Divergence and convergence of commercial and scientific priorities in drug development: The case of Zelmid, the first SSRI antidepressant.

Based on a realist conceptualization of interests, this paper explores how commercial and scientific priorities appear to have converged and diverged during the development of the antidepressant Zelmid. The drug represents the first of the selective serotonin reuptake inhibitors (SSRIs) to reach the market. Zelmid was synthesized in 1971 and launched by the Swedish firm Astra in 1982, but subsequently withdrawn the next year because of adverse neurological effects. This paper draws on in-depth interviews with scientists representing both industry and academia who had high-level involvement in various phases of the project (experimental, pre-clinical and clinical), as well as on textual sources such as scientific articles and memoirs. Zelmid was a product of mechanism-based or "rational" drug discovery from the early 1960s and the associated intermingling of science and commerce. It is argued that both scientists and the pharmaceutical company shared an interest in embracing mechanism-based drug discovery because it simultaneously promised medico-scientific advances and profits. However, the intermingling of science and commerce also strained the relationship between scientific and commercial priorities further along the trajectory of the drug; for example, concerning issues such as dosage strategy and drug use in primary care, where corporate management allegedly took decisions contrary to the recommendations of both academic and company scientists. On such occasions the asymmetry in power became apparent in scientists' narratives: commercial considerations trumped those of science since, ultimately, decisions rest with management, not with scientists. In addition, temporality appears to be associated with the divergence of commercial and scientific priorities. While rare during experimental and pre-clinical phases, divergence was concentrated downstream to the clinical testing and post-marketing phases. It is hypothesized that a similar pattern of convergence and divergence of commercial and scientific priorities may exist in the trajectory of other drugs.

A controlled study of a serotonin reuptake blocker, zimelidine, in the treatment of chronic pain.

Zimelidine inhibits the central neuronal reuptake of serotonin and has undergone clinical evaluation as an antidepressant. Twenty patients with chronic pain of non-malignant origin (mean duration 15.8 years) were entered into a double blind cross-over study of the analgesic efficacy of zimelidine and placebo. The duration of each treatment phase was 6 weeks and there was a comprehensive assessment of each patient prior to the commencement and at the completion of the study, during a brief period of hospitalisation. Zimelidine was superior (P less than 0.05) to placebo with respect to pain relief based on a global assessment (by the clinical investigators) performed at the completion of each treatment phase. However, there was no significant difference in analgesic efficacy between the zimelidine and placebo treatment phases based on the following criteria: (a) changes in the minimum effective blood concentration of pethidine necessary to provide pain relief in each patient, measured during a pethidine infusion of 1.67 mg/min for 60 min; (b) changes in pain scores estimated by patients using the visual analogue pain scale (VAPS); (c) changes in patients' estimates of pain intensity associated with various daily activities. Significant pain relief was apparent within 2-3 days in those patients who had a beneficial effect, which contrasts with the documented 3-4 weeks for maximal antidepressant effects. The results of this study suggest that serotonin reuptake blockers do not provide consistent pain relief in patients with chronic pain, but may contribute an analgesic effect in the treatment of some patients.

The side effect profile and safety of fluoxetine.

The side effect profile and safety of fluoxetine are reviewed. Side effects reported more frequently with fluoxetine than with tricyclic antidepressants are nausea, nervousness, and insomnia. Anticholinergic side effects are reported less often with fluoxetine. Analysis of adverse experiences leading to discontinuations suggests that this drug has very few serious side effects. There is no evidence that fluoxetine produces a flu-like syndrome or neuropathy similar to that seen with zimelidine. It does not appear to cause phospholipidosis in humans. Fluoxetine appears to have no epileptogenic potential except at extremely high doses. It is usually well tolerated in overdoses.

Clinical overview of serotonin reuptake inhibitors.

The clinical pharmacology, adverse event profiles, and clinical efficacy of several serotonin reuptake inhibitors are summarized and compared with those of the classic tricyclic antidepressants. Serotonin reuptake inhibitors discussed are sertraline, zimelidine, fluoxetine, fluvoxamine, and paroxetine. While they do not differ from tricyclics in efficacy or onset of action, the serotonin reuptake inhibitors clearly have a different side effect potential. Unlike tricyclics, serotonin reuptake inhibitors provide effective antidepressant activity without sedating, anticholinergic, or cardiotoxic reactions. In comparison, tricyclics lower the seizure threshold, have anticholinergic and hypotensive effects, affect cardiac conduction, are dangerous in overdose, and may cause weight gain. The primary adverse events associated with serotonin reuptake inhibitors involve the gastrointestinal system, although side effects may be less frequent at lower dosage levels. It is important to choose antidepressant therapy on the basis of a patient's ability to tolerate the specific adverse reactions that may occur with a given agent. Although serotonin reuptake inhibitors have not replaced the tricyclics, they are a useful addition to the variety of drugs currently used for the treatment of depression.

The new generation antidepressants: promising innovations or disappointments?

"New generation" antidepressants are generally considered to include all agents introduced in recent years which are neither tricyclic in structure nor monoamine oxidase inhibitors. They include the tetracyclics (mianserin and maprotiline), the bicyclic serotonergic compounds (fluoxetine and citalopram), and the unicyclics (bupropion), as well as the triazolobenzodiazepine derivatives (alprazolam), the triazolopyridines (trazodone) and the tetrahydroisoquinolines (nomifensine). Methodologic and economic considerations have hampered attempts to develop agents with significantly greater specificity or safety than traditional agents. Traditional agents, while lacking specificity, do have extensive records of efficacy and long-term safety and are usually less expensive than new agents. Patients not responding to traditional agents often have medical or characterologic problems that exclude them from participating in controlled studies of new agents. These problems are discussed and potential approaches to the development of new agents are presented.

Double blind study comparing the efficacy of zimelidine and amitriptyline in endogenous depression.

Thirty-nine (39) patients entered a double blind study conducted to compare the therapeutic efficacy and safety of Zimelidine and amitriptyline in endogenous depression. Following a 3-5 day washout period, patients were randomly allocated to Zimelidine or amitriptyline for 6 weeks period and were assessed regularly. 63% of Zimelidine and 65% of amitriptyline patients showed significant clinical improvement. Side effects recorded with amitriptyline were predominantly anticholinergic and headaches with Zimelidine. It is concluded that while Zimelidine and amitriptyline show equally efficacous antidepressant properties, zimelidine may offer a slight therapeutic advantage due to lack of anticholinergic side-effects.

Second-generation antidepressants.

The host of newly developed antidepressant drugs offer important clinical advantages to some patients, although their promises of improved therapeutic efficacy and reduced adverse effects compared with conventional treatments are not fully realized. Increased biochemical specificity and unique mechanistic or clinical profiles render these compounds valuable in research into the pathophysiology of affective disorders and mode of action of antidepressant agents.

Six-month open trial with Zimelidine in alcohol-dependent patients: reduction in days of alcohol intake.

In an open study, 14 alcohol-dependent male patients were treated with the selective serotonin reuptake inhibitor (SSRI) Zimelidine, 200 mg daily, for six months. They were given psychosocial therapy before and during the study. The number of days of alcohol intake was statistically significantly reduced from a mean of 14 days per month before to 1-5 days during drug treatment. No effect was observed on the amount of daily alcohol intake on drinking days. No tolerance to the effect of Zimelidine was observed during the study. The findings suggest an effect of combined psychosocial support with SSRI treatment that seems to be of clinical significance.

Treatment of bipolar affective illness with zimeldine, a 5-HT uptake inhibitor.

A small group of patients who had been successfully treated with lithium for a number of years were treated with zimeldine in order to determine whether this antidepressant could be substituted for lithium in patients with a bipolar affective illness. The proposed treatment period of 6 months was not reached by any patient due to depression, hypomania, mania or unusual adverse symptoms. The results of this pilot study suggest that bipolar patients being treated with lithium should not then be treated by antidepressants including those which are potent and selective inhibitors of 5-HT uptake.

Plasma-level response relationships with fluoxetine and zimelidine.

The results of pharmacokinetic studies of two recent 5-HT uptake inhibitors, zimelidine and fluoxetine, have pointed to the inadequacy of open-dose rising studies for establishing the most appropriate dose of new antidepressants. High plasma concentrations of the active metabolites, norzimelidine and norfluoxetine, were associated with a poorer therapeutic response in patients suffering from major depression. High drug plasma concentrations are also associated with increased side effects. Large fixed-dose placebo controlled studies with fluoxetine have confirmed the findings of the small pharmacokinetic study that lower doses are more effective. Fixed-dose pharmacokinetic studies are recommended as part of the program to establish the best dose of new antidepressants.

The effect of zimelidine, a serotonin-reuptake blocker, on cataplexy and daytime sleepiness of narcoleptic patients.

Narcolepsy is a neurological syndrome characterized by two major symptoms: excessive daytime sleepiness and cataplexy. Pharmacological and biochemical evidence support the hypothesis that dopaminergic mechanisms are involved in excessive daytime sleepiness. The pathophysiology of cataplexy and the action mechanisms of anticataplectic agents remain controversial issues. Cataplexy is usually controlled by tricyclic antidepressants, but these drugs interact with several central monoamine systems and also exert an anticholinergic effect. In the present study, zimelidine, a selective serotonin reuptake inhibitor without anticholinergic activity, was administered to 11 narcoleptic patients for 1-16 months. Cataplexy improved markedly in all patients, while no changes could be documented on excessive daytime sleepiness, either by self-report or polysomnographic nap recording. These results confirm the hypothesis that hypersomnolence and cataplexy are subject to different control mechanisms; support a serotoninergic, but not a cholinergic, theory of cataplexy; and suggest that selective serotonin reuptake inhibitors may be the treatment of choice for cataplexy.

The specificity of the zimelidine reaction.

The first of a series of 5HT reuptake inhibitors, zimelidine was withdrawn because of associated hypersensitivity reactions. There was concern that such reactions might be seen with other compounds of this class. Two depressed patients who had a sensitivity reaction to treatment with zimelidine were crossed over to treatment with fluoxetine and no abnormalities were observed. Both patients remained well during uneventful long term treatment with fluoxetine.

Effect of zimeldine and its metabolites on [3H]thymidine incorporation in lymphocyte cultures from psychiatric patients with or without a hypersensitivity reaction during zimeldine therapy.

Lymphocyte transformation test (LTT) was applied to 28 patients who had developed a hypersensitivity syndrome (HSS) during treatment with the antidepressant drug zimeldine. Twenty-seven patients treated with zimeldine without any symptom of an HSS were matched controls. Zimeldine and its metabolites norzimeldine and CPP 200 all induced statistically significant increased [3H]thymidine incorporation in cultured lymphocytes from the HSS patients compared with the controls, norzimeldine being the most potent inducer. The results indicate an immunoreactive process in the development of the HSS induced by zimeldine.

Adverse experiences during treatment with zimeldine on special licence in Sweden.

Adverse experiences during licensed treatment with the antidepressant serotonin (5-HT) reuptake inhibitor zimeldine in Sweden are presented. Data were obtained from a written inquiry of 694 patients and 67 reports to the Medical Products Agency. The spectrum of adverse symptoms was in agreement with those reported in previous studies on zimeldine. The most frequent adverse experiences were headache, nausea, myalgia, signs of liver function disturbance, arthralgia, neurological symptoms, fever and insomnia. No new case of the Guillain-Barré syndrome was found. The estimated frequency of the zimeldine-induced hypersensitivity syndrome (HSS), comprising fever, myalgia and/or arthralgia and signs of liver function disturbance, ranged from 1.4% to 13% in the inquiry and from 0.63% to 3.4% in the report part of the study. Adverse experiences usually had a considerably higher incidence during the first 6 weeks of zimeldine treatment than thereafter. This is in agreement with the clinical experience that most of the adverse reactions occur early during zimeldine treatment. However, a number of adverse experiences did occur with a later onset. This may justify a prolongation of the compulsory 4 weeks' testing of liver function that is required during licensed treatment. There were significantly fewer patients who developed fever among the patients who had experienced previous zimeldine treatment than among those who had not. Otherwise there was no statistically significant difference in frequency of adverse symptoms between these two groups. Consequently zimeldine treatment per se does not seem to predispose to development of an HSS or other types of adverse reactions during subsequent therapy.

Antidepressant-induced weight gain: a comparison study of four medications.

Body weight change was monitored in 73 hospitalized depressed patients treated with one of four antidepressants for 1 month. After a 2-week medication-free period, patients were randomly assigned to treatment with amitriptyline, nortriptyline, desipramine, or zimelidine. By the end of 1 month, treatment with all three tricyclic compounds promoted weight gain, with the greatest increase observed during amitriptyline treatment; less weight was gained by patients treated with nortriptyline and desipramine. In contrast, most patients treated with zimelidine showed no weight gain and, in many cases, demonstrated weight loss. Weight change during treatment was not associated with age, sex, severity of depression, obesity, weight loss during depression, or clinical response.

Treatment of toxic epidermal necrolysis and a review of six cases.

Six cases of drug-induced toxic epidermal necrolysis treated in a burns unit are presented. The mean skin loss was 67.3 per cent of the total body surface area. Two patients developed renal failure and two had ocular symptoms. The mortality rate was 50 per cent, with two patients dying from septicaemia and one from respiratory and renal failure. The diagnosis of toxic epidermal necrolysis can be confirmed by skin biopsy. We recommend that this disease is treated in a burns unit so that both adequate wound care and essential intensive supportive treatment can be given. Antibiotics are indicated only for specific infections such as septicaemia or pneumonia. Steroids have been shown to increase greatly the mortality from septic complications and are not recommended. The mortality ranges from 10 per cent to 70 per cent and bad prognostic factors include increasing age, greater than 50 per cent of body surface skin loss and neutropenia.

Adverse reactions in connection with zimeldine treatment--a review.

The results of clinical trials have shown that the general level of side-effects is substantially lower with zimeldine than with tricyclic antidepressants. Data from ordinary clinical usage in Sweden and the U.K. (as opposed to clinical research experience) shows a similar picture. Hypersensitivity reactions, characterized by fever, myalgia and/or arthralgia, and transient increases in transaminases, occur in approximately 1.5% of patients. In rare cases potentially serious neuropathies have been reported.