a replacement for the pathogenic sequence.This type of gene surgery is currently being practised on plants and isolated animal species. In humans its application will be limited to mononuclear hereditary diseases, and in rare cases it has already been applied successfully. It is hardly conceivable that a sufficient number of the vast array of susceptibility genes for schizophrenia thus far identified could be modified by means of gene surgery in order to prevent the genetic risk for schizophrenia from materialising. Gene surgery is simply not practical in schizophrenia because it is impossible to remove and replace such a large number of risk genes—each of which carries only a weak effect—and not to produce undesirable side-effects.The main factor underlying schizophrenia risk seems to be genetic in nature. But schizophrenia is not a hereditary disorder. The mode of transmission involved is a complex one. The manifestation of schizophrenia is governed by a combination of intrinsic and extrinsic risk factors, which not only produce psychosis as the core syndrome, but also determine the actual disease process, including negative symptoms and social impairment.The social consequences patients suffer as a consequence of their negative symptoms and social impairment vary with the cultural environment, while the core symptoms largely show no cultural variation.The core syndrome of schizophrenia—psychosis—is not a discrete disorder with a unitary cause. It can be caused by multiple factors. For example, a psychosis can be developed as a reaction to certain intoxications  or be caused by acute severe brain dysfunction . It can also occur as a preliminary symptom of neurobiological degenerative processes, for example, at early stages of Alzheimer's disease, or be caused by central lesions in multiple sclerosis and in rare hereditary diseases such as Huntington's chorea.Schizophrenia is a traditional notion with a more than a century-long history. Today, as a result of our accumulated knowledge, it is better seen in a more differentiated way and broken down to its components. The core disorder, constituted by delusions and hallucinations, is a type of dysfunctional unit, probably representing a preformed pattern of reaction of the human brain. As mentioned, it can be triggered by a variety of brain disorders or cerebral processes. In these cases the only way to treat it is to target the underlying pathology. By medications capable of downregulating the overactive functional network of transmitters and synapses merely a symptomatic treatment of the core syndrome can be achieved, but hardly any alleviation of the negative and cognitive symptoms and socioeconomic consequences.The core syndrome of the disease construct called schizophrenia—hallucinations, delusions, and thought disorders—occurs in the same form and its lifetime risk shows approximately the same frequency anywhere in the world where these questions have been studied. Underlying the symptom pattern of psychosis is probably one of the rare preformed reaction patterns of the human brain. This seems to be true of the reaction patterns of depression and dementia, too. The underlying causes of psychosis—different types of neurobiological dysfunctioning in the brain—are heterogeneous. Their causal treatment is rarely possible and can only be achieved by treating the underlying pathology provided that it can be identified. The only treatment available for psychosis in schizophrenia is symptomatic therapy. The core pathology in schizophrenia is associated with a variety of aetiological risk factors that lead to the manifestation of the core syndrome and some of its components, such as depression or social impairment.These aetiological risk factors comprise in the first place primary risk factors such as genetic load, pre-, peri-, and postnatal complications and early infections of the brain, e.g., childhood virus encephalitis. Further risk factors are age, sex, and a few socially relevant behavioural predispositions, e.g., young men's socially negative behaviour, a phenomenon encountered both in persons with schizophrenia and likewise in healthy individuals.The multiplicity of the causes underlying schizophrenia is reflected in the great variety of types of illness course. In around a fifth of all cases schizophrenia produces just one psychotic episode and no socioeconomic consequences. A small proportion of schizophrenia cases are progressive in type and associated with impairment in several domains of life as well as slightly reduced brain volumes.Most persons diagnosed with schizophrenia show mild brain volume reduction, which is locally accentuated  and already there at illness onset. In a small proportion of patients brain volume reduction progresses slowly, mostly accompanied by growing cognitive deficits, but no dementia comparable to Alzheimer's type.As stated, the main risk factor for schizophrenia is genetic in type, but its impact grows the weaker the later illness onset occurs. Genes carrying a high risk for schizophrenia are rare and are usually attributable to chromosomal defects or other similar severe anomalies. A majority of patients with schizophrenia possess risk genes, but each of these genes accounts only for 2% of the total risk at most , 64, andThere are also multiplicity of environmental factors that enhance the risk for schizophrenia.The first psychotic episode is usually preceded by a prepsychotic prodromal stage unfolding over several years. It is followed by a shorter psychotic prodromal stage prior to the first treatment contact. Most of the unfavourable consequences the disorder leads to occur at these early stages of illness. A lengthy untreated prodromal period is a predictor of an unfavourable illness course.The treatment of choice for psychosis caused by an underlying condition is a therapy targeted at that condition. There is no causal therapy for schizophrenia available yet. The current medical treatment of psychotic symptoms is capable of reducing acute psychotic symptoms and of preventing psychotic relapses. The greatest problem in the treatment of schizophrenia is the lack of effective therapy for negative symptoms and cognitive deficits, the main causes of the social consequences associated with the disorder. A further problem is posed by depressive mood, the most frequent symptom patients present over the illness course. It, too, requires targeted therapy.


Colorectal cancer (CRC) is one of the most common causes of cancer mortality in the world. The incidence is related to increases with age and western dietary habits. Early detection through screening by colonoscopy has been proven to effectively reduce disease-related mortality. Currently, it is generally accepted that most colorectal cancers originate from adenomas. This is known as the “adenoma–carcinoma sequence”, and several studies have shown that early detection and removal of adenomas can effectively prevent the development of colorectal cancer. The other two pathways for CRC development are the Lynch syndrome pathway and the sessile serrated pathway. The adenoma detection rate is an established indicator of a colonoscopy’s quality. A 1% increase in the adenoma detection rate has been associated with a 3% decrease in interval CRC incidence. However, several factors may affect the adenoma detection rate during a colonoscopy, and techniques to address these factors have been thoroughly discussed in the literature. Interestingly, despite the use of these techniques in colonoscopy training programs and the introduction of quality measures in colonoscopy, the adenoma detection rate varies widely. Considering these limitations, initiatives that use deep learning, particularly convolutional neural networks (CNNs), to detect cancerous lesions and colonic polyps have been introduced. The CNN architecture seems to offer several advantages in this field, including polyp classification, detection, and segmentation, polyp tracking, and an increase in the rate of accurate diagnosis. Given the challenges in the detection of colon cancer affecting the ascending  colon, which is more common in women aged over 65 years old and is responsible for the higher mortality of these patients, one of the questions that remains to be answered is whether CNNs can help to maximize the CRC detection rate in proximal versus distal colon in relation to a gender distribution. This review discusses the current challenges facing CRC screening and training programs, quality measures in colonoscopy, and the role of CNNs in increasing the detection rate of colonic polyps and early cancerous lesions. Colorectal cancer (CRC) is responsible for approximately 10% of cancer-related mortality in western countries and is considered the second leading cause of death from cancers in the United States and the United Kingdom . SeveralColonic adenomas may be flat, sessile, sub-pedunculated, or pedunculated. According to current opinion, CRC can develop via three different pathways . First, This review focuses on colonic polyps (adenomatous polyps) and the factors that increase their risk of becoming cancerous, the significance of screening for CRC, colonoscopy training programs, quality measures in colonoscopy, the current opinion on the role of convolutional neural networks (CNNs) in the early detection of colonic polyps and cancerous lesions, and future research directions in this field.Colonoscopy is the cornerstone of CRC screening programs. It can enable the early detection of cancerous lesions or be used as a follow-up to another screening test. Adhering to the nationally recognized guidelines for determining the interval between colonoscopies helps to minimize the development of cancer . HoweverQuality assurance in colonoscopy has emerged as a necessity over the last decade. As stated above, this is based on evidence from several studies that show that colonoscopy outcomes are operator-dependent, and that some colonoscopists miss more polyps than others. The research on quality measures for colonoscopies continues to evolve, particularly with respect to the advantages and limitations of each measure and the degree to which each measure can reduce the burden of CRC; it is recommended that each endoscopist’s colonoscopy performance should be tested regularly. There is general agreement that three main measures warrant consideration.The first measure is the adenoma detection rate (ADR), which is defined as the proportion of screening colonoscopies where at least one adenoma is detected. The current ADR benchmarks are 20–25% or higher for men and 15% or higher for women . This meThe second measure is the cecal intubation rate. This is a quality metric that is used to ensure that a colonoscopist has the ability to perform a complete examination of the cecum in almost all procedures. For the current benchmark, colonoscopists must demonstrate the ability to intubate the cecum in 90% or more of all examined cases. Interestingly, patients who underwent an examination by colonoscopists whose cecal intubation rates were 95% or higher were found to be less likely to have interval cancers, compared with patients who underwent an examination by colonoscopists whose intubation rates were less than 80%. Therefore, evaluating the cecal intubation rate is another important metric in assessing colonoscopy quality ,28.The third measure is the withdrawal time (WT). This metric is used to evaluate whether a colonoscopist has spent sufficient time to perform a thorough mucosal examination between intubating the cecum and removing the colonoscope from the patient. The current benchmark for withdrawal time is 6 min or more in examinations where no biopsies or polypectomies are performed . VariabiOther measures of quality in colonoscopy include the accreditation and professional registration of the center, the number of performed colonoscopies, the number of conducted polypectomies, the comfort score , and complication rates during colonoscopy (defined as the percentage of colonoscopies performed by the colonoscopist in which complications occur up to 30 days after the procedure). These complications include perforation rates associated with the colonoscopy, polypectomy bleeding, and the polypectomy perforation rate ,34.These measures of colonoscopy quality have been shown to be useful in assessing colonoscopists’ performance and in planning training programs to individualize feedback depending on deficiencies found in the evaluation. However, there is a need for studies that assess their long-term impacts on CRC incidence and mortality. To date, these measures have not resolved difficulties in discriminating between hyperplastic polyps and adenomas using conventional white-light observations and chromoendoscopy . CurrentConvolutional neural networks (CNNs), which form a division of deep learning architecture, were initiated by the discovery of “natural visual perception” mechanisms in animals. The story dates back to the early 1960s when David Hubel and Torsten Wiesel made a breakthrough discovery in the visual system, the visual cortex, and visual processing at Harvard University. Their discovery triggered much research in the area that earned them the Nobel Prize in Physiology in 1980 . Their fApproximately 16 years later, several studies explored these ideas and several methods were established to solve challenges in training deep learning CNNs. For example, the work of Krizhevsky et al. at the University of Toronto, Canada, produced a significant improvement in image classification through the introduction of AlexNet . FurtherResNet has been shown to have approximately 20 times the deep learning capability of AlexNet, and 8 times that of VGGNet . DespiteImage classification: AlexNet was the first CNN architecture that was capable of image classification. The classification methods are based on sharing information using a hierarchy of classes. Some methods are based on the decomposition of a task into a series of steps, which led gradually into fine category classifiers and further processing. This architecture is known as the coarse-to-fine classification model. Other methods are based on subcategory classification. For example, a CNN architecture could provide a system for colorectal polyp grouping into subcategories that increases the rate of correct diagnosis and improves the quality of colonoscopic examinations. A study by Komeda et al. showed that the accuracy of the 10-fold cross-validation was 0.751, where the accuracy is measured as the ratio of the number of correct answers to the total number of answers produced by the CNN. This means that the decisions made by the CNN were correct in 7 of 10 cases . StudiesObject detection: This involves the use of CNNs in the detection and localization of objects. The methods that are currently used are based on obtaining generic measurements to test whether a sampled window is a potential object or not, and further pass the proposed output object to a more sophisticated detector to differentiate between a specific object and the surrounding background. This method constitutes the basis of the use of CNNs for automatic polyp detection and localization ,45,46,47Object tracking: This function relies on how robust the representation of the target’s appearance is against challenges, such as viewpoint changes, illumination changes, or occlusions. The CNN architecture is built to discriminate object patches from their surrounding background using all of the available low-level cues. Consequently, the CNN architecture is able to classify image frames, including distinguishing polyp parts from normal non-polyp image frames. Thus, it can be used to improve a colonoscopy’s diagnostic performance ,54.Visual saliency detection: This technique aims to localize important regions or cues in an image. This function could help to identify specific changes that could confirm a clinical diagnosis. Another related feature is known as sparse representation, which comprises the ability to perform sparse representation tasks . These functions are essential to increasing the accuracy and discriminatory capabilities of the CNN architecture. An example is the reconstruction of images and the ultra-magnification of a tissue type and nuclear features followed by a machine-learning analysis and segmentation ,50,52,53Over the last six to seven years, there has been significant improvement in CNNs. The current applications of CNNs in the detection of colonic polyps and other medical images can be summarized as follows:n = 2), 2017 (n = 6), 2018 (n = 3), and 2019 (n = 2). The clinical applications that use a CNN for the early detection of CRC can be grouped into the following: (i) identification and classification of colonic polyps [c polyps ,47,48,54c polyps , (iii) dc polyps , (iv) hic polyps , (v) segc polyps , and  colon. Several factors may be responsible for the higher rates of proximal colon cancer in women. One of these is socio-cultural barriers that prevent women from enrolling in screening programs and receiving an early diagnosis. A second factor could be related to the higher incidence of colon cancer in the proximal colon because of difficulties with detection and the higher rates of missed lesions during colonoscopies. A third factor could be related to the fact that individuals with cancer of the proximal colon, particularly the cecum, are less likely to present with bleeding from the rectum or abdominal pain, thus making them unlikely to seek medical attention until the late stages of the disease . With thMore work is required to improve the accuracy, sensitivity, and specificity of results obtained from CNN models for the detection and classification of colorectal polyps. The next steps should also address the following fundamental questions:First, how much can the use of CNN architecture improve colonoscopy outcomes and quality metrices? It is expected that we will obtain an appropriate answer to this question over the next few years. In the meantime, we can improve the CNN architecture and compare the results obtained using CNN models with results obtained using other techniques developed in artificial intelligence that could help colonoscopists to enhance their diagnostic abilities and make better clinical decisions.Second, will the use of a CNN architecture in colonoscopy help to reduce the rates of proximal CRC, which have currently not been reduced compared to distal CRC? This is a challenging area, and we hope to reduce these rates through the use of CNN technology. Studies that focus on examining this question should be given priority.Third, will the use of a CNN architecture with colonoscopy procedures help to reduce CRC incidence and/or mortality? This is a central question that should be answered. We also need to assess the impact that an integration of a CNN and a colonoscopy has on reducing complications/limitations associated with the use of a colonoscopy only.The use of a CNN architecture along with colonoscopy procedures is expected to improve colonoscopists’ performance, diagnostic accuracy and skills in polyp detection, classification, and segregation. These changes could result in a higher ADR and ultimately reduce CRC incidence and mortality. Although the use of CNNs over the last seven to eight years has shown promise, particularly with respect to enhancing the diagnostic capabilities of colonoscopists, the reported sensitivities, specificities, and accuracies of the CNNs in the literature vary significantly. Therefore, validation of reported results in a large multicenter trial is needed to improve the efficacy and specificity of CNN systems. Therefore, the use of CNNs seems to have had a significant impact in colonoscopy practice and gastrointestinal training programs. Considering the reported challenges with the detection of aggressive cancers affecting the ascending  colon in females, we believe that the use of CNNs to enhance the CRC detection rates could help to resolve this issue and possibly reduce the CRC mortality in these patients.


Post-traumatic stress disorder (PTSD) is diagnosed in 3% of German and 14–16% of US military following deployment abroad. The treatment of PTSD in soldiers is often challenging and thus new, additional interventions supporting traditional trauma therapy are employed, like animal-assisted interventions (AAI). In this pilot study, 29 soldiers with PTSD received four sessions of 3 h once a week of dog-assisted intervention in addition to inpatient standard treatment at the military hospital, while the control group of 31 soldiers with PTSD received standard treatment only. The dog-assisted intervention sessions included a walk, different play and grooming activities and just relaxing together toward the end. What was new in our approach was that the AAI sessions were delivered by military personnel, military dog-handlers with their own dogs (either military or privately owned). Data on psychiatric symptoms, perceived stress, work and social life, and the therapeutic relationship were answered before the first AAI session, during the days following the last AAI session, 1 month later, and 3 months later. Only the intervention group also answered a questionnaire on trauma confrontation, consumption of alcohol/drugs, mental wellness, and perceived stress each week during intervention. Analyses showed a trend for worse values in work and social adjustment in the control group and a significant trend toward better values in the intervention group. On the other parameters differences between control and intervention group were not significant. The mental wellness of the intervention group improved over the 4 weeks of therapy, particularly regarding the ability to experience joy. There was no clear trend for perceived stress, but the relationship to the dog handler improved significantly over the course of the intervention. This is noteworthy in patients with PTSD who usually have difficulties trusting others, especially new people. Keeping in mind that the AAI took place only four times, our findings point toward the value of dog-assisted interventions. With a longer treatment period the positive effects and trends might become more distinct. While many people will experience traumatic events during their lifetime, only some will develop a post-traumatic stress disorder (PTSD) or related problems, while others show resilience and can cope successfully. Certain populations are more likely to experience traumatic events, such as members of the military, firefighters, police, first aid, but also refugees or people living in war zones. Internationally, the military is faced with an increasing number of soldiers who receive the diagnosis of PTSD and is working on improving the therapeutic interventions for this group of patients. In the U.S., several organizations for veterans include animal assisted interventions (AAI), usually with horses or dogs, in their treatment programs, to alleviate symptoms of PTSD and to improve quality of life. Only few studies on the effects of AAI for PTSD in general, and for PTSD in veterans in particular, exist today. Therefore, a pilot project of the German military (Deutsche Bundeswehr) to support standard therapy for soldiers with PTSD via a short-term dog-assisted intervention was developed and evaluated; both will be reported here.A brief introduction into the symptoms of PTSD and their treatment is given, followed by a short overview of effects of AAI in general and for PTSD. Also, possible underlying mechanisms explaining potential positive effects of human-animal interactions are addressed, prior to the report of the actual dog-assisted intervention and study.In the DSM-5  the acute stress disorder (ASD), also called acute stress reaction (ASR), and the post-traumatic stress disorder (PTSD) are both described as reactions toward a traumatic event. The acute stress disorder describes an acute stress reaction directly after a stressful, or even traumatic, experience and, in some cases, may also be present as a pre-stage of PTSD. For both diagnoses, the event needs to meet certain criteria to be considered traumatic. There is a wide variety of potentially traumatic experiences, including sexual or physical abuse, natural disasters, war, respectively large-scale acts of violence or accidents. For the diagnosis of PTSD, the experience must have included exposure to death or threat of death for oneself or others or the violation of one's physical integrity. The experience of the event must have been direct and accompanied by feelings of horror, fear and helplessness, and increased arousal and dissociation. In addition at least four of the following criteria need to apply: intrusive thoughts, flashbacks or nightmares, avoiding situations that could trigger the memory (and possibly re-experiencing), hyper arousal (those three are the main criteria for PTSD), and negative alterations in mood and/or cognition, which frequently relate to negative expectations about the future and the world in general, feelings of guilt, and self-blame.Prevalence data for PTSD vary widely between countries and populations. While for US-American adults from the general population lifetime prevalence is estimated at 7–12% . The preIn Germany, the lifetime prevalence for PTSD is estimated at 1.5–2.3%. However, some estimate it at 6% for men and 10% for women , either assessed within the frame of AAI, experiments, or animal ownership, might be helpful in the treatment of patients with PTSD [for review and references not otherwise specified see ].Well documented are the social effects of HAI. Humans of all ages, with and without clinical disorders, communicate more and more positively, verbally and non-verbally, in the presence of friendly animals. This is called the “social catalyst effect” of animals. Persons accompanied by a friendly looking animal receive more positive attention from others also, people in the company of animals (dogs) are trusted more by others. All these social effects of HAI could be important for therapy for soldiers with PTSD, because an animal involvement could facilitate establishing the necessary therapeutic alliance between therapist and client.Among the psychological effects of HAI are an increase of the person's concentration and motivation in completing different tasks –19. AnimThis reduction of psychological stress is also mirrored in the physiological effects: HAI has been shown to buffer human stress reactions, of the hypothalamic-pituitary-adrenal system (HPA-axis), as well as of the autonomic nervous system (ANS). Cortisol levels and cardiovascular parameters (heart rate and blood pressure) are positively influenced by HAI, with largest effects being found for stressful situations. The physical contact between the human and the animal seems to be especially effective, and also the level of familiarity with the animal, or the closeness of the relationship seems to be important, e.g., in increasing the level of the hormone oxytocin and the neurotransmitter dopamine.The many different effects of HAI cannot be explained by one single theory. Their explanation requires a set of theories and processes, which are linked to each other [for review see ]. Some oJulius et al.  describeAnimals can contribute to human relaxation, not only via the biophilia effect, which requires no direct contact, but also via the activation of the oxytocin system, primarily via physical contact between human and animal. This seems to be a neurobiological mechanism which can explain many of the positive social, psychological and physiological effects of HAI , 22, sinThe activation of the oxytocin system seems to be a key for the explanation of additional positive effects of AAI supporting standard trauma therapy in a human-only setting. In AAI, nearly all patients want to pet the animals and therapy animals usually allow this kind of physical closeness and might even enjoy it. Even though this has not yet been investigated for patients with PTSD, it can be assumed from existing research documenting positive effects of AAI  that theFurther processes which might be based at least partly on biophilia and the attention humans pay to animals, involve distraction , e.g., fDuring the recent years, several studies and reviews  documenOwen et al.  describeHowever, no detailed description of such complementary adjunct dog-assisted interventions have been published, nor have they been evaluated. Therefore, our pilot project was aimed at both developing and implementing such a dog-assisted intervention and providing some empirical evidence. Another special feature of our project is the involvement of military service dogs and their handlers in delivering the dog-assisted intervention, in addition to the standard psychiatric treatment for veterans with PTSD.Based on the knowledge about PTSD and its challenges in treatment and the potential positive effects of AAI supporting conventional trauma therapy/psychotherapy, the following research question was investigated: Does an AAI, delivered by military dog-handlers with their dogs supporting conventional standard treatment have additional positive effects for soldiers with PTSD in comparison to conventional treatment of PTSD without AAI?To answer the research question, a controlled trial was conducted. The animal-assisted intervention which was evaluated had been developed for this purpose and had not been tested before. Therefore, the study has the character of a pilot study.The intervention group, which received the standard treatment plus the AAI (for a detailed description see below) included 29 patients (soldiers) of the Bundeswehr Central Hospital Koblenz, 26 men and three women, average age 38 ± 7 years (mean ± SD), with a diagnosed PTSD. Seven of those patients were single or divorced while 19 were married or lived with a partner. A higher level of school education was reached by eight patients, a medium level by twelve, and a lower degree by five participants (some patients did not give this information).The control group consisted of 31 male soldiers with a diagnosed PTSD, who received the standard treatment, and were 38 ± 7 years of age. Seven of those patients were single or divorced while 23 were married or lived with a partner. A higher level of school education was reached by eight participants, a medium level by 15, and a lower degree by six participants.Participants were asked for participation 2–3 weeks prior to the first AAI, when starting therapy at the hospital. Participation was voluntary. Written informed consent was obtained from all participants of this study.Even though participants were not randomly selected for intervention or control group, they were comparable regarding age, level of education and relationship status. Data from the intervention group were collected during the spring and summer months, since the intervention with the dogs took place mostly outdoors. Each patient of the intervention group attended an AAI session of ca. 3 h, once a week, for a duration of 4 weeks, in addition to standard treatment. To avoid negative effects due to not receiving a special intervention while seeing that other patients did, data of the control group were collected the following year, during approximately the same time of the year. Patients were selected due to their voluntary participation, the diagnosis of a PTSD, absence of allergy to or fear of dogs, and being in psychotherapeutic treatment at the Bundeswehr Hospital Koblenz during the relevant time .Frequently in the field of AAI, the intervention is delivered by specially trained teams of a “therapy dog” and its handler. This handler is sometimes but not always a person with a therapeutic, educational or medical degree. However, such teams from outside the Bundeswehr were not approached due to several reasons. It was planned to continue the adjuvant dog-assisted intervention, if results of the pilot study would turn out positive, and thus to establish such teams within the Bundeswehr itself, because this has several advantages. Therefore, different from usual approaches in AAI, in our pilot-study soldiers handling a military service dog were selected to carry out the intervention. Being a soldier himself/herself, the dog-handlercan a more easily relate to the patient due to similar experiences, like deployment abroad and knowledge about the challenges of working in the military. This is especially important for soldiers with PTSD who mistrust most people. For this project it was also relevant that due to the geographical closeness of the Bundeswehr School of Dog Handling to the Bundeswehr Central Hospital Koblenz, a larger group of such service dog teams could be employed for AAI than external non-military teams were available in the direct surrounding.For organizational reasons the dog-assisted intervention in our study was delivered to 10 patients at a time, who were driven from the hospital to the Bundeswehr School of Dog Handling together, once a week, for one morning . Each patient worked with his/her service dog team on the premises of the School of Dog Handling, but apart from the other patients and their dog teams. While the 3 h are a much longer time of intervention than usually found in AAI, it should be mentioned that this was planned this way to give the patients enough time to adjust to the situation  and not feel rushed. Also different from other AAI, in our project the sessions did not involve therapy but rather aimed at improving general well-being, distracting from symptoms and providing the patients with experiences they had not had for a long time. Therefore, session included mainly a walk, play, grooming, feeding, and just relaxing together, and were partly standardized by these activities.During the intervention units, patient and dog initially had the opportunity to get accustomed to each other and to familiarize themselves with the environment within the scope of a walk.Subsequent “activation modules” were about performing a variety of exercises with the dog. This was done in the form of playful exercises from the field of dog sport, such as obedience, agility, dummy work, retrieval and search. In this context the service dog team was able to show its full individual repertoire (excluding rough tug-of-war games) and responding flexibly to a patient's wishes. The aim was to quickly develop a trusting relationship with the dog and—with some delay—also with the dog handler. By way of active movement, fun and joint activity and by talking about something harmless, an attempt was also made to find a distraction from the illness. Breaks between these modules were made when patient or dog needed them.In a “slow-down module” at the end of the intervention unit, the physical contact with the “four-legged comrade” was explicitly promoted by having the patient perform tasks of maintenance and care on the dog  to reduce stress parameters and contribute to mental relaxation.The service dog handlers were instructed not to engage in conversations about the trauma or PTSD and change the subject when the patient would start to talk about these topics. The AAI was intended as a break from the trauma-focused therapy at the hospital. Furthermore, the dog handlers did not have the necessary therapeutic training. Also, the teams were instructed not to engage in any kind of fighting games between human and dog or work that involves aggression of the dog. Before the start of the intervention, the service dog handler teams received information about PTSD, what to avoid when dealing with patients with PTSD and what to do when symptoms like dissociation would occur.Either a nurse or a therapist knowing the patients accompanied the patients to the Bundeswehr School for Dog Handling and stayed on site, but only got involved if a patient needed help .Since it is a new approach to employ the military service dogs and their handlers, soldiers, in this kind of dog-assisted intervention, the selection of the service dog teams for this project will be described in more detail. In contrast to common dog-handler teams in AAI, that have usually been tested by some larger organization in the field of AAI, most of the dogs in this study were trained for military purposes and thus needed to be tested for their suitability for the AAI.All 18 service-dog teams that were involved in the project, volunteered for participation in the study. These were experienced service dog teams that had worked closely together usually for several years (at least for 7 months). The breeds of the dogs were Labrador Retriever or Malinois. Service dogs were selected for dog-assisted intervention against the background of minimizing the risks for patients, and maintaining the well-being of the animals. Due to their technical expertise and the detailed knowledge of their service dogs, the dog handlers are able to identify stressors and potential risks and to respond adequately. The selected dogs distinguished themselves by a high level of social competence and friendliness toward humans. Furthermore, in the run-up to deployment the selected teams had to undergo a character test and were, thus, certified for this special project. Dogs to be considered for this task needed to be social with humans in general, and attached to their handler, friendly, curious, trusting, calm, with strong nerves and stamina, even in surprising or scary situations. They needed to not mind being touched or cuddled, and to show a high tolerance for unusual human behavior . It was important that the dog would not react aggressively even when feeling insecure or frustrated. Due to animal welfare concerns, strong avoidance behavior was an exclusion criterion for the dog-assisted intervention. There will always be a risk when working with dogs. To minimize this risk, the pre-selected dog was exposed to situations that are known to evoke aggressive behavior according to the “Training and Examination Regulations for Dog-Assisted Intervention of the Federal Armed Forces.” This is necessary for the safety of potential clients, the dog handler and the dog itself. In a continuing AAI project, the testing would be repeated at least once each year. The minimum age for a dog to take the test is 15 months. Passing the test is a requirement to be considered fit for service. Particularly, the test includes situations that the dog will be exposed to, to make sure that only especially suitable dogs will be chosen, regardless of the dog's breed. The “Training and Examination Regulations for Dog-Assisted Intervention of the Federal Armed Forces” include dogs' state of mental development, their conflict behavior and their willingness to work, especially with humans unknown to them. Testing takes place on one day and is divided into five tasks: (1) Everyday situations are created, e.g., being confronted with a person limping, stumbling, or walking using a white cane. A threatening situation is included, and the dog will be stared at. (2) For the second task, the dog has to demonstrate good obedience. It needs to return reliably when called, walk on a leash in an orderly fashion next to the dog handler, and wait for the dog handler in a specified place when told to. (3) Indoor situations: humans who cry, shout, make noise, embrace the dog without warning, or manipulate it physically. (4) For the fourth task, the dog is taken to inner city situations. The dog needs to be at ease with huge events and large numbers of people, as well as on public transport. (5) When confronted with other dogs, the dog needs to remain friendly or at least neutral. Overly aggressive behavior is not called for.For each service dog team who had successfully completed the exam, an information sheet including a picture of the team was created informing about the respective characteristics of the service dogs and including some basic information about the handler. Thus, the therapists at the hospital could assign the service-dog teams in a targeted manner to the respective patients on basis of the described nature of the dogs and their knowledge about their patients.The following questionnaires (base questionnaires) were given to the participants of the intervention and the control group. The intervention group answered these questionnaires once 2 days before the first AAI session (t1), during the days following the last AAI session (t2), 1 month later (t3), and 3 months later (t4). The control group answered the questionnaire set at corresponding times during their therapy.Questionnaire on sociodemographic data, military service , substance use  and current medicationHopkins Symptom Checklist 25 : This sPerceived Stress Scale (PSS) 14 : This inSkala zur Einstufung des Arbeits- und Soziallebens : This iFragen zur Therapeutischen Beziehung (Questions about the therapeutic relationship—self developed set of questions). The nine items are answered on a 5-point Likert scale; higher scores indicate a better therapeutic relationship. The internal consistency of this questionnaire is high, with Cronbach's alpha for positive affect between 0.854 and 0.986 at the different times and within the two groups.Each questionnaire was evaluated by adding up the items. All patients who answered at least 15% of the questions of a questionnaire were included in its evaluation. Missing items were replaced with the average of the remaining items .t-test . Trends over the four measurements were to be tested by Page's trend test; however, it turned out that several participants of the intervention group did not turn in their final questionnaire (at t4). Since the Page test requires measurements at all time points, these participants would have to be excluded from the analysis. Therefore, it was decided to carry out the main analysis only for the first three time points with inclusion of all those participants who answered the corresponding first three questionnaires. The final time point t4 was then analyzed only as a secondary evaluation with all those participants who answered all four questionnaires.Differences between intervention and control group at a given time were tested by independent weekly questionnaire T1” aboutOnly the intervention group receiving the AAI answered the following additional weekly questionnaires to capture immediate, short-term effects of the dog-assisted intervention. These questionnaires were developed for this project, since no suitable instruments were available. Directly before leaving the hospital for the Bundeswehr School for Dog Handling where the AAI took place, the patients answered the “trauma confrontation during trauma therapy during the last 7 days, stressors besides the trauma therapy,consumption of coffee, cigarettes, alcohol and drugs during the last 7 days,questions about mental wellness during the last 7 days , andthe Perceived Stress Scale 4 .Before the intervention, the symptoms, as measured by the Hopkins Symptom Checklist 25, were equal in both groups. During the course of the therapy, the intervention group improved slightly, whereas the control group deteriorateddecreasing null hypothesis, then it would have rejected this null hypothesis for the control group with very high statistical significance. The differences between the two groups were not statistically significant.. The PagThe perceived stress was generally higher in the intervention group than in the control group. It decreased a bit directly after the intervention in both groups and increased again in the following months . None ofp = 0.038) if all four questionnaires were included, because there was a sharp drop toward better values in the intervention group toward t4. Otherwise there was no statistical significance.The work and social adjustment had a trend toward worse values in the control group and a trend toward better values in the intervention group . This laThere was no clear trend in the therapeutic relationship over the course of the therapy . Accordip = 0.007). The values taken on the morning after the intervention were always better than the values before , but they deteriorated again over time until the next therapy session. Among the items in this questionnaire was a question about the ability to experience joy. This item displayed the greatest improvement over the course of the therapy (p < 0.001).The mental wellness improved over the 4 weeks of the intervention ; this trThere was no clear trend for the perceived stress scores . Accordip = 0.002; The relationship to the dog handler improved with statistical significance over the course of the intervention (All of these results are reported without Bonferroni correction as this was a pilot study.The comparison of intervention and control group over the four times of measurement did not indicate a significant advantage of the dog assisted intervention regarding PTSD symptom severity (HSCL-25), perceived stress (PSS-14), functional problems with emotions and actions due to the PTSD (SEASL), and the therapeutic alliance. Both groups did not show any significant improvement over time with regard to the investigated parameters. While this lack of a significant effect of the AAI in contrast to the control group is not what we expected, the lack of any improvement in neither group shows how difficult it is to achieve significant improvements for veterans with PTSD in the investigated time frame of 4 months. However, while there was no significant positive effect of the AAI or the standard treatment, neither on the full HSCL-25 nor on individual parameters, the control group in fact displayed a trend toward worse symptoms during and after the treatment. This was surprising, since other studies with veterans with PTSD from the German Bundeswehr document significant improvements of symptoms of PTSD and depression after 4 weeks of EMDR therapy (2–3 times per week) . ObviousIn our project, the dog assisted intervention only took place four times—a rather short intervention, leaving relatively little time for getting really acquainted and then already again having to prepare for an end of the meetings with the dog-team. However, the organizational framework  did not allow for more intervention units in this pilot project.Thus, it is noteworthy that descriptive evaluation reveals less negative trends on the parameters under investigation for the intervention group than in the control group and stronger positive trends (improvement of symptoms etc.) in the intervention group. This suggests that there might be a positive effect of the dog-assisted intervention which possibly could reach statistical significance in further studies working with more AAI sessions over a longer intervention period , and with larger samples of patients.The weekly collected data from the intervention group also suggest some positive effects of the dog-assisted intervention. There were significant positive trends. Subjective well-being the day following the dog-assisted intervention was significantly improved in contrast to the morning before the AAI. Also, over the course of the 4 weeks well-being improved, and for the item “feeling happiness” in particular a large effect was found. Since the loss of enjoyment is a severe problem for patients with PTSD, this improvement, being able to feel “happy” again, at least once in a while, is an important effect of the AAI. Similarly important is the observation that also the relationship to the service dog handler improved significantly over the course of the 4 weeks. Since mistrust toward other persons is another problem of patients with PTSD, which makes establishment of a therapeutic alliance very difficult, this result points toward the opportunity such a dog-assisted intervention provides. Opening up the patient for trusting other beings again, maybe first trusting the dog, then the handler, could be utilized to support trusting the therapist as well and establishing the necessary therapeutic alliance for a successful trauma therapy. The free answers from the participants describing their experiences with the dog-assisted intervention further support our assumption that the contact with the animals can support positive mood, trust and other factors relevant for a good quality of life, even if this was not captured via the employed instruments and the controlled trial.Obviously, this pilot project and study have limitations, first and foremost the low number of intervention units (four times) and the sample size. However, even with these limitations the positive findings point to a high likelihood that future, larger scale studies with a longer intervention period will find positive effects of the dog-assisted intervention in addition to standard treatment, also in comparison with a control group.Overall, our data point toward a positive potential of dog assisted interventions supporting standard treatment for veterans with PTSD. Since treatment of this patient group is challenging, AAI may be an ideal candidate for an effective form of adjuvant interventions supporting trauma therapy.Our result are further supported by the statements of the participants of this study about their experiences with the dog assisted intervention [these data have been reported in German in Ernst et al. ; EnglishVia the interaction with the dog I was able to relax and calm down. He helped me to trust myself again, to be able to do at least some things right.I felt completely relaxed, as if I had no problems at all. I was able to laugh again and just be myself. The feeling of happiness was overwhelming, I have not felt that for a very long time. Really great!From my first contact with the dog until I had to say goodbye, I have not thought once about my PTSD and my problems.The datasets generated for this study are available on request to the corresponding author.The project was reviewed with regard to patient welfare, data protection and animal welfare by the ethics committee of the State Chamber of Medicine of Rheinland-Pfalz, Germany.AB, IS, RB, and CE planned the project. CE, IS, and RB were responsible for conducting the AAI. AB and IS planned and conducted the evaluation. RG was responsible for the data analysis. Background and Method were written by AB, IS, and CE, the result section by RG, and the discussion by RG and AB.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.