dtb

Vol 47 | No 11 | November 2009

122 Aspirin for primary prevention of
in this issue

cardiovascular disease?
125 Over-the-counter weight loss
with orlistat?
128 Management of seasonal
affective disorder

Uncommon knowledge
Statins are of unquestioned value in the prevention of
Drug and
cardiovascular events and are used by increasing numbers
of people. However, when new data emerges on their
unwanted effects, it is crucial that they are incorporated into
Therapeutics
the product information so that prescribers and patients can
assess benefits and risks of treatment. This has yet to happen
with regards to the knowledge that the use of a statin may
Bulletin
cause depression.

In February 2008, the Medicines and Healthcare products

Regulatory Agency (MHRA) stated that “Following a review
of clinical trial data, spontaneous reports of suspected
adverse drug reactions, and published literature, product
information for statins is being updated to reflect a number
of different side-effects as class effects of all statins.”1 The
new advice included that “Patients should be made aware
that treatment with any statin may sometimes be associated
with depression, sleep disturbances, memory loss, and
sexual dysfunction” but, unfortunately, no information on
the size of these risks. (There was also to be a new warning
about how, very rarely, statin therapy may be associated
with interstitial lung disease.) Many months on, product
information for statins has yet to be updated as trailed by
the MHRA – why?

We have discovered from the MHRA that implementation

of the changes in the statins’ summaries of product
characteristics and patient information leaflets has been
delayed throughout the European Union (EU) because “one
of the innovator MA [marketing authorisation] Holders
was not in agreement with this wording.” In other words,
a drug company has been able to stall the inclusion of key
safety warnings. In our view, this situation is unacceptable
and should be rectified quickly. The longer it persists, the
bigger the impression that EU regulatory systems are more
sensitive to the needs of the pharmaceutical industry than
to the welfare of patients.
1. Medicines and Healthcare products Regulatory Agency. Statins: class effects identified. Drug
Safety Update 2008; 1: 2.
THE INDEPENDENT REVIEW
DOI: 10.1136/dtb.2009.10.0044 OF MEDICAL TREATMENT
To comment on DTB editorials or reviews,
please email dtbeditor@bmjgroup.com

dtb.bmj.com 121
 Aspirin for primary prevention of cardiovascular disease?
Cardiovascular disease (CVD) is a leading cause of mortality.1 For example, in 2000, it accounted directly for around
2 million deaths in the European Union.2 Worldwide, many people take aspirin daily in the belief that doing so
helps to prevent CVD. This approach is established for the secondary prevention of recurrent vascular events.1,3,4,5
However, there has been some uncertainty about the place of aspirin for the primary prevention of cardiovascular
events.6 In particular, there have been doubts about whether any benefits of aspirin in people with no history of
CVD outweigh the risks (e.g. the fact that long-term low-dose aspirin therapy almost doubles the likelihood of
gastrointestinal haemorrhage7,8). Here we consider the place of low-dose aspirin in primary prevention of CVD.
BNF 2.9

regimen) versus a control and involved a total of 135,640

Guidelines on primary prevention
Various guidelines (published between 2005 and 2008) have
recommended aspirin for the primary prevention of CVD in various
groups of patients1,5,8,9 (an unlicensed indication in the UK).10
A guideline from the National Institute for Health and Clinical
Excellence (NICE) published in 2008 recommends that, for patients
with type 2 diabetes mellitus, aspirin 75mg daily should be offered
to those aged at least 50 years if their blood pressure is below
145/90mmHg, and to younger patients with other significant
cardiovascular risk factors (e.g. smoking, hypertension).9
Guidance from the Scottish Intercollegiate Guideline
Network (SIGN) states that asymptomatic individuals without
established atherosclerotic disease, but with a calculated
cardiovascular risk of 20% or more over 10 years, should be
considered for treatment with aspirin 75mg daily; it also
states that patients with hypertension with the same 10-
year risk should receive aspirin, but only once their blood
pressure has been treated to below 150/90mmHg.8 SIGN
currently also recommends aspirin 75mg daily for all people
with type 2 diabetes aged over 50 years, and for selected
younger individuals with diabetes who are considered to be at
increased cardiovascular risk.
The Fourth Joint Taskforce of the European Society of
Cardiology guidelines, published in 2007, recommend aspirin
75mg daily for asymptomatic individuals if their 10-year risk of
CVD mortality is over 10% and blood pressure is controlled as
closely as possible to the goal of less than 140/90mmHg.1,11
The Joint British Societies’ 2005 guidance recommends aspirin
75mg daily for all people aged over 50 years who have a total
CVD risk of 20% or more over 10 years, and in selected people
with diabetes (i.e. those aged at least 50 years, or younger
patients who have had the disease for over 10 years, or who
are already receiving treatment for hypertension), once blood
pressure has been controlled to below 150/90mmHg.5
Evidence on aspirin in primary prevention
Evidence prior to the guidelines
A meta-analysis (published in 2002) included 195
randomised trials of aspirin alone (or another antiplatelet
patients at high risk of occlusive vascular events (i.e. over
about 2% per year).3 Most patients had already had one
vascular event, but others had not and, consequently, the
overall results of the analysis were extrapolated by some
observers as indicating the potential benefits of aspirin
in primary prevention. The analysis found that 7,705
serious vascular events had been recorded among 71,912
patients allocated to antiplatelet therapy compared with an
adjusted total of 9,502 among 72,139 allocated to control
treatment (10.7% vs. 13.2%, p<0.0001).3 However, more of
the patients receiving antiplatelet treatment experienced
major extracranial bleeding (1.13% vs. 0.71%; odds ratio
[OR] 1.6, 95% CI 1.4 to 1.8). The findings led the reviewers
to recommend that aspirin 75–150mg daily (or some other
effective antiplatelet regimen) be considered routinely for
all patients at high or intermediate risk of occlusive vascular
events (more than about 2% per year), including those with
an acute myocardial infarction or acute stroke and those
with a previous infarction, or stroke or transient ischaemic
attack, and also some groups of patients who had not had
a major cardiovascular event (e.g. those with stable angina,
atrial fibrillation, peripheral arterial disease). The reviewers
pointed out “an unanswered question, however, is whether it
is possible to identify particular groups of apparently healthy
people who may be at increased risk of myocardial infarction
or stroke and for whom the benefits of daily aspirin outweigh
the hazards”.
Four meta-analyses,12-15 which all looked specifically at aspirin
(dose range from 75–659mg daily) for primary prevention of
CVD, included either four13 or five12,14,15 of six key trials.16-21
In one meta-analysis, the reviewers suggested that, because
of an equivocal effect in terms of reducing the likelihood of
myocardial infarction, aspirin for primary prevention would
most benefit people at “special risk” for myocardial infarction,
such as those with diabetes.12
In another meta-analysis, the reviewers concluded that aspirin
was safe and worthwhile at a coronary event risk of 1.5% or
more per year, of limited value at a risk of 1% per year and
unsafe at a risk of 0.5% per year, meaning that aspirin could
not be prescribed safely for primary prevention without formal
estimation of the coronary event risk of the individual person.13

122 DTB | Vol 47 | No 11 | November 2009 dtb.bmj.com


In a third meta-analysis, the reviewers concluded that aspirin
appeared to help prevent non-fatal myocardial infarction
but increased the likelihood of gastrointestinal bleeding and
possibly haemorrhagic stroke.14
In a fourth meta-analysis, the reviewers concluded that the
evidence provided strong support that aspirin reduces the
risk of a first myocardial infarction in apparently healthy
individuals, but that consideration of whether to use the
treatment for such benefits should also include assessment of
the person’s 10-year risk of having a first coronary event and
the likelihood of unwanted effects with long-term aspirin use.15
Direct evidence in hypertension
One systematic review pooled data from five randomised
controlled trials assessing the use of antiplatelet agents in
people with hypertension (blood pressure generally at least
160/100mmHg) for primary and secondary prevention.22 It
included people with elevations of both systolic and diastolic
blood pressure, or with isolated elevations of either systolic
or diastolic blood pressure, and it addressed the following
hypothesis: antiplatelet agents reduce total deaths and/or
major thrombotic events when compared to placebo or other
active treatment. The reviewers concluded that aspirin did not
reduce the likelihood of stroke or “all cardiovascular events”
compared to placebo in patients with elevated blood pressure
and no prior CVD. In one large trial20 (involving 19,193 low-
risk patients) included in the review, aspirin taken for 5 years
reduced the likelihood of myocardial infarction (absolute
risk reduction 0.5%, number needed to treat [NNT] 200 for 5
years), but also increased the likelihood of major haemorrhage
(absolute risk increase 0.65%, number needed to harm [NNH]
154 for 5 years), and did not reduce cardiovascular mortality
or all-cause mortality. The reviewers concluded that aspirin
cannot be recommended for primary prevention in patients
with elevated blood pressure because the magnitude of
benefit is similar to the magnitude of harm.
Direct evidence in diabetes
A randomised controlled trial16 included in one of the meta-
analyses discussed above12 compared aspirin (650mg daily)
and placebo for the early treatment of diabetic retinopathy in
3,711 patients, around half of whom had no history of CVD.
There was no difference between the two groups in mortality
from all causes (the primary outcome measure for assessing the
systemic effects of aspirin) or in cardiovascular mortality, in fatal
or non-fatal myocardial infarction, or fatal or non-fatal stroke.
More recent evidence
A recent publication6 included a collaborative meta-analysis
of six randomised controlled trials (involving a total of 95,000
participants) that had investigated aspirin for the primary
prevention of CVD.17-21,23 It looked at individual participant
data, the availability of which allowed for more reliable
evaluation of the relative benefits and hazards of aspirin
in apparently healthy people primarily at low risk. In the
six trials, randomisation to aspirin resulted in an absolute
reduction in serious vascular events of about 0.07% per year
(0.51% per year with aspirin vs. 0.57% per year with control
dtb.bmj.com DTB | Vol 47 | No 11 | November 2009
Aspirin for primary prevention of cardiovascular disease?
treatment, rate ratio 0.88, 95% CI 0.82 to 0.94; p=0.0001).
This was due mainly to an absolute reduction of about 0.05%
in the likelihood of non-fatal myocardial infarction (0.18%
per year vs. 0.23% per year, p<0.0001; NNT per year around
2,000). Aspirin increased the likelihood of having major
gastrointestinal or other extracranial bleeding (absolute risk
increase of about 0.03% per year; 0.10% per year vs. 0.07%
per year; relative risk [RR] 1.54 95% CI 1.30 to 1.82; p<0.0001;
NNH per year around 3,300). The rates of all-cause mortality,
of death due to coronary heart disease and of stroke did
not differ between the aspirin and the control groups. The
proportional reduction in serious vascular events did not
depend significantly on age, gender, blood pressure, history
of diabetes or predicted risk of coronary heart disease. The
reviewers concluded that, with aspirin for primary prevention
“the net absolute reduction in disabling or fatal occlusive
events is likely to be small, and at least partially offset by a
small increase in serious intracranial and extracranial bleeds”.
They commented that currently available trials did not seem
to justify general guidelines advocating the routine use of
aspirin in all apparently healthy individuals with a more than
moderate risk of coronary heart disease.
Effects according to gender
In a gender-specific meta-analysis, which included the same
six primary prevention trials17-21,23 as the analysis discussed
above,6 aspirin was associated with a decrease in major
cardiovascular events in both women and men.24 Based on
the absolute risk reduction during the trials (mean follow-
up of 6.4 years) of 0.30% in women (OR 0.88, 95% CI 0.79
to 0.99; p=0.03) and 0.37% in men (OR 0.86, 95% CI 0.78 to
0.94; p=0.01), the NNT to prevent 1 cardiovascular event
during 6.4 years of follow-up was 333 women and 270
men, respectively. In women, aspirin was associated with a
reduction in the overall occurrence of stroke (OR 0.83, 95%
CI 0.70 to 0.97; p=0.02; NNT 411) and in ischaemic stroke
(OR 0.76, 95% CI 0.63 to 0.93; p=0.008; NNT 419), but not
haemorrhagic stroke (p=0.89), myocardial infarction (p=0.95),
cardiovascular mortality (p=0.56) or all-cause mortality
(p=0.62). In men, aspirin was associated with a reduction in
myocardial infarction (OR 0.68, 95% CI 0.54 to 0.86; p=0.001;
NNT 118), but not overall stroke (p=0.14) or ischaemic stroke
(p=0.98); and there was an increase in the occurrence of
haemorrhagic stroke (OR 1.69, 95% CI 1.04 to 2.73; p=0.03).
Also, in men, aspirin had no effect on cardiovascular
mortality (p=0.87) or all-cause mortality (p=0.15). Aspirin
therapy increased the risk of major bleeding in both women
(absolute risk increase 0.25%, NNH over 6.4 years for 1 major
bleeding event 400; OR 1.68, 95% CI 1.13 to 2.52; p=0.01) and
men (absolute risk increase 0.33%, NNH 303; OR 1.72, 95% CI
1.35 to 2.20; p<0.001).
The reviewers concluded that treatment with aspirin for a
mean of 6.4 years resulted in an average absolute benefit of
around 3 cardiovascular events prevented per 1,000 women
and 4 cardiovascular events prevented per 1,000 men.
However, this was offset by an additional 2.5 major bleeding
events per 1,000 women and 3 major bleeding events per
1,000 men.
123
 Aspirin for primary prevention of cardiovascular disease?
Patients with diabetes
Two recently published randomised controlled trials
specifically investigated the use of aspirin for primary
prevention in people with diabetes..25,26
One of the trials, based in Scotland, was double-blind and
included 1,276 people aged 40 years or more with type 1 or
type 2 diabetes plus asymptomatic peripheral arterial disease
as detected by a lower than normal ankle brachial pressure
index (at most 0.99; a reading that would not usually trigger
intervention), but no symptomatic CVD.25 After a median
follow-up of 6.7 years, compared with ‘no aspirin’, aspirin
100mg daily had not reduced the proportion of people
experiencing the following two composite primary end
points: death from coronary heart disease or stroke, non-fatal
myocardial infarction or stroke, or amputation above the ankle
for critical limb ischaemia (18.2% with aspirin vs. 18.3% with
no aspirin; hazard ratio [HR] 0.98, 95% CI 0.76 to 1.25; p=0.86);
and death from coronary heart disease or stroke (HR 1.23, 95%
CI 0.79 to 1.93, p=0.36).
The other trial, based in Japan, was non-blinded and involved
2,539 patients with type 2 diabetes without a history of
atherosclerotic disease who were randomised to low-dose
aspirin (81mg or 100mg daily) or to no aspirin.26 At a median
of 4.37 years, there was no difference between the two groups
in the primary outcome of all atherosclerotic events.
Implications for practice
Overall, we believe that the currently available evidence does
not justify the routine use of low-dose aspirin for the primary
prevention of CVD in apparently healthy individuals, including
those with elevated blood pressure or diabetes; this is because of
the potential risk of serious bleeds and lack of effect on mortality.
Recent advice from the Medicines and Healthcare products
Regulatory Agency has recommended that, if aspirin is used in
primary prevention, “the balance of benefits and risks should
be considered for each individual, particularly the presence of
risk factors for vascular disease…and the risk of gastrointestinal
bleeding”.10 In practice, this means reviewing individually all
those patients currently taking aspirin for primary prevention
(either as prescribed or over-the-counter treatment), with the
decision to stop or continue treatment being made with the
patients after fully informing them of the available evidence.
Furthermore, in our view, current evidence makes it hard to
recommend starting aspirin for primary prevention.
Conclusion
Low-dose aspirin is established in the secondary prevention
of cardiovascular disease. Such treatment is also widely used
for the primary prevention of cardiovascular disease (an
unlicensed indication). However, current evidence for primary
prevention suggests the benefits and harms of aspirin in
this setting may be more finely balanced than previously
thought, even in individuals estimated to be at high risk of
experiencing cardiovascular events, including those with
diabetes or elevated blood pressure. We believe, therefore,
124 DTB | Vol 47 | No 11 | November 2009 dtb.bmj.com
that low-dose aspirin prophylaxis should not be routinely
initiated for primary prevention. With respect to those people
already taking low-dose aspirin for primary prevention, the
decision about whether to continue with the treatment should
be taken by both the patient and a healthcare professional in
light of the available evidence. This also includes people who
purchase aspirin over the counter for primary prevention.
[R=randomised controlled trial; M=meta-analysis]
1. Office for National Statistics, 2009. Health Statistics Quarterly; No. 43, Autumn
2009 [online]. Available: http://www.statistics.gov.uk/downloads/theme_
health/HSQ43.pdf [Accessed 21 October 2009].
2. Fourth Joint Taskforce of the European Society of Cardiology and other societies
on cardiovascular disease prevention in clinical practice (constituted by
representatives of nine societies and by invited experts). European guidelines
on cardiovascular disease prevention in clinical practice: an executive summary.
Eur J Cardio Prev Rehab 2007; 14: E1–40.
M 3. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of
randomised trials of antiplatelet therapy for prevention of death, myocardial
infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86.
4. Scottish Intercollegiate Guidelines Network, 2007. Risk estmation and the
prevention of cardiovasular disease. A national clinical guideline. 97 [online].
Available: http://www.sign.ac.uk/pdf/sign97.pdf [Accessed 21 October 2009].
5. British Cardiac Society et al. JBS 2: Joint British Societies’ guidelines on
prevention of cardiovascular disease in clinical practice. Heart 2005; 91: v1–52.
M 6. Antithrombotic Trialists’ Collaboration. Aspirin in the primary and secondary
prevention of vascular disease: collaborative meta-analysis of individual
participant data from randomised trials. Lancet 2009; 373: 1849–60.
M 7. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of
aspirin: meta-analysis. BMJ 2000; 321: 1183–7.
8. de Abajo FJ, García Rodríguez LA. Risk of upper gastrointestinal bleeding
and perforation associated with low-dose aspirin as plain and enteric-coated
formulations. BMC Clin Pharmacol 2001; 1: 1.
9. The National Collaborating Centre for Chronic Conditions, 2008. Type 2
diabetes. National clinical guideline for management in primary and secondary
care (update) [online]. Available: http://www.nice.org.uk/nicemedia/pdf/
CG66FullGuideline0509.pdf [Accessed 21 October 2009].
10. Medicines and Healthcare products Regulatory Agency, 2009. Aspirin: not
licensed for primary prevention of thrombotic vascular disease. Drug Safety
Update 2009; 3: 10–1
11. Fourth Joint Taskforce of the European Society of Cardiology and other societies
on cardiovascular disease prevention in clinical practice (constituted by
representatives of nine societies and by invited experts). European guidelines
on cardiovascular disease prevention in clinical practice: full text. Eur J Cardio
Prev Rehab 2007; 14: S1–113.
M 12. Hart RG et al. Aspirin for the primary prevention of stroke and other major
vascular events: meta-analysis and hypothesis. Arch Neurol 2000; 57: 326–32.
M 13. Sanmuganathan PS et al. Aspirin for primary prevention of coronary heart
disease: safety and absolute benefit related to coronary risk derived from meta-
analysis of randomised trials. Heart 2001; 85: 265–71.
M 14. Hayden M et al. Aspirin for the primary prevention of cardiovascular events: a
summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern
Med 2002; 136: 161–72.
M 15. Eidelman RS et al. An update on aspirin in the primary prevention of
cardiovascular disease. Arch Intern Med 2003; 163: 2006–10.
R 16 ETDRS Investigators. Aspirin effects on mortality and morbidity on patients with
diabetes mellitus. Early Treatment Diabetes Retinopathy Study Report14. JAMA
1992; 268: 1292–300.
R 17. Peto R et al. Randomised trial of prophylactic daily aspirin in British male
doctors. BMJ 1988; 296: 313–6.
R 18. Steering Committee of the Physicians’ Health Study Research Group. Final
report on the aspirin component of the ongoing Physicians’ Health Study. N
Engl J Med 1989; 321: 129–35.
R 19. The Medical Research Council’s General Practice Research Framework.
Thrombosis prevention trial: randomised trial of low-intensity oral
anticoagulation with warfarin and low-dose aspirin in the primary prevention of
ischaemic heart disease in men at increased risk. Lancet 1998; 351: 233–41.
R 20. Hansson L et al. Effects of intensive blood-pressure lowering and low-dose
aspirin in patients with hypertension: principal results of the Hypertension
Optimal Treatment (HOT) randomised trial. Lancet 1998; 351: 1755–2.
R 21. Collaborative Group of the Primary Prevention Project (PPP). Low-dose aspirin
and vitamin E in people at cardiovascular risk: a randomised trial in general
practice. Lancet 2001; 357: 89–95.
M 22 Lip GYH, Felmeden DC. Antiplatelet agents and anticoagulants for
hypertension. Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.:
CD003186. DOI: 10.1002/14651858.CD003186.pub2. [Last assessed as up-to-
date 24 May 2004].
R 23. Ridker PM et al. A randomized trial of low-dose aspirin in the primary
prevention of cardiovascular disease in women. N Engl J Med 2005; 352:
1293–304.
 Aspirin for primary prevention of cardiovascular disease?

M 24. Berger JS et al. Aspirin for the primary prevention of cardiovascular events in
women and men: a sex-specific meta-analysis of randomized controlled trials.
JAMA 2006; 295: 306–13.
R 25. Belch J et al. The prevention of progression of arterial disease and diabetes
(POPADAD) trial: factorial randomised placebo controlled trial of aspirin and
antioxidants in patients with diabetes and asymptomatic peripheral arterial
disease. BMJ 2008; 337: a1840.
R 26. Ogawa H et al. Low-dose aspirin for primary prevention of atherosclerotic
events in patients with type 2 diabetes. JAMA 2008; 300: 2134–41.
DOI: 10.1136/dtb.2009.10.0045

Over-the-counter weight loss with orlistat?

Orlistat first became available (as 120mg capsules [Xenical]) around 10 years ago as a prescription-only treatment
for obesity.1 Earlier this year, orlistat 60mg capsules (alli – GlaxoSmithKline Consumer Healthcare) became
available for sale without a prescription to the public in the European Union. Orlistat 60mg is available in the
UK as a Pharmacy (P) medicine and so can be purchased over-the-counter (OTC) from pharmacies. OTC orlistat is
promoted as a new weight loss aid, “boosting weight loss by 50%” when added to a reduced calorie, lower-fat diet.
Here we review the place of OTC orlistat in tackling obesity.

are obese (i.e. their BMI is at least 30kg/m2) or who are

Background
Around a quarter of adults in England are obese (i.e. have a
BMI of 30kg/m2 or more).2 Obesity reduces life expectancy3
and is associated with hypertension, dyslipidaemia, type 2
diabetes mellitus, gallbladder disease, coronary heart disease,
osteoarthritis of the hip and knee, many cancers and adverse
outcomes in pregnancy.4-6
overweight (BMI at least 28kg/m2) and also have associated
risk factors.10 When used at the licensed dose of 120 mg three
times daily, the drug reduces absorption of ingested fat by
around 30%.11 The summary of product characteristics (SPC)
recommends that treatment with orlistat 120mg should be
discontinued after 12 weeks if less than 5% of initial body
weight has been lost.10

The mainstay of managing people who are overweight
involves modification of diet, physical activity levels and
behaviour. For instance, a diet with a 600 calorie per day
deficit may be expected to produce a weight loss of 5.3kg
(95% CI 4.8kg to 5.9kg) over 1 year, with exercise and
behavioural therapy providing additional weight loss of
approximately 2.0kg (95% CI 0.7kg to 3.2kg) and 7.7kg (95%
CI 3.4kg to 12.0kg), respectively.7 The National Institute for
Health and Clinical Excellence (NICE) advises that lifestyle
changes should form the mainstay of management in
obesity and that drug treatment should be considered only
after lifestyle changes, including behavioural approaches,
have been started.8 NICE recommends bariatric surgery as a
treatment option for people with a BMI of at least 40mg/m2 or
with a BMI of 35–40kg/m2 plus other significant disease that
could be improved with weight loss, if all appropriate non-
surgical measures have been tried but have failed to achieve
or maintain adequate, clinically beneficial weight loss for at
least 6 months.8
What is orlistat?
Orlistat is an inhibitor of gastrointestinal lipase, an enzyme
that catalyses hydrolysis of dietary fat. By inhibiting fat
hydrolysis, orlistat reduces fat absorption and thereby
reduces overall calorie intake. The drug is minimally
absorbed; animal studies indicate that it is metabolised
mainly in the intestinal wall.9
Prescription-only orlistat
Orlistat 120mg is available as a prescription-only medicine
(Xenical) for the treatment, for up to 2 years, of adults who
Orlistat 120mg three times daily, when administered with
a hypocaloric diet, has been shown to aid weight loss in
patients who are obese.1 The average weight lost at 1 year
with orlistat beyond that with placebo is around 2.9kg (95%
CI 2.5kg to 3.2kg).12 Also, results from a 4-year double-blind
randomised placebo-controlled trial involving 3,305 adults
with obesity, showed that the addition of orlistat 120mg three
times daily to lifestyle changes reduced the risk of progressing
to type 2 diabetes from 9.0% to 6.2% (p=0.0032).13 Whether
these benefits are sustained in the long term or reduce
mortality is unknown.
OTC orlistat
The licensed dose of OTC orlistat is 60mg three times daily
for adults who are overweight or obese (i.e. BMI at least
28kg/m2). Orlistat 60mg reduces absorption of ingested fat
by around 25%.9 The SPC states that a dose should be taken
immediately before, during or up to 1 hour after, each main
meal, and that if a meal is missed or contains no fat, the dose
should be omitted.9 The SPC also states that a patient who
has not lost weight after 12 weeks’ treatment with the drug
should consult a doctor or pharmacist, as it may be necessary
to discontinue treatment. Orlistat 60mg is licensed for use for
up to 6 months.9
How is OTC orlistat being sold?
Orlistat 60mg is advertised directly to the public and sold
through pharmacies, including internet pharmacies and
pharmacy phone-lines. The cost of 6 months’ treatment with
orlistat 60mg three times daily is around £325.

dtb.bmj.com DTB | Vol 47 | No 11 | November 2009 125

 Over-the-counter weight loss with orlistat?
The Royal Pharmaceutical Society of Great Britain has issued
practice guidance for pharmacists on the sale of orlistat
60mg.14 This recommends that they should be satisfied that
the individual is aged 18 years or over and has a BMI of at least
28kg/m2, and that they should refuse sale to those who may
be misusing the medicine.
The company marketing OTC orlistat has provided training
programmes on selling OTC orlistat and weight management
to UK pharmacists and their staff via online, distance learning
and face-to-face workshops.
For customers, the company provides a “support
programme”, consisting of booklets and a website including
advice on calorie and fat intake targets, tips on healthier
eating and exercise, a food diary and recipes, and an online
discussion forum.
Of relevance, the Centre for Pharmacy Postgraduate Education
(www.cppe.manchester.ac.uk) has produced a training pack
for pharmacists entitled Weight management – understanding
the causes, prevention, assessment and management of obesity.
This covers various aspects of weight management including
ways to give information and how to address individuals’
weight management issues.
Efficacy of orlistat 60mg
Two published double-blind randomised placebo-controlled
trials have assessed orlistat 60mg three times daily.15,16
One trial involved 796 adults who were obese (BMI of
30–44kg/m2).15 All the participants took part in a run-in phase
during which they received (single blind) placebo for 4 weeks.
Participants who completed this phase with at least 75%
adherence to the regimen (80% of those who entered the
trial), were randomised to orlistat (60mg or 120mg three times
daily) or placebo, for 2 years. All participants were prescribed
a reduced-energy diet for the first year, a weight-maintenance
diet for the second year and were encouraged to walk briskly
for 20–30 minutes three to five times each week throughout
the study period. They did not receive formal counselling
from dieticians or behavioural psychologists. After 1 year,
mean weight loss in the 635 randomised patients, (from a
mean weight of around 100kg at trial entry) was greater in
those receiving orlistat 60mg (7.1kg, 7.1%) and orlistat 120
mg (7.9kg, 7.9%) than with placebo (4.1kg, 4.1%; p<0.01 for
both comparisons). Roughly two-thirds of this weight loss
was maintained at the end of the second year in those on
orlistat 60mg (4.5kg, 4.4%) and orlistat 120mg (5.0kg, 5.0%),
and the losses were still greater than with placebo (1.7kg,
1.6%; p=0.001 for both comparisons). The percentage of
participants achieving a weight loss of 5% or more with
orlistat 60mg was 48.8% after 1 year and 33.8% after 2 years
and greater than with placebo (30.7% [p<0.001] and 24.1%
(p<0.03], respectively). This compares to 50.5% and 34.3%,
respectively, for orlistat 120mg. Nearly half of people on
orlistat withdrew early from the study (46% with either dose),
although the number was fewer than with placebo (57%),
126 DTB | Vol 47 | No 11 | November 2009 dtb.bmj.com
mainly because of loss to follow-up; 11% on orlistat 120mg
and 6.6% on orlistat 60mg withdrew because of unwanted
effects (vs. 7.1% of those on placebo).
In a similar study, 729 adults who were overweight or obese
(BMI 28–43kg/m2) were randomised (following a 4-week
single-blind placebo run-in phase, after which 54 patients
with poor adherence were withdrawn) to orlistat 60mg or
120mg three times daily or placebo, for 2 years.16 Participants
had a reduced-calorie diet in the first year and a weight-
maintenance diet in the second year. They received dietary
advice from dieticians but no formal advice appears to have
been given on physical exercise. After 1 year, mean weight
loss was greater in those on orlistat 60mg (8.5kg, 8.6%) and
orlistat 120mg (9.4kg, 9.7%) than with placebo (6.4kg, 6.6%;
p<0.001 for both comparisons). Most of the weight loss was
maintained at the end of the second year with orlistat 60mg
(6.6kg, 6.8%; p=0.005 ) and 120mg (7.4kg, 7.6%; p<0.001), and
was greater than with placebo (4.3kg, 4.5%). During the first
year of the trial, around 25% of people withdrew from orlistat
therapy (vs. 35% of those on placebo). Withdrawal was due
to unwanted effects in 6–7% of those on orlistat (vs. 1.6% of
those on placebo).
Data from the above two trials were reanalysed and pooled
to provide evidence for the European Medicines Agency on 6
months’ treatment with orlistat 60mg (the licensed maximum
treatment duration). This information is presented in the
SPC for alli, which states that in both trials, most weight loss
occurred within the first 6 months of treatment. At 6 months,
people on orlistat 60mg had lost 4.4kg (vs. 2.1kg with placebo,
p<0.001) from after the placebo run-in; the proportion who
had lost at least 5% of weight was 46.7% (vs. 26.4% with
placebo, p<0.001).9
Limitations of the data
It is important to remember that the trial results were from a
select group of patients more likely to adhere to treatment.
Whether they apply directly to the general population must
therefore be in question. What happens after cessation
of treatment with OTC orlistat is also not clear. This is of
significance given the well-recognised phenomenon of
rebound weight gain after weight loss interventions are
stopped. For example, published data from one randomised
controlled trial of orlistat 120mg suggest that much of
the weight lost while on orlistat is regained by 1 year after
stopping the drug.17
Unwanted effects with OTC orlistat
The most common unwanted effects with orlistat are
gastrointestinal, in keeping with its mechanism of action.
In clinical trials with orlistat 60mg, at least 10% of people
reported experiencing one or more of the following: oily
spotting, flatus with discharge, faecal urgency, fatty oily stool,
oily evacuation, flatulence and soft stools; and 1–10% of
patients reported abdominal pain, faecal incontinence, liquid
stools and increased defecation.9 These effects are more likely
if a meal or the diet is high in fat. Other unwanted effects

include anxiety (in 1–10% of people); the SPC states that it
is plausible that anxiety might occur in anticipation of, or
secondary to, the gastrointestinal effects of orlistat.9
Cautions and contraindications
OTC orlistat is contraindicated in people with cholestasis or
chronic malabsorption syndrome, and (because of a lack of
data) in women who are pregnant or breastfeeding.9
Due to its action on fat absorption, orlistat has the potential
to impair the absorption of fat-soluble vitamins (A, D, E and K).
However, in most patients who took orlistat 120mg three times
daily in trials for 4 years, vitamin concentrations stayed within the
normal range.9 Even so, the SPC recommends that patients on
OTC orlistat should take a multivitamin supplement at bedtime,
which would need to be purchased separately so incurring
additional cost to the customer. (For orlistat 120mg, the SPC says
that a multivitamin supplement could be considered.10)
The SPC advises that the patient should consult a doctor or
pharmacist before taking orlistat if they are on medication for
diabetes, or while taking orlistat if they are on medication for
hypertension or hypercholesterolaemia, as weight loss may be
accompanied by improvement in these conditions.9
Concurrent use of OTC orlistat with ciclosporin is
contraindicated because plasma concentrations of
ciclosporin have been found to decrease under such
circumstances. Concurrent use of OTC orlistat with warfarin
and other oral anticoagulants is also contraindicated
because coagulation times might be affected through
reduced absorption of vitamin K.9 The SPC advises that
orlistat may reduce plasma concentrations of amiodarone,
which may require a change in the dose of amiodarone.
Concurrent use of orlistat and acarbose (an antidiabetic drug
that delays digestion and absorption of starch and sucrose)
is not recommended in the SPC because of a lack of data.9
If orlistat causes diarrhoea, the bioavailability of the oral
contraceptive pill may be reduced; the SPC therefore
recommends that women who experience an episode of
severe diarrhoea with orlistat should use an additional form
of contraception.9
In theory, OTC orlistat may be used repeatedly or misused.
We have found four case reports of misuse of the
prescription-only version of orlistat by patients with a history
of an eating disorder.18-20
Conclusion
An over-the-counter (OTC) version of the weight-loss drug
orlistat (orlistat 60mg – alli) is available in the UK for purchase
dtb.bmj.com DTB | Vol 47 | No 11 | November 2009
Over-the-counter weight loss with orlistat?
without a prescription from pharmacies, by adults who are
overweight or obese (body mass index [BMI] 28kg/m2 or
more) for up to 6 months’ use. Published evidence indicates
that, over a course of 6 months, people on orlistat together
with a reduced calorie diet, shown likely to adhere well to
the treatment, lost an average of 2.3kg in addition to the
2.1kg lost with lifestyle measures alone. It is not known
how effective orlistat 60mg is in the general, non-selected,
population. Also it is not clear what happens at the end of a
6-month course of treatment.
OTC orlistat provides a reasonable choice for motivated
individuals who can afford the drug (around £55 per month plus
the cost of multivitamins). People who want to buy it should
receive full counselling about the unwanted gastrointestinal
effects and how these relate to diet. Weight regain is likely to be
a problem when the drug is stopped and individuals should be
advised to discuss long-term weight management options with
a healthcare professional at an early stage.
[R=randomised controlled trial; M=meta-analysis]
1. Why and how should adults lose weight? DTB 1998; 36: 89–92.
2. NHS Information Centre. Statistics on obesity, physical activity and diet: England,
February 2009 [online]. Available: http://www.ic.nhs.uk/webfiles/publications/
opan09/OPAD%20Feb%202009%20final.pdf [Accessed 21 October 2009].
3. Olshansky SJ et al. A potential decline in life expectancy in the United States in
the 21st century. N Engl J Med 2005; 352: 1138–45.
4. Jung RT. Obesity as a disease. Br Med Bull 1997; 53: 307–21.
5. Wilson PWF et al. Overweight and obesity as determinants of cardiovascular
risk: the Framingham experience. Arch Intern Med 2002; 162: 1867–72.
6. Villamor E, Cnattingius S. Interpregnancy weight change and risk of adverse
pregnancy outcomes: a population-based study. Lancet 2006; 368: 1164–70.
M 7. Avenell A et al. Systematic review of the long-term effects and economic
consequences of treatments for obesity and implications for health
improvement. Health Technol Assess 2004; 8: 21.
8. National Institute for Health and Clinical Excellence, 2006. Obesity: guidance
on the prevention, identification, assessment and management of overweight
and obesity in adults and children [online]. Available: http://www.nice.org.uk/
nicemedia/pdf/CG43NICEGuideline.pdf [Accessed 21 October 2009].
9. Alli 60 mg hard capsules. Summary of product characteristics, EU. Glaxo Group
Limited, July 2007.
10. Xenical 120mg hard capsules. Summary of product characteristics, EU. Roche
Registration Limited, March 2009.
11. Zhi J et al. Retrospective population-based analysis of the dose-response (fecal
fat excretion) relationship of orlistat in normal and obese volunteers. Clin
Pharmacol Ther 1994; 56: 82–5.
M 12. Rucker D et al. Long term pharmacotherapy for obesity and overweight:
updated meta-analysis. BMJ 2007; 335: 1194-9.
R 13. Torgerson JS et al. XENical in the prevention of diabetes in obese subjects
(XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle
changes for the prevention of type 2 diabetes in obese patients. Diabetes Care
2004; 27: 155–61.
14. Royal Pharmaceutical Society of Great Britain, 2009. Practice guidance: OTC
orlistat [online]. Available: http://www.rpsgb.org/pdfs/otcorlistatguid.pdf
[Accessed 21 October 2009].
R 15. Hauptman J et al. Orlistat in the long-term treatment of obesity in primary care
settings. Arch Fam Med 2000; 9: 160–7.
R 16. Rössner S et al. Weight loss, weight maintenance, and improved cardiovascular risk
factors after 2 years treatment with orlistat for obesity. Obes Res 2000; 8: 49–61.
R 17. Sjöström L et al. Randomised placebo-controlled trial of orlistat for weight loss
and prevention of weight regain in obese patients. Lancet 1998; 352: 167–72.
18. Fernández-Aranda F et al. Bulimia nervosa and misuse of orlistat: two case
reports. Int J Eat Disord 2001; 30: 458–61.
19. Malhotra S, McElroy SL. Orlistat misuse in bulimia nervosa. Am J Psychiatry 2002;
159: 492–3.
20. Cochrane C, Malcolm R. Case report of abuse of orlistat. Eat Behav 2002; 3:167–9.
DOI: 10.1136/dtb.2009.10.0046
127
 Management of seasonal affective disorder
Low mood associated with a certain season (usually winter) is very common. For example, in the UK, up to 6% of
adults have “recurrent major depressive episodes with seasonal pattern”, commonly known as seasonal affective
disorder (SAD).1-3 People with SAD consult in primary care more often than age- and gender-matched control
groups; patients also receive more prescriptions and are referred more often to secondary care.4 Around 6–35% of
patients require hospitalisation for SAD at some point.5 Here we discuss the management of adults with SAD, and
in particular light therapy.

About SAD Box 2

SAD involves symptoms typical for depression (e.g. lowered
mood, energy loss, fatigue) and also atypical symptoms (e.g.
hypersomnia, increased appetite and eating, carbohydrate
craving, weight gain).1,2,6 Some specialists have questioned
the value of considering “SAD” as a separate diagnostic
category from non-seasonal depression;7 and of note it
is classified as a subset of recurrent major depressive or
bipolar disorder rather than as a separate category by both
the Diagnostic and Statistical Manual of Mental Disorders
(DSM-IV; see Box 1) and the World Health Organization’s
International Statistical Classification of Diseases and Related
Health Problems (ICD-10).1,8
What causes SAD?
Evidence suggests that SAD has a genetic element, with genes
affecting serotonin metabolism (which has a seasonal pattern)
being implicated in seasonal mood variations.9,10 Melatonin,
a hormone secreted by the pineal gland during darkness, has
also been implicated in the aetiology of SAD. It is important in
the regulation of daily or ‘circadian’ rhythms (e.g. the sleep-
wake cycle) and seasonal or ‘circannual’ rhythms (e.g. regulating
reproduction in many mammals).11 The time at which the
plasma melatonin concentration rises occurs later in patients
with than without SAD.12 Nocturnal melatonin secretion can be
Box 1
DSM-IV criteria for “with seasonal pattern”
within recurrent major depressive disorder or
major depressive episodes in bipolar disorder1
• regular temporal relationship between the onset of
major depressive episodes and a particular time of the
year (e.g. fall [autumn] or winter);
• full remissions (or a change from depression to mania or
hypomania) at a characteristic time of year (e.g. spring);
• in the last 2 years, two major depressive episodes that
demonstrate the seasonal relationship and no non-
seasonal episodes;
• seasonal episodes substantially outnumber non-
seasonal episodes that may have occurred over the
individual’s lifetime.
Examples of light intensities measured in lux14,15
Moonlight: 0.2 lux
Winter’s day: 20,000 lux
Bright sunny summer’s day: 100,000 lux
suppressed by light (e.g. a light intensity of around 3,000 lux
suppresses melatonin secretion by around 70%; see Box 2 for
examples of light intensities measured in lux).13,14
Who gets SAD?
The mean age of onset of SAD is around 27 years; it can occur
in childhood, when rates among girls and boys are similar.5,16
Women are up to four times more likely than men to be
affected during the reproductive years. 9,17 In older adults,
prevalence rates decline and the genders are equally likely to
be affected.
Clinical course
Episodes of SAD last around 4 months.5,18 Around 60% of
patients diagnosed with SAD continue to have a seasonal
disturbance of mood and/or behaviour in the long term,
while around 20% have complete remission within several
years of first diagnosis.9 Some patients have manic or
hypomanic epidoses in spring and summer.19 SAD can
markedly impair quality of life in winter, but this may return
to normal in summer.20,21
Diagnosis
Various rating scales have been used to measure symptoms
in SAD (e.g. the 21-item and 17-item versions of the
Hamilton Depression Rating Scale [HAM-D21 and HAM-D17,
respectively] and the 6-item depression subscale [HAM-D6]).18
The gold standard of diagnosis is a structured interview to
determine whether patients fulfil DSM-IV criteria (see Box 3).9
Conventional antidepressants
Acute treatment of SAD
The suggestion that serotonin metabolism is disordered in SAD
underlies the use of selective serotonin reuptake inhibitors (SSRIs)
for acute treatment of patients with the condition; however, there
have been few good-quality clinical trials of such intervention.26

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One 5-week randomised placebo-controlled trial, involving 68
adults with SAD, found a higher response rate with fluoxetine
20mg daily (59% vs. 34% with placebo, p<0.05).27 A second,
8-week, placebo-controlled trial, involving 187 adults with
SAD and a mean baseline HAM-D29 of around 36, found a
greater change in mean HAM-D29 with sertraline 50–200mg
daily (-17.90 vs. -13.39 with placebo, difference 4.51, 95% CI
0.76 to 8.28).23
Fluoxetine and sertraline are licensed for major depressive
episodes, although SAD is not specifically mentioned in the
summaries of product characteristics (SPCs) for these drugs.28,29
Prevention of SAD episodes
Given that SAD may recur, long-term and maintenance
treatment may be needed.30
Pooled data from three randomised trials, involving a total
of 1,042 patients who started treatment before onset of SAD
symptoms in autumn, suggested that compared with people
on placebo, there was a lower recurrence rate among those on
bupropion 150–300mg daily (a noradrenaline and dopamine
reuptake inhibitor not licensed in the UK for this indication,
and not commonly used for SAD in UK practice; 16% vs. 28%;
relative risk [RR] 0.56).5,31 However, no p values were stated for
this difference.
Light therapy
Why use light therapy?
No clear mechanism of action has been established for light
therapy in SAD. One theory is that morning bright light
counters disordered circadian rhythms in patients with
SAD.32,33 Other theories suggest that light may also have direct
effects on some neurotransmitters (e.g. serotonin).10
What does light therapy involve?
Light therapy involves daily scheduled exposure to fluorescent
light boxes, dawn simulators (devices that slowly increase the
room illumination over a period of around 90 minutes during
sleep), or incandescent light visors (shaped like baseball
caps with light sources shining from the brim down into the
wearer’s eyes). The ‘dose’ of light is determined by the intensity
and duration of exposure.34
Assessing light therapy
Methodological difficulties
Several factors make designing trials of light therapy difficult.
For example, the appropriate ‘minimum dose’ of treatment is
unclear, and it is hard to find a credible control condition since
patients are not ‘blind’ to therapy, and treatment expectations
may contribute to a positive outcome.34,35 The acceptable
maximum dose for a low-light control is not known.
In addition, it is difficult to combine the results of light therapy
trials in a meta-analysis due to differences between studies in
terms of the doses of light used; the methods of delivery (e.g.
light box, dawn simulation or visor); comparator treatments;
and populations.36
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Management of seasonal affective disorder
Clinical efficacy of light therapy
A systematic review of randomised controlled trials of bright
light therapy (at least 3,000 lux-hours daily) for SAD found
eight studies involving a total of 360 patients with a maximum
of 300 lux for controls, and lasting 7–42 days.37 The effect
sizes for a significant reduction in depression symptom
severity with bright light were consistently positive across the
studies. However, there was significant heterogeneity among
the studies, indicating that they should probably not be
combined statistically.
The same review also identified five randomised controlled
trials (involving a total of 133 patients) assessing dawn
simulation (increasing light exposure from 0 lux to around
200–300 lux, over 1.5–2.5 hours) with controls receiving less
than 5 lux and/or less than 15 minutes of treatment; the
effect size for a significant reduction in symptom severity was
reported as moderate to large.37
In a meta-analysis of five randomised controlled trials of light
visors, no difference between light intensities of 3,500–7,600
lux, 400–650 lux, and under 100 lux was found; however, the
authors stated that the combined statistical power of the
studies was insufficient to demonstrate a significant effect.35
A forthcoming update of the National Institute for Health
and Clinical Excellence (NICE) guideline on the management
of depression in adults (due for publication in October 2009)
has reviewed the data on light therapy for depression with
a seasonal pattern.36 This review included 20 randomised
controlled trials, comparing light therapy (ranging from 176
lux to 15,000 lux daily) with waiting list control management,
“attentional” control (e.g. sham light box), or active
treatment controls (e.g. cognitive behavioural therapy [CBT],
fluoxetine). Compared with waiting-list control, bright light
reduced depressive symptoms more (e.g. weighted mean
difference [WMD] in SIGH-SAD score -10.4, 95% CI -15.99 to
-4.81); however, bright light did not differ significantly from
attentional control or active treatments. The review concluded
that it was unclear whether the superior effectiveness of
the light therapy compared with waiting list management
was more than a placebo effect. Another possibility is that
light therapy was as effective as fluoxetine or CBT. The NICE
Box 3
Structured Interview Guide Hamilton
depression rating Seasonal Affective Disorder
(SIGH-SAD): an interview covering HAM-D21
plus Atypical Depression Supplement of 8
items giving HAM-D2922-24
• current SAD episode criteria: total SIGH-SAD 20 or more,
including HAM-D21 10 or more and Atypical Depression
Supplement 5 or more;
• response: a reduction of at least 50% from baseline;
• remission: score falls to below 8.25
129
 Management of seasonal affective disorder
review also concluded that dawn simulation did not reduce
symptoms more than attentional control.36
No published randomised controlled trials have assessed the
combination of light therapy and antidepressants in SAD.33
Unwanted effects of light therapy
Unwanted effects of light therapy include eye strain or visual
disturbances (in 19–27% of patients), headache (13–21%),
agitation (6–13%), nausea (7%), sweating (7%) and sedation
(6–7%).9 These effects are generally mild and subside with time
or with reduction of the dose.9 Hypomania can also occur.9,24
Practicalities of light therapy
Regulations
Light therapy devices intended as treatment for disease,
which do not achieve their principal intended action on
the human body by pharmacological, immunological or
metabolic means, come within the scope of the Medical
Device Directive and should carry a CE mark.38
Cost
Light boxes and other appliances are available for sale or hire
in the UK both online and in high street stores (at around
£200), but are not currently available on prescription in the
NHS.39 People defined as “chronically sick or disabled” do not
have to pay VAT when they buy equipment (relating to the
specific disability) supplied for their personal or domestic
use.40,41 Where required for treating SAD, light boxes are
classified as zero-rated for VAT.40,41
Stopping and restarting light therapy
There are few data on stopping and restarting light therapy.
Specialists suggest that patients on light therapy generally
continue treatment until the time of their usual spontaneous
remission; it can be stopped abruptly.24 In rare cases where a
patient experiences a relapse, treatment can be resumed for
several weeks.
If light therapy is felt to be effective, it can be resumed in
subsequent years before, or with the appearance of, the
first symptoms (e.g. difficulty waking, daytime fatigue,
carbohydrate craving) prior to the onset of depression.
However, this may be unnecessary, as patients do not always
become depressed every winter.
Other treatments
Cognitive behavioural therapy
Two randomised controlled trials of CBT in patients with SAD
have been published.42,43
The first was a pilot study involving 23 patients who received
group CBT tailored to SAD (1.5-hour sessions twice weekly,
with 4–6 participants per group), light therapy (10,000 lux for
45 minutes in the morning and 45 minutes in the evening),
or both, for 6 weeks.42 SIGH-SAD scores improved from pre-
to post-treatment with no significant difference between
groups (only graphical information presented). At the 1-year
130 DTB | Vol 47 | No 11 | November 2009 dtb.bmj.com
follow-up, no patients treated with CBT (with or without light
therapy) the previous winter met SIGH-SAD criteria for relapse,
compared with 62.5% of patients who had received light
therapy only (p=0.005).
The second study, involving 61 patients with a mean pre-
treatment SIGH-SAD score of around 28.6, compared four
strategies for SAD: CBT (1.5-hour sessions twice weekly,
with 4–8 participants per group, for 6 weeks); light therapy
(10,000 lux for 45 minutes in the morning and 45 minutes
in the evening for 1 week, then flexible dosing for 5 weeks);
both of these treatments for 6 weeks; and waiting list
control management (minimal contact monitoring for 6
weeks; then treatment with light therapy).43 All three active-
treatment groups had a significant fall in SIGH-SAD scores
(post‑treatment scores: CBT only 12.9; light only 12.7; CBT
plus light 8.5) and scores in all these groups were lower than
that in the waiting list control group (23.1; p<0.05 for each
active treatment).
Self-help and complementary treatments
An NHS Direct patient leaflet on SAD recommends lifestyle
changes to reduce symptoms, including exercise, a healthy
diet and trying to get as much natural sunlight as possible.39
A systematic review of complementary and self-help
treatments for depression identified one randomised
controlled trial that assessed vitamin D therapy as treatment
for SAD (involving only 15 patients but suggesting the
treatment was more effective than light therapy); one that
assessed vitamin B12 as treatment for SAD (involving 27
patients, which found no benefit); and one that assessed
ginkgo biloba for prevention of SAD relapse (involving 27
patients, which also found no benefit).44
One randomised trial, involving 27 patients with SAD,
compared bright light (2,500 lux between 2pm and 4pm
daily), physical exercise (training on a stationary bicycle
between 1pm and 2pm daily), and “no treatment” for 1 week.45
The two active treatments reduced depressive symptoms
(HAM-D21 fell by 64.5% with light and 68.5% with exercise,
each p<0.001 vs. baseline) while “no treatment” did not
(change in score 4.9%, not significant).
Negative ion generators
The environmental concentration of negative air ions
varies greatly (for example, it is higher in humid, vegetated
environments and at the seashore, and lower in urban
environments and heated or air conditioned interiors).24 It is
thought that sustained exposure to negative air ionisation may
elevate mood, although no definitive mechanism of action for
this effect has been established.25
One double-blind randomised controlled trial involved only 25
patients with SAD, who received negative ions from an electronic
device for 30 minutes shortly after rising (between 5.30am and
8.30am), for 20 days, at one of two doses.46 More of those who
received the higher density of ions achieved remission (58% with
2.7x106 ions/cm3 vs. 15% with 104 ions/cm3, p=0.025).

What do guidelines say?
American Psychiatric Association guidelines published in 2000
suggest that the entire range of treatments for major depressive
disorder may also be used to treat patients with SAD, either
in combination with, or as an alternative to, light therapy.47 As
first-line treatment, the guidelines recommend light therapy
as a time-limited trial, primarily in out-patients with clear
seasonal patterns of symptoms. For patients with more severe
depression, the guidelines recommend light therapy as a
potential adjunct to psychopharmacologic intervention.
British Association for Psychopharmacology guidelines
published in 2008 state that antidepressants are a first-line
treatment for moderate and severe major depression in
adults irrespective of depression type, and that CBT may be
used in addition.26 For SAD, the guidelines state that light
therapy is a first-line acute treatment but that effective
prophylaxis against relapse is then needed, including
consideration of an antidepressant. The limited evidence
available suggests that bupropion or CBT help to prevent
recurrence the following winter.
Canadian Network for Mood and Anxiety Treatments (CANMAT)
guidelines published in October 2009 recommend “second-
generation” antidepressants (e.g. SSRIs) or CBT first line for major
depressive disorder, and medication plus CBT as second-line
treatment.48,49 For SAD, they recommend light therapy first-line.33
The final draft of the NICE guideline on depression in adults,
updated for publication in October 2009, suggests that people
with depression with a seasonal pattern should be treated
according to the strategy offered in the guideline for major
depressive disorder in general.36 Recommendations include an
antidepressant (normally an SSRI) or CBT for mild to moderate
depression, or both for moderate or severe depression; and that
CBT should be offered for relapse prevention. The draft guideline
also states that although there are a large number of studies
that address the efficacy of light therapy in people with seasonal
depression, they are difficult to interpret due to methodological
differences. It goes on to propose that patients with winter
depression who wish to try light therapy in preference to
antidepressant or psychological treatment should be advised
that the evidence for the efficacy of such therapy is uncertain.
The various guidelines appear to have reached different
conclusions about light therapy because they included different
studies and analysed primary data or published meta-analyses.50
Conclusion
Seasonal affective disorder (SAD) describes a subtype of
major depression which has a seasonal pattern (usually winter
depression and remission or hypomania during spring and
summer). It includes atypical symptoms such as hypersomnia,
carbohydrate craving and weight gain. A common approach
is to treat the condition as for non-seasonal depression,
for example, using SSRI antidepressants and/or cognitive
behavioural therapy (CBT).
dtb.bmj.com DTB | Vol 47 | No 11 | November 2009
Management of seasonal affective disorder
Light therapy has been suggested for treating people
with SAD. Trials of such therapy are complex as they need
a plausible control arm, and methodological differences
between published trials have made the results hard to
interpret. In addition, reviews and guidelines of light therapy
have included different trials and reached contradictory
conclusions. Nevertheless, bright light therapy in the early
morning, using a light box or dawn simulation, appears to be a
reasonable first-line approach to relieve depressive symptoms,
instead of, or as well as, drug therapy and/or CBT when the
patient has mild or moderate symptoms; people with more
severe symptoms should be treated with antidepressant drugs,
with or without light therapy and/or CBT.
For prevention of subsequent episodes, there is limited
evidence for a benefit of CBT or bupropion (an unlicensed
indication in the UK).
[R=randomised controlled trial; M=meta-analysis]
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental
Disorders. Fourth edition, text revision. Washington, DC: American Psychiatric
Association, 2000.
2. Michalak EE et al. Seasonal affective disorder: prevalence, detection and current
treatment in North Wales. Br J Psychiatry 2001; 179: 31–4.
3. Thompson C et al. Prevalence of seasonal affective disorder in primary care;
a comparison of the seasonal health questionnaire and the seasonal pattern
assessment questionnaire. J Affect Disord 2004; 78: 219–26.
4. Eagles JM et al. Use of health care services in seasonal affective disorder. Br J
Psychiatry 2002; 180: 449–54.
R 5. Modell JG et al. Seasonal affective disorder and its prevention by anticipatory
treatment with bupropion XL. Biol Psychiatry 2005; 58: 658–67.
6. Rosenthal NE et al. Seasonal affective disorder: a description of the syndrome
and preliminary findings with light therapy. Arch Gen Psychiatry 1984; 41: 72–80.
7. Hansen V et al. What is this thing called “SAD”? A critique of the concept of
seasonal affective disorder. Epidemiol Psichiatr Soc 2008; 17: 120–7.
8. World Health Organization, 2007. International Statistical Classification of
Diseases and Related Health Problems 10th Revision, Version for 2007 (ICD-10)
[online]. Available: http://apps.who.int/classifications/apps/icd/icd10online
[Accessed 21 October 2009].
9. Lam RW, Levitt AJ (Eds), 1999. Canadian Consensus Guidelines for the Treatment
of Seasonal Affective Disorder [online]. Available: http://ubcsad.bc-alter.net/
CCG%20SAD%201999.pdf [Accessed 21 October 2009].
10. Sohn CH, Lam RW. Update on the biology of seasonal affective disorder. CNS
Spectr 2005; 10: 635–46.
11. European Medicines Agency, 2007. Assessment report for Circadin [online].
Available: http://www.emea.europa.eu/humandocs/PDFs/EPAR/circadin/H-695-
en6.pdf [Accessed 21 October 2009].
12. Lewy AJ et al. Morning vs evening light treatment of patients with winter
depression. Arch Gen Psychiatry 1998; 55: 890–6.
13. Macchi MM, Bruce JN. Human pineal physiology and functional significance of
melatonin. Front Neuroendocrinol 2004; 25: 177–95.
14. McIntyre IM et al. Human melatonin suppression by light is intensity
dependent. J Pineal Res 1989; 6: 149–56.
R 15. Avery DH et al. Dawn simulation and bright light in the treatment of SAD: a
controlled study. Biol Psychiatry 2001; 50: 205–16.
16. Swedo SE et al. Rates of seasonal affective disorder in children and adolescents.
Am J Psychiatry 1995; 152: 1016–9.
17. Magnusson A, Stefansson JG. Prevalence of seasonal affective disorder in
Iceland. Arch Gen Psychiatry 1993; 50: 941–6.
R 18. Martiny K et al. Relapse prevention by citalopram in SAD patients responding to
1 week of light therapy. A placebo-controlled study. Acta Psychiatr Scand 2004;
109: 230–4.
19. Magnusson A, Partonen T. The diagnosis, symptomatology, and epidemiology
of seasonal affective disorder. CNS Spectr 2005; 10: 625–34.
20. Michalak EE et al. Generic and health-related quality of life in patients with
seasonal and nonseasonal depression. Psychiatry Res 2004; 128: 245–51.
R 21. Michalak EE et al. Quality of life as an outcome indicator in patients with
seasonal affective disorder: results from the Can-SAD study. Psychol Med 2007;
37: 727–36.
22. Williams JBW. A structured interview guide for the Hamilton Depression Rating
Scale. Arch Gen Psychiatry 1988; 45: 742–7.
R 23. Moscovitch A et al. A placebo-controlled study of sertraline in the treatment of
outpatients with seasonal affective disorder. Psychopharmacology 2004; 171:
390–7.
24. Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression:
131
 Management of seasonal affective disorder
efficacy, protocol, safety, and side effects. CNS Spectr 2005; 10: 647–63.
R 25. Terman M et al. A controlled trial of timed bright light and negative air
ionization for treatment of winter depression. Arch Gen Psychiatry 1998; 55:
875–82.
26. Anderson IM et al. Evidence-based guidelines for treating depressive
disorders with antidepressants: a revision of the 2000 British Association for
Psychopharmacology guidelines. J Psychopharmacol 2008; 22: 343–96.
R 27. Lam RW et al. Multicenter, placebo-controlled study of fluoxetine in seasonal
affective disorder. Am J Psychiatry 1995; 152: 1765–70.
28. Prozac 20mg hard capsules, and 20mg per 5ml oral liquid. Summary of product
characteristics,UK. Eli Lilly and Company Limited, February 2009.
29. Sertraline 50mg and 100mg film-coated tablets. Summary of product
characteristics,UK. Wockhardt UK Ltd, January 2009.
30. Westrin A, Lam RW. Long-term and preventative treatment for seasonal
affective disorder. CNS Drugs 2007; 21: 901–9
31. Terman JS et al. Circadian time of morning light administration and therapeutic
response in winter depression. Arch Gen Psychiatry 2001; 58: 69–75.
32. Zyban 150 mg prolonged release film-coated tablets. Summary of product
characteristics. GlaxoSmithKline UK, January 2009.
33. Ravindran AV et al. Canadian Network for Mood and Anxiety Treatments
(CANMAT) clinical guidelines for the management of major depressive disorder
in adults. V. Complementary and alternative medicine treatments. J Affect Disord
2009; 117: S54–64
34. Eastman CI. Is bright light therapy a placebo? In: Partonen T, Magnusson A
(Eds). Seasonal affective disorder, practice and research. Oxford University Press,
2001.
M 35. Thompson C. Evidence-based treatment. In: Partonen T, Magnusson A (Eds).
Seasonal affective disorder: practice and research. Oxford University Press, 2001.
36. National Institute for Health and Clinical Excellence, 2009. Final draft. Depression
in adults (update) [online]. Available: http://www.nice.org.uk/nicemedia/pdf/
DepressionUpdateFullGuideline.pdf [Accessed 21 October 2009].
M 37. Golden RN et al. The efficacy of light therapy in the treatment of mood disorders:
a review and meta-analysis of the evidence. Am J Psychiatry 2005; 162: 656–62.
38. EurLex, 1993. 31993L0042. Council Directive 93/42/EEC of 14 June 1993 concerning
medical devices [online]. Available: http://eur-lex.europa.eu/LexUriServ/
LexUriServ.do?uri=CELEX:31993L0042:EN:HTML [Accessed 21 October 2009.
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39. NHS Direct. Seasonal affective disorder [online]. Available: http://cks.library.
nhs.uk/patient_information_leaflet/seasonal_affective_disorder [Accessed 21
October 2009].
40. Directgov, 2009. VAT relief on products and services for disabled people [online].
Available: http://www.direct.gov.uk/en/DisabledPeople/FinancialSupport/
Taxreliefandreductions/DG_10028495 [Accessed 21 October 2009.
41 National Light Hire Co, 2009. VAT exemption [online]. Available: http://www.sad-
lighthire.co.uk/exemption.html [Accessed 21 October 2009].
R 42. Rohan KJ et al. A randomized controlled trial of cognitive-behavioral therapy,
light therapy, and their combination for seasonal affective disorder. J Consult
Clin Psychol 2007; 75: 489–500.
R 43. Rohan KJ et al. Cognitive-behavioral therapy, light therapy, and their
combination in treating seasonal affective disorder. J Affect Disord 2004; 80:
273–83.
44. Jorm AF et al. Effectiveness of complementary and self-help treatments for
depression. MJA 2002; 176: S84–96.
R 45. Pinchasov BB et al. Mood and energy regulation in seasonal and non-seasonal
depression before and after midday treatment with physical exercise or bright
light. Psychiatry Res 2000; 94: 29–42.
R 46. Terman M, Terman JS. Treatment of seasonal affective disorder with a high-
output negative ionizer. J Altern Complement Med 1995; 1: 87–92.
47. American Psychiatry Association. Practice guideline for the treatment of
patients with major depressive disorder (revision). Am J Psychiatry 2000; 157 (4
suppl): 1–45
48. Parikh SV et al. Canadian Network for Mood and Anxiety Treatments (CANMAT)
clinical guidelines for the management of major depressive disorder in adults. II.
Psychotherapy alone or in combination with antidepressant medication. J Affect
Disord 2009; 117: S15–25
49. Lam RW et al. Canadian Network for Mood and Anxiety Treatments (CANMAT)
clinical guidelines for the management of major depressive disorder in adults.
III. Pharmacotherapy. J Affect Disord 2009; 117: S26–43
50. Anderson IM, Haddad PM. CANMAT guidelines for depression: clear and user-
friendly. J Affect Disord 2009; 117: S3–4
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