Causality, drug-effect

Sudden death has occurred in patients with preexisting heart disease on antidepressant therapy. It may be difficult, however, to separate a causally related drug effect from a cardiovascular incident precipitated by other factors and only by chance coincident with drug therapy. Furthermore, Roose ( 418), who has summarized the literature, noted that major depressive disorder occurs frequently after a myocardial infarct and may adversely affect the recovery process. 

On September 12, 1989, Anello reported within the FDA on Triazolam and Temazepam—Comparison Reporting Rates. He found that adverse drug reactions were reported 11 times more frequently with triazolam than with temazepam. The relative reporting rate was 46 to 1 for amnesia, 9 to 1 for agitation, anxiety and nervousness, 16 to 1 for psychosis ( psychosis, hallucinations, paranoid reaction, and acute brain syndrome ), and 19 to 1 for hostility and intentional injury. Anello s (1989) analysis indicated that there were no convincing explanations for these differences other than actual drug effects, but he did not make a formal determination of causality. However, in a handwritten analysis attached to the document, obtained through the Freedom of Information Act, there is a summary titled Other Evidence in Favor of Effect of Triazolam, which I quote in full ... 

The nodules can appear at any time during treatment, with or without concomitant cutaneous vasculitis, and are usually found in patients with erosive disease and a high titer of rheumatoid factor. This has raised the question as to whether they are a reason to modify treatment, and whether they are rheumatic or represent a true adverse effect of methotrexate certainly, methotrexate-associated nodulosis is very similar to idiopathic rheumatoid arthritis nodulosis and sometimes disappears despite continuation of methotrexate. However, prompt regression on methotrexate withdrawal and recurrence on rechallenge in several patients strongly argue for a causal drug-related effect. 

Not all associations represent a cause-effect relationship. Because most epidemiologic studies of drug effects do not employ random allocation, it is important to determine if a legitimate cause-effect relationship exists. A central methodologic concern in observational studies is confounding—i.e., the possibility that the apparent effect of an exposure or intervention is due wholly or partly to other factors associated with it that have their own impact on the outcome of interest. Criteria have been proposed to help determine if an association is causal. The fewer criteria that are met, the less likely it is that an association is causal. Table 9-3 is adapted from the work of Hill and Stolly. Practitioners should ask the series of questions listed in the table to interpret findings from studies to determine if an association is likely to be causal. 

Temporal Relationships of Adverse Events. The temporal relationship between duration of product exposure and development of an adverse event is important in assessing causality. But how can data on temporal relationships be systematically summarized in a database containing thousands or even hundreds of thousands of subjects Temporal relationships cannot be clearly elicited if only frequencies of adverse events between treatment and control groups are compared. There can be many disparities in the subjects time of exposure or time at risk. Toxic manifestations of drugs may not occur until several months or even years after the initial exposure to the drug. How do we systematically assess delayed toxicity of a previously prescribed drug from the effect of a newly prescribed drug Such a scenario occurred with reported cases of pancreatitis associated with valproic acid therapy, in which some cases appeared several years after therapy [2]. 

The primary limiting effect of reserpine is depression. Depletion of central monoamines is believed to be the mechanism for this effect (Heninger et al. 1996 Charney 1998). The depression may occur in a gradual and insidious manner, and the causal association between the drug and depression may be missed (Oates 1996). Rauwolfia alkaloids are contraindicated in anyone with a history of depression, and careful vigilance is required to ensure that they do not induce depression in otherwise normal individuals. Additional side effects are sedation and difficulty with concentration and performing complex mental tasks. 

Mesolimbic dopamine pathways are thought to be involved in the rewarding effects of drugs of abuse and an imbalance of this pathway is thought to be causal in psychoses. Several studies have revealed that 5-HT3 receptor antagonists can correct such imbalances. Thus, ondansetron inhibits the behavioural hyperactivity resulting from direct stimulation of this... 

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