CONFLICT OF INTEREST IN NEUROPSYCHOPHARMACOLOGY: Marketing vs. Education
By Thomas A. Ban
The term, “conflict of interest” is defined in the Webster dictionary as “a conflict between private interests and official responsibilities of a person in a position of trust” (Merriam-Webster 1985). It is used in reference to situations in which fiduciary interest, founded on trust or obligation, is compromised by another interest (Black 1978). If people act contrary to their fiduciary interest they act in “conflict of interest”.
Prior to the 1980s, little attention was paid to “conflict of interest” in science and medicine. At present, authors in most medical journals and speakers, at most medical conferences are required to disclose their financial involvement with the pharmaceutical industry (Krimsky 2006; Lemmens 2008). While receiving funds from industry is a financial motivation, it may or may not lead to an act in conflict of interest.
Neuropsychopharmacology studies the mode of action of psychotropic drugs for obtaining information on the biochemical underpinning of mental pathology in order to develop rational pharmacological treatments (Hollister 1996; Wikler 1957). Psychotropic drugs are the means and the end products of neuropsychopharmacological research. Developed by drug companies and registered by regulatory authorities, the prescription of psychotropic drugs is dependent on interaction between (academic) education and (industrial) marketing. The objectives of marketing (industry) and education (academy) are in conflict. The objective of marketing is to get a product prescribed in the widest possible population, whereas the objective of education is to guide the judicious and discriminate use of available drugs. Both successful education about the clinical use of psychotropic drugs and neuropsychopharmacological research, are dependent on established therapeutic effects of a drug in a well defined population, whereas successful marketing is dependent on demonstrated therapeutic efficacy, as defined by regulation, in the widest possible population in which the substance my have an effect in some patients.
Introduction of psychotropic drugs, during the 1950s, focused attention on the pharmacological heterogeneity within psychiatric diagnoses (Ban 1969. 1987). To meet educational and research objectives, there was a need to resolve this heterogeneity by identifying the treatment responsive sub-populations within the diagnostic groups (Ban 1969, 1987, 2007; Freyhan 1959; Klein 1973, 2008). This did not happen (Ban 2008; Klein 2008). Instead, in keeping with marketing interests, the randomized clinical trial was adopted for the demonstration of efficacy in a diagnostically defined but pharmacologically heterogeneous population. Efficacy is a statistical concept relevant to the population rather than to the individual patient. . Statistically significant efficacy of a drug indicates that the study population as a whole responds differently to a particular substance than to an inactive placebo with an arbitrarily defined statistical probability to qualify for a significant difference (Ban 1964, 2006; Hamilton 1961). It implies that there is a treatment responsive sub-population in the diagnostic group, but it does not identify the treatment responsive subpopulation (Ban 2006).
Introduction of the first neuroleptics, in the mid-1950s, coincided with the publication of Karl Leonhard’s monograph on the Classification of Endogenous Psychoses (Ban 2006; Leonhard 1957). In Leonhard’s classification, schizophrenia was split into two major classes of disease, referred to as “systematic schizophrenia” and “unsystenmatic schizophrenia”, with several forms and sub-forms in which moderate to marked responsiveness to neuroleptics varied from less than 1 in 4 patients in the “systematic hebephrenias”, to more than 4 in 5 patients in “affect-laden paraphrenia”, one of the three forms of “unsystematic schizophrenia” (Astrup 1859; Fish 1964). The differences in responsiveness were not restricted to therapeutic effects but were present also in susceptibility to adverse effects (Ban 1990). Findings of an international survey carried out in the 1980s showed that the prevalence of tardive dyskinesia was over 20% in the treatment refractory subpopulation in Leonhard’s classification, and below 5% in the treatment responsive one (Guy, Ban and Wilson 1985, 1986). Adoption of Leonhard’s classification of “schizophrenias” would have been in-keeping with educational needs by providing at least orientation points for prescribing neuroleptics more discriminately in patients with schizophrenia. It would have also provided neuropsychopharmacological research a pharmacologically sufficiently homogeneous population to study the mode of action of neuroleptics in order to get information about the biochemical underpinning of “affect-laden paraphrenia”. Again, this did not happen. Instead, a dopamine hypothesis of “schizophrenia” and not of “affect-laden paraphrenia” was formulated; and a series of new “haloperidol type” of potent dopamine receptor blocker neuroleptics gradually replaced generic “chlorpromazine-type of neuroleptics” in the entire schizophrenic population, including the subpopulation in which in Fish’s study, they had virtually no beneficial effect (Carlsson and Lindqvist 1963; Snyder 1975; Van Rossum 1966). Since “haloperidol–type of neuroleptics” have stronger affinity to dopamine than to serotonin receptors, whereas “chlorpromazine type of neuroleptics” have stronger affinity to serotonin than to dopamine receptors, it led to severe extrapyramidal signs in many patients with a high prevalence of tardive dyskinesia (Gyermek 1955; Gyermek, Lázár and Csák 1956; Lambert et al. 1959). Then, to undo the harm, prescription practices were reversed, and again, in keeping with marketing interests, a series of new “clozapine-type of neuroleptics”, which similar to chlorpromazine-type of neuroleptics have stronger affinity to serotonin than to dopamine receptors, gradually replaced generic haloperidol-type of neuroleptics in the entire schizophrenic population including the subpopulation in which more than 4 in 5 patients responded to them (Ban 2004; Ban and Ucha Udabe 2006; Meltzer, Matsubara and Lee 1989). The net result was a shift from neurological to metabolic side effects. Both shifts, the shift from “chlorpromazine-type of neuroleptics” to “haloperidol-type of neuroleptcs“, and from “haloperidol-type of neuroleptics” to “clozapine-type of neuroleptics”, were led by academics. A full circle was closed, half a century passed without a single clinically more effective or selective neuroleptic than chlorpromazine for the treatment of schizophrenia.
The story of antidepressants in the treatment of depression is similar to the story of neuroleptics in the treatment of schizophrenia (Ban 1974, 2001, 2004).
At the time of its introduction, imipramine was found to be powerfully effective in 1 of 3 patients with endogenous depression, an umbrella diagnosis that no longer exists (Ban 1974; Klerman and Cole 1965). Endogenous depression included syndromes, which arose, assumedly from a primary pathology of mood, which, in typical cases, shared common characteristics of sudden onset, episodic course and full remission between episodes (Ban 2000, 2002; Kraepelin 1896; Leonhard 1957; Schneider 1920). Patients diagnosed with one or another form of endogenous depression, were clearly distinguishable from each other and from the general population (Ban 1987). Today, these “prototype-based diagnoses” are history; they are swallowed up by broad “consensus-based diagnoses”, like “major depression” in the classification of the American Psychiatric Association, and “depressive episode”, in the classification of the World Health Organization, in which incomplete remission occurs in around one-third of all cases (American Psychiatric Association 1994; Keller et al. 1995; Kessler et al. 1994; Michalak and Lam 2002; World Health Organization 1992). Consensus-based diagnoses cover up prototype-based diagnoses to the extent that even if a severely ill patient displays all the symptoms of “major depression” or “depressive episode,” one still would not know whether the patient qualifies for “vital depression,” the form of depression that Kuhn maintained, allowed him to discover imipramine’s “antidepressant” effect (Ban 2000; Kuhn 1957, 1986).
The problem is further compounded by the drastic increase of the depressive population in epidemiological surveys in the first 20 years after the introduction of imipramine and other antidepressant drugs. These studies indicate that even the lowest prevalence figures of depression are seven to ten times higher in the “antidepressant era”, i.e., after the introduction of the first antidepressants with demonstrated therapeutic efficacy, than before (Hoenig 1980; Silverman 1968). Prescribing antidepressants to this large population, in which even with an optimal 1 to 3 response rate to the pharmacological action of antidepressants, implies that more patients are exposed to potential side effects than one could expect to benefit from these drugs (Ban 2001, 2006, 2008; Szendi 2004). The shift from “prototype–based diagnoses” of depression to “consensus-based” unitary concepts of “depression”, such as “major depression” in the DSM-III and “depressive episode” in the ICD-10, has perpetuated this state of affairs. It has also precluded the possibility for using old prototype based diagnoses for the identification of the treatment responsive subpopulation within “major depression” or “depressive episode”. Yet, the shift was lead by academics.
Clinical development of psychotropic drugs entered a new phase, during the 1980s with the replacement of single-center isolated clinical studies by multi-center, centrally coordinated clinical investigations, designed with power statistics to prevent Type II error, i.e., missing of a statistically significant difference because of insufficient sample size. These studies are conducted in order to meet regulatory requirements for introducing a compound into clinical use. Yet, the findings of this research provide the evidence base for both, marketing and education, thereby confounding, by the dawn of the 21st century, education in pharmacotherapy with the marketing of psychotropic drugs (Ban 2006).
Today, most “evidence-based” information in education about the use of psychotropic drugs is generated in such multi-center studies. Treatment guidelines prepared by opinion leaders and reports reviewing evidence-based information by task forces are no exceptions. By disqualifying papers from the first thirty years of pharmacotherapy on grounds of methodological shortcomings, one relatively current such report on “Antidepressant medications and other treatments of depressive disorders” justified, on the basis of “a review of evidence”, the preferential prescription of the newest and most expensive antidepressants over the old ones (Baghai, Grunze and Sartorius 2007; Ban 2008). .
In the current state of confusion the contrary objective of education to marketing, no longer provides the necessary balance for the optimal use of psychotropic drugs. The blurring of education with marketing has created a situation in which educators in pharmacotherapy may inadvertently pursue activities in conflict with their fiduciary interests. Addressing monetary incentive alone in this confound, an ethical-legal issue, however important it is, distracts attention from the heart of the problem: that until the pharmacological heterogeneity within the diagnostic groups is not resolved pharmacotherapy with psychotropic drugs will inevitably be dominated by marketing interests (Ban 2007).
Insofar as pharmacotherapy with psychotropic drugs is concerned, the pharmacologically heterogeneous diagnoses have restricted the relevance of pharmacodynamic information generated by neuropharmacological research to the side effect profile of psychotropic drugs. And, insofar as neuropsychopharmacology is concerned, the lack of pharmacologically valid psychiatric diagnoses has deprived neuropharmacological research from clinical feedback to the extent that no clinically more selective or effective pharmacological treatment has developed since the introduction of the first set of therapeutically effective psychotropic drugs in the 1950s.
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Thomas A. Ban
December 26, 2013