Hypothalamic–pituitary–adrenal axis

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Schematic of the HPA axis (CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone).

 

Hypothalamus, pituitary gland and adrenal cortex.

The hypothalamic–pituitary–adrenal axis (HPA axis or HTPA axis) is a complex set of direct influences and feedback interactions among three components: the hypothalamus, the pituitary gland (a pea-shaped structure located below the thalamus), and the adrenal (also called "suprarenal") glands (small, conical organs on top of the kidneys).

These organs and their interactions constitute the HPA axis, a major neuroendocrine system that controls reactions to stress and regulates many body processes, including digestion, the immune system, mood and emotions, sexuality, and energy storage and expenditure. It is the common mechanism for interactions among glands, hormones, and parts of the midbrain that mediate the general adaptation syndrome (GAS). While steroid hormones are produced mainly in vertebrates, the physiological role of the HPA axis and corticosteroids in stress response is so fundamental that analogous systems can be found in invertebrates and monocellular organisms as well.

The HPA axis, HPG axis, HPT axis, and the hypothalamic–neurohypophyseal system are the four major neuroendocrine systems through which the hypothalamus and pituitary direct neuroendocrine function.

Anatomy

The key elements of the HPA axis are from the paraventricular nucleus of the hypothalamus, which contains neuroendocrine neurons that synthesize and secrete vasopressin and corticotropin-releasing hormone (CRH). These two peptides regulate:

• The anterior lobe of the pituitary gland. In particular, CRH and vasopressin stimulate the secretion of adrenocorticotropic hormone (ACTH), once known as corticotropin. ACTH in turn acts on:
• the adrenal cortex, which produces glucocorticoid hormones (mainly cortisol in humans) in response to stimulation by ACTH. Glucocorticoids in turn act back on the hypothalamus and pituitary (to suppress CRH and ACTH production) in a negative feedback cycle.

CRH and vasopressin are released from neurosecretory nerve terminals at the median eminence. CRH is transported to the anterior pituitary through the portal blood vessel system of the hypophyseal stalk and vasopressin is transported by axonal transport to the posterior pituitary gland. There, CRH and vasopressin act synergistically to stimulate the secretion of stored ACTH from corticotrope cells. ACTH is transported by the blood to the adrenal cortex of the adrenal gland, where it rapidly stimulates biosynthesis of corticosteroids such as cortisol from cholesterol. Cortisol is a major stress hormone and has effects on many tissues in the body, including the brain. In the brain, cortisol acts on two types of receptor – mineralocorticoid receptors and glucocorticoid receptors, and these are expressed by many different types of neurons. One important target of glucocorticoids is the hypothalamus, which is a major controlling centre of the HPA axis.

Vasopressin can be thought of as "water conservation hormone" and is also known as "antidiuretic hormone." It is released when the body is dehydrated and has potent water-conserving effects on the kidney. It is also a potent vasoconstrictor.

Important to the function of the HPA axis are some of the feedback loops:

• Cortisol produced in the adrenal cortex will negatively feedback to inhibit both the hypothalamus and the pituitary gland. This reduces the secretion of CRH and vasopressin, and also directly reduces the cleavage of proopiomelanocortin (POMC) into ACTH and β-endorphins.
• Epinephrine and norepinephrine (E/NE) are produced by the adrenal medulla through sympathetic stimulation and the local effects of cortisol (upregulation enzymes to make E/NE). E/NE will positively feedback to the pituitary and increase the breakdown of POMCs into ACTH and β-endorphins.

Function

Release of CRH from the hypothalamus is influenced by stress, physical activity, illness, by blood levels of cortisol and by the sleep/wake cycle (circadian rhythm). In healthy individuals, cortisol rises rapidly after wakening, reaching a peak within 30–45 minutes. It then gradually falls over the day, rising again in late afternoon. Cortisol levels then fall in late evening, reaching a trough during the middle of the night. This corresponds to the rest-activity cycle of the organism. An abnormally flattened circadian cortisol cycle has been linked with chronic fatigue syndrome, insomnia and burnout.

The HPA axis has a central role in regulating many homeostatic systems in the body, including the metabolic system, cardiovascular system, immune system, reproductive system and central nervous system. The HPA axis integrates physical and psychosocial influences in order to allow an organism to adapt effectively to its environment, use resources, and optimize survival.

Anatomical connections between brain areas such as the amygdala, hippocampus, prefrontal cortex and hypothalamus facilitate activation of the HPA axis. Sensory information arriving at the lateral aspect of the amygdala is processed and conveyed to the amygdala's central nucleus, which then projects out to several parts of the brain involved in responses to fear. At the hypothalamus, fear-signaling impulses activate both the sympathetic nervous system and the modulating systems of the HPA axis.

Increased production of cortisol during stress results in an increased availability of glucose in order to facilitate fighting or fleeing. As well as directly increasing glucose availability, cortisol also suppresses the highly demanding metabolic processes of the immune system, resulting in further availability of glucose.

Glucocorticoids have many important functions, including modulation of stress reactions, but in excess they can be damaging. Atrophy of the hippocampus in humans and animals exposed to severe stress is believed to be caused by prolonged exposure to high concentrations of glucocorticoids. Deficiencies of the hippocampus may reduce the memory resources available to help a body formulate appropriate reactions to stress.

Immune system

There is bi-directional communication and feedback between the HPA axis and immune system. A number of cytokines, such as IL-1, IL-6, IL-10 and TNF-alpha can activate the HPA axis, although IL-1 is the most potent. The HPA axis in turn modulates the immune response, with high levels of cortisol resulting in a suppression of immune and inflammatory reactions. This helps to protect the organism from a lethal overactivation of the immune system, and minimizes tissue damage from inflammation.

The CNS is in many ways "immune privileged," but it plays an important role in the immune system and is affected by it in turn. The CNS regulates the immune system through neuroendocrine pathways, such as the HPA axis. The HPA axis is responsible for modulating inflammatory responses that occur throughout the body.

During an immune response, proinflammatory cytokines (e.g. IL-1) are released into the peripheral circulation system and can pass through the blood brain barrier where they can interact with the brain and activate the HPA axis. Interactions between the proinflammatory cytokines and the brain can alter the metabolic activity of neurotransmitters and cause symptoms such as fatigue, depression, and mood changes. Deficiencies in the HPA axis may play a role in allergies and inflammatory/ autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis.

When the HPA axis is activated by stressors, such as an immune response, high levels of glucocorticoids are released into the body and suppress immune response by inhibiting the expression of proinflammatory cytokines (e.g. IL-1, TNF alpha, and IFN gamma) and increasing the levels of anti-inflammatory cytokines (e.g. IL-4, IL-10, and IL-13) in immune cells, such as monocytes and neutrophils.
  
The relationship between chronic stress and its concomitant activation of the HPA axis, and dysfunction of the immune system is unclear; studies have found both immunosuppression and hyperactivation of the immune response.

Stress

Schematic overview of the hypothalamic-pituary-adrenal (HPA) axis.Stress activates the HPA-axis and thereby enhances the secretion of glucocorticoids from the adrenals.

Stress and disease

The HPA axis is involved in the neurobiology of mood disorders and functional illnesses, including anxiety disorder, bipolar disorder, insomnia, posttraumatic stress disorder, borderline personality disorder, ADHD, major depressive disorder, burnout, chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, and alcoholism. Antidepressants, which are routinely prescribed for many of these illnesses, serve to regulate HPA axis function.

Experimental studies have investigated many different types of stress, and their effects on the HPA axis in many different circumstances. Stressors can be of many different types—in experimental studies in rats, a distinction is often made between "social stress" and "physical stress", but both types activate the HPA axis, though via different pathways. Several monoamine neurotransmitters are important in regulating the HPA axis, especially dopamine, serotonin and norepinephrine (noradrenaline). There is evidence that an increase in oxytocin, resulting for instance from positive social interactions, acts to suppress the HPA axis and thereby counteracts stress, promoting positive health effects such as wound healing.

The HPA axis is a feature of mammals and other vertebrates. For example, biologists studying stress in fish showed that social subordination leads to chronic stress, related to reduced aggressive interactions, to lack of control, and to the constant threat imposed by dominant fish. Serotonin (5HT) appeared to be the active neurotransmitter involved in mediating stress responses, and increases in serotonin are related to increased plasma α-MSH levels, which causes skin darkening (a social signal in salmonoid fish), activation of the HPA axis, and inhibition of aggression. Inclusion of the amino acid L-tryptophan, a precursor of 5HT, in the feed of rainbow trout made the trout less aggressive and less responsive to stress. However, the study mentions that plasma cortisol was not affected by dietary L-tryptophan. The drug LY354740 (also known as Eglumegad, an agonist of the metabotropic glutamate receptors 2 and 3) has been shown to interfere in the HPA axis, with chronic oral administration of this drug leading to markedly reduced baseline cortisol levels in bonnet macaques (Macaca radiata); acute infusion of LY354740 resulted in a marked diminution of yohimbine-induced stress response in those animals.

Studies on people show that the HPA axis is activated in different ways during chronic stress depending on the type of stressor, the person's response to the stressor and other factors. Stressors that are uncontrollable, threaten physical integrity, or involve trauma tend to have a high, flat diurnal profile of cortisol release (with lower-than-normal levels of cortisol in the morning and higher-than-normal levels in the evening) resulting in a high overall level of daily cortisol release. On the other hand, controllable stressors tend to produce higher-than-normal morning cortisol. Stress hormone release tends to decline gradually after a stressor occurs. In post-traumatic stress disorder there appears to be lower-than-normal cortisol release, and it is thought that a blunted hormonal response to stress may predispose a person to develop PTSD.

It is also known that HPA axis hormones are related to certain skin diseases and skin homeostasis. There is evidence shown that the HPA axis hormones can be linked to certain stress related skin diseases and skin tumors. This happens when HPA axis hormones become hyperactive in the brain.

Stress and development

Schematic overview of the hypothalamic-pituary-adrenal (HPA) axis. Stress activates the HPA-axis and thereby enhances the secretion of glucocorticoids from the adrenals.

Prenatal stress

There is evidence that prenatal stress can influence HPA regulation. In animal experiments, exposure to prenatal stress has been shown to cause a hyper-reactive HPA stress response. Rats that have been prenatally stressed have elevated basal levels and abnormal circadian rhythm of corticosterone as adults. Additionally, they require a longer time for their stress hormone levels to return to baseline following exposure to both acute and prolonged stressors. Prenatally stressed animals also show abnormally high blood glucose levels and have fewer glucocorticoid receptors in the hippocampus. In humans, prolonged maternal stress during gestation is associated with mild impairment of intellectual activity and language development in their children, and with behaviour disorders such as attention deficits, schizophrenia, anxiety and depression; self-reported maternal stress is associated with a higher irritability, emotional and attentional problems.

There is growing evidence that prenatal stress can affect HPA regulation in humans. Children who were stressed prenatally may show altered cortisol rhythms. For example, several studies have found an association between maternal depression during pregnancy and childhood cortisol levels. Prenatal stress has also been implicated in a tendency toward depression and short attention span in childhood. There is no clear indication that HPA dysregulation caused by prenatal stress can alter adult behavior.

Early life stress

The role of early life stress in programming the HPA Axis has been well-studied in animal models. Exposure to mild or moderate stressors early in life has been shown to enhance HPA regulation and promote a lifelong resilience to stress. In contrast, early-life exposure to extreme or prolonged stress can induce a hyper-reactive HPA Axis and may contribute to lifelong vulnerability to stress. In one widely replicated experiment, rats subjected to the moderate stress of frequent human handling during the first two weeks of life had reduced hormonal and behavioral HPA-mediated stress responses as adults, whereas rats subjected to the extreme stress of prolonged periods of maternal separation showed heightened physiological and behavioral stress responses as adults.

Several mechanisms have been proposed to explain these findings in rat models of early-life stress exposure. There may be a critical period during development during which the level of stress hormones in the bloodstream contribute to the permanent calibration of the HPA Axis. One experiment has shown that, even in the absence of any environmental stressors, early-life exposure to moderate levels of corticosterone was associated with stress resilience in adult rats, whereas exposure to high doses was associated with stress vulnerability.

Another possibility is that the effects of early-life stress on HPA functioning are mediated by maternal care. Frequent human handling of the rat pups may cause their mother to exhibit more nurturant behavior, such as licking and grooming. Nurturant maternal care, in turn, may enhance HPA functioning in at least two ways. First, maternal care is crucial in maintaining the normal stress hypo responsive period (SHRP), which in rodents, is the first two weeks of life during which the HPA axis is generally non-reactive to stress. Maintenance of the SHRP period may be critical for HPA development, and the extreme stress of maternal separation, which disrupts the SHRP, may lead to permanent HPA dysregulation. Another way that maternal care might influence HPA regulation is by causing epigenetic changes in the offspring. For example, increased maternal licking and grooming has been shown to alter expression of the glutocorticoid receptor gene implicated in adaptive stress response. At least one human study has identified maternal neural activity patterns in response to video stimuli of mother-infant separation as being associated with decreased glucocorticoid receptor gene methylation in the context of post-traumatic stress disorder stemming from early life stress. Yet clearly, more research is needed to determine if the results seen in cross-generational animal models can be extended to humans.

Though animal models allow for more control of experimental manipulation, the effects of early life stress on HPA axis function in humans has also been studied. One population that is often studied in this type of research is adult victims of childhood abuse. Adult victims of childhood abuse have exhibited increased ACTH concentrations in response to a psychosocial stress task compared to healthy controls and subjects with depression but not childhood abuse. In one study, adult victims of childhood abuse that are not depressed show increased ACTH response to both exogenous CRF and normal cortisol release. Adult victims of childhood abuse that are depressed show a blunted ACTH response to exoegenous CRH. A blunted ACTH response is common in depression, so the authors of this work posit that this pattern is likely to be due to the participant's depression and not their exposure to early life stress.

Heim and colleagues have proposed that early life stress, such as childhood abuse, can induce a sensitization of the HPA axis, resulting in particular heightened neuronal activity in response to stress-induced CRF release. With repeated exposure to stress, the sensitized HPA axis may continue to hypersecrete CRF from the hypothalamus. Over time, CRF receptors in the anterior pituitary will become down-regulated, producing depression and anxiety symptoms. This research in human subjects is consistent with the animal literature discussed above.

The HPA Axis was present in the earliest vertebrate species, and has remained highly conserved by strong positive selection due to its critical adaptive roles. The programming of the HPA axis is strongly influenced by the perinatal and early juvenile environment, or “early-life environment.”  Maternal stress and differential degrees of caregiving may constitute early life adversity, which has been shown to profoundly influence, if not permanently alter, the offspring's stress and emotional regulating systems. Widely studied in animal models (e.g. licking and grooming/LG in rat pups), the consistency of maternal care has been shown to have a powerful influence on the offspring's neurobiology, physiology, and behavior. Whereas maternal care improves cardiac response, sleep/wake rhythm, and growth hormone secretion in the neonate, it also suppresses HPA axis activity. In this manner, maternal care negatively regulates stress response in the neonate, thereby shaping his/her susceptibility to stress in later life. These programming effects are not deterministic, as the environment in which the individual develops can either match or mismatch with the former's “programmed” and genetically predisposed HPA axis reactivity. Although the primary mediators of the HPA axis are known, the exact mechanism by which its programming can be modulated during early life remains to be elucidated. Furthermore, evolutionary biologists contest the exact adaptive value of such programming, i.e. whether heightened HPA axis reactivity may confer greater evolutionary fitness.

Various hypotheses have been proposed, in attempts to explain why early life adversity can produce outcomes ranging from extreme vulnerability to resilience, in the face of later stress. Glucocorticoids produced by the HPA axis have been proposed to confer either a protective or harmful role, depending on an individual's genetic predispositions, programming effects of early-life environment, and match or mismatch with one's postnatal environment. The predictive adaptation hypothesis (1), the three-hit concept of vulnerability and resilience (2) and the maternal mediation hypothesis (3) attempt to elucidate how early life adversity can differentially predict vulnerability or resilience in the face of significant stress in later life. These hypotheses are not mutually exclusive but rather are highly interrelated and unique to the individual.

(1) The predictive adaptation hypothesis: this hypothesis is in direct contrast with the diathesis stress model, which posits that the accumulation of stressors across a lifespan can enhance the development of psychopathology once a threshold is crossed. Predictive adaptation asserts that early life experience induces epigenetic change; these changes predict or “set the stage” for adaptive responses that will be required in his/her environment. Thus, if a developing child (i.e., fetus to neonate) is exposed to ongoing maternal stress and low levels of maternal care (i.e., early life adversity), this will program his/her HPA axis to be more reactive to stress. This programming will have predicted, and potentially be adaptive in a highly stressful, precarious environment during childhood and later life. The predictability of these epigenetic changes is not definitive, however – depending primarily on the degree to which the individual's genetic and epigenetically modulated phenotype “matches” or “mismatches” with his/her environment.

(2) Three-Hit Concept of vulnerability and resilience: this hypothesis states that within a specific life context, vulnerability may be enhanced with chronic failure to cope with ongoing adversity. It fundamentally seeks to explicate why, under seemingly indistinguishable circumstances, one individual may cope resiliently with stress, whereas another may not only cope poorly, but consequently develop a stress-related mental illness. The three “hits” – chronological and synergistic – are as follows: genetic predisposition (which predispose higher/lower HPA axis reactivity), early-life environment (perinatal – i.e. maternal stress, and postnatal – i.e. maternal care), and later-life environment (which determines match/mismatch, as well as a window for neuroplastic changes in early programming). (Figure 1) The concept of match/mismatch is central to this evolutionary hypothesis. In this context, it elucidates why early life programming in the perinatal and postnatal period may have been evolutionarily selected for. Specifically, by instating specific patterns of HPA axis activation, the individual may be more well equipped to cope with adversity in a high-stress environment. Conversely, if an individual is exposed to significant early life adversity, heightened HPA axis reactivity may “mismatch” him/her in an environment characterized by low stress. The latter scenario may represent maladaptation due to early programming, genetic predisposition, and mismatch. This mismatch may then predict negative developmental outcomes such as psychopathologies in later life.

Ultimately, the conservation of the HPA axis has underscored its critical adaptive roles in vertebrates, so, too, various invertebrate species over time. The HPA Axis plays a clear role in the production of corticosteroids, which govern many facets of brain development and responses to ongoing environmental stress. With these findings, animal model research has served to identify what these roles are – with regards to animal development and evolutionary adaptation. In more precarious, primitive times, a heightened HPA axis may have served to protect organisms from predators and extreme environmental conditions, such as weather and natural disasters, by encouraging migration (i.e. fleeing), the mobilization of energy, learning (in the face of novel, dangerous stimuli) as well as increased appetite for biochemical energy storage. In contemporary society, the endurance of the HPA axis and early life programming will have important implications for counseling expecting and new mothers, as well as individuals who may have experienced significant early life adversity.

Attention deficit hyperactivity disorder controversies

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Methylphenidate (Ritalin) 10 mg Pill (Ciba/Novartis), a drug commonly prescribed to treat ADHD

Attention deficit hyperactivity disorder (ADHD) controversies include concerns about its existence, causes, perceived overdiagnosis, and methods of treatment, especially with the use of stimulant medications in children. These controversies have surrounded the subject since at least the 1970s.

Status as a disorder

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the leading authority in the US on clinical diagnosis and psychological behavior published by the APA in 2013, ADHD is a neurodevelopmental disorder with a prevalence rate in most cultures of about 5% in children and 2.5% in adults. Today, the existence of ADHD is widely accepted, but controversy around the disorder has existed since at least the 1970s. Adult ADHD continues to be a source of debate. According to the DSM-5, symptoms must be present before age 12, but it's not uncommon for ADHD to continue into adulthood. Parents and educators sometimes still question a perceived overdiagnosis in children and the effectiveness of treatment options, especially stimulant medications. However, according to sociology professor Vincent Parrillo, "Parent and consumer groups, such as CHADD (Children and Adults with Attention Deficit Hyperactivity Disorder), tend to support the medical perspective of ADHD."

In 2009, Dr. Leon Eisenberg, who had coined the term ADDD in the 1950s, said "ADHD is a prime example of a fictitious disease". Snopes, a popular fact checking website found this to be mostly true.

Causes

The pathophysiology of ADHD is unclear and there are a number of competing theories.

ADHD as a biological illness

Frequently observed differences in the brain between ADHD and non-ADHD patients have been discovered, but it is uncertain if or how these differences give rise to the symptoms of ADHD. Results from various types of neuroimaging techniques suggest there are differences in the brain, such as thinner regions of the cortex, between individuals with and without ADHD.

ADHD is said to be highly heritable: twin studies suggest that genetics explain 70-80% in the variation of ADHD. However, interest in the potential role of gene-environment interactions in ADHD is also increasing; maternal alcohol or tobacco use during pregnancy may be one contributor. It has also been argued that ADHD is a heterogeneous disorder with multiple genetic and environmental factors converging on similar neurological changes. Authors of a review of ADHD etiology in 2004 noted: "Although several genome-wide searches have identified chromosomal regions that are predicted to contain genes that contribute to ADHD susceptibility, to date no single gene with a major contribution to ADHD has been identified." However, many further studies have occurred since, and the same is true for many other heritable human traits (e.g., schizophrenia). The Online Mendelian Inheritance in Man (OMIM) database has a listing for ADHD under autosomal dominant heritable conditions, claiming that multiple genes contribute to the disorder. As of 2014, OMIM listed 6 genes with variants that have been associated with ADHD.

Social construct theory of ADHD

It has been argued that even if it is a social construct, this does not mean it is not a valid condition; for example obesity has different cultural constructs but yet has demonstrable adverse effects associated with it. A minority of these critics maintain that ADHD was "invented and not discovered". They believe that the disorder does not exist and that the behavior observed is not abnormal and can be better explained by environmental causes or just the personality of the "patient".

Diagnosis

Methods of diagnosis

There is no blood test or brain scan for ADHD. Diagnosis is based on a clinical interview with the child and parents.

Over the past two decades more research on the functioning of the brain is being done to help support the idea that Attention Deficit Hyperactivity Disorder is an executive dysfunction issue. The brains of males and females are showing differences, which could potentially help to explain why ADHD presents differently in boys and girls. Studies conducted using EEGs between boys and girls suggest that we can no longer ignore sex difference between boys and girls when identifying ADHD. There are EEG differences between girls and boys in their maturational pattern and this suggests that more studies regarding sex differences in ADHD should be conducted.

Over- and under-diagnosis

Overdiagnosis typically refers to children who are diagnosed with ADHD but should not be. These instances are termed as "false positives". However, the "presence of false positives alone does not indicate overdiagnosis". There may be evidence of overdiagnosis if inaccuracies are shown consistently in the accepted prevalence rates or in the diagnostic process itself. "For ADHD to be overdiagnosed, the rate of false positives (i.e., children inappropriately diagnosed with ADHD) must substantially exceed the number of false negatives (children with ADHD who are not identified or diagnosed)." Children aged 8 to 15 years living in the community, indicated an ADHD prevalence rate of 7.8%. However, only 48% of the ADHD sample had received any mental health care over the past 12 months.

Evidence also exists of possible differences of race and ethnicity in the prevalence of ADHD. The prevalence of ADHD dramatically varies across cultures despite the fact that the same methodology has been used. Some believe this may be due to different perceptions of what qualifies as disruptive behavior, inattention and hyperactivity.

It is argued that over-diagnosis occurs more in well-off or more homogeneous communities, whereas under-diagnosis occurs more frequently in poorer and minority communities due to lack of resources and lack of financial access. Those without health insurance are less likely to be diagnosed with ADHD. It is further believed that the "distribution of ADHD diagnosis falls along socioeconomic lines", according to the amount of wealth within a neighborhood. Therefore, the difficulty of applying national, general guidelines to localized and specific contexts, such as where referral is unavailable, resources are lacking or the patient is uninsured, may assist in the establishment of a misdiagnosis of ADHD.

Development can also influence perception of relevant ADHD symptoms. ADHD is viewed as a chronic disorder that develops in childhood and continues into adulthood. However, some research shows a decline in the symptoms of ADHD as children grow up and mature into adulthood. As children move into the stage of adolescence, the most common reporters of ADHD symptoms, parents and teachers, tend to focus on behaviors affecting academic performance. Some research has shown that the primary symptoms of ADHD were strong discriminators in parent ratings, but differed for specific age groups. Hyperactivity was a stronger discriminator of ADHD in children, while inattentiveness was a stronger discriminator in adolescents.

Issues with comorbidity is another possible explanation in favor of the argument of overdiagnosis. As many as 75% of diagnosed children with ADHD meet criteria for some other psychiatric diagnosis. Among children diagnosed with ADHD, about 25% to 30% have anxiety disorders, 9% to 32% have depression, 45% to 84% have oppositional defiant disorder, and 44% to 55% of adolescents have conduct disorder. Learning disorders are found in 20% to 40% of children with ADHD.

Another possible explanation of over-diagnosis of ADHD is the "relative-age effect", which applies to children of both sexes. Younger children are more likely to be inappropriately diagnosed with ADHD and treated with prescription medication than their older peers in the same grade. Children who are almost a year younger tend to appear more immature than their classmates, which influences both their academic and athletic performance.

The debate of underdiagnosis, or giving a "false negative", has also been discussed, specifically in literature concerning ADHD among adults, girls and underprivileged communities. It is estimated that in the adult population, rates of ADHD are somewhere between 4% and 6%. However, as little as 11% of these adults with ADHD actually receive assessment, and furthermore, any form of treatment. Between 30% and 70% of children with ADHD report at least one impairing symptom of ADHD in adulthood, and 30% to 50% still meet diagnostic criteria for an ADHD diagnosis.

Research on gender differences also reveals an argument for underdiagnosis of ADHD among girls. The ratio for male-to-female is 4:1 with 92% of girls with ADHD receiving a primarily inattentive subtype diagnosis. This difference in gender can be explained, for the majority, by the different ways boys and girls express symptoms of this particular disorder. Typically, females with ADHD exhibit less disruptive behaviors and more internalizing behaviors. Girls tend to show fewer behavioral problems, show fewer aggressive behaviors, are less impulsive, and are less hyperactive than boys diagnosed with ADHD. These patterns of behavior are less likely to disrupt the classroom or home setting, therefore allowing parents and teachers to easily overlook or neglect the presence of a potential problem. The current diagnostic criteria appear to be more geared towards males than females, and the ADHD characteristics of men have been over-represented. This leaves many women and girls with ADHD neglected. Studies have shown that girls with ADHD, especially those with signs of impulsivity, were three to four times more likely to attempt suicide when compared with female controls. Additionally, these girls were two to three times more likely to engage in self-harming behaviors.

As stated previously, underdiagnosis is also believed to be seen in more underprivileged communities. These communities tend to be poorer and inhabit more minorities. More than 50% of children with mental health needs do not receive assessment or treatment. Access to mental health services and resources differs on a wide range of factors, such as "gender, age, race or ethnicity and health insurance". Therefore, children deserving of an ADHD diagnosis may never receive this confirmation and are not identified or represented in prevalence rates.

In 2005, 82 percent of teachers in the United States considered ADHD to be over diagnosed while three percent considered it to be under diagnosed. In China 19 percent of teachers considered ADHD to be over diagnosed while 57 percent considered it to be under diagnosed.

Treatment

ADHD management recommendations vary by country and usually involves some combination of counseling, lifestyle changes, and medications. The British guideline only recommends medications as a first-line treatment in children who have severe symptoms and for them to be considered in those with moderate symptoms who either refuse or fail to improve with counseling. Canadian and American guidelines recommend that medications and behavioral therapy be used together as a first-line therapy, except in preschool-aged children.

Stimulants

The National Institute of Mental Health recommends stimulants for the treatment of ADHD, and states that, "under medical supervision, stimulant medications are considered safe". A 2007 drug class review found no evidence of any differences in efficacy or side effects in the stimulants commonly prescribed.

Between 1993 and 2003 the worldwide use of medications that treat ADHD increased almost threefold. Most ADHD medications are prescribed in the United States. In the 1990s, the US accounted for 90% of global use of stimulants such as methylphenidate and dextroamphetamine. By the early 2000s, this had fallen to 80% due to increased usage in other countries.

 In 2003, doctors in the UK were prescribing about a 10th of the amount per capita of methylphenidate used in the US, while France and Italy accounted for approximately one twentieth of US stimulant consumption. These assertions appear to contradict the 2006 World Drug Report published by the United Nations Office on Drugs and Crime, which indicate the US constituted merely 17% of the world market for dextroamphetamine. They assert that in the early 2000s amphetamine use was "widespread in Europe."

In 1999, a study constructed with 1,285 children and their parents across four U.S. communities has shown 12.5% of children that met ADHD criteria had been treated with stimulants during the previous 12 months. In May 2000, the testimony of DEA Deputy Director Terrance Woodworth has shown that the Ritalin quota increased from 1,768 kg in 1990 to 14,957 kg in 2000. In addition, IMS Health also revealed the numerous use of Adderall prescription have increased from 1.3 million in 1996 to nearly 6 million in 1999.

Adverse effects

Some parents and professionals have raised questions about the side effects of drugs and their long-term use. Magnetic resonance imaging studies suggest that long-term treatment with amphetamine or methylphenidate decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function of the right caudate nucleus.

On February 9, 2006, the U.S. Food and Drug Administration voted to recommend a "black-box" warning describing the cardiovascular risks of stimulant drugs used to treat ADHD. Subsequently, the USFDA commissioned studies which found that, in children, young adults, and adults, there is no association between serious adverse cardiovascular events (sudden death, myocardial infarction, and stroke) and the medical use of amphetamine or other ADHD stimulants.

The effects of amphetamine and methylphenidate on gene regulation are both dose- and route-dependent. Most of the research on gene regulation and addiction is based upon animal studies with intravenous amphetamine administration at very high doses. The few studies that have used equivalent (weight-adjusted) human therapeutic doses and oral administration show that these changes, if they occur, are relatively minor. The long-term effects on the developing brain and on mental health disorders in later life of chronic use of methylphenidate is unknown. Despite this, between 0.51% to 1.23% of children between the ages of 2 and 6 years take stimulants in the US. Stimulant drugs are not approved for this age group.

In individuals who experience sub-normal height and weight gains during stimulant therapy, a rebound to normal levels is expected to occur if stimulant therapy is briefly interrupted. The average reduction in final adult height from continuous stimulant therapy over a 3 year period is 2 cm.

Effectiveness

Reviews of clinical stimulant research have established the safety and effectiveness of long-term amphetamine use for ADHD. An evidence review noted the findings of a randomized controlled trial of amphetamine treatment for ADHD in Swedish children following 9 months of amphetamine use. During treatment, the children experienced improvements in attention, disruptive behaviors, and hyperactivity, and an average change of +4.5 in IQ. It noted that the population in the study had a high rate of comorbid disorders associated with ADHD and suggested that other long-term amphetamine trials in people with less associated disorders could find greater functional improvements.

A 2008 review found that the use of stimulants improved teachers' and parents' ratings of behavior; however, it did not improve academic achievement. The same review also indicates growth retardation for children consistently medicated over three years, compared to unmedicated children in the study. Intensive treatment for 14 months has no effect on long-term outcomes 8 years later. No significant differences between the various drugs in terms of efficacy or side effects have been found.

School enforcement

Some schools have attempted to require treatment with medications before allowing a child to attend school. The United States has passed a bill against this practice.

Potential for misuse

Stimulants used to treat ADHD are classified as Schedule II controlled substances in the United States.

Controversy has surrounded whether methylphenidate is as commonly abused as other stimulants with many proposing that its rate of abuse is much lower than other stimulants. However, the majority of studies assessing its abuse potential scores have determined that it has an abuse potential similar to that of cocaine and d-amphetamine.

Both children with and without ADHD abuse stimulants, with ADHD individuals being at the highest risk of abusing or diverting their stimulant prescriptions. Between 16 and 29 percent of students who are prescribed stimulants report diverting their prescriptions. Between 5 and 9 percent of grade/primary and high school children and between 5 and 35 percent of college students have used nonprescribed stimulants. Most often their motivation is to concentrate, improve alertness, "get high," or to experiment.

Stimulant medications may be resold by patients as recreational drugs, and methylphenidate (Ritalin) is used as a study aid by some students without ADHD.

Non-medical prescription stimulant use is high. A 2003 study found that non prescription use within the last year by college students in the US was 4.1%. A 2008 meta analysis found even higher rates of non prescribed stimulant use. It found 5% to 9% of grade school and high school children and 5% to 35% of college students used a nonprescribed stimulant in the last year.

As of 2009, 8% of all United States Major League Baseball players had been diagnosed with ADHD, making the disorder common among this population. The increase coincided with the League's 2006 ban on stimulants, which has raised concern that some players are mimicking or falsifying the symptoms or history of ADHD to get around the ban on the use of stimulants in sport.

Conflicts of interest

In 2008 five pharmaceutical companies received warning from the FDA regarding false advertising and inappropriate professional slide decks related to ADHD medication. In September 2008 the FDA sent notices to Novartis Pharmaceuticals and Johnson & Johnson regarding advertisings of Focalin XR and Concerta in which they overstated products' efficacies. A similar warning was sent to Shire plc with respect to Adderall XR.

Russell Barkley, a well-known ADHD researcher who has published diagnostic guidelines, has been criticized for his works because he received payment from pharmaceutical companies for speaking and consultancy fees.

In 2008, it was revealed that Joseph Biederman of Harvard, a frequently cited ADHD expert, failed to report to Harvard that he had received $1.6 million from pharmaceutical companies between 2000 and 2007. E. Fuller Torrey, executive director of the Stanley Medical Research Institute which finances psychiatric studies, said "In the area of child psychiatry in particular, we know much less than we should, and we desperately need research that is not influenced by industry money."

Children and Adults with Attention-Deficit/Hyperactivity Disorder, CHADD, an ADHD advocacy group based in Landover, MD received a total of $1,169,000 in 2007 from pharmaceutical companies. These donations made up 26 percent of their budget.

Stigma

Russell Barkley believes labeling is a double-edged sword; there are many pitfalls to labeling but by using a precise label, services can be accessed. He also believes that labeling can help the individual understand and make an informed decision how best to deal with the diagnoses using evidence-based knowledge. Furthermore studies also show that the education of the siblings and parents has at least a short-term impact on the outcome of treatment. Barkley states this about ADHD rights: "... because of various legislation that has been passed to protect them. There are special education laws with the Americans with Disabilities Act, for example, mentioning ADHD as an eligible condition. If you change the label, and again refer to it as just some variation in normal temperament, these people will lose access to these services, and will lose these hard-won protections that keep them from being discriminated against. ..." Psychiatrist Harvey Parker, who founded CHADD, states, "we should be celebrating the fact that school districts across the country are beginning to understand and recognize kids with ADHD, and are finding ways of treating them. We should celebrate the fact that the general public doesn't look at ADHD kids as "bad" kids, as brats, but as kids who have a problem that they can overcome". However, children may be ridiculed at school by their peers for using psychiatric medications including those for ADHD.

Perspectives on ADHD

Medical perspectives outside of North America

In 2009, the British Psychological Society and the Royal College of Psychiatrists, in collaboration with the National Institute for Clinical Excellence (NICE), released a set of diagnosis and treatment guidelines for ADHD. These guidelines reviewed studies by Ford et al. that found that 3.6 percent of boys and 0.85 percent of girls in Britain qualified for a diagnosis of ADHD using the American DSM-IV criteria. The guidelines go on to state that the prevalence drops to 1.5% when using the stricter criteria for the ICD-10 diagnosis of hyperkinetic disorder used mainly in Europe.

A systematic review of the literature in 2007 found that the worldwide prevalence of ADHD was 5.29 percent, and that there were no significant differences in prevalence rates between North America and Europe. The review did find differences between prevalence rates in North America and those in Africa and the Middle East, but cautioned that this may be due to the small number of studies available from those regions.

Norwegian National Broadcasting (NRK) broadcast a short television series in early 2005 on the increase in the use of Ritalin and Concerta for children. Sales were six times higher in 2004 than in 2002. The series included the announcement of a successful group therapy program for 127 unmedicated children aged four to eight, some with ADHD and some with oppositional defiant disorder.

Politics and media

North America

The validity of the work of many of the ADHD experts (including Biederman) has been called into question by Marcia Angell, former editor in chief of the New England Journal of Medicine, in her book review, "Drug Companies & Doctors: A Story of Corruption." Newspaper columnists such as Benedict Carey, science and medical writer for The New York Times, have also written controversial articles on ADHD.

In 1998, the US National Institutes of Health (NIH) released a consensus statement on the diagnosis and treatment of ADHD. The statement, while recognizing that stimulant treatment is controversial, supports the validity of the ADHD diagnosis and the efficacy of stimulant treatment. It found controversy only in the lack of sufficient data on long-term use of medications and in the need for more research in many areas.

In 2014, a preliminary retrospective analysis on the effect of increased use of methylphenidate among children in Quebec due to a policy change found little evidence of positive effects and limited evidence of negative effects.

United Kingdom

The National Institute for Health and Care Excellence (NICE) concluded that while it is important to acknowledge the body of academic literature which raises controversies and criticisms surrounding ADHD for the purpose of developing clinical guidelines, it is not possible to offer alternative methods of assessment (i.e. ICD 10 and DSM IV) or therapeutic treatment recommendations. NICE stated that this is because the current therapeutic treatment interventions and methods of diagnosis for ADHD are based on the dominant view of the academic literature. NICE further concluded that despite such criticism, ADHD represented a valid clinical condition, with genetic, environmental, neurobiological, and demographic factors. The diagnosis has a high level of support from clinicians and medical authorities.

Baroness Susan Greenfield, a leading neuroscientist, wanted a wide-ranging inquiry in the House of Lords into the dramatic increase in the diagnosis of ADHD in the UK and its possible causes. This followed a BBC Panorama programme in 2007 which highlighted US research (The Multimodal Treatment Study of Children with ADHD by the University of Buffalo showing treatment results of 600) suggesting drugs are no better than therapy for ADHD in the long-term. In the UK medication use is increasing dramatically. Other notable individuals have made controversial statements about ADHD. Terence Kealey, a clinical biochemist and vice-chancellor of University of Buckingham, has stated his belief that ADHD medication is used to control unruly boys and girls behavior.

The British Psychological Society said in a 1997 report that physicians and psychiatrists should not follow the American example of applying medical labels to such a wide variety of attention-related disorders: "The idea that children who don't attend or who don't sit still in school have a mental disorder is not entertained by most British clinicians." The National Institute for Health and Care Excellence (NICE), in collaboration with others, release guidelines for the diagnosis and treatment of ADHD. They are currently devising an update for 2018.

Scientology

An article in the Los Angeles Times stated that "the uproar over Ritalin was triggered almost single-handedly by the Scientology movement." The Citizens Commission on Human Rights, an anti-psychiatry group formed by Scientologists in 1969, conducted a major campaign against Ritalin in the 1980s and lobbied Congress for an investigation of Ritalin. Scientology publications claimed the "real target of the campaign" as "the psychiatric profession itself" and said that the campaign "brought wide acceptance of the fact that (the commission) [sic] and the Scientologists are the ones effectively doing something about ... psychiatric drugging".

Tom Cruise has described the medications Ritalin (methylphenidate) and Adderall (a mixed-salt amphetamine formulation) as "street drugs". Ushma S. Neill criticized this view, stating that the doses of stimulants used in the treatment of ADHD do not cause addiction and that there is some evidence of a reduced risk of later substance addiction in children treated with stimulants.

Other

In the UK, Susan Greenfield spoke out publicly in 2007 in the House of Lords about the need for a wide-ranging inquiry into the dramatic increase in the diagnosis of ADHD, and possible causes. Her comments followed a BBC Panorama program that highlighted research that suggested medications are no better than other forms of therapy in the long term. In 2010, the BBC Trust criticized the 2007 Panorama program for summarizing the research as showing "no demonstrable improvement in children's behaviour after staying on ADHD medication for three years" when in actuality "the study found that medication did offer a significant improvement over time" although the long-term benefits of medication were found to be "no better than children who were treated with behavior therapy." In 2017, Senator Johnny Isakson was criticized by his constituents when he stated that ADD is not a learning disability but a "parental deficit disorder", and that it is a result of parents not "raising their kids like they should".

Methylphenidate

From Wikipedia, the free encyclopedia

Methylphenidate

Clinical data
Pronunciation	/ˌmɛθəlˈfɛnɪdeɪt, -ˈfiː-/
Trade names	Ritalin, Concerta, Aptensio, Biphentin, Daytrana, Equasym, Medikinet, Metadate, Methylin, QuilliChew, Quillivant, Tranquilyn
AHFS/Drugs.com	Monograph
MedlinePlus	a682188
License data	US FDA: Methylphenidate
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Dependence liability	Physical: None Psychological: Moderate
Addiction liability	Moderate
Routes of administration	By mouth, insufflation, intravenous, transdermal
ATC code	N06BA04 (WHO)
Legal status
Legal status	AU: S8 (Controlled) CA: Schedule III DE: Anlage III (Special prescription form required) UK: Class B US: Schedule II
Pharmacokinetic data
Bioavailability	~30% (range: 11–52%)
Protein binding	10–33%
Metabolism	Liver (80%) mostly CES1A1-mediated
Elimination half-life	2–3 hours
Excretion	Urine (90%)
Chemical and physical data
Formula	C14H19NO2
Molar mass	233.31 g/mol
Melting point	74 °C (165 °F)
Boiling point	136 °C (277 °F)

Methylphenidate, sold under various trade names, Ritalin being one of the most commonly known, is a central nervous system (CNS) stimulant of the phenethylamine and piperidine classes that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. The original patent was owned by CIBA, now Novartis Corporation. It was first licensed by the US Food and Drug Administration (FDA) in 1955 for treating what was then known as hyperactivity.

Medical use began in 1960; the drug has become increasingly prescribed since the 1990s, when the diagnosis of ADHD became more widely accepted. Between 2007 and 2012, methylphenidate prescriptions increased by 50% in the United Kingdom and in 2013 global methylphenidate consumption increased to 2.4 billion doses, a 66% increase from the year before. The United States continues to account for more than 80% of global consumption.

ADHD and other similar conditions are believed to be linked to sub-par performance of the dopamine and norepinephrine functions in the brain, primarily in the prefrontal cortex, responsible for executive function (e.g., reasoning, inhibiting behaviors, organizing, problem solving, planning, etc.). Methylphenidate's mechanism of action involves the inhibition of catecholamine reuptake, primarily as a dopamine reuptake inhibitor. Methylphenidate acts by blocking the dopamine transporter and norepinephrine transporter, leading to increased concentrations of dopamine and norepinephrine within the synaptic cleft. This effect in turn leads to increased neurotransmission of dopamine and norepinephrine. Methylphenidate is also a weak 5HT_1A receptor agonist.

Uses

Medical

Methylphenidate is a commonly prescribed psychostimulant and works by increasing the activity of the central nervous system. It produces such effects as increasing or maintaining alertness, combating fatigue, and improving attention. The short-term benefits and cost effectiveness of methylphenidate are well established. Methylphenidate is not approved for children under six years of age. Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of bipolar disorder and major depressive disorder.

Meta-analyses and systematic reviews of magnetic resonance imaging (MRI) studies suggest that long-term treatment with ADHD stimulants (specifically, amphetamine and methylphenidate) decreases abnormalities in brain structure and function found in subjects with ADHD. Moreover, reviews of clinical stimulant research have established the safety and effectiveness of the long-term use of ADHD stimulants for individuals with ADHD. In particular, the continuous treatment effectiveness and safety of both amphetamine and methylphenidate have been demonstrated in controlled drug trials with durations of several years; however, the precise magnitude of improvements in ADHD symptoms and quality of life that are produced by methylphenidate treatment remains uncertain as of November 2015.

Attention deficit hyperactivity disorder

Methylphenidate is approved by the US Food and Drug Administration (FDA) for the treatment of attention deficit hyperactivity disorder. The addition of behavioural modification therapy can have additional benefits on treatment outcome. The dosage used can vary quite significantly among individuals; consequently, dosage must be titrated precisely.

Current models of ADHD suggest that it is associated with functional impairments in some of the brain's neurotransmitter systems, particularly those involving dopamine and norepinephrine. Psychostimulants like methylphenidate and amphetamine may be effective in treating ADHD because they increase neurotransmitter activity in these systems. Approximately 70% of those who use these stimulants see improvements in ADHD symptoms. Children with ADHD who use stimulant medications generally have better relationships with peers and family members, generally perform better in school, are less distractible and impulsive, and have longer attention spans. People with ADHD have an increased risk of substance use disorders, and stimulant medications reduce this risk. Some studies suggest that since ADHD diagnosis is increasing significantly around the world, using the drug may cause more harm than good in some populations with ADHD. This applies to people who potentially may be experiencing a different issue and are misdiagnosed with ADHD. People in this category can then experience negative side-effects of the drug which worsen their condition, and make it harder for them to receive adequate care as providers around them may believe the drugs are sufficient and the problem lies with the user.

Neuroprotective effects

Methylphenidate may provide possible protection from methamphetamine induced dopamine neuron damage and possible protection from Parkinson disease according to 1 review. Methylphenidate has also been shown to increase brain plasticity in the amygdala of mice and enhance the speed of learning according to one study.

Narcolepsy

Narcolepsy, a chronic sleep disorder characterized by overwhelming daytime drowsiness and sudden need for sleep, is treated primarily with stimulants. Methylphenidate is considered effective in increasing wakefulness, vigilance, and performance. Methylphenidate improves measures of somnolence on standardized tests, such as the Multiple Sleep Latency Test (MSLT), but performance does not improve to levels comparable to healthy controls.

Other

Methylphenidate may be used in addition to an antidepressant for refractory major depressive disorder. It can also improve depression in several groups including stroke, cancer, and HIV-positive patients. However, the use of stimulants such as methylphenidate in cases of treatment-resistant depression is controversial. Stimulants may have fewer side-effects than tricyclic antidepressants in the elderly and medically ill. In individuals with terminal cancer, methylphenidate can be used to counteract opioid-induced somnolence, to increase the analgesic effects of opioids, to treat depression, and to improve cognitive function.

Methylphenidate and other stimulants are also used to improve vasoconstriction in the treatment of orthostatic intolerance (OI), a dysautonomic/autonomic nervous system (ANS) disorder.

Enhancing performance

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that therapeutic doses of amphetamine and methylphenidate result in modest yet unambiguous improvements in cognition, including working memory, episodic memory, and inhibitory control, in normal healthy adults; the cognition-enhancing effects of these drugs are known to occur through the indirect activation of both dopamine receptor D₁ and adrenoceptor α₂ in the prefrontal cortex.

Methylphenidate and other ADHD stimulants also improve task saliency and increase arousal. Stimulants such as amphetamine and methylphenidate can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid. Based upon studies of self-reported illicit stimulant use, performance-enhancing use, rather than use as a recreational drug, is the primary reason that students use stimulants.

Excessive doses of methylphenidate, above the therapeutic range, can interfere with working memory and cognitive control. Like amphetamine and bupropion, methylphenidate increases stamina and endurance in humans primarily through reuptake inhibition of dopamine in the central nervous system. Similar to the loss of cognitive enhancement when using large amounts, large doses of methylphenidate can induce side effects that impair athletic performance, such as rhabdomyolysis and hyperthermia. While literature suggests it might improve cognition, most authors agree that using the drug recreationally as a study aid when ADHD diagnosis is not present does not actually improve GPA. Moreover, it has been suggested that students who use the drug for studying may be self-medicating for potentially deeper underlying issues.

Contraindications

Methylphenidate is contraindicated for individuals using monoamine oxidase inhibitors (e.g., phenelzine and tranylcypromine), or individuals with agitation, tics, or glaucoma, or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.

The US FDA gives methylphenidate a pregnancy category of C, and women are advised to only use the drug if the benefits outweigh the potential risks. Not enough animal and human studies have been conducted to conclusively demonstrate an effect of methylphenidate on fetal development. In 2007, empirical literature included 63 cases of prenatal exposure to methylphenidate across three empirical studies.

Adverse effects

Addiction experts in psychiatry, chemistry, pharmacology, forensic science, epidemiology, and the police and legal services engaged in delphic analysis regarding 20 popular recreational drugs. Methylphenidate was ranked 13th in dependence, 12th in physical harm, and 18th in social harm.

Methylphenidate is generally well tolerated. The most commonly observed adverse effects with a frequency greater than placebo include appetite loss, dry mouth, anxiety/nervousness, nausea, and insomnia. Gastrointestinal adverse effects may include abdominal pain and weight loss. Nervous system adverse effects may include akathisia (agitation/restlessness), irritability, dyskinesia (tics), lethargy (drowsiness/fatigue), and dizziness. Cardiac adverse effects may include palpitations, changes in blood pressure and heart rate (typically mild), tachycardia (rapid resting heart rate), and Raynaud's phenomenon (reduced blood flow to the hands and feet). Ophthalmologic adverse effects may include blurred vision and dry eyes, with less frequent reports of diplopia and mydriasis. Other adverse effects may include depression, emotional lability, confusion, and bruxism. Hyperhidrosis (increased sweating) is common. Chest pain is rarely observed.

There is some evidence of mild reductions in growth rate with prolonged treatment in children, but no causal relationship has been established and reductions do not appear to persist long-term.  Hypersensitivity (including skin rash, urticaria, and fever) is sometimes reported. The Daytrana patch has a much higher rate of dermal reactions than oral methylphenidate.

Methylphenidate can worsen psychosis in psychotic patients, and in very rare cases it has been associated with the emergence of new psychotic symptoms. It should be used with extreme caution in patients with bipolar disorder due to the potential induction of mania or hypomania. There have been very rare reports of suicidal ideation, but evidence does not support a link. Logorrhea is occasionally reported. Libido disorders, disorientation, and hallucinations are very rarely reported. Priapism is a very rare adverse event that can be potentially serious.

USFDA-commissioned studies from 2011 indicate that in children, young adults, and adults there is no association between serious adverse cardiovascular events (sudden death, heart attack, and stroke) and the medical use of methylphenidate or other ADHD stimulants.

Because some adverse effects may only emerge during chronic use of methylphenidate, a constant watch for adverse effects is recommended.

Overdose

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomiting, agitation, tremors, hyperreflexia, muscle twitching, euphoria, confusion, hallucinations, delirium, hyperthermia, sweating, flushing, headache, tachycardia, heart palpitations, cardiac arrhythmias, hypertension, mydriasis, and dryness of mucous membranes. A severe overdose may involve symptoms such as hyperpyrexia, sympathomimetic toxidrome, convulsions, paranoia, stereotypy (a repetitive movement disorder), rapid muscle breakdown, coma, and circulatory collapse. A methylphenidate overdose is rarely fatal with appropriate care. Severe toxic reactions involving abscess and necrosis have been reported following injection of methylphenidate tablets into an artery.

Treatment of a methylphenidate overdose typically involves the application of benzodiazepines, with antipsychotics, α-adrenoceptor agonists, and propofol serving as second-line therapies.

Addiction and dependence

ΔFosB accumulation from excessive drug use. Top: this depicts the initial effects of high dose exposure to an addictive drug on gene expression in the nucleus accumbens for various Fos family proteins (i.e., c-Fos, FosB, ΔFosB, Fra1, and Fra2). Bottom: this illustrates the progressive increase in ΔFosB expression in the nucleus accumbens following repeated twice daily drug binges, where these phosphorylated (35–37 kilodalton) ΔFosB isoforms persist in the D1-type medium spiny neurons of the nucleus accumbens for up to 2 months.  Pharmacological texts describe methylphenidate as a stimulant with effects, addiction liability, and dependence liability similar to amphetamine, a compound with moderate liability among addictive drugs; accordingly, addiction and psychological dependence are possible and likely when methylphenidate is used at high doses as a recreational drug. When used above the medical dose range, stimulants are associated with the development of stimulant psychosis. As with all addictive drugs, the overexpression of ΔFosB in D1-type medium spiny neurons in the nucleus accumbens is implicated in methylphenidate addiction.

Methylphenidate has shown some benefits as a replacement therapy for individuals who are addicted to and dependent upon methamphetamine. Methylphenidate and amphetamine have been investigated as a chemical replacement for the treatment of cocaine addiction in the same way that methadone is used as a replacement drug for physical dependence upon heroin. Its effectiveness in treatment of cocaine or psychostimulant addiction or psychological dependence has not been proven and further research is needed.

Biomolecular mechanisms

Methylphenidate has the potential to induce euphoria due to its pharmacodynamic effect (i.e., dopamine reuptake inhibition) in the brain's reward system. At therapeutic doses, ADHD stimulants do not sufficiently activate the reward system, or the reward pathway in particular, to the extent necessary to cause persistent increases in ΔFosB gene expression in the D1-type medium spiny neurons of the nucleus accumbens; consequently, when taken as directed in doses that are commonly prescribed for the treatment of ADHD, methylphenidate use lacks the capacity to cause an addiction. However, when methylphenidate is used at sufficiently high recreational doses through a bioavailable route of administration (e.g., insufflation or intravenous administration), particularly for use of the drug as a euphoriant, ΔFosB accumulates in the nucleus accumbens. Hence, like any other addictive drug, regular recreational use of methylphenidate at high doses eventually gives rise to ΔFosB overexpression in D1-type neurons which subsequently triggers a series of gene transcription-mediated signaling cascades that induce an addiction.

Interactions

Methylphenidate may inhibit the metabolism of coumarin anticoagulants, certain anticonvulsants, and some antidepressants (tricyclic antidepressants and selective serotonin reuptake inhibitors). Concomitant administration may require dose adjustments, possibly assisted by monitoring of plasma drug concentrations. There are several case reports of methylphenidate inducing serotonin syndrome with concomitant administration of antidepressants.

When methylphenidate is coingested with ethanol, a metabolite called ethylphenidate is formed via hepatic transesterification, not unlike the hepatic formation of cocaethylene from cocaine and alcohol. The reduced potency of ethylphenidate and its minor formation means it does not contribute to the pharmacological profile at therapeutic doses and even in overdose cases ethylphenidate concentrations remain negligible.

Coingestion of alcohol (ethanol) also increases the blood plasma levels of d-methylphenidate by up to 40%.

Liver toxicity from methylphenidate is extremely rare, but limited evidence suggests that intake of β-adrenergic agonists with methylphenidate may increase the risk of liver toxicity.

Pharmacology

Pharmacodynamics

Binding profile

Neurotransmitter transporter	Measure (units)	dl-MPH	d-MPH	l-MPH
DAT	Ki (nM)	121	161	2250
	IC50 (nM)	20	23	1600
NET	Ki (nM)	788	206	>10000
	IC50 (nM)	51	39	980
SERT	Ki (nM)	>10000	>10000	>6700
	IC50 (nM)	—	>10000	>10000
GPCR	Measure (units)	dl-MPH	d-MPH	l-MPH
5-HT1A	Ki (nM)	5000	3400	>10000
	IC50 (nM)	10000	6800	>10000
5-HT2B	Ki (nM)	>10000	4700	>10000
	IC50 (nM)	>10000	4900	>10000

Methylphenidate primarily acts as a norepinephrine–dopamine reuptake inhibitor (NDRI). It is a benzylpiperidine and phenethylamine derivative which also shares part of its basic structure with catecholamines.
Methylphenidate is most active at modulating levels of dopamine (DA) and to a lesser extent norepinephrine. Methylphenidate binds to and blocks dopamine transporters (DAT) and norepinephrine transporters. Variability exists between DAT blockade, and extracellular dopamine, leading to the hypothesis that methylphenidate amplifies basal dopamine activity, leading to nonresponse in those with low basal DA activity. On average, methylphenidate elicits a 3–4 times increase in dopamine and norepinephrine in the striatum and prefrontal cortex.

Both amphetamine and methylphenidate are predominantly dopaminergic drugs, yet their mechanisms of action are distinct. Methylphenidate acts as a norepinephrine–dopamine reuptake inhibitor while amphetamine is both a releasing agent and reuptake inhibitor of dopamine and norepinephrine. Methylphenidate's mechanism of action in the release of dopamine and norepinephrine is fundamentally different from most other phenethylamine derivatives, as methylphenidate is thought to increase neuronal firing rate, whereas amphetamine reduces firing rate, but causes monoamine release by reversing the flow of the monoamines through monoamine transporters via a diverse set of mechanisms, including TAAR1 activation and modulation of VMAT2 function, among other mechanisms. The difference in mechanism of action between methylphenidate and amphetamine results in methylphenidate inhibiting amphetamine's effects on monoamine transporters when they are co-administered.

Methylphenidate has both dopamine transporter and norepinephrine transporter binding affinity, with the dextromethylphenidate enantiomers displaying a prominent affinity for the norepinephrine transporter. Both the dextrorotary and levorotary enantiomers displayed receptor affinity for the serotonergic 5HT_1A and 5HT_2B subtypes, though direct binding to the serotonin transporter was not observed. A later study confirmed the d-threo- enantiomer binding to the 5HT_1A receptor, but no significant activity on the 5HT_2B receptor was found.

Methylphenidate may protect neurons from the neurotoxic effects of Parkinson's disease and methamphetamine abuse. The hypothesized mechanism of neuroprotection is through inhibition of methamphetamine/DAT interactions, and through reducing cytosolic dopamine, leading to decreased production of dopamine related reactive oxygen species.

The dextrorotary enantiomers are significantly more potent than the levorotary enantiomers, and some medications therefore only contain dexmethylphenidate.

Methylphenidate has been identified as a sigma-1 receptor agonist in rats.

Pharmacokinetics

Methylphenidate taken orally has a bioavailability of 11–52% with a duration of peak action around 2–4 hours for instant release (i.e. Ritalin), 3–8 hours for sustained release (i.e. Ritalin SR), and 8–12 hours for extended release (i.e. Concerta). The half-life of methylphenidate is 2–3 hours, depending on the individual. The peak plasma time is achieved at about 2 hours.

Dextromethylphenidate is much more bioavailable than levomethylphenidate when administered orally, and is primarily responsible for the psychoactivity of racemic methylphenidate.

Contrary to the expectation, taking methylphenidate with a meal speeds absorption.

Methylphenidate is metabolized into ritalinic acid by CES1A1. Dextromethylphenidate is selectively metabolized at a slower rate than levomethylphenidate.

Chemistry

Four isomers of methylphenidate are possible, since the molecule has two chiral centers. One pair of threo isomers and one pair of erythro are distinguished, from which primarily d-threo-methylphenidate exhibits the pharmacologically desired effects. The erythro diastereomers are pressor amines, a property not shared with the threo diastereomers. When the drug was first introduced it was sold as a 4:1 mixture of erythro:threo diastereomers, but it was later reformulated to contain only the threo diastereomers. "TMP" refers to a threo product that does not contain any erythro diastereomers, i.e. (±)-threo-methylphenidate. Since the threo isomers are energetically favored, it is easy to epimerize out any of the undesired erythro isomers. The drug that contains only dextrorotatory methylphenidate is sometimes called d-TMP, although this name is only rarely used and it is much more commonly referred to as dexmethylphenidate, d-MPH, or d-threo-methylphenidate. A review on the synthesis of enantiomerically pure (2R,2'R)-(+)-threo-methylphenidate hydrochloride has been published.

Methylphenidate synthesis:

Method 1: Methylphenidate preparation elucidated by Axten et al. (1998) via Bamford-Stevens reaction.

Method 2: Classic methylphenidate synthesis.

Method 3: Another synthesis route of methylphenidate which applies Darzens reaction to obtain aldehyde as an intermediate. This route is significant for its selectivity.

Detection in biological fluids

The concentration of methylphenidate or ritalinic acid, its major metabolite, may be quantified in plasma, serum or whole blood in order to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage.

Pharmaceutical products

Names

German "Ritalin" brand methylphenidate

Methylphenidate is produced in the United States, Mexico, Spain, Sweden, Pakistan, and India. It is also sold in Canada, Australia, the United Kingdom, Spain, Germany, Belgium, Brazil, Portugal, Argentina, Thailand, and several other European countries (although in much lower volumes than in the United States). Brand names for methylphenidate include Ritalin, Concerta, Inspiral, Addwize, Aptensio, Biphentin, Daytrana, Equasym, Medikinet, Metadate, Methylin, and Quillivant. Generic forms are produced by numerous pharmaceutical companies throughout the world.

Available forms

Clockwise from top: Concerta 18 mg, Medikinet 5 mg, Methylphenidat TAD 10 mg, Ritalin 10 mg, Medikinet XL 30 mg.

Methylphenidate is available in numerous forms, and a doctor will determine the appropriate formulation of the drug to prescribe based on the patient's history, the doctor's experiences treating other patients with methylphenidate products, and product pricing/availability. Currently available forms include a variety of tablets and capsules, an adhesive-based matrix transdermal system (transdermal patch), and an oral suspension (liquid syrup).

The dextrorotary enantiomer of methylphenidate, known as dexmethylphenidate, is sold as a generic and under the brand names Focalin and Attenade in both an immediate-release and an extended-release form. In some circumstances it may be prescribed instead of methylphenidate, however it has no significant advantages over methylphenidate at equipotent dosages and so it is sometimes considered to be an example of an evergreened drug.

Immediate-release

Structural formula for the substance among Ritalin tablet series. (Ritalin, Ritalin LA, Ritalin SR.) The volume of distribution was 2.65±1.11 L/kg for d-methylphenidate and 1.80±0.91 L/kg for l-methylphenidate subsequent to swallow of Ritalin tablet.

Methylphenidate was originally available as an immediate-release racemic mixture formulation under the Novartis trademark name Ritalin, although a variety of generics are now available, some under other brand names. Generic brand names include Ritalina, Rilatine, Attenta, Medikinet, Metadate, Methylin, Penid, Tranquilyn, and Rubifen.

Extended-release

Structural formula for the substance inside Concerta tablet. Following administration of CONCERTA®, plasma concentrations of the l-isomer were approximately 1/40 the plasma concentrations of the d-isomer.

Extended-release methylphenidate products include:

Brand name(s)	Generic name(s)	Duration	Dosage form
Aptensio XR (US); Biphentin (CA)	Currently unavailable	12 hours	XR capsule
Concerta (US/CA); Concerta XL (UK)	methylphenidate ER (US/CA); methylphenidate ER‑C (CA)	12 hours	OROS tablet
Quillivant XR (US)	Currently unavailable	12 hours	oral suspension
Daytrana (US)	Currently unavailable	11 hours	transdermal patch
Metadate CD (US); Equasym XL (UK)	methylphenidate ER (US)	8–10 hours	CD/XL capsule
QuilliChew ER (US)	Currently unavailable	8 hours	chewable tablet
Ritalin LA (US); Medikinet XL (UK)	methylphenidate ER (US)	8 hours	ER capsule
Ritalin SR (US/CA/UK); Rubifen SR (NZ)	Metadate ER (US); Methylin ER (US); methylphenidate SR (US/CA)	5–8 hours	CR tablet

Concerta tablets are marked with the letters "ALZA" and followed by: "18", "27", "36", or "54", relating to the mg dosage strength. Approximately 22% of the dose is immediate release, and the remaining 78% of the dose is released over 10–12 hours post ingestion, with an initial increase over the first 6 to 7 hours, and subsequent decline in released drug.

Ritalin LA capsules are marked with the letters "NVR" (abbrev.: Novartis) and followed by: "R20", "R30", or "R40", depending on the (mg) dosage strength. Ritalin LA provides two standard doses – half the total dose being released immediately and the other half released four hours later. In total, each capsule is effective for about eight hours.

Metadate CD capsules contain two types of beads; 30% are immediate release, and the other 70% are evenly sustained release.

Quillivant XR is an extended-release oral suspension (after reconstitution with water): 25 mg per 5 mL (5 mg per mL). It was designed and is patented and made by Pfizer. The medication comes in various sizes from 60ml to 180ml (after reconstitution). Each bottle is shipped with the medication in powder form containing roughly 20% instant-release and 80% extended-release methylphenidate, to which water must be added by the pharmacist in an amount corresponding with the total intended volume of the bottle. The bottle must be shaken vigorously for ten seconds prior to administration via included oral syringe to ensure proper ratio.

Cost

Ritalin 10 mg tablet

Generic immediate-release methylphenidate is relatively inexpensive. The average wholesale cost is about US$0.15 per defined daily dose (retail pharmacies normally charge more). However, the most expensive brand-name extended-release tablets may retail for as much as $12.40 per defined daily dose.

There are two main reasons for this price difference:

• Generic formulations are less expensive than brand-name formulations.
• Immediate-release tablets are less expensive than 8-hour extended-release tablets, which are much less expensive than 12-hour extended-release tablets.

History, society, and culture

Methylphenidate was first synthesized in 1944, and was identified as a stimulant in 1954.

Methylphenidate was synthesized by Ciba (now Novartis) chemist Leandro Panizzon. He named the drug after his wife, nicknamed Rita, who used Ritalin to compensate for low blood pressure.

Originally it was marketed as a mixture of two racemates, 80% (±)-erythro and 20% (±)-threo. Subsequent studies of the racemates showed that the central stimulant activity is associated with the threo racemate and were focused on the separation and interconversion of the erythro isomer into the more active threo isomer.

Methylphenidate was first used to allay barbiturate-induced coma, narcolepsy and depression. It was later used to treat memory deficits in the elderly. Beginning in the 1960s, it was used to treat children with ADHD or ADD, known at the time as hyperactivity or minimal brain dysfunction (MBD) based on earlier work starting with the studies by American psychiatrist Charles Bradley on the use of psychostimulant drugs, such as Benzedrine, with then called "maladjusted children". Production and prescription of methylphenidate rose significantly in the 1990s, especially in the United States, as the ADHD diagnosis came to be better understood and more generally accepted within the medical and mental health communities.

In 2000 ALZA Corporation received US Food and Drug Administration (FDA) approval to market "Concerta", an extended-release form of methylphenidate.

Legal status

Legal warning printed on Ritalin packaging

• Internationally, methylphenidate is a Schedule II drug under the Convention on Psychotropic Substances.
• In the United States, methylphenidate is classified as a Schedule II controlled substance, the designation used for substances that have a recognized medical value but present a high potential for abuse.
• In the United Kingdom, methylphenidate is a controlled 'Class B' substance. Possession without prescription carries a sentence up to 5 years or an unlimited fine, or both; supplying methylphenidate is 14 years or an unlimited fine, or both.
• In Canada, methylphenidate is listed in Schedule III of the Controlled Drugs and Substances Act and is illegal to possess without a prescription, with unlawful possession punishable by up to three years imprisonment, or (via summary conviction) by up to one year imprisonment and/or fines of up to two thousand dollars. Unlawful possession for the purpose of trafficking is punishable by up to ten years imprisonment, or (via summary conviction) by up to eighteen months imprisonment.
• In New Zealand, methylphenidate is a 'class B2 controlled substance'. Unlawful possession is punishable by six-month prison sentence and distribution by a 14-year sentence.
• In Australia, methylphenidate is a 'Schedule 8' controlled substance. Such drugs must be kept in a lockable safe until dispensed and possession without prescription is punishable by fines and imprisonment.
• In Sweden, methylphenidate is a List II controlled substance with recognized medical value. Possession without a prescription is punishable by up to three years in prison.
• In France, methylphenidate is covered by the "narcotics" schedule, prescription and distribution conditions are restricted with hospital-only prescription for the initial treatment and yearly consultations.
• In India, methylphenidate is a schedule X drug and is controlled by the Drugs and Cosmetics Rule, 1945. It is dispensed only by physician's prescription.^[156] Legally, 2 grams of methylphenidate are classified as a small quantity, and 50 grams as a large or commercial quantity.

Controversy

Methylphenidate has been the subject of controversy in relation to its use in the treatment of ADHD. The prescription of psychostimulant medication to children to reduce ADHD symptoms has been a major point of criticism. The contention that methylphenidate acts as a gateway drug has been discredited by multiple sources, according to which abuse is statistically very low and "stimulant therapy in childhood does not increase the risk for subsequent drug and alcohol abuse disorders later in life". A study found that ADHD medication was not associated with increased risk of cigarette use, and in fact stimulant treatments such as Ritalin seemed to lower this risk.

 One of the highest use of methylphenidate medication is in Iceland, where research shows that the drug was the most commonly abused substance among intravenous substance abusers. The study involved 108 intravenous substance abusers and 88% of them had injected methylphenidate within the last 30 days and for 63% of them, methylphenidate was the most preferred substance.

Treatment of ADHD by way of methylphenidate has led to legal actions, including malpractice suits regarding informed consent, inadequate information on side effects, misdiagnosis, and coercive use of medications by school systems.

In the US and the UK, it is approved for use in children and adolescents. In the US, the Food and Drug Administration approved the use of methylphenidate in 2008 for use in treating adult ADHD. In the UK, while not licensed for use in adult ADHD, NICE guidelines suggest it be prescribed off-license for the condition. Methylphenidate has been approved for adult use in the treatment of narcolepsy.

Research

Methylphenidate may have benefit as a treatment of apathy in patients with Alzheimer's disease. It may be useful in losing weight.