Controversies in Management: New or old antidepressants? New is better
BMJ 1994; 309 doi: https://doi.org/10.1136/bmj.309.6964.1280 (Published 12 November 1994) Cite this as: BMJ 1994;309:1280
To justify a claim that a new drug is much better than old and well tried formulations it is necessary to show greater effectiveness, fewer side effects, or significantly reduced costs to the purchaser. There is no evidence that the “new” antidepressants, such as lofepramine and the selective serotonin reuptake inhibitors, are any more effective than older treatments, but they are certainly equally effective.1,2 Some of the new antidepressants have already been in use for several years and acquired a sound track record in general clinical experience. Though further prospective trials are needed in severe and chronic forms of depression,3 experimental evidence for tricyclic antidepressants in these conditions is similarly limited.
Benefits of new drugs
The advantages of the new treatments are that they have fewer unpleasant side effects.4 Because of the absence of antimuscarinic effects, most of the new antidepressants have few of the troublesome effects of dry mouth, constipation, blurred vision, and tachycardia, and sedation is less of a problem because new treatments cause little blockade of histamine receptors. Less ataxia and incoordination in elderly people reduce the risk of falls, and postural hypotension is uncommon because of the absence of (alpha)1 receptor blockade. Weight gain and carbohydrate craving, a serious concern of many patients, are much reduced. These side effects are always unpleasant for patients, sometimes distressing, and occasionally fatal.
Tricyclic antidepressants are a well recognised cause of cardiotoxicity and death in overdose. The selective serotonin reuptake inhibitors and other new antidepressants have weaker membrane stabilising properties at high doses and are thus much safer in patients with cardiac disease and those at risk of overdoses, which includes almost all depressed patients. Safer drugs offer incalculable benefits in terms of the human cost of suicide.
The main drawback of safer antidepressants is the higher incidence of nausea and gastrointestinal side effects. These complaints are often relatively mild, however, and tend to lessen with continued use. Data suggesting that fluoxetine increases violent and suicidal thoughts or that selective serotonin reuptake inhibitors are more likely to precipitate mania are not convincing.5
Compliance with treatment
The benefits of the newer antidepressants in terms of side effects are evident to all but those still clinging to the dubious view that “if it isn't hurting it isn't working.” The critical issue, however, is whether they actually affect the way patients comply with treatment. Between 0 and 14% of patients taking placebo drop out of clinical trials because of emerging side effects (median 5%) compared with 7-23% (median 15%) taking selective serotonin reuptake inhibitors and 7-44% (median 21%) taking tricyclics.4 An increased rate of compliance of around 6% seems modest but represents recovery in around 4-5% of depressed patients (assuming a partial response rate) who would otherwise fall out of treatment.
In addition, drop out rates for patients who have been recruited to clinical trials on the basis that they will take part in placebo controlled treatment conditions may not represent the rate among ordinary general practice attenders. People who are not on the conveyor belt of a clinical trial are likely to be much more sceptical about their drugs and more sensitive to side effects and therefore more likely to drop out. If less toxic treatments are prescribed first appreciable inroads could be made into the 30% of patients who probably do not comply with treatment at all6 and the 25% of patients placed on inadequate doses by doctors worried about side effects.7
Because many modern antidepressants, especially the selective serotonin reuptake inhibitors, can be given in a one tablet daily dose without the need for increments, treatment is straightforward and easy to follow. This further increases the potential for compliance and fewer patients are given subtherapeutic doses. Few reliable data are available for rates of compliance with either new or old antidepressants in the maintenance treatment of depression (often required for up to 12 months and longer). But giving such patients drugs with fewer side effects especially less sedation means that they can return to work and resume driving.
There is growing concern about road safety and the use of psychotropic drugs. In the United Kingdom recent draft guidelines from the medical advisory branch of the Driver and Vehicle Licensing Agency suggest that drivers suffering from “serious psychoneurotic episodes” (including depression) affecting or likely to affect driving should be advised not to drive and notified to the agency. All patients must be warned about the possible effects of drugs on fitness to drive. People who drive in the course of their work should stop driving until symptom free and “off all psychotropic medication.” Concern also exists about the sedative effects of older tricyclic antidepressants and fitness to drive, even where they are prescribed for less serious psychoneurotic episodes. Though considerable caution is required in translating experimental data, such as choice reaction times, into estimates of risk for car accidents, the impairment produced by tricyclic antidepressants is greater than that produced by blood alcohol concentration over 80 mg/100 ml (the legal limit in Britain).8 Lofepramine, although a tricyclic antidepressant, does not possess the same degree of sedative effect, and neither do selective serotonin reuptake inhibitors and reversible monoamine oxidase inhibitors. In addition, most of the newer antidepressants do not augment the sedative effects of alcohol, further reducing the risk of road traffic accidents.
Cost issues
At first glance the newer antidepressants lose out on costs. A 20-30 times higher price seems hard to justify if new treatments differ only in terms of side effects and better compliance. Is it worth saving one life through the prescription of non-toxic drugs if the overall increase in costs averages at several hundreds of thousands of pounds? More lives might be saved for the same outlay on, for example, kidney transplantation or health education. Costs are therefore central to the debate about new versus old.
On closer scrutiny the cost advantages of the cheap tricyclic antidepressants may be more apparent than real. Firstly, the cost differentials, although wide, are starting to narrow. Secondly, the costs of treatment abandoned because of unwanted side effects of tricyclic antidepressants, failure of recovery, and the increased risks of suicide must be taken into account. Thirdly, the side effects of tricyclic antidepressants could result in extra expenditure on treatment for dental decay, hip fractures, and trauma from road traffic accidents. A simulated costing analysis based on data available from clinical trials estimated that when the cost of drop outs and poor compliance are taken into account, the selective serotonin reuptake inhibitors are no more expensive than tricyclics, despite the higher initial prescription costs.9
Of course, an old friend such as amitriptyline is not yet ready to be pensioned off completely. Not all patients respond to their first antidepressant treatment and certain depressed patients may require a broader spectrum of synaptic blockade than that offered by the selective serotonin reuptake inhibitors. Tricyclics will continue to form an important part of doctors' armoury. But for the first line treatment of patients seen everyday in surgeries and psychiatric clinics, new is better.