Attention Deficit Hyperactivity Disorder (ADHD) is a developmental neurological condition affecting functioning in a number of domains, but in particular, the ability to focus and concentrate, and regulate activity levels. This is a common disorder with 2.5-4.0% of adults meeting diagnostic criteria for ADHD (Fayyad et al, 2007), and this condition has significant impact on a persons life, as well as those around them.
The impact of ADHD includes increased risk of mental health problems, substance misuse, lower educational attainment, and increased likelihood of unemployment as well as associations with family and social interaction difficulties (Biederman et al 2006). In addition studies have indicated that ADHD is highly prevalent amongst prisoners. In one study, 40% of long term prisoners fulfilled diagnostic criteria for ADHD (Ginsberg et al, 2010).
The first line treatment for ADHD are medications such as psychostimulants (methylphenidate and amphetamines) and non-stimulants such as atomoxetine. Atomoxetine is a selective noradrenaline reuptake inhibitor (NRI), not to be confused with SNRIs or SSRIs which are popular antidepressants.
As with all medications there is a cost:benefit ratio to consider with the use of atomoxetine as it has some significant side-effects and adverse effects that need to be considered when prescribing and monitoring the effects. Side effects include cardiovascular (prolonged Q-T wave intervals, arrhythmia’s, hypotension), gastrointestinal, neurological (seizures) and psychiatric (psychosis, suicidal feelings). So in summary, the clinical benefits to the individual must outweigh these potential risks in order for it to be an efficacious treatment.
Aims of the new review
The authors of this recent systematic review and meta-analysis (Cunill et al, 2013) note that clinical symptom reduction is typically used as the outcome end point in clinical trials, but this has been criticised as it doesn’t always correlate with clinical consequence (i.e. the adverse impact of ADHD such as accidents, legal problems, family problems etc).
In addition, there is an attrition bias in clinical trials with those who drop-out of treatment differing from those who are retained. This means that often, the most stable people remain in a trial and they are not representative of people with ADHD. There is a more objective way of assessing cost:benefit of medicines using ‘all cause treatment discontinuation’ which is the number of people who leave a trial for any reason. The theory is that if symptom improvement outweighs side-effects then drop-out should be lower than placebo, thus demonstrating objective efficacy.
So the aim of the review was to undertake a systematic review and meta-analysis of all trials of atomoxetine using all cause treatment discontinuation as the primary outcome.
The authors developed and published an a priori protocol. Inclusion criteria were clinical trials of atomoxetine using outpatient populations in any language. Search was conducted in June 2012 (n.b. there is a possibility that other studies have since been published that could affect this analysis). Twelve studies were included for data extraction and assessment of risk of bias (Cochrane Assessment of Bias tool) and these were selected by two independent reviewers. They undertook an assessment of publication bias and found no evidence of this.
The main findings were that:
- There was a higher rate of overall treatment discontinuation with atomoxetine compared with placebo (odds ratio 1.39)
- There was a higher rate of adverse events induced treatment discontinuation with atomoxetine compared with placebo
- When considering symptom improvement, atomoxetine showed a moderate effect in improving symptoms rated by self or researcher
The reviewers concluded that evidence for the use of atomoxetine in adults with ADHD is weak, based on the review of available clinical trials.
However, the authors point out some limitations of the studies which could affect this outcome. There was evidence of risk of bias in the study designs in blinding failure and detection bias. In addition, all the studies were undertaken in North America. Whilst there was some evidence of moderate effect on symptom improvement, none of the studies had measured clinically significant outcomes such as work, legal and family impact. However, there was no evidence of publication bias and the meta-regression found no between sub-group differences using patient and study characteristics as factors.
This was a well conducted review and meta-analysis by authors who had no declared conflict of interest. They recognised the strengths and limitations of the review.
Atomoxetine has significant unpleasant and potentially life-threatening side-effects and therefore the benefit to the person needs to significantly outweigh the risks and costs. At this time, the evidence for effectiveness is weak when discontinuation is used as the endpoint measure.
One of the most important issues this review raises is the role of medication in a condition that significantly affects the social functioning of a person with this diagnosis. Drug trials take a reductionist approach in measuring efficacy with symptom reduction and often have short follow-up periods.
In order to more thoroughly understand the benefits of medication for people with ADHD, studies should consider gathering data on clinically meaningful outcomes such as employment, offending, family and relationship functioning.
Cunill, R., Castells, X., Tobias, A. and Capellà, D. (2013), Atomoxetine for attention deficit hyperactivity disorder in the adulthood: a meta-analysis and meta-regression. Pharmacoepidem. Drug Safe., 22: 961–969. doi: 10.1002/pds.3473. [PubMed abstract]
Fayyad J, De Graaf R, Kessler R, et al. Cross-national prevalence and correlates of adult attention-deficit hyperactivity disorder (PDF). British Journal of Psychiatry 2007; 190: 402–9.
Biederman J, Faraone SV, Spencer TJ, et al. Functional impairments in adults with self-reports of diagnosed ADHD: a controlled study of 1001 adults in the community. Journal of Clinical Psychiatry 2006; 67: 524–540. [PubMed abstract]
Ginsberg Y, Hirvikoski T, Lindefors N. Attention Deficit Hyperactivity Disorder (ADHD) among longer-term prison inmates is a prevalent, persistent and disabling disorder. BMC Psychiatry. 2010 Dec 22;10:112. doi: 10.1186/1471-244X-10-112.
Atomoxetine for adult ADHD: the harms outweigh the benefits, according to new systematic review: Attention Def… http://t.co/9jBUUPc48k
@LizHughesDD summaries the findings of a new systematic review on atomoxetine for adults with ADHD http://t.co/nTpK4Nabwr
2.5 – 4.0% of adults meet the diagnostic criteria for ADHD http://t.co/nTpK4Nabwr
Research shows that 40% of long term prisoners fulfil the diagnostic criteria for ADHD http://t.co/nTpK4Nabwr
Atomoxetine for adult ADHD: the harms outweigh the benefits, according to new systematic review… http://t.co/KCiXi0KNq7
Becca Wilson useful?
High overall treatment discontinuation rate with atomoxetine compared to placebo for adults w/ ADHD (odds ratio 1.39) http://t.co/nTpK4Nabwr
Atomoxetina (Strattera) para adultos con TDAH: los daños superan los beneficios, según una nueva revisión sistemática http://t.co/qaK1dEumgz
Adult ADHD: higher rate of adverse events induced treatment discontinuation with atomoxetine compared with placebo http://t.co/nTpK4Nabwr
Don’t miss: Atomoxetine for adult ADHD: the harms outweigh the benefits, according to new systematic review http://t.co/nTpK4Nabwr
MT @anitaphillipson @Mental_Elf Don’t miss: Atomoxetine for adult ADHD: the harms outweigh the benefits http://t.co/vRRiWtf8RZ
Mental Elf: Atomoxetine for adult ADHD: the harms outweigh the benefits, according to new systematic review http://t.co/vTsZz0qUaA
Atomoxetine for adult ADHD: the harms outweigh the benefits, according to new systematic review http://t.co/sMJBOIRcJy from @Mental_Elf
Here’s the link to the blog http://t.co/wXbvv35WCx
@Mental_Elf discusses review for atomoxetine for adults with #adhd http://t.co/atNAN1xrtg
Atomoxetine for adult ADHD: the harms outweigh the benefits …: Keeping you up to date with reliable mental h… http://t.co/1wmuYVc6tF
Well if anybody does, I have ADHD.
But previously I had a bad reaction to a drug simular to Atomoxetine, Reboxetine. It put in my in a very disturbed feeling, dark mind state. I felt this profound sense that everything in the world was wrong and cruel. I did identify that my reaction was obviously a result of the medication, and while I feel pretty terrible, I did not do anything drastic. However I wonder if the psychostimulants are the only main avenue left for effective ADHD treatment. I would appreciate any comments. I mean is there any basis to think I would react different to Atomoxetine than Reboxetine?
I’d like to make a few more comments on this article.
“There was a higher rate of overall treatment discontinuation with atomoxetine compared with placebo”- whoa really? You mean people who took an actual active drug has reason to occasionally discontinue it more than people who took absolutely nothing? This means nothing. Also why is this fact separate from people discontinuing from adverse events? Obviously if somebody discontinues it above the placebo rate, it suggests some form of adverse event.
Seriously does anybody know any active drug that does not meet the following criteria:
“There was a higher rate of adverse events induced treatment discontinuation with atomoxetine compared with placebo”. No shit. I mean an active drug with real effects, may have variably (we don’t know if its occasional to frequent) caused discontinuation more than taking nothing at all? Shit I am certain people discontinue asprin more than the placebo too. I am I drunk and clueless or is this stupid?
“When considering symptom improvement, atomoxetine showed a moderate effect in improving symptoms rated by self or researcher”
It has always claimed to be moderate in effect. Considering it might cause discontinuation more than taking nothing, well I can understand how somebody who for whatever reason cannot take stimulants would prefer moderate symptoms relief over nothing.
“Atomoxetine has significant unpleasant and potentially life-threatening side-effects and therefore the benefit to the person needs to significantly outweigh the risks and costs.”
Well what unpleasant and potentially life-threatening side effects? Perhaps occasional upset stomach, and loss of appetite meet this criteria.. BS. No offense.
That is one of the most stupid methodologies I’ve ever come across. How would more people drop out of taking a placebo? You can react badly to a drug, you can’t react badly (or worse than you otherwise would have done) to nothing… Alleviation of symptoms Vs unwanted effects is the only comparison for medicines