Statin and cholesterol update

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In summing up more than 500 articles around cholesterol and the statin drugs used to treat cholesterol all I can conclude is that it is The Great Cholesterol Deception. To sum it up, however, the medical industry fudges the figures to fool the doctors that cholesterol is Public Enemy Number One. In fact, cholesterol is one of the most important bio-chemicals in the body and not a single life has ever been saved by lowering cholesterol. Many people suffer serious side effects as a result of taking statin drugs like Lipitor®, Zocor®, Crestor®, Pravachor and others.

Cholesterol is a normal part of our biochemistry and high levels—above six or seven—may be a symptom of an underlying health condition. But it is not the health condition itself. Elevated cholesterol predicts less than 35% of cardiovascular disease. In fact, most heart attack and stroke events occur in individuals without elevated cholesterol, at least half of all cardiac arrests occur in people with normal cholesterol levels and 20% occur in people without any traditional risk factors. But now the drug industry wants to lower the normal level of cholesterol even further so that almost everyone will have “high cholesterol.” At worst cholesterol is simply a messenger telling us there is stress on the liver, and it is not the killer it is made out to be. Cholesterol is a part of our immune, nervous and endocrine system and if high is only doing its job to protect us.

A significantly better predictor of the risk of heart attack or stroke is the concentration of Omega 3 oils in the blood: the higher the concentrations, the lower the risk ^{1,2,3,4,5,6,7,8}, which predict up to 90% of CVD compared to 35% prediction from cholesterol readings. But there is no money to be made in prescribing Omega 3 oils. Omega 3 oils also reduce triglycerides and other risk factors for CVD, as well as reducing the risk of many other forms of chronic illness, from Alzheimer’s to arthritis and cancer. This is due to the anti-inflammatory effect of fish oils. Imagine if the specialists prescribed a few fish oils to patients. No one would require a specialist.

Millions of people are prescribed cholesterol-lowering drugs, statins like Pravachol®, Zocor® and Lipitor® each year, with no measurable benefit. Despite the media hype from poor and lazy journalism at best these drugs lower the actual risk of heart attack by around 0.3 percent and at the same time have side effects in 15% to 40% of people given statins ^9,10,11,12 and serious side effects in as many as five percent of the population of users. And the studies of the side effects have only been short term. Most doctors will simply tell you that statins are safe and hand you a prescription. However if your GP reads the fine print there are two and a half pages of side effects. In some cases up to 65% of people started on statins stop taking them ^13,14. Unfortunately, far too many people take statins and far too many prescriptions are dished out by GPs and specialists whom they trust but who do not read or understand the scientific literature and who have become the retail arm of the pharmaceutical industry.

One of the side effects of statin drugs is that they lower the levels of CoenzymeQ10 ¹⁵. Coenzyme Q10 is not only required for energy production in cells, but also protects against free radicals by acting as an essential fat-soluble antioxidant. Clinical evidence also shows a beneficial effect of Coenzyme Q10 in cardiac arrhythmias, irregular heartbeats, and lowering the risk of heart attack ¹⁶. A recent study found Coenzyme Q10 (CoQ10) for treating people with severe heart failure reduced the mortality and morbidity by around 50%. In essence CoQ10 is essential for our health and is important in lowering the risks of heart attack or stroke and statin drugs lower levels of this essential nutrient.

Major side effects associated with statin drugs include muscle wastage including a form of muscle disease, rhabdomyolysis, that is fatal, memory loss and amnesia. Not only is cholesterol not the enemy but also it is essential to good health and wellbeing. Every cell in the body needs cholesterol in its membrane where it plays a critical role in cell communication. Without cholesterol, cell membranes are incomplete and as a result their functional role deteriorates.

Cholesterol is also used in the mitochondria, the powerhouse of the cell, and plays a vital role in cell energy production not to mention its essential role in the brain structure and function. Cholesterol is the starting material of many essential chemicals including vitamin D, steroid hormones and bile acids for digestion. Cholesterol is metabolised into vital body steroids such as the steroid hormones, these include: sex hormones, oestrogen, progesterone, testosterone and DHEA, as well as the adrenal hormones aldosterone and cortisol. When you lower cholesterol levels you reduce your production of your hormones. As a result statin use can induce gynecomastia, an abnormal enlargement of one or both breasts in men and the proliferation of the glandular component of the breast tissue ¹⁷.

Numerous studies have shown that cholesterol is an important part of your immune system. Low cholesterol levels have also been shown in studies to increase a person’s susceptibility to infections ¹⁸ This is due to cholesterol’s functional role in preventing infections in the body. The lipoproteins that carry cholesterol through our bloodstream aid in our protection against the harmful effects of bacterial endotoxins that are released during infection. Studies have also found cholesterol may have protective properties against some cancers ¹⁹.

Cholesterol is the most abundant organic molecule in the brain and is a vital component required for synapse function ^20,21,22. In fact the person who discovered this essential role in the brain won a Nobel Prize in biochemistry. Cholesterol is also required for the function of serotonin receptors in the brain. Serotonin is the chemical in our brain that makes us feel happy. Cholesterol is a significant component of the cell membrane that influences its fluidity. It therefore indirectly affects neurotransmitters by interfering with their membrane bound receptors ²³. It also forms part of the myelin that surrounds our nerves aiding in the fast transmission of nerve signals. Lower cholesterol levels in the blood are correlated with slower visuomotor speed ²⁴ and has potential implications for some diseases like multiple sclerosis and motor neurone disease.

Statin statistics: lies and deception

Various independent studies in prestigious, peer-reviewed journals have shown that statin use in primary prevention—that is to prevent heart attacks—have minimal or no value in reducing mortality. It does not matter how one processes the statistics, the results just aren’t there. In data gathered in 2009 from six trials, a review of their ability to lower the risk of death with statins found virtually no difference between the treatment group who received the drug and the control group ²⁵. And there are many more of these studies.

The problem really comes down to vested interests and the abuse of statistics. As readers of the scientific journals we should not get confused between statistical significance and clinical significance. Statistically significant means that the outcome was likely (95% chance) a result of the treatment whether it was 100% effective or less than 0.1% effective. That is, if you treat 1,000 people to save one life (0.1%) it may be statistically significant but it is not clinically significant. Clinical significance refers to the expectations doctors and patients have for the success of the treatment and is usually 30% or more. That is, if ten people get the drug at least three will benefit. The best studies on statins by the drug companies report statistical significance, mostly less than half of one percent usually around 0.3%, around 100 times less than our expectations of clinical significance and none at all have so far found any clinical significance. GPs just do not understand the difference between statistical and clinical significance. So if the professionals don’t understand how do we expect the media or public to understand?

Interestingly, the use of other cholesterol lowering drugs (non statins) that reduce cholesterol just as effectively as the statins don’t even reach clinical significance, that is they don’t even reach 0.1 percent. So we know the effect of the statins is not the effect of lowering cholesterol that gives the drugs their incredibly small but statistically significant 0.3% effect. Otherwise the other cholesterol lowering drugs would work at the same rate. As the statin drugs are a synthetic mimic of a natural cholesterol treatment, “red rice yeast,” which had been used successfully for decades before the drug companies patented the statins. Red rice yeast works just as effectively as the statins but with many fewer side effects. Red rice yeast also has small anti-inflammatory and anti oxidative properties. It seems the small benefit the statins have (0.3%) is because they act like nutrition. Not because they lower cholesterol.

The studies on statins also report relative risk not absolute or real risk. This really fools the GPs. The relative risk reduction is highly misleading and deceptive. An example of relative risk is if you have four people out of 1,000 in a study who die in the placebo group (no drug) compared to three people out of 1,000 who die in the drug treatment group, that is four were likely to die but only three did, then for most of us it is a change of 0.1% (1 in 1,000, not much) but when you use relative risks it shoots up to 25%. They compare three to four and say four is 25% higher than three so the relative risk is 25%. It is still only one person in 1,000 a reduction of 0.1% but the doctors who believe the drug companies obviously never mastered statistics. Relative risk is like adding 1+1 to get 11 or 2+5 to get 25 or more.

The well known JUPITER Study (which I like calling the STUPITOR study if you believe the sales hype) found that treatment with statins went from 68 heart attacks in the placebo group (no drug) to 31 heart attacks in the drug treatment group a 58% relative risk reduction and 64 strokes in the placebo group to 33 strokes in the treatment group a relative risk reduction of 48% ²⁶. Sounds good doesn’t it? However, the drug treatment group had 8,901 participants in it.  In real terms the heart attack risk went from a very low 0.76% to 0.35% and the risk of stroke went from 0.72% to 0.37%. That is, they had about a 0.35% reduction. Effectively if you treat 300 people with expensive and dangerous drugs you might save one life. Under the best possible scenario the real risk reduction was well under one half of one percent. Interestingly while the heart attack risk was reduced by around 0.35% the number of deaths increased with the drug use. Oops… no one reported this.

References

1.     Kris-Etherton et al. 2002;

2.     Wang et al. 2006;

3.     Schacky and Harris 2006;

4.     Psota et al. 2006;

5.     Harris et al. 2006;

6.     Robinson J.G. and Stone 2006;

7.     Reiffel J.A. and McDonald 2006;

8.     Jacobson 2006

9.     Wierzbicki et al. 1999;

10.  Nawrocki et al. 1995;

11.  Bertolini et al. 1997;

12.  Marz et al. 1999

13.  Jackerviciua et al. 2002;

14.  Benner et al. 2002

15.  Folkers et al. 1990

16.  Rosenfeldt et al. 2005

17.  Romao 2007

18.  Leardi S. et al. 2000

19.  Goldstein et al. 2009

20.  Mauch et al. 2001;

21.  Koudinov and Koudinova 2001

22.  Göritz et al. 2002

23.  Heron et al. 1980

24.  Zhang J. et al. 2004

25.  Bartolucci et al. 2009

26.  Ridker et al. 2008

Statin drugs lower omega 3 oils

A recent review suggests that the benefits of taking omega 3 fatty acids (vegetable oils) is cancelled out by taking statin drugs to lower cholesterol.

Omega 3(fish, krill) oils have multiple benefits beyond heart health. Omega 3 oils have been shown to reduce inflammation in various tissues and organs which is associated with almost every form of chronic illness (if not all) including diabetes, cancers, cardiovascular disease, auto immune diseases (including asthma and arthritis) osteoporosis, multiple scelosis, dementia and even depression, obesity and premature aging.

Although inflammation is natural it can be seriously problematic if it is reoccurring as a result of our body being out of balance. Numerous studies have also shown the real problem related to heart attacks is inflammation in the arteries not cholesterol.

In this review they reported

"Recent RCTs (random controlled trials) testing n-3 against arrhythmias suggest that n-3 reduce the risk only in patients not taking a statin. Other recent RCTs in secondary prevention were negative although, in a post-hoc analysis separating statin users and non-users, non-significant protection of n-3 was observed among statin non-users whereas statin users had no effect. Recent RCTs testing statins - after the implementation of the New Clinical Trial Regulation in 2007 - are negative (or flawed) suggesting that the lack of effect of n-3 cannot be attributed to a parallel protection by statins. Finally, statins favor the metabolism of omega-6 fatty acids (n-6), which in turn inhibits n-3 and, contrary to n-3, they increase insulin resistance and the risk of diabetes. Thus, n-3 and statins are counteractive at several levels and statins appear to inhibit n-3.

It seems that we have a choice. Omega 3 oils which make up a natural part of a healthy diet and have multiple positive side effects or statin drugs that have questionable benefits at best and serious side effects.

Antidepressants dont work

Depression is a debilitating condition and a major public health problem. It is the top-ranking cause of non-fatal disease burden in Australia, accounting for eight percent of the total years lost due to disability in 1996 ¹. It is predicted to be the second largest cause of disability in Australia by the year 2020 ². Depression is a mental disorder that has the potential to greatly impact one’s everyday activities. The experience of depressed mood, insomnia, loss of energy, irritability and other symptoms are commonly linked with depression. Further, recent research demonstrates its association with inflammation.

Unfortunately, although we continue to diagnose and medicate people for depression, there is little science and certainly no evidence to continue to prescribe antidepressants to most individuals. There are more myths in this area than there are facts and, as a result, many people are led astray by an industry that makes huge amounts of money from people’s suffering.

Depression theory

It is important to understand that most of what we know about the biochemistry and physiology of depression is theory and not fact. It is an hypothesis but is often presented by professionals as truth, with the connotation that these professionals know the full truth about depression. No, in fact, they do not. What we do know is that serotonin is located in the pineal gland, blood platelets, the digestive tract and the brain. Serotonin acts as a chemical messenger that transmits nerve signals between nerve cells and also causes blood vessels to narrow ³. We know that there are many other chemical messengers in the body that can have an impact on our mood and state of wellbeing.

Traditionally it has been thought that drugs most commonly used to treat depression—the selective serotonin reuptake inhibitors (SSRIs) such as Prozac® and Zoloft®—act according to the serotonin hypothesis. This hypothesis purports that levels of serotonin in the brain determine how we feel: high levels of serotonin cause heightened happiness, while decreased levels lead to sadness. Clinical depression has been attributed to low levels of serotonin transmission in the brain ⁴. The serotonin transporter 5-HT is a reuptake molecule that removes serotonin, so it is thought that the SSRIs act to interfere with the action of 5-HT and therefore allow serotonin to accumulate and levels to increase ⁴. This theory is still strongly supported by the pharmaceutical industry ⁵, which even uses it to encourage people to “correct” their serotonin levels in advertising for the drugs ⁶.

More recently, this theory has received much criticism as neuroscience research has failed to confirm “any serotonergic lesion in any mental disorder” ⁶. That is, the theory is just not supported by evidence. A growing body of research disagrees with the serotonin hypothesis ^6,7,8. In support of this, a Cochrane review found that tricyclic antidepressants are of the same efficacy as SSRIs ⁸. Since tricyclics do not impact serotonin levels, this would suggest that the serotonin hypothesis has been disproved. But someone forgot to tell the drug companies and professionals who continue to aggressively dish out these drugs.

Despite the blind acceptance of the serotonin theory, the GlaxoSmithKline website has posted: “There is no clear cut reason for depression, and a number of factors may be at play, including altered levels of chemical messengers (neurotransmitters) in the brain, such as serotonin and noradrenaline” ⁹. If antidepressants were a cure for depression, there would be a definite illness, with definitive symptoms and causes that the drugs are targeting. GlaxoSmithKline’s statement does not support this case.

Antidepressants describe the broad range of medications prescribed to alleviate the symptoms of certain depression- and anxiety-related mood disorders and include a number of different groups of medications. These include monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), tetracyclic antidepressants (TeCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and the current standard treatment group: selective serotonin reuptake inhibitors (SSRIs), which became immensely popular in the 1990s ¹⁰.

The first antidepressant that came along with a huge fanfare was Prozac®. Prozac® appeared on the market in 1988 and is still being prescribed today. It has become one of the most prescribed drugs to date ¹¹. Prozac® is part of a class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs).

The prescription of antidepressants has skyrocketed over recent decades ¹⁰. From 1996 to 2005, individuals treated with antidepressants became more likely to also receive treatment with antipsychotic medications and less likely to undergo psychotherapy—the net result is more drugs and less treatment. The percentage of the U.S. population using at least one psychotropic medication increased from 5.9% in 1996 to 8.1% in 2001 ¹². Among the psychotropic drugs, antidepressants are the most frequently prescribed medications. The U.S. CDC found that antidepressant use in the United States jumped nearly 400% by the 2005-2008 survey period, compared with the 1988-1994 period, with 11% of those over age 12 taking the drugs (U.S. CDC and Prevention’s National Center for Health Statistics) up from six percent in 1996 ¹³.

Antidepressants are now used by more than 27 million Americans, most of whom are women ¹⁴. Women are twice as likely as men to be diagnosed with major depressive disorder and up to three times more likely to be diagnosed with dysthymic disorder ¹⁵. However, despite the absence of any scientific evidence, antidepressants are increasingly being prescribed for other conditions such as hot flashes, headache, back pain, neuropathy, sleep-related conditions, anxiety spectrum disorders, eating disorders and fibromyalgia ¹⁶. Once prescribed, many people continue taking antidepressants, with more than 60% of Americans who use the drugs reporting being on them for two years or more. And about 14% of Americans taking antidepressant medication have done so for 10 years or longer. Patients who take the drugs often get them from their regular doctor rather than a so-called mental health professional.

Last year in Australia, there were 29 million prescriptions written for medications related to mental health issues. Antidepressant medications accounted for nearly 60% of these scripts, followed by anti-anxiety and anti-psychotic drugs ¹⁷. This suggests that around 2.4 million Australians are using medication to deal with mental health issues.

In the United States, “The number of visits by patients for depression was 24.5 million in 2001, a 70% increase since 1987” ¹⁸. The ambiguous nature of depression has provided leeway for significant misdiagnosis. The difficulty in identifying valid cases of depressive disorder lies within its tendency to share unclear boundaries with other mental disorders and normality ¹⁹. The distinction between major depression and sadness, for instance, has become completely obscure. Previously, depression was classed as either endogenous or reactive ¹⁹. Endogenous depression was regarded as a rare biological condition, whereas reactive depression was exogenous and triggered by stressful events outside our control, such as the loss of a loved one ¹⁹.

Under the Diagnostic and Statistical Manual (DSM-III), the diagnosis of clinical depression requires the presence of at least five of the possible nine symptoms for at least two weeks. Some of these symptoms include loss of interest in usual activities, depressed mood, fatigue, insomnia and lowered appetite. Yet many of these symptoms can be seen in natural responses to stress, loss ¹⁹, illness, fatigue and poor sleep. Unfortunately this weak criterion translates into a “low threshold for diagnosing clinical depression” ²⁰. This suggests that there are huge risks in misdiagnosing normal emotional states as clinical illnesses. As an example, chronic fatigue is also commonly mistaken for depression due to the large overlap in symptoms. In one study involving 3,200 individuals, patients who were depressed in the beginning of the study were found to be four times more likely to be fatigued, rather than “depressed” ²¹. Alas, due to the reinforcing nature of depression and fatigue, diagnosis becomes difficult.

Considering the major ambiguities surrounding the concept of depression, it is not surprising that the quantity of prescriptions for antidepressant medication is so high. What is of most concern is the number of people who are taking antidepressants and exposing themselves to unnecessary risk and, in too many cases, are not taking action to resolve underlying issues.

In 2002, a group of researchers studying the “placebo effect” compared studies on those taking sugar pills (placebo) and those taking antidepressants—a group of drugs the researchers expected to be effective—and found the opposite of what they expected. The meta analysis, written by Professor Irving Kirsch, was titled “The Emperor’s New Drugs: An Analysis of Antidepressant Medication Data Submitted to the U.S. Food and Drug Administration.” Kirsch obtained data from the FDA and reported that antidepressants were no more effective than a placebo. However, he did state that antidepressants might have a small effect and that in severe depression the placebo did not function as well as normal while the drug did show some efficacy ²². Professor Kirsch has also published a book of the same title (The Emperor’s New Drugs) that is well worth reading.

In a later analysis of additional data, Kirsch supported his earlier findings and reported antidepressants may be more effective than a placebo only in severe depression ²³. Now with more than a dozen major meta analyses, the research continues to show there is little supporting evidence that antidepressants work when placebos appear to be just as—and in some case more—effective. The research also shows the long-term effects tend to be severe ^{22,23,24,25,26,27}. In the majority of studies, antidepressants performed the same as inactive placebo pills.

A recent study found that a minority of antidepressant users actually fared worse than placebo users. In this study, researchers randomly assigned 156 depression patients to either take the antidepressant sertraline (Zoloft® and other brands) daily for 16 weeks or be in a placebo group given inactive pills. After 16 weeks, there were no overall differences in how the groups fared ²⁸. Of the antidepressant patients, 31% were treatment “responders,” meaning they had fallen below a certain score on a standard measure of depression symptoms, or had seen their score drop at least 50%. The same was true of about 28% of patients in the talk-therapy group, and 24% in the placebo group. The differences among the three groups were so small as to likely be due to chance ²⁸.

Two even bigger reviews in 2010 came to the same conclusions. A review of four meta analyses of efficacy trials submitted to the U.S. Food and Drug Administration (FDA) suggests that antidepressants are only “marginally efficacious” compared with placebo and “document profound publication bias that inflates their apparent efficacy.” In addition, when the researchers analysed the largest antidepressant effectiveness trial ever conducted, they found that “the effectiveness of antidepressant therapies was probably even lower than the modest one reported... with an apparent progressively increasing dropout rate across each study phase” due to side effects ²⁹. A review of nine studies involving 751 participants found that, from the results presented, antidepressants had only a small positive effect when compared to an active placebo ³⁰. Other studies have also shown St John’s Wort to be more effective than an SSRI ³¹ and exercise to be at least as effective in older patients ³².

Other irregularities were seen in the data. It was noted that published data consisted entirely of positive outcomes and that many of the negative trials’ reports were not published or that negative data were displayed in a positive manner ^25,26.  Publication bias, where only the positive results are reported and published, is well known in the drug industry and just a part of the drug companies’ everyday lies and deception.

Despite the findings of researchers, the FDA in the U.S. reports that 94% of its studies have shown positive results, with antidepressants found to be effective in treating depression ³³. However, publication of antidepressant studies by the FDA is highly selective: “The studies that the FDA judged as positive were approximately 12 times as likely to be published in a way that agreed with the FDA analysis as were studies with non-positive results according to the FDA” (Turner et al. 2008). Why have the FDA in the U.S. and Australian regulatory authorities continued to go against the scientific evidence?

The likely benefit of antidepressants is the placebo effect ^23,25. In trials, the patients on placebos would see the doctor on a weekly basis for check-ups and to update the analysts for the report. In addition, the patients were within easy access to help 24 hours a day ^26,34. Thus, the amount of human contact, attention and care skews the results ²⁶. This could possibly reveal the reason the placebo had such a strong effect. Imagine the positive feeling from being closely cared for by your medical practitioner, including having his or her phone number, rather than just in and out of the office in 12 minutes. The amount of attention and care influenced the strength of the placebo. Under real-world conditions, the patient sees the doctor less frequently and is less likely to seek help ^26,34.

The actual efficacy of SSRIs, therefore, remains in question and often subject to the merits and interests of those conducting a particular study. Many people drop out of drug trials because of the seriousness of side effects. The serotonin receptors are responsible for a variety of functions unrelated to mood, such as sleep, appetite and sexual function, as well as symptoms such as pain, nausea, depression, and anxiety ³⁵. Common side effects of taking an SSRI include nausea, dizziness, gastrointestinal disturbances, anxiety, agitation, insomnia, sexual dysfunction and weight gain ³⁵. Significant literature exists documenting the symptoms of SSRI discontinuation syndrome, which range from moderate to severe ³⁶. There can also be more serious consequences: SSRI use has been linked to serotonin syndrome, birth defects and high risk of suicide. The link between antidepressants and suicide has been recognised for at least 20 years and the United States FDA requires that antidepressants carry a label warning of this increased risk on each box ³⁷. In such cases it would seem antidepressants are not effective at all and, in fact, can have serious and even deadly side effects.

Despite these findings that have now been repeated many times, “professionals” working in the field still state that antidepressants work and continue to prescribe them to more and more people.

It is also worth pointing out that in the United States, until 1990 tryptophan dietary supplements were being taken by approximately 15 million Americans. On March 22, 1990, the Food and Drug Administration (FDA) banned the sale of L‑tryptophan in response to several deaths during the previous year from a deadly flu‑like condition called EMS ³⁸. This is despite L-tryptophan having been used as a supplement for decades prior to this, by a large number of people, without any adverse side effects. The problem was caused by a contaminated batch of tryptophan, not the tryptophan itself. One wonders why it was banned, as most drugs including antidepressants would be removed from the marketplace if this principle were applied across the board, including drugs that have been linked with hundreds of thousands of deaths.

However, on March 26, 1990, only four days after the banning of L-tryptophan, Prozac®, the wonder drug in the treatment of depression, was introduced with great fanfare after more than 10 years of development. What a coincidence. As mentioned earlier, Prozac® is an SSRI, whilst tryptophan actually increases the serotonin levels in the body.

Other interesting facts about this controversy:

L‑tryptophan was banned as a dietary supplement in the United States and Australia until 2005. It could, however, be imported from Japan and became available as a prescription-only drug. One hundred 500 mg capsules cost approximately $75.00. This is about five times more expensive than its previous cost as a dietary supplement.

L‑tryptophan is still used in baby food produced and sold in the United States.

Farmers are still allowed to use it in stock feed for animals. I wonder if this is because happy animals are more likely to gain weight?

1.     Mathers et al. 2000

2.     Minas et al. 2007

3.     MedicineNet 2003

4.     Schafer 1999

5.     Cowen 2008

6.     Lacasse and Leo 2005

7.     Murphy 1998

8.     Geddes et al. 2005

9.     GlaxoSmithKline 2008

10.  Olfsen et al. 1998

11.  Wrobel 2007

12.  Zuvekas 2005  

13.  Olfson et al. 2009

14.  Cosgrove et al.

15.  American Psychiatric Association 2000

16.  Roberts 2007

17.  Australian Institute of Health and Welfare

18.  Fergusson et al. 2006

19.  Parker 2007

20.  Lucassen et al. 2007

21.  Skapinakis 2004

22.  Kirsch 2002

23.  Johnson and Kirsch 2008

24.  Kirsch and Moncrieff 2005

25.  Ioannidis et al 2008

26.  Posternak and Zimmerman 2007

27.  Crawford and Parker 2007

28.  Barber 2011

29.  Pigott et al. 2010

30.  Moncrieff et al. 2010

31.  Szegedi et al. 2005

32.  Blumenthal et al. 1999

33.  Turner et al. 2008

34.  Blier 2008;

35.  Ferguson 2001

36.  Haddad 1998

37.  Reeves and Ladner 2010

38.  Manders 1995

Acknowledgements

Shannon Fitzgerald , Ben Gundry, Kahlia Belli, Noratiah Larry, Grant Swan and Jan van der Walt, Geraldine Treloar