Thursday, 8 July 2010

The SSRI story - corruption of medical research goes back to the 1960s

The story of the development of the SSRI (selective serotonin-reuptake inhibitor) drugs – the Prozac’ group of ‘antidepressants’ has been investigated thoroughly by David Healy (http://en.wikipedia.org/wiki/David_Healy_%28psychiatrist%29) in several books and papers such as The Antidepressant Era (1998) and Let them eat Prozac (2004) - http://www.healyprozac.com/.

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In the late 1960s Arvid Carlsson (later a Nobel prizewinner) realized that there was something different about the tricyclic antidepressant Clomipramine – which was used in treating obsessive compulsive disorder and various types of unusual or resistant ‘depression’. He discovered that this was probably because it had a greater effect on blocking the reuptake of serotonin (5-HT) than noradrenaline, and measured this difference in several drugs. Carlsson published a paper in 1969 which identified the antihistamines chlorpheniramine (especially) and diphenhydramine as very likely to be valuable drugs of a type similar to Clomipramine (but with different side effects, less cardio-toxic and safer in overdose) (http://www.medical-hypotheses.com/article/S0306-9877%2805%2900647-X/abstract).

Chlorpheniramine has many properties including the well known formulation Piriton which is used in Hay Fever; while diphenhydramine was often used as a nocturnal cough suppressant (e.g. in one of the Benylin formulations) and as a sleeping medication (e.g. Nytol).

So, here were antihistamine drugs which were already used by millions and considered safe enough to be available without prescription; and with a profile suggesting that they might make a new category of psychotropic drug with similar uses to clomipramine. In effect Carlsson discovered the SSRIs in 1969 or thereabouts.

But the pharmaceutical companies would not do trials on these agents, since their patents had expired, and this knowledge was not disseminated – indeed it is barely known even today. Instead, the pharmaceutical companies ‘concealed’ this knowledge for a decade and a half until they had developed patent-protected compounds – first zimelidine (which was too toxic), then later fluoxetine, (Prozac) and the other drugs later marketed as ‘SSRIs’.

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Clearly Big Pharma, and the university scientists and academic/ research-oriented psychiatrists, were not even *trying* to discover useful new treatments - if anything they were concealing them. Neither were clinicians sufficiently interested (or knowledgeable) to read and understand the scientific literature which implied that already existing antihistamines would have a valuable role in psychiatry – so psychiatrists were not trying to discover drugs to help their patients – they were only interested when these were ‘new’, glamorous and prescription-only drugs – not old-fashioned drugs available without prescription at the local drugstore or chemist.

Then when SSRIs came along to the point of pre-marketing trials around the early 1980s the pharmaceutical companies were not really interested in trying to find out what these drugs *really* did, how they might best be used, or their harms and dangers. The obvious use was in the treatment of anxiety – but David Healy (in The Antidepressant Era, 1998) has documented how -anxiety drugs were at that point regarded as intrinsically addictive due to emerging concerns about the benzodiazepines (the Valium group of drugs), and there was no interest in trying to launch new anti-anxiety agents into a market where they would be regarded as addictive. So the focus was on developing SSRIs as ‘antidepressants’.

Irving Kristol (in The Emperor’s New Drugs) has documented that by objective and rigorous criteria applied to the randomized trial evidence, the SSRIs are *not* effective as antidepressants. Yet, by selective and distorted reporting of the trials, the SSRIs were nonetheless licensed and marketed as antidepressants.

So the pharmaceutical corporations were not – as of the late 1970s early 1980s - interesting in telling the truth about what they did know, and were prepared to distort and to conceal even thirty years ago – this kind of behavior is not a recent phenomenon.

Another distortion and concealment related to SSRIs and suicide. Thanks mainly to the work of David Healy, it is now acknowledged ‘officially’ that SSRIs do indeed have a rare side-effect of inducing suicidal behaviour – for this reason they were labelled with a ‘black box’ by the FDA (Federal Drug Administration in the USA). Having found a raised rate of suicide and suicide attempts in the early placebo controlled trials of SSRIs, Healy gave SSRIs to some normal control subjects, and a couple reported unfamiliar violent impulses. Indeed this kind of feeling (akathisia) and behaviour is found with the neuroleptic/ antipsychotic drugs, that are chemically related to the SSRIs (also being chemically modified from antihistamines). The behaviour is somewhat paradoxical, given that both SSRIs and antipsychotics usually tend to reduce or flatten emotions in most people – making them unemotional. Nonetheless in some people at some times both classes of drugs seem to produce aggressive impulses.

So, it is clear that, as of the 1980s at least, pharmaceutical companies were actively concealing the harmfulness of harmful drugs.

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I do not believe that SSRIs are ineffective drugs, but I do agree that they are ineffective ‘antidepressants’ when depression is conceived in the classic way as endogenous depression or melancholia (a state of despairing emotional un-reactivity, reduced thought and movement, reduced food intake etc). SSRIs are sometimes effective in treating people with emotional instability, and in reducing anxiety – and that is where they seem to have found their niche, in the treatment of anxiety, panic, phobias, post-traumatic stress, obsessive compulsive disorder etc.

But getting to this point of understanding the value of SSRIs took a long time, much longer than it should have done – and drug company marketing and the medical research ‘evidence’ hindered rather than helped the process. Presumably many millions of people have been ineffectively or harmfully treated with SSRIs, while others who would perhaps have benefited were not tried on the drugs because they were not ‘depressed’.

Taking the SSRI story in overview, it is deeply worrying in terms of what it tells us about the motivations of pharmaceutical companies, and clinicans, over the past several decades – and its implications for interpreting the medical research literature.

Because science is hard to do: and if you are not even trying to discover useful treatments you certainly will not succeed. And if you are not even trying to be truthful, you will certainly not generate truth by accident.

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In sum, what this story tells us that:

1. Pharmaceutical companies were concealing information of clinical value as long ago as the late 1960s. This is not a recent development – although it has gotten worse.

2. SSRIs were not a new class of drugs. Pharmaceutical companies were not primarily trying to discover useful new classes of drugs, but chemically to slightly-modify old drugs to produce patentable agents which were then hyped as entirely new classes of wonder drugs. No new class of useful drugs has been discovered in psychiatry since the 1950s. Shocking.

3. There was a delay of about 15 years between discovery of the concept of SSRIs and the marketing of patented SSRIs – and although for those 15 years it was known that SSRI-type drugs were available for use, they were never used. This exhibits complete disregard for the needs of patients.

4. Some old drugs (e.g. chlorpheniramine, diphenhydramine) are cheaply available without prescription and ‘over the counter’ that are of the same class as new and expensive drugs (Prozac, Paxil) available only on prescription. While they are more sedative than modern ‘SSRIs’, these OTC drugs are likely to be similarly effective but safer due to greater experience in their usage.

5. When SSRIs were being investigated the investigation was focused on developing them as antidepressants, because the market for antidepressants was more promising than the market for anti-anxiety drugs – or any other type of drug. So, the SSRIs were never investigated for what they actually did, they were investigated in relation to what the pharmaceutical companies hoped they would do.

6. When the trials were conducted, it was discovered that the SSRIs were all-but-ineffective as antidepressants (i.e. ineffective at treating endogenous depression/ melancholia) – i.e. SSRIs were ineffective at doing what the pharmaceutical companies hoped they would do, but instead of acknowledging this fact, the strategy was to distort and misrepresent the trails and also redefine ‘depression’ and expand its diagnosis - to pretend that the drugs were effective antidepressants.

7. The rare but extremely serious problem of increased rates of suicide attempts and actual accomplished suicides among SSRI-takers compared with controls (an effect which is biologically understandable and plausible given the chemical structure and ancestry of the SSRIs) was concealed and denied – for decades!

8. Overall, the official SSRI research literature is pervasively unsound and untrustworthy. I cannot see any way of correcting for such an extreme and bottom-up degree of selection and bias, and I believe therefore that the official medical research literature on SSRIs should be ignored by serious scientists and physicians of integrity.

9. The second implication is that (unless the case of the SSRIs is unique – which seems highly unlikely, given that they were such a big selling and profitable example of modern drug marketing) - the *whole official medical research literature* going back at least three decades, is pervasively unsound and untrustworthy, and therefore must be ignored.

10. In such a situation as prevails now, it seems that there is no reliable or discernable relationship between the official medical research literature and the actualities of science; and also no relationship between the clinical literature and the reality of clinical experience. Since there is no effective mechanism to maintain the quality of the medical research literature, and no motivation to do this, and no honesty; it is quite possible that overall medicine is getting worse, rather than better.

11. But – such is the pervasiveness of corruption and dishonesty in relation to medical research and treatment - apparently nobody with any influence is interested by any of this.

12. In other words, nobody with influence is nowadays interested in *really* discovering, or even significantly improving, medical treatments. Even worse, nobody with influence is even *trying* to tell the truth about medical treatments.

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So how are things in the real world of science and medicine, underneath the hype and deception?

The answer is that I do not know, indeed nobody knows. Indeed, you cannot get ‘underneath’ the hype and deception, because the hype and deception goes all the way down.