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No new drugs for mood and anxiety disorders have reached the market for over a decade. Why is there so little innovation in a sector that accounts for the largest proportion by far of sales of psychiatric drugs?
The current division between anxiety and depression is increasingly recognised as inadequate. In the community, most mood disorders present as a combination of depression and anxiety. Yet the Food and Drug Administration in the United States, which has become the world bellwether of drug approval, indicates drugs either for major depression or for the various forms of anxiety recognised by the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM). As a result, the pharmaceutical industry is compelled to develop drugs for diagnoses that are of questionable clinical relevance. This is one reason for the big slowdown in drug discovery in psychiatric drugs. A return to the former unitary classification of mood and anxiety disorders as nervousness or cothymia might represent a way out of this blind alley.
In 1980, the American Psychiatric Association revised its standard system of diagnoses in the third edition of its diagnostic manual (DSM-III).1 This document erected a firewall between depression and anxiety. Indeed, in drafting this edition the association appointed separate committees to study depression and anxiety and stated that any overlap between the two disorders would henceforth be considered mainly as comorbidity. Although this division was controversial at the time, DSM-III became the accepted psychiatric nosology worldwide, and its successors dominate the picture today.2 Recent observers, however, suggest that
Admittedly, the manual allows for diagnoses such as dysthymic disorder, a chronic form of depression that merges closely with major depression, and adjustment disorder, a lost diagnosis originally offered as a political sop to the large American psychotherapeutic community.6 However, neither diagnosis has proved particularly helpful.
The crucial point is that the Food and Drug Administration accepts psychiatric drugs almost exclusively for DSM-style indications; European regulators seem to be headed in the same direction. For example, the European Agency for the Evaluation of Medicinal Products has decided to “re-evaluate the existing requirements” for the treatment of anxiety by focusing on generalised anxiety disorder.7 So the name of the disease determines how it is treated: depression is treated with antidepressants, anxiety with anxiolytics.
Officially, diagnostic decisions are made through scientific consensus by the World Health Organization and the American Psychiatric Association. Small committees of experts decide whether, for example, schizophrenia is one disease or several, and the process of decision making should be transparent and based on good scientific evidence. But sometimes the evidence is poor and influenced heavily by the pharmaceutical industry. The industry exerts a major influence through publication of sponsored supplements to journals, which are often poorly peer reviewed and promote unapproved treatments.8 Such supplements are particularly common for drugs for anxiety and depression as these are the most common treated conditions. Worldwide sales of antidepressants dwarf sales of drugs for all other psychiatric disorders.
Industry is said to prefer the disease based approach of DSM-III to any dimensional approach to illness definition. This is because the separate DSM-style diseases represent tidy diagnostic market niches. Every new diagnosis represents a new licensing opportunity. Companies only have to show the effectiveness of an existing drug over placebo for the new diagnosis in large clinical trials. This is expensive but not difficult if the same methods can be used as for previous studies with the old diagnoses.
The increase in the number of diagnoses of anxiety and depression has occurred at the same time as an equivalent slowdown in production of new drugs (figure). Although this association may not be causal, it does raise the question: what are these new diagnoses for? The basic drugs used most commonly for mood and anxiety disorders were largely discovered in the 1950s and 1960s or even before—valproic acid was first described in 1882. Only four new drugs apart from benzodiazepines and selective serotonin reuptake inhibitors were patented in the 1970s compared with 15 in the 1960s (table). The four drugs were bupropion, buspirone, modafinil, and mirtazapine—and mirtazapine is an analogue of mianserin, which Organon patented in 1967.
Just four drugs for mood and anxiety were patented in the 1980s—two hypnotics (zaleplon and zolpidem), venlafaxine, and the serotonin reuptake inhibitor sertraline. Since 1990, no drugs have been patented in the mood and anxiety area that have reached the US market. (Escitalopram, the most recent marketed selective serotonin uptake inhibitor and an isomer of citalopram, was patented in July 1990.) Among the popular drugs currently prescribed in the United Kingdom, trazodone was patented in 1968, buspirone in 1973, moclobemide in 1977, and reboxetine in 1979.
Why has development of drugs for mood largely come to an end? We believe it is connected to the artificial separation of anxiety and depression.9 Before DSM-III, treatments tended to be for symptoms, not diseases. The drugs developed before this time, including amphetamines, benzodiazepines, and tricyclic antidepressants, were used to treat both depression and anxiety. Later, drug indications were linked clearly to disease states, so that antipsychotics, anxiolytics, and antidepressants became mutually exclusive categories.10 Thus, nosology suddenly became the prime force in shaping the indications for a drug. The regulators encouraged industry to produce antidepressants, so they were duly introduced, but more accurate labels would have been antifatigue drugs, tonics, or psychic energisers.energisers.
The growing search for blockbusters in the 1970s resulted in a trend to rubbish earlier drugs in order to put new patent protected drug classes on the market. Despite clear evidence that benzodiazepines were effective, they were dismissed as drugs for neurotic women, who then become addicted.11 The tricyclic antidepressants were castigated for their adverse effects, and in 1998, a consensus conference on tricyclics compared with selective serotonin reuptake inhibitors agreed that tricyclic antidepressants should not be considered as first line antidepressant treatment except in patients admitted to hospital with depression.12 Eli Lilly, which patented fluoxetine, paid for the conference.
This backlash against established drugs obscured the notion that certain drug classes were effective for both anxiety and depression, particularly the benzodiazepines. With the decline of the benzodiazepines in the 1980s, anxiolytic therapy was placed on the back burner and antidepressants rushed into the spotlight, in the form of selective serotonin reuptake inhibitors. In the world of pharmacotherapy, anxiety and depression had become as different as chalk and cheese.
But while drug discovery has faltered, the proliferation of niche diagnoses continues apace and mixed diagnoses are scorned.13 For example, each new anxiety diagnosis seems to create an opportunity for the promotion of a phoney new drug indication, so we have paroxetine for social anxiety disorder, fluvoxamine for obsessive compulsive disorder, and sertraline for post-traumatic stress disorder.
Industry has been busy behind the scenes in this handy convergence of eccentric new diagnoses and the market nicheing of compounds. For example, in May 1984, Robert Spitzer, the chief disease designer of DSM-III and DSM-III-R, convoked a meeting of the anxiety working group, cosponsored by “the Psychopharmacology Unit of the Division of Medical Affairs of the Upjohn Company.” At the end of the discussion of the relation between panic and agoraphobia, Spitzer announced, “Consensus favors the Upjohn model.”14 It is now routine for psychopharmacologists, such as Brown University's Martin Keller, to receive as much as $500 000 (£320 000) in consulting fees from industry in a given year.15 USA Today has calculated that at 55% of the meetings of the various advisory committees of the FDA, “half or more of the FDA advisers had a conflict of interest.”16
Sometimes the relation between academic psychiatrists and industry veers over the line of acceptability in the form of ghost writing—academics lending their names to articles drafted by industry hacks. This has been a problem in psychopharmacology since the 1950s.17 But only last year, Vienna psychiatry professor Siegfried Kasper was identified in the Austrian press as signing an industry ghostwritten article about an antidepressant.18 Under normal circumstances, the interpenetration of industry and academe can be fruitful, as talent and ideas wash back and forth. Yet when drugs start earning the kind of money usually associated with the oil industry, there is potential for trouble.
Since 1980 anxiety and depression have been considered as discrete diseases
Drug development has subsequently been tailored to new diagnoses
The increase in the number of mood and anxiety diagnoses has coincided with a fall in the rate of development of new drug types
The proliferation of niche diagnoses is liked by industry because it creates new licensing opportunities for drugs
The focus of drug development needs to return to mixed anxiety-depression disorders
We believe that the failure to advance the treatment of anxiety and depression is related to wrong classification. If you don't have natural disease categories, you can't develop drugs for them. If the Food and Drug Administration will accept only drugs that are effective for DSM diagnoses, and if the diagnoses are artefacts, the drugs are bound to be less valuable, even if in the short term they increase their market share. Companies must start developing drugs for mixed anxiety and depression and forget about dividing this giant illness segment into salami slices. Doctors could encourage this change by being more cynical about pitches from drug representatives claiming to have “the latest” in anxiolytic medication. Ask instead for the latest in nervousness.19
Contributors and sources: ES has carried out research on historical aspects of psychiatry over many years, wherever possible studying documents that are key to the making of decisions by policy makers and psychiatric bodies. Most recently, he has worked in the archives of the US Food And Drug Administration and the American Psychiatric Association. PT has carried out clinical trials into the drug and psychological treatment of anxiety and depression since 1969 and has been involved in field trials for the 10th revision of the International Classification of Diseases (ICD-10).
Competing interests: PT has received support from the Mental Health Foundation to evaluate the outcome of anxiety and depressive disorders.