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FDA study -- stimulant triggered psychosis, violence sometimes doesn't resolve

FDA Review ADHD Drugs Induce-Psychosis, Mania, Homicide, Suicide http://www.fda.gov/ohrms/dockets/ac/06/briefing/2006-4210B-Index.htm DATE: March 3, 2006 TO: Thomas Laughren, M.D., Director Division of Psychiatric Products (DPP), FDAOffice of Counter-Terrorism and Pediatric Drug Development (OCTAP) Memorandum. FROM: Kate Gelperin, M.D., M.P.H., Medical Epidemiologist Kate Phelan, R.Ph., Safety Evaluator The DDRE ADHD Psychiatric Review Team Office of Drug Safety (ODS) 1 EXECUTIVE SUMMARY / INTRODUCTION A BPCA (Best Pharmaceuticals for Children Act) review of methylphenidate products, prompted by Concerta pediatric exclusivity requirements, identified psychiatric adverse events as a possible concern. The review found some psychiatric adverse events mentioned in labeling, but a need for improved clarity was identified. The Pediatric Advisory Committee1 agreed at the June 2005 meeting at which the methylphenidate reviews were discussed, that the issue of psychiatric adverse events with all drugs indicated to treat ADHD should be examined with the goal of better characterizing these events so that drug labeling could be updated and made consistent between products. Thus, DDRE embarked on reviews of postmarketing and clinical trial reports of psychiatric adverse events associated with drugs used to treat ADHD. This document presents the results of the review of postmarketing reports. A companion document2, from Dr. Andrew Mosholder, presents the results of the review of clinical trial reports.  Information pertaining to selected psychiatric adverse event reports received since January 1, 2000 was requested from the manufacturers of products approved or with pending applications for the treatment of ADHD. Sponsors were asked to provide information regarding four broad categories of psychiatric adverse events: 1) signs and/or symptoms of psychosis or mania; 2) suicidal ideation and behavior; 3) aggression and violent behavior; and, 4) miscellaneous serious adverse psychiatric events. In addition, searches of the FDA AERS safety database were conducted covering the same time period, and the identified cases were assessed by a DDRE Review Team. Duplicates, and reports which were considered to be of poor quality or highly unlikely to be related to the drug of interest were excluded from this analysis.  Cases received from Sponsors, as well as those identified from the FDA AERS safety database, were systematically reviewed and analyzed to assess the probability of adverse drug reactions and to describe characteristics or risk factors observed in these reports. This review focuses on postmarketing safety data from the first three search categories. The miscellaneous category was considered to be beyond the scope of this current analysis due to the large volume of data for review. The most important finding of this review is that signs and symptoms of psychosis or mania, particularly hallucinations, can occur in some patients with no identifiable risk factors, at usual doses of any of the drugs currently used to treat ADHD. Current approved labeling for drug treatments of ADHD does not clearly address the risk of drug induced signs or symptoms of psychosis or mania (such as hallucinations) in patients without identifiable risk factors, and occurring at usual dosages. In addition, current labeling does not clearly state the importance of stopping drug therapy in any patient who develops hallucinations, or other signs or symptoms of psychosis or mania, during drug treatment of ADHD. We recommend that these issues be addressed.  A substantial proportion of psychosis-related cases were reported to occur in children age ten years or less, a population in which hallucinations are not common. The occurrence of such symptoms in young children may be particularly traumatic and undesirable, both to the child and the parents. The predominance in young children of hallucinations, both visual and tactile, involving insects, snakes and worms is striking, and deserves further evaluation. Positive rechallenge (i.e., recurrence of symptoms when drug is re-introduced) is considered a hallmark for causality assessment of adverse events. Cases of psychosisrelated events which included a positive rechallenge were identified in this review for each of the drugs included in this analysis.  In many patients, the events resolved after stopping the drug. In the FDA AERS review, resolution of the events after stopping the drug was reported in 58% of amphetamine /dextroamphetamine cases, 60% of modafinil cases, 33% of atomoxetine cases, and 48% of methylphenidate cases. (Note: Outcome of the psychiatric adverse events was not reported in 21% of amphetamine / dextroamphetamine cases, 9% of modafinil cases, 41% of atomoxetine cases, and 30% of methylphenidate cases.) For drugs currently approved for ADHD treatment, no risk factors were identified which could account for the majority of reports of psychosis-related events. For instance, drug abuse was reported in fewer than 3% of overall cases from the FDA AERS analysis of psychosis-related events. Also of note, in the overwhelming majority of cases (roughly 90% overall), the patient had no prior history of a similar condition. Numerous postmarketing reports of aggression or violent behavior during drug therapy of ADHD have been received, most of which were classified as non-serious, although approximately 20% of cases overall were considered life-threatening or required hospital admission.

Dopamine toggling governs decision making

The voltammetry results showed that fluctuations in brain dopamine level were tightly associated with the animal's decision. The scientists were actually able to accurately predict the animal's upcoming choice of lever based on dopamine concentration alone. Interestingly, other mice that got a treat by pressing either lever (so removing the element of choice) experienced a dopamine increase as trials got under way, but in contrast their levels remained above baseline (didn't fluctuate below baseline) the entire time, indicating dopamine's evolving role when a choice is involved. "We are very excited by these findings because they indicate that dopamine could also be involved in ongoing decision, beyond its well-known role in learning," adds the paper's co-first author, Christopher Howard, a Salk research collaborator. To verify that dopamine level caused the choice change, rather than just being associated with it, the team used genetic engineering and molecular tools -- including activating or inhibiting neurons with light in a technique called optogenetics -- to manipulate the animals' brain dopamine levels in real time. They found they were able to bidirectionally switch mice from one choice of lever to the other by increasing or decreasing dopamine levels. Jin says these results suggest that dynamically changing dopamine levels are associated with the ongoing selection of actions. "We think that if we could restore the appropriate dopamine dynamics -- in Parkinson's disease, OCD and drug addiction -- people might have better control of their behavior. This is an important step in understanding how to accomplish that."

A Test That Finds the Perfect Drug? - The Atlantic

“Psychiatry remains the only discipline of medicine that has no test to predict treatment response,” said Evian Gordon, the founder of one such company, Brain Resource. “This is providing, for the first time, an objective step as to which drug might be responsive.”

Cardiovascular fitness, cortical plasticity, and aging. - PubMed - NCBI

Cardiovascular fitness is thought to offset declines in cognitive performance, but little is known about the cortical mechanisms that underlie these changes in humans. Research using animal models shows that aerobic training increases cortical capillary supplies, the number of synaptic connections, and the development of new neurons. The end result is a brain that is more efficient, plastic, and adaptive, which translates into better performance in aging animals. Here, in two separate experiments, we demonstrate for the first time to our knowledge, in humans that increases in cardiovascular fitness results in increased functioning of key aspects of the attentional network of the brain during a cognitively challenging task. Specifically, highly fit (Study 1) or aerobically trained (Study 2) persons show greater task-related activity in regions of the prefrontal and parietal cortices that are involved in spatial selection and inhibitory functioning, when compared with low-fit (Study 1) or nonaerobic control (Study 2) participants. Additionally, in both studies there exist groupwise differences in activation of the anterior cingulate cortex, which is thought to monitor for conflict in the attentional system, and signal the need for adaptation in the attentional network. These data suggest that increased cardiovascular fitness can affect improvements in the plasticity of the aging human brain, and may serve to reduce both biological and cognitive senescence in humans.

How each generation gets the drugs it deserves | Aeon Essays

‘This is a big shift from the old model,’ says Cowles. ‘It used to be: “I am Henry. I am ill in some way. A pill can help me get back to being Henry, and then I’m off it.” Whereas now: “I am only Henry when I’m on my meds.” Between 1980, 2000, and now, the proportion of people on that kind of maintenance pill with no end in sight is just going to keep going up and up.’

How each generation gets the drugs it deserves | Aeon Essays

But, Cowles argues, one might just as easily say that ‘these drugs were created with various sub-populations in mind and they end up making available a new kind of housewife or a new kind of working woman, who is medicated in order to enable this kind of lifestyle’. In short, Cowles says: ‘The very image of the depressed housewife emerges only as a result of the possibility of medicating that.’

Abuse of ADHD drugs following path of opioids

Meanwhile, among those 26 and older, recreational use of Adderall, an amphetamine, rose fourfold, from 345,000 people in 2006 to 1.4 million in 2014, according to the latest available federal data. In emergency departments around the country, the number of cases involving two common ADHD drugs nearly quadrupled over seven years. And at morgues in Florida, a bellwether state for drug abuse problems, overdose deaths involving amphetamines increased more than 450% between 2008 and 2014.

Do ADHD Drugs Take a Toll on the Brain? - Scientific American

Research hints that hidden risks might accompany long-term use of the medicines that treat attention-deficit hyperactivity disorder

Adhd and Temporality: A Desynchronized Way of Being in the World. - PubMed - NCBI

ADHD is, I argue, an impairment in sense of time and a matter of difference in rhythm; it can be understood as a certain being in the world, or more specifically, as a disruption in the experience of time and a state of desynchronization and arrhythmia. Through excerpts of interviews with adults diagnosed with ADHD and observations, I illustrate how impairment in time is manifested in an embodied experience of being out of sync. I suggest that the experience of ADHD is characterized as 1) an inner restlessness and bodily arrhythmia; 2) an intersubjective desynchronization between the individual and its surroundings; and 3) a feeling of lagging behind socially due to difficulties in social skills. In closing, I argue that an increasingly accelerating society is augmenting the experience of being out of sync rather than eliminating it.

Generation Adderall - The New York Times

During the first weeks of finally giving up Adderall, the fatigue was as real as it had been before, the effort required to run even a tiny errand momentous, the gym unthinkable. The cravings were a force of their own: If someone so much as said “Adderall” in my presence, I would instantly begin to scheme about how to get just one more pill. Or maybe two. I was anxious, terrified I had done something irreversible to my brain, terrified that I was going to discover that I couldn’t write at all without my special pills. I didn’t yet know that it would only be in the amphetamine-free years to follow that my book would finally come together.

Rumor: Doctor Prescribes Donald Trump "Cheap Speed"

Rumors of Trump’s predilection for stimulants first started really popping up in 1992, when Spy magazine wrote, “Have you ever wondered why Donald Trump has acted so erratically at times, full of manic energy, paranoid, garrulous? Well, he was a patient of Dr. [Joseph] Greenberg’s from 1982 to 1985.” At the time, Dr. Greenberg was notorious for allegedly doling out prescription stimulants to anyone who could pay.

Persistent ADHD associated with overly critical parents: High levels of criticism over time related to continuation of symptoms, study says -- ScienceDaily

Parents were asked to talk about their relationship with their child uninterrupted for five minutes. Audio recordings of these sessions were then rated by experts for levels of criticism (harsh, negative statements about the child, rather than the child's behavior) and emotional over-involvement (overprotective feelings toward the child). Measurements were taken on two occasions one year apart. Only sustained parental criticism (high levels at both measurements, not just one) was associated with the continuance of ADHD symptoms in the children who had been diagnosed with ADHD. "The novel finding here is that children with ADHD whose families continued to express high levels of criticism over time failed to experience the usual decline in symptoms with age and instead maintained persistent, high levels of ADHD symptoms," said Musser.

Dopamine and memory

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, stimulants produce unambiguous improvements in working memory, episodic memory, and inhibitory control in adults.[83][84]

Distractibility trait predisposes some to attentional lapses -- ScienceDaily

"Everyone, including the highly distractible people , who reported higher levels of ADHD symptoms and who responded up to 41% slower when the cartoon distractor was present, benefited from increasing the task difficulty, which may be contrary to common expectations," says Lavie.

Running as medicine for ADD

Back in the early '80s, a marathoner came to me and said, look, I think I have adult-onset attention deficit disorder[…]the guy was - had a dual appointment at MIT and Harvard as a professor, was a MacArthur Fellow, had all the credentials in the world; and he was a marathoner. And he had to stop marathoning because he hurt his knee and couldn't run his typical seven to eight miles a day. So he said that at first, he got depressed, which happens to most marathoners. But secondly, after his depression resolved, he couldn't pay attention. He was like a child with attention deficit disorder - was always off in dreamland or would forget things, would get aggressive too easily, ignored his friends; all the things that we see in attention deficit disorder. […]I put him on medicine and that helped quite a lot but then, eventually, he got back to running, and he dropped the medicine because it was no longer necessary. And that's what we see at times with many of the people who have attentional issues or mood issues; that exercise can be self-medicating.

Ben Bradlee had trouble focusing

Mr. Bradlee had a notoriously short attention span. He rarely dug into the details of an issue himself, leaving that to the people he had hired. He managed The Post newsroom with a combination of viscera and intellect, often judging people by his personal reaction to them. He or she “makes me laugh” was perhaps Mr. Bradlee’s greatest compliment. He never enjoyed the minutiae of management and spent as little time on administrative work as he could get away with.

Exercise Is ADHD Medication

The study, published April 22 in the journal Psychological Science, included 108 adults. They took either Ritalin or a placebo an hour before they attempted two consecutive computer-based tasks that tested their self-control. The participants who took Ritalin retained higher levels of self-control in the second test than those who took the placebo. The results indicate that Ritalin can help prevent depletion of self-control, the researchers said. The drug may do this by giving a boost to specific brain circuits that are normally weakened after maintaining self-control for long periods.