4th May 2011
A systematic review concluded that selective serotonin reuptake inhibitors (SSRIs, e.g. sertraline or citalopram) are probably the antidepressants of first choice in people with depression and chronic physical health problems, given their effect in improving quality of life and their apparent safety in cardiovascular disease.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Healthcare professionals should continue to follow NICE clinical guideline 91 with regard to the treatment of depression in adults with chronic physical health problems. According to the NICE Full Guideline, where antidepressants are indicated, SSRIs should generally be the first-line treatment for depression associated with physical health problems. Of the SSRIs, sertraline and citalopram (available as generics) probably have the lowest interaction potential, appear to be safe and possibly protective of further cardiac events so generally should be the drugs of first choice. Tricyclic antidepressants (TCAs), despite evidence supporting their therapeutic activity, should generally be avoided as there is evidence of cardio-toxicity and poor tolerability.
What is the background to this?
Depression is commonly associated with a wide range of chronic physical health problems. In October 2009, NICE published a clinical guideline covering all aspects of the management of depression in adults with chronic physical health problems (CG91), alongside an updated Clinical Guideline for the Management of Depression (CG 90). As part of the process of developing CG91, a systematic review and meta-analysis (this study) was carried out to evaluate the safety and efficacy of antidepressants in the context of chronic physical conditions.
What does this study claim?
The study included 63 randomised controlled trials (RCTs) (n=5794). Antidepressants of all types appeared to be effective in the context of chronic physical conditions but no particular drug or group was shown to have clear superiority in respect of efficacy or tolerability. The effect sizes calculated for antidepressants (changes in observer- or patient-rated depression rating scores) in physical illness were similar to those seen in depression not associated with physical health problems. SSRIs were found to improve quality of life, whereas there was insufficient information on this outcome for other antidepressants. SSRIs were considered preferable to TCAs, as they may be better tolerated, have been shown to improve quality of life, and may be less likely to be involved in pharmacodynamic interactions. The authors also suggest that “ the use of SSRIs (such as sertraline and citalopram) and mirtazapine is safe post-myocardial infarction (MI) and may confer benefits on cardiac mortality”.
How does this relate to other studies?
The results of this study are broadly consistent with those of a 2010 Cochrane review, which included 51 placebo-controlled studies (n=3603). The Cochrane review found that antidepressants were more effective than placebo in producing a response (odds ratio 2.33, 95% confidence interval [CI] 1.80 to 3.00, P<0.00001, 25 studies, n=1674) after 6–8 weeks. Patients taking an antidepressant were more likely to experience sexual dysfunction and dry mouth, and were more likely to stop taking their medication after 6–8 weeks of treatment. The authors of the Cochrane review considered there were no grounds to recommend one antidepressant over another on the basis of this review. A recent meta-analysis of SSRIs in patients with depression and coronary heart disease, despite a paucity of high-quality evidence, suggested that SSRIs may be safely administered to these patients and might even contribute to improve their cardiovascular prognosis.
Although antidepressants can be poorly tolerated in patients with chronic physical illness, this systematic review and meta-analysis, which was part of the clinical evidence review carried out for NICE CG91, demonstrates that antidepressants can be used safely and effectively in these people. Despite concerns over adverse effects (AEs) and drug interactions, antidepressants should not be withheld unnecessarily in these people.
In developing CG91, NICE recognised that the clinical and economic evidence base for pharmacological interventions for people with depression and chronic physical health problems was more limited than that identified for depression in the absence of chronic physical health problems. However, the broad pattern of evidence was similar. The guideline development group’s view was that the nature of depression in chronic physical health problems was not fundamentally different from depression in the absence of such problems, and it was appropriate to draw on the evidence base for depression more generally in drawing up its recommendations. With regard to choice of antidepressant, consistent with this systematic review, NICE CG91 recommends that:
- When prescribing an antidepressant, take into account:
- the presence of other physical health problems
- side effects (which may impact on the underlying physical disease)
- that there is currently no evidence supporting using specific antidepressants for patients with particular physical health problems.
- Be aware of drug interactions and:
- refer to appendix 1 of the British National Formulary (BNF) and the table of interactions in appendix 16 of the full guideline
- seek specialist advice if there is uncertainty
- if necessary, refer the patient to specialist mental health services for continued prescribing.
- First prescribe an SSRI in generic form unless there are interactions with other drugs – consider citalopram or sertraline.
- Dosulepin should not be prescribed.
- Non-reversible monoamine oxidase inhibitors (for example, phenelzine), combined antidepressants and lithium augmentation should normally be prescribed only by specialist mental health professionals.
- Take into account toxicity in overdose when choosing an antidepressant for patients at significant risk of suicide. Be aware that:
- compared with other equally effective antidepressants, venlafaxine is associated with a greater risk of death from overdose
- tricyclic antidepressants, except for lofepramine, are associated with the greatest risk in overdose.
A quick reference guide for CG91 summarises other aspects of antidepressant treatment, other treatment options and the management of depression generally in adults with chronic physical health problems.
The authors of the review acknowledge that the study is limited in a number of ways. Trials included in the analysis were generally rated as only of low to moderate quality and many only included small numbers of patients. With the exception of the three safety studies in patients with coronary heart disease, the analysis grouped all physical conditions together, and did not attempt to identify any difference in effects for individual chronic conditions. Only seven studies of SSRIs included data on quality of life and, with the exception of SSRIs, there were too few data with other drugs to examine their effects on this outcome.
Study details –
Taylor D, Meader N, Bird V, et al. Pharmacological interventions for people with depression and chronic physical health problems: systematic review and meta-analyses of safety and efficacy
Systematic review and meta-analyses of RCTs (63 studies, n=5794).
Adults with depression and chronic physical health problems (including cardiovascular disease, cancer, Parkinson’s disease, diabetes, rheumatoid arthritis, COPD, asthma, epilepsy, renal disease, multiple sclerosis, HIV).
Intervention and comparison
|Outcome (all studies)||SSRIs vs. placebo||TCAs vs. placebo|
|Response (e.g. 50% improvement in depression rating score)||RR 0.83, 95%CI 0.71 to 0.97||RR 0.55, 95%CI 0.43 to 0.70|
|Remission (e.g. no longer meeting cut-off depression diagnosis on rating score)||RR 0.81, 95%CI 0.73 to 0.91||RR 0.70, 95%CI 0.40 to 1.25 (NS)|
|Health related quality of life||SMD –0.27, 95%CI –0.44 to –0.10||Insufficient data|
|Leaving the study early due to AEs||RR 1.80, 95%CI 1.16 to 2.78||RR 1.88, 95% CI 0.99 to 3.57 (NS)|
|Reduction in depression rating score (observer rated)||SMD –0.34, 95%CI –0.48 to –0.20||SMD –0.70, 95%CI –0.97 to –0.43|
|Reduction in depression rating score (patient rated)||SMD –0.19, 95%CI –0.36 to –0.02||SMD –0.58, 95%CI –1.14 to –0.02|
|Key: RR= risk ratio; SMD = standardised mean difference; NS = not statistically significant|
Studies comparing antidepressants versus placebo or each other were included. Outcomes included remission, response, discontinuation for any reason, discontinuation due to adverse events (AEs), mean score on a validated depression scale, mean score on quality of life measure and physical health outcomes.
See Table 1 for selected results.
Table 1. Selected outcome effect sizes from the meta-analysis
In placebo-controlled studies, antidepressants showed an advantage in respect to remission and/or response. SSRIs showed a statistically significant efficacy advantage over placebo with regard to remission and response, whereas a statistically significant advantage was only found for response with TCAs. Statistically significant advantages over placebo were identified for both SSRIs and TCAs in reducing observer- and patient-rated depression scores, although the mean effect sizes were larger for TCAs. Only SSRIs were shown to improve quality of life (insufficient data for TCAs). Direct comparisons of SSRIs and TCAs revealed no advantage for either group for remission, response, effect size or tolerability. Three safety studies of antidepressants (two considered sertraline, the other mirtazapine followed by citalopram if no response) after MI suggested antidepressants have a neutral or beneficial effect on mortality or cardiovascular events in participants with recent MI.
The study was carried out by the pharmacology subgroup of the NICE Guideline Development Group for Depression in Chronic Physical Health Problems.
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