Why Are SSRIs better than tricyclics

Although depression is the most common and costly mental health problem managed in primary care, treatment recommendations are based predominantly on studies of patients in subspecialty centers. Research indicates that primary care patients with major depression may have a different disease etiology and progression. This has led to concern about the relevance of current recommendations, particularly those based on drug efficacy. MacGillivray and colleagues reviewed the evidence for efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) and tricyclic anti-depressants in the treatment of depression in patients managed in primary care.

The authors searched the Cochrane Collaboration database, reviewed reference lists of previously identified studies, and contacted experts to identify all studies comparing SSRIs with tricyclic antidepressants in adult primary care patients with depression. The primary outcomes were differences in depression scores and the proportion of patients who responded to treatment. Secondary outcomes were the total number of patients who withdrew from treatment and the number who withdrew because of side effects.

The authors identified 284 studies, of which only 11, involving a total of 2,954 patients, met criteria for inclusion in the review. Study participants were predominantly white Europeans averaging 40 to 45 years of age. About three fourths of the participants were women. The studies varied considerably in quality, and four failed to meet minimum criteria on at least one key methodologic component. All of the studies had some form of commercial sponsorship.

Only six studies met criteria for inclusion in the efficacy analysis based on changes in depression scores. Of these studies, only three reported data in an unambiguous format. Overall, the two classes of antidepressants did not differ significantly in efficacy. The slightly better performance of tricyclics that emerged when all six studies were analyzed disappeared when only the three unambiguous studies were analyzed. Three studies (totaling 740 patients) that reported clinical global impression as the measure of improvement also failed to show a statistically significant difference between the two classes of antidepressants.

Assessment of tolerability was based on six studies (2,375 patients). A significantly lower proportion of patients withdrew from treatment with an SSRI (20.7 percent) than from treatment with a tricyclic antidepressant (27.9 percent). The relative risk of withdrawal was calculated as 0.78 in favor of SSRIs. Seven studies provided data specifically on withdrawal because of adverse events. A significantly lower proportion of patients withdrew because of adverse events during treatment with SSRIs (11.6 percent) than with tricyclics (17 percent).

The authors emphasize that although only limited high-quality data are currently available, SSRIs and tricyclics appear to be comparable in short-term efficacy in primary care, but SSRIs appear to be better tolerated by patients. The authors call for much more high-quality research on the management of depression in primary care.

Although antidepressants have similar efficacy in clinical trials, this will only be realised in clinical practice if patients take a therapeutic dose. Studies in primary care consistently show that patients are more likely to be prescribed a recommended therapeutic dose of an SSRI than a TCA. This difference remains when allowance is made for the fact that the elderly often respond to doses of TCAs below those recommended in

younger adults.

The authors highlight the greater toxicity of TCAs in overdose. Another aspect of safety that deserves consideration is side-effects. The elderly are particularly prone to develop these due to concurrent illness, drug interactions and changes of normal ageing. Compared to newer agents the TCAs have more potential to cause serious side effects due to their non-selective action; alpha-1 blockade can cause postural hypotension leading to falls and fractures; muscarinic blockade can cause urinary retention, impaired cognitive functioning and delirium; the membrane stabilising effect can cause cardiac arrhythmias. A record linkage study showed a significantly increased risk of admission with acute urinary retention among those prescribed TCAs versus SSRIs4. The number of contraindications to and cautions against use is greater for TCAs than

SSRIs.

A recent review5 concluded that newer antidepressants were preferred in the elderly though previous antidepressant response may modify this recommendation. Data is strongest for the SSRIs. TCAs are useful second line agents but those with high antimuscarinic activity are best avoided. Irrespective of the antidepressant chosen it is important when treating elderly patients to start with a low dose, increase gradually and monitor

for side effects.

Peter Haddad Consultant psychiatrist Moorside Unit Trafford General Hospital, Moorside Road, Davyhulme,

Manchester M41 5SL

Competing interests: The author has received lecture fees and conference expenses from the manufacturers of several antidepressants

including SSRIs.

1 Livingston, MG & Livingston, HM. New antidepressants for old
people? BMJ 1999; 318: 1640-1.

2 Anderson, IM & Tomenson, BM. Treatment discontinuation with selective serotonin re-uptake inhibitors compared with tricyclic

antidepressants: a meta-analysis. BMJ 1995: 310: 1433-1438.

3 Martin, RM, Hilton, SR, Kerry, SM, Richards, NM. General practitioners' perceptions of the tolerability of antidepressant drugs: a comparison of selective serotonin reuptake inhibitors and tricyclic

antidepressants. BMJ 1997; 314; 646-651.

4 MacDonald, TM, McMahon, AD, Reid, IC, Fenton, GW, McDevitt, DG. Antidepressant drug use in primary care: a record linkage study in

Tayside, Scotland. BMJ 1996; 313: 860-1.

5 Spigset, O & Martensson, B. Clinical review: Drug treatment of
depression. BMJ 1999; 318: 1188-91.

Competing interests: No competing interests

To compare the efficacy, completion rates, and adverse event rates of selective serotonin reuptake inhibitors (SSRIs) with tricyclic antidepressants (TCAs) in treating depression.

Studies were identified by searching Medline, Embase, PsycINFO, International Pharmaceutical Abstracts, Pascal, Health Planning & Administration, Mental Health Abstracts, PharmacoEconomics & Outcomes News, and Current Contents databases (1980 to May 1996); scanning bibliographies of retrieved articles; hand searching journals; and consulting researchers.

Studies were selected if they were double blind, randomised controlled trials, used antidepressant treatment for 4–12 weeks, and reported numerical or graphical data. Studies were excluded if they reanalysed data from previous studies.

Data were extracted on efficacy, study completion, and adverse events.

162 randomised controlled trials were reviewed. SSRIs and TCAs were equally effective and the study completion rates did not differ. 7 adverse events increased and 3 decreased for SSRIs compared with TCAs (table⇓). There were no differences in palpitations, urinary disturbance, fatigue, tremor, hypotension, {blurred vision, anorexia, and sweating}*.

Selective serotonin reuptake inhibitors (SSRI) v tricyclic antidepressants (TCA)*

Serotonin selective reuptake inhibitors do not differ from tricyclic antidepressants in efficacy or completion rates, but have different adverse events: more nausea, diarrhoea, anxiety, agitation, insomnia, nervousness, and headache, and less dry mouth, constipation, and dizziness.

Choosing whether to use a tricyclic or SSRI as first line treatment of depression remains a controversial problem despite many trials and meta-analyses. This detailed systematic review by the Canadian Coordinating Office for Health Technology Assessment (CCOHTA) examines the issue in more depth than most of its predecessors and reaches conclusions which agree with much (but not all) previous work. What is new is the exploration of dosage of tricyclics and side effects.

There has long been a consensus that tricyclics are only effective in doses >100 mg of amitriptyline or equivalent.1 Despite this consensus, there is considerable evidence that general practitioners treat depression with low dose tricyclics. One strong argument in favour of SSRIs is the relative ease with which therapeutic doses may be attained. However, this review shows that even when standard SSRIs doses are compared with low dose tricyclics there is no difference in efficacy. This is less surprising than it may seem; the evidence that high doses of tricyclics are required is flimsy and based on a handful of small trials.

SSRIs are pharmacologically “cleaner” and therefore, we are often told, have fewer side effects. This is the first systematic review to assess the frequency of side effects and unsurprisingly shows that patients on SSRIs report nausea and anxiety, whereas those on tricyclics complain of constipation and dry mouth. SSRIs were associated with a greater total number of side effects than tricyclics: a finding which may have many interpretations but runs counter to most promotional literature. Which drug is better tolerated? This question is usually answered by using the proxy measure of dropout rates from trials, and this review found similar dropout rates for both treatments except in adult outpatients who were more likely to drop out on tricyclics.

Whereas previous meta-analyses generally agreed with the conclusions of the CCOHTA's first report, their economic modelling will be more contentious. To explore the cost of prescribing SSRIs v tricyclics, the CCOHTA examined 3 treatment protocols: (1) give tricyclics only; (2) give tricyclics first, then give an SSRI if the patient cannot tolerate it; and (3) start with an SSRI and then go onto a tricyclic. Most previous economic analyses based on decision modelling have favoured SSRIs. This report suggests that using tricyclics alone is not cost effective, but starting tricyclics and moving to SSRIs if not tolerated (second option) is more cost effective than the third option.

There is much here to commend. The report used data derived from ran-domised trials wherever possible. The authors presented a more realistic therapeutic alternative to that used in many other economic models in this field. The main problem with the approach is that it is often based on multiple assumptions.2 The authors partially overcame this by presenting a number of sensitivity analyses with different dropout rates and tricyclic doses, and the main findings are reasonably robust. However, they still had to cobble together results of other studies to estimate resource use on either treatment. They also assumed that rates and costs of overdose, suicide, and road traffic accidents are similar on the 2 treatments—outcomes which are always difficult to model, but are probably rarer on SSRIs. Finally, costs are not constant between countries: what applies in one healthcare setting may not in another. Whereas efficacy data are likely to be generalisable, cost effectiveness data are not.

Despite these caveats, these are important and useful reports. SSRIs have undoubted advantages, and as their price falls they may become first line treatment. For the time being, however, tricyclics remain the most cost effective first line treatment for depression.

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