Regulation of SSRI antidepressants
remains chaotic and misconceived

 Abstract
The need for and value of drug treatment for severe and moderate depression is not in question. Depression at its worst causes great distress, tends to be severely disabling, and may threaten life. The need for effective treatment in such cases is obvious and paramount. However, over 10 million SSRI antidepressant prescriptions are written in the UK each year for patients with ‘mild depression’ and, although SSRIs have been prescribed for 10-15 years, there is still no good evidence they are effective when so used. The available evidence indicates that SSRI drug treatment for mild depression benefits very few patients, but exposes many to risk. This continuing regulatory failure harms many patients, misinforms many doctors, and leads to over-prescribing, medicalisation and substantial waste. A simple remedy is available and urgently needed.

1. Background to this complaint
1.1 This complaint alleges maladministration by the Medicines and Healthcare products Regulatory Agency (MHRA), the executive agency of the Department of Health responsible for licensing medicines. The MHRA took over from the Medicines Control Agency (MCA) in April 2003. Both the MHRA and the MCA have relied on advice from a number of advisory bodies, notably the Committee on Safety of Medicines (CSM). The Agency’s stated aims "are to safeguard public health by ensuring that medicines for human use, sold or supplied in the UK, are of an acceptable standard of safety, quality and efficacy … (and) promoting the safe use of medicines …" (MHRA website).

1.2 This complaint specifically concerns the regulation of a class of antidepressant drugs collectively known as SSRIs (Selective Serotonin Reuptake Inhibitors).[1] The main SSRIs were first licensed between 1988 and 1995. They are now widely prescribed, mainly for depression (80%), less commonly for other kinds of mental distress (20%). Some 16.5 million NHS prescriptions are written for these drugs each year (England, 2003).

1.3 SSRIs have the notable advantage of low toxicity in overdose, but it is now generally accepted that SSRIs are no more effective in treating depression than other kinds of antidepressants. However, SSRIs have been marketed intensively, with the emphasis on promoting their use for an ever wider range of milder states of emotional distress. Since the SSRIs were first introduced, the prescriptions for antidepressants have more than trebled, and now match those of the benzodiazepine tranquillisers at their peak, 25 years ago. [2] See Table:

Prescriptions (millions) for antidepressants, England only [3]

1971	7.1
1981	7.9
1991	8.9
2001	27.0

1.4 SSRIs cause a wide range of adverse effects – e.g. weight gain, loss of libido, mood disturbances, and mental distress - but to illustrate this complaint reference is mainly made to the risk of drug withdrawal reactions indicative of drug dependence, and to the risk of SSRI-induced suicidal and violent behaviour. The MCA/CSM had formally reviewed these problems on several occasions, but this never led to significant action. The suicidality question was first investigated in 1990/1; withdrawal problems were investigated in 1993, 1996 and 1998. The MCA organised a further review of both problems in late 2002, but abandoned it in April 2003, following criticism about conflicts of interest involving leading figures on the review team. By this time, the Agency had received more reports of suspected adverse reactions to SSRIs relating to drug-induced suicidal behaviour and withdrawal reactions than for any other drugs. The Table shows the top ranking drugs (SSRIs highlighted) in each of these categories:

Rank	Withdrawal problems	Suicidal behaviour
		Accomplished	Attempted	Ideation
1	paroxetine	fluoxetine	fluoxetine	fluoxetine
2	venlafaxine	paroxetine	paroxetine	bupropion
3	tradamol	clozapine	isotretinoin	paroxetine
4	fluoxetine	venlafaxine	triazolam	isotretinoin
5	sertraline	sertraline	venlafaxine	mefloquine
6	citalopram	isotretinoin	sertraline	citalopram
7	zopiclone	citalopram	olanzapine	efavirenz
8	lorazepam	dothiepin	paracetamol	mirtazepine
9	fenfluramine	moclobemide	amitryptyline	sertraline
10	diazepam	risperidone/zopiclone	fluvoxamine et al	venlafaxine

1.5 The MHRA set up another enquiry in May 2003, under an Expert Working Group (EWG) of the CSM. By the time its final report was released, in December 2004, two main problems had been revealed. [4] First, the EWG established that antidepressants in general, and SSRIs in particular, were indeed capable of precipitating suicidal behaviour. Secondly, it was at last recognised that SSRI withdrawal symptoms were commonplace and sometimes severe.

• Following a detailed review of the available evidence, the MHRA issued warnings (10 December 2003) against the use of SSRIs in children and adolescents. [5] Importantly, the underlying reason for this decision was not so much the evidence of an increased risk of suicidal or violent behaviour, as the finding that there was no reliable evidence of efficacy. Lack of efficacy was clearly the main concern because the EWG found that one SSRI (fluoxetine) produced the same level of harm as the others - but because there was also a little evidence of modest efficacy, its use in children was tentatively approved. [6]
• The EWG concluded there might be a small increased risk of suicidal behaviour in the 19-29 year old age group, and that, with older patients, "a modest increase in the risk of suicidal thoughts and self-harm for SSRIs compared with placebo cannot be ruled out."
• The EWG overturned earlier MCA/CSM estimates, based on four previous investigations, that SSRI withdrawal reactions were rare and generally mild. The Group acknowledged that of the order of 25% of patients would experience withdrawal symptoms on stopping treatment, even after attempting gradual withdrawal. It was estimated that, in about one in five such cases, symptoms were disabling and severe.

2. Specifics of this complaint
2.1 It is generally relevant to this complaint, that a recent inquiry by the House of Commons Health Committee cast serious doubts on the fitness and competence of the MHRA. This Committee identified excessive and unwarranted drug prescribing as a real and growing danger to health, and questioned whether the Agency was equal to the task of containing it. The Committee (para 376) thought not:

"During this long inquiry we became aware of serious weaknesses in the MHRA. Worryingly, in both its written and oral evidence the Agency seemed oblivious to the critical views of outsiders and unable to accept that it had any obvious shortcomings, except those that could be remedied by more transparency. The Agency’s attitude to its public health responsibilities suggested some complacency and a lack of requisite competency, reducing our confidence in its ability to undertake the reforms needed to earn and deserve public trust. Nor did we conclude that the MHRA provides the discipline and leadership that this powerful industry needs. We recommend that there be an independent review of the MHRA …"

2.2 This complaint specifically concerns the failure of the MHRA to take due account of the balance of benefit:risk for different users of SSRIs, and to reflect this in the terms of the product licences granted to ‘Marketing Authorisation Holders’ (MAHs). At the heart of critical, effective and ethical drug evaluation and prescribing is the balance between the anticipated benefits and risks of treatment. The so-called, benefit:risk profile of a drug clearly differs for different users and in different circumstances; it will also depend on the anticipated value of alternative treatments (including non-intervention). Risk:benefit determinations may be complex, but the point is simply that ‘drug safety’ assessment is essentially meaningless without due consideration of drug efficacy and the patient’s need for treatment. [7]

2.2. The MHRA accordingly advises patients: "The expected benefit of your medicine will generally be greater than the risk of you suffering any harmful side effects. All medicines can cause problems and your patient information leaflet will list all the known side effects associated with your medicine.[8] However, it is important to note that most people take medicines without suffering any side effects." The main allegation in this complaint is that, for most users - and specifically for those suffering from ‘mild depression’ - the expected benefits of SSRI antidepressant treatment are plainly outweighed by the risk of harm.

2.3 In spite of its strictures about the need always to balance benefit and risk, the EWG review involved a detailed analysis of the risks of suicidal behaviour and withdrawal reactions from SSRIs, but included no systematic assessment of the efficacy of these drugs. Instead, the report contained a short overview of the "Burden of depressive illness and self harm". Moreover, the evaluations of SSRI efficacy in the treatment of adult depression, on which the MHRA relies, are grossly biased and consistently over-estimate drug effectiveness. Briefly, the MHRA judges SSRI efficacy to be ‘proved’, provided at least one clinical trial demonstrates superiority over placebo – but even when greater numbers of clinical trials fail to produce positive results.

"Drug regulatory agencies worldwide routinely rely on selective data presented by companies. For example, the pivotal requirement for drug approval by the US Food and Drug Administration (FDA) is evidence of superiority of active drug over placebo from two studies of sufficient size to establish statistical (if not clinical) significance. However, so long as companies provide evidence from two such studies, the FDA discounts the results of studies in which evidence of drug efficacy is lacking. Thus, drugs may be licensed even when evidence of efficacy is weak. Only meta-analysis would reveal this fault, but regulators rarely attempt it and secrecy prevents others from doing so.

"A leading academic psychiatrist and industry consultant recently noted that the manufacturers of SSRI antidepressants have now established that they need to plan for eight placebo-controlled efficacy studies in order to get positive results from two. Over half of all such studies on SSRIs have reportedly failed to show efficacy, and the proportion could be higher. The same source commented that Pharmacia (Pfizer) had failed to get US marketing approval for reboxetine because "they had the bad luck of only 1 of the 8 studies definitively showing that it works".[9] Reboxetine was licensed in the EU in 1997: it may be inferred that European regulatory standards for efficacy are no higher than in the USA." [10]

2.4 It is central to this complaint that most SSRI antidepressant prescriptions (67%) are written for states of ‘mild depression’. Mild depression is distinguishable from both severe and moderate states of depression. The MHRA has estimated that prescriptions for depression are written in the following proportions:

Diagnostic classification	Percentage of scripts
Mild depression	67%
Moderate depression	30%
Severe depression	3%

2.5 The nub of this complaint is that the MHRA has allowed and continues to allow the manufacturers to promote SSRIs for the treatment of ‘mild depression’, though relatively very few patients could expect to benefit from such drug treatment, and appreciably greater numbers could be expected to suffer from the experience. As the EWG report concluded: "The effectiveness of SSRIs in mild depression has not been clearly demonstrated in RCTs (randomised clinical trials). Without clinical trials in mild depression it is not possible to assess the balance between benefit and harm for these drugs in this indication." (11.2) This absence of evidence applied to all SSRIs and had been lacking, in the case of fluoxetine (Prozac), for some 15 years. [11]

2.6 It is relevant here that treatment guidelines for depression developed by the National Institute for Clinical Excellence (NICE) state: "Antidepressants are not recommended for the initial treatment of mild depression, because the risk–benefit ratio is poor." This advice is consistent with recommendations from Drug & Therapeutics Bulletin, [12] and with the current views of the Royal Colleges of Psychiatrists and General Practitioners. Moreover, both the EWG and CSM refer to the NICE guidelines to underline that good alternatives to drug treatment are available for the treatment of mild depression. [13]

 2.7 Although the need to distinguish between mild, moderate and severe states of depression in making prescribing decisions can no longer be in doubt, the MHRA has, by default and otherwise, failed to take appropriate action to emphasise the importance of this. Following publication of the EWG report, the Agency issued unhelpful and misleading advice to users[14] and, above all, failed to require appropriate restrictions to product licence terms.

2.8 Notwithstanding its insistence on the need to balance benefit:risk, and the evidence of poor benefit:risk equation in mild depression, the MHRA proposed no changes relating to severity of depressive illness to the Summary of Product Characteristics (SPC). The SPC is a critically important document with two functions. First, it provides the ‘current product information’ about a drug, and therefore the basis of prescribing decisions. Secondly, it legally defines what drugs may and may not be promoted for – and therefore has a decisive effect on the nature and impact of drug marketing and the uptake of commercially sponsored prescribing recommendations. Following the EWG review, the only changes the Agency recommended for the SPC related specifically to risks relating to suicidal behaviour and withdrawal reactions, and to drug dosage. No reference was made to the acceptability of those risks for patients suffering from mild, moderate or severe depression.

2.9 It is relevant to mention the UK and EU requirements for drug advertising and promotion: "No person shall issue an advertisement relating to a relevant medicinal product unless that advertisement encourages the rational use of that product by presenting it objectively and without exaggerating its properties". Though this requirement might seem very fanciful, it clearly implies that advertisements that failed to advise against the initial treatment of mild depression with an SSRI antidepressant would be inadequate, if not illegal. By failing to require MAHs to acknowledge the poor benefit:risk ratio of drug treatment in mild depression, the MHRA allows their continuing promotion for such use.

3. Complaint summary and proposed resolution
3.1 The relevance and urgency of this complaint is underlined by compelling testimony from unprecedented numbers of patients of grievous loss and harm. However, the emphasis in this complaint is on regulatory negligence and failure. In summary: through failures of drug evaluation and licensing, many patients have been and are being prescribed SSRIs when there is no scientifically credible evidence of drug effectiveness, but ample evidence of exposure to risk of harm; in spite of this, and in violation of basic principles of drug evaluation, the MHRA has failed to issue appropriate advice and warnings, and systematically concealed both the evidence of risks and the Agency’s failure to contain them. The Agency’s present policies expose many patients to unacceptable and unnecessary risks, allow doctors to be ill-informed, fail to contain inappropriate and excessive drug prescribing, and thereby promote medicalisation and waste.

3.2 This complaint might be readily resolved. It simply requires the MHRA to insert appropriate text into both the Summary of Product Characteristics (SPC) and the Patient Information Leaflets (PILs) of all SSRIs and equivalent drugs, to emphasise that antidepressant drug treatment should not be initiated by general medical practitioners (other than specialists in mental health) in the absence of a confident diagnosis that the patient is suffering from a moderate to severe depressive state.

4. References
1. This complaint refers to all antidepressants listed in Table 1.1 at para 1.2 of the report of the Committee on Safety of Medicines Expert Working Group on the Safety of Selective Serotonin Reuptake Inhibitor antidepressants (6 December 2004), including fluvoxamine (Faverin), fluoxetine (Prozac), sertraline (Lustral), paroxetine (Seroxat), citalopram (Cipramil), venlafaxine (Efexor), mirtazapine (Zispin) and escitalopram (Cipralex).

2. Committee on the Review of Medicines, Systematic Review of the Benzodiazepines. Br Med J. 29 March 1980, 910-912.

3. The number of NHS prescriptions issued in England represents about 80% of the total for the whole UK

4. One other major problem was identified, but forms no part of this complaint: contrary to previous beliefs and advice, the EWG reported that there was no additional benefit from increasing the dose of most SSRIs above the recommended daily dose.

5. "On the basis of a review of the safety and efficacy of the SSRI class in the treatment of paediatric major depressive disorder undertaken by the Expert Working Group of the Committee on Safety of Medicines (CSM), the CSM has advised that the balance of risks and benefits for the treatment of major depressive disorder in under 18s is judged to be unfavourable for sertraline, citalopram and escitalopram and unassessable for fluvoxamine. Only fluoxetine (Prozac) has been shown in clinical trials to have a favourable balance of risks and benefits for the treatment of MDD in the under 18s."

6. "The efficacy of fluoxetine in the short-term (eight and nine weeks) treatment of major depressive disorder was demonstrated in two placebo-controlled clinical trials with 315 paediatric patients aged eight and above. The size of the effect was modest but consistent with that seen in the adult population. (EWG report, 6.1.4) …. With the exception of fluoxetine, the clinical trial data for the SSRIs and related antidepressants failed to demonstrate efficacy in the treatment of depressive illness in children and adolescents. (Ibid 6.1.9)

7. The MHRA chairman recently emphasised the importance of the concept of a balance between risk:benefit, and the public’s need to take full account of it. In oral (uncorrected) evidence (Q777: 20 January, 2005), Professor Sir Alasdair Breckenridge was asked if there were "any particular key areas where you perhaps would suggest there is a need for change?" Breckenridge replied: "I think that the other area that I would pick up is that of the education of the public in terms of risk and benefit. A lot of the discussions which have taken place in the Select Committee have been about the safety of medicines and relatively little about this concept of risk and benefit. When we change a licence, we do not do this purely based on a safety profile of a drug. If we did this, there would be no anti-cancer drugs available and there would be no anti-HIV drugs because the adverse reactions to them are huge. They have got to be balanced against the benefits which these drugs have and the one thing which I would like to see you concentrating on, with all respect, is this concept of risk and benefit. We are going to be communicating that very strongly with our new communications set-up, but I would like to see that as one important aspect coming through from this Committee."

8. The ‘play word’ is "known". Patient Information Leaflets typically list only a small proportion of the suspected adverse drug effects listed in the Summary of Product Characteristics (SPC).

9. Thase M. Assessing efficacy of antidepressants: clinician and FDA perspectives. http://www.medscape.com/ viewprogram/2546 (accessed June 1, 2004).

10. Medawar C, Hardon A, Herxheimer A: Depressing Research: Lancet, 363, 19 June 2004, 2087.

11. "Two fixed dose trials were conducted. The first of these was analysed as two trials; one in mild depression and one in moderate/severe depression. There was no evidence that fluoxetine was efficacious in mild depression, with none of the doses being superior to placebo. For moderate/severe depression, there was evidence that the 20mg dose was more efficacious than placebo, however the data provided no evidence that there is an efficacy advantage from using doses above 20mg, with the results on 20mg being numerically better than those for the higher doses." (9.3.4)

12.  Mild depression in general practice: time for a rethink? DTB, 41, 8, August 2003, 1-5.

13."This guideline recommends a stepped care approach to treatment. For mild depression treated in primary care, the recommended approach includes watchful waiting, guided self-help, computerised cognitive behavioural therapy (CBT), exercise or brief psychological interventions, with drug treatment and longer psychological interventions normally being introduced only for moderate or severe depression." (para 3.1.5).

14. See, in particular the MHRA’s "Questions and Answers" on findings of CSM Expert Working Group". This gives no hint that the benefit:risk equation is affected by severity of depressive illness: "The advice being communicated to health professionals focuses on the use of SSRIs in adults and concludes that the balance of risks and benefits of all SSRIs in adults remains positive." In spite of the EWG finding that "suicide is a rare event", this document characterises depression by reference to more severe states: "Depressive illness is itself associated with an increased risk of suicide". Overlooking the fact that severe depression accounts for only 3% of antidepressant prescriptions, this document also emphasises that, "These drugs are beneficial for the majority of patients with depressive illness and anxiety disorders. These conditions can be life-threatening and have a huge impact on the lives of those that suffer from them, and effective treatments are to be welcomed."

 Charles Medawar
20 April 2005

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