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What are the manifestations of methamphetamine toxicity?

Mini Quiz: Methamphetamine Neurotoxicity

For information on treatment of amphetamine related disorders, please refer to the articles at the end of this case.This case vignette illustrates some common features of patients presenting with methamphetamine dependence. Comorbidities are often present, with psychiatric comorbidites prominent throughout the addiction, and physical problems developing with persistent methamphetamine use.Although valiant efforts have been made to reduce access to the chemical precursors of methamphetamine, it is likely that methamphetamine use will remain accessible and inexpensive, and costs associated with increased use will continue to rise.This case is based on a Psychiatric Times article, "Treatment for Methamphetamine Dependence," by Kevin P. Hill, MD, MHS. Dr Hill is author of Marijuana: The Unbiased Truth about the World's Most Popular Weed (Hazelden, release date March 31, 2015). Twitter: @DrKevinHill.Also see: Intoxication With Street Drugs

A 28-year-old married mother of 2 with a history of depression is brought to the emergency department after 6 months of near-daily methamphetamine use.

Psychiatric Emergency: Methamphetamine Abuse

In this brief podcast, Dr Edward Nunes discusses the latest evidence from research studies on stimulant and cocaine dependence. Dr Nunes is Professor at Columbia University Medical Center Department of Psychiatry, in New York.

Along with presenters Andrew Saxon, MD, University of Washington; Theresa Winhusen, PhD, University of Cincinnati College of Medicine; and Madhukar Trivedi, MD, University of Texas Medical Center, Dr Edward Nunes will chair a symposium at the AAAP annual meeting titled "Cocaine and Stimulant Dependence: New Strategies for an Old Problem."

The symposium will cover some of the latest evidence on cocaine dependence, which is often difficult to treat. So far, there have been no medications that have clearly been effective for cocaine dependence, a frustrating fact in the field of addiction medicine. Tobacco dependence, opioid dependence, alcohol dependence-each has effective medications. Cocaine dependence does not yet have any effective medications. The National Institute of Drug Abuse and other agencies have been funding research to try to find medications.

This session will present some different studies that have been done very recently. One such study is of a combination of naltrexone and buprenorphine for treatment of cocaine dependence. The reason it is thought it might work is because buprenorphine is a kappa-opioid receptor antagonist and naltrexone is also an a kappa-opioid receptor antagonist. Naltrexone has the advantage blocking the other effects of buprenorphine. Because buprenorphine is an opiate, you do not want to give it to patients who are not opioid-dependent because you would risk making them opioid-dependent. Naltrexone gets rid of that because it blocks the new opiate receptor which is the main opiate receptor that produces addiction.

The idea here was to block kappa receptors. There are reasons to think that is important. Chronic cocaine dependence causes up-regulation in kappa receptors in the brain, and kappa receptors inhibit the release of dopamine in the brain and dopamine is important for motivation and energy. Dopamine is also depleted in chronic cocaine dependence. So this is an effort to correct the dopamine dysregulation that occurs in cocaine dependence.

The results are still a secret. We don't know what they are going to be but they will be presented at the meeting and so we will see what comes out of that session. This is what's fun about these up-to-date presentations and research studies because sometimes it's the first time the results are presented in a public forum.

A small pilot study on buspirone, which is an anti-anxiety medication that has been around for a long time for cocaine dependence, will be discussed. Buspirone was well tolerated but the results are inconclusive.

Finally, a study that was done, not on medication, but on exercise for cocaine dependence. Exercise is a compelling idea as a way of helping to treat addiction. There are many people in the field that are actually working with patients day to day who believe out of their experience that exercise is helpful for drug dependence.

For example, one of the residential treatment programs in New York City that [Columbia Psychiatry] collaborates with has a very robust exercise program as part of what they offer to their clients.

There are a number of animal models and animal research studies that have suggested that exercise might be helpful for tobacco dependence, cocaine dependence, and other addictions. One study was directed by Dr Madhukar Trivedi, and he knows the data much better than I do, but I have been a collaborator and I know the data, so I can talk a little bit about it. Patients who were cocaine dependent were randomly assigned either to an exercise condition or to a health education condition.

The exercise condition was pretty rigorous. The patients were asked to run on a treadmill for 30 to 45 minutes, 4 times a week, at 70% to 80% of VO2 max. So it was a fairly vigorous exercise program and it was obviously a pretty big time commitment. Patients were asked over a 6-month period to show up 4 times a week for very nice and knowledgeable exercise instructors . . . it was an attractive, welcoming exercise situation.

The study showed that there was no difference in cocaine outcome unfortunately between the patients assigned to exercise and the patients assigned to control condition. But there is a twist because participation in exercise was associated with less cocaine use so those patients who participated in the exercise used less cocaine over time than those in the control condition and those who did not participate in exercise.

What happened is that those who were assigned to exercise were more likely to drop out of treatment so being assigned to exercise caused more individuals to drop out. My hunch about this is that some people like to exercise inherently, they find it inherently fun and important. Many other individuals do not find it inherently fun, which may explain why being assigned to exercise resulted in a higher dropout rate. It is an intriguing study that indicates more work needs to be done to figure out how to make exercise fun and appealing for everybody and then we will get a better sense of what the impact can be on cocaine and other substance use disorders.

Exercise by the way has been shown to be effective for anxiety and depressive disorders, so for those mood and anxiety disorders, does have good evidence of being effective. In terms of the cocaine study that will be presented, it is an interesting first try and will make for interesting discussion.

Dr Edward Nunes discusses the latest evidence from research studies on stimulant and cocaine dependence in this podcast.

Treatment for Cocaine Dependence

It’s easy to give advice, hard to receive it, harder still to live it. The privilege of youth is action; of age, experience. Nature resists combining both. Experience is a comb you get when you’re bald.

I teach ignorance. Four years of medical school; and 4 more years of residency. Tens of thousands of dollars of debt, and years of minimum wage labor. You must think you have bought something with those funds and that toil; you must finally know something special. You graduate, and you get to work in this bewildering business. People pay you-and so you must know something. If decades pass and you keep getting paid and you don’t pause to reflect, you may end your life thinking that you know much. In fact, as newer generations come up, they see what you don’t.

I teach we don’t know; I teach that knowledge only increases our ignorance. This is what knowledge is: knowing what we know and, just as importantly, knowing what we don’t know.

Knowledge is 2-edged: it illuminates a fact or a part of experience. Usually, in so doing, it shows that what previously seemed sunlit truth is now utter darkness. As you learn something, you realize that much of what you “knew” was actually false. You become more ignorant as you become more wise.

Young psychiatrists need to learn, foremost, that they are ignorant. And they need to learn that their elders are even more ignorant, sometimes because they are wise-because the more you know, the more ignorant you are-sometimes because they are blind.

There is a beneficial and a baleful ignorance. The harmful kind is the ignorance of he who thinks he knows-end of story. This fellow doesn’t know and is simply “mind-blind.”

 He is not wisely ignorant: he doesn’t know that what seemed “true” is false; he just thinks it’s true. Most of your teachers are of this variety, and most of your patients, and most of your colleagues-and, most likely, you.

Look for the dogma. Whatever is believed by most, is likely to be untrue. The truth is not a matter of popular vote; it tends to prefer solitary homes.

Live on the sunny side of doubt. Some doubt darkly: they disbelieve everything and everyone; the truth saunters in front of them and is treated like a vagrant. Take a naive, childlike attitude toward ideas: accept everything-initially, then think on it and reject what seems wrong. Most of your colleagues do the reverse: they reject everything immediately, so as not to disrupt the feeble furniture of their minds; rarely, and with great languidity, do they ever come to accept a new idea.

Reject a superficial worldly skepticism: don’t read 

 as your main supply of psychiatric discourse. Read the old books and the journals-not the new books

 and the newspapers. Why do we all wrangle about the disputations in 

 is sent to an entire department e-mail list; the poor 

 meta-analysis sits ignored, except by an occasional half-dozen–member journal club.

So on our heels a fresh perfection treads
. . . born of us
And fated to excel us.

The best go unnoticed, and the least are loudest.

The greatest danger for your work is not that you don’t know enough about mental illness . . . it’s that you think you know more than you do. The danger is complacency and conformity, above all-above everything else. You will constantly be pressed to comply, to go along. Do so, on all that is unimportant. But where it is important, resist. Kick up, kiss down-if you dare; the world will punish you, but you will improve it.

 You think you know, or you think you don’t know, but in either case, you’re satisfied. Be dissatisfied. Your profession has not lived up-for over a century-to what it could be. It has gerrymandered diagnoses like politicians make up voting districts: on “pragmatic” grounds, for the good of the profession.

 Nature doesn’t obey politicians, whether in state houses or hospitals. And so the genetic and drug and biology studies refuse to line up with DSM labels. Science was degraded (previously) or applauded (recently)-and ignored, for the good of the profession. Your profession hasn’t fully accepted that what is good for the profession is to get at the truth.

Some say there are no truths, only powers that seek to hide behind claims to truth. God is dead, we are told, but the pharmaceutical industry lives. And science is just another interest group: there is no scientific truth, just the opinions of scientists.

I would like to visit God’s grave; someone tell me where it is. I think I will find Reason interred next door, and Science just beneath a weeping angel. With Him died Truth. No capital T’s are allowed, and even small t’s are suspected. But when your patients die, because of something you did-or, more commonly, didn’t do-then there are truths. The dead body attests to it, as do the living bodies you could save.

This postmodern belief that there are no truths, only wills to power, produces a dangerously medieval mindset that imagines itself to be avant-garde. The mind becomes blind and a profession stands still.

 Half a century ago, you would have pledged allegiance to the Trinity of id, ego, and superego-and you would have spent your time and inheritance in formal psychoanalysis. Today, you will treat your patients with the Trinity of antidepressants, antipsychotics, and anxiolytics-and you will buy the drug textbooks with the appealing synaptic cartoons. In each epoch, you conform to your profession; it is the standard of care, and you will be legally protected. You’ll have to make a living, and you’ll have children and mortgages, and you’ll need to protect them. I don’t fault you. But the profession needs something else. 

Your drugs aren’t as good as your colleagues believe, nor are they as bad as our critics say. Your colleague will say it’s easy: give a drug for a symptom-an anxiolytic for anxiety, antidepressant for sadness, neuroleptic for mood swings, amphetamine for concentration and energy and sex. It’s easy-like being a Volkswagen mechanic.

 But your patients’ brains are Porsches. They break down if treated this way. It’s easy: you don’t need an MD for 

We disparage the “medical model,” as if the phrase itself is proof of its fallacy. But we use the MD degree as a badge of expertise, and we practice with a legal privilege of dispensing potentially harmful drugs. It’s no sin to acknowledge biology; it’s a sin to say it, and not mean it.

Our siblings in medicine have already shown us the way. A century ago, we didn’t understand diseases and everyone got potions for symptoms-bleeding in particular. About half a century ago, we began curing, with antibiotics, then with other specific drugs (such as insulin and steroids).

 In medicine, we sometimes understand diseases; in psychiatry, we distrust the concept of disease. In medicine, we sometimes use drugs that cure; in psychiatry, we disbelieve in cure.

Of course, not all psychiatric problems are diseases; most aren’t. But some are. Not all drugs cure; most don’t. But some do. Until we realize which is which-which syndrome is a disease and which is not, which drugs cure and which don’t-we’ll keep guessing, mostly wrongly, while we complacently conform with the profession.

The mental and social aspects of illness matter, you will say; certainly, but not always, and not in the same way for all conditions. Until we know what’s what, all generalizations are false. And since you will want to prescribe pills to make your living, you should at least try to understand well what is biological and what is not.

We despise ourselves too little, and too much. Too much because our medical colleagues disparage us and we have enemies in the public, making us feel inferior. We are criticized wrongly, and rightly, and we protest both criticisms equally instead of rebutting the first and embracing the second. Don’t respond to stigma with stigma, doubting yourself: reject it as worse than racism, the deepest human intolerance, based not on a moral baseness, but on pure ignorance.

We despise ourselves too little: we reject too much and circle around each other, back-to-back. Our colleagues act as if criticizing their drugs is a personal offense against them. Child psychiatry can survive without overuse of amphetamines, and adult psychiatry, without excess antidepressants and neuroleptics. Here is where our loss of science hurts most, for the essence of science is to be self-critical. It’s not about being conventionally honest with others, it’s about being utterly honest with yourself.

 This attitude, which is the scientific attitude, is completely unnatural. Often we aren’t scientific enough, and then our practice becomes uneducated guessing, which we comfortably accept as just the way it is: “Behold, I show you the most despicable man of all: he who cannot despise himself.”

You have entered a difficult profession, not an impossible one. It is a profession that deeply needs honest workers who are willing to seek a knowing ignorance, to be dissatisfied, and to refuse to conform-doing so in the interest of the truth and of the profession, seeing both as inseparable. You need to make a living, but you also need to breathe life into your profession.

In a word, half of what you know is true, and half false, and you don’t know which is which. If you know this, you know all you can now know-a good start. Act so that future generations can have a better starting place.

 Ghaemi SN. Volkswagen psychopharmacology. 

http://www.psychiatrictimes.com/display/article/10168/1870665

Bad Medicine: Doctors Doing Harm Since Hippocrates.

 New York: Oxford University Press; 2006.

 Feynman RP. Cargo cult science. Some remarks on science, pseudoscience, and learning how not to fool yourself. Caltech’s 1974 commencement address. 

http://calteches.library.caltech.edu/3043/1/CargoCult.pdf

 Del Caro A, ed. Pippin R, trans. Cambridge, United Kingdom: Cambridge University Press; 2006.

Psychiatry is a profession that deeply needs honest workers who are willing to seek a knowing ignorance, to be dissatisfied, and to refuse to conform-doing so in the interest of the truth and of the profession, seeing both as inseparable.

Letter to a Young Psychiatrist

Psychiatrists are waking up to the world of sleep and behavior. Just as the biological revolution witnessed a collapse of barriers between the physical and the mental, so the boundary between sleep and wakefulness is crumbling. The emerging discipline of sleep medicine, baptized in the discovery of REM sleep in 1953 and by the characterization of sleep cycles a few years later, initially focused on adult physiology and sleep disorders.

Only in the past 2 decades has the study of children produced a substantial, if sometimes controversial, body of knowledge concerning sleep and its effects on development. Although many findings have been perplexing, the relevance of sleep pathology for behavioral and mental development has been securely established, and some of the most interesting research developments concern the role of sleep in ADHD.

Serious sleep problems usually imply either too much or too little sleep. Too little sleep can mean abbreviated sleep episodes, as might be imposed by external demands or by insomnia, or longer episodes punctuated by arousals that fragment sleep. Pilcher and Huffcutt

 examined the effects of prolonged sleep deprivation (more than 45 hours), brief sleep deprivation (45 hours or less), or partial sleep deprivation (less than 5 hours of sleep in a 24-hour period) on measures of cognitive and motor performance or mood. The overall performance decrement for all measures was 1.37 standard deviations (SDs). This is comparable to a drop in IQ from 100 to about 80. Under the conditions of partial sleep deprivation-not unlike a typical Monday morning for many of us-mood scores dropped by over 4 SDs.

Although children are not suitable subjects for such experiments, Sadeh and colleagues

 demonstrated that very modest changes in sleep duration can substantially affect the neurobehavioral function of children. His team monitored 77 fourth and sixth graders in regular classrooms with actigraphy for 5 nights. For the first 2 nights, children slept as usual; on the remaining 3 nights, they were asked to either extend or restrict their sleep time by 1 hour. Children who failed to change their sleep duration by at least 30 minutes were analyzed as “no change.” On a simple reaction time test, performance of both the sleep restriction and no-change groups deteriorated, whereas on measures of digit span and continuous reaction time, children in the extended-sleep group performed significantly better than the others.

 applied a single hour’s sleep restriction to 11 children with ADHD and to 32 controls over 6 days, neurobehavioral function in both groups deteriorated, as assessed by a continuous performance test. For children with ADHD, two-thirds of the continuous performance test measures dropped from the subclinical to the clinical range of impairment.

If the slight manipulations in sleep duration have measurable effects after just 3 nights, what might the effects be when sleep is shortened or fragmented long-term by busy family schedules, sleep-related breathing disorders (SRBD), behavioral insomnia of childhood, or other sleep problems? Would it be possible to produce the full clinical picture of ADHD under such circumstances?

What is already known about the
correlation between ADHD and sleep disorders in children?


? ADHD has been linked to many types of sleep problems in numerous and methodologically diverse studies. Parent-reported sleep complaints may occur in as many as 50% of children with ADHD.

What new information does this article provide?


? This article reviews current thinking on the association between ADHD and sleep disorders that is especially relevant to practicing psychiatrists.

What are the implications for psychiatric practice?


? Children presenting with ADHD or ADHD symptoms frequently have sleep problems that parents can describe on a questionnaire or in an interview. Sleep disturbances may aggravate an underlying psychiatric disorder or even fully account for the psychiatric presentation; such information may be critical in diagnosis, referral, and treatment planning.

Sleep problems described in children with ADHD include behavioral problems that often manifest as resistance to bedtime or difficulty in going back to sleep in the middle of the night without caregiver presence, parasomnias, sleep-disordered breathing, restless legs and periodic leg movements, and circadian rhythm disorders.

 Similarly, children with ADHD experience alterations in sleep architecture, such as delayed onset of REM, reduced time in REM, and arousals with sleep fragmentation.

 Inattention, hyperactivity, neuropsychological deficits, syndromic ADHD, and behavior disorders are also common among children who present with sleep problems. Yet despite abundant evidence of these comorbidities, the extent and nature of possible causal relationships between disturbances in sleep and behavior remain largely a mystery.

Prevalence estimates vary because of the way sleep disorders are operationally defined. Subjective parent complaints about resistance to bedtime, a behavior that is not unusual in children, may be counted as a significant problem or disorder by one investigator but not by another. Laboratories may use different procedures or scoring schemes that produce somewhat inconsistent counts of polysomnographic events, such as leg movements and hypopneas. Similarly, heterogeneous diagnostic rules may yield disparate rates of disorder, ie, if 5 rather than 1 apnea or hypopnea episodes per hour define obstructive sleep apnea, fewer cases with more severe symptoms on average will result. Finally, deviations in sleep architecture detected on polysomnography may be consequential yet may not be indicative of a specific sleep diagnosis. Similarly, diagnoses of ADHD depend on the criteria set, subjective thresholds for counting a behavior as symptomatic, and whether diagnoses are based on rating scales, clinical interviews, or structured and comprehensive clinical assessments.

Rates of sleep disorder in ADHD also depend, sometimes dramatically, on how and where data are obtained. Parent checklists almost always generate high sleep symptom rates, exceeding those that can be demonstrated during formal sleep studies. Research subjects recruited in specialty clinics (such as psychiatry or sleep disorders clinics) often display both sleep and behavior problems, whereas children assessed in regular school settings exhibit fewer problems from either domain.

Further complexity arises from potential nonlinearity in the impact of sleep problems on both behavior and behavioral diagnosis. Thus, mild to moderate levels of sleepiness could produce excessive activity and reduced attention, while very high levels of sleep disturbance may cause torpor and inattention so obviously related to sleep that a separate diagnosis of ADHD would be improvident even if criteria were technically fulfilled.

For all of these reasons, the nature and extent of the relationship between ADHD and sleep remains unsettled. One widely quoted estimate for the prevalence of sleep disorders in ADHD places the rate of parent-reported sleep problems at 25% to 50% in the absence of medication.

citing this study, give a guess-estimated rate of sleep problems in children with ADHD as 5-fold greater than that in healthy controls.

High-end estimates of sleep disorder prevalence in ADHD populations include a report from an Italian clinic that yielded polysomnography-confirmed sleep disorders, such as periodic limb movements in 40%, restless legs syndrome in 26%, SRBD in 18%, and confusional arousals in 36%.

 Findings from one study showed that 73% of children with ADHD had sleep problems and 45% of those had moderate to severe problems.

Inconsistencies among reports have clouded interpretation of findings relative to sleep morbidity and ADHD. A recent meta-analysis produced compelling findings for both subjective and objective sleep measures in children with ADHD. In their analysis, Cortese and associates

 minimized the likelihood that comorbid conditions could account for sleep problems by excluding studies in which children were receiving pharmacological treatment or had comorbid depressive or anxiety disorders. Compared with controls, children with ADHD had significantly higher bedtime resistance and more sleep onset difficulties, night awakenings, morning wakening difficulty, sleep-disordered breathing, and daytime sleepiness. Among objective measures, sleep onset latency, stage shift frequency, and apnea-hypopnea index were increased in children with ADHD, while sleep efficiency, true sleep time, and average time to fall asleep were lower than in controls.

Notwithstanding our inability to identify true prevalence rates, studies purporting to show frequent sleep disorders are probably a fair reflection of the rate at which clinicians who see children with ADHD can expect to hear complaints of sleep problems after a careful inquiry using some combination of rating scale or checklist and interview. Children referred for diagnosis and treatment of sleep disorders or for adenotonsillectomy are likely to display psychiatric problems in which inattention, hyperactivity, or both are prominent.

Restless legs syndrome and periodic limb movements

In their meta-analyses, Sadeh and colleagues

 found that the frequency of periodic limb movements was consistently elevated in children with ADHD. The comorbidity of restless legs syndrome symptoms in ADHD has been reported to be as high as 24%.

 Frequent parent reports of prominent periodic limb movements, restless legs syndrome, and growing pains in their children with ADHD offer a plausible mechanistic link between sleep movement disorders and ADHD, namely, a functional dopamine deficit.

 Both restless legs syndrome and periodic limb movement disorder can be successfully treated with dopamine agonists, much as ADHD usually responds to stimulant medication.

The diagnosis of restless legs syndrome is based on history and requires that the child offer some description of subjective symptoms. Children describe the discomfort that compels movement in restless legs syndrome in idiosyncratic ways; patience and creativity may be needed to understand such communications.

Most patients who experience restless legs syndrome also have periodic limb movements, although the converse is not necessarily true. In contrast to the voluntary movements of restless legs syndrome, periodic limb movements are involuntary and have a distinctively “neurological” appearance. The movements last from 0.5 to 5 seconds and recur in cycles of 5 to 90 seconds, typically in clusters, during non-REM sleep.

Both restless legs syndrome and periodic limb movement disorder can reduce the amount or quality of sleep. Restless legs syndrome prevents sleep onset and the return to sleep after awakenings at night, whereas periodic limb movement disorder may cause arousal and sleep fragmentation. Occasional limb movements are not necessarily problematic. Treatment recommendations for periodic limb movement disorder and restless legs syndrome are sleep hygiene, iron supplementation, and medications.

The elements of good sleep hygiene are presented in the 

. Common over-the-counter drugs such as antihistamines, cold preparations, and antiemetics aggravate restless legs syndrome symptoms. Recently, SSRIs have been implicated as a cause of periodic limb movements in nearly one-third of the children who receive these drugs.

Iron deficiency, which is usually diagnosed in children as a ferritin level of 50 ng/mL or less, is associated with restless legs syndrome and periodic limb movement disorder. Small trials of iron supplementation have shown promise in children.

The literature contains limited guidance for treating children with medications commonly recommended for adults with restless legs syndrome, such as the first-line, nonergot dopamine agonists (ropinirole and pramipexole); levodopa/carbidopa; and other agents, including clonidine, clonazepam, opioids, and gabapentin. Ropinirole and gabapentin enacarbil, a gabapentin prodrug, are the only agents approved for the restless legs syndrome indication in adults. None of these drugs have been approved or systematically studied in children. Use of dopaminergic agents may be complicated by the phenomenon of augmentation, in which symptoms begin to develop earlier in the day or spread to other parts of the body, giving rise to a condition suspiciously similar to akathisia.

Obstructive sleep apnea is the prototypical SRBD that includes but is not limited to conditions characterized by conspicuous apneas. Most psychiatrists are familiar with the obstructive sleep apnea syndrome in adults, but the SRBD of children differs mechanistically from that of adult sleep apnea and the treatment is usually different as well. In many children with obstructive sleep apnea, enlarged adenoids and palatine tonsils are the underlying anatomic problem.

Described in vivid detail by Sir William Osler

 in 1892, SRBD can have dramatic neurobehavioral consequences: “Chronic enlargement of the tonsillar tissues is an affection of great importance, and may influence in an extraordinary way the mental and bodily development of children. . . .”

Patients with obstructive sleep apnea present with snoring, sleepiness during the day, difficulty in rising in the morning, unsatisfying sleep, nasal speech, mouth breathing, a damp pillow from drooling while asleep, and a distinctive appearance known as adenoid facies. Sleep-disordered breathing is more likely in the presence of developmental anomalies that affect the size or tone of the upper airway, such as deviated nasal septum, retrognathia, midline clefts, or Down syndrome. As Osler emphasizes, severe cases predictably cause mental dullness and typically languid, sluggish behavior rather than locomotor hyperactivity. The treatment is adenotonsillectomy.

Numerous studies have examined the impact of sleep-disordered breathing on inattention, hyperactivity, syndromal ADHD, and other disruptive behavior and on neuropsychological dysfunction, with remarkably inconsistent findings. Compared with controls, children referred for adenotonsillectomy had greater neuropsychological impairment and higher rates of ADHD and oppositional-defiant behavior.

 Unexpectedly, postsurgical improvement in these neurobehavioral indices was no greater among the children whose presurgical sleep studies confirmed SRBD.

Other studies of adenotonsillectomy confirm improvement in preoperative behavior and cognitive problems postoperatively, but it is not clear whether changes in sleep or sleep apnea measures explain the effects of surgery.

 In most correlative studies of sleep-disordered breathing, behavior, and cognitive problems, the relationships among sleep and behavioral variables have been difficult to demonstrate. For example, in a community sample of 571 school-aged children who underwent overnight polysomnography, no relationship between mild sleep apnea and multiple measures of neuropsychological functioning were detected.

 In contrast, another group of children who underwent similar examinations displayed neurocognitive deficits at all levels of sleep-disordered breathing.

It is reasonable to say that there is an association between sleep-disordered breathing and neurobehavioral problems. Adenotonsillectomy often remediates these problems, but the nature of the association and of the treatment effects has been elusive. For children in whom adenotonsillectomy is ineffective or inappropriate, nasal continuous positive airway pressure may be effective. For especially severe cases, tracheostomy is an option.

It was long supposed that medication treatment accounted for most sleep problems associated with ADHD that could not be attributed to parenting. Consistent with this view, insomnia is a common adverse effect of stimulant medications. Similarly, the medication rebound effect-the return of baseline symptoms, perhaps even heightened symptoms, at day’s end following 2 or 3 doses of short-acting medication-often coincides with bedtime. Furthermore, some children fall asleep more readily after receiving an evening dose of stimulant medication.

Sleep-onset insomnia is not always evident when sleep latency is assessed objectively under controlled conditions. O’Brien and colleagues

 found no differences in sleep characteristics between medicated and unmedicated children with ADHD, although both groups had reduced REM and more sleep disturbances than children without ADHD. Sleep latencies for each of the groups were close to 30 minutes, which suggests that some aspect of the setting might have kept them all awake, thereby reducing any contrast that could be attributed to either ADHD or medication.

 reached different conclusions in a study that included both within-subject comparisons (children with ADHD on and off methylphenidate) and across-subjects comparisons (children with ADHD versus controls). Children with ADHD who were taking the drug had an increase in sleep latency of 29 minutes and a decrement in overall sleep time by 1.2 hours, while children with ADHD who had not received medication were indistinguishable from controls.

 obtained mixed results, finding that sleep latency increased by 39 minutes in children who received methylphenidate 3 times a day, while total sleep interval and the frequency and duration of interruptions decreased.

Longer-acting methylphenidate preparations reportedly have a minimal effect on sleep. Huang and colleagues

 recently reported that “randomized, double-blind, placebocontrolled trials have demonstrated that CNS stimulants do not cause a statistically significant increase in sleep problems, but showed that some beneficial effects were noted on the sleep of both children and adults with ADHD.” This would seem a very optimistic appraisal of the literature, which might be better characterized as showing mixed results: the most well-documented effect of stimulants is initial insomnia, the impact of which may be counterbalanced by fewer interruptions once sleep has been attained.

Atomoxetine, which for many clinicians is the preferred ADHD agent when trials of methylphenidate and amphetamine have failed, commonly produces somnolence, especially when used in higher doses or titrated rapidly. Compared with children who were being treated with methylphenidate, children treated with atomoxetine fell asleep faster, arose more easily, and slept better.

Various sedating drugs are popular adjuncts to stimulant treatment. Patients are likely to receive clonidine or guanfacine, both of which are available in long- or short-acting preparations, for target symptoms of insomnia, hyperactivity/impulsivity, and aggression.

 Clonidine reduces REM sleep and may be effective in treating bruxism, but the drug may be difficult to discontinue. Morning sedation is also a common effect of taking clonidine at bedtime.

Neither clonidine nor guanfacine is approved for sleep or for ADHD, although extended-release formulations of both, which presumably are less soporific than their shorter-life parent drugs, have FDA indications for ADHD. Melatonin can be used to promote sleep and may be especially useful with a delayed sleep phase disorder.

Although treatment recommendations always include simple nostrums about sleep hygiene, these amount to mere tautologies absent a focused therapeutic effort to help parents establish a realistic bedtime routine. In adolescents, these disrupted routines may be aggravated by stimulating beverages, urgent social matters, daytime naps, and other lifestyle changes. An Australian project has developed a protocol designed to offer guidance to parents that is based on the nature of sleep problems in children who have ADHD. For example, in sleep-onset association disorder, parents are instructed to gradually fade their presence at bedtime. For limit-setting disorder, children are rewarded for adherence to bedtime routines and are ignored when protesting the bedtime rules. Delayed sleep phase disorder is managed by a combination of fixed morning awakening time, gradually earlier bedtime, and morning phototherapy.

There are several parent questionnaires for sleep disorder screening, including the Pediatric Sleep Questionnaire.

 offer a simple and popular acronym to guide screening: BEARS reminds us to inquire about bedtime problems, excessive daytime sleepiness, awakenings during the night, regular bedtime and awakening time, and snoring or difficulty in breath-ing during sleep. The University of Chicago’s detailed “Pediatric Sleep Medicine Questionnaire,” along with a 2-week pediatric sleep diary, can be downloaded from the University of Chicago, Comer Children’s Hospital.

Sleep changes associated with psychotropic drugs are common enough to justify routinely obtaining a baseline sleep diary before beginning treatment, even when the initial screening for sleep disorders indicates that no further investigation is needed.

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 Sadeh A, Pergamin L, Bar-Haim Y. Sleep in children with attention-deficit hyperactivity disorder: a meta-analysis of polysomnographic studies. 

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 Cortese S, Konofal E, Lecendreux M, et al. Restless legs syndrome and attention-deficit/hyperactivity disorder: a review of the literature. 

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ADHD and Sleep Disorders in Children

Ongoing shortages of several psychotropic medications have wreaked havoc among patients and their families, caused frustration and reluctant prescription switches among physicians, and prompted investigations by Congress. Drug shortages reached an all-time high in 2011. According to the University of Utah Drug Information Service, 267 drugs-primarily injectables-were in short supply, up from 211 in 2010 and 58 in 2004.

While numerous press reports have publicized the shortage of medications for ADHD, there are also shortages of drugs for psychiatric disorders such as schizophrenia and addiction.

Ann Richards, PharmD, BCPP, a past President of the 

College of Psychiatric and Neurologic Pharmacists

Texas Department of State Health Services

, said that according to data collected by the 

American Society of Health-System Pharmacists

, there are shortages of diazepam injection, diphenhydramine hydrochloride for injection, haloper-idol decanoate injection (Haldol), haloperidol lactate injection, lorazepam injection (Ativan), naltrexone oral tablets (Revia), and thiothixene capsules (Navane).

Adelaide Robb, MD, Chair of the Pediatric Psychopharmacology Initiative of the American Academy of Child and Adolescent Psychiatry (AACAP), told 

 “We are having shortages of most if not all of the stimulants, and it’s nationwide.” Patients and their families are experiencing diffi-culty in obtaining mixed amphetamine salts (Adderall), methylphenidate immediate-release (Ritalin, Concerta, and Daytrana), and dexmethylphenidate (Focalin). “Even Dexedrine spansules [dextroamphetamine], which is one of the oldest ADHD drugs besides Ritalin, has been in short supply. The only one that is still fairly easy to get is Vyvanse [lisdexamfetamine], which is not available in a generic form,” says Robb.

A benzodiazepine shortage is causing problems for alcohol and substance abuse detoxification programs. Last year, there were shortages of such mood stabilizers as divalproex (Depakote) and lamotrigine (Lamictal), and of the first-generation antipsychotic haloperidol.

Ruth Hughes, PhD, psychologist and Chief Executive Officer of Children and Adults with Attention-Deficit/Hyperactivity Disorder (

), a nonprofit educational and advocacy organization, said the shortages in ADHD medications that began with a shortage of short-acting generic versions of Adderall “have been going on for more than a year.”

A January survey of CHADD members revealed that nearly half (49.9%) of the 5500 respondents were having difficulty in getting their medications and of that group, 37% had to switch medications. “In our survey, every single stimulant medication, name-brand and generic, long-acting and short-acting, was named as a medication that was difficult to obtain,” said Hughes. With 15 million people who have ADHD in the United States, “we have a very significant segment of the population that can’t get their medications.”

The ADHD medication shortage has serious life ramifications for children and adults with the disorder, Hughes explained. CHADD has “received a dozen reports of adults who tried to tough it out without medication, made serious mistakes on their jobs and were subsequently fired,” she said. “We have reports of college students who were kicked out of school. We have reports of children with ADHD doing very poorly in school or being suspended or expelled, because their parents were unable to get their medication.” In addition, adolescents who are driving automobiles and are unable to get their ADHD medications are of great concern because they are 3 times more likely to have car accidents than are teens without ADHD and 4 times more likely to have fatal accidents.

Reports of price gouging have also emerged. “Some CHADD members have gone to pharmacies for generic ADHD medications and been told it would be more than $1000 for a month’s supply. Yet pharmaceutical manufacturers have told me they have not increased their prices,” said Hughes.

Medication shortages are influencing prescribing patterns. The best medication for the individual may not be the one that is being prescribed, according to both Robb and Richards.

In the DC metropolitan area (Washington, DC; Maryland; and Virginia), some parents of children with ADHD cannot get a 30-day supply of their child’s medicine at local pharmacies or a 90-day supply through large mail-order companies, Robb said. “So then we have to either switch medications or the parents have to run around to 5 or 6 different pharmacies, trying to find enough to fill a 30-day prescription,” she said.

The shortage of benzodiazepines has also caused a change in detoxification treatments for adolescents and young adults, Robb said. “Normally, what we would do is have a benzodiazepine taper and now those medicines are in short supply, so we have to use very old-fashioned medications like phenobarbital.”

Richards reported that most hospitals in her system “will use either diphenhydramine injection, lorazepam injection, haloperidol injection, or a combination of these products to treat adults experiencing behavioral emergencies. But all 3 drugs are in a shortage situation. Thus, we are looking for alternative treatments for these emergencies.”

Clinicians who would ordinarily prescribe haloperidol decanoate for a patient with adherence issues, she added, are forced to determine whether a switch to another long-acting injection might be more beneficial than prescribing oral haloperidol. “Switching to another long-acting injection can lead to therapeutic failure or side effects, but adherence is guaranteed if the medication is administered. On the other hand, switching to an oral product of the same medication ideally leads to a similar response, but if the individual has adherence issues, then the medication may not be taken as prescribed. Furthermore, the dosing of the oral product may be challenging, as the blood concentration of the long-acting medication will slowly decline.”

In response to the increasing frequency and severity of drug shortages in recent years, the FDA conducted a review, the results of which they published in October.

 The leading causes of drug shortages were quality problems-glass shards, fungi, or other contaminants-at a drug manufacturing facility (43%); delays in manufacturing or shipping (15%); and a shortage of the active pharmaceutical ingredient (10%).

Other causes included increases in demand, business choices, and other companies discontinuing the product lines.

 On the basis of 127 drug shortages between January 1, 2010, and August 26, 2011, the FDA review found that injectable medications accounted for 102 (80%) of the drugs in short supply.

One of the companies with manufacturing problems is the injectable drugs manufacturer Ben Venue Laboratories, which has 4 factories in Bedford, Ohio. The Boehringer Ingelheim–owned company manufactures valproate sodium injection, haloperidol lactate injection, and buprenorphine injection, among other injectable drugs. Last year, Ben Venue voluntarily suspended manufacturing “to permit implementation of lasting corrective actions to address manufacturing-related issues as noted in FDA and other global regulatory agency inspections,” said spokesperson Jason Kurtz. He added that in the past 3 years, the company has invested more than $250 million to upgrade its facilities. A public statement posted on its Web site stated, “. . . no products manufactured in the North facility will be available to patients and healthcare professionals before the fourth quarter of 2012.

In some cases, only one company manufactures a particular drug. For example, Hospira, the sole supplier of diazepam injection used to treat anxiety disorders (short-term) and alcohol withdrawal symptoms (among other disorders), is experiencing manufacturing delays. But according to the company spokesperson, Daniel Rosenberg, the company expects a full recovery by summer.

Obtaining active pharmaceutical ingredients for the manufacturing of controlled substances has been particularly challenging, according to manufacturers and others. In testimony before the House Committee on Energy and Commerce Subcommittee on Health last year, Jonathan Kafer, Vice President of Sales and Marketing for Teva Pharmaceuticals, described the dilemma as follows

From our work with the DEA [Drug Enforcement Agency] and FDA, we know that it is a difficult balancing act to ensure availability of controlled substances to patients in need while also striving to curb abuse and diversion. In an effort to control the supply of these medicines, the DEA makes yearly allocations of controlled drugs to the respective manufacturers of these products. In many instances, however, the use of a drug product changes over the year due to increased usage or shifting of markets. This can result in a shortage of these products, because without access to more of the controlled active ingredient, manufacturers are unable to increase supply. Currently, there are a number of controlled drugs on the American Society of Health-System Pharmacists shortage list.

Robb pointed to the DEA’s quota system for the shortages in ADHD medication as well as to demand outstripping supply: “Diagnosis and treatment with medication for ADHD in both pediatric and adult fields have increased in the last 5 years, so there is a larger demand for the products. But at the same time, the supply of ready materials to make the medications has not increased through the DEA.”

Jeffrey Scott, a DEA agent and spokesperson, said the quota for amphetamine salts has been “bumped up” for 2012 and that the quota can be revised mid-year. “Part of our mission is to ensure uninterrupted supply to meet legitimate medical and scientific needs, but we are only part of a chain that gets the medications to the public-the part that determines the quota of amphetamine salts used in ADHD medications. We develop the quota based on established medical need, retail consumption, manufacturers’ estimates, past quota history, etc. It is our best educated guess.”

Manufacturing companies that make decisions on how best to use their quota allocation, such as for brand-name versus generic forms of the drugs, are the next link in the chain, he added.

On October 31, 2011, President Obama issued an Executive Order that directed the FDA, as well as the Department of Justice, to take action to reduce and prevent drug shortages through expedited reviews and to identify market participants who are stockpiling medications or pricing drugs exorbitantly.

 On the congressional front, the Committee on Energy and Commerce, Subcommittee on Health last fall examined drug shortages.

Several health care professional organizations (eg, AACAP, the American Psychiatric Association, and the American Academy of Pediatrics) along with several ADHD groups have formed an ADHD drug short-age coalition. The coalition has arranged visits to key congressional leaders and FDA officials, called for more transparency in the DEA quota-setting process, and recommended an interagency agreement between the FDA and DEA so that when a controlled-medication shortage is identified, the agencies can work together on an action plan.

[Editor's note: For further information, see 

FDA warns consumers about counterfeit version of Teva’s Adderall

, published subsequent to this article.] 

 American Society of Health-System Pharmacists. Drug shortages: current drugs. 

http://www.ashp.org/DrugShortages/Current

 Ongoing shortages of several psychotropic medications have wreaked havoc among patients and their families, caused frustration and reluctant prescription switches among physicians, and prompted investigations by Congress. 

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