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How reversible is DAT upregulation from long-term ADHD medication use?

How reversible is DAT upregulation from long-term ADHD medication use?


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A mechanism for ADHD stimulant medication tolerance has now been found. See http://neurosciencenews.com/adhd-medication-patient-brains-adapt-dat/.

Here's the thing though: what exactly is the "signal" that the body uses to interpret whether or not it needs to upregulate the amount of DAT (dopamine transporter) that exist? Is it a dopamine-based signal that somehow then gets carried to a transcription factor that gets carried to the nucleus for additional transcription?


First the boring (but most important part) looking at the study:

It is important to critique the study design FIRST to see what kind of information we can actually obtain from this study. This is a meta-analysis of cross-sectional studies (meaning there is no record of change over time) that include a variety of age ranges of ADHD patients (some on treatment, some not) who were compared with age, gender and IQ-matched non-ADHD people to measure DAT levels in the stratum measured with PET and SPECT.

What they found:

There were very heterogeneous results from all the studies, there was no statistically significant difference between DAT in ADHD and normal (note that they use the word "trends"). The only thing statistically significant that they found was that there was a wide spread of DAT in the ADHD population, and that exposure to treatment accounted for half of this spread (variance).

What can we say about this?

This is not a very conclusive study, but studies like this are often necessary to merit doing higher resource intensive studies. This study did not reach statistical significance in it's primary outcome, and on further search was able to only find a single outcome of significance. My summary of this would be: maybe this could represent a method of medication tolerance.

To answer your question If hypothetically this was the cause and I had to make up a possible method of transcription control, I would say something similar to your answer. I would guess there is some transcription factor that is inhibited by dopamine in the cell. When there isn't dopamine (b/c it is being blocked from returning), it would somehow become active and start transcribing the gene for DAT.

Disclaimer I am not a neurobiologist, this is my opinion after reading the article. Feel free to add to my comments

Reference:

Fusar-Poli, P., Rubia, K., Rossi, G., Sartori, G., & Balottin, U. (2012). Striatal dopamine transporter alterations in ADHD: pathophysiology or adaptation to psychostimulants? A meta-analysis. American Journal of Psychiatry, 169(3), 264-272.[Link]


Cannabis Addiction and the Brain: a Review

Cannabis is the most commonly used substance of abuse in the United States after alcohol and tobacco. With a recent increase in the rates of cannabis use disorder (CUD) and a decrease in the perceived risk of cannabis use, it is imperative to assess the addictive potential of cannabis. Here we evaluate cannabis use through the neurobiological model of addiction proposed by Koob and Volkow. The model proposes that repeated substance abuse drives neurobiological changes in the brain that can be separated into three distinct stages, each of which perpetuates the cycle of addiction. Here we review previous research on the acute and long-term effects of cannabis use on the brain and behavior, and find that the three-stage framework of addiction applies to CUD in a manner similar to other drugs of abuse, albeit with some slight differences. These findings highlight the urgent need to conduct research that elucidates specific neurobiological changes associated with CUD in humans.


Introduction

Despite improvements in diagnosis and treatment, breast cancer remains the second-leading cause of cancer-related deaths among women in the United States (1). This is due largely to the recurrence of disease following surgery and adjuvant therapy. Recurrent breast cancer is common, affecting nearly 25% of breast cancer patients, and these recurrent tumors are frequently resistant to drugs used to treat primary breast tumors. Recurrent tumors are thought to arise from a population of residual cells that survive treatment. Consistent with this notion, the extent of residual disease following neoadjuvant therapy is correlated with the risk of developing recurrence (2). In addition, between 30% and 50% of breast cancer patients have disseminated tumor cells (DTC) in their bone marrow, and the presence of these cells and their persistence following therapy are strongly correlated with poor prognosis (3–5). Therapies that can eliminate residual tumor cells or prevent their emergence as recurrent breast cancers may prolong the survival of patients with breast cancer. However, the development of such therapies is limited by our poor understanding of the pathways that enable the long-term survival of residual cells following treatment.

We have previously used conditional genetically engineered mouse (GEM) models to identify pathways that mediate the survival and recurrence of residual cells following oncogene inhibition (6). In these models, doxycycline-dependent, mammary gland–specific expression of an oncogene (e.g., Her2, Myc, or Wnt1) drives the formation of invasive mammary adenocarcinomas (7–9). Removal of doxycycline from mice with primary tumors leads to oncogene downregulation and tumor regression. However, a population of residual cells survives oncogene downregulation and persists in a dormant, nonproliferative state (10). Following a variable latency period, these residual cells resume proliferation to form recurrent tumors (6, 11).

To identify pathways that regulate the survival of residual cells and their eventual recurrence, we compared gene expression profiles of primary and recurrent tumors from the Her2, Myc, and Wnt1 oncogene models. This analysis revealed that the tumor suppressor protein Par-4 is downregulated in recurrent tumors from all three models (6). Par-4 is a proapoptotic protein that induces apoptosis in cancer cells through a variety of mechanisms, primarily through inhibition of the prosurvival pathways NFκB, Akt, and PKCζ (12). Our functional studies showed that Par-4 is a critical negative regulator of residual cell survival and recurrence. Specifically, cells with low Par-4 expression preferentially survive and persist as residual cells following Her2 downregulation. Similar results were observed in breast cancer patients treated with neoadjuvant chemotherapy (NAC): low Par-4 expression in primary tumors is associated with increased residual cancer burden following NAC, and residual tumors that remain following NAC have low Par-4 expression (6). These results identify Par-4 as a negative regulator of residual cell survival following therapy.

However, little is known about how Par-4 expression is regulated in response to treatment. Studies in Her2-driven tumors showed that Her2 inhibition leads to acute upregulation of Par-4, thereby limiting the survival of residual tumor cells (6). However, the mechanistic basis of Par-4 upregulation remains unknown. In addition, the relevance of Par-4 in regulating residual tumor cell survival in human cancer cells, and in cells driven by activation of other oncogenic pathways, remains unknown. In this study, we investigate the mechanism and functional significance of Par-4 upregulation following oncogene inhibition in human breast cancer cells. We show that Foxo3a directly binds to the Par-4 promoter and transcriptionally upregulates Par-4 following inhibition of the PI3K–Akt–mTOR pathway. We further show that this Foxo3a-dependent Par-4 expression prevents the long-term survival of residual cells following oncogene inhibition.


Subjects and methods

Subjects

All animal procedures were approved by the Institutional Animal Care and Use Committee. The subjects were αCamKII-tTA (tTA) 34 (gift from Dr T Abel, U Penn) single-transgenic and TRE-Cal/tTA (Cal OE ) double-transgenic mice bred from matings of tTA and TRE-Cal single-transgenic parents, and identified by PCR of genomic DNA isolated from mouse tails. 39 Before carrying out the present studies, the TRE-Cal and tTA mice were backcrossed to C57Bl/6 for eight generations. Mice were housed two to three per cage with food and water freely available on a 12:12 h light–dark cycle, lights on at 0700 hours. All mice were kept with mothers for at least 3 weeks after birth, and the dams were provided with nesting material (cotton batting). Dox (20 mg ml) was administered ad libitum via tinfoil-wrapped standard cage bottles filled with a 5% sucrose solution in water, renewed three times a week. 42

Behavioral procedures

Mice were handled for a week before the behavioral training. All training was done between 1100 and 1700 hours. All behaviors were videotaped and analyzed by an experimenter blinded to the animal's genotype.

The apparatus was 260-mm long, 30 mm at the floor and 85 mm at the top. The floor metal plates were separated by 5 mm. Each mouse was allowed to explore the apparatus for 5 min. On the following day, after a 45-s habituation period in the apparatus, each mouse received three foot shocks, 0.75 mA (Figures 1 and 3) and 0.5 mA (Figure 4), 45 s apart, and was removed 45 s after the last foot shock. Freezing behavior, identified as immobility except that needed for breathing, was recorded for each 45-s period. Extinction was started 24 h after CFC training by placing mice in the apparatus for 5 min per day for 4 days no foot shocks were delivered. The first day of extinction training (day 1) was also used as a measure of CFC memory.

Cal OE mice are impaired in fear extinction after contextual fear conditioning (CFC). Percent of time exhibiting freezing behavior during: (a) acquisition of CFC and daily CFC extinction training (b) as a whole, as well as (c) on a per minute basis. * P<0.01 compared with control mice.

Water Maze task

The apparatus was a tank, 120 cm in diameter. It was surrounded by walls on three sides on which salient extramaze cues were mounted. Titanium dioxide in the water made the submerged square platform (12 cm) not visible from the surface. The water temperature was 23 °C, and the platform was submerged at 11 cm below the surface in one of the four fixed locations. The center of each location was 23 cm off the wall and equidistant from the two closest starting points. The initial training consisted of five daily sessions of three trials per day. At the beginning of the training, each mouse was placed on the platform for 30 s and the trials were initiated 30 s later. Each trial consisted of releasing a mouse into the water maze from one of the four starting locations in a pseudorandom order, allowing it to swim to location 1 until it mounted the platform and remained on it for 10 s. Latency to reach the platform was scored with a maximum of 60 s. The intertrial interval was 30 s. The reversal training consisted of four daily sessions (three trials per day). All parameters were kept the same, except that the platform was moved to location 2, which was diametrically opposite to location 1.

Spatial memory test

Spatial memory was assessed with probe tests conducted 2 days after the end of initial training (probe test 1) and reversal training (probe tests 2 and 3, Supplemental Figure 2). During a probe test, all procedures were the same as during training, except that the platform was removed. Performance was evaluated by measuring time spent in the target and opposite zones, proximity to the target location, initial latency to the target and the opposite platform locations, and number of crossings of these locations. Target and opposite zones were defined as circles (17 cm in radius) centered on the center of the respective platform locations. These zones covered 1/12th (8%) of the water maze surface. Analysis was done with EthoVision XT 7 (Noldus, Leesburg, VA, USA).

Working memory training

A week after the second probe test, the mice were subjected to 3 days of delayed match-to-sample training (four trials per day) according to the following protocol: (1) on each trial, the submerged platform was placed in one of the three fixed locations, none of which was location 2 (2) a platform of the same size was placed over the submerged platform, such that it was just above the water (3) a mouse was placed on the above-water platform for 10 s (4) the mouse was picked up from the above-water platform and that platform was removed (the submerged platform stayed in place) and (5) after a 10-s delay period, the mouse was released into the pool from a constant starting point and allowed 30 s to locate the platform. The performance of each mouse was evaluated by scoring the number of errors before reaching the current trial target area. An error was scored when the mouse swam through an area that was not a target for the current trial. Each area was defined as a circle with a 17 cm radius centered on the center of the respective platform position. As the area around location 2 was never a target, it was never reinforced. The mice tested for spatial reference memory and working memory had completed fear extinction testing 2 weeks earlier.

Immunohistochemistry

Mice were anesthetized with isoflurane, and the brains were quickly flash frozen in 2-methyl butane (Sigma, St Louis, MO, USA). The 20 mm-thick sections containing the dorsal hippocampus (HPC) and PFC were captured on slides and used for immunohistochemistry as described previously. 37 The anti-hCal antibody (Ab) was affinity-purified polyclonal rabbit Ab (1:100). 38 This Ab does not detect endogenous mouse calcyon. 39 Rabbit polyclonal or murine monoclonal antibodies specific for GluR1 and GluR2/3 were used at 1:50. The secondary antibodies were biotinylated anti-rabbit and anti-mouse Abs (1:600, Vector Laboratories, Burlingame, CA, USA). The signal from the secondary Abs was amplified with an ABC kit and visualized with cyanine 3 (CY3) TSA fluorescence system (PerkinElmer Life Sciences, Waltham, MA, USA). Nuclei were counterstained with SYTOX Green (Invitrogen, Carlsbad, CA, USA) or DAPI (Invitrogen) nucleic acid stains. Specificity of the staining was established by incubating control slides without either the primary or secondary antibodies.

Imaging and quantification

Mosaics of image stacks (z-stacks) from the HPC were collected with a × 25 objective on a Zeiss AxioImager/Apotome system (Thornwood, NY, USA). Excitation source intensity and exposure settings were first optimized and then kept constant for all brains. GluR1 and GluR2/3 labeling in the dendritic zone stratum radiatum of CA1 was quantified by measuring the ‘per pixel’ intensity from ∼ 40 000 pixels per image, representing a dendritic volume of ∼ 130 000 μm 3 in two to three images per animal. The values were expressed as percent of the average of the control mice.

Immunoblots

Forebrains of Cal OE mice were homogenized with eight times volume using lysis buffer (150 m M NaCl, 2 m M EDTA and 1% Triton-X-100 in 50 m M Tris-Cl, pH 7.4) containing protease inhibitors (Roche) and nutated for an hour at 4 °C. Postnuclear supernatant fractions were obtained by centrifugation at 1000 g for 5 min at 4 °C. Proteins were resolved by SDS gel electrophoresis on step-gradient gels containing 8, 10 and 12% polyacrylamide, and transferred to polyvinylidene fluoride (PVDF) membranes. Blots were blocked with 5% non-fat dry milk in 1 × PBST, probed with anti-FLAG HRP (Sigma) at 1:1000 dilution, and the signal developed using Amersham ECL Plus (GE, Piscataway, NJ, USA). The blots were stripped and reprobed with anti-Hsp90 antibody (BD Biosciences, Rockville, MD, USA) at 1:1000 dilution, followed by anti-mouse HRP (Jackson Immuno Research, West Grove, PA, USA) at 1:20 000.

Tissue for brain regional immunoblot studies was obtained from behaviorally naïve adult male Cal OE (n=4) and tTA (n=4) mice. Samples of infralimbic/prelimbic PFC (IL/PrL) and dorsal HPC were taken using a tissue puncher (0.3 μm diameter) (Stoetling Instruments, Wood Dale, IL, USA) from 1 mm-thick sections of flash-frozen brains. Tissue was homogenized on ice in 0.1% SDS containing protease and phosphatase inhibitors (Roche) by brief (10 s) sonication. The blots were probed with rabbit polyclonal or murine monoclonal antibodies specific for GluR1 (CalBiochem, San Diego, CA, USA, 1:50), GluR2/3 (Chemicon, Temecula, CA, USA, 1:200) and glyceraldehyde 3-phosphate dehydrogenase (GAPDH, Applied Biosystems/Ambion, Austin, TX, USA) (1:200 000). Immunoreactive bands were quantified using Image J (NIH), and the GluR band intensity normalized to that of GAPDH-immunoreactive bands in the same lane.

Glutathione-S-transferase pull-down and immunoprecipitation studies

Equivalent amounts of glutathione-S-transferase (GST) or GST–GluR1 or GST–GluR2 or GST–GluR3 ‘C’ terminus 43 were bound to glutathione resin (Amersham Biosciences) and blocked using 1% bovine serum albumin in binding buffer (150 m M NaCl and 1% Triton-X-100 dissolved in 20 m M Tris-Cl, pH 7.4) containing protease inhibitors (Roche, Basel, Switzerland). An equivalent amount of purified S-tagged hCal (residues 93-217) 18 was added to each sample, and nutated for an hour at room temperature in the binding buffer containing 1% bovine serum albumin. The resin was transferred to spin filters, washed five times with binding buffer and protein complexes eluted in gel-loading buffer as above. Blots were probed with S-protein HRP (Novagen) at 1:5000 dilution.

For the immunoprecipitation studies, Cal OE forebrain postnuclear supernatant fractions (precleared with non-immune immunoglobulin G resin) were added to equivalent amounts of either immunoglobulin G resin or anti-FLAG resin, and nutated overnight at 4 °C. After washing the resin in spin filters, proteins were eluted by boiling for 5 min in 2 × SDS gel-loading buffer with 5% beta-mercaptoethanol (β-ME). Blots were probed with anti-GluR1 antibodies (Calbiochem) at 1:50 dilution, and reprobed with anti-GluR2/3 antibody (Chemicon International) at 1:500, anti-FLAG HRP (Sigma) at 1:1000 or anti-Hsp90 antibody (BD Biosciences) at 1:1000 dilution.

Statistical analyses

Group differences were evaluated with factorial and factorial mixed-design analysis of variance tests with between-group factors genotype and Dox treatment and within-group factor training or extinction, as appropriate. For the experiments where more than two groups were evaluated, a priori hypotheses were evaluated with Bonferonni/Dunn post hoc tests. Evaluating above chance levels for each group was done with a one-sample t-test where the hypothesized mean was the ‘at chance’ level. The level of significance was set at 0.05.


Abstract

Synthetic riboswitches based on small molecule-responsive self-cleaving ribozymes (aptazymes) embedded in the untranslated regions (UTRs) allow chemical control of gene expression in mammalian cells. In this work, we used a guanine-responsive aptazyme to control transgene expression from a replication-incompetent vesicular stomatitis virus (VSV) vector. VSV is a nonsegmented, negative-sense, cytoplasmic RNA virus that replicates without DNA intermediates, and its applications for vaccines and oncolytic viral therapy are being explored. By inserting the guanine-activated ribozyme in the 3′ UTRs of viral genes and transgenes, GFP expression from the VSV vector in mammalian cells was repressed by as much as 26.8-fold in the presence of guanine. Furthermore, we demonstrated reversible regulation of a transgene (secreted NanoLuc) by adding and withdrawing guanine from the medium over the course of 12 days. In summary, our riboswitch-controlled VSV vector allows robust, long-term, and reversible regulation of gene expression in mammalian cells without the risk of undesirable genomic integration.


Risperidone (Risperdal)

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Mental health conditions

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800-950-NAMI

Brand names:

  • Risperdal®
    • Tablet: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg
    • Orally disintegrating tablet: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg
    • Solution: 1 mg/ml
    • Extended-release injectable suspension: 12.5 mg, 25 mg, 37.5 mg, 50 mg
    • Extended-release injectable suspension: 90mg, 120 mg

    Generic name: risperidone (ris PER i done)

    All FDA black box warnings are at the end of this fact sheet. Please review before taking this medication.

    What Is Risperidone And What Does It Treat?

    Risperidone is a medication that works in the brain to treat schizophrenia. It is also known as a second generation antipsychotic (SGA) or atypical antipsychotic. Risperidone rebalances dopamine and serotonin to improve thinking, mood, and behavior.

    Symptoms of schizophrenia include:

    • Hallucinations &mdash imagined voices or images that seem real
    • Delusions &mdash beliefs that are not true (e.g., other people are reading your thoughts)
    • Disorganized thinking or trouble organizing your thoughts and making sense
    • Little desire to be around other people
    • Trouble speaking clearly
    • Lack of motivation

    Risperidone may help some or all of these symptoms.

    Risperidone is also FDA approved for the following indications:

    • Acute treatment of manic or mixed episodes of bipolar disorder
    • Maintenance (long-term) treatment of bipolar disorder
    • Irritability associated with autistic disorders

    This medication sheet will focus primarily on schizophrenia. Find more information about bipolar disorder and autism spectrum disorders here.

    Risperidone may also be helpful when prescribed &ldquooff-label&rdquo for adjunctive treatment of major depression disorder (risperidone is used in addition to an antidepressant), delusional parasitosis, post-traumatic stress disorder (PTSD), Tourette syndrome, and other mental health conditions. &ldquoOff-label&rdquo means that it has not been approved by the Food and Drug Administration for this condition. Your mental health provider should justify his or her thinking in recommending an &ldquooff-label&rdquo treatment. They should be clear about the limits of the research around that medication and if there are any other options.

    What Is The Most Important Information I Should Know About Risperidone?

    Schizophrenia requires long-term treatment. Do not stop taking risperidone, even when you feel better.

    With input from you, your health care provider will assess how long you will need to take the medicine.

    Missing doses of risperidone may increase your risk for a relapse in your symptoms.

    Do not stop taking risperidone or change your dose without talking to with your healthcare provider first.

    For risperidone to work properly, the tablet form should be taken every day as ordered by your healthcare provider. One of the long-acting injectable forms, known as Risperdal Consta®, should be received every 2 weeks as ordered by your healthcare provider. The other long-acting injectable form, known as Perseris®, should be received every month. Both of the long-acting injections are the same medication as in the tablet form.

    Are There Specific Concerns About Risperidone And Pregnancy?

    If you are planning on becoming pregnant, notify your healthcare provider to best manage your medications. People living with schizophrenia who wish to become pregnant face important decisions. This is a complex decision since untreated schizophrenia has risks to the fetus, as well as the mother. It is important to discuss the risks and benefits of treatment with your doctor and caregivers.

    Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and/or withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor these effects may be self-limiting or require hospitalization.

    Caution is advised with breastfeeding since risperidone does pass into breast milk.

    What Should I Discuss With My Healthcare Provider Before Taking Risperidone?

    • Symptoms of your condition that bother you the most
    • If you have thoughts of suicide or harming yourself
    • Medications you have taken in the past for your condition, whether they were effective or caused any adverse effects
    • If you ever had muscle stiffness, shaking, tardive dyskinesia, neuroleptic malignant syndrome, or weight gain caused by a medication
    • If you experience side effects from your medications, discuss them with your provider. Some side effects may pass with time, but others may require changes in the medication.
    • Any psychiatric or medical problems you have, such as heart rhythm problems, long QT syndrome, heart attacks, diabetes, high cholesterol, or seizures
    • If you have a family history of diabetes or heart disease
    • All other medications you are currently taking (including over the counter products, herbal and nutritional supplements) and any medication allergies you have
    • Other non-medication treatment you are receiving, such as talk therapy or substance abuse treatment. Your provider can explain how these different treatments work with the medication.
    • If you are pregnant, plan to become pregnant, or are breast-feeding
    • If you smoke, drink alcohol, or use illegal drugs

    How Should I Take Risperidone?

    Risperidone tablets and solution are usually taken 1 or 2 times per day with or without food.

    Typically patients begin at a low dose of medicine and the dose is increased slowly over several weeks.

    The oral dose usually ranges from 1mg to 6 mg. The dose of the injection usually ranges from 12.5 mg to 50 mg. Only your healthcare provider can determine the correct dose for you.

    Use a calendar, pillbox, alarm clock, or cell phone alert to help you remember to take your medication. You may also ask a family member or a friend to remind you or check in with you to be sure you are taking your medication.

    Risperidone orally disintegrating tablets must remain in their original packaging. Open the package with clean dry hands before each dose. Do not try to put tablets in a pillbox if you take the orally disintegrating tablets.

    Risperidone orally disintegrating tablets will dissolve in your mouth within seconds and can be swallowed with or without liquid.

    Risperidone liquid should be measured with a dosing spoon or oral syringe, which you can get from your pharmacy.

    Risperdal Consta® (risperidone long-acting injection) should be received every 2 weeks. It should be administered by your health care professional through an injection into your upper arm or buttocks area. The medication effects last for approximately 2 weeks. If you are new to taking Risperdal Consta® (risperidone long-acting injection), your health care provider may want you to take the tablet form or risperidone daily for up to 3 weeks.

    Perseris® (risperidone long-acting injection) should be received every month. It should be administered by your health care professional through an injection under the skin of your abdominal area. After establishing tolerability with oral risperidone, you may be switched to Perseris® (risperidone long-acting injection). Supplemental oral risperidone is not recommended after receiving your first Perseris® (risperidone long-acting injection) dose. After receiving the injection, you may have a lump for several weeks that will decrease in size over time. It is important that you not rub or massage the injection site and to be aware of the placement of any belts or clothing waistbands.

    What Happens If I Miss A Dose Of Risperidone?

    If you miss a dose of risperidone, take it as soon as you remember, unless it is closer to the time of your next dose. Discuss this with your healthcare provider. Do not double your next dose or take more than what is prescribed. If you miss a dose of Risperdal Consta® or Perseris® (risperidone long-acting injections), see your healthcare provider to receive your dose as soon as possible.

    What Should I Avoid While Taking Risperidone?

    Avoid drinking alcohol or using illegal drugs while you are taking risperidone. They may decrease the benefits (e.g., worsen your confusion) and increase adverse effects (e.g., sedation) of the medication.

    What Happens If I Overdose With Risperidone?

    If an overdose occurs call your doctor or 911. You may need urgent medical care. You may also contact the poison control center at 1-800-222-1222.

    A specific treatment to reverse the effects of risperidone does not exist.

    What Are Possible Side Effects Of Risperidone?

    Common side effects

    Sedation, drowsiness, extrapyramidal symptoms, insomnia, fatigue, headache, anxiety, dizziness, drooling, restlessness, increased prolactin, weight gain, increased appetite, vomiting, constipation, upper abdominal pain, nausea, urinary incontinence, tremor, cold symptoms, cough, runny nose, fever

    Risperdal Consta® (risperidone long-acting injection): injection site pain

    Perseris® (risperidone long-acting injection): injection site pain, redness, and a lump that may be present for several weeks

    Rare/serious side effects

    Risperidone may increase the blood levels of a hormone called prolactin. Side effects of increased prolactin levels include females losing their period, production of breast milk and males losing their sex drive or possibly experiencing erectile problems. Long term (months or years) of elevated prolactin can lead to osteoporosis, or increased risk of bone fractures.

    Some people may develop muscle related side effects while taking risperidone. The technical terms for these are &ldquoextrapyramidal symptoms&rdquo (EPS) and &ldquotardive dyskinesia&rdquo (TD). Symptoms of EPS include restlessness, tremor, and stiffness. TD symptoms include slow or jerky movements that one cannot control, often starting in the mouth with tongue rolling or chewing movements.

    Temperature regulation: Impaired core body temperature regulation may occur caution with strenuous exercise, heat exposure, and dehydration.

    Second generation antipsychotics (SGAs) increase the risk of weight gain, high blood sugar, and high cholesterol. This is also known as metabolic syndrome. Your healthcare provider may ask you for a blood sample to check your cholesterol, blood sugar, and hemoglobin A1c (a measure of blood sugar over time) while you take this medication.

    Information on healthy eating and adding exercise to decrease your chances of developing metabolic syndrome may be found at the following sites:

    SGAs have been linked with higher risk of death, strokes, and transient ischemic attacks (TIAs) in elderly people with behavior problems due to dementia.

    All antipsychotics have been associated with the risk of sudden cardiac death due to an arrhythmia (irregular heartbeat). To minimize this risk, antipsychotic medications should be used in the smallest effective dose when the benefits outweigh the risks. Your doctor may order an EKG to monitor for irregular heartbeat.

    Neuroleptic malignant syndrome is a rare, life threatening adverse effect of antipsychotics which occurs in <1% of patients. Symptoms include confusion, fever, extreme muscle stiffness, and sweating. If any of these symptoms occur, contact your healthcare provider immediately.

    All antipsychotics can cause sedation, dizziness, or orthostatic hypotension (a drop in blood pressure when standing up from sitting or lying down). These side effects may lead to falls which could cause bone fractures or other injuries. This risk is higher for people with conditions or other medications that could worsen these effects. If falls or any of these symptoms occur, contact your healthcare provider.

    Are There Any Risks For Taking Risperidone For Long Periods Of Time?

    Tardive dyskinesia (TD) is a side effect that develops with prolonged use of antipsychotics. Medications such as risperidone have been shown to have a lower risk of TD compared to older antipsychotics, such as Haldol® (haloperidol). If you develop symptoms of TD, such as grimacing, sucking, and smacking of lips, or other movements that you cannot control, contact your healthcare provider immediately. All patients taking either first or second generation antipsychotics should have an Abnormal Involuntary Movement Scale (AIMS) completed regularly by their healthcare provider to monitor for TD.

    Second generation antipsychotics (SGAs) increase the risk of diabetes, weight gain, high cholesterol, and high triglycerides. (See &ldquoSerious Side Effects&rdquo section for monitoring recommendations).

    What Other Medications May Interact With Risperidone?

    Risperidone may block the effects of agents used to treat Parkinson&rsquos disease such as levodopa/carbidopa (Sinemet®), bromocriptine, pramipexole (Mirapex®), ropinirole (Requip®), and others.

    Risperidone may lower your blood pressure. Medications used to lower blood pressure may increase this effect and increase your risk of falling. Propranolol (Inderal®) is an example of this type of medication.

    The following medications may increase the levels and effects of risperidone: divalproex sodium (Depakote®), fluoxetine (Prozac®), paroxetine (Paxil®), and verapamil (Calan®).

    The following medications may decrease the levels and effects of risperidone: carbamazepine (Tegretol®, Equetro®), phenytoin (Dilantin®), phenobarbital, or rifampin (Rifadin®).

    How Long Does It Take For Risperidone To Work?

    It is very important to tell your doctor how you feel things are going during the first few weeks after you start taking risperidone. It will probably take several weeks to see big enough changes in your symptoms to decide if risperidone is the right medication for you. If you take Risperdal Consta® (risperidone long-acting injection), it will take about three weeks before risperidone is fully absorbed and at an adequate level to begin treating your symptoms. After starting Risperdal Consta® (risperidone long-acting injection) for the first time, or re-starting it after a time of no medication, it is important to continue taking risperidone tablets for at least three weeks. If you take Perseris® (risperidone long-acting injection), it is not recommended to take oral risperidone after the first injection.

    Antipsychotic treatment is generally needed lifelong for persons with schizophrenia. Your doctor can best discuss the duration of treatment you need based on your symptoms and illness.

    • Hallucinations, disorganized thinking, and delusions may improve in the first 1-2 weeks
    • Sometimes these symptoms do not completely go away
    • Motivation and desire to be around other people can take at least 1-2 weeks to improve
    • Symptoms continue to get better the longer you take risperidone
    • It may take 2-3 months before you get the full benefit of risperidone

    Summary of FDA Black Box Warnings

    Increased mortality in elderly patients with dementia-related psychosis

    • Both first generation (typical) and second generation (atypical) antipsychotics are associated with an increased risk of mortality in elderly patients when used for dementia related psychosis.
    • Although there were multiple causes of death in studies, most deaths appeared to be due to cardiovascular causes (e.g. sudden cardiac death) or infection (e.g. pneumonia).
    • Antipsychotics are not indicated for the treatment of dementia-related psychosis.

    ©2019 The College of Psychiatric and Neurologic Pharmacists (CPNP) and the National Alliance on Mental Illness (NAMI). CPNP and NAMI make this document available under the Creative Commons Attribution-No Derivatives 4.0 International License. Last Updated: January 2016.

    This information is being provided as a community outreach effort of the College of Psychiatric and Neurologic Pharmacists. This information is for educational and informational purposes only and is not medical advice. This information contains a summary of important points and is not an exhaustive review of information about the medication. Always seek the advice of a physician or other qualified medical professional with any questions you may have regarding medications or medical conditions. Never delay seeking professional medical advice or disregard medical professional advice as a result of any information provided herein. The College of Psychiatric and Neurologic Pharmacists disclaims any and all liability alleged as a result of the information provided herein.


    Metabolism𠄾pigenetics in cell-fate specification

    The metabolic reprogramming of chromatin modifications is associated with several functional outcomes that include cell-fate specification, and by extension, processes such as development, ageing, immunology and the aetiology of diseases such as cancer ( Figure 3 ). It is essential to understand whether or in what contexts metabolism per se drives cell fate transitions, or whether metabolic changes during cellular transitions occur independently of the driving events. Accumulating evidence has begun to demonstrate that metabolically driven chromatin dynamics directly affect the expression of genes related to cellular functions, and that their functional outcomes can be at least partially reversed by interfering with the metabolic changes or metabolically driven epigenomic changes, indicating that metabolism drives cell fate transition through regulation of the epigenome in many circumstances.

    The intersection between metabolism and epigenetics is implicated in a variety of physiological contexts including lineage specification at the embryonic level, immune regulation and the oncogenic transformation of cells. The maintenance of stemness and pluripotency and the process of differentiation are characterized by changes to metabolism and subsequent dynamic changes to epigenetic modifications. This reprogramming is also implicated in the activation or retroactive suppression of a variety of immune cell types including T cells, B cells and macrophages, and the ability to mount an immune response in response to invading pathogens. Finally, the oncogenic transformation of cells can be driven by mutations in metabolic enzymes, or by genomic drivers that reprogram metabolism. These molecular networks offer therapeutic targets in the fields of developmental biology, immunotherapy and oncology. αKG, α-ketoglutarate FH, fumarate hydratase HDAC, histone deacetylase IDH, isocitrate dehydrogenase m 6 A, N 6 - methyladenosine SDH, succinate dehydrogenase.

    Differentiation.

    The regulation of pluripotency and lineage-specification involves the participation of a variety of metabolic pathways in a context-dependent manner, which have been reported to fulfil bioenergetic demands during these transitions, and aid in cellular signalling pathways 130 . Metabolic pathway activity and nutrient availability have been associated with cell-fate-related outcomes, such as induced pluripotency 131,132 , maintenance of stemness 133� , and differentiation towards specific lineages 137� . Notably, these changes in fluxes through metabolic pathways can also modify the epigenome, in response to differentiation cues or nutrient availability.

    Disruption to one-carbon metabolism has been shown to regulate embryonic stem cell (ESC) differentiation due to changes in SAM levels in culture 49,50 and in mice 15 , along with changes to histone methylation and DNA methylation. Maintenance of the intracellular αKG/succinate ratio in mouse ESCs 141 , epiblast stem cells and primed human pluripotent stem cells 142 , can regulate differentiation by modulating TET- & JHDM-dependent DNA and histone methylation respectively. Modulating acetyl-CoA levels can affect the differentiation of ESCs and muscle stem cells, with concurrently occurring changes in histone acetylation 16,143 and chromatin accessibility 16 . Emerging metabolically regulated modifications, including histone serotonylation (H3K4me3Q5ser) and histone homocysteinylation, have also been recently shown to play some role in cell-fate specification. As mentioned above, histone serotonylation at a particular site (H3K4me3Q5ser) can potentiate the differentiation of serotonergic neurons in cell culture and during mouse development 94 . Also as mentioned above, histone homocysteinylation has been shown to associate with increased Hcy levels in human fetal brains and the decreased expression of genes important for neural tube closure during development 91 .

    Immunology.

    The immune system is comprised of a diverse milieu of specialized cells that are activated or repressed in response to environmental inputs such as the presence of a pathogen and undergo dynamic changes in gene expression that regulate their function 144 . Metabolic reprogramming has been reported to drive the proliferation and differentiation of a myriad of immune cell populations, which also show concurrently occurring changes in chromatin state. Antigen receptor engagement in T-cells, for example, has been shown to increase metabolic flux through the methionine cycle, which upregulates DNA and histone methylation 54 . Methionine uptake has also been shown to maintain SAM synthesis and H3K4me3 levels in CD4 + T helper (Th) cells in culture, which regulates T-cell-mediated immune responses in vivo in a mouse model of multiple sclerosis 55 . The upregulation of SAM synthesis and levels of H3K36me3 are observed during lipopolysaccharide (LPS)-induced macrophage activation, which corresponds to increased IL-1β expression and production 17 . The metabolic regulation of TETs and JHDMs also regulates several aspects of immune cell biology. αKG production via glutaminolysis and other metabolic pathways, for example, is important for the activation of M2-macrophages and endotoxin clearance and involves the demethylation of repressive histone modifications at activating loci 145 . Glutamine availability in microenvironments of tumour-bearing mice, has conversely been shown to suppress T-cell activation, and promote tumorigenesis. Using a glutamine antagonist in these mice promoted T-cell activation by inducing a variety of changes including the reduction of αKG levels, and hypermethylation of activating histone modifications 60 . Iron availability in humans has recently been shown to correlate strongly with antibody production in response to vaccination. When these findings were further explored in cell culture and mice, iron (II) deficiency was found to induce defects in the humoral immune response [G] due to impaired activities of iron-dependent JHDMs and H3K9 hypermethylation at the promoter region of cyclin E, an important element for B-cell proliferation 61 .

    The metabolic regulation of histone acetylation and acylation has also been reported during immune cell activation. The induction of glycolysis due to the upregulation of lactate dehydrogenase (LDHA) generates acetyl-CoA and histone acetylation in T-cells, which regulates production of the cytokine IFNγ 146 . Competition for nutrients such as glucose in tumour microenvironments can also restrict T-cell activation, which can be rescued by acetate supplementation. Acetate supplementation rescues histone acetylation, chromatin accessibility and subsequently cytokine and IFNγ production 147 . Lactate, the end product of glucose metabolism, can be utilized for histone lactylation and the activation of homeostatic genes during M1 macrophage polarization in response to bacterial infection 85 . Transcriptional responses in LPS-induced macrophage activation are regulated by the SCFA crotonate and its derivative crotonyl-CoA, which crotonylates histones at promoters of the activated genes and stimulates the production of chemokines and cytokines 25 . Each of these metabolic processes is likely to have some epigenetic/chromatin component to its function.

    Cancer biology.

    Metabolic reprogramming can underlie or support the transformation of non-malignant cells into tumour cells. This is driven either by upstream factors such as aberrations in oncogenes and tumour suppressors, or through direct mutations to metabolic genes, and has been hypothesized to support various cellular functions including the anabolic demands of uncontrolled proliferation 148� . Metabolically driven epigenomic conditioning is emerging as a key component of this reprogramming during tumorigenesis.

    Oncogenic mutations exist in genes encoding all classes of the epigenetic machinery, including histones 152 , chromatin modifiers 153,154 , epigenetic ‘readers’ 155 and chromatin-remodellers 156 , indicating a selective pressure favouring epigenomic reprogramming for tumour progression 14,157� . Similarly, metabolic genes involved in producing chromatin-modifying metabolites are also frequently mutated in cancers, suggesting that the metabolically regulated epigenomic landscape has critical roles in cancer biology 161,162 . The most well-known example is the mutation of IDH1 or IDH2. According to an analysis of tumour exomes from The Cancer Genome Atlas project, mutant IDH1 serves as an oncogenic driver in at least seven cancer types, including those not typically known to harbour IDH mutations such as breast cancer 162 . As discussed previously, mutant IDH1 or IDH2 can lead to DNA and histone hypermethylation through the accumulation of 2-HG, resulting in the downregulation of genes associated with tumour suppression 62,163� . These findings have led to the development of inhibitors targeting mutant IDH that have been approved for use in acute myeloid leukaemia (AML), and are being studied in other malignancies 168 . However, in leukaemia cells, mutant IDH and accumulation of 2-HG have interestingly also been shown to suppress cancer cell proliferation by inhibiting the RNA demethylase FTO and destabilizing oncogenic MYC transcripts by increasing m 6 A, suggesting dual roles for 2-HG in cancer biology 127 .

    Also frequently mutated in cancer are genes encoding the metabolic enzymes FH and SDH 169,170 , whose deficiency leads to the accumulation of fumarate and succinate respectively, both of which inhibit TETs and JHDMs 171,172 , resulting in genome-wide DNA and histone hypermethylation. This has been shown to enable oncogenic promoter𠄾nhancer interactions 63 , and to induce epithelial-to-mesenchymal-transition (EMT) 64 . A recent study has further shown that histone hypermethylation caused by 2-HG, succinate and fumarate disrupts DNA repair, rendering cancer cells harbouring IDH, FH and SDH mutations vulnerable to PARP inhibition 173 . Similar to IDH, FH and SDH mutations, branched-chain amino acid [G] (BCAA) catabolism has recently been shown to induce oncogenic DNA hypermethylation in leukaemia cells by consuming αKG 174 . In renal cell carcinomas, the metabolic enzyme MTHFD2 [G] is overexpressed, contributing to increased global levels of m 6 A mRNA methylation by promoting the recycling of methionine through the folate cycle. This was shown in these cancers to increase HIF2α mRNA translation, and HIF2α-driven tumorigenesis 175 .

    In addition to mutations in metabolic enzymes, cancer cells often exhibit altered metabolism in response to upstream drivers which can also reprogram the epigenome. Inactivation of the tumour suppressor LKB1 in a mouse model of KRAS-mutant pancreatic cancer resulted in the upregulation of one-carbon and methionine metabolism and DNA hypermethylation through the accumulation of SAM 176 , whereas expression of the p53 tumour suppressor increased levels of αKG and 5hmC, an intermediate of active DNA demethylation, resulting in premalignant differentiation and tumour suppression 177 .

    Nearly all aspects of cancer cell metabolism, including the Warburg effect [G] , hypoxia 66,67 , and dysregulated amino acid metabolism, result in epigenomic reprogramming to some extent, accompanied by changes in gene expression. Tumour initiating cells isolated from primary lung tumours have increased methionine cycle activity and histone methylation compared to their non-tumourigenic counterparts, rendering them sensitive to MAT2A inhibition 18 . Methionine uptake by cancer cells regulates global levels of H3K4me3 and the expression of cancer-associated genes, which can be modulated by restricting methionine in culture media 51,52 . This effect of methionine restriction on cancer-related gene expression could be associated with reduced tumour growth in mice 178 . Glutamine deficiency in the core region of melanoma tumours has been shown to result in histone hypermethylation compared to the periphery due to a decrease in αKG. Reducing glutamine levels was subsequently shown to impair cancer cell differentiation and lead to therapeutic resistance in these tumours 59 . In addition to histone methylation, histone acetylation can be modulated in cancers by regulating HDACs 179 , sirtuins 180 , and acetyl-CoA, which by titrating glucose or acetate in culture media has been shown to influence the expression of genes associated with cancer growth and metastasis 181� .


    Type 2 diabetes is a reversible condition

    A body of research putting people with Type 2 diabetes on a low calorie diet has confirmed the underlying causes of the condition and established that it is reversible.

    Professor Roy Taylor at Newcastle University, UK has spent almost four decades studying the condition and will present an overview of his findings at the European Association For The Study Of Diabetes (EASD 2017) in Lisbon.

    In the talk he will be highlighting how his research has revealed that for people with Type 2 diabetes:

    • Excess calories leads to excess fat in the liver
    • As a result, the liver responds poorly to insulin and produces too much glucose
    • Excess fat in the liver is passed on to the pancreas, causing the insulin producing cells to fail
    • Losing less than 1 gram of fat from the pancreas through diet can re-start the normal production of insulin, reversing Type 2 diabetes
    • This reversal of diabetes remains possible for at least 10 years after the onset of the condition

    "I think the real importance of this work is for the patients themselves," Professor Taylor says. "Many have described to me how embarking on the low calorie diet has been the only option to prevent what they thought -- or had been told -- was an inevitable decline into further medication and further ill health because of their diabetes. By studying the underlying mechanisms we have been able to demonstrate the simplicity of type 2 diabetes."

    Get rid of the fat and reverse Type 2 diabetes

    The body of research by Professor Roy Taylor now confirms his Twin Cycle Hypothesis -- that Type 2 diabetes is caused by excess fat actually within both liver and pancreas.

    This causes the liver to respond poorly to insulin. As insulin controls the normal process of making glucose, the liver then produces too much glucose. Simultaneously, excess fat in the liver increases the normal process of export of fat to all tissues. In the pancreas, this excess fat causes the insulin producing cells to fail.

    The Counterpoint study which was published in 2011, confirmed that if excess food intake was sharply decreased through a very low calorie diet, all these abnormal factors would be reversed.

    The study showed a profound fall in liver fat content resulting in normalisation of hepatic insulin sensitivity within 7 days of starting a very low calorie diet in people with type 2 diabetes. Fasting plasma glucose became normal in 7 days. Over 8 weeks, the raised pancreas fat content fell and normal first phase insulin secretion became re-established, with normal plasma glucose control.

    Keep the weight off and keep the diabetes at bay

    "The good news for people with Type 2 diabetes is that our work shows that even if you have had the condition for 10 years, you are likely to be able to reverse it by moving that all important tiny amount of fat out of the pancreas. At present, this can only be done through substantial weight loss," Professor Taylor adds.

    The Counterbalance study published in 2016, demonstrated that Type 2 diabetes remains reversible for up to 10 years in most people, and also that the normal metabolism persists long term, as long as the person doesn't regain the weight.

    Professor Taylor explained the science behind the mechanisms: "Work in the lab has shown that the excess fat in the insulin producing cell causes loss of specialised function. The cells go into a survival mode, merely existing and not contributing to whole body wellbeing. Removal of the excess fat allows resumption of the specialised function of producing insulin. The observations of the clinical studies can now be fully explained."

    He added: "Surprisingly, it was observed that the diet devised as an experimental tool was actually liked by research participants. It was associated with no hunger and no tiredness in most people, but with rapidly increased wellbeing. The 'One, Two' approach used in the Counterbalance study was a defined two phase programme. The Phase 1 is the period of weight loss -- calorie restriction without additional exercise. A carefully planned transition period leads to Phase 2 -- long term supported weight maintenance by modest calorie restriction with increased daily physical activity."

    This approach consistently brings about 15kg of weight loss on average.

    After the details were posted on the Newcastle University, UK website, this has been applied clinically and people who were highly motivated have reported that they have reversed their type 2 diabetes and continued to have normal glucose levels (normoglycaemic) over years.

    A further study in general practice, the Diabetes Remission Clinical Trial (DiRECT) funded by Diabetes UK is now underway to determine the applicability of this general approach to routine Primary Care practice with findings due before the end of the year.

    Patients or GPs who would like more information about the diet that reverses Type 2 diabetes see the Magnetic Resonance Centre website.


    New study suggests ADHD- like behavior helps spur entrepreneurial activity

    Many people have experienced a few nights of bad sleep that resulted in shifting attention spans, impulsive tendencies and hyperactivity the next day -- all behaviors resembling ADHD. A new study found that this dynamic may also be linked to increased entrepreneurial behavior.

    "We're not advocating depriving yourself of sleep to get ahead," said Jeff Gish, a professor of business at the University of Central Florida and co-author of the paper. "We're saying that there appears to be an interesting link between sleep and entrepreneurship. ADHD-like tendencies can be a benefit, rather than a hindrance in spurring ventures. But there is a potential downside. Even though sleep problems might lure an individual to an entrepreneurial career, if the sleep problems persist they can subsequently leave the individual without the cognitive and emotional competency to be an effective entrepreneur in-practice."

    This paper suggests that sleep problems might nudge aspiring entrepreneurs to enter self-employment, but does not test the efficacy of subsequent venturing efforts.

    Anecdotal information would appear to support the idea. According to multiple media reports, Bill Gates, Walt Disney, Richard Branson, Cisco Systems CEO John T. Chambers, actor Jim Carrey and Hollywood personality Howie Mandel all have ADHD. They are recognized impresarios who have significantly impacted their industries.

    The results of the study published today in the journal Entrepreneurship Theory and Practice complement previous research that links sleep deprivation with lower productivity, lethargy and the hindrance of the longer-term success by suggesting that unhealthy sleep may have a limited upside.

    Although the findings may engender contrasts to recent work advocating for adequate sleep, the results may also "contribute to the de-stigmatization of individuals whose social or personal circumstances place healthy sleep out of reach, [contributing to] greater social acceptance of diversity in sleep patterns."

    The authors reached their findings by conducting four distinct studies that connected the dots from sleep quality to temporary ADHD-like tendencies and then to entrepreneurial intentions.

    Sleep Deprivation and ADHD-like Tendencies

    The first study, an experiment with 350 participants, had them fill out pre-experiment surveys. The participants were asked about their sleep and ADHD tendencies in the past six months. Questions aimed to gauge ADHD-like tendencies included things like:

      How often do you have trouble wrapping up the fine details of a project, once the challenging parts have been done?

    How often do you have difficulty getting things in order when you have to do a task that requires organization?

    To gauge entrepreneurial intention, they were asked about their intention to start or acquire a business in the next 5-10 years.

    Then the group was split into two and they filled out additional surveys under two conditions. One group had an uninterrupted night of sleep and woke up the next day to fill out the survey, which asked questions about their sleep quality, ADHD-like tendencies and intent to start a new business.

    The second group filled out a total of 10 surveys beginning at 10 pm one night and every hour on the hour until 7 am the following day. This was to elicit sleep deprivation.

    The results provided experimental evidence for a causal relationship between sleep problems and ADHD-like tendencies. "Our results suggest that disrupted sleep may help nudge people toward acting on their entrepreneurial ideas rather than continuing to ponder them," said Brian Gunia, a coauthor and associate professor at the Johns Hopkins Carey Business School.

    Sleep, ADHD-like Tendencies, and Entrepreneurial Intentions: Studies 2-3

    About 300 people filled out surveys that measured entrepreneurial intentions, followed by measures of ADHD-like tendencies, and sleep problems. Finally, they completed some demographic questions. The results were similar.

    Poor sleep quality was associated with heightened ADHD-like tendencies, which was associated with heightened entrepreneurial intentions poor sleep quality was also directly associated with heightened entrepreneurial intentions.

    Extension to Practicing Entrepreneurs: Study 4

    The previous studies looked at general populations, but the researchers wanted to see whether their predictions extended to practicing entrepreneurs. So, they surveyed a multi-national panel of 176 practicing entrepreneurs recruited from a mailing list maintained by a business planning software company on the U.S. West Coast. The participants in this group on average were 43 years-old, had started about two businesses and had been self-employed for at least seven years. Slightly more than half were men. They had the participants fill out similar surveys on sleep, ADHD behavior and their intent to start another business.

    The results: Impermanent sleep problems elicit ADHD-like tendencies and can spur on entrepreneurial intent even among practicing entrepreneurs.

    "We were surprised that sleep problems so consistently influenced the entrepreneurial intentions of people who know the challenges of starting a business," says Brian C. Gunia, an associate professor at John Hopkins University's Carey Business School and co-author of the paper.

    The paper concludes by saying that we need to carefully weigh the costs and benefits of sleep problems. On the one hand, they may nudge people toward entrepreneurship. On the other, they may undermine entrepreneurial performance if they continue unabated.


    People with ADHD are twice as likely to die prematurely, often due to accidents

    People with attention deficit hyperactivity disorder (ADHD) have a lower life expectancy and are more than twice as likely to die prematurely as those without the disorder, according to new research published in The Lancet. Accidents are the most common cause of death in people with ADHD, and the relative risk of dying is much higher for women than men with ADHD and individuals diagnosed in adulthood. The study is the first to shed light on the role of ADHD in premature death.

    Led by Søren Dalsgaard from Aarhus University in Denmark, the large nationwide cohort study followed nearly 2 million individuals from the Danish national registers, including more than 32000 people with ADHD, from their first birthday to 2013 (a maximum of 32 years). The causes of premature death were assessed to compare individuals with and without ADHD.

    During follow-up, 107 individuals with ADHD died. People diagnosed with ADHD were about twice as likely to die prematurely as people without the disorder, even after adjusting for factors known to affect the risk of early death including age, sex, family history of psychiatric disorders, maternal and paternal age, and parental education.

    This increased risk of premature death in people with ADHD was mainly driven by deaths from unnatural causes, more than half of which were caused by accidents (42 deaths among 79 people for whom the cause of death was known). The risk of dying prematurely increased with age at diagnosis. For example, individuals diagnosed at age 18 years or older were more than four times as likely to die early compared with those without ADHD at the same age whereas children diagnosed before the age of 6 years were at around double the risk of death compared with their healthy counterparts. The findings also reveal that girls and women with ADHD have a higher relative risk of premature death compared with boys and men with ADHD.

    Previous research has shown that individuals with ADHD are more likely to have a range of co-existing disorders including oppositional defiant disorder, conduct disorder, and substance use disorders. People with ADHD who also had all three of these disorders were more than eight times as likely to die early than individuals without ADHD or any of these co-existing disorders.

    According to Dr Dalsgaard, "Our findings emphasise the importance diagnosing ADHD early, especially in girls and women, and treating any co-existing antisocial and substance use disorders. It is however important to emphasise that although the relative risk of premature death is increased in ADHD, the absolute risk is low."

    Writing in a linked Comment, Stephen Faraone, Professor of Psychiatry and Director of Child and Adolescent Psychiatry Research at SUNY Upstate Medical University in New York, USA, says, "For too long, the validity of ADHD as a medical disorder has been challenged. Policy makers should take heed of these data and allocate a fair share of health care and research resources to people with ADHD. For clinicians, early identification and treatment should become the rule rather than the exception."

    Dr Faraone cautions, "Although talk of premature death will worry parents and patients, they can seek solace in the knowledge that the absolute risk for premature death is low and that this and other risks can be greatly reduced with evidenced-based treatments for the disorder."



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