Methylphenidate: researchers urge caution in prescribing commonly used drug to treat ADHD

ADHD medication: is it a good idea?

Authors of new Cochrane Review remain uncertain about effect of widely used medicine on ADHD symptoms, despite large amount of research. Some evidence of increased sleeplessness and loss of appetite leads researchers to encourage more caution in use of methylphenidate. Methylphenidate, the most commonly used medication, is more commonly known by its brand names Ritalin, Concerta, Medikinet and Equasym, among others. It has been used to treat ADHD for over 50 years, but the new research, which focuses on the benefits and harms, encourages caution in use. Image friendshipcircle.

2015 Study Abstract

Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed and treated psychiatric disorders in childhood. Typically, children with ADHD find it difficult to pay attention, they are hyperactive and impulsive.

Methylphenidate is the drug most often prescribed to treat children and adolescents with ADHD but, despite its widespread use, this is the first comprehensive systematic review of its benefits and harms.

To assess the beneficial and harmful effects of methylphenidate for children and adolescents with ADHD.

Search methods
In February 2015 we searched six databases (CENTRAL, Ovid MEDLINE, EMBASE, CINAHL, PsycINFO, Conference Proceedings Citations Index), and two trials registers. We checked for additional trials in the reference lists of relevant reviews and included trials. We contacted the pharmaceutical companies that manufacture methylphenidate to request published and unpublished data.

Selection criteria
We included all randomised controlled trials (RCTs) comparing methylphenidate versus placebo or no intervention in children and adolescents aged 18 years and younger with a diagnosis of ADHD. At least 75% of participants needed to have an intellectual quotient of at least 70 (i.e. normal intellectual functioning). Outcomes assessed included ADHD symptoms, serious adverse events, non-serious adverse events, general behaviour and quality of life.

Data collection and analysis
Seventeen review authors participated in data extraction and risk of bias assessment, and two review authors independently performed all tasks. We used standard methodological procedures expected within Cochrane. Data from parallel-group trials and first period data from cross-over trials formed the basis of our primary analyses; separate analyses were undertaken using post-cross-over data from cross-over trials. We used Trial Sequential Analyses to control for type I (5%) and type II (20%) errors, and we assessed and downgraded evidence according to the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach for high risk of bias, imprecision, indirectness, heterogeneity and publication bias.

Main results
The studies.We included 38 parallel-group trials (5111 participants randomised) and 147 cross-over trials (7134 participants randomised). Participants included individuals of both sexes, at a boys-to-girls ratio of 5:1, and participants’ ages ranged from 3 to 18 years across most studies (in two studies ages ranged from 3 to 21 years). The average age across all studies was 9.7 years. Most participants were from high-income countries.

The duration of methylphenidate treatment ranged from 1 to 425 days, with an average duration of 75 days. Methylphenidate was compared to placebo (175 trials) or no intervention (10 trials).

Risk of Bias.All 185 trials were assessed to be at high risk of bias.
Primary outcomes. Methylphenidate may improve teacher-rated ADHD symptoms (standardised mean difference (SMD) -0.77, 95% confidence interval (CI) -0.90 to -0.64; 19 trials, 1698 participants; very low-quality evidence). This corresponds to a mean difference (MD) of -9.6 points (95% CI -13.75 to -6.38) on the ADHD Rating Scale (ADHD-RS; range 0 to 72 points; DuPaul 1991a). A change of 6.6 points on the ADHD-RS is considered clinically to represent the minimal relevant difference. There was no evidence that methylphenidate was associated with an increase in serious (e.g. life threatening) adverse events (risk ratio (RR) 0.98, 95% CI 0.44 to 2.22; 9 trials, 1532 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 0.91 (CI 0.02 to 33.2).

Secondary outcomes.Among those prescribed methylphenidate, 526 per 1000 (range 448 to 615) experienced non-serious adverse events, compared with 408 per 1000 in the control group. This equates to a 29% increase in the overall risk of any non-serious adverse events (RR 1.29, 95% CI 1.10 to 1.51; 21 trials, 3132 participants; very low-quality evidence). The Trial Sequential Analysis-adjusted intervention effect was RR 1.29 (CI 1.06 to 1.56). The most common non-serious adverse events were sleep problems and decreased appetite. Children in the methylphenidate group were at 60% greater risk for trouble sleeping/sleep problems (RR 1.60, 95% CI 1.15 to 2.23; 13 trials, 2416 participants), and 266% greater risk for decreased appetite (RR 3.66, 95% CI 2.56 to 5.23; 16 trials, 2962 participants) than children in the control group.

Teacher-rated general behaviour seemed to improve with methylphenidate (SMD -0.87, 95% CI -1.04 to -0.71; 5 trials, 668 participants; very low-quality evidence).

A change of seven points on the Child Health Questionnaire (CHQ; range 0 to 100 points; Landgraf 1998) has been deemed a minimal clinically relevant difference. The change reported in a meta-analysis of three trials corresponds to a MD of 8.0 points (95% CI 5.49 to 10.46) on the CHQ, which suggests that methylphenidate may improve parent-reported quality of life (SMD 0.61, 95% CI 0.42 to 0.80; 3 trials, 514 participants; very low-quality evidence).

Authors’ conclusions
The results of meta-analyses suggest that methylphenidate may improve teacher-reported ADHD symptoms, teacher-reported general behaviour, and parent-reported quality of life among children and adolescents diagnosed with ADHD. However, the low quality of the underpinning evidence means that we cannot be certain of the magnitude of the effects. Within the short follow-up periods typical of the included trials, there is some evidence that methylphenidate is associated with increased risk of non-serious adverse events, such as sleep problems and decreased appetite, but no evidence that it increases risk of serious adverse events.

Better designed trials are needed to assess the benefits of methylphenidate. Given the frequency of non-serious adverse events associated with methylphenidate, the particular difficulties for blinding of participants and outcome assessors point to the advantage of large, ‘nocebo tablet’ controlled trials. These use a placebo-like substance that causes adverse events in the control arm that are comparable to those associated with methylphenidate. However, for ethical reasons, such trials should first be conducted with adults, who can give their informed consent.

Future trials should publish depersonalised individual participant data and report all outcomes, including adverse events. This will enable researchers conducting systematic reviews to assess differences between intervention effects according to age, sex, comorbidity, type of ADHD and dose. Finally, the findings highlight the urgent need for large RCTs of non-pharmacological treatments.

Sources and more information
  • Methylphenidate for children and adolescents with attention deficit hyperactivity disorder (ADHD), Cochrane Developmental, Psychosocial and Learning Problems Group, DOI: 10.1002/14651858.CD009885.pub2, 25 NOV 2015.
  • Researchers urge caution in prescribing commonly used drug to treat ADHD, Cochrane Library, November 24, 2015.
  • ADHD medication: is it a good idea?, medicalnewstoday, 25 November 2015.

Class-action lawsuit in Canada about Zofran morning sickness drug use in pregnancy

Woman, whose daughter died at 14 months, sues GSK over drug she took while pregnant

Zofran image
Woman, whose daughter died at 14 months, sues GSK and Novartis over Zofran drug she took while pregnant.

Nov 27, 2015 – CALGARY – The makers of an anti-nausea drug prescribed to pregnant women for morning sickness are being sued for $11-million by an Alberta woman whose daughter died 10 years ago.

In 2012, the US Department of Justice announced that GlaxoSmithKline, maker of Zofran, would pay more than $1 billion to settle claims that it illegally marketed Zofran and other medications for off-label, unapproved uses. Specifically, GlaxoSmithKline allegedly “promoted certain forms of Zofran, approved only for post-operative nausea, for the treatment of morning sickness in pregnant women.” Although doctors are free to prescribe Zofran for off-label use, it is illegal for a drug company to market its medications for unapproved uses.

Sources and more information

  • Woman, whose daughter died at 14 months, sues GSK over drug she took while pregnant, cnews, Nov 27, 2015.
  • Zofran Birth Defects, lawyersandsettlements, Feb-3-15.

Valproate et dérivés: nouvelles conditions de prescription et de délivrance le 31 décembre 2015

Le contenu de ce post est publié par l’Agence nationale de sécurité du médicament et des produits de santéagit au nom de l’Etat pour des produits de santé sûrs, efficaces et innovants.

Valproate et dérivés (Dépakine®, Dépakote®, Dépamide®, Micropakine® et génériques) : Rappel de l’échéance du 31 décembre relative à la mise en application des nouvelles conditions de prescription et de délivrance.

Lettre aux professionnels de santé – ANSM 26/11/2015

Information destinée aux spécialistes en neurologie, psychiatrie, pédiatrie (expérimentés dans la prise en charge de l’épilepsie), médecins généralistes, gynécologues, gynécologues-obstétriciens, pharmaciens, centres de planning familial, sages-femmes, services de PMI

Les spécialités à base de valproate et dérivés ne doivent pas être prescrites chez les filles, adolescentes, femmes en âge de procréer et femmes enceintes, sauf en cas d’inefficacité ou d’intolérance aux alternatives médicamenteuses.

Après le 31 décembre 2015, aucune délivrance de ces spécialités ne pourra se faire aux patientes sans présentation :

  • de la prescription initiale annuelle par un spécialiste ;
  • et du formulaire d’accord de soins signé.

Les patientes en âge de procréer ou susceptibles de l’être un jour et actuellement traitées par ces spécialités doivent donc consulter un médecin spécialiste dans les meilleurs délais (si cela n’a pas déjà été fait), afin qu’il réévalue la nécessité du traitement et qu’il leur fasse signer un accord de soins en cas de maintien du traitement.

Supplemental progesterone may not help for repeated miscarriage

Progesterone May Not Lower Risk of Repeated Miscarriage

Distribution of gestational age according to study group assignment. Image @NEJM.
Giving progesterone to women who have had three or more miscarriages does not increase their chances of carrying a pregnancy to term, according to a new study.

2015 Study Abstract

Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain.

We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation.

A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, −4.0 to 9.0). There were no significant between-group differences in the rate of adverse events.

Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages.

Sources and more information
  • Progesterone May Not Help Women With History of Miscarriages, Study Finds, NYtimes, NOV. 25, 2015.
  • A Randomized Trial of Progesterone in Women with Recurrent Miscarriages, The New England Journal of Medicine, DOI: 10.1056/NEJMoa1504927, November 26, 2015.
  • Progesterone May Not Lower Risk of Repeated Miscarriage, livescience, NOV. 25, 2015.

The Price of Prescription Drugs

Infographic – how the price of prescription meds may affect your family

The U.S. spends nearly $1,000 per person per year on pharmaceuticals, which is about 40% more than Canada and more than twice as much as counties including France and Germany.

This infographic explains the price of prescription drugs in the U.S., compared to other countries.

The-Price-of-Prescription-Drugs infographic
This infographic explains the price of prescription drugs in the U.S., compared to other countries.
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Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of DES

Human Molecular Genetics, 2005

Effects of estrogen and stress on activation of the ER and repression of the WNT genes.

2005 Study Abstract

Hsp90 is a chaperone for over 100 ‘client proteins’ in the cell, most of which are involved in signaling pathways. For example, Hsp90 maintains several nuclear hormone receptors, such as the estrogen receptor (ER), as agonist-receptive monomers in the cytoplasm. In the presence of agonist, Hsp90 dissociates and the receptors dimerize, enter the nucleus and ultimately activate transcription of the target genes. Increasing evidence suggests that Hsp90 also has a role in modifying the chromatin conformation of many genes. For example, Hsp90 has recently been shown to increase the activity of the histone H3 lysine-4 methyltransferase SMYD3, which activates the chromatin of target genes. Further evidence for chromatin-remodeling functions is that Hsp90 acts as a capacitor for morphological evolution by masking epigenetic variation. Release of the capacitor function of Hsp90, such as by environmental stress or by drugs that inhibit the ATP-binding activity of Hsp90, exposes previously hidden morphological phenotypes in the next generation and for several generations thereafter. The chromatin-modifying phenotypes of Hsp90 have striking similarities to the trans-generational effects of the ER agonist diethylstilbestrol (DES). Prenatal and perinatal exposure to DES increases the predisposition to uterine developmental abnormalities and cancer in the daughters and granddaughters of exposed pregnant mice. In this review, we propose that trans-generational epigenetic phenomena involving Hsp90 and DES are related and that chromatin-mediated WNT signaling modifications are required. This model suggests that inhibitors of Hsp90, WNT signaling and chromatin-remodeling enzymes might function as anticancer agents by interfering with epigenetic reprogramming and canalization in cancer stem cells.

Sources and more information
  • Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer, NCBI PMID: 15809267, 2005 Apr 15;.
  • Full study Oxford Journals, Medicine & Health & Science & Mathematics, Human Molecular Genetics doi: 10.1093/hmg/ddi103, February 23, 2005.
More DES DiEthylStilbestrol Resources

Big Pharma Whistleblower speaks out at the AZK in Germany, 2009

Dr John Rengen Virapen ex big pharmaceutical executive turned whistle blower

Dr John Rengen Virapen – writer of Side Effects: Death. Confessions of a Pharma-Insider –  ex big pharmaceutical executive turns whistle blower.

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STILBOESTROL 25 mg Tablets by British Drug Houses Ltd

Diethylstilbestrol or DES was sold under many names

image of a Stilboestrol-25-mg bottle
Diethylstilbestrol or DES was sold under many names. Image credit © Science Museum.

Diethylstilbestrol or DES was sold under many names including Distilbène®, Stilbetin®, Stilboestrol-Borne®, Benzestrol®, Chlorotrianisene®, Estrobene® and Estrosyn® to name just a few.

Many different companies manufactured and marketed this drug under more than 200 different brand names.

This glass bottle of Stilboestrol tablets 25 mg was manufactured by:
The British Drug Houses Ltd,
London, Greater London, England,
United Kingdom.

DES drugs pictures
More DES DiEthylStilbestrol Resources

Occurrence of tumours in the descendants of CBA male mice prenatally treated with diethylstilbestrol

Statistically significant increased incidence of tumours observed in females

DiEthylStilbestrol usage review buttress the need for adequate and rigorous research into the use of drugs in pregnancy and ensure that they do more good than harm before being introduced for consumption.

1992 Study Abstract

There is well documented evidence both in humans and in experimental animals that exposure to diethylstilbestrol (DES) during pregnancy results in an increased incidence of tumours in the progeny. The increased cancer risk has been reported to persist in the second generation descendants of DES-exposed pregnant mice. In the present experiment, female mice of the CBA strain were treated at day 17 of pregnancy with 1 microgram/g body weight of DES. The descendants of DES-treated mothers, described as F1DES, were mated among each other or with untreated animals. The F1DES females were found to be sterile when mated with either F1DES or untreated males. F1DES males were successfully mated with untreated females. In the female offspring so obtained, but not in the male, a statistically significant increased incidence of tumours was observed, in particular of uterine sarcomas, and also of benign ovarian tumours and of lymphomas.

Sources and more information
  • Occurrence of tumours in the descendants of CBA male mice prenatally treated with diethylstilbestrol, International journal of cancer, NCBI PMID: 1728603, 1992 Jan 2.
More DES DiEthylStilbestrol Resources

Ask your doctor if nature is right for you

Nature Rx Part 1

Behind the humor and parody of Nature Rx is good science. Research shows that spending more time in nature improves your health, wellbeing, and leads to making better environmental decisions.

More info and videos