Why maximum tolerated dose?

A long-established approach to the pharmacological treatment of disease has been to start low and go slow. However, clinicians often prescribe up to maximum tolerated dose (MTD), especially when treating acute and more severe disease, without evidence to show that MTD is more likely to improve outcomes. Cardiovascular guidelines for some indications advocate MTD even in prevention, for example hypercholesterolaemia, without compelling evidence of better outcomes. This review explores the origins and potential problems of prescribing medications at MTD. Oral effective dose 50 (ED50) may be a useful guide for balancing efficacy and safety.

Efficacy and toxicity of antihypertensive pharmacotherapy relative to effective dose 50.

Antihypertensive drugs have usually been approved at doses near the top of their respective dose-response curves. Efficacy plateaus but adverse drug reactions (ADRs), such as falls, cerebral or renal ischaemia, increase as dose is increased, especially in older patients with comorbidities. ADRs reduce adherence and may be difficult to ascertain reliably. Higher doses have generally not been shown to reduce total mortality, which provides a summary of efficacy and safety. Weight loss and other lifestyle measures are essential and may be sufficient treatment in many young and low risk patients. Most antihypertensive drug lower systolic blood pressure by around 10 mmHg, which reduces stroke and heart failure by about a quarter. Clinical trials have not been designed to demonstrate specific blood pressure treatment thresholds and targets, which are mostly extrapolated from epidemiology. Mean population oral effective dose 50 may be the most appropriate dose at which to commence antihypertensive drugs. The dose can then be titrated up if greater efficacy is demonstrated, or lowered if ADRs develop. Lower dose combination therapy may best balance benefit and harms with fewer ADRs and additive, potentially synergistic, efficacy.

The pharmacodynamic and clinical trial evidence for statin dose.

Statin doses around estimated effective dose 50 (ED50) can reduce myocardial infarction by over 25% and mortality by around 10%. Being a competitive enzyme inhibitor, statin efficacy plateaus at doses that are multiples above the ED50, whilst on- and off-target adverse events increase in number and severity with increasing dose. For example, myopathy has been shown to increase by up to 29-fold and liver dysfunction by up to nine-fold as statin dose is increased. Doses of up to 40-fold ED50 have been promoted, but above five-fold ED50, for example 10 mg of atorvastatin, there is no randomized controlled clinical trial evidence that coronary mortality is lowered, or that survival is increased.

Cholesterol trials and mortality.

An overview of clinical trials can reveal a class effect on mortality that is not apparent from individual trials. Most large trials of lipid pharmacotherapy are not powered to detect differences in mortality and instead assess efficacy with composite cardiovascular endpoints. We illustrate the importance of all-cause mortality data by comparing survival in three different sets of the larger controlled lipid trials that underpin meta-analyses. These trials are for fibrates and statins. Fibrate treatment in five of the six main trials was associated with a decrease in survival, one fibrate trial showed a non-significant reduction in mortality that can be explained by a different target population. In secondary prevention, statin treatment increased survival in all five of the main trials, absolute mean increase ranged from 0.43% to 3.33%, the median change was 1.75%, which occurred in the largest trial. In primary prevention, statin treatment increased survival in six of the seven main trials, absolute mean change in survival ranged from -0.09% to 0.89%, median 0.49%. Composite safety endpoints are rare in these trials. The failure to address composite safety endpoints in most lipid trials precludes a balanced summary of risk-benefit when a composite has been used for efficacy. Class effects on survival provide informative summaries of the risk-benefit of lipid pharmacotherapy. We consider that the presentation of key mortality/survival data adds to existing meta-analyses to aid personal treatment decisions.

ß-adrenoceptor blockers valuable but higher doses not necessary.

ß-adrenoceptor blockers have an important role in the treatment of heart disease and are useful as an adjunct in systemic hypertension. They are often prescribed at unnecessarily high doses, near the top of the dose-response curve. Higher doses are associated with more adverse events, have not been shown to improve clinical outcomes in cardiac failure and may worsen outcome in hypertension. ß-adrenoceptor blockers can be very effective in lower doses, guided by close monitoring of heart rate and blood pressure and, when used in combination with low dose vasodilators and diuretics, give a better risk benefit profile.

Circadian rhythms: keeping pace with developments.

How far has our understanding of chronobiology come in the past 40 years?

Low drug doses may improve outcomes in chronic disease.

The relationship between drug dose and clinical outcome has not been established for many medications used to treat chronic disease. Evidence is emerging that chronic diseases can be treated effectively with low doses. Adverse drug reactions account for significant morbidity and mortality and are generally dose related. Optimal drug dose - the best balance of benefit and risk - varies between individuals and may change over time. When treating chronic disease it is important to establish and maintain the optimal dose for each patient by close clinical monitoring.

Reliability of circadian heart pattern analysis in psychiatry.

The assessment of circadian heart patterns represents a new methodology for documenting physiological dysregulation associated with psychiatric illness. Previous research has demonstrated abnormal heart rate patterns, especially during the bedtime interval, that are associated with depression, generalized anxiety disorder, panic disorder, and schizophrenia. These patterns are derived from heart rate data obtained while wearing an unobtrusive, two-lead heart rate monitor over a 24-hour period. To establish basic reliability, the second author blindly rated heart-monitored data from 50 subjects on two occasions, separated by an average of 6.6 weeks (range = 2.9-15.7 weeks). Subjects were classified as "definitely psychiatric," "probably psychiatric," "borderline," "broadly normal," and "signature normal." The exact category agreement rate was 78%. If a one-category difference is permitted (e.g., "definitely psychiatric" and "probably psychiatric" counted as an agreement), the agreement rate was 92%. Circadian heart pattern analysis is a promising new technology in psychiatric research and warrants further investigation.