Attention Deficit-Hyperactivity Disorder an Illustrated Historical Overview

ADHD

Attention deficit-hyperactivity disorder An illustrated historical overview

Edited by Andreas Warnke and Christian Riederer The hyperkinetic child – Moving forward by looking back

215 years ago, the Scottish physician Alexander Crichton presented cases of children who exhibited attention deficits, hallmarks of a disorder today known as attention deficit-hyperactivity disorder (ADHD), one of the most common childhood onset psychological problem.

Since that time there has been a fascinating history of clinical and basic research on ADHD symptomatology: research into its clinical features and subtypes, disorder-specific aspects of social interaction, the course from childhood to adulthood and gender differences, non-genetic and genetic etiologies, the association with brain structure and cerebral functioning, the relevance of neurotransmitter systems, research concerning developmental comorbidity and quality of life and investigations of treatment approaches, including psychotherapeutic and psychopharmacological research.

In this illustrated brochure, we have compiled some chapters which briefly sum- marize the main steps of this fascinating history on ADHD-associated research. We have put a special focus on topics with rich graphical material and are there- fore especially indebted to the Struwwelpeter-Museum, the Emma Pendleton Bradley Hospital and the Firmenarchiv Novartis AG for providing photos and il- lustrations from their vast archives.

We also thank Paul Foley for contributing texts and translations, Aribert Roth- enberger for his approval to include photos and pictures in the Kramer/Pollnow chapter, Siebke Melfsen and Susanne Walitza for their article on Heinrich Hoff- mann, Regina Taurines for her contribution on developmental comorbidity and This brochure is supported by: Ludger Tebartz van Elst and Marcel Romanos for contributing graphical material to the chapter on neuroimaging.

We hope you enjoy this history!

Andreas Warnke and Christian Riederer, May 2013. WORLD Verein zur Durchführung FEDERATION The authors can be reached at [email protected], and welcome suggestions and ideas! Neurowissenschaftlicher Tagungen e.V. Part I The idea of "uncontrolled" behaviour as a medical problem Savvy observers

hile stories of restive and undisciplined children are as old as humanity it- Wself, reports of fidgety and restless children in a more closely medical context can be traced back at least as far as 1798, when the Scottish-born physician and author Alexander Crichton (1763–1856) described in his book An inquiry into the nature and origin of mental derangement a mental state reminiscent of the inattentive subtype of ADHD. In this work, he observed clinical cases of mental illness and dedicated a chapter “on attention, and its diseases.”

"The incapacity of attending with a necessary degree of constancy to any one object, almost always arises from an unnatural or morbid sensibility of the nerves, by which means this faculty is incessantly withdrawn from one impression to another. It may be either born with a person, or it may be the effect of accidental diseases. When born with a person it becomes evident at a very early period of life, and has a very bad effect, inasmuch as it renders him incapable of attending with constancy to any one object of education. But it seldom is in so great a degree as totally to impede all instruction; and what is very fortunate, it is gener- ally diminished with age.”

Crichton, 1798, Vol. 1, p. 271f.

few years later, in 1809, the English physician John Haslam (1764–1844) pro- A vided the case history of a ten year old boy who was “the creature of volition and the terror of the family”, or, in brief, a destructive lad with uncontrollable impulsivity.

"At the age of two years, the subject of the present relation, became so mischievous and uncontrollable, that he was sent from home to be nursed by his aunt. In this situation at the request of his parents, and with the concurrence of his relation, he was indulged in every wish, and never corrected for any per- verseness or impropriety of conduct. Thus he continued until he was nearly nine years old, the creature of volition and the terror of the family."

Haslam, 1809, p. 199f. Some more observations

t about the same time, in 1812, the multi-talented American Benjamin Rush aluable observations in the 19th century were also made by the famous A(1745–1813), among whose achievements was the signing of the Declaration VFrench psychiatrist Jean-Étienne Dominique Esquirol (1772–1840) and by the of Independence, added his observations on uncontrollable children and adults British psychiatrist Henry Maudsley (1835–1918), who in his book The physiology and speculated on the “defective organization in those parts of the body which and pathology of the mind (1867) described a child “driven by an impulse of which are occupied by the moral faculties of the mind.” it can give no account, to a destructive act, the real nature of which it does not appreciate: a natural instinct is exaggerated and perverted by disorder of the nerve centre, and the character of its morbid manifestation is often determined by accidents of external circumstances.”

"In the course of my life, I have been consulted "The insane, no longer enjoy the faculty of fixing, in three cases of the total perversion of the moral and directing their attention, and this priva- faculties. One of them was in a young man, the tion is the primitive cause of all their errors. We second in a young woman, both of Virginia, observe this among children, who, although very and the third was in the daughter of a citizen impressible, have nevertheless few sensations, for of Philadelphia. The last was addicted to every want of attention." kind of mischief. Her wickedness had no intervals while she was awake, except when she was kept Esquirol, 1845, p. 28f. busy in some steady and difficult employment. In all these cases of innate, preternatural moral depravity, there is probably an original defective organization in those parts of the body, which are occupied by the moral faculties of the mind."

Rush, 1812, p. 359f. States of explosiveness

homas Smith Clouston (1840–1915) was a notable Scottish psychiatrist of the Tlate 19th century who wrote prolifically on the nature of mental illness and theories of treatment. For most of his career, he served as physician superinten- dent at the Edinburgh Royal Asylum.

In 1899, Clouston published a remarkable article on states of over-excitability and mental explosiveness, in which he described cases of impulsive children with learning problems. He outlined a therapy consisting of individual dietary and social treatments, including environmental improvements, and a pharmacological intervention consisting of carefully dosed grains of potassium bromide.

“I do not advocate bromide treatment alone […] I think milk will be found the sheet anchor in dieting all such neurotic children. Environment too, fresh air, suitable amusements, companionship, control, Thomas Smith Clouston around 1900. Source: Wikimedia Commons. employment must be looked to, and the schoolmaster must be regarded for the time as an aid to treatment and so under the doctor´s order.”

T.S. Clouston, 1899. London 1902

hile working at King’s College Hospital in London, George Frederic Still W(1868–1941) presented a series of three lectures on March 4, 6 and 11, 1902 to the Royal Society of Medicine in London, the Goulstonian Lectures on “some abnormal psychical conditions in children”, which were also published in April 1902 in the Lancet. In these lectures, Still described the cases of 23 examined children from his practice, aged between three and twelve years, who showed diminished “moral control”, were excessively passionate and emotional, and had problems at school. As these children came mainly from normal families and had no general impairment of intellect, Still concluded that the underlying cause of the defect was some morbid physical condition. He described a number of diseases that might be responsible, and also linked the moral defect to morbid nervous and mental conditions.

„Another boy, aged six years, with marked moral defect was unable to keep his attention even to a game for more than a very short time, and, as might be expected, the failure of attention was very noticeable at school, with the result that in some cases the child was backward in school attainments, although in manner and ordinary conversation he appeared as bright and intelligent as any child could be.”

Still, Goulstonian Lectures, Lecture III.

Some abnormal psychical conditions in children: The Goulstonian Lectures of 1902.

Lecture 1 held on March 4, published on April 12. Lecture 2 held on March 6, published on April 19. Lecture 3 held on March 11, published on April 26.

The Goulstonian Lectures are named for the English physician Theodore Goulston (1572–1632).

George Frederic Still in the 1920s. Source: U.S. National Library of Medicine. Mental deficiency and inattention

lfred Tredgold (1870–1952), a highly respected member of the English Royal ACommission on Mental Deficiency and author of Mental Deficiency (Amentia; first published 1908), extended Stills’ theory and observations and suggested that some forms of brain damage could present as behaviour or learning problems in early school years. He was also the first to propose the existence of what would later be termed "minimal brain damage".

Tredgold and Still were well aware of the legal and social importance of their findings. While the initial clinical description of ADHD is usually attributed to Still, Tredgold’s writings had a lasting impact on the social and political debate at the beginning of the 19th century on how to deal with the feeble minded, as well as upon the classification of mental disorders through the landmark Mental Deficiency Act of 1913. As attendance at public elementary and other schools had been compulsory in England since 1876, Tredgold and other researchers had access to a vast set of data and reports, but it was some time before effective management of these children was developed.

"Attention – In the lethargic, inert type of feeble-mindedness there is a defect of spontaneous attention; but this is never so marked in this degree as in the more serious grades of amentia. The general stir and excitement aroused by a visitor is much more pronounced in the special school than in the imbecile ward. On the other hand, active or voluntary attention is commonly in defect, both with regard to its intensity and its duration. The most trifling thing serves to distract these children from their occupation, so that even where the attention is readily gained, it is with difficulty held. Many of them become capable of pursuing a congenial task with a certain amount of patience, but the majority have neither power of concentration nor will sufficient to be capable of sustained mental effort against inclination or interposed obstacles. They must go with, for they cannot fight against, the stream; and this lack of willpower and driving force is one of the most distinguishing characteristics of aments at all ages."

Alfred Tredgold, Mental Deficiency, 4th edition, 1922. "Brain damage" and behaviour disorder

etween 1917 and the late 1920s, fect on adolescents was the subject of and claimed to have been compelled other neurologic condition, with the Bencephalitis lethargica was an epi- parliamentary debate and government to act as they did. The link between possible exception of traumatic brain demic and often lethal neurologic enquiries. Special institutes for the care the approximately contemporaneous injury. The ultimate fate of such chil- disease. In adults, it typically elicited of such children, with varying success, “Spanish” influenza epidemic and en- dren could hardly be more tragic: their severe somatic effects, and in particu- were established in various countries, cephalitis lethargica remains unclear, behavioural problems receded during lar, various forms of cranial nerve and including Germany, France, the United but it is possible that influenza played their early 1920s, only to be replaced motor dysfunction. In children, the Kingdom and the United States. Many a direct or indirect role in the etiology by rapidly advancing parkinsonism psychiatric effects were often as se- neurological and psychological theo- of the disorder. Encephalitis lethargica from which there was no recovery. vere as the physical ries were advanced to triggered behavioural changes in chil- consequences. Ap- explain these severe dren that are not duplicated by any By Paul Foley, Sydney, Australia. proximately one third behavioural changes, of affected children and the therapeu- underwent a rapid tic approaches em- transformation from ployed ranged from normal behaviour to training in dedicated impulsiveness, emo- schools to frontal leu- tional lability, preco- cotomy. Neither intel- cious sexuality, self ligence nor memory mutilation, a tenden- were consistently im- cy to wander, and de- paired in the disorder, linquency, often to a but concentration and degree requiring con- sleep were commonly finement in psychi- affected: the children atric or penal institu- tend to be overactive tions. The onset of the final and largest through the night but slept through epidemic in 1924 caused a great deal most of the day. Doctors also noted of public and political concern caused that although children suffering post- by “a disease which makes criminals” encephalitic psychiatric disturbances (The Times, London, August 20, 1924). could exhibit the cruellest behaviour Encephalitis lethargica was cited in the – for example, removing their own defence of youths arraigned for vari- eyes or killing a sibling – they exhib- Articles of Ebaugh (1923) and Stryker (1925) describing behavioural consequences of ous crimes during the 1920s, and its ef- ited genuine remorse after the fact, encephalitis in children. Constantin von Economo

longside the protagonists of the Second Viennese Medical School, Theodor AMeynert (who described the basal nucleus named for him) and Julius Wag- ner-Jauregg (Nobel laureate 1927), the cosmopolitan Constantin von Economo (1876–1931) made significant contributions to neuroscience.

He was born in Romania, the son of a wealthy Greek family who later moved to Trieste and finally settled in Vienna where von Economo spent most of his aca- demic career, although he studied some years abroad in Munich, Berlin and at La Salpêtrière in Paris. Among his teachers were some of the most prominent scientist of the beginning 20th century, Alois Alzheimer, Emil Kraepelin, Hermann Oppenheim, Theodor Ziehen, Pierre Marie and Fulgence Raymond.

His own masterpiece was the seminal description of encephalitis lethargica in 1917, including accounts of the neuropathological basis and its clinical spectrum. Subsequent work explored its role as a major trigger of postencephalitic parkinsonism as its late sequela. Von Economo made also important contributions to the cytoarchitectonics of the cerebral cortex and sleep regulation and served as military pilot in WW1.

Constantin von Economo in 1910. Source: Wikimedia Commons. Part II Towards the concept of ADHD Towards terminology

n the 19th century, behaviour problems, uncontrollability and impropriety of Such observations on social milieu and life quality were made as early as 1935 by I conduct as medical problems were associated with morbid nervous condi- A.T. Childers and ultimately gained ground in the 1970s and 1980s with the works tions, brain damage and brain dysfunction. This emphasis on biological factors of Virginia Douglas, from the McGill University in Montreal. Douglas argued that continued in the early 20th century in the works of George Frederic Still and Alfred the major disability of hyperactive children involved an inability to sustain atten- Tredgold, who claimed that forms of brain damage were involved, an argument tion and to inhibit impulsive responding during tasks and situations requiring brought forward in the 1930s and 1940s, too, particularly in the publications of organized and focused efforts. Alfred Strauss and co-workers who coined the term "brain-injured child". This terminology reflected the assumption that some injury is the cause of behaviour disturbances, but it was called into question when further research examined the causes of behaviour problems in childhood and a shift towards psychological factors occured.

Article of Paul Levin, 1938.

Article of A.T. Childers, 1935.

Kahn and Cohen (1934) describe 3 cases in which hyperkinesis is a predominant feature that they term “organic driveness”, considered to be the result of a subacute encephalitis affecting brain stem and basal ganglia. nother strong input throughout "hyperkinetic reaction of childhood", Amost of the 20th century was the then "attention-deficit disorder" in concept of hyperkinesia, culminating DSM-III (1980), and "attention-deficit/ in the work of Kramer/Pollnow, and hyperactivity disorder" in DSM-III-R further investigated by Maurice Laufer (1987) and DSM-IV (1994). The most and Stella Chess. Laufer and co-work- recent edition (DSM-V, 2013) will not ers described the “Hyperkinetic Behav- make vital changes on the diagnostic ior Syndrome in Children” and the „Hy- concept, but relevant modifications perkinetic Impulse Disorder” in 1957, include the age of onset, the symp- while Chess published an influential tomatic threshold for adults, and the Article of Neill Hobhouse, 1928. article in 1960 in which she presented removal of autism spectrum disorder her experiences with hyperactive chil- from the exclusion criteria. In the WHO dren as well as therapeutic options. manual, the disorder was labeled as "hyperkinetic reaction of childhood" Reflecting this thought, the disorder in ICD-8 (1974) as well as "hyperkinetic was mentioned in the 2nd edition of syndrome" (ICD-9) and "hyperkinetic the Diagnostic and Statistical Manual of disorders" (ICD-10), the latter term in- Mental Disorders (DSM II) in 1968 as the cluding subtypes of ADHD.

Laufer and Denhoff, both working at the Emma Pendleton Bradley Home, described in an article with Gerald Solomons in 1957 the “Hyperkinetic Impulse Disorder”.

Virginia Douglas investigated specific disabilities of hyperactive children in 1972, suggesting that a core group of The landmark article of Kramer/Pollnow appeared 1932 in the "Monatsschrift für Psychiatrie und Neurologie". symptoms involving inability to sustain attention and to control impulsivity can account for most of the deficits. Struwwelpeter

einrich Hoffmann (1809–1894) was born in Frankfurt/Main, Germany, the n 1816 Hoffmann was enrolled in in Peru. Their daughter Antonie Caro- Hson of the architect Jacob Hoffmann and his wife Caroline née Lausberg. I school, and during his elementary line (Lina) was born in 1844; her hus- His mother, who belonged to the upper class, was in poor health and died in school years was tormented by some band later left her a young widow, and 1810, when Heinrich was only six months old. Three years after her death, Jacob of his classmates. He was said, on the she and her children moved into her Hoffmann married her sister, Antoinette Lausberg. Hoffmann described her as a one hand, to be a feeble and anxious father´s house until she died. The third loving mother to him and his two step-sisters, Sophie and Berta. Hoffmann left child, but also, on the other, lively, talk- child, Eduard, born in 1848, was very a versatile life´s work, as a citizen of Frankfurt, as a children's author, as a writer ative, funny and inventive. It is also re- successful, but remained single and of poems and satires, as a psychiatrist, and as a family man. Hoede and Bauer ported that he hardly took school seri- childless. characterized Hoffmann´s life as lying between "wit and delusion". ously until tertiary level, and that he was initially a rather lazy and distracted pupil. In 1828, he finished high school with the German Abi- tur. From 1829 to 1832, Hoff- mann studied medicine in Heidelberg, then continued his studies in Halle, where he obtained his doctorate. He then lived in Paris for a few months. When his father fell ill and died, the young doctor returned to Frank- furt and settled as general practitioner and obstetrician. Some doctors in Frankfurt had founded a clinic for the poor and underprivileged that Hoffmann later joined. In 1840, Hoffmann married Therese Donner; their son

The house of Hoffmann´s birth in the Photos and pictures contributed by the Carl Philipp was born a year Fressgass, Frankfurt, Germany. Struwwelpeter-Museum, Frankfurt, Germany. later, but died young in 1868 A famous children´s book

offmann was a creative personality who wrote poetry and sketched pictures outsider. The next tale recounts "The Story of Bad Frederick", who is very impul- Hthroughout his life, not only for publication. His first and most famous book, sive and aggressive: he tortures animals and people, until he is finally injured by "Slovenly Peter" ("Struwwelpeter"), has been translated into almost all languages a resisting dog. While the dog enjoys thereafter the amenities of Frederick´s life, of the world. Hoffmann could not find a suitable gift for his son Carl in the he must remain in bed. "The Dreadful Story of the Matches" warns of the dangers bookstores of Frankfurt, so he originally designed the small book as a Christ- of fire: Paulinchen ignores the warnings of two cats and the prohibition of her mas present in 1844. The picture book includes a series of self-contained, illus- parents, and plays with matches while at home alone, and is ultimately burned trated stories that warn against the devastating consequences of disobedience to death. "Fidgety Philip", the most cited story in the context of ADHD, exhibits a and wickedness. "Slovenly Peter", for example, willfully and defiantly refused to restlessness that is a burden on family life. The plight of the parents becomes ap- have his hair and nails cut for a year. Unkempt, and thus offending all the rules of parent when Philip once more "flutters", "rocks", "fidgets" and "clatters" at table: personal hygiene, he finally stands defiantly on his podium, labeled by others an in their helplessness, they react with anger. n "The Story of Johnny Head in-Air", a dreamy, distracted and inattentive child the stories lack background and do not explain why the children acted in evil, I is described, who ends up falling into the water he has not seen before him. dangerous or naughty ways. The book shows no evolution and no explanations The book was not only acknowledged immediately after its publication by loud are sought or supplied. The book explains neither why Frederick becomes so ag- applause, but was also subject to fierce criticism directed against the terrifying gressive, why "Slovenly Peter" is not willing to have his hair cut, nor why "Soup- images, the cruelty of the punishments, and the underlying pedagogic concept, Kaspar" refuses to eat his food. For this reason, no detailed depiction of mental described as "repressive and impatient" (Tresnak, 2005). However, Hoffmann's disorders by the book can be derived. It might nevertheless be asserted that work can only be seen in the context of bourgeois society with its strict moral Hoffmann was among the first authors who addressed behavioural disorders in notions and civic values that specified how a well-behaved child was to behave. children and adolescents. The behavioural patterns probably depict precursors of mental disorders in children such as anorexia, disorders of social behaviour, and hyperactivity. However, Drawing of the front page by H. Hoffmann and various covers of international editions of the "Struwwelpeter", contributed by the Struwwelpeter-Museum, Frankfurt, Germany. The Story of Fidgety Philip

offmann felt comfortable as a physician, especially as medical director of Let me see if Philip can Catches at the cloth, but then Hthe "lunatic asylum". Prior to 1851, when he commenced as physician at the Be a little gentleman That makes matters worse again Frankfurt "Asylum for the Insane and Epileptic", he had never set foot in a "lunatic Let me see if he is able Down upon the ground they fall To sit still for once at table: Glasses, plates, knives, forks, and all. asylum", but quickly showed that he was the right man in the right place. As usual Thus Papa bade Phil behave How Mamma did fret and frown in the mid-19th century, Hoffmann and his family lived in the hospital and he was And Mamma looked very grave When she saw them tumbling down! in permanent contact with his patients and responsible for their daily care. He But fidgety Phil And Papa made such a face! He won’t sit stil Philip is in sad disgrace attempted to apply the latest advances in psychiatry and managed to introduce He wriggles proper employment, reasonable nutrition, and humane treatment, as well as or- And giggles Where is Philip, where is he? derliness and cleanliness. From 1851 to 1852 Hoffmann undertook several trips And then, I declare Fairly covered up you see! to visit other European "lunatic asylums" and became convinced that conditions Swings backwards and forwards Cloth and all are lying on him And tilts up his chair He has pulled down all upon him for the mentally ill in Frankfurt were unacceptable. He successfully organized a Just like any rocking-horse- What a terrible to-do! huge crusade to motivate citizens to donate money for a new "asylum" in Frank- “Philip! I am getting cross! Dishes, glasses, snapped in two! furt which finally opened in Frankfurt´s Westend in 1864. Here a knife, and there a fork! See the naughty, restless child Philip, this is cruel work Growing still more rude and wild Table all so bare, and ah! Till his chair falls over quite Poor Papa, and poor Mamma Philip screams with all his might Look quite cross, and wonder how They shall have their dinner now.

"...when a physician enters a hospital department, it should have some traits of a sunrise, it must spread warmth and light; and so it should be in every patient's room." Hoffmann also warned: "What you cannot give the patient through your knowledge and art, try to give through emotional participation and love."

Advice of Hoffmann for fellow doctors on the occasion of his 50th anniversary as physician in 1883, quoted in Siefert and Herzog-Hoinkis, 2009, p. 108f.

All texts by Siebke Melfsen and Susanne Walitza, Zurich, Switzerland. Photos and pictures contributed by the Struwwelpeter-Museum, Frankfurt, Germany. Berlin´s Charité

ramer and Pollnow worked togeth- and appointed Kramer its head. Simi- Another leading figure at the Charité Tragically, most of the fruitful efforts Ker at the psychiatric and neurologi- lar wards were opened at that time was Adalbert Czerny (1863–1941), who at the Charité ended unhappily. Kram- cal hospital at Berlin’s Charité under throughout Berlin and in other Ger- became full professor for paediatrics in er left Germany in 1938 and spent the Karl Bonhoeffer, a renowned psychia- man cities, a development that was 1913. Czerny emphasized in his works rest of his life in the Netherlands where trist who led Germany’s most prestig- pioneered by the famous paediatri- the correlation between nutritional he was able to find work as a doctor ious and influential clinic from 1912 cian August Homburger (1873–1930) disturbance and the behaviour of the in Amsterdam and Den Dolder. Poll- to 1938. In view of the rising number in Heidelberg, who opened one of the child and several diseases were named now emigrated in 1933 to Paris, but as of hospitalized children, Bonhoeffer first centers where parents could seek after him (Czerny-anaemia, Czerny−di- war raged he was caught by German had opened a special ward dedicated advice on psychiatric matters affecting athesis, Czerny-respiration). troops in southern France and later to the observation of children in 1921 their children. murdered in Mauthausen.

Karl Bonhoeffer (1868–1948). Letter of recommendation for Franz Kramer by Source: Wikimedia Commons. Ferdinand Sauerbruch. Charité, May 25, 1938. Kramer and Pollnow

ranz Kramer (1878–1967) and Hans Pollnow (1902–1943) owe their place in Fthe history of child and adolescent psychiatry to their work on the description of hyperkinetic syndromes and conditions that culminated in their landmark article Über eine hyperkinetische Erkrankung im Kindesalter, published in 1932. In this article, Kramer and Pollnow described a case series of 17 children who presented with aggressive behaviour, impulsivity, chaotic motor restlessness and learning difficulties, syndromes consistent with what is now regarded as ADHD or hyperkinetic syndrome. This clinical picture was later named Kramer-Pollnow syndrome.

Franz Kramer (on the left of the first row), Hans Pollnow (standing in the second row, two from the right) and colleagues of the “Kinder-Kranken- und Beobachtungsstation” at the Charité around 1929.

All photos and pictures courtesy of Aribert Rothenberger from: Rothenberger, A., Neumärker, K. J. (2005). Wissenschaftsgeschichte der ADHS - Kramer-Pollnow im Spiegel der Zeit. Steinkopff Verlag, Darmstadt. Medical record written by Franz Kramer. Charité, March 17, 1926. Part III Towards medication of "uncontrolled" behaviour The Emma Pendleton Bradley Home

he Emma Pendleton Bradley Home was America’s first neuropsychiatric hospi- Ttal for children, and named for George and Helen Bradley’s only child Emma Pendleton Bradley (1879–1907), who had been stricken with encephalitis as a young child. In his will, the affluent businessman George Bradley (1846–1906), who among other activities had helped Graham Bell to market the telephone, requested that the Baton House, the family’s Providence estate, be converted into a treatment facility for children. The institution opened its doors in 1931 in a new, less urban, setting and in accordance with the terms of George Bradley’s will, the facility gave first preference to poor, needy children from Rhode Island and families were only billed if they had the means to pay.

Owing to its focus on child psychiatry, the Emma Pendleton Bradley Home at- tracted many talented researchers who made seminal contributions to the inves- tigation of ADHD.

Photo of Bradley Hospital in the 1930s. Courtesy of Emma Pendleton Bradley Hospital, East Providence, Rhode Island, USA.

George Bradley. Courtesy of Emma Pendleton Bradley Hospital, East Providence, Rhode Island, USA. Emma Bradley

mma Bradley was stricken with encephalitis at the age of seven. The disease Eleft her with multiple disabilities, including epilepsy, mental retardation and cerebral palsy. This tragedy sparked the Bradleys to conduct a worldwide search for a cure or treatment for Emma‘s condition. As psychiatry and neurology were in their infancy, hospitals were solely for adults and pediatric services were not yet available, the Bradleys arranged around-the-clock medical care for Emma at their summer home in Pomfret, Connecticut. After eighteen years of treatment, Emma showed no improvement, and George and Helen began to accept their daughter‘s fate.

Emma Bradley. Courtesy of Emma Pendleton Bradley Hospital, East Providence, Rhode Island, USA. OH Psychostimulants

sychostimulants, drugs employed Amphetamine was first synthesized in CH3 Pto elevate mood, are regarded as 1887 by the Romanian chemist Lazar useful tools in managing a range of Edeleanu at the Humboldt University disorders, including depression and in Berlin, but was largely unknown un- the akinesia of Parkinson’s disease. til the Philadelphia-based company HN Pharmacological agents have been Smith, Kline and French introduced CH used with this aim for centuries; in an inhaler and bronchodilator in 1932 3 the 19th century they were known as under the trade name “Benzedrine”. It “nerve tonics”, and included a num- was freely available through the 1930s, ber of plant-derived agents, including when its stimulant properties were first strychnine and cocaine. recognized, leading to its widespread NH use by troops during the Second World 2 A traditionally, well-known agent to War. stimulate and to enhance concentration was ephedrine, a salt that was iso- Although it might seem counter-intui- lated from the plant Ephedra vulgaris tive, psychostimulants have proved to in 1885 by the Japanese chemist Na- be particularly effective in the manage- gayoshi Nagai. Similar in structure to ment of ADHD and a panel of drugs the synthetic derivatives amphetamine has been researched and used to treat and methamphetamine, ephedrine is ADHD, particularly amphetamine and still used in kampo, the traditional Chi- methylphenidate. nese herbal medicine practiced in Ja- pan, and is still very popular in China While other medications are pre- O O as ma-huang. Nagai later synthesized scribed to manage symptoms of the methamphetamine from ephedrine, disorder as well as co-existing symp- and his compatriot Akira Ogata (1887– toms of mood disorder or anxiety, a H 1978) succeeded in crystallizing it in non-stimulant substance used to treat N 1919. ADHD is atomoxetine.

By Paul Foley, Sydney, Australia. From Japan

agayoshi Nagai (1845–1929) was Nborn in Tokushima, Japan, the son of a doctor, and commenced studying medicine at the Dutch Medical School of Nagasaki in 1864. He continued his studies in Tokyo and Berlin, and studied chemistry in the laboratory of A.W. Hofmann (1819–1892). He lived in Ber- lin from 1871–1886, and was married to Therese Schumacher who spent the rest of her life with him in Japan.

Nagai isolated ephedrine from the plant Ephedra vulgaris in 1885 and recognized it to be the active compo- nent of the plant. Later, he synthesized methamphetamine from ephedrine. Nagai was a staunch supporter of scientific and cultural exchange between Germany and Japan, and the first pres- Nagayoshi Nagai in 1917. From Lepenies and Chiaki, 2000. ident of the Pharmaceutical Society of Japan.

Formula of ephedrine, drawn by Nagayoshi Nagai. From Lepenies and Chiaki, 2000. School performance

ne year after the opening of the 30 children with behaviour problems OEmma Pendleton Bradley Home, showed a spectacular change in be- the grandnephew of George Bradley, haviour and improved school perfor- Charles Bradley (1902–1979), joined mance during one week of treatment the staff and soon became medical with benzedrine. director. Bradley treated children with post-pneumoencephalography head- Bradley’s observations were important aches (supposedly due to spinal fluid discoveries, and follow-up studies es- loss) with benzedrine that he received tablished the benefit of psychostimu- from Smith, Kline and French Laborato- lants in the treatment of ADHD. Well ries in Philadelphia. He presumed that aware that most of the psychological a stimulant drug would stimulate the afflictions of children had no effective choroid plexus to produce spinal fluid. treatment, Bradley felt that more peo- While the drug did not do much for the ple needed to be educated and trained headaches, teachers noted that some in child psychiatry, and moved in 1948 of these children performed markedly to the University of Oregon Medical better at school, obviously due to the School to found and direct a depart- benefical effects of benzedrine. Brad- ment of child psychiatry. ley pursued this serendipitous discovery in a controlled trial and reported in his landmark article of 1937 that 14 of

„Possibly the most striking change in behaviour during the week of benzedrine therapy occurred in the school activities of many of these patients […] …a great increase of interest in school material was noted immediately. There appeared a definite “drive” to accomplish as much as possible during the school period, and often to spend extra time completing additional work […] The improvement was noted in all school subjects. It appeared promptly the first day benzedrine was given and disappeared on the first day it was discontinued.“

Charles Bradley, 1937, p. 578.

Photo of Charles Bradley courtesy of Emma Pendleton Bradley Hospital, East Providence, Rhode Island, USA. Benzedrine

enzedrine is the trade name of the Bracemic mixture of amphetamine (dl-amphetamine) and was marketed under this brand name in the United States in the form of inhalers. Benze- drine was used to enlarge nasal and Dub and Lurie describe the effect of benzedrine on bronchial passages and is closely relat- 48 depressed female patients in 1939. ed to other stimulants, such as Dexe- drine (d-amphetamine) and methamphetamine. Benzedrine was initially employed for medical purposes, but early users soon discovered its eu- Bradley's landmark article of 1937. phoric stimulant effect, making it one of the earliest synthetic stimulants for recreational purposes and brain dop- ing. In the 1940s and 1950s, reports began to emerge about the abuse of One of the many follow-up studies, inhalers, and the FDA finally listed it as Bradley and Bowen, 1940. a restricted drug in the United States.

Molitch and Sullivan report on the beneficial effects of benzedrine on children taking the “New Stanford Achievement Test” in 1937.

Ephedra vulgaris. © Otto Wilhelm Thomé (1885). Flora von Deutschland, Österreich und der Schweiz, Gera, Germany. GNU Free Document License. The Italian

orn in Italy in 1907, Leandro Paniz- Bzon grew up in Milan and studied chemistry at the University of Basel. Having completed his dissertation and postdoctoral study in Birmingham, Panizzon was hired by the Swiss pharmaceutical company CIBA, where he was in charge of researching nitroge- nous organic compounds, particularly derivatives of pyridine. One of his early successes was the discovery (together Building 122 of CIBA Pharmaceuticals in Basel in with Marx Hartmann) of a diuretic in 1952, where Panizzon’s laboratory was located. the 1930s, later marketed under the brand name Esidron. His masterpiece, however, was the synthesis of methylphenidate in 1944. While he was not overly impressed by the results of a self-experiment, the enthusiasm of his wife Marguerite, nicknamed Rita, was Panizzon’s famous article in the Helvetica Chimica Acta. greater, and she enjoyed the stimu- lating effects of the substance before playing tennis. Pannizon thus named the substance Ritaline, also its brand name when CIBA introduced it in Ger- many and Switzerland in 1954 pro- moting the drug as a psychotonicum to relieve chronic fatigue and mild de- pressions. A box of Ritaline for the Turkish market.

Leandro Panizzon at work in 1937. All photos courtesy of Firmenarchiv Novartis AG, Basel, Switzerland. Part IV From etiology to understanding and management of ADHD A family affair

he clustering of ADHD in certain studies showing a heritability that ex- Environmental family risks associated ADHD is thus a disorder influenced by Tfamilies is a well known phenom- plains on average about 80% of the with ADHD include unspecific pre- and a complex interaction of genetic, non- enon early described in the scientific phenotypic variance in the popula- perinatal disorders, exposure to alco- genetic-organic, and environmental literature. It has been discussed with tion (such as papers by the groups of hol and smoking during pregnancy, etiological factors. There exists a be- regard to predisposing psychosocial Biederman, Faraone, Thapar and oth- and psychosocial adversities such as havioural disposition of the individual, family risk factors, genetic influenc- ers). Molecular genetic studies indicate severe deprivation in early childhood. but it is almost always a family issue, es as well as gene-environment and the multifocal genetic influence of a Studies of family interaction and fam- too. gene-gene interactions. remarkable number of different gene ily life quality indicate a long lasting loci distributed on different chromo- irritating influence on this behavioural "Genetic influences are known to be strong. Genes play a significant role as etio- somes. Further genetic investigations disorder. Morrison and Stewart (1971) Nevertheless, naïve reductionism is unlikely to logical factors of ADHD, and Kramer reinforce the hypothesis that abnor- were the first authors who presented be enough for understanding. What is inherited and Pollnow already mentioned a case malities in the neurotransmitter sys- empirical results with regard to the appears to be a set of traits rather than an illness, of monozygotic twins with the core tem are a crucial predisposing factor, high prevalence of increased alcohol and a set of dispositions to react to the environ- symptoms of ADHD in their seminal e.g. that there is an association with abuse, antisocial behaviour and hyste- mental associations of ADHD.“ article. Initial family studies were later multiple transporter genes. ria in parents of children with ADHD. Eric Taylor, 2011. supplemented by adoption and twin Their results were confirmed one year later by Dennis Cantwell in a cohort ADHD of similar size. Lon- subclinical symptoms gitudinal studies no ADHD which showed not known that ADHD may persist into adulthood commenced in the late 1960s with the paper by Men- kens et al. (1967) and the studies by Mendelson (1971) and Stew- Multigenerational family with high density of ADHD. art (1973). Contributed by the Clinical Research Program CRU 125, University of Würzburg, Germany. Picture contributed by the Struwwelpeter-Museum, Frankfurt, Germany. Neurotransmitters

eurotransmitters are the chemical mediate product in the synthesis of the ing involved in systems required for ciated with aggression and suicidal be- Nmessengers which convey mes- other two catecholamine transmitters, controlling impulsivity and risk avoid- haviour in humans. The exact nature of sages between nerve cells in the brain. adrenaline and noradrenaline, it is now ance, particularly in forebrain systems; this role remains, however, to be eluci- A perhaps surprisingly small panel of recognized that dopamine is essen- indeed, there is some evidence that dated; one of the major problems for chemicals have been selected by evo- tially involved in a variety of functions, the dopaminergic agents employed in investigators is the existence of at least lution to execute the complex func- including the control and modulation ADHD achieve their effect by down- 14 serotonin receptor subtypes, some tions of the central nervous system, of emotivity and reactivity, concentra- stream effects on noradrenergic trans- of which are modulated by catechola- with differences in the distribution of tion, reasoning, and the co-ordination mission. Atomoxetine, an inhibitor of mine transmitters. There are currently different receptor types and the re- of motor function. An abnormally low noradrenaline re-uptake, is currently no ADHD medications which target sponses they induce inside the cells level of effective dopamine can cause employed in some countries in the serotonergic transmission. Impaired which carry them, and the different the three primary symptoms of ADHD: management of ADHD. glutamatergic transmission in the pre- topographical distribution of differ- inattention, impulsiveness, and hyper- frontal cortex has been linked with in- ent nervous pathways which allows activity. Mechanisms involved in the Serotonin has long been viewed as creased impulsivity in animal studies, the complexity of communication and metabolism of dopamine may cause being involved in inhibitory pathways but has not yet been investigated in response which characterizes the hu- this low level: reduced production, in- which reduce impulsive behaviour. Low humans. man brain. This limited panel of neuro- creased re-uptake by transporter mol- brain serotonin levels have been asso- By Paul Foley, Sydney, Australia. transmitters has both advantages and ecules or catabolism, reduced receptor disadvantages for the development response to released dopamine. The of agents to ameliorate the effects of fact that stimulants increase the levels brain disorders. The major disadvan- of dopamine and other neurotransmit- tage is that even if one identifies that ters (including epinephrine and sero- a chemical deficit, imbalance or other tonin) and help reduce ADHD symp- abnormal condition primarily involves toms suggests that complex interac- a particular transmitter system, it is tions between these neurotransmitters difficult to achieve the desired re-ad- underlie ADHD. justment by chemical means without affecting – perhaps in a negative fash- A disorder as complex as ADHD is, ion – other aspects of brain function. however, unlikely to be based upon the dysfunction of a single neural sys- The neurotransmitter most commonly tem and other transmitters may thus implicated in ADHD is dopamine. Once be involved. Noradrenaline has been considered nothing more than an inter- implicated in animal studies as be-

Arvid Carlsson. Nobel laureate in 2000 for his work on the transmitter dopamine. Source: Wikimedia Commons. © Vogler. Developmental comorbidity

n the majority of individuals affected “Developmental comorbidity” de- by symptoms of oppositional defiant 2013). As distinct trajectories of symp- I by ADHD, co-existing problems as scribes the concept of the age- and disorder, conduct disorder and, final- tom progression and comorbidity im- well as psychiatric and non-psychiatric development-dependent occurrence ly, depression (Ostrander et al. 2006, pact on therapy, long-term outcome comorbid disorders occur (Gillberg et of comorbid disorders, thereby dif- Loeber et al. 2009). Another possible and prognosis of ADHD (e.g. Connor al. 2004, Biederman et al. 2006). Co- ferentiating between distinct trajec- trajectory is the sequence of ADHD, et al. 2010), not only the manifestation morbidity often results in serious func- tories of symptom course (Taurines et tic disorder and obsessive compulsive of ADHD core symptoms, but also of tional and psychosocial problems in al. 2010). Concerning temporal order disorder (Freeman et al. 2007). How- developmental comorbidity should be everyday life. of manifestation, comorbid conditions ever, somatic comorbidity also has to accounted for in the diagnostic and may appear before the identification be mentioned in this context; in some therapeutic process. The expression “co-morbidity” in of definite ADHD symptoms - as ‘‘pre- patients, early atopic eczema precedes clinical epidemiological research was comorbidity’’. In this context, tempera- ADHD symptoms, with a modulatory By Regina Taurines, Würzburg, Germany. coined in the 1970s by Alvan Feinstein ment factors, sleep disturbance, autism role for sleep disruption (Schmitt et al. to denote “any additional co-existing spectrum disorders and atopic eczema ailment” in addition to index disease have been described. (Feinstein 1970). In the context of psychiatric literature, the term “comorbid- Comorbidity may coincide with the 31% 40% ity” was applied for the first time in emergence of clinically significant No comorbid disorder Oppositional-defiant the mid 1980s (e.g. Barlow et al. 1986, ADHD symptoms, as ‘‘simultaneous disorder McGlashan 1987, Sanderson et al. comorbidity’’ (e.g. developmental dys- 1990). Biederman and colleagues re- lexia, enuresis, encopresis). However, 11% viewed the topic of ADHD and associ- most comorbid disorders are mani- Tic disorder ated disorders in 1991, using the term fested after the onset of ADHD in the 38% “comorbidity” (Biederman et al. 1991). course of disease, including anxiety Affective and Aims of research on comorbidity were disorders, tic disorder, depression and 14% anxiety disorder to define more homogeneous sub- suicidality, obsessive compulsive dis- Conduct disorder groups of patients and to contribute order, conduct and substance use dis- to an aetiology-based classification orders, bipolar disorder, obesity and system. Different theoretical models personality disorders (‘‘post-comor- evolved to explain possible causal links bidity’’). A typical example of distinct between ADHD and comorbid condi- symptom progression is the initial ap- Baseline characteristics regarding comorbidity in ADHD. tions (e.g. Rhee et al. 2008). pearance of ADHD symptoms, followed Data according to the MTA Cooperative Group Study, 1999 (n=579). Baseline characteristics regarding comorbidity ADHD in the MTA Cooperative Group Study of 1999 (n=579). Images of the brain

ue to its sensivity to brain me- vations came from Hans Lou and his ured cerebral glucose metabolism in a Dtabolism, local or generalized group, who studied three-dimensional group of 25 hyperactive adults and 50 blood flow, brain lesions and chemical regional cerebral blood flow (rCBF) in control subjects and found a signifi- agents, electroencephalography (EEG) children with dysphasia and/or atten- cant decrease of metabolic activity in has been used to analyse behaviour tion deficit disorder by applying Xenon frontal and striatal regions. disorders throughout the 20th cen- 133 inhalation, a technique pioneered tury. One of the first relevant contri- in Scandinavia in the 1960s. In all elev- Also at the beginning of the 1990s, butions was a study by the EEG pio- en patients with attention deficits in researchers deployed magnetic reso- neer Herbert H. Jasper (together with the 1984 study, Lou found hypoperfu- nance imaging (MRI), together with Philip Solomon and Charles Bradley) in sion in the white matter of the frontal its related procedure functional MRI 1938 that showed distinctly abnormal lobes, and also hyperperfusion in the (fMRI) a widely used technique based electroencephalograms in the major- caudate region in seven. In a similar on the work of Raymond Damadian, Exemplary iodine-123-beta-CIT SPECT-imaging measuring striatal dopamine transporter density (yel- ity of a group of 71 behaviour prob- study in 1989, Lou and colleagues re- Paul Lauterbur and Peter Mansfield in low: highest density, black: lowest density). Unpub- lem children from the Emma Pendleton fined their selection of patients and the 1970s. The first studies were per- lished data (Romanos et al., in preparation). Bradley Home. Further EEG studies (e.g. confirmed their previous results. Ad- formed by Hynd and colleagues and evoked potentials, brain mapping) also ditionally, they observed that striatal aimed to observe deviations in pat- cerebellar regions may be due to a de- shed light on the effects of psycho- dysfunctions can be partly reversed terns of brain asymmetry. lay in structural brain maturation and stimulants and revealed that the EEG with methylphenidate, evidence that that widespread neural deficits in mul- of ADHD patients is characterized by low striatal activity is involved in ADHD. Since these initial efforts, various stud- tiple interconnected systems of the increased slow and decreased fast ac- ies have produced seminal results for brain are present. More research, how- tivity (Barry et al. 2003). Another interesting contribution was a the understanding of ADHD by sug- ever, is necessary to find out if non- study by Zametkin et al. in 1990. Using gesting that frontostriatal dysfunc- frontostriatal regions are affected, too, Along with such new insights, the positron emission tomography (PET), tion is central to pathophysiology, that what their contribution to the disorder 1980s saw the deployment of other pioneered in the 1960s by David Kuhl abnormalities of frontostriatal circuits, may be and if brain stimulation tech- imaging techniques. Important obser- and Roy Edwards, the authors meas- modulated by dopamine, exist, that niques may serve as additional non- structural abnormalities observed in pharmacological treatment options for children in frontal, striatal, parietal and ADHD patients. SPM analysis showing a significant decrease of gray matter volume in both occipital lobes. Sagittal, axial and coronar view. Images courtesy of L.T. van Elst, Freiburg, Germany. Are drugs enough?

iven its sedative effects, potas- la Chess in the 1960s and of Virginia Gsium bromide was among the first Douglas („Are drugs enough?“) in the medications used to alleviate the bur- 1970s. Further support came from Su- den of ADHD like symptoms. With the san Campell, a colleague of Douglas seminal experiments of Charles Brad- at Montreal´s McGill University, and ley, amphetamine sulfates were intro- interesting contributions regarding duced as treatment options, as were classroom environment were provid- later more refined psychostimulants. ed by Teodoro Ayllon and his group. Additionally, several other agents have been tested in adult studies, among Their suggestions included parent them bupropion, clonidine, guanfa- counselling and guidance, special re- "Treatment of the hyperactive child utilizes […] guidance of parents, direct psychotherapy, medication, cine, modafinil, pargyline, MAO-B-in- quirements for educational staff and and auxiliary technics such as remedial reading and tutoring.“ hibitors and l-deprenyl (selegiline). classroom management, cognitive training programs for children to im- Stella Chess, 1960, p. 2382. As controversy remains about the prove cognitive tasks, social perfor- use of psychostimulants in children, mance and disruptive behaviour, and other valid treatment options include psychotherapy. They stressed self- "In 22 cases, or in more than 60 per cent of the physiologically hyperactive children in the study, it was therapies and measures directed to evaluation and self-control of affected possible to work successfully with the parents on a consultative basis without direct work with the chil- improve behaviour, social skills and children, and looked to behavioural dren and without the use of drugs.“ environmental aspects. Such com- alternatives to control hyperactivity, Stella Chess, 1960, p. 2383. prehensive approaches have been an approach more valid than ever for advocated throughout the history of those interested in long term solutions therapeutic options and ultimately for treating children with ADHD. "The use of pharmacological agents, such as amphetamine sulfate, offers a supplementary and relatively gained ground with the works of Stel- untried approach to the treatment of children´s psychiatric problems. This approach in no sense replaces that of modifying a child’s surroundings and so removing the sources of conflict. Neither can it offer the same assurance of mental health as do forms of psychotherapy which enable a child to work out his emotional problems, or which train him to deal with future difficulties. However, distressing surroundings cannot always be altered, and lack of facilities frequently make effective psychotherapy impossible. In such situations the simple administration of a drug that produces an improved social adjustment or accelerated school progress may offer considerable assistance to some children.“

Bradley and Bowen (1941) on the use of pharmacological agents. A lifespan issue

hen Time magazine headlined ing decades along with research on Won July 18, 1994, that "not just neuroanatomy, comorbidity, genetics kids“ suffered from ADHD, there was and therapy. While the chances of full already strong agreement that ADHD regression of ADHD symptoms dur- "Environmental contributions have been rather under-researched and under-emphasised affects adults as well as children. The ing early adulthood are not great, an until recently; and I would argue that social and cultural influences have yet to be given hypothesis of a lifespan disorder was interesting social aspect seems to be their full importance. There are probably strong cultural influences, not on the neurobio- tested in various studies from the late life quality of all affected age groups logical variation, but on the extent to which it leads to impairment or to disability – and 1960s on, when Miriam Menkes and as well as only indirectly affected her group presented data of a 25-year healthy parents. As recent longitudinal especially to diagnosis. The differences between cultures in recognition and acceptance are follow up study on hyperkinetic chil- comparisons between patients with not just trivial nuisances in ascertaining a “true” prevalence rate. They emphasise that the dren. Of 18 fully re-examined patients, simple disorders of activity and atten- extent of impairment is a function not only of the children but of the context in which they "hyperactivity was still present in three tion and patients with a hyperkinetic are growing up. I suggest that public and professional attitudes can be helped by learning subjects aged 22 to 23 years and had conduct disorder by Remschmidt and from history the interplay between scientific understanding and social change.“ disappeared between the ages of 8 Mattejat (2010) have shown, the latter and 21 in the others.“ Further longitu- group underperformed in life quality Eric Taylor, 2011. dinal studies in the following two dec- improvements, and their parents suf- ades (e.g. Mendelson and colleagues; fered more. Weiss and colleagues; Gittelmann and colleagues) showed that symptoms in- It may thus be a worthwhile future deed persisted into adulthood, a diag- endeavor to focus greater attention nosis also supported by studies on the on life quality issues, on the effect of efficacy of psychostimulants in adults ADHD on daily life and work environ- (Wood and colleagues 1976 and stud- ment, and to transfer knowledge to ies by Paul Wender). geographic areas where social aware- ness is not yet as high as in countries As one of today´s burgeoning areas of with a strong historical background in inquiry, research on ADHD in adults ADHD research. will surely have its place in the upcom- References

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