More misunderstandings about antidepressant prescribing in Scotland

Just before Christmas most papers in Scotland were reporting on recent data published by the Information Service Division (ISD) of NHS Scotland. ISD crunch most the health service information in Scotland. In many cases, they make useful and helpful information available on their website. Sometimes, there's an attempt at understanding and interpreting the data. But not always.

Here's a typical report from the Scottish Television website. The headline of 'One in ten adults' on antidepressants is followed by the comment that "One in ten adults in Scotland are thought to be on antidepressants, according to official figures published." They don't say who thinks this, however. The ISD data release doesn't say this because they don't know how many patients actually took the antidepressants dispensed: "It should be noted that the proportion of the population taking any of the drugs listed is purely an estimate; the actual patient numbers are unknown."

How can they not know how many people took the antidepressants? Well, lets look at how the numbers are calculated. The first problem is that quantities of antidepressant drugs are often reported as Defined Daily Doses (DDDs). A DDD is defined by the World Health Organisation as:

"...the assumed average maintenance dose per day for a drug used for its main indication in adults."

The DDD for different drugs varies. For example, it is 75mg/ day for Amitriptyline and 20mg/ day for Fluoxetine. The starting dose for Fluoxetine is 20mg/ day so you're getting one DDD from day one. With Amitriptyline there may be a more gradual dose increase, meaning that you're not getting a full DDD until later on.

That's not the only problem, though. For most people, 75mg/ day of Amitripytline (or other tricyclic drug) is sub-therapeutic. That means that you need a bigger dose to get maximum benefit. For many people, a therapeutic dose is around 150mg/ day (two DDDs); and for some people, it might be even higher. Some even consider a proper trial of a tricyclic antidepressant (TCA) to be at least 200mg/ day (2 1/2 DDDs). A study done in Scotland in 1996 found that in primary care, tricyclic antidepressants were given in subtherapeutic doses (MacDonald, 1996). This confirmed a similar study that reported that only 13% of patients received a TCA for depression at an effective dose (Donoghue, 1996).

What does this mean for understanding Defined Daily Doses? Well, it tells us that if we see the total number of DDDs of antidepressants per year increasing, this increase could be due to a number of things (or a combination):

1. The same number of patients getting higher doses of drugs. In many cases, this might mean patients getting effective doses of antidepressants - this has to be a good thing.
2. The same number of patients getting antidepressants for longer. Since antidepressant prescription in primary care tends to be for short periods, ensuring that patients get treatment that is guideline-based and prevents recurrence has to be a good thing.
3. More people getting the same quality of prescribing. This isn't necessarily a good thing.
4. Different types of drugs being prescribed. A dose of 50mg of Amitriptyline is only 2/3 of a DDD yet 20mg of Fluoxetine is 1 DDD. Simply changing the type of drug being given can increase the number of DDDs by 1/3 or more. Over the last 10 years, we've certainly seen a preference in primary care for Selective Serotonin Reuptake Inhibitors (SSRIs) over TCAs. Again, this is in accordance with good clinical practice and guideliness - SSRIs are equally effective; better tolerated; and safer in overdose.

The point is that counting DDDs tells us nothing about numbers of patients or the quality of prescribing. The Scottish Government have assumed that more DDDs are bad because it means more people getting antidepressants. Let's remember that the Scottish Government made a 2007 Election Manifesto pledge to "...to reduce the use of anti depressants by 10 per cent by 2009." This was translated into a HEAT target shortly after. Unfortunately, they didn't really understand whether the current antidepressant usage was too high, too low, or just right. They simply made a rather ill-informed pledge. This point was made by the Public Audit Committee last year when they made this clear to the Government:

"However the target did not take account of initial prescribing levels in each NHS board. It
was also unclear what the correct rate of prescribing should be and whether reducing the rate of prescribing was always appropriate."

and:

"...we do not know whether the difference in DDD levels is due to more people receiving antidepressants and/or prescribing at a higher dose and/or prescribing for a longer duration”. The Scottish Government also acknowledged in written evidence that “information regarding the number of people on antidepressants is not currently collected so we do not know whether the number of people taking antidepressants has increased'"

That's a pretty explicit indictment on the Government not really knowing what it was talking about when it set the HEAT target. However, this is still the case. ISD do not know any better than anyone else whether increases in the total number of antidepressants reflects better treatment or not. We don't even know whether the antidepressants are being prescribed for depression, anxiety, pain, nocturnal enuresis, or a range of valid indications. The Scottish Government has generally tried to move away from its daft HEAT target and has tried to say that the target was about better treatment all along.

Fortunately, people have looked at the possibility that antidepressants are being prescribed for longer periods. Tony Kendrick and colleagues examined whether observed rises in antidepressants were due to the drugs being prescribed for longer periods, rather than in more people. It seemed that it was the case that prescriptions were for longer periods. Over time, the number of new cases of depression over time actually falling, and prescribing for longer periods (as per guidelines) increasing (Moore, 2009). See image below.

There remain many myths about antidepressant prescribing. Some of them have entered the population consciousness because of daft government targets and the media haven't really helped to increase understanding of some of the issues. After all, 'depression treatment getting a bit better over time' is not as good a story as 'Scotland struggles to kick its antidepressant habit'.

References
MACDONALD, T. M., MCMAHON, A. D., REID, I. C., FENTON, G. W. & MCDEVITT, D. G. (1996) Antidepressant drug use in primary care: a record linkage study in Tayside, Scotland. BMJ, 313, 860-861.

DONOGHUE, J., TYLEE, A. & WILDGUST, H. (1996) Cross sectional database analysis of antidepressant prescribing in general practice in the United Kingdom, 1993-5. BMJ, 313, 861-862. [PDF]

MOORE, M., YUEN, H. M., DUNN, N., MULLEE, M. A., MASKELL, J. & KENDRICK, T. (2009) Explaining the rise in antidepressant prescribing: a descriptive study using the general practice research database. BMJ, 339, b3999. [Full Paper]

New Paper on STAR*D - Is all as it seems?

A recent paper commenting on the outcomes from the STAR*D Study (Full paper for download: Pigott, H. E., Leventhal, A. M., Alter, G. S., et al (2010) Efficacy and Effectiveness of Antidepressants: Current Status of Research. Psychotherapy and Psychosomatics, 79(5): 267-279 revisits some of the ground covered by Irving Kirsch but interestingly looks again at the outcomes from STAR*D.

Most people will recall that STAR*D was a large (over 4,000 patients enrolled) and expensive (about $35 million) trial which attempted to determine what the 'real world' outcomes were for four steps of antidepressant therapy (drugs and psychological therapy). It covered a range of different comparisons, and perhaps the 'quickest' overview of what was a complex trial can be found in this paper: Rush, A. J., Trivedi, M. H., Wisniewski, S. R., et al (2006)American Journal of Psychiatry, 163(11): 1905-1917 Acute and Longer-Term Outcomes in Depressed Outpatients Requiring One or Several Treatment Steps: A STAR*D Report. [Link to Journal Website]

A summary of the steps (and to some extent, outcomes) is shown below:

STAR*D used the Quick Inventory of Depressive Symptomatology (16-items) as one of their main outcome measures, and outcomes from each treatment step, using the QIDS-16 were as follows:

• Step 1 = 36.8%
• Step 2 = 30.6%
• Step 3 = 13.7%,
• Step 4 = 13.0% 

The overall [cumulative] remission rate was 67%. This means that overall, two thirds of patients achieved remission. It also means that after four treatment trials, one third had not remitted.

It's important to note that this cumulative remission rate was "hypothetical" in that it assumed no drop-outs. Of course, every trial has drop-outs, and this is what Pigott et al have taken into account. They also make some other criticisms of STAR*D:

1. The use of the QIDS-16 as a primary outcome measure instead of the 30-item scale. The main reason for this was apparently the large number of missing measurements on the latter. However, the QIDS-16 is critiqued by Pigott et al as being used as a 'clinical' measure rather than a 'research' measure throughout the study, and that its use as a study outcome might be unjustified.
2. They also comment on the cut-offs that were used on the Hamilton Rating Scale for Depression (HRSD, or HAM-D). Pigott et al report that 931 patients who should have been excluded because their HRSD score was ≤ 14 (an exclusion criterion for the study, which excludes those with very mild depression - i.e. non-major depression). They argue that this "inflated" the original remission rate for Step 1 from 32.8% to 36.8%.

They go on to present slightly modified remission rates for each step, along with the drop-out rates for each step:

Pigott et al conclude by discussing the fact that remission from major depression is hard to achieve. Perhaps this is not surprising to those who treat depression. Of course, we know that antidepressants aren't as effective for those with milder forms of the illness but antidepressants are probably one of the treatments for depression with the greatest evidence base. STAR*D also included Cognitive Behavioural Therapy (CBT) which is probably the best-evidenced psychological treatment for this population.

Should it really be a surprise that antidepressants don't work for everyone? Hopefully not. However, it is not clear what the authors might be suggesting as an alternative until you get to the 'Conflicts of Interest' section:

H. Edmund Pigott, PhD, and Gregory S. Alter, PhD, are founders of NeuroAdvantage, LLC, a for-profit neurotherapy company. During the past 3 years, Dr. Pigott has consulted for CNS Response, Midwest Center for Stress and Anxiety, and SmartBrain Technologies.

That's right, the authors own their own company, Neuroadvantage, which will sell you (for $995), a device that plays sounds and lights in order to synchronise your brain waves. They claim that it "Helps to Decrease Symptoms of Depression & Anxiety". No wonder that they were keen to weaken the case for drugs and psychological therapies - they have a product which they wish to sell that is targeted at the same market.

As with all such products, "This patented technology is based on over 70 years of research and takes advantage of our mind’s natural tendency to synchronize with pleasant rhythmic stimulation". Not only is the 'technology' old (and therefore established), it links in to natural tendencies.

So keen are the authors/ salesmen to ensure that you consider their product, they provide a link to the paper above (it is free to download) to viewers of the website. This is, arguably, a classic case of 'bait and switch'. There is a very good article on 'bait and switch' available here, but essentially the bait is a treatment that avoids the side effects and apparent ineffectiveness of drugs and therapy, and once lured in, the switch is to unproven therapies with much less evidence.

How much less will be the subject of a subsequent post.