Is Attention-Deficit/Hyperactivity Disorder a Risk Syndrome for Parkinson's Disease?

ABSTRACT: Recent epidemiological evidence indicates that diagnosis of attention-deficit/hyperactivity disorder (ADHD) is associated with increased risk for diseases of the basal ganglia and cerebellum, including Parkinson's disease (PD). The evidence reviewed here indicates that deficits in striatal dopamine are a shared component of the causal chains that produce these disorders. Neuropsychological studies of adult ADHD, prodromal PD, and early-stage PD reveal similar deficits in executive functions, memory, attention, and inhibition that are mediated by similar neural substrates. These and other findings are consistent with the possibility that ADHD may be part of the PD prodrome. The mechanisms that may mediate the association between PD and ADHD include neurotoxic effects of stimulants, other environmental exposures, and Lewy pathology. Understanding the nature of the association between PD and ADHD may provide insight into the etiology and pathogenesis of both disorders. The possible contribution of stimulants to this association may have important clinical and public health implications.

Deinstitutionalization of American public hospitals for the mentally ill before and after the introduction of antipsychotic medications.

Deinstitutionalization following the introduction of antipsychotic medications in 1954 has received much attention as a major narrative in psychiatry. Little attention has been given, however, to deinstitutionalization before 1954. Using United States census data on discharge and readmission rates of US mental hospitals from 1935 to 1964, this article analyzes deinstitutionalization using an interrupted time-series model, with particular attention to the statistical significance of trends before and after the advent of antipsychotics. Discharge rates significantly increased in the period before antipsychotics, indicating that deinstitutionalization began before 1954, although readmissions during that same period increased at the same rate as discharges. A reasonable inference is that patients discharged in the pre-antipsychotic period were unable to live independently outside the hospital. After 1954, both discharges and readmissions increased significantly, but due to a continuing increase in admissions, no significant decrease in mental hospital populations occurred during the seven-year period after 1954. The decline began in 1961 and coincided with changes in federal policy. The fate of mental patients discharged from hospitals during this second period of deinstitutionalization is examined. The central conclusions are (1) the overall reduction in the population of mental hospitals did not coincide with the 1954 introduction of antipsychotic medications, and (2) deinstitutionalization before and after drugs has been met with inadequate community-based care.

The chlorpromazine enigma.

Two revolutionary drugs were introduced into psychiatry in the early 1950s for the treatment of agitated mental patients - reserpine and chlorpromazine. These drugs initiated the modern era of drug treatment for schizophrenia and other psychoses. Early research revealed that, although the pharmacological profiles of the two drugs overlapped considerably, they had different mechanisms of action. The mechanism of action of reserpine was determined first: it depletes monoamines from the brain and other tissues. By contrast, chlorpromazine has little or no effect on brain monoamine concentrations. The mystery created by two drugs that have similar pharmacological profiles but different mechanisms of action is the chlorpromazine enigma. For about eight years after the mechanism of action of reserpine was determined, researchers followed several false leads about the mechanism of action of chlorpromazine. Then, in 1963, Arvid Carlsson and Margit Lindqvist proposed that chlorpromazine (and haloperidol) work by blocking "monoaminergic" receptors. It was quickly determined that dopamine receptor blockade was the most important action. Although the idea of chemical communication between central neurons had yet to gain wide acceptance, this idea was central to resolving the chlorpromazine enigma.

Prevalence and incidence of severe mental illness in the United States: an historical overview.

The nineteenth century witnessed growing alarm among professionals and the public in the United States and Europe that the number of people in mental hospitals was rapidly rising. Whether this growth was caused by an increase in the incidence or prevalence of mental illness or by other factors has been debated for over 150 years. Those who believe that mental illness did increase attribute the change mainly to a rise in alcoholism, functional psychoses, syphilis, and disorders related to senescence. The hypothesis that functional psychoses increased has generated the most debate and is the focus of the present article. Those who believe that mental illness did not increase attribute the growth in mental hospital populations to various other factors that influence hospitalization. This article presents an historical overview of this long and complex debate. It is a balanced presentation of the arguments for and against a rise in mental illness. Original data from U.S. censuses and national reporting of mental hospital statistics are incorporated.

The early history of the neuroscience of attention-deficit/hyperactivity disorder.

Research on the neurobiology and pharmacotherapy of attention-deficit/hyperactivity disorder (ADHD) has grown exponentially since 1980. A reasonable question is whether this research has improved our understanding and treatment of ADHD. This article describes relevant developments that took place roughly between 1900 and 1970. During this time, the efficacy of stimulant therapy for the disorder was established and the symptoms of ADHD were linked to many possible nervous system disorders including in the brain-stem, reticular formation, diencephalon, basal ganglia, frontal lobes, and cortex. In 1970, the catecholamine hypothesis of ADHD was proposed. It is concluded that early theories about the neurobiologic basis of ADHD anticipated core ideas of modern theory.

The role of serendipity in the discovery of the clinical effects of psychotropic drugs: beyond of the myth.

The serendipity is the faculty for making a discovery through a combination of accident and sagacity. In psychopharmacology, the serendipity played a key role in the discovery of many psychotropic drugs, although there are marked disputes in this regard, possibly due to semantic differences in relation to the meaning of this term. We have implemented an operational definition of serendipity based on the discovery of something unexpected or not sought intentionally, irrespective of the systematic process leading to the accidental observation. The present paper analyses some representative examples of discoveries in the field of psychopharmacology according to different serendipitous intervention patterns. Following this approach there would be four different imputability patterns: pure serendipitous discoveries (valproic acid/valproate); serendipitous observation leading to a non-serendipitous discoveries (imipramine); non-serendipitous discoveries secondarily associated with serendipitous observation (barbiturates); non-serendipitous discoveries (haloperidol). We can conclude that pure serendipitous discoveries in this field are not very frequent, most common being a mixed pattern; an initial serendipitous observation which leads to a non-serendipitous discovery of clinical utility. This is the case of imipramine, lithium salts, chlorpromazine or meprobamate.

El papel de la serendipia en el descubrimiento de los efectos clínicos de los psicofármacos: más allá del mito / The role of serendipity in the discovery of the clinical effects of psychotropic drugs: beyond of the myth

La serendipia es la facultad de realizar un descubrimiento mediante una combinación de accidente y sagacidad. En el ámbito de la psicofarmacología, la serendipia jugó un papel fundamental en el descubrimiento de muchos agentes psicotrópicos, aunque existen marcadas controversias en este particular, posiblemente debido a divergencias semánticas en relación al significado de este término. Nosotros hemos aplicado una definición operativa de serendipia basada en el hallazgo de algo no esperado o no buscado intencionalmente, independientemente del proceso sistemático que condujo a la observación accidental. En el presente trabajo, se analizan algunos ejemplos representativos de descubrimientos en el campo de la psicofarmacología según diferentes patrones de intervención serendípica. De acuerdo con este criterio existirían cuatro patrones diferentes de imputabilidad serendípica: descubrimientos serendípicos puros(ácido valproico/valproato); descubrimientos serendípicos iniciales que conducen a descubrimientos no serendípicos (imipramina); descubrimientos no serendípicos asociados secundariamente a descubrimientos de caracter serendípico(barbitúricos); descubrimientos no serendípicos (haloperidol). Podemos concluir que los descubrimientos serendípicos puros en este campo no son muy frecuentes, siendo más habitual un patrón mixto, que parte de una observación inicial serendípica que conduce a un descubrimiento no serendípico de utilidad clínica. Este es el caso de la imipramina, las sales de litio, la clorpromazina o el meprobamato (AU)

The serendipity is the faculty for making a discovery through a combination of accident and sagacity. In psychopharmacology, the serendipity played a key role in the discovery of many psychotropic drugs, although there are marked disputes in this regard, possibly due to semantic differences in relation to the meaning of this term. We have implemented an operational definition of serendipity based on the discovery of something un expected or not sought intentionally, irrespective of the systematic process leading to the accidental observation. The present paper analyses some representative examples of discoveries in the field of psychopharmacology according to different serendipitous intervention patterns. Following this approach there would be four different imputability patterns: pure serendipitous discoveries (valproic acid/valproate); serendipitous observation leading to a non-serendipitous discoveries (imipramine); non-serendipitous discoveries secondarily associated with serendipitous observation (barbiturates); non-serendipitous discoveries (haloperidol). We can conclude that pure serendipitous discoveries in this field are not very frequent, most common being a mixed pattern; an initial serendipitous observation which leads to a non-serendipitous discovery of clinical utility. This is the case of imipramine, lithium salts, chlorpromazine or meprobamate (AU)

Toward standardized usage of the word serendipity in the historiography of psychopharmacology.

Contradictory views are expressed in the literature about the role played by serendipity in discoveries that led to modern psychopharmacology. This article attempts to resolve these contradictions by providing an operational definition of serendipity. The utility of the proposed definition is explored in the context of 18 discoveries. The results show that the most common pattern in the development of early psychiatric medications is serendipitous observation leading to non-serendipitous demonstration of clinical utility. The analysis also reveals examples of relatively pure serendipitous and non-serendipitous discoveries. The proposed definition appears to be reliable and valid.

Effects of selective serotonin2 ligands on behaviors evoked by stress in the rat.

Serotonin (5-HT) has been implicated in the regulation of the stress response. Two experiments were conducted to investigate the possibility that the 5-HT(2A), 2C agonist DOI would reduce behavioral responsiveness to stress, and that selective blockade of one or both of these receptor subtypes would reverse this effect. Stressors employed were mild tail pinch and an illuminated open field. In Experiment 1 DOI (0.1, 0.5, 1.0 mg/kg, s.c.) was found to decrease stress-evoked oral behavior directed at food and to increase rearing behavior in a dose-dependent fashion. Neither of these effects was reversed by spiperone (5-HT(2A) antagonist) or SDZ SER-082 (5-HT(2C) antagonist). DOI also increased the frequency of head shaking. This effect was reversed by SDZ SER-082. In Experiment 2 DOI was injected singly or in combination with ketanserin (5-HT(2A). 2C antagonist). DOI decreased tail pinch-evoked oral behavior directed at food, the amount of food eaten, and increased vocalization. In the open field DOI decreased rearing, increased the number of head shakes, and increased the incidence of flat body posture. While ketanserin alone (0.5, 2.5, 5.0 mg/kg) had no effect on any behavioral measure, coadministration of ketanserin (5.0 mg/kg) with DOI (0.5 and 1.0 mg/kg) significantly blocked the effects of DOI on oral behavior directed at food, eating, rearing, head shaking, and flat body posture. It is concluded that the observed effects of DOI on behaviors evoked by stress were mediated by activation of both 5-HT(2A) and 5-HT(2C) receptors.

An evaluation of stimulant medication on the reinforcing effects of play.

Although a vast literature has indicated that stimulant medications are effective for reducing inappropriate behavior in children with attention deficit hyperactivity disorder (ADHD), the effects of stimulant medication on ancillary behaviors (e.g., play) have yet to be investigated with the same rigor. We used a reinforcer assessment procedure to evaluate the effects of medication on the play and social behavior of 5 preschool children who had been diagnosed with ADHD. Conditions included (a) social reinforcement (i.e., playing with friends), (b) alone play, and (c) quiet time (i.e., resting). Results indicated that 1 of the 5 participants selected fewer social reinforcers and more nonsocial reinforcers (alone play or quiet time) while on medication. The findings indicate that the reinforcer assessment procedure may be a viable way to evaluate medication effects on an ongoing basis and to inform treatment decisions.

Serendipity and the cerebral localization of pleasure.

Most accounts of the discovery of "pleasure" circuits in the brain begin with the observation by James Olds and Peter Milner in 1953 that electrical brain stimulation can condition operant responses in rats. Less well-known, pleasurable brain stimulation was previously observed in schizophrenic patients by Robert Heath. However, Heath failed to recognize the significance of this observation, at least in part, because of preconceived notions he held about the etiology of schizophrenia. This episode in the history of neuroscience illustrates the importance of sagacity in serendipitous scientific discoveries. It also shows that "mental preparedness" can be an obstacle to progress.

Continuity and discontinuity in the historical development of modern psychopharmacology.

In the middle of the twentieth century psychiatry underwent a transition that is often referred to as the "psychopharmacology revolution." Implicit in the term revolution is the idea that a paradigm shift occurred. Specifically, it has been argued that psychiatry abandoned the psychoanalytic paradigm in favor of a qualitatively distinct conceptual system based on brain chemistry. The validity of this view requires that psychoanalysis had the status of a paradigm. This paper presents evidence that psychoanalysis did not constitute a paradigm and that the advent of psychopharmacology was not, technically, a scientific revolution. Instead, the rise of modern psychopharmacology was the culmination of a linear growth of biological knowledge that began to develop in the nineteenth century.

The serotonin hypothesis of schizophrenia: a historical case study on the heuristic value of theory in clinical neuroscience.

Clinical examination of the reliability and coherence of the evidence concerning modern neurochemical theories of mental disorders has led some scholars to conclude that support for many of these theories is weak. Nevertheless, these theories continue to be widely promoted. One explanation that has been offered for continued adherence to questionable theory is that it stimulates and gives direction to research. The heuristic value of theory is examined in the present paper by tracing the discoveries that followed from an old theory of schizophrenia, which is--by current consensus--false. It is shown that the original serotonin hypothesis of schizophrenia did, in fact, lead to significant advances in neuropharmacology, neurology and psychiatry.

The myth of reserpine-induced depression: role in the historical development of the monoamine hypothesis.

For five decades it has been generally accepted that reserpine, an antihypertensive and antipsychotic drug, causes depression. The discovery that reserpine depletes brain monoamines was an important factor in the development of the monoamine hypothesis of depression, and it continues to be widely cited in support of this hypothesis. The present paper argues that, contrary to prevailing belief, reserpine is not depressogenic. The reason for perpetuation of this myth is reluctance to discard the monoamine hypothesis. This hypothesis ushered the modern biochemical paradigm into psychiatry and is still of great importance. It serves as a heuristic to guide research, it enhances psychiatry's prestige, and it helps to validate and promote drug therapy for depression and other mental disorders.

Historical development of the dopamine hypothesis of schizophrenia.

This review examines the history of discoveries that contributed to development of the dopamine hypothesis of schizophrenia. The origin of the hypothesis is traced to the recognition that neuroleptic drugs interfere with brain dopamine function. This insight was derived from two distinct lines of research. The first line originated from the discovery in 1956 that reserpine depletes brain serotonin. This finding resulted in a sequence of studies that led to the discovery that brain dopamine is involved in neuroleptic-induced extrapyramidal motor disturbances. The second line of research was aimed at determining the mechanism of action of psychomotor stimulants. This research produced evidence that stimulants directly or indirectly activate brain dopamine receptors. Because nonreserpine neuroleptics such as chlorpromazine block stimulant-induced movement, these findings suggested that neuroleptics were dopamine antagonists. Most previous accounts of the development of the dopamine hypothesis of schizophrenia emphasize the first line of research and ignore the second.

Behavioral responses to stress following central and peripheral injection of the 5-HT(2) agonist DOI.

Evidence suggests that serotonin (5-HT) systems are involved in the regulation of an organism's response to stress. Experiments were conducted to evaluate the possibility that central (20, 100, or 200 microg icv), peripheral (0.1, 0.5, or 1.0 mg/kg sc), or combined central (200 microg) plus peripheral (0.1 mg/kg) injections of the selective 5-HT(2) agonist (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl (DOI) would alter behavioral responses to stress in rats. Animals were evaluated during tail pinch stress, in an open field, and on a rotarod task. Across the three modes of administration (icv, sc, icv+sc), DOI resulted in a dose-related decrease in five of seven classes of behaviors observed during tail pinch. This reduction was most pronounced following subcutaneous injections, but occurred following intracerebroventricular and combined subcutaneous and intracerebroventricular injections as well. An additive effect of combined intracerebroventricular and subcutaneous administration was suggested by the fact that doses which were ineffective when given singly by these two routes resulted in a reduction in stress-evoked behavior when given together. Reduced responding seemed not to be attributable to general motoric impairment as DOI did not affect locomotion, grooming, or rotarod performance. The results suggest that activation of 5-HT(2) receptors produces an anxiolytic effect in rats subjected to acute tail pinch stress.