Tag: ADHD: Attention Deficit Hyperactivity Disorder

What is Lisdexamfetamine?

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Introduction

Lisdexamfetamine, sold under the brand names Vyvanse and Elvanse among others, is a stimulant medication that is used to treat attention deficit hyperactivity disorder (ADHD) in children and adults and for moderate-to-severe binge eating disorder in adults. Lisdexamfetamine is taken by mouth. Its effects generally begin within two hours and last for up to 14 hours.

Common side effects of lisdexamfetamine include loss of appetite, anxiety, diarrhoea, trouble sleeping, irritability, and nausea. Rare but serious side effects include mania, sudden cardiac death in those with underlying heart problems, and psychosis. It has a high potential for substance abuse. Serotonin syndrome may occur if used with certain other medications. Its use during pregnancy may result in harm to the baby and use during breastfeeding is not recommended by the manufacturer.

Lisdexamfetamine is an inactive prodrug that works after being converted by the body into dextroamphetamine, a central nervous system (CNS) stimulant. Chemically, lisdexamfetamine is composed of the amino acid L-lysine, attached to dextroamphetamine.

Lisdexamfetamine was approved for medical use in the United States in 2007, and in the European Union in 2012. In 2022, it was the 69th most commonly prescribed medication in the United States, with more than 9 million prescriptions. It is a Class B controlled substance in the United Kingdom, a Schedule 8 controlled drug in Australia, and a Schedule II controlled substance in the United States.

Brief History

Lisdexamfetamine was developed by New River Pharmaceuticals, who were bought by Takeda Pharmaceuticals through its acquisition of Shire Pharmaceuticals, shortly before it began being marketed. It was developed to create a longer-lasting and less-easily abused version of dextroamphetamine, as the requirement of conversion into dextroamphetamine via enzymes in the red blood cells delays its onset of action, regardless of the route of administration.

In February 2007, the US Food and Drug Administration (FDA) approved lisdexamfetamine for the treatment of ADHD. In August 2009, Health Canada approved the marketing of lisdexamfetamine for prescription use.

In January 2015, lisdexamfetamine was approved by the FDA for the treatment of binge eating disorder in adults.

The FDA gave tentative approval to generic formulations of lisdexamfetamine in 2015. The expiration date for patent protection of lisdexamfetamine in the US was 24 February 2023. The Canadian patent expired 20 years from the filing date of 01 June 2004.

Production quotas for 2016 in the United States were 29,750 kg.

Uses

Medical

Lisdexamfetamine is used primarily as a treatment for attention deficit hyperactivity disorder (ADHD) and binge eating disorder; it has similar off-label uses as those of other pharmaceutical amphetamines such as narcolepsy. Individuals over the age of 65 were not commonly tested in clinical trials of lisdexamfetamine for ADHD. According to a 2019 systematic review, lisdexamfetamine was the most effective treatment for adult ADHD.

ADHD

Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage, but, in humans with ADHD, long-term use of pharmaceutical amphetamines at therapeutic doses appears to improve brain development and nerve growth. Reviews of magnetic resonance imaging (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus of the basal ganglia.

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD. Randomised controlled trials of continuous stimulant therapy for the treatment of ADHD spanning 2 years have demonstrated treatment effectiveness and safety. Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e. hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes across 9 categories of outcomes related to academics, antisocial behaviour, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e. academic, occupational, health, financial, and legal services), and social function. Additionally, a 2024 meta-analytic systematic review reported moderate improvements in quality of life when amphetamine treatment is used for ADHD. One review highlighted a nine-month randomised controlled trial of amphetamine treatment for ADHD in children that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviours and hyperactivity. Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult. A 2025 meta-analytic systematic review of 113 randomized controlled trials demonstrated that stimulant medications significantly improved core ADHD symptoms in adults over a three-month period, with good acceptability compared to other pharmacological and non-pharmacological treatments.

Models of ADHD suggest that it is associated with functional impairments in some of the brain’s neurotransmitter systems; these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex. Stimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems. Approximately 80% 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, perform better in school, are less distractible and impulsive, and have longer attention spans. The Cochrane reviews on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that short-term studies have demonstrated that these drugs decrease the severity of symptoms, but they have higher discontinuation rates than non-stimulant medications due to their adverse side effects. A Cochrane review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.

Binge Eating Disorder

Binge eating disorder (BED) is characterised by recurrent and persistent episodes of compulsive binge eating. These episodes are often accompanied by marked distress and a feeling of loss of control over eating. The pathophysiology of BED is not fully understood, but it is believed to involve dysfunctional dopaminergic reward circuitry along the cortico-striatal-thalamic-cortical loop. As of July 2024, lisdexamfetamine is the only USFDA- and TGA-approved pharmacotherapy for BED. Evidence suggests that lisdexamfetamine’s treatment efficacy in BED is underpinned at least in part by a psychopathological overlap between BED and ADHD, with the latter conceptualised as a cognitive control disorder that also benefits from treatment with lisdexamfetamine.

Lisdexamfetamine’s therapeutic effects for BED primarily involve direct action in the central nervous system after conversion to its pharmacologically active metabolite, dextroamphetamine. Centrally, dextroamphetamine increases neurotransmitter activity of dopamine and norepinephrine in prefrontal cortical regions that regulate cognitive control of behaviour. Similar to its therapeutic effect in ADHD, dextroamphetamine enhances cognitive control and may reduce impulsivity in patients with BED by enhancing the cognitive processes responsible for overriding prepotent feeding responses that precede binge eating episodes. In addition, dextroamphetamine’s actions outside of the central nervous system may also contribute to its treatment effects in BED. Peripherally, dextroamphetamine triggers lipolysis through noradrenergic signalling in adipose fat cells, leading to the release of triglycerides into blood plasma to be utilized as a fuel substrate. Dextroamphetamine also activates TAAR1 in peripheral organs along the gastrointestinal tract that are involved in the regulation of food intake and body weight. Together, these actions confer an anorexigenic effect that promotes satiety in response to feeding and may decrease binge eating as a secondary effect. While lisdexamfetamine’s anorexigenic effects contribute to its efficacy in BED, evidence indicates that the enhancement of cognitive control is necessary and sufficient for addressing the disorder’s underlying psychopathology. This view is supported by the failure of anti-obesity medications and other appetite suppressants to significantly reduce BED symptom severity, despite their capacity to induce weight loss.

Medical reviews of randomised controlled trials have demonstrated that lisdexamfetamine, at doses between 50–70 mg, is safe and effective for the treatment of moderate-to-severe BED in adults. These reviews suggest that lisdexamfetamine is persistently effective at treating BED and is associated with significant reductions in the number of binge eating days and binge eating episodes per week. Furthermore, a meta-analytic systematic review highlighted an open-label, 12-month extension safety and tolerability study that reported lisdexamfetamine remained effective at reducing the number of binge eating days for the duration of the study. In addition, both a review and a meta-analytic systematic review found lisdexamfetamine to be superior to placebo in several secondary outcome measures, including persistent binge eating cessation, reduction of obsessive-compulsive related binge eating symptoms, reduction of body-weight, and reduction of triglycerides. Lisdexamfetamine, like all pharmaceutical amphetamines, has direct appetite suppressant effects that may be therapeutically useful in both BED and its comorbidities. Based on reviews of neuroimaging studies involving BED-diagnosed participants, therapeutic neuroplasticity in dopaminergic and noradrenergic pathways from long-term use of lisdexamfetamine may be implicated in lasting improvements in the regulation of eating behaviours that are observed.

Narcolepsy

Narcolepsy is a chronic sleep-wake disorder that is associated with excessive daytime sleepiness, cataplexy, and sleep paralysis. Patients with narcolepsy are diagnosed as either type 1 or type 2, with only the former presenting cataplexy symptoms. Type 1 narcolepsy results from the loss of approximately 70,000 orexin-releasing neurons in the lateral hypothalamus, leading to significantly reduced cerebrospinal orexin levels; this reduction is a diagnostic biomarker for type 1 narcolepsy. Lateral hypothalamic orexin neurons innervate every component of the ascending reticular activating system (ARAS), which includes noradrenergic, dopaminergic, histaminergic, and serotonergic nuclei that promote wakefulness.

Amphetamine’s therapeutic mode of action in narcolepsy primarily involves increasing monoamine neurotransmitter activity in the ARAS. This includes noradrenergic neurons in the locus coeruleus, dopaminergic neurons in the ventral tegmental area, histaminergic neurons in the tuberomammillary nucleus, and serotonergic neurons in the dorsal raphe nucleus. Dextroamphetamine, the more dopaminergic enantiomer of amphetamine, is particularly effective at promoting wakefulness because dopamine release has the greatest influence on cortical activation and cognitive arousal, relative to other monoamines. In contrast, levoamphetamine may have a greater effect on cataplexy, a symptom more sensitive to the effects of norepinephrine and serotonin. Noradrenergic and serotonergic nuclei in the ARAS are involved in the regulation of the REM sleep cycle and function as “REM-off” cells, with amphetamine’s effect on norepinephrine and serotonin contributing to the suppression of REM sleep and a possible reduction of cataplexy at high doses.

The American Academy of Sleep Medicine (AASM) 2021 clinical practice guideline conditionally recommends dextroamphetamine for the treatment of both type 1 and type 2 narcolepsy. Treatment with pharmaceutical amphetamines is generally less preferred relative to other stimulants (e.g. modafinil) and is considered a third-line treatment option. Medical reviews indicate that amphetamine is safe and effective for the treatment of narcolepsy. Amphetamine appears to be most effective at improving symptoms associated with hypersomnolence, with three reviews finding clinically significant reductions in daytime sleepiness in patients with narcolepsy. Additionally, these reviews suggest that amphetamine may dose-dependently improve cataplexy symptoms. However, the quality of evidence for these findings is low and is consequently reflected in the AASM’s conditional recommendation for dextroamphetamine as a treatment option for narcolepsy.

Enhancing Performance

Cognitive Performance

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults; these cognition-enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine D1 receptor and α2-adrenergic receptor in the prefrontal cortex. A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information. Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals. Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior. Stimulants such as amphetamine 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, 5–35% of college students use diverted ADHD stimulants, which are primarily used for enhancement of academic performance rather than as recreational drugs. However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.

Physical Performance

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness; however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies. In healthy people at oral therapeutic doses, amphetamine has been shown to increase muscle strength, acceleration, athletic performance in anaerobic conditions, and endurance (i.e. it delays the onset of fatigue), while improving reaction time. Amphetamine improves endurance and reaction time primarily through reuptake inhibition and release of dopamine in the central nervous system. Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a “safety switch”, allowing the core temperature limit to increase in order to access a reserve capacity that is normally off-limits. At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance; however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.

Available Forms

Lisdexamfetamine is available as the dimesylate salt in the form of both oral capsules and chewable tablets. A dose of 50 mg of lisdexamfetamine dimesylate is approximately equimolar to a 20 mg dose of dextroamphetamine sulfate or to 15 mg dextroamphetamine free-base in terms of the amount of dextroamphetamine contained. Lisdexamfetamine capsules can be swallowed intact, or they can be opened and mixed into water, yogurt, or applesauce and consumed in that manner.

Contraindications

Pharmaceutical lisdexamfetamine is contraindicated in people with hypersensitivity to amphetamine products or any of the formulation’s inactive ingredients.[7] It is also contraindicated in patients who have used a monoamine oxidase inhibitor (MAOI) within the last 14 days. Amphetamine products are contraindicated by the United States Food and Drug Administration (USFDA) in people with a history of drug abuse, heart disease, or severe agitation or anxiety, or in those currently experiencing arteriosclerosis, glaucoma, hyperthyroidism, or severe hypertension. However, a European consensus statement on adult ADHD noted that stimulants do not worsen substance misuse in adults with ADHD and comorbid substance use disorder and should not be avoided in these individuals. In any case, the statement noted that immediate-release stimulants should be avoided in those with both ADHD and substance use disorder and that slower-release stimulant formulations like OROSTooltip osmotic-controlled release oral delivery system methylphenidate (Concerta) and lisdexamfetamine should be preferred due to their lower misuse potential. Prescribing information approved by the Australian Therapeutic Goods Administration further contraindicates anorexia.

Adverse Effects

Products containing lisdexamfetamine have a comparable drug safety profile to those containing amphetamine. The major side effects of lisdexamfetamine in short-term clinical trials (≥5% incidence) have included decreased appetite, insomnia, dry mouth, weight loss, irritability, upper abdominal pain, nausea, vomiting, diarrhoea, constipation, increased heart rate, anxiety, dizziness, and feeling jittery. Rates of side effects may vary in adults, adolescents, and children. Rare but serious side effects of lisdexamfetamine may include mania, sudden cardiac death in those with underlying heart problems, stimulant psychosis, and serotonin syndrome.

Interactions

  • Acidifying agents: Drugs or foods that acidify the urine, such as ascorbic acid, increase urinary excretion of dextroamphetamine, thus decreasing the half-life and effectiveness of dextroamphetamine in the body.
  • Alkalinising agents: Drugs or foods that alkalinise the urine, such as sodium bicarbonate, decrease urinary excretion of dextroamphetamine, thus increasing the half-life and effectiveness of dextroamphetamine in the body.
  • CYP2D6 inhibitors: Hydroxylation via the cytochrome P450 enzyme CYP2D6 is the major pathway of metabolism of dextroamphetamine. Potent CYP2D6 inhibitors, such as paroxetine, fluoxetine, bupropion, and duloxetine, among others, may inhibit the metabolism of dextroamphetamine and thereby increase exposure to it. Studies characterising this potential interaction are currently lacking. Concomitant use of lisdexamfetamine with CYP2D6 inhibitors may increase the risk of serotonin syndrome due to greater drug exposure.
  • Monoamine oxidase inhibitors: Concomitant use of MAOIs and central nervous system stimulants such as lisdexamfetamine can cause a hypertensive crisis.
  • Norepinephrine reuptake inhibitors (NRIs) like atomoxetine prevent norepinephrine release induced by amphetamines and have been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans.

Pharmacology

Mechanism of Action

Lisdexamfetamine is an inactive prodrug that is converted in the body to dextroamphetamine, a pharmacologically active compound that is responsible for the drug’s activity. After oral ingestion, lisdexamfetamine is broken down by enzymes in red blood cells to form L-lysine, a naturally occurring essential amino acid, and dextroamphetamine. The half-life of this conversion is roughly 1 hour. The conversion of lisdexamfetamine to dextroamphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times. Studies show a linear relationship between peak plasma concentration of dextroamphetamine and lisdexamfetamine dose up to lisdexamfetamine doses of 250mg.

The optical isomers of amphetamine, i.e. dextroamphetamine and levoamphetamine, are TAAR1 agonists and vesicular monoamine transporter 2 inhibitors that can enter monoamine neurons; this allows them to release monoamine neurotransmitters (dopamine, norepinephrine, and serotonin, among others) from their storage sites in the presynaptic neuron, as well as prevent the reuptake of these neurotransmitters from the synaptic cleft.

Lisdexamfetamine was developed to provide a long-duration effect that is consistent throughout the day, with reduced potential for abuse. The attachment of the amino acid lysine slows down the relative amount of dextroamphetamine available in the bloodstream. Because no free dextroamphetamine is present in lisdexamfetamine capsules, dextroamphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. A relatively sophisticated biochemical process is needed to produce dextroamphetamine from lisdexamfetamine. As opposed to Adderall, which contains amphetamine salts in a 3:1 dextro:levo ratio, lisdexamfetamine is a single-enantiomer dextroamphetamine formula. Studies conducted show that lisdexamfetamine dimesylate may have less abuse potential than dextroamphetamine and an abuse profile similar to diethylpropion at dosages that are FDA-approved for treatment of ADHD, but still has a high abuse potential when this dosage is exceeded by over 100%.

Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH; it is well absorbed from the gut, and bioavailability is typically 90%. Amphetamine is a weak base with a pKa of 9.9; consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium. Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed. Approximately 20% of amphetamine circulating in the bloodstream is bound to plasma proteins. Following absorption, amphetamine readily distributes into most tissues in the body, with high concentrations occurring in cerebrospinal fluid and brain tissue.

The half-lives of amphetamine enantiomers differ and vary with urine pH. At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively. Highly acidic urine will reduce the enantiomer half-lives to 7 hours; highly alkaline urine will increase the half-lives up to 34 hours. The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively. Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH. When the urinary pH is basic, amphetamine is in its free base form, so less is excreted. When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively. Following oral administration, amphetamine appears in urine within 3 hours. Roughly 90% of ingested amphetamine is eliminated 3 days after the last oral dose.

Lisdexamfetamine is a prodrug of dextroamphetamine. It is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract. Following absorption into the blood stream, lisdexamfetamine is completely converted by red blood cells to dextroamphetamine and the amino acid L-lysine by hydrolysis via undetermined aminopeptidase enzymes. This is the rate-limiting step in the bioactivation of lisdexamfetamine. The elimination half-life of lisdexamfetamine is generally less than 1 hour. Due to the necessary conversion of lisdexamfetamine into dextroamphetamine, levels of dextroamphetamine with lisdexamfetamine peak about one hour later than with an equivalent dose of immediate-release dextroamphetamine. Presumably due to its rate-limited activation by red blood cells, intravenous administration of lisdexamfetamine shows greatly delayed time to peak and reduced peak levels compared to intravenous administration of an equivalent dose of dextroamphetamine. The pharmacokinetics of lisdexamfetamine are similar regardless of whether it is administered orally, intranasally, or intravenously. Hence, in contrast to dextroamphetamine, parenteral use does not enhance the subjective effects of lisdexamfetamine. Because of its behaviour as a prodrug and its pharmacokinetic differences, lisdexamfetamine has a longer duration of therapeutic effect than immediate-release dextroamphetamine and shows reduced misuse potential.

CYP2D6, dopamine β-hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butyrate-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are the enzymes known to metabolise amphetamine or its metabolites in humans. Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone. Among these metabolites, the active sympathomimetics are 4-hydroxyamphetamine, 4-hydroxynorephedrine, and norephedrine. The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.

Chemistry

Lisdexamfetamine is a substituted amphetamine with an amide linkage formed by the condensation of dextroamphetamine with the carboxylate group of the essential amino acid L-lysine. The reaction occurs with retention of stereochemistry, so the product lisdexamfetamine exists as a single stereoisomer. There are many possible names for lisdexamfetamine based on IUPAC nomenclature, but it is usually named as N-[(2S)-1-phenyl-2-propanyl]-L-lysinamide or (2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide.

Amine functional groups are vulnerable to oxidation in air and so pharmaceuticals containing them are usually formulated as salts where this moiety has been protonated. This increases stability, water solubility, and, by converting a molecular compound to an ionic compound, increases the melting point and thereby ensures a solid product. In the case of lisdexamfetamine, this is achieved by reacting with two equivalents of methanesulfonic acid to produce the dimesylate salt, a water-soluble (792 mg mL−1) powder with a white to off-white colour.

Comparison to other Formulations

Lisdexamfetamine dimesylate is one marketed formulation delivering dextroamphetamine.

Society and Culture

Name

Lisdexamfetamine is the International Nonproprietary Name (INN) and is a contraction of L-lysine-dextroamphetamine.

As of November 2020, lisdexamfetamine is sold under the following brand names: Aduvanz, Elvanse, Juneve, Samexid, Tyvense, Venvanse, and Vyvanse.

Research

Depression

Amphetamine was used to treat depression starting in the 1930s and has been described as the first antidepressant. In clinical studies in the 1970s and 1980s, psychostimulants, including amphetamine and methylphenidate, were found to transiently improve mood in a majority of people with depression and to increase psychomotor activation in almost all individuals.

Some clinical trials that used lisdexamfetamine as an add-on therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for treatment-resistant depression indicated that this is no more effective than the use of an SSRI or SNRI alone. Other studies indicated that psychostimulants potentiated antidepressants, and were under-prescribed for treatment-resistant depression. In those studies, patients showed significant improvement in energy, mood, and psychomotor activity. Clinical guidelines advise caution in the use of stimulants for depression and advise them only as second- or third-line adjunctive agents.

In February 2014, Shire announced that two late-stage clinical trials had found that Vyvanse was not an effective treatment for depression, and development for this indication was discontinued. A 2018 meta-analysis of randomised controlled trials of lisdexamfetamine for antidepressant augmentation in people with major depressive disorder—the first to be conducted—found that lisdexamfetamine was not significantly better than placebo in improving Montgomery–Åsberg Depression Rating Scale scores, response rates, or remission rates. However, there was indication of a small effect in improving depressive symptoms that approached trend-level significance. Lisdexamfetamine was well-tolerated in the meta-analysis. The quantity of evidence was limited, with only four trials included. In a subsequent 2022 network meta-analysis, lisdexamfetamine was significantly effective as an antidepressant augmentation for treatment-resistant depression.

Although lisdexamfetamine has shown limited effectiveness in the treatment of depression in clinical trials, a phase II clinical study found that the addition of lisdexamfetamine to an antidepressant improved executive dysfunction in people with mild major depressive disorder but persisting executive dysfunction.

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What is Atomoxetine?

Published on by Andrew Marshall1 Comment

Introduction

Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndrome (CDS). It may be used alone or along with stimulant medication. It enhances the executive functions of self-motivation, sustained attention, inhibition, working memory, reaction time, and emotional self-regulation. Use of atomoxetine is only recommended for those who are at least six years old. It is taken orally. The effectiveness of atomoxetine is comparable to the commonly prescribed stimulant medication methylphenidate.

Common side effects of atomoxetine include abdominal pain, decreased appetite, nausea, feeling tired, and dizziness. Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression. There is a lack of data regarding its safety during pregnancy; as of 2019, its safety during pregnancy and for use during breastfeeding is not certain.

It was approved for medical use in the US in 2002. In 2022, it was the 213th most commonly prescribed medication in the United States, with more than 1 million prescriptions.

Brief History

Atomoxetine is manufactured, marketed, and sold in the United States as the hydrochloride salt (atomoxetine HCl) under the brand name Strattera by Eli Lilly and Company, the original patent-filing company and current US patent owner. Atomoxetine was initially intended to be developed as an antidepressant, but it was found to be insufficiently efficacious for treating depression. It was, however, found to be effective for ADHD and was approved by the US Food and Drug Administration (FDA) in 2002, for the treatment of ADHD. Its patent expired in May 2017. On 12 August 2010, Lilly lost a lawsuit that challenged its patent on Strattera, increasing the likelihood of an earlier entry of a generic into the US market. On 01 September 2010, Sun Pharmaceuticals announced it would begin manufacturing a generic in the US. In a 29 July 2011 conference call, however, Sun Pharmaceutical’s Chairman stated “Lilly won that litigation on appeal so I think [generic Strattera]’s deferred.”

In 2017, the FDA approved the generic production of atomoxetine by four pharmaceutical companies.

Medical Uses

Atomoxetine is indicated for the treatment of ADHD.

Attention Deficit Hyperactivity Disorder

Atomoxetine is approved for use in children, adolescents, and adults. However, its efficacy has not been studied in children under six years old. One of the primary differences with the standard stimulant treatments for ADHD is that it has little known abuse potential. Meta-analyses and systematic reviews have found that atomoxetine has comparable efficacy and equal tolerability to methylphenidate in children and adolescents. In adults, efficacy and tolerability are equivalent.

While its efficacy may be less than that of lisdexamphetamine, there is some evidence that it may be used in combination with stimulants. Doctors may prescribe non-stimulants including atomoxetine when a person has bothersome side effects from stimulants; when a stimulant was not effective; in combination with a stimulant to increase effectiveness; when the cost of stimulants is prohibitive; or when there is concern about the abuse potential of stimulants in a patient with a history of substance use disorder.

Atomoxetine alleviates ADHD symptoms through norepinephrine reuptake inhibition and by indirectly increasing dopamine in the prefrontal cortex, sharing 70-80% of the brain regions with stimulants in their produced effects.

Unlike α2-adrenergic receptor agonists such as guanfacine and clonidine, atomoxetine’s use can be abruptly stopped without significant withdrawal symptoms being observed.

The initial therapeutic effects of atomoxetine usually take 1 to 4 weeks to become apparent. A further 2 to 4 weeks may be required for the full therapeutic effects to be seen. Incrementally increasing response may occur up to 1 year or longer. The maximum recommended total daily dose in children and adolescents is 70 mg and adults is 100 mg.

Other Uses

Cognitive Disengagement Syndrome

Atomoxetine may be used to treat cognitive disengagement syndrome (CDS), as multiple randomised controlled clinical trials (RCTs) have found that it is an effective treatment. In contrast, multiple RCTs have shown that it responds poorly to the stimulant medication methylphenidate.

Traumatic Brain Injury

Atomoxetine is sometimes used in the treatment of cognitive impairment and frontal lobe symptoms due to conditions like traumatic brain injury (TBI). It is used to treat ADHD-like symptoms such as sustained attentional problems, disinhibition, lack of arousal, fatigue, and depression, including symptoms from cognitive disengagement syndrome. A 2015 Cochrane review identified only one study of atomoxetine for TBI and found no positive effects. Aside from TBI, atomoxetine was found to be effective in the treatment of akinetic mutism following subarachnoid haemorrhage in a case report.

Contraindications

Contraindications include:

  • Any cardiovascular disease including:
    • Moderate to severe hypertension
    • Atrial fibrillation
    • Atrial flutter
    • Ventricular tachycardia
    • Ventricular fibrillation
    • Ventricular flutter
    • Advanced arteriosclerosis
  • Severe cardiovascular disorders
  • Uncontrolled hyperthyroidism
  • Pheochromocytoma
  • Concomitant treatment with monoamine oxidase inhibitors (MAOIs)
  • Narrow-angle glaucoma

Adverse Effects

Common side effects include abdominal pain, decreased appetite, nausea, feeling tired, and dizziness. Serious side effects may include angioedema, liver problems, stroke, psychosis, heart problems, suicide, and aggression. A 2020 meta-analysis found that atomoxetine was associated with anorexia, weight loss, and hypertension, rating it as a “potentially least preferred agent based on safety” for treating ADHD. As of 2019, safety in pregnancy and breastfeeding is not clear; a 2018 review stated that, “[b]ecause of lack of data, the treating physician should consider stopping atomoxetine treatment in women with ADHD during pregnancy.”

The US Food and Drug Administration (FDA) has issued a black box warning for suicidal behaviour/ideation. Similar warnings have been issued in Australia. Unlike stimulant medications, atomoxetine does not have abuse liability or the potential to cause withdrawal effects on abrupt discontinuation.

Overdose

Atomoxetine is relatively non-toxic in overdose. Single-drug overdoses involving over 1500 mg of atomoxetine have not resulted in death.

Interactions

Atomoxetine is a substrate for CYP2D6. Concurrent treatment with a CYP2D6 inhibitor such as bupropion, fluoxetine, or paroxetine has been shown to increase plasma atomoxetine by 100% or more, as well as increase N-desmethylatomoxetine levels and decrease plasma 4-hydroxyatomoxetine levels by a similar degree.

Atomoxetine has been found to directly inhibit hERG potassium currents with an IC50 of 6.3 μM, which has the potential to cause arrhythmia. QT prolongation has been reported with atomoxetine at therapeutic doses and in overdose; it is suggested that atomoxetine not be used with other medications that may prolong the QT interval, concomitantly with CYP2D6 inhibitors, and caution to be used in poor metabolisers.

Other notable drug interactions include:

  • Antihypertensive agents, due to atomoxetine acting as an indirect sympathomimetic.
  • Indirect-acting sympathomimetics, such as pseudoephedrine, other norepinephrine reuptake inhibitors (NRIs), or MAOIs.
  • Direct-acting sympathomimetics, such as phenylephrine or other α1-adrenergic receptor agonists, including vasopressors such as dobutamine or isoprenaline and β2-adrenergic receptor agonists.
  • Highly plasma protein-bound drugs: atomoxetine has the potential to displace these drugs from plasma proteins which may potentiate their adverse or toxic effects. In vitro, atomoxetine does not affect the plasma protein binding of aspirin, desipramine, diazepam, paroxetine, phenytoin, or warfarin.

Atomoxetine prevents norepinephrine release induced by amphetamines and has been found to reduce the stimulant, euphoriant, and sympathomimetic effects of dextroamphetamine in humans.

Pharmacology

Pharmacodynamics

Atomoxetine inhibits the presynaptic norepinephrine transporter (NET), preventing the reuptake of norepinephrine throughout the brain along with inhibiting the reuptake of dopamine in specific brain regions such as the prefrontal cortex, where dopamine transporter (DAT) expression is minimal. In rats, atomoxetine increased prefrontal cortex catecholamine concentrations without altering dopamine levels in the striatum or nucleus accumbens; in contrast, methylphenidate, a dopamine reuptake inhibitor, was found to increase prefrontal, striatal, and accumbal dopamine levels to the same degree. In addition to rats, atomoxetine has also been found to induce similar region-specific catecholamine level alteration in mice.

Atomoxetine’s status as a serotonin transporter (SERT) inhibitor at clinical doses in humans is uncertain. A PET imaging study on rhesus monkeys found that atomoxetine occupied >90% and >85% of neural NET and SERT, respectively. However, both mouse and rat microdialysis studies have failed to find an increase in extracellular serotonin in the prefrontal cortex following acute or chronic atomoxetine treatment. Supporting atomoxetine’s selectivity, a human study found no effects on platelet serotonin uptake (a marker of SERT inhibition) and inhibition of the pressor effects of tyramine (a marker of NET inhibition).

Atomoxetine has been found to act as an NMDA receptor antagonist in rat cortical neurons at therapeutic concentrations. It causes a use-dependent open-channel block and its binding site overlaps with the Mg2+ binding site. Atomoxetine’s ability to increase prefrontal cortex firing rate in anaesthetised rats could not be blocked by D1 or α1-adrenergic receptor antagonists, but could be potentiated by NMDA or an α2-adrenergic receptor antagonist, suggesting a glutaminergic mechanism. In Sprague Dawley rats, atomoxetine reduces NR2B protein content without altering transcript levels. Aberrant glutamate and NMDA receptor function have been implicated in the aetiology of ADHD.

Atomoxetine also reversibly inhibits GIRK currents in Xenopus oocytes in a concentration-dependent, voltage-independent, and time-independent manner. Kir3.1/3.2 ion channels are opened downstream of M2, α2, D2, and A1 stimulation, as well as other Gi-coupled receptors. Therapeutic concentrations of atomoxetine are within range of interacting with GIRKs, especially in CYP2D6 poor metabolisers. It is not known whether this contributes to the therapeutic effects of atomoxetine in ADHD.

4-Hydroxyatomoxetine, the major active metabolite of atomoxetine in CYP2D6 extensive metabolizers, has been found to have sub-micromolar affinity for opioid receptors, acting as an antagonist at μ-opioid receptors and a partial agonist at κ-opioid receptors. It is not known whether this action at the kappa-opioid receptor leads to CNS-related adverse effects.

Pharmacokinetics

Orally administered atomoxetine is rapidly and completely absorbed. First-pass metabolism by the liver is dependent on CYP2D6 activity, resulting in an absolute bioavailability of 63% for extensive metabolisers and 94% for poor metabolisers. Maximum plasma concentration is reached in 1–2 hours. If taken with food, the maximum plasma concentration decreases by 10–40% and delays the tmax by 3 hours. Drugs affecting gastric pH have no effect on oral bioavailability.

Following intravenous delivery, atomoxetine has a volume of distribution of 0.85 L/kg (indicating distribution primarily in total body water), with limited partitioning into red blood cells. It is highly bound to plasma proteins (98.7%), mainly albumin, along with α1-acid glycoprotein (77%) and IgG (15%). Its metabolite N-desmethylatomoxetine is 99.1% bound to plasma proteins, while 4-hydroxyatomoxetine is only 66.6% bound.

The half-life of atomoxetine varies widely between individuals, with an average range of 4.5 to 19 hours. As atomoxetine is metabolised by CYP2D6, exposure may be increased 10-fold in CYP2D6 poor metabolisers. Among CYP2D6 extensive metabolisers, the half-life of atomoxetine averaged 5.34 hours and the half-life of the active metabolite N-desmethylatomoxetine was 8.9 hours. By contrast, among CYP2D6 poor metabolisers the half-life of atomoxetine averaged 20.0 hours and the half-life of N-desmethylatomoxetine averaged 33.3 hours. Steady-state levels of atomoxetine are typically achieved at or around day 10 of regular dosing, with trough plasma concentrations (Ctrough) residing around 30–40°ng/mL; however, both the time to steady-state levels and Ctrough are expected to vary based on a patient’s CYP2D6 profile.

Atomoxetine, N-desmethylatomoxetine, and 4-hydroxyatomoxetine produce minimal to no inhibition of CYP1A2 and CYP2C9, but inhibit CYP2D6 in human liver microsomes at concentrations between 3.6 and 17 μmol/L. Plasma concentrations of 4-hydroxyatomoxetine and N-desmethylatomoxetine at steady state are 1.0% and 5% that of atomoxetine in CYP2D6 extensive metabolisers, and are 5% and 45% that of atomoxetine in CYP2D6 poor metabolizers.

Atomoxetine is excreted unchanged in urine at <3% in both extensive and poor CYP2D6 metabolisers, with >96% and 80% of a total dose being excreted in urine, respectively. The fractions excreted in urine as 4-hydroxyatomoxetine and its glucuronide account for 86% of a given dose in extensive metabolisers, but only 40% in poor metabolisers. CYP2D6 poor metabolizers excrete greater amounts of minor metabolites, namely N-desmethylatomoxetine and 2-hydroxymethylatomoxetine and their conjugates.

Pharmacogenomics

Chinese adults homozygous for the hypoactive CYP2D6*10 allele have been found to exhibit two-fold higher area-under-the-curve (AUCs) and 1.5-fold higher maximum plasma concentrations compared to extensive metabolisers.

Japanese men homozygous for CYP2D6*10 have similarly been found to experience two-fold higher AUCs compared to extensive metabolisers.

Chemistry

Atomoxetine, or (−)-methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropylamine, is a white, granular powder that is highly soluble in water.

Detection in Biological Fluids

Atomoxetine may be quantitated in plasma, serum, or whole blood to distinguish extensive versus poor metabolisers 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.

Society and Culture

The drug was originally known as tomoxetine. It was renamed to avoid medication errors, as the name may be confused with tamoxifen.

Brand Names

In India, atomoxetine is sold under brand names including Axetra, Axepta, Attera, Tomoxetin, and Attentin. In Australia, Canada, Italy, Portugal, Romania, Spain, Switzerland, and the US, atomoxetine is sold under the brand name Strattera. In France, hospitals dispense atomoxetine under the brand name Strattera (it is not marketed in France). In the Czech Republic, it is sold under brand names including Mylan. In Poland, it is sold under the brand name Auroxetyn. In Iran, atomoxetine is sold under brand names including Stramox. In Brazil, it is sold under the brand name Atentah. In Turkey, it is sold under the brand names Attex, Setinox, and Atominex. In 2017, a generic version was approved in the United States.

Research

There has been some suggestion that atomoxetine might be a helpful adjunct in people with major depression, particularly in cases with concomitant ADHD.

Atomoxetine may be used in those with ADHD and bipolar disorder although such use has not been well studied. Some benefit has also been seen in people with ADHD and autism. As with other norepinephrine reuptake inhibitors it appears to reduce anxiety and depression symptoms, although attention has focused mainly on specific patient groups such as those with concurrent ADHD or methamphetamine dependence.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Atomoxetine >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Dexmethylphenide?

Published on by Andrew MarshallLeave a comment

Introduction

Dexmethylphenidate, sold under the brand name Focalin among others, is a potent central nervous system (CNS) stimulant used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years. It is taken by mouth. The immediate release formulation lasts up to five hours while the extended release formulation lasts up to twelve hours. It is the more active enantiomer of methylphenidate.

Common side effects include abdominal pain, loss of appetite, and fever. Serious side effects may include abuse, psychosis, sudden cardiac death, mania, anaphylaxis, seizures, and dangerously prolonged erection. Safety during pregnancy and breastfeeding is unclear. Dexmethylphenidate is a central nervous system (CNS) stimulant. How it works in ADHD is unclear.

Dexmethylphenidate was approved for medical use in the United States in 2001. It is available as a generic medication. In 2020, it was the 130th most commonly prescribed medication in the United States, with more than 4 million prescriptions.

Medical Uses

Dexmethylphenidate is used as a treatment for ADHD, usually along with psychological, educational, behavioural or other forms of treatment. It is proposed that stimulants help ameliorate the symptoms of ADHD by making it easier for the user to concentrate, avoid distraction, and control behaviour. Placebo-controlled trials have shown that once-daily dexmethylphenidate XR was effective and generally well tolerated.

Improvements in ADHD symptoms in children were significantly greater for dexmethylphenidate XR versus placebo. It also showed greater efficacy than osmotic controlled-release oral delivery system (OROS) methylphenidate over the first half of the laboratory classroom day but assessments late in the day favoured OROS methylphenidate.

Contraindications

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

Pregnant women are advised to only use the medication if the benefits outweigh the potential risks. Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on foetal development. In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it “is not a major human teratogen”.

Adverse Effects

Products containing dexmethylphenidate have a side effect profile comparable to those containing methylphenidate.

The most common side effects associated with methylphenidate (in standard and extended-release formulations) are 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), Oromandibular dystonia, lethargy (drowsiness/fatigue), and dizziness. Cardiac adverse effects may include palpitations, changes in blood pressure, and heart rate (typically mild), and tachycardia (rapid heart rate). Ophthalmologic adverse effects may include blurred vision caused by pupil dilatation and dry eyes, with less frequent reports of diplopia and mydriasis.

Smokers with ADHD who take methylphenidate may increase their nicotine dependence, and smoke more often than before they began using methylphenidate, with increased nicotine cravings and an average increase of 1.3 cigarettes per day.

There is some evidence of mild reductions in height with prolonged treatment in children. This has been estimated at 1 centimetre (0.4 in) or less per year during the first three years with a total decrease of 3 centimetres (1.2 in) over 10 years.

Hypersensitivity (including skin rash, urticaria, and fever) is sometimes reported when using transdermal methylphenidate. The Daytrana patch has a much higher rate of skin reactions than oral methylphenidate.

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

US Food and Drug Administration-commissioned studies in 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.

A 2018 Cochrane review found that methylphenidate might be associated with serious side effects such as heart problems, psychosis, and death. The certainty of the evidence was stated as very low.

The same review found tentative evidence that it may cause both serious and non-serious adverse effects in children.

Overdose

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomiting, nausea, 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), rhabdomyolysis, coma, and circulatory collapse. A methylphenidate overdose is rarely fatal with appropriate care. Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.

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

Addiction and Dependence

Methylphenidate is a stimulant with an addiction liability and dependence liability similar to amphetamine. It has 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.

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; 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.

Interactions

Methylphenidate may inhibit the metabolism of vitamin K 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 ethanol. 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.

Mode of Activity

Methylphenidate is a catecholamine reuptake inhibitor that indirectly increases catecholaminergic neurotransmission by inhibiting the dopamine transporter (DAT) and norepinephrine transporter (NET), which are responsible for clearing catecholamines from the synapse, particularly in the striatum and meso-limbic system. Moreover, it is thought to “increase the release of these monoamines into the extraneuronal space.”

Although four stereoisomers of methylphenidate (MPH) are possible, only the threo diastereoisomers are used in modern practice. There is a high eudysmic ratio between the SS and RR enantiomers of MPH. Dexmethylphenidate (d-threo-methylphenidate) is a preparation of the RR enantiomer of methylphenidate. In theory, D-TMP (d-threo-methylphenidate) can be anticipated to be twice the strength of the racemic product

Pharmacology

Dexmethylphenidate has a 4–6 hour duration of effect. A long-acting formulation, Focalin XR, which spans 12 hours is also available and has been shown to be as effective as DL (dextro-, levo-)-TMP (threo-methylphenidate) XR (extended release) (Concerta, Ritalin LA), with flexible dosing and good tolerability. It has also been demonstrated to reduce ADHD symptoms in both children and adults. d-MPH has a similar side-effect profile to MPH and can be administered without regard to food intake.

This page is based on the copyrighted Wikipedia article < https://en.wikipedia.org/wiki/Dexmethylphenidate >; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Methylphenidate?

Published on by Andrew Marshall2 Comments

Introduction

Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a central nervous system (CNS) stimulant used medically to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a primary medication for ADHD (e.g. in the UK); it may be taken by mouth or applied to the skin, and different formulations have varying durations of effect, commonly ranging from 2–4 hours.

Common adverse reactions of methylphenidate include: tachycardia, palpitations, headache, insomnia, anxiety, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, and abdominal pain. Withdrawal symptoms may include: chills, depression, drowsiness, dysphoria, exhaustion, headache, irritability, lethargy, nightmares, restlessness, suicidal thoughts, and weakness.

Methylphenidate is believed to work by blocking the reuptake of dopamine and norepinephrine by neurons. It is a central nervous system (CNS) stimulant of the phenethylamine and piperidine classes.

Etymology

The word methylphenidate is a portmanteau of the chemical name, Methyl-2-phenyl-2-(piperidin-2-yl) acetate.

Brief History

Methylphenidate was first synthesized in 1944 was approved for medical use in the United States in 1955. It was synthesized by chemist Leandro Panizzon and sold by Swiss company CIBA (now Novartis). He named the drug after his wife Margarita, nicknamed Rita, who used Ritalin to compensate for low blood pressure. Methylphenidate was not reported to be a stimulant until 1954. The drug was introduced for medical use in the United States in 1957. Originally, it was marketed as a mixture of two racemates, 80% (±)-erythro and 20% (±)-threo, under the brand name Centedrin. 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. The erythro isomer was eliminated and now modern formulations of methyphenidate contain only the threo isomer at a 50:50 mixture of d- and l-isomers.

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 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 FDA (Food and Drug Administration) approval to market Concerta, an extended-release form of methylphenidate.

It was estimated that the number of doses of methylphenidate used globally in 2013 increased by 66% compared to 2012. In 2020, it was the 41st most commonly prescribed medication in the United States, with more than 15 million prescriptions. It is available as a generic medication.

Uses

Methylphenidate is most commonly used to treat ADHD and narcolepsy.

Attention Deficit Hyperactivity Disorder

Methylphenidate is used for the treatment of attention deficit hyperactivity disorder. The addition of behavioural modification therapy can have additional benefits on treatment outcome. The dosage may vary and is titrated to effect, with some guidelines recommending initial treatment with a low dose. Immediate-release methylphenidate is used daily along with the longer-acting form to achieve full-day control of symptoms. Methylphenidate is not approved for children under six years of age.

In children over age 6 and adolescents, the short-term benefits and cost effectiveness of methylphenidate are well established. A number of reviews have established the safety and effectiveness for individuals with ADHD over several years.

Approximately 70% of those who use methylphenidate see improvements in ADHD symptoms. Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans. There is evidence to suggest that children diagnosed with ADHD who do not receive treatment will have an increased risk of substance use disorders as adults.

The precise magnitude of improvement in ADHD symptoms and quality of life produced by methylphenidate treatment remains uncertain as of March 2023. Methylphenidate is not included in the World Health Organisation (WHO) Essential Medicines List, as findings by the WHO indicate evidence of benefit versus harm to be unclear in the treatment of ADHD. A 2021 systematic review did not find clear evidence for using IR methylphenidate (immediate-release) for adults.[34]

Since ADHD diagnosis has increased around the world, methylphenidate may be misused as a “study drug” by some populations, which may be harmful. This also applies to people who 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.

Narcolepsy

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

Other Medical Uses

Methylphenidate may also be prescribed for off-label use in treatment-resistant cases of bipolar disorder and major depressive disorder. It can also improve depression in several groups including stroke, cancer, and HIV-positive patients. There is weak evidence in favour of methylphenidate’s effectiveness for depression, including providing additional benefit in combination with antidepressants. 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. A 2021 systematic review and meta-analysis found that all studies on geriatric depression reported positive results of methylphenidate use; the review recommended short-term use in combination with citalopram. A 2018 review found low quality evidence supporting its use to treat apathy as seen in Alzheimer’s disease in addition to slight benefits for cognition and cognitive performance.

Enhancing Performance

Methylphenidate’s efficacy as a athletic performance enhancer, cognitive enhancer, aphrodisiac, and euphoriant is supported by research. However, the manner in which methylphenidate is used for these purposes (high doses and temperatures, alternate routes of administration, etc.) can result in severe unintended side effects. A 2015 review found that therapeutic doses of amphetamine and methylphenidate result in modest 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 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, glaucoma, heart defects or a hypersensitivity to any ingredients contained in methylphenidate pharmaceuticals.

Pregnant women are advised to only use the medication if the benefits outweigh the potential risks. Not enough human studies have been conducted to conclusively demonstrate an effect of methylphenidate on foetal development. In 2018, a review concluded that it has not been teratogenic in rats and rabbits, and that it “is not a major human teratogen”.

Adverse Effects

The most common side effects associated with methylphenidate (in standard and extended-release formulations) are 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), oromandibular dystonia, lethargy (drowsiness/fatigue), and dizziness. Cardiac adverse effects may include palpitations, changes in blood pressure, and heart rate (typically mild), and tachycardia (rapid heart rate). Ophthalmologic adverse effects may include blurred vision caused by pupil dilatation and dry eyes, with less frequent reports of diplopia and mydriasis.

Smokers with ADHD who take methylphenidate may increase their nicotine dependence, and smoke more often than before they began using methylphenidate, with increased nicotine cravings and an average increase of 1.3 cigarettes per day.

There is some evidence of mild reductions in height with prolonged treatment in children. This has been estimated at 1 centimetre (0.4 in) or less per year during the first three years with a total decrease of 3 centimetres (1.2 in) over 10 years.

Hypersensitivity (including skin rash, urticaria, and fever) is sometimes reported when using transdermal methylphenidate. The Daytrana patch has a much higher rate of skin reactions than oral methylphenidate.

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

U.S. Food and Drug Administration-commissioned studies in 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.

A 2018 Cochrane review found that methylphenidate might be associated with serious side effects such as heart problems, psychosis, and death. The certainty of the evidence was stated as very low.

The same review found tentative evidence that it may cause both serious and non-serious adverse effects in children.

Overdose

The symptoms of a moderate acute overdose on methylphenidate primarily arise from central nervous system overstimulation; these symptoms include: vomiting, nausea, 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), rhabdomyolysis, coma, and circulatory collapse. A methylphenidate overdose is rarely fatal with appropriate care. Following injection of methylphenidate tablets into an artery, severe toxic reactions involving abscess formation and necrosis have been reported.

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

Addiction and Dependence

Methylphenidate is a stimulant with an addiction liability and dependence liability similar to amphetamine. It has 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.

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; 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.

Interactions

Methylphenidate may inhibit the metabolism of vitamin K 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 ethanol. 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

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 a psychostimulant and increases the activity of the central nervous system through inhibition on reuptake of the neurotransmitters norepinephrine and dopamine. As models of ADHD suggest, it is associated with functional impairments in some of the brain’s neurotransmitter systems, particularly those involving dopamine in the mesocortical and mesolimbic pathways and norepinephrine in the prefrontal cortex and locus coeruleus. Psychostimulants like methylphenidate and amphetamine may be effective in treating ADHD because they increase neurotransmitter activity in these systems. When reuptake of those neurotransmitters is halted, its concentration and effects in the synapse increase and last longer, respectively. Therefore, methylphenidate is called a norepinephrine–dopamine reuptake inhibitor. By increasing the effects of norepinephrine and dopamine, methylphenidate increases the activity of the central nervous system and produces effects such as increased alertness, reduced fatigue, and improved attention.

Methylphenidate is most active at modulating levels of dopamine (DA) and to a lesser extent norepinephrine (NE). Methylphenidate binds to and blocks dopamine transporters (DAT) and norepinephrine transporters (NET). 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. 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.

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 5HT1A and 5HT2B subtypes, though direct binding to the serotonin transporter was not observed. A later study confirmed the d-threo-methylphenidate (dexmethylphenidate) binding to the 5HT1A receptor, but no significant activity on the 5HT2B receptor was found.

There exist some paradoxical findings that oppose the notion that methylphenidate acts as silent antagonist of the DAT (DAT inhibitor). 80% occupancy of the DAT is necessary for methylphenidate’s euphoriant effect, but re-administration of methylphenidate beyond this level of DAT occupancy has been found to produce similarly potent euphoriant effects (despite DAT occupancy being unchanged with repeated administration). By contrast, other DAT inhibitors such as bupropion have not been observed to exhibit this effect. These observations help corroborate the hypothesis that methylphenidate may act as a “DAT inverse agonist” or “negative allosteric modifier of the DAT” by reversing the direction of the dopamine efflux by the DAT at higher dosages.

Methylphenidate may protect neurons from the neurotoxic effects of Parkinson’s disease and methamphetamine use disorder. 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. The studied maximised daily dosage of OROS methylphenidate appears to be 144 mg/day.

Pharmacokinetics

Methylphenidate taken by mouth has a bioavailability of 11–52% with a duration of 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. Methylphenidate has a low plasma protein binding of 10–33% and a volume of distribution of 2.65 L/kg.

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

The oral bioavailability and speed of absorption for immediate-release methylphenidate is increased when administered with a meal. The effects of a high fat meal on the observed Cmax differ between some extended-release formulations, with combined IR/ER and OROS formulations showing reduced Cmax levels while liquid-based extended-release formulations showed increased Cmax levels when administered with a high-fat meal, according to some researchers. A 2003 study, however, showed no difference between a high-fat meal administration and a fasting administration of oral methylphenidate.

Methylphenidate is metabolised into ritalinic acid by CES1A1 enzymes in the liver. Dextromethylphenidate is selectively metabolised at a slower rate than levomethylphenidate. 97% of the metabolised drug is excreted in the urine, and between 1 and 3% is excreted in the faeces. A small amount, less than 1%, of the drug is excreted in the urine in its unchanged form.

Society and Culture

Names

Methylphenidate is sold in the majority of countries worldwide.  Brand names for methylphenidate include Ritalin (in honour to Rita, the wife of the molecule discoverer), Rilatine (in Belgium to avoid a conflict of commercial name with the RIT pharmaceutical company), Concerta, Medikinet, Adaphen, Addwize, Inspiral, Methmild, Artige, Attenta, Cognil, Equasym, Foquest, Methylin, Penid, Phenida, Prohiper, and Tradea.

Available Forms

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 equally potent doses, and so it is sometimes considered to be an example of an “evergreened” drug.

Immediate-Release

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

Extended-Release

Concerta tablets are marked with the letters “ALZA” and followed by: “18”, “27”, “36”, or “54”, relating to the dosage strength in milligrams. 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.

Medikinet Retard/CR/Adult/Modified Release tablets is an extended-release oral capsule form of methylphenidate. It delivers 50% of dosage as IR MPH and the remaining 50% in 3–4 hours.

Skin Patch

A methylphenidate skin patch is sold under the brand name Daytrana in the United States. It was developed and marketed by Noven Pharmaceuticals and approved in the US in 2006. It is also referred to as methylphenidate transdermal system (MTS). It is approved as a once-daily treatment in children with ADHD aged 6–17 years. It is mainly prescribed as a second-line treatment when oral forms are not well tolerated, or if people have difficulty with compliance. Noven’s original FDA submission indicated that it should be used for 12 hours. When the FDA rejected the submission, they requested evidence that a shorter time period was safe and effective; Noven provided such evidence and it was approved for a 9-hour period.

Orally administered methylphenidate is subject to first-pass metabolism, by which the levo-isomer is extensively metabolised. By circumventing this first-pass metabolism, the relative concentrations of ℓ-threo-methylphenidate are much higher with transdermal administration (50–60% of those of dexmethylphenidate instead of about 14–27%).

A 39 nanograms/mL peak serum concentration of methylphenidate has been found to occur between 7.5–10.5 hours after administration. However, the onset to peak effect is 2 hours, and the clinical effects remain up to 2 hours after the patch has been removed. The absorption is increased when the transdermal patch is applied onto inflamed skin or skin that has been exposed to heat. The absorption lasts for approximately 9 hours after application (onto normal, unexposed to heat and uninflamed skin). 90% of the medication is excreted in the urine as metabolites and unchanged drug.

Parenteral Formulation

When it was released in the United States, methylphenidate was available from CIBA in a parenteral for use by medical professionals. It came in 10mL multiple dose vials containing 100 mg methylphenidate HCl and 100 mg lactose in lyophilized (freeze-dried) form. It was also available as single dose ampoules of containing 20 mg methylphenidate HCl. Instructions were to reconstitute with 10mL sterile solvent (water). The indication was 10 to 20 mg (1.0mL from MDV’s, up to one full single use ampoule) to produce a focused, talkative state that could help certain patients breakdown the resistance to therapy. Parenteral methylphenidate was discounted out of a concern for the actual benefit and of inducing a psychic dependence. This is not truth serum in the normal sense as it does not impair ability to control the flow of information like a barbiturate agent (Pentothal©) or similar might.

Cost

Brand-name and generic formulations are available.

Legal Status

  • 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 recognised medical value but present a high potential for misuse.
  • 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 Russia, methylphenidate is a List I controlled psychotropic substance without recognized medical value. The Constant Committee for Drug Control of the Russian Ministry of Health has put methylphenidate and its derivatives on the National List of Narcotics, Psychotropic Substances and Their Precursors, and the Government banned methylphenidate for any use on 25 October 2014.
  • 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. Legally, 2 grams of methylphenidate is classified as a small quantity, and 50 grams as a large or commercial quantity.
  • In Hong Kong, methylphenidate is controlled under the schedule 1 of the Dangerous Drugs Ordinance (cap. 134).

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. People treated with stimulants such as methylphenidate during childhood were less likely to have substance use disorders in adulthood.

Among countries with the highest rates of use of methylphenidate medication is Iceland, where research shows that the drug was the most commonly used substance among people who inject drugs. The study involved 108 people who inject drugs 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.

Research

Methylphenidate may be effective as a treatment for apathy in Alzheimer’s disease.

Replacement Therapy

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. Its effectiveness in treatment of cocaine, psychostimulant addiction or psychological dependence has not been proven.

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What is Disruptive Mood Dysregulation Disorder?

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Introduction

Disruptive mood dysregulation disorder (DMDD) is a mental disorder in children and adolescents characterised by a persistently irritable or angry mood and frequent temper outbursts that are disproportionate to the situation and significantly more severe than the typical reaction of same-aged peers.

DMDD was added to the DSM-5 as a type of depressive disorder diagnosis for youths. The symptoms of DMDD resemble those of attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), anxiety disorders, and childhood bipolar disorder.

DMDD first appeared as a disorder in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) in 2013 and is classified as a mood disorder. Treatments include medication to manage mood symptoms as well as individual and family therapy to address emotion-regulation skills. Children with DMDD are at risk for developing depression and anxiety later in life.

Brief History

Beginning in the 1990s, some clinicians began observing children with hyperactivity, irritability, and severe temper outbursts. These symptoms greatly interfered with their lives at home, school, and with friends. Because other diagnoses, like ADHD and ODD, did not capture the severity of children’s irritability and anger, many of these children were diagnosed with bipolar disorder. Longitudinal studies showed that children with chronic irritability and temper outbursts often developed later problems with anxiety and depression, and rarely developed bipolar disorder in adolescence or adulthood. Consequently, the developers of DSM-5 created a new diagnostic label, DMDD, to describe children with persistent irritability and angry outbursts. In 2013, the American Psychiatric Association (APA) added DMDD to the DSM-5 and classified it as a depressive disorder.

Signs and Symptoms

Children with DMDD show severe and recurrent temper outbursts three or more times per week. These outbursts can be verbal or behavioural. Verbal outbursts often are described by observers as “rages”, “fits”, or “tantrums”. Children may scream, yell, and cry for excessively long periods of time, sometimes with little provocation. Physical outbursts may be directed toward people or property. Children may throw objects; hit, slap, or bite others; destroy toys or furniture; or otherwise act in a harmful or destructive manner.

Children with DMDD also display persistently irritable or angry mood that is observable by others. Parents, teachers, and classmates describe these children as habitually angry, touchy, grouchy, or easily “set off”. Unlike the irritability that can be a symptom of other childhood disorders, such as ODD, anxiety disorders, and major depressive disorder (MDD), the irritability displayed by children with DMDD is not episodic or situation-dependent. In DMDD, the irritability or anger is severe and is shown most of the day, nearly every day in multiple settings, lasting for one or more years.

The DSM-5 includes several additional diagnostic criteria which describe the duration, setting, and onset of the disorder: the outbursts must be present for at least 12 months and occur in at least two settings (e.g. home and school), and it must be severe in at least one setting. Symptoms appear before the age of 10, and diagnosis must be made between ages 6 and 18.

Comorbidity

The core features of DMDD – temper outbursts and chronic irritability – are sometimes seen in children and adolescents with other psychiatric conditions. Differentiating DMDD from these other conditions can be difficult. Three disorders that most closely resemble DMDD are ADHD, oppositional defiant disorder (ODD), and bipolar disorder in children.

ADHD

ADHD is a neurodevelopmental disorder characterised by problems with inattention and/or hyperactivity-impulsivity.

ODD

ODD is a disruptive behaviour disorder characterised by oppositional, defiant, and sometimes hostile actions directed towards others.

Bipolar Disorder

One of the main differences between DMDD and bipolar disorder is that the irritability and anger outbursts associated with DMDD are not episodic; symptoms of DMDD are chronic and displayed constantly on an almost daily basis. On the other hand, bipolar disorder is characterised by distinct manic or hypomanic episodes usually lasting a few days, or a few weeks at most, that parents should be able to differentiate from their child’s typical mood and behaviour in between episodes. The DSM precludes a dual diagnosis of DMDD and bipolar disorder. Bipolar disorder alone should be used for youths who show classic symptoms of episodic mania or hypomania.

Prior to adolescence, DMDD is much more common than bipolar disorder. Most children with DMDD see a decrease in symptoms as they enter adulthood, whereas individuals with bipolar disorder typically display symptoms for the first time as teenagers and young adults. Children with DMDD are more at risk for developing MDD or generalised anxiety disorder when they are older rather than bipolar disorder.

Causes

Youth with DMDD have difficulty attending, processing, and responding to negative emotional stimuli and social experiences in their everyday lives. For example, some studies have shown youths with DMDD to have problems interpreting the social cues and emotional expressions of others. These youths may be especially bad at judging others’ negative emotional displays, such as feelings of sadness, fearfulness, and anger. Functional MRI studies suggest that under-activity of the amygdala, the brain area that plays a role in the interpretation and expression of emotions and novel stimuli, is associated with these deficits. Deficits in interpreting social cues may predispose children to instances of anger and aggression in social settings with little provocation. For examples, youths with DMDD may selectively attend to negative social cues (e.g. others scowling, teasing) and minimize all other information about the social events. They may also misinterpret the emotional displays of others, believing others’ benign actions to be hostile or threatening. Consequently, they may be more likely than their peers to act in impulsive and angry ways.

Children with DMDD may also have difficulty regulating negative emotions once they are elicited. To study these problems with emotion regulation, researchers asked children with DMDD to play computer games that are rigged so that children will lose. While playing these games, children with DMDD report more agitation and negative emotional arousal than their typically-developing peers. Furthermore, youths with DMDD showed markedly greater activity in the medial frontal gyrus and anterior cingulate cortex compared to other youths. These brain regions are important because they are involved in evaluating and processing negative emotions, monitoring one’s own emotional state, and selecting an effective response when upset, angry, or frustrated. Altogether, these findings suggest that youths with DMDD are more strongly influenced by negative events than other youths. They may become more upset and select less effective and socially acceptable ways to deal with negative emotions when they arise.

Treatment

Medication

Evidence for treatment is weak, and treatment is determined based on the physician’s response to the symptoms that people with DMDD present. Because the mood stabilizing medication, lithium, is effective in treating adults with bipolar disorder, some physicians have used it to treat DMDD although it has not been shown to be better than placebo in alleviating the signs and symptoms of DMDD.[7] DMDD is treated with a combination of medications that target the child’s symptom presentation. For youths with DMDD alone, antidepressant medication is sometimes used to treat underlying problems with irritability or sadness. For youths with unusually strong temper outbursts, an atypical antipsychotic medication, such as risperidone, may be warranted. Both medications, however, are associated with significant side effects in children. Finally, for children with both DMDD and ADHD, stimulant medication is sometimes used to reduce symptoms of impulsivity.

Psychosocial

Several cognitive-behavioural interventions have been developed to help youths with chronic irritability and temper outbursts. Because many youths with DMDD show problems with ADHD and oppositional-defiant behaviour, experts initially tried to treat these children using contingency management. This type of intervention involves teaching parents to reinforce children’s appropriate behaviour and extinguish (usually through systematic ignoring or time out) inappropriate behaviour. Although contingency management can be helpful for ADHD and ODD symptoms, it does not seem to reduce the most salient features of DMDD, namely, irritability and anger.

Epidemiology

There are not good estimates of the prevalence of DMDD, but primary studies have found a rate of 0.8 to 3.3%. Epidemiological studies show that approximately 3.2% of children in the community have chronic problems with irritability and temper, the essential features of DMDD. These problems are probably more common among clinic-referred youths. Parents report that approximately 30% of children hospitalised for psychiatric problems meet diagnostic criteria for DMDD; 15% meet criteria based on the observations of hospital staff.

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What is Logorrhoea?

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Introduction

In psychology, logorrhea or logorrhoea (from Ancient Greek λόγος logos “word” and ῥέω rheo “to flow”), is a communication disorder that causes excessive wordiness and repetitiveness, which can cause incoherency.

Logorrhoea is sometimes classified as a mental illness, though it is more commonly classified as a symptom of mental illness or brain injury. This ailment is often reported as a symptom of Wernicke’s aphasia, where damage to the language processing centre of the brain creates difficulty in self-centred speech.

Refer to Tangential Speech.

Characteristics

Logorrhoea is characterised by the constant need to talk. Occasionally, patients suffering from logorrhoea may produce speech with normal prosody and a slightly fast speech rate. Other related symptoms include the use of neologisms (new words without clear derivation, e.g. hipidomateous for hippopotamus), words that bear no apparent meaning, and, in some extreme cases, the creation of new words and morphosyntactic constructions. From the “stream of unchecked nonsense often under pressure and the lack of self-correction” that the patient may exhibit, and their circumlocution (the ability to talk around missing words) we may conclude that they are unaware of the grammatical errors they are making.

Examples of Logorrhoea

When a clinician said, “Tell me what you do with a comb”, to a patient suffering from mild Wernicke’s aphasia (which produces the symptom of logorrhoea), the patient responded:

“What do I do with a comb … what I do with a comb. Well a comb is a utensil or some such thing that can be used for arranging and rearranging the hair on the head both by men and by women. One could also make music with it by putting a piece of paper behind and blowing through it. Sometimes it could be used in art – in sculpture, for example, to make a series of lines in soft clay. It’s usually made of plastic and usually black, although it comes in other colors. It is carried in the pocket or until it’s needed, when it is taken out and used, then put back in the pocket. Is that what you had in mind?”

In this case, the patient maintained proper grammar and did not exhibit any signs of neologisms. However, the patient did use an overabundance of speech in responding to the clinician, as most people would simply respond, “I use a comb to comb my hair.”

In a more extreme version of logorrhoea aphasia, a clinician asked a male patient, also with Wernicke’s aphasia, what brought him to the hospital. The patient responded:

“Is this some of the work that we work as we did before? … All right … From when wine [why] I’m here. What’s wrong with me because I … was myself until the taenz took something about the time between me and my regular time in that time and they took the time in that time here and that’s when the time took around here and saw me around in it’s started with me no time and I bekan [began] work of nothing else that’s the way the doctor find me that way…”

In this example, the patient’s aphasia was much more severe. Not only was this a case of logorrhoea, but this included neologisms (such as “taenz” for “stroke” and “regular time” for “regular bath”) and a loss of proper sentence structure.

Causes

Logorrhoea has been shown to be associated with traumatic brain injuries in the frontal lobe[7] as well as with lesions in the thalamus] and the ascending reticular inhibitory system and has been associated with aphasia. Logorrhoea can also result from a variety of psychiatric and neurological disorders including tachypsychia, mania, hyperactivity, catatonia, ADHD and schizophrenia.

Aphasias

Wernicke’s Aphasia, amongst other aphasias, are often associated with logorrhoea. Aphasia refers to the neurological disruption of language that occurs as a consequence of brain dysfunction. For a patient to truly have an aphasia, they cannot have been diagnosed with any other medical condition that may affect their cognition. Logorrhoea is a common symptom of Wernicke’s Aphasia, along with circumlocution, paraphasias, and neologisms. Often a patient with aphasia may present all of these symptoms at one time.

Treatment

Excessive talking may be a symptom of an underlying illness and should be addressed by a medical provider if combined with hyperactivity or symptoms of mental illness, such as hallucinations. Treatment of logorrhoea depends on its underlying disorder, if any. Antipsychotics are often used, and lithium is a common supplement given to manic patients. For patients with lesions of the brain, attempting to correct their errors may upset and anger the patients, since the language centre of their brain may not be able to process that what they are saying is incorrect and wordy.

This page is based on the copyrighted Wikipedia article <https://en.wikipedia.org/wiki/Logorrhea_(psychology)&gt;; it is used under the Creative Commons Attribution-ShareAlike 3.0 Unported License (CC-BY-SA). You may redistribute it, verbatim or modified, providing that you comply with the terms of the CC-BY-SA.

What is Mazindol?

Published on by Andrew Marshall2 Comments

Introduction

Mazindol (brand names Mazanor, Sanorex) is a stimulant drug which is used as an appetite suppressant.

It was developed by Sandoz-Wander in the 1960s.

Medical Uses

Mazindol is used in short-term (i.e. a few weeks) treatment of obesity, in combination with a regimen of weight reduction based on caloric restriction, exercise, and behaviour modification in people with a body mass index greater than 30, or in those with a body mass index greater than 27 in the presence of risk factors such as hypertension, diabetes, or hyperlipidaemia. Mazindol is not currently available as a commercially marketed and US Food and Drug Administration (FDA)-regulated prescription agent for the treatment of obesity.

There is a Swiss study investigating its efficacy in treating ADHD.

Pharmacology

Mazindol is a sympathomimetic amine, which is similar to amphetamine. It stimulates the central nervous system, which increases heart rate and blood pressure, and decreases appetite. Sympathomimetic anorectics (appetite suppressants) are used in the short-term treatment of obesity. Their appetite-reducing effect tends to decrease after a few weeks of treatment. Because of this, these medicines are useful only during the first few weeks of a weight-loss program.

Although the mechanism of action of the sympathomimetics in the treatment of obesity is not fully known, these medications have pharmacological effects similar to those of amphetamines. Like other sympathomimetic appetite suppressants, mazindol is thought to act as a reuptake inhibitor of norepinephrine. In addition, it inhibits dopamine and serotonin reuptake. The recommended dosage is 2 mg per day for 90 days in patients 40 kg overweight and under; 4 mg a day in patients more than 50 kg overweight; divided into two doses separated by a 12-hour window between each dose.

Overdose

Symptoms of a mazindol overdose include: restlessness, tremor, rapid breathing, confusion, hallucinations, panic, aggressiveness, nausea, vomiting, diarrhoea, an irregular heartbeat, and seizures.

Analogues

From available QSAR data, the following trends are apparent:

  • Desoxylation of the tertiary alcohol in mazindol improves DAT and SERT binding without substantially reducing NET affinity.
  • Removal of the p-chlorine atom from the phenyl ring of mazindol increases NET affinity and substantially reduces DAT and SERT affinity.
  • Expansion of the imidazoline ring system in mazindol to the corresponding six-membered homolog increases DAT affinity by ~10 fold.
  • Replacement of the phenyl moiety with a naphthyl ring system results in a ~50 fold increase in SERT affinity without significant decreases in NET or DAT affinities.
  • Halogenation of 3′ and/or 4′ position of the phenyl ring of mazindol results in increased potency at NET, DAT, and SERT.
  • Fluorination of the 7′ position of the tricyclic phenyl ring results in a ~2 fold increase in binding affinity to the DAT.

Research

As of 2016 mazindol was being studied in clinical trials for attention-deficit hyperactivity disorder.

What is Reboxetine?

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Introduction

Reboxetine, sold under the brand name Edronax among others, is a drug of the norepinephrine reuptake inhibitor (NRI) class, marketed as an antidepressant by Pfizer for use in the treatment of major depression, although it has also been used off-label for panic disorder and attention deficit hyperactivity disorder (ADHD).

It is approved for use in many countries worldwide, but has not been approved for use in the United States. Although its effectiveness as an antidepressant has been challenged in multiple published reports, its popularity has continued to increase.

Brief History

Reboxetine was discovered at Farmitalia-Carlo Erba and was first published in 1984; Farmitalia did the first clinical studies. Farmitalia was acquired by Pharmacia in 1993, and Pharmacia in turn was acquired by Pfizer in 2003.

It was first approved in Europe in 1997 and was provisionally approved by the US Food and Drug Administration (FDA) in 1999. In 2001 the FDA issued Pfizer a “not approvable” letter based on clinical trials the FDA had required when it issued the preliminary approval letter.

In 2010, the German Institute for Quality and Efficiency in Health Care (IQEHC) published results of a meta-analysis of clinical trial data for reboxetine in acute depression, which included data on about 3,000 subjects that Pfizer had never published but had mentioned; IQEHC had combed through Pfizer’s publications and reboxetine approvals and had determined this data was missing from the publication record. The analysis of the complete data set yielded a result that reboxetine was not more effective than placebo but had more side effects than placebo and more than fluoxetine; the paper led to widespread and sharp criticism of Pfizer, and stronger calls for publication of all clinical trial data.

Medical Uses

Major Depressive Disorder

There has been much debate as to whether reboxetine is more efficacious than placebo in the treatment of depression. According to a 2009 meta-analysis of 12 second-generation antidepressants, reboxetine was no more effective than placebo, and was “significantly less” effective, and less acceptable, than the other drugs in treating the acute-phase of adults with unipolar major depression.

The UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) said in September 2011 that the study had several limitations, and that “Overall the balance of benefits and risks for reboxetine remains positive in its authorised indication.” A UK and Europe-wide review of available efficacy and safety data has confirmed that reboxetine has benefit over placebo in its authorised indication. Efficacy was clearly shown in patients with severe or very severe depression.

According to a systematic review and meta-analysis by IQWiG, including unpublished data, published data on reboxetine overestimated the benefit of reboxetine versus placebo by up to 115% and reboxetine versus SSRIs by up to 23%, and also underestimated harm, concluding that reboxetine was an ineffective and potentially harmful antidepressant. The study also showed that nearly three quarters of the data on patients who took part in trials of reboxetine had not been published by Pfizer.

A 2018 systematic review and network meta-analysis comparing the efficacy and acceptability of 21 antidepressant drugs concluded that reboxetine was significantly less efficacious than other antidepressants tested.

Panic Disorder

In a randomised double-blind placebo-controlled trial reboxetine significantly improved the symptoms of panic disorder. Another randomised controlled trial that compared paroxetine to reboxetine found that paroxetine significantly outperformed reboxetine as a treatment for panic disorder. Despite this discouraging finding an open-label trial examining the efficacy of reboxetine in SSRI-resistant panic disorder demonstrated significant benefit from reboxetine treatment.

Attention Deficit Hyperactivity Disorder

Numerous clinical trials have provided support for the efficacy of reboxetine in the treatment of attention deficit hyperactivity disorder (ADHD) in both the short and long-term and in both children/adolescents and adults.

Other Uses

A case series and open-label pilot study demonstrated the efficacy of reboxetine in treating bulimia nervosa. Reboxetine may also have efficacy in treating therapy-resistant paediatric nocturnal enuresis. A pilot study demonstrated the efficacy of reboxetine in the treatment of narcolepsy. Individual trials and meta-analysis suggest that reboxetine can attenuate antipsychotic-induced weight gain and there is some evidence of a benefit on depressive, and possibly other symptoms of schizophrenia when added to antipsychotic treatment.

Contraindications

Reboxetine is contraindicated in narrow-angle glaucoma, cardiovascular disease, epilepsy, bipolar disorder, urinary retention, prostatic hypertrophy, patients concomitantly on MAOIs and those hypersensitive to reboxetine or any of its excipients.

Adverse Effects

Very common (>10% incidence) adverse effects include insomnia, dizziness, dry mouth, constipation, nausea, and excessive sweating.

Common (1-10%) adverse effects include loss of appetite, agitation, anxiety, headache, restlessness, tingling sensations, distorted sense of taste, difficulty with seeing near or far (problems with accommodation), fast heart beat, heart palpitations, relaxing of blood vessels leading to low blood pressure, high blood pressure, vomiting, rash, sensation of incomplete bladder emptying, urinary tract infection, painful or difficult urination, urinary retention, erectile dysfunction, ejaculatory pain or delay, and chills.

A 2009 meta-analysis found that reboxetine was significantly less well tolerated than the other 11 second-generation antidepressants compared in the analysis

Overdose

Reboxetine is considered a relatively low-risk antidepressant in overdose.[26] The symptoms are as follows:

  • Sweating.
  • Tachycardia.
  • Changes in blood pressure.

Interactions

Because of its reliance on CYP3A4, reboxetine O-desethylation is markedly inhibited by papaverine and ketoconazole. It weakly inhibits CYP2D6 and CYP3A4.[25] Reboxetine is an intermediate-level inhibitor of P-glycoprotein, which gives it the potential to interact with ciclosporin, tacrolimus, paroxetine, sertraline, quinidine, fluoxetine, fluvoxamine.

Pharmacology

Pharmacodynamics

Reboxetine is a fairly selective norepinephrine reuptake inhibitor (NRI), with approximately 20-fold selectivity for the norepinephrine transporter (NET) over the serotonin transporter (SERT). Despite this selectivity, reboxetine does slightly inhibit the reuptake of serotonin at therapeutic doses. It does not interact with or inhibit the dopamine transporter (DAT).

Reboxetine has been found to inhibit both brain and cardiac GIRKs, a characteristic it shares with the NRI atomoxetine.

Pharmacokinetics

Both the (R,R)-(–) and (S,S)-(+)-enantiomers of reboxetine are predominantly metabolised by the CYP3A4 isoenzyme. The primary metabolite of reboxetine is O-desethylreboxetine, and there are also three minor metabolites – Phenol A, Phenol B, and UK1, Phenol B being the most minor

Chemistry

Reboxetine has two chiral centres. Thus, four stereoisomers may exist, the (R,R)-, (S,S)-, (R,S)-, and (S,R)-isomers. The active ingredient of reboxetine is a racemic mixture of two enantiomers, the (R,R)-(–)- and (S,S)-(+)-isomer.

Society and Culture

Brand Names

Edronax is the brand name of reboxetine in every English-speaking country that has approved it for clinical use. Brand names include (where † denotes a product that is no longer marketed):

  • Davedax (IT).
  • Edronax (AU, AT, BE, CZ, DK, FI, DE, IE, IL, IT, MX, NZ, NO, PH, PL, PT, ZA, SE, CH, TH, TR, UK).
  • Irenor (ES).
  • Norebox (ES).
  • Prolift (AR,† BR, CL, VE†).
  • Solvex (DE).
  • Yeluoshu (CN).
  • Zuolexin (CN).

What is a Paradoxical Reaction?

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Introduction

A paradoxical reaction or paradoxical effect is an effect of a chemical substance, typically a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.

Paradoxical reactions are more commonly observed in people with attention deficit hyperactivity disorder (ADHD).

Substances

Amphetamines

Amphetamines are a class of psychoactive drugs that are stimulants. Paradoxical drowsiness can sometimes occur in adults.

Antibiotics

The paradoxical effect or Eagle effect (named after H. Eagle who first described it) refers to an observation of an increase in survivors, seen when testing the activity of an antimicrobial agent. Initially when an antibiotic agent is added to a culture media, the number of bacteria that survive drops, as one would expect. But after increasing the concentration beyond a certain point, the number of bacteria that survive, paradoxically, increases.

Antidepressants

In rare cases antidepressants can make users obsessively violent or have suicidal compulsions, which is in marked contrast to their intended effect. This can be regarded as a paradoxical reaction but, especially in the case of suicide, may in at least some cases be merely due to differing rates of effect with respect to different symptoms of depression: If generalised overinhibition of a patient’s actions enters remission before that patient’s dysphoria does and if the patient was already suicidal but too depressed to act on their inclinations, the patient may find themselves in the situation of being both still dysphoric enough to want to commit suicide but newly free of endogenous barriers against doing so. Children and adolescents are more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking antidepressants but cases are still very rare.

Antipsychotics

Chlorpromazine, an antipsychotic and antiemetic drug, which is classed as a “major” tranquilizer may cause paradoxical effects such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states.

Barbiturates

Phenobarbital can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days. Prerequisity for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital.

Benzodiazepines

Benzodiazepines, a class of psychoactive drugs called the “minor” tranquilisers, have varying hypnotic, sedative, anxiolytic, anticonvulsant, and muscle relaxing properties, but they may create the exact opposite effects. Susceptible individuals may respond to benzodiazepine treatment with an increase in anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behaviour, and even convulsions. Paradoxical adverse effects may even lead to criminal behaviour. Severe behavioural changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity, and hypomania.

Paradoxical rage reactions due to benzodiazepines occur as a result of an altered level of consciousness, which generates automatic behaviours, anterograde amnesia and uninhibited aggression. These aggressive reactions may be caused by a disinhibiting serotonergic mechanism.

Paradoxical effects of benzodiazepines appear to be dose related, that is, likelier to occur with higher doses.

In a letter to the British Medical Journal, it was reported that a high proportion of parents referred for actual or threatened child abuse were taking medication at the time, often a combination of benzodiazepines and tricyclic antidepressants. Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilisers may precipitate a child abuse event.

Self aggression has been reported and also demonstrated in laboratory conditions in a clinical study. Diazepam was found to increase people’s willingness to harm themselves.

Benzodiazepines can sometimes cause a paradoxical worsening of EEG readings in patients with seizure disorders.

Barbiturates such as pentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of attention deficit hyperactivity disorder. Intravenous caffeine administration can return these patients’ behaviour to baseline levels.

Causes

The mechanism of a paradoxical reaction has as yet (2019) not been fully clarified, in no small part due to the fact that signal transfer of single neurons in subcortical areas of the human brain is usually not accessible.

There are, however, multiple indications that paradoxical reactions upon – for example – benzodiazepines, barbiturates, inhalational anaesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABAA receptors. The combination of the five subunits of the receptor (see image) can be altered in such a way that for example the receptor’s response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one.

There are estimates that about 2-3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.

Book: CBT Toolbox for Children and Adolescents

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Book Title:

CBT Toolbox for Children and Adolescents: Over 220 Worksheets & Exercises for Trauma, ADHD, Autism, Anxiety, Depression & Conduct Disorders.

Author(s): Lisa Phifer.

Year: 2017.

Edition: First (1st).

Publisher: PESI Publishing & Media.

Type(s): Spiral-bound, Paperback and Kindle.

Synopsis:

The CBT Toolbox for Children and Adolescents gives you the resources to help the children in your life handle their daily obstacles with ease. Inside this workbook you’ll find hundreds of worksheets, exercises, and activities to help treat:

  • Trauma.
  • ADHD.
  • Autism.
  • Anxiety.
  • Depression.
  • Conduct Disorders.

Written by clinicians and teachers with decades of experience working with kids, these practical and easy-to-use therapy tools are vital to teaching children how to cope with and overcome their deepest struggles. Step-by-step, you’ll see how the best strategies from cognitive behavioural therapy are adapted for children.