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National Collaborating Centre for Mental Health (UK). Depression in Adults with a Chronic Physical Health Problem: Treatment and Management. Leicester (UK): British Psychological Society; 2010. (NICE Clinical Guidelines, No. 91.)

8PHARMACOLOGICAL INTERVENTIONS IN THE TREATMENT AND MANAGEMENT OF DEPRESSION IN ADULTS WITH A CHRONIC PHYSICAL HEALTH PROBLEM

8.1. INTRODUCTION

Since the introduction of monoamine oxidase inhibitors (MAOIs) and the first TCA, imipramine, in the late 1950s, many new antidepressants have been introduced and approximately 35 different antidepressants in a number of classes are currently available worldwide. There has been intensive research on the effects of drug therapy on depression and how drugs might alter the natural history of the disorder. A large number of reviews and meta-analyses have been conducted that sought to synthesise this vast literature, which includes those conducted for the first NICE depression guideline (NCCMH, 2004a) and the update (NCCMH, 2010).

There have been rather fewer studies of antidepressants for people with depression and a chronic physical health problem. Many of the meta-analyses of antidepressants exclude people with a physical health problem (for example, NCCMH, 2004a) and therefore it is difficult to assess the safety and efficacy of these medications in people with a physical health problem.

However, it should also be noted that treating depression in people with a chronic physical health problem is potentially more challenging in terms of the adverse effects of medication (because physical adverse effects are of much greater consequence in people with a chronic physical health problem). In addition, this population is likely to be taking a number of different medications related to their physical health problem and so there is a greater likelihood of potential interactions with antidepressants.

8.2. EFFICACY OF PHARMACOLOGICAL INTERVENTIONS

8.2.1. Introduction

There have been systematic reviews assessing the efficacy of antidepressants in various populations of people with a chronic physical health problem including stroke (for example, Hackett et al., 2004), heart disease (for example, Dowlati et al., 2010), cancer (for example, Rodin et al., 2007) and HIV (Himelhoch & Medoff, 2005). It appears from these reviews that antidepressants are effective in a range of physically ill populations.

Definition and aim of review

The purpose of this review was to assess the efficacy of antidepressants for the treatment of depression in people with a chronic physical health problem. The search took the most inclusive approach setting filters only for RCTs and depression. Therefore, to minimise the risk of missing relevant references, no limits were placed on pharmacological interventions. The inclusion criteria of the review were limited to RCTs of the most commonly used antidepressants in clinical practice including SSRIs, TCAs, MAOIs, duloxetine, venlafaxine, bupropion, reboxetine, mirtazapine, trazodone, mianserin and psychostimulants (see Table 57 for further details). Outcomes were focused on depression, physical health and quality of life.

Table 57. Databases searched and inclusion/exclusion criteria for clinical evidence.

Table 57

Databases searched and inclusion/exclusion criteria for clinical evidence.

8.2.2. Databases searched and inclusion/exclusion criteria

Information about the databases searched and the inclusion/exclusion criteria used for this section of the guideline can be found in Table 57 (further information about the search for health economic evidence can be found in Section 8.6).

8.2.3. Studies considered48

The review team conducted a new systematic search for RCTs that assessed the efficacy and safety of antidepressants (and related health economic evidence, see Section 8.6).

Sixty-one trials relating to clinical evidence met the eligibility criteria set by the GDG, providing data on 5,794 participants. Of these, one (SCT-MD-24) was unpublished and 60 were published in peer-reviewed journals between 1984 and 2008. In addition, 80 studies were excluded from the analysis. The most common reason for exclusion was insufficient evidence of depression in participants (further information about both included and excluded studies can be found in Appendix 18).

Of the 61 included trials, 49 compared antidepressants with placebo: 35 trials compared SSRIs with placebo, nine compared TCAs, two compared third generation antidepressants, two compared mianserin and one compared trazodone. In addition, trials were head-to-head comparisons of antidepressants: 14 compared SSRIs with TCAs, one compared an SSRI with another SSRI, one compared a tetracyclic with mianserin and one compared a TCA with nomifensine.

No studies were identified concerning switching and sequencing of antidepressants in patients with a chronic physical health problem. However, when forming recommendations the GDG considered evidence reviewed in Chapters 10 and 11 of the depression guideline update (see NCCMH, 2010).

8.2.4. Clinical evidence on antidepressants versus placebo

Summary study characteristics of the included studies are in Table 58 with full details in Appendix 18, which also includes details of excluded studies.

Table 58. Summary study characteristics of included studies of antidepressants versus placebo.

Table 58

Summary study characteristics of included studies of antidepressants versus placebo.

SSRIs

The majority of research in this area has investigated the use of SSRIs. A total of 36 RCTs compared SSRIs with placebo in people with depression and a chronic physical health problem. The summary evidence profiles are presented in Table 59 and Table 60. The full evidence profiles and associated forest plots can be found in Appendix 21 and Appendix 19, respectively.

Table 59. GRADE evidence profile for SSRIs versus placebo.

Table 59

GRADE evidence profile for SSRIs versus placebo.

Table 60. GRADE evidence profile for SSRIs versus placebo (continuous data).

Table 60

GRADE evidence profile for SSRIs versus placebo (continuous data).

There were mixed data concerning tolerability of SSRIs. No differences were found with placebo for leaving the study for any reason (RR = 1.11; 95% CI, 0.96, 1.27). However participants receiving SSRIs were more likely to leave the study due to adverse events (RR = 1.89; 95% CI, 1.23, 2.89).

There was consistent evidence that SSRIs had a small-to-medium benefit on depression outcomes in comparison with placebo. SSRIs were associated with lower levels of non-remission (all studies: RR = 0.81; 95% CI, 0.74, 0.88; double blind only: RR = 0.86; 95% CI, 0.78, 0.94) and non-response (all studies: RR = 0.83; 95% CI, 0.71, 0.97; double blind only: RR = 0.85; 95% CI, 0.76, 0.94) compared with placebo.

A robust positive effect was also found for mean change in depression rating scale score (see Table 60) although there were differences in the size of the effect depending on whether patient-rated (all studies: SMD = −0.17, 95% CI, −0.30, −0.04; double blind only: SMD = −0.17, 95% CI, −0.30, −0.04) or observer-rated (all studies SMD = −0.33, 95% CI, −0.47, −0.19; double blind only: SMD = −0.29, 95% CI, −0.41, −0.29) scales were used.

There were many fewer data on both quality of life and physical health outcomes. In addition, where these were reported, measures differed substantially between studies. In total there were seven studies that provided data on quality of life indicating a small benefit in favour of SSRIs (SMD = −0.27; 95% CI, −0.44, −0.10). However, there were a further five studies reporting the physical subscale of the SF-36 that showed no difference between groups (SMD = 0.02; 95% CI, −0.19, 0.23).

It was problematic to pool data on physical health outcomes because of differences between physical health conditions and because of varied reporting of outcomes. Few conclusions can be drawn on the impact of SSRIs on such outcomes.

TCAs

Nine trials compared TCAs with placebo in people with depression and a chronic physical health problem. The summary evidence profile is presented in Table 61. The full evidence profiles and associated forest plots can be found in Appendix 21 and Appendix 19, respectively.

Table 61. GRADE evidence profile for TCAs versus placebo.

Table 61

GRADE evidence profile for TCAs versus placebo.

There were only nine RCTs that compared TCAs with placebo and these were mostly conducted in the 1980s and 1990s. There was consistent evidence that TCAs were less well tolerated compared with placebo (see Table 61). People on TCAs were more likely to leave the study for any reason (RR = 1.33; 95% CI 0.88, 2.01) and because of adverse events (RR = 2.00; 95% CI, 1.06, 3.78).

There appeared to be evidence of medium-to-large benefits on most depression outcomes. Participants receiving TCAs were more likely to respond to treatment (RR = 0.53; 95% CI 0.41, 0.68). However, including only double-blinded studies reduced the size of the effect, resulted in very high heterogeneity (I2 = 85.4%) and the difference was no longer statistically significant (RR = 0.64; 95% CI, 0.34, 1.21).

There was no statistically significant effect on non-remission (RR = 0.71; 95% CI, 0.40, 1.29), but this may be due to a lack of power as only two small studies reported this outcome. Mean differences on observer-rated depression scales were also of a medium-to-large magnitude (all studies: SMD = −0.69; 95% CI, −0.92, −0.47; just double blinded: SMD = −0.55; 95% CI, −0.95, −0.15). Similar effects were found on patient-rated scales (all studies double blinded: SMD = −0.58; 95% CI, −1.14, −0.02), but only two studies reported such data.

There were very limited data on quality of life and physical health outcomes, therefore a meta-analysis of these outcomes was not prudent.

Other drugs

There was only one study on trazodone (RAFFAELE1996), which indicated large benefits in comparison with placebo for mean depression rating scale score (SMD = −1.03; 95% CI, −1.93, −0.13). However, this study was not double blinded therefore it is difficult to draw conclusions.

There was also one study on mirtazapine (VANDENBRINK2002). Participants in the mirtazapine group were less likely to leave the study for any reason compared with placebo (RR = 0.57; 95% CI, 0.35, 0.94). There were small benefits in favour of mirtazapine in terms of non-remission (RR = 0.87; 95% CI 0.63, 1.21), non-response (RR = 0.83; 95% CI, 0.58, 1.20), and mean difference (SMD = −0.21; 95% CI, − 0.62, 0.20) in depression scale data. None of these effects was statistically significant.

WISE2007 conducted a trial on duloxetine, which was found to be associated with a small-to-medium benefit in terms of mean difference on depression scale score (patient rated: SMD = −0.37; 95% CI, −0.67, −0.14; observer rated: SMD = −0.43; 95% CI, −0.71, −0.16).

There were two studies examining mianserin versus placebo (COSTA1985, VANHEERINGEN1996), which found strong benefits favouring mianserin on leaving the study for any reason (RR = 0.43; 95% CI, 0.25, 0.75), non-response (RR = −0.47; 95% CI, 0.30, 0.74) and mean difference for depression score as measured on the HDRS (WMD = −5.97; 95% CI, −9.14. −2.80, SMD = −0.64; 95% CI, −1.00, −0.29).

There was only one trial on psychostimulants (WAGNER2000) for people with HIV, which lasted 2 weeks. There was a small, but not statistically significant, effect on depression (SMD = −0.36; 95% CI, −1.20, 0.49). There was a large effect on fatigue (SMD = −1.64; 95% CI, −2.64, −0.65).

8.2.5. Examining possible confounding effects on antidepressants versus placebo analyses

While there was reasonable consistency in the findings comparing antidepressants and placebo, the impact of different physical health problems, diagnosis of depression, baseline severity of depression and funding of the trial were considered important potential confounding factors. The impact of the type of physical health problem was assessed by subgroup analysis. All other outcomes were assessed with meta-regression using double-blinded trials on clinician-rated mean depression score (as this outcome had the largest number of trials). Given the lack of data for all other drug classes, sensitivity analyses were limited to SSRIs and TCAs.

SSRIs

Assessing the impact of differences in the type of chronic physical health problem targeted by studies on depression outcome was limited by the dearth of studies for each physical illness. There was considerable overlap in CIs for most physical health problems including the illnesses that had the largest number of studies: stroke (SMD = −0.28; 95% CI, −0.70, 0.13), cardiovascular disease (SMD = −0.22; 95% CI, −0.39, −0.05) and diabetes (SMD = −0.24; 95% CI, −0.51, 0.03). This suggests that the type of physical health problem had little impact on antidepressant effect.

Whether or not a trial was sponsored by a drug company was not associated with treatment effect (β = −0.03; −0.34, 0.27, p = 0.82). Furthermore, mean baseline depression score was not associated with effect size (β = −0.01; −0.05, 0.01, p = 0.27). The effect of studies recruiting for people with a DSM/ICD diagnosis of depression had a slightly greater impact, but this was also not statistically significant (β = −0.21; −0.63, 0.20, p = 0.30).

TCAs

For TCAs, only the impact of mean baseline depression score and DSM/ICD diagnosis of depression could be assessed due to lack of data. Mean baseline depression score did not appear to predict mean change in depression (β = −0.02; −0.12, 0.08, p = 0.63). But having a DSM/ICD diagnosis was associated with an increase in effect (β = −0.41; −1.18, 0.37, p = 0.23), although this was not statistically significant.

8.2.6. Clinical evidence for head-to-head trials of antidepressants

Summary study characteristics of the included studies are in Table 62 with full details in Appendix 18, which also includes details of excluded studies.

Table 62. Summary study characteristics of included studies of head-to-head trials of antidepressants.

Table 62

Summary study characteristics of included studies of head-to-head trials of antidepressants.

SSRIs versus TCAs

Table 63 and Table 64 summarises the main outcomes of the analysis comparing SSRIs and TCAs. The full evidence profiles and associated forest plots can be found in Appendix 21 and Appendix 19, respectively.

Table 63. GRADE evidence profile for SSRIs versus TCAs.

Table 63

GRADE evidence profile for SSRIs versus TCAs.

Table 64. GRADE evidence profile for SSRIs versus TCAs – continuous data.

Table 64

GRADE evidence profile for SSRIs versus TCAs – continuous data.

There is consistent evidence that SSRIs were associated with better tolerability. For example, people who received SSRIs were less likely (although this was not statistically significant) to leave the study early for any reason (RR = 0.77; 95% CI, 0.58, 1.01) and less likely (although this was not statistically significant) to leave the study due to adverse events (RR = 0.81; 95% CI, 0.52, 1.27).

Efficacy did not differ between these two classes of drug with no statistically significant differences on non-remission (RR = 1.22; 95% CI, 0.88, 1.67), non-response (RR = 0.97; 95% CI, 0.83, 1.14) or mean differences (SMD = 0.04; 95% CI, −0.14, 0.22).

Other comparisons

There was a paucity of data comparing other drug classes. Only five head-to-head trials included comparisons besides SSRIs versus TCAs; all trials indicated little benefit of one drug class over another. The trials covered a range of physical health problems including diabetes (GULSEREN2005), epilepsy (ROBERTSON1985), stroke (ZHAO2005) and general medical illness (SCHIFANO1990), and included participants with both mild and moderate depression.

One study comparing two different SSRIs (GULSEREN2005) did not indicate any benefit for either drug (fluoxetine and paroxetine) in terms of efficacy and tolerability, with no statistically significant differences on leaving the study early (RR = 0.46; 95% CI, 0.05, 4.38), non-remission (RR = 0.76; 95% CI, 0.32, 1.80), non-response (RR =1.15; 95% CI, 0.41, 3.21) or mean differences (SMD = 0.00; 95% CI, −0.88, 0.88). One study comparing citalopram and venlafaxine (ZHAO2005) did not indicate any benefit for either drug. The results for leaving the study early (RR = 0.69; 95% CI, 0.31, 1.55), non-remission (RR = 0.90; 95% CI, 0.71, 1.13) and non-response (RR = 0.81; 95% CI, 0.50, 1.13) were not statistically significant. Based on one small study (ROBERTSON1985), there was no benefit in terms of efficacy for TCAs when compared with nomifensine, with non-response data indicating no statistically significant differences (RR = 3.50 (0.89, 13.78). SCHIFANO1990 compared maprotiline and mianserin but failed to indicate any statistically significant differences between the two. For example, results for leaving the study early (RR = 0.58; 95% CI, 0.22, 1.51), non-response (RR = 0.75 (0.47, 1.19) and mean differences (SMD = −0.47, 95% CI, −1.15, 0.21) did not indicate that one drug was more efficacious than the other.

8.2.7. Effectiveness studies on antidepressants

There were two studies that met the eligibility criteria of the review on the use of antidepressants in effectiveness trials (Myocardial Infarction and Depression-Intervention Trial [MIND-IT] and ENRICHD). These studies used a slightly different methodological approach to the efficacy studies reviewed above and therefore were not included in the meta-analysis but are discussed narratively in this section.

The advantages of effectiveness trials are, first, that sample sizes tend to be larger and provide longer follow-up than efficacy studies in this area, and second, that they seek to minimise differences between study conditions and routine clinical practice so such findings are more readily applicable to clinical practice. Therefore, it is important to compare the results found in these trials with the efficacy trials reviewed above to assess whether they confirm conclusions of the efficacy studies and/or provide additional data not usually reported in other trials. However, it should also be noted that there are clear disadvantages—given the complexity and the reduced level of control usually associated with these studies, it is difficult to draw firm conclusions on causality.

Myocardial Infarction and Depression-Intervention Trial

The MIND-IT is the largest European trial of interventions for people with depression and a chronic physical health problem. This study focused on the safety of antidepressants in people who had a myocardial infarction; within this study a nested RCT was conducted comparing mirtazapine and placebo, which is included in the meta-analysis above (VANDENBRINK2002).

In total, 209 participants were randomised to receive an intervention and 122 to receive care as usual. Of those assigned to treatment, however, 115 were subsequently excluded (87 broke with the protocol and 28 did not have a depressive disorder). Of the remaining 94 in the treatment group, three dropped out, 47 received double-blind mirtazapine (in addition, 15 of these did not respond and then received open-label citalopram after 8 weeks), 23 received double-blind placebo followed by citalopram after 8 weeks and 21 only received placebo. Of those who received care as usual, 20 also received antidepressants. Given the large dropout after randomisation and the many differences within groups regarding their treatment, it is difficult to draw firm conclusions. However, this is a large study with relatively long follow-up data (18 months) and given the general paucity of data it is still of some importance in assessing the effectiveness of antidepressants.

It was observed (van Melle et al., 2007) that non-remission (according to ICD–10 depression diagnosis) of 30.5% in the intervention group and 32.1% in the control group occurred, which was not statistically significant (OR = 0.93; 0.53, 1.63). For intention-to-treat analyses a similar lack of difference was found (OR = 1.09; 0.70, 1.70). This lack of effect may partly be explained by the often short-lived nature of depression after an myocardial infarction.

There were also no differences in the incidence of cardiac events (14% in the intervention group and 13% in the control group). Specifically comparing those receiving pharmacological treatment with those who did not in the usual care arm similarly found little difference (OR = 0.84; 95% CI 0.38, 1.84). This effect is reduced further when using an intention-to-treat (ITT) analysis (OR = 0.95; 0.41, 2.19). This suggests the use of mirtazapine is safe in people who have had a myocardial infarction but does not indicate a protective effect on further cardiac events.

Enhancing Recovery in Coronary Heart Disease

ENRICHD is a US study (Berkmann et al., 2003) mainly consisting of participants who had a relatively recent myocardial infarction (median 6 days; compared with a minimum period of 3 months' post-myocardial infarction for the MIND-IT trial). This section will focus on the antidepressant treatment aspect of the trial (for further details on the results of this trial, see Chapter 7).

Berkmann and colleagues (2003) reported the main findings of this trial. The sample size was very large, with a total of 1238 patients randomised to receive an intervention and 1243 to receive usual care. There was high usage of antidepressants (mainly SSRIs) in both the treatment group (baseline 9.1%, at 6 months 20.5%, at end of follow-up 28%) and usual care group (baseline 3.8%, at 6 months 9.4%, at end of follow-up 20.6%). Although this study does not provide randomised data on antidepressant use versus control, it is still a large dataset that may be informative on evaluating the effectiveness of antidepressants.

For the primary outcome of the study, death or non-fatal myocardial infarction, there was a reduced risk for those taking antidepressants (adjusted hazard ratio = 0.63; 0.46, 0.87). Specifically for SSRI use, there was a further reduction in risk (adjusted hazard ratio = 0.57; 0.36, 0.85).

8.2.8. Clinical evidence summary

Antidepressants were associated with a reduction in depression outcomes of a small-to-medium magnitude. Most of the studies compared SSRIs with placebo and these reductions in depression were consistent across a range of physical health problems including cancer, diabetes, stroke and heart disease. There was also some evidence for benefit for TCAs compared with placebo. There was limited evidence for all other drugs. A number of trials compared SSRIs with TCAs and there appeared to be little difference in efficacy, but SSRIs appeared to be better tolerated and safer than TCAs.

Data on physical health outcomes and quality of life were limited and this was further hampered by inconsistent reporting in the efficacy trials. There was better reporting of cardiac outcomes in the two effectiveness trials. MIND-IT found no difference between people using antidepressants and those who did not on cardiac events. However, ENRICHD found a relatively large reduction in hazard ratio for fatal or non-fatal myocardial infarction particularly for participants receiving SSRIs (Berkmann et al., 2003). Therefore, there is some evidence that SSRIs and mirtazapine are safe for people who have had a myocardial infarction, and that SSRIs may actually be protective of further cardiovascular events.

8.3. ADVERSE EFFECTS OF PHARMACOLOGICAL INTERVENTIONS

8.3.1. Introduction

At the time of writing there are few reviews that seek to evaluate comprehensively antidepressants for people with depression and a chronic physical health problem in terms of effectiveness, adverse effects and interactions with other medications. This is particularly important given that treating depression in people with a physical health problem is potentially more challenging in terms of the adverse effects of medication (as the physical illness may make people more vulnerable to effects such as gastrointestinal bleeding and cognitive deficits). In addition, such people are likely to be taking a number of different medications related to their physical condition and there is, therefore, a greater likelihood of potential interactions with antidepressants. This issue of interactions is dealt with in detail in Section 8.4.

Definition and aim of review

The purpose of this review was to assess the adverse effects and adverse-effect burden of antidepressants for the treatment of depression in people with a chronic physical health problem. Following discussion with the GDG, the search was limited to systematic reviews assessing adverse effects related to weight (gain/loss), sexual functioning, cognition, gastrointestinal symptoms, cardiotoxicity and mortality. In addition, antidepressants were limited to those most commonly used in clinical practice including SSRIs, third-generation antidepressants, TCAs and MAOIs.

8.3.2. Databases searched and inclusion/exclusion criteria

Information about the databases searched and the inclusion/exclusion criteria used for this section of the guideline can be found in Table 65 (further information about the search for health economic evidence can be found in Section 8.4).

Table 65. Databases searched and inclusion/exclusion criteria for clinical evidence.

Table 65

Databases searched and inclusion/exclusion criteria for clinical evidence.

8.3.3. Studies considered49

The review team conducted a new systematic search for RCTs that assessed the efficacy and safety of antidepressants and related health economic evidence (see Section 8.4).

Nineteen systematic reviews relating to clinical evidence met the eligibility criteria set by the GDG. All were published in peer-reviewed journals between 1999 and 2008. In addition, 58 studies were excluded from the analysis. The most common reason for exclusion was that no relevant outcomes were reported in the review (further information about both included and excluded studies can be found in Appendix 18).

8.3.4. Clinical evidence on adverse effects of antidepressants

The key characteristics of the included systematic reviews are summarised in Table 66.

Table 66. Summary characteristics of included systematic reviews on adverse effects.

Table 66

Summary characteristics of included systematic reviews on adverse effects.

Cardiovascular symptoms

Cardiovascular symptoms have received the most extensive attention in the literature in comparison with other adverse effects.

There is broad consensus that SSRIs are well tolerated in people with cardiovascular and cerebrovascular diseases (for example, Swenson et al., 2006; Taylor, 2008). In addition, SSRIs do not appear to be associated with an increase in risk of cardiovascular adverse effects (Ramasubbu, 2004; Swenson et al., 2006; Taylor, 2008). For example, in a meta-analysis assessing cardiovascular adverse effects in a variety of physical health problems, Swenson and colleagues (2006) found that the SSRI group had reduced risk of cardiovascular adverse events compared with placebo (OR = 0.69; 95% CI, 0.39, 1.21) and TCAs (OR = 0.46; 95% CI, 0.24, 0.86). This is also supported by a relatively low Fatal Toxicity Index (FTI; number of poisoning deaths per million prescriptions) for SSRIs of 2 (Taylor, 2008), suggesting a low risk of arrhythmia.

TCAs have been found to be associated with a greater risk of cardiovascular-related adverse effects in comparison with SSRIs, as discussed above. As a consequence of their Na+ channel blocking properties (Class I anti-arrhythmic effect), TCAs are likely to be pro-arrhythmic in patients with recent myocardial infarction and their use is contraindicated (BNF; British Medical Association & the Royal Pharmaceutical Society of Great Britain, 2008). Following the Cardiac Arrhythmia Suppression Trial (CAST) I study (Echt et al., 1991), all Class I anti-arrhythmics are used extremely cautiously in all patients with significant structural heart disease hence the same should apply to TCAs. In addition, they have been found to be highly cardiotoxic in overdose and may induce cardiovascular disease (Taylor, 2008). The FTIs for TCAs range from 12 to 43. However, lofepramine is an exception with a low FTI of between 1.3 and 2.7. In TCA overdose, cardiac arrhythmia and seizures probably account for the majority of deaths (Taylor, 2008).

Other antidepressants were associated with possible risk of cardiovascular problems, although further data is required to confirm this. Duloxetine appears to be associated with small increases in diastolic blood pressure, tachycardia and cholesterol compared with placebo (Duggan & Fuller, 2004; Wernicke et al., 2007). In addition, bupropion was found to increase blood pressure in two case reports (Dhillon et al., 2008). The FTI for venlafaxine is estimated at between 13 and 18, which indicates moderate acute toxicity. However, it appears not to effect changes in ECG in standard doses or be associated with arrhythmia in overdose (Taylor, 2008). In contrast, for mirtazapine, reboxetine and mianserin the FTIs are of a similar magnitude to those of the SSRIs (Taylor, 2008), suggesting that they are relatively safe with regards to pro-arrhythmic effects.

Bleeding

Two systematic reviews were identified concerning the association between SSRIs and bleeding (Weinrieb et al., 2003; Yuan et al., 2006). Evidence on this association is provided from several observational studies often using data from national prescribing databases. A study utilising data from the General Practice Research Database in the UK (De Abajo et al., 1999) found an increased risk of bleeding for people on SSRIs (adjusted rate ratio = 3.0; 95% CI, 2.1, 4.4); this risk was magnified with concurrent SSRI and NSAID use (rate ratio of 15.6). Similar findings were also identified when using a Danish prescribing database (Dalton et al., 2003); SSRI use (RR = 3.6; 95% CI, 2.7, 4.7), and particularly concurrent NSAID and SSRI use (RR = 12; 95% CI, 7.1, 19.5), were associated with gastrointestinal bleeding. Both systematic reviews concluded that extreme caution was required when prescribing SSRIs in populations at risk of bleeding disorders.

Gastrointestinal symptoms

There was some evidence that SSRIs were associated with a greater risk of gastrointestinal symptoms such as nausea, vomiting and diarrhoea. This was slightly higher in fluoxetine than other SSRIs, TCAs and placebo (Beasley et al., 2000; Brambilla et al., 2005). Citalopram was associated with a lower risk of nausea compared with fluvoxamine (Keller, 2000). TCAs were associated with higher risk of constipation when compared with fluoxetine (Beasley et al., 2000)

Sexual dysfunction

The association between antidepressants and sexual dysfunction was considered specifically in two of the included systematic reviews (Gregorian et al., 2002; Werneke et al., 2006) but also as an outcome in a number of other included reviews.

There was consistent evidence of sexual adverse effects in association with SSRI use (Beasley et al., 2000; Gregorian et al., 2002; Keller, 2000; Werneke et al., 2006). The prevalence of sexual adverse effects appeared to be particularly high in paroxetine (Werneke et al., 2006). There was also evidence of increased risk of sexual adverse effects in citalopram (Werneke et al., 2006), fluoxetine (Beasley et al., 2000) and most other SSRIs in comparison with placebo. Comparisons between SSRIs and other antidepressants show lower risk of sexual adverse effects in bupropion compared with both sertraline and fluoxetine. There was more sparse evidence showing amitryptiline and nefazodone were also associated with lower risk of sexual dysfunction compared with SSRIs.

TCAs as a class had the highest risk with up to 90% of participants reporting adverse effects, although there were marked differences between TCAs with clomipramine associated with the highest risk and amitriptyline and doxepin the lowest.

Venlafaxine (Werneke et al., 2006) and duloxetine (Duggan & Fuller, 2004) also appeared to increase risk of sexual adverse effects compared with placebo. Although duloxetine (50.2%) was associated with a slightly lower prevalence of sexual dysfunction than paroxetine (61.5%), the risk was much higher than with placebo. As discussed above, bupropion seems to have a low risk of sexual adverse effects; this was also found for reboxetine (Werneke et al., 2006).

Weight

There was consistent evidence that fluoxetine was associated with greater loss in weight compared with placebo (Beasley et al., 2000), TCAs and other SSRIs (Brambilla et al., 2005). However, as noted by Demyttenaere and Jaspers (2008), these effects are reported early on in treatment. When assessing continuation studies there is a possibility that paroxetine and fluoxetine may actually be associated with weight gain but this needs further research to establish this finding.

There was evidence that some other antidepressants have an impact on weight. People taking bupropion were twice as likely to experience greater than 2 kg reduction in weight than people on placebo (Dhillon et al., 2008). Duloxetine was also associated with weight loss with a mean reduction of 2.2 kg compared with 1 kg for placebo (Duggan & Fuller, 2004). In contrast, mirtazapine was associated with weight gain of approximately 2 kg over 8 to 13 weeks (Hansen et al., 2005). There is also some evidence from early studies that TCAs were also associated with weight gain (Berken et al., 1984; Fava, 2000).

8.4. INTERACTIONS BETWEEN MEDICATIONS FOR TREATING PHYSICAL HEALTH PROBLEMS AND ANTIDEPRESSANTS

8.4.1. Introduction

Drug interactions are classified as pharmacokinetic or pharmacodynamic in nature. In pharmacokinetic interactions, one drug affects the absorption, distribution, metabolism or elimination of other co-administered drugs. In pharmacodynamic interactions, one drug opposes or enhances the pharmacological action of another through, for example, competition for receptor sites or by affecting the same physiological process in different ways. Antidepressant drugs are associated with both pharmacokinetic and pharmacodynamic interactions, the former being more clinically relevant with SSRIs and lithium, and the latter with TCAs.

The BNF includes a summary appendix dedicated to drug interactions. More detailed information can be found in Stockley's Drug Interactions (Baxter, 2008). These sources should be checked before adding new drugs to a prescription, particularly if: (1) any of the drugs prescribed have a narrow therapeutic index, that is are ineffective at low doses/plasma levels and potentially toxic at higher doses/plasma levels; or (2) are known to affect cardiac or renal function. The narrative summary below is illustrative only; it is not a comprehensive account of all drug interactions with antidepressants. For further details see Appendix 16.

8.4.2. Pharmacokinetic interactions

The most significant pharmacokinetic interactions involving antidepressants are mediated through inhibition of hepatic cytochrome P450 (CYP) metabolising enzymes. Some SSRIs are potent inhibitors of individual or multiple CYP pathways. It should be noted that the clinical consequences of pharmacokinetic interactions in an individual patient can be difficult to predict – the degree of enzyme inhibition, the relationship between plasma level and pharmacodynamic effect for each affected drug, and patient-specific factors such as variability in the role of primary and secondary metabolic pathways and the presence of comorbid physical health problems will all influence outcome.

In general, inhibition of a specific CYP enzyme will lead to increased plasma levels and enhanced effect (possibly frank toxicity) from other co-administered drugs that are metabolised by the same CYP enzyme. Examples of antidepressant mediated interactions can be seen in Table 67.

Table 67. Pharmacokinetic interactions (Greenblatt et al., 1998; HIV InSite, 2008; Lin & Lu, 1998; Mitchell, 1997; Richelson, 1998; Taylor, 1997).

Table 67

Pharmacokinetic interactions (Greenblatt et al., 1998; HIV InSite, 2008; Lin & Lu, 1998; Mitchell, 1997; Richelson, 1998; Taylor, 1997).

Inducers of CYP have the potential to reduce plasma levels of co-prescribed drugs leading to treatment failure. Known inducers include cigarette smoke (CYP1A2), carbamazepine (CYP1A2, 2D6 and 3A4) and rifampicin (CYP3A4). A patient, for example, who is prescribed a TCA and who stops smoking may experience increased side effects or even toxicity from the TCA. While no licensed antidepressants are known inducers of CYP, the herbal preparation St John's wort can precipitate a number of significant interactions in this way.

Most SSRIs are CYP inhibitors and the magnitude of the effect is dose related. Notable examples are: (1) fluvoxamine, a potent inhibitor of CYP1A2 that results in a significant interaction potential with a variety of other drugs, for example increased bleeding risk with warfarin, and increased seizure risk with clozapine; (2) fluoxetine and paroxetine, potent inhibitors of CYP2D6 and CYP3A4; (3) citalopram, escitalopram, sertraline and duloxetine, moderate inhibitors of CYP2D6.

TCAs are thought to have minimal effects on CYP enzymes, but there are few clinical studies to support this assumption. The metabolism of TCAs is inhibited (TCA levels increased with an associated increased risk of side effects) by drugs that inhibit CYP1A2, CYP2C9/19, CYP2D6 and CYP3A4. For example, the addition of fluoxetine to imipramine or nortriptyline can result in an up to four-fold increase in serum levels of the TCA. Other commonly prescribed drugs that can raise TCA levels include ciprofloxacin, erythromycin and cimetidine.

St John's wort is a herbal preparation that can be bought without a prescription. It is a known potent inducer of several CYP enzymes, an effect that can lead to increased metabolism of co-prescribed drugs and consequent treatment failure. Clinically significant interactions with St John's wort include anticonvulsant drugs, digoxin, protease inhibitors, theophylline, ciclosporin, oral contraceptives and warfarin (Committee on Safety of Medicines, 2000). In addition, being a serotonergic drug, St John's wort can precipitate serotonin syndrome when used in combination with SSRIs or other serotonergic drugs.

Pharmacokinetic interactions involving lithium

Unlike antidepressants, lithium is not metabolised by the liver. It is primarily excreted unchanged in urine; to the kidney, lithium is indistinguishable from sodium. Lithium has a narrow therapeutic index; the differences between a sub-therapeutic, therapeutic and toxic plasma level are small. It therefore follows that other drugs that alter the way in which the kidney handles sodium, or reduce the glomerular filtration rate, can precipitate clinically significant interactions with lithium. In addition, lithium is often prescribed for older patients many of whom also require treatment with drugs that have the potential to decrease renal elimination of lithium (Juurlink et al., 2004). These drugs include angiotensin-converting enzyme (ACE) inhibitors, diuretics (used to treat cardiovascular disease) and NSAIDs (used to treat pain and inflammation). Such drugs can be co-prescribed safely with lithium if the interacting drug is taken regularly and lithium levels are checked (and the dose altered as necessary) after the interacting drug is initiated or the dose is changed.

ACE inhibitors can increase lithium serum levels. The magnitude of this effect is unpredictable and ranges from no increase to four-fold. The full effect can take several weeks to develop. ACE inhibitors can also precipitate renal failure, so extra care is needed in monitoring both serum creatinine and lithium, if these drugs are prescribed together. Care is also required with angiotensin-2 antagonists.

Diuretics can increase serum lithium levels, any effect usually being apparent within 10 days of a thiazide diuretic being prescribed; again, the magnitude of the rise is unpredictable and can vary from 25 to 400%. Loop diuretics are somewhat safer. Patients taking diuretics may have been advised to restrict their salt intake and this may contribute to the risk of lithium toxicity in these individuals. The addition of diuretic therapy to ongoing lithium treatment can cause severe lithium toxicity.

NSAIDs can increase serum lithium levels. Both the onset (from a few days to several months) and magnitude of the rise (10% to over 400%) are unpredictable for any given patient. Ibuprofen can be obtained without a prescription and so patients should be aware of the potential interaction. Lithium toxicity has also been reported with cyclooxygenase-2 inhibitors.

8.4.3. Pharmacodynamic interactions

TCAs are involved in a number of pharmacodynamic interactions (Watsky & Salzman, 1991). They are antagonists at histamine, H1, receptors and show additive effects with other sedative drugs and alcohol. TCAs also possess anticholinergic properties that exacerbate dry mouth, constipation, blurred vision and problems with cognition associated with other anticholinergic drugs. They cause postural hypotension by antagonising adrenergic alpha-1 receptors and may show additive effects with other alpha blockers and hypotensive drugs in general; this may, for example, increase the risk of falls. All TCAs are cardiac sodium channel antagonists and are associated with arrhythmogenic activity and QRS prolongation. Their use should be avoided in patients taking drugs that affect cardiac conduction (for example, antiarrhythmics and moxifloxacin) and caution is required with drugs likely to lead to electrolyte disturbance (for example, diuretics). TCAs also lower seizure threshold; caution is required when prescribing other procon-vulsive drugs and in epilepsy. Some TCAs (amitriptyline, clomipramine) are serotonergic and may have additive effects (risk of serotonin syndrome) with other serotonergic drugs (for example, SSRIs, selegiline, tramadol, triptans, St John's wort).

SSRIs (Edwards & Anderson, 1999; Mitchell, 1997) increase serotonergic transmission and show additive effects with other serotonergic drugs (for example, tramadol, selegiline, triptans and St John's wort), increasing the risk of serotonin syndrome. SSRIs also inhibit platelet aggregation and are associated with an increased risk of bleeding. Upper gastrointestinal bleeding is a particular concern in older patients receiving SSRIs in combination with aspirin or NSAIDs (Loke et al., 2008). SSRIs may also lower seizure threshold, which can complicate the management of epilepsy and may cause osteopaenia (which complicates the management of osteoporosis). They seem to be more likely than other antidepressants to cause hyponatraemia, particularly in older people; the risk may be increased by other drugs that increase sodium loss, such as diuretics. Duloxetine and venlafaxine have a similar profile.

MAOIs (Livingston & Livingston, 1996) are involved in potentially serious pharmacodynamic interactions with sympathomimetic drugs, pressor agents and serotonergic or noradrenergic drugs. Hypertensive crisis and serotonin syndrome can result.

Mirtazapine causes additional drowsiness and cognitive impairment when taken with other sedatives. It should not be used at the same time as MAOIs and should be used with caution with other serotonergic or noradrenergic drugs.

Reboxetine should not be given at the same time as MAOIs or ergot derivatives.

8.5. ANTIDEPRESSANT DISCONTINUATION SYMPTOMS

8.5.1. Introduction

There can be confusion over the use of the terms ‘addiction’, ‘psychological dependence’ and ‘physical dependence’ when referring to drugs. This has been associated with concern in the mind of the public about whether antidepressants (and indeed other psychotropic drugs) may be addictive. The DSM–IV (APA, 1994) definition of ‘substance dependence’ consists of a combination of psychological, physiological and behavioural effects that together comprise what is commonly called addiction. The diagnosis of substance dependence/addiction requires at least three of the following:

  1. tolerance (marked increase in amount; marked decrease in effect)
  2. characteristic ‘withdrawal’ symptoms or substance taken to relieve withdrawal
  3. substance taken in larger amount and for longer period than intended
  4. persistent desire or repeated unsuccessful attempt to quit
  5. much time/activity to obtain, use, recover from the substance
  6. important social, occupational or recreational activities given up or reduced
  7. use continues despite knowledge of adverse consequences (for example, failure to fulfil role obligation, using when physically hazardous).

Physical dependence refers to the first two features (tolerance to the effect and ‘withdrawal’ symptoms) and substance dependence/addiction can be with or without physical dependence. There is no evidence that antidepressants cause psychological dependence or adverse behavioural and functional effects in the sense defined by criteria 3 to 7 above, and therefore antidepressants are not ‘addictive’ in the accepted sense of the word used to describe dependence on drugs like alcohol or opioids. There is also no good evidence to support tolerance to the therapeutic effect of antidepressants (Zimmerman & Thongy, 2007) and therefore the debate about whether or not antidepressants cause physical dependence centres on the symptoms some people experience when stopping antidepressants. It is important is to understand the nature of the phenomenon and its implications for people with depression who have antidepressant treatment. In this guideline these are described as ‘discontinuation symptoms’, which is a term that makes no assumption about their status.

Discontinuation symptoms can be broadly divided into six groups; affective (for example, irritability), gastrointestinal (for example, nausea), neuromotor (for example, ataxia), vasomotor (for example, sweating), neurosensory (for example, paraesthesia), and other neurological (for example, dreaming; Delgrado, 2006). They may be new or hard to distinguish from some of the original symptoms of the underlying illness. By definition they must not be attributable to other causes. They are experienced by at least a third of patients (Lejoyeux et al., 1996; Medicine and Healthcare products Regulatory Agency [MHRA], 2004) and are seen to some extent with all antidepressants (Taylor et al., 2006). Of the commonly used antidepressants, the risk of discontinuation symptoms seems to be greatest with paroxetine, venlafaxine and amitriptyline (Taylor et al., 2006). There have been prospective studies, including some RCTs and quasi-randomised trials, which have examined the effect of discontinuation in people taking paroxetine and other antidepressants. These studies suggest an increase in discontinuation symptoms in those taking paroxetine compared with escitalopram (Baldwin et al., 2006), fluoxetine (Bogetto et al., 2002; Judge et al., 2002; Hindmarch et al., 2000; Michelson et al., 2000; Rosenbaum et al., 1998), sertraline (Hindmarch et al., 2000; Michelson et al., 2000), and citalopram (Hindmarch et al., 2000). In addition, two RCTs measuring discontinuation symptoms when stopping antidepressants after 8 weeks of treatment found that these were more common with venlafaxine than escitalopram (Montgomery et al., 2004), and moderate and severe symptoms were more common on venlafaxine compared with sertraline (Sir et al., 2005).

The onset is usually within 5 days of stopping treatment, or occasionally during taper or after missed doses (Michelson et al., 2000; Rosenbaum et al., 1998). This is influenced by a number of factors, which may include a drug's half-life. Symptoms can vary in form and intensity, and can occur in any combination. They are usually mild and self-limiting, but can be severe and prolonged, particularly if withdrawal is abrupt. Some symptoms are more likely with individual drugs, for example dizziness and electric shock-like sensations with SSRIs, and sweating and headache with TCAs (Haddad, 2001; Lejoyeux et al., 1996).

8.5.2. Factors affecting the development of discontinuation symptoms

Although anyone can experience discontinuation symptoms, the risk is increased in those prescribed short half-life drugs (Rosenbaum et al., 1998), such as paroxetine and venlafaxine (Fava et al., 1997; Hindmarch et al., 2000; MHRA, 2004). They can also occur in patients who do not take their medication regularly. Two-thirds of patients prescribed antidepressants skip a few doses from time to time (Meijer et al., 2001). The risk is also increased in those who have been taking antidepressants for 8 weeks or longer (Haddad, 2001); those who developed anxiety symptoms at the start of antidepressant treatment (particularly with SSRIs); those receiving other centrally acting medication (for example, antihypertensives, antihistamines, antipsychotics); children and adolescents; and those who have experienced discontinuation symptoms before (Haddad, 2001; Lejoyeux & Ades, 1997).

Discontinuation symptoms may also be more common in those who relapse on stopping antidepressants (Zajecka et al., 1998; Markowitz et al., 2000).

8.5.3. Clinical relevance

The symptoms of a discontinuation reaction may be mistaken for a relapse of illness or the emergence of a new physical illness (Haddad, 2001) leading to unnecessary investigations or reintroduction of the antidepressant. Symptoms may be severe enough to interfere with daily functioning. Another point of clinical relevance is that patients who experience discontinuation symptoms may assume that this means that antidepressants are addictive and not wish to accept further treatment. It is very important to counsel patients before, during and after antidepressant treatment about the nature of this syndrome.

8.5.4. How to avoid discontinuation symptoms

Although it is generally advised that antidepressants (except fluoxetine) should be discontinued over a period of at least 4 weeks, preliminary data suggest that it may be the half-life of the antidepressant rather than the rate of taper that ultimately influences the risk of discontinuation symptoms (Tint et al., 2008).

When switching from one antidepressant to another with a similar pharmacological profile, the risk of discontinuation symptoms may be reduced by completing the switch as quickly as possible (a few days at most). A different approach may be required at the end of treatment where a slower taper is likely to be beneficial.

The half-life of the drug should be taken into account. The end of the taper may need to be slower as symptoms may not appear until the reduction in the total daily dosage of the antidepressant is substantial. Patients receiving MAOIs may need dosage to be tapered over a longer period. Tranylcypromine may be particularly difficult to stop. It is not clear if the need for slow discontinuation of MAOIs, and particularly tranylcypromine, is due to the discontinuation syndrome or the loss of other neurochemical effects of these drugs. Since it is not possible to disentangle these phenomena, the clinical advice is that patients on MAOIs and those at-risk patients need a slower taper (Haddad, 2001).

Many patients experience discontinuation symptoms despite a slow taper. For these patients, the option of abrupt withdrawal should be discussed. Some may prefer a short period of intense symptoms over a prolonged period of milder symptoms.

8.5.5. How to treat

There are no systematic randomised studies in this area. Treatment is pragmatic. If symptoms are mild, reassure the patient that these symptoms are not uncommon after discontinuing an antidepressant and that they will pass in a few days. If symptoms are severe, reintroduce the original antidepressant (or another with a longer half-life from the same class) and taper gradually while monitoring for symptoms (Haddad, 2001; Lejoyeux & Ades, 1997).

8.6. HEALTH ECONOMIC EVIDENCE

8.6.1. Literature review

The guideline systematic literature search identified one economic study on pharmacological interventions in people with depression and a chronic physical health problem. The study by O'Connor and colleagues (2005) compared the costs and benefits of sertraline versus placebo.

The study, conducted in the US, evaluated the potential economic and clinical implications associated with sertraline in the treatment of patients with major depressive disorder (DSM–IV) hospitalised for acute coronary syndrome. The effectiveness evidence was derived from the Sertraline Antidepressant Heart Attack Randomised Trial (SADHART), a randomised, double-blind, 24-week trial. Patients were given a 50 mg per day dosage of sertraline for the first 6 weeks and, depending on response and tolerability, it was increased to a maximum of 200 mg per day at week 12. A minimum daily dose of 50 mg was maintained.

Direct costs relating strictly to inpatient services were estimated from the perspective of the third-party payer using Medicare fee schedules and average wholesale prices. Resource use data were collected prospectively on the same sample of patients as that used in the clinical trial.

The clinical study highlighted that fewer adverse events, that is psychiatric and/or cardiovascular hospitalisations, were observed in the intervention group than in the placebo group, although the difference was not statistically significant. The mean cost per patient in the intervention group was $2,733 (+/− $6,764) and $3,326 (+/− $7,195) in the placebo group (p = 0.32); these costs excluded the cost of medication. The costs for the intervention group increased to $3,093 after inclusion of the cost of medication compared with $3,326 for the placebo group.

The authors concluded that sertraline appeared to be a cost-effective strategy in the treatment of major depressive disorder following hospitalisation for a recent myocardial infarction or unstable angina. They also noted that their results were likely to have underestimated real cost differences because some potential cost savings associated with sertraline, such as reduced outpatient use, were not considered. This trial was conducted in multiple sites including Europe, thereby suggesting that the results are generalisable to many patient populations.

Summary

The pharmacoeconomic evidence identified was limited to one study. The evidence is on patients with acute coronary syndrome and may not be representative of all patients with depression and a chronic physical health problem. This limits the use of the economic evidence in making any solid conclusions about a pharmacological intervention in this population.

When making treatment decisions regarding the use of an antidepressant, many factors should be taken into consideration (that is, patient choice, clinical history, current medication, side-effect profiles and the cost of the drug) (see Table 68). In this population, a special emphasis is placed on the side-effect profile and potential drug interactions, because many service users may already be on other treatments for their physical condition and this increases the potential for such events to occur. People with comorbidities tend to be high utilisers of services and incur many costs over the course of their treatment. Therefore, when selecting an antidepressant, explore the potential of any adverse events because it may reduce further costs being incurred. This may result in cost savings, because the potential costs of treating such events are preventable.

Table 68. Drug acquisition costs.

Table 68

Drug acquisition costs.

8.6.2. Network meta-analysis of newer antidepressants

A network meta-analysis conducted by Cipriani and colleagues (2009) was published at the end of the guideline development process and was briefly considered by the GDG in view of its methodology and importance. A full discussion of the study and a preliminary de novo economic analysis based on its findings are presented in the depression guideline update (NCCMH, 2010).

In summary, a multiple-treatments meta-analysis, using both direct and indirect comparisons, assessed the effects of 12 new-generation antidepressants on major depression in terms of efficacy (response) and tolerability (dropouts). The results showed that mirtazapine, escitalopram, venlafaxine and sertraline were ranked as the four most efficacious treatments whilst escitalopram, sertraline, bupropion and citalopram were ranked as the four most tolerated antidepressants. The results of the economic analysis ranked mirtazapine, sertraline, escitalopram and citalopram as the four most cost-effective treatments. Mirtazapine dominated (cheaper and more effective) all other antidepressants considered in the analysis. Overall, given the considerable uncertainty surrounding both the results of the original meta-analysis and the de novo economic analysis, it was decided that any recommendations on specific pharmacological treatments in the depression guideline update (NICE, 2009) would not be influenced by the findings of Cipriani and colleagues (2009). In addition, as the study was not based on participants with a chronic physical health problem, the findings may be of limited relevance to this guideline.

8.7. OVERALL SUMMARY ON EFFICACY, SAFETY, ADVERSE EFFECTS AND INTERACTIONS, AND ECONOMIC EVIDENCE

Antidepressants are effective in the treatment of depression in people with a chronic physical health problem. Effect sizes are small to moderate, similar to those seen in depression not associated with physical illness. There is a clear distinction between the acute effects of antidepressants and placebo, but there is very little information on the longer-term therapeutic effects of antidepressants in people with a chronic physical health problem.

With regard to therapeutic effects, there appears to be little to choose between individual antidepressants or antidepressant groups. SSRIs tend to be better tolerated than TCAs. Newer non-SSRI antidepressants are also effective and appear to be reasonably well tolerated.

Interaction potential differs somewhat between individual antidepressants, but, generally speaking, no particular drug can be recommended for all clinical conditions. TCAs are involved in a wide range of interactions and are contra-indicated in some physical health problems particularly those involving in cardiac disease. SSRIs, particularly fluoxetine and paroxetine, are potent enzyme inhibitors involved in a wide range of interactions. SSRIs in general are linked to anti-platelet effects, which precludes their use in a number of cardiovascular and other conditions. In some cases, the use of alternatives to SSRIs and TCAs may be necessary. These alternatives may include widely used drugs such as mirtazapine and trazodone, but may also include rarely used drugs such as mianserin and moclobemide.

8.8. FROM EVIDENCE TO RECOMMENDATIONS

As has been noted in this chapter, the clinical and economic evidence base for pharmacological interventions for people with depression and a chronic physical health problem is more limited than that identified for depression in the absence of a chronic physical health problem. However, the broad pattern of evidence is similar. Given that the GDG's view was that the nature of depression in people with a chronic physical health problem is not fundamentally different from depression in the absence of such a problem, the group considered it appropriate to draw on the evidence base for depression more generally in developing its recommendations. In doing so, the GDG employed a number of principles when extrapolating from the general depression evidence base.

First, when there were data on people with a chronic physical health problem that were largely consistent with the depression guideline update (for example, the use of sertraline due to lower propensity for interactions), evidence from the latter guideline was taken into account when forming recommendations. Second, when there was uncertainty as to whether evidence concerning people with a chronic physical health problem was consistent with that found in the depression guideline update then extrapolation was not attempted. Third, when there was no evidence available concerning the population for this guideline and the GDG considered the recommendation to be important (for example, switching antidepressants), extrapolation was made from evidence in the depression guideline update.

Generally, SSRIs should be first-line treatment for depression in people with a chronic physical health problem. Of the SSRIs, sertraline and citalopram 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. These are generic drugs and are available relatively cheaply. Their low interaction potential and protective properties make it potentially worthwhile from a cost-effectiveness perspective, as it may result in cost savings due to potential adverse events that are prevented and offer a potential for additional QALY gains. The economic study conducted by O'Connor and colleagues (2005) evaluated sertraline versus placebo in a hospitalised population with acute coronary syndrome and found it to be cost effective. This evidence, although limited to one study, supports recommending sertraline in this population.

TCAs, despite evidence supporting their therapeutic activity, should generally be avoided as there is evidence of cardiotoxicity and poor tolerability. Where SSRIs are contra-indicated, suitable alternatives include mirtazapine, trazodone, mianserin and moclobemide. The choice of drug can be expected to be largely dependent upon relevant contra-indications related to the physical health problem and potential for interaction with co-administered drugs. It is on these latter issues that many of the recommendations focus.

For the pharmacological treatment of patients who have responded poorly to initial pharmacological interventions and have more complex depression, the NICE depression guideline update (NICE, 2009) should be consulted.

8.9. RECOMMENDATIONS

Drug treatment in step 2

8.9.1.1.

Do not use antidepressants routinely to treat subthreshold depressive symptoms or mild depression in patients with a chronic physical health problem (because the risk–benefit ratio is poor), but consider them for patients with:

  • a past history of moderate or severe depression or
  • mild depression that complicates the care of the physical health problem or
  • initial presentation of subthreshold depressive symptoms that have been present for a long period (typically at least 2 years) or
  • subthreshold depressive symptoms or mild depression that persist(s) after other interventions.
8.9.1.2.

Although there is evidence that St John's wort may be of benefit in mild or moderate depression, practitioners should:

  • not prescribe or advise its use by patients with depression and a chronic physical health problem because of uncertainty about appropriate doses, persistence of effect, variation in the nature of preparations and potential serious interactions with other drugs (including oral contraceptives, anticoagulants and anticonvulsants)
  • advise patients with depression of the different potencies of the preparations available and of the potential serious interactions of St John's wort with other drugs50.

Treatment options in step 3

8.9.1.3.

For patients with persistent subthreshold depressive symptoms or mild to moderate depression and a chronic physical health problem who have not benefited from a low-intensity psychosocial intervention, discuss the relative merits of different interventions with the patient and provide:

  • an antidepressant (normally a selective serotonin reuptake inhibitor [SSRI]) or
  • one of the following high-intensity psychological interventions:

    group-based CBT or

    individual CBT for patients who decline group-based CBT or for whom it is not appropriate, or where a group is not available or

    behavioural couples therapy for people who have a regular partner and where the relationship may contribute to the development or maintenance of depression, or where involving the partner is considered to be of potential therapeutic benefit51.

8.9.1.4.

For patients with initial presentation of severe depression and a chronic physical health problem, consider offering a combination of individual CBT and an antidepressant52.

8.9.1.5.

The choice of intervention should be influenced by the:

  • duration of the episode of depression and the trajectory of symptoms
  • previous course of depression and response to treatment
  • likelihood of adherence to treatment and any potential adverse effects
  • course and treatment of the chronic physical health problem
  • patient's treatment preference and priorities53.

Choice of antidepressants54

8.9.1.6.

When an antidepressant is to be prescribed for a patient with depression and a chronic physical health problem, take into account the following:

  • the presence of additional physical health disorders
  • the side effects of antidepressants, which may impact on the underlying physical disease (in particular, SSRIs may result in or exacerbate hyponatraemia, especially in older people)
  • that there is no evidence as yet supporting the use of specific antidepressants for patients with particular chronic physical health problems
  • interactions with other medications.
8.9.1.7.

When an antidepressant is to be prescribed, be aware of drug interactions and:

  • refer to appendix 1 of the BNF55 and the table of interactions in Appendix 16 [of this guideline] for information
  • seek specialist advice if there is uncertainty
  • if necessary, refer the patient to specialist mental health services for continued prescribing.
8.9.1.8.

First prescribe an SSRI in generic form unless there are interactions with other drugs; consider using citalopram or sertraline because they have less propensity for interactions.

8.9.1.9.

When prescribing antidepressants, be aware that:

  • dosulepin should not be prescribed
  • non-reversible monoamine oxidase inhibitors (MAOIs; for example, phenelzine), combined antidepressants and lithium augmentation of antidepressants should normally be prescribed only by specialist mental health professionals.
8.9.1.10.

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 recommended for routine use in primary care, venlafaxine is associated with a greater risk of death from overdose
  • tricyclic antidepressants (TCAs), except for lofepramine, are associated with the greatest risk in overdose56.

Interactions of SSRIs with other medication

8.9.1.11.

Do not normally offer SSRIs to patients taking non-steroidal anti-inflammatory drugs (NSAIDs) because of the increased risk of gastrointestinal bleeding. Consider offering an antidepressant with a lower propensity for, or a different range of, interactions, such as mianserin, mirtazapine, moclobemide or trazodone.

8.9.1.12.

If no suitable alternative antidepressant can be identified, SSRIs may be prescribed at the same time as NSAIDs if gastroprotective medicines (for example, proton-pump inhibitors) are also offered.

8.9.1.13.

Do not normally offer SSRIs to patients taking warfarin or heparin because of their anti-platelet effect.

8.9.1.14.

Use SSRIs with caution in patients taking aspirin. When aspirin is used as a single agent, consider alternatives that may be safer, such as trazodone or mianserin.

8.9.1.15.

If no suitable alternative antidepressant can be identified, SSRIs may be prescribed at the same time as aspirin if gastroprotective medicines (for example, proton-pump inhibitors) are also offered.

8.9.1.16.

Consider offering mirtazapine to patients taking heparin, aspirin or warfarin (but note that when taken with warfarin, the international normalised ratio [INR] may increase slightly).

8.9.1.17.

Do not offer SSRIs to patients receiving ‘triptan’ drugs for migraine. Offer a safer alternative such as mirtazapine, trazodone or mianserin.

8.9.1.18.

Do not normally offer SSRIs at the same time as monoamine oxidase B (MAO-B) inhibitors such as selegiline and rasagiline. Offer a safer alternative such as mirtazapine, trazodone or mianserin.

8.9.1.19.

Do not normally offer fluvoxamine to patients taking theophylline, clozapine, methadone or tizanidine. Offer a safer alternative such as sertraline or citalopram.

8.9.1.20.

Offer sertraline as the preferred antidepressant for patients taking flecainide or propafenone, although mirtazapine and moclobemide may also be used.

8.9.1.21.

Do not offer fluoxetine or paroxetine to patients taking atomoxetine. Offer a different SSRI.

Starting treatment

8.9.1.22.

When prescribing antidepressants, explore any concerns the patient with depression and a chronic physical health problem has about taking medication, explain fully the reasons for prescribing, and provide information about taking antidepressants, including:

  • the gradual development of the full antidepressant effect
  • the importance of taking medication as prescribed and the need to continue treatment after remission
  • potential side effects
  • the potential for interactions with other medications
  • the risk and nature of discontinuation symptoms with all antidepressants, particularly with drugs with a shorter half-life (such as paroxetine and venlafaxine), and how these symptoms can be minimised
  • the fact that addiction does not occur with antidepressants.

Offer written information appropriate to the patient's needs57.

8.9.1.23.

Prescribe antidepressant medication at a recognised therapeutic dose for patients with depression and a chronic physical health problem (that is, avoid the tendency to prescribe at subtherapeutic doses in these patients).

8.9.1.24.

For patients started on antidepressants who are not considered to be at increased risk of suicide, normally see them after 2 weeks. See them regularly thereafter, for example at intervals of 2 to 4 weeks in the first 3 months, and then at longer intervals if response is good58.

8.9.1.25.

A patient with depression started on antidepressants who is considered to present an increased suicide risk or is younger than 30 years (because of the potential increased prevalence of suicidal thoughts in the early stages of antidepressant treatment for this group) should normally be seen after 1 week and frequently thereafter as appropriate until the risk is no longer considered clinically important59.

8.9.1.26.

If a patient with depression and a chronic physical health problem develops side effects early in antidepressant treatment, provide appropriate information and consider one of the following strategies:

  • monitor symptoms closely where side effects are mild and acceptable to the patient or
  • stop the antidepressant or change to a different antidepressant if the patient prefers or
  • in discussion with the patient, consider short-term concomitant treatment with a benzodiazepine if anxiety, agitation and/or insomnia are problematic, but:

    do not offer benzodiazepines to patients with chronic symptoms of anxiety

    use benzodiazepines with caution in patients at risk of falls

    in order to prevent the development of dependence, do not use benzodiazepines for longer than 2 weeks.

Continuing treatment

8.9.1.27.

Support and encourage a patient with a chronic physical health problem who has benefited from taking an antidepressant to continue medication for at least 6 months after remission of an episode of depression. Discuss with the patient that:

  • this greatly reduces the risk of relapse
  • antidepressants are not associated with addiction60.
8.9.1.28.

Review with the patient with depression and a chronic physical health problem the need for continued antidepressant treatment beyond 6 months after remission, taking into account:

  • the number of previous episodes of depression
  • the presence of residual symptoms
  • concurrent physical health problems and psychosocial difficulties61.

Failure of treatment to provide benefit

8.9.1.29.

If the patient's depression shows no improvement after 2 to 4 weeks with the first antidepressant, check that the drug has been taken regularly and in the prescribed dose62.

8.9.1.30.

If response is absent or minimal after 3 to 4 weeks of treatment with a therapeutic dose of an antidepressant, increase the level of support (for example, by weekly face-to-face or telephone contact) and consider:

  • increasing the dose in line with the SPC if there are no significant side effects or
  • switching to another antidepressant as described in Section 1.8 of the Depression guideline (CG90)63 if there are side effects or if the patient prefers64.
8.9.1.31.

If the patient's depression shows some improvement by 4 weeks, continue treatment for another 2 to 4 weeks. Consider switching to another antidepressant as described in Section 1.8 of the Depression guideline (CG90)65 if:

  • response is still not adequate or
  • there are side effects or
  • the patient prefers to change treatment66.
8.9.1.32.

When switching from one antidepressant to another, be aware of:

  • the need for gradual and modest incremental increases in dose
  • interactions between antidepressants
  • the risk of serotonin syndrome when combinations of serotonergic antidepressants are prescribed67.
8.9.1.33.

If an antidepressant has not been effective or is poorly tolerated:

  • consider offering other treatment options, including high-intensity psychological treatments
  • prescribe another single antidepressant (which can be from the same class) if the decision is made to offer a further course of antidepressants.

Stopping or reducing antidepressants

8.9.1.34.

Advise people with depression and a chronic physical health problem who are taking antidepressants that discontinuation symptoms68 may occur on stopping, missing doses or, occasionally, on reducing the dose of the drug. Explain that symptoms are usually mild and self-limiting over about 1 week, but can be severe, particularly if the drug is stopped abruptly69.

8.9.1.35.

When stopping an antidepressant, gradually reduce the dose, normally over a 4-week period, although some patients may require longer periods particularly with drugs with a shorter half-life (such as paroxetine and venlafaxine). This is not required with fluoxetine because of its long half-life70.

8.9.1.36.

Inform the patient that they should seek advice from their practitioner if they experience significant discontinuation symptoms. If discontinuation symptoms occur:

  • monitor symptoms and reassure the patient if symptoms are mild
  • consider reintroducing the original antidepressant at the dose that was effective (or another antidepressant with a longer half-life from the same class) if symptoms are severe, and reduce the dose gradually while monitoring symptoms71.

8.10. RESEARCH RECOMMENDATIONS

The GDG has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future.

8.10.1. Antidepressant medication compared with placebo in patients with depression and chronic obstructive pulmonary disease

What is the clinical and cost effectiveness of antidepressant medication compared with placebo in patients with depression and COPD?

Why this is important

There is limited evidence for the effectiveness of antidepressant treatment in patients with depression and a chronic physical health problem. Of particular concern to the GDG was the high incidence of depression in patients with COPD (which is also known to be associated with a high incidence of anxiety disorders). The GDG considered it important to measure the effectiveness of antidepressant medication in the treatment of COPD. The answer to this question has important practical implications for service delivery, particularly for a patient group with mental health needs that are traditionally under-treated within the NHS.

The question should be answered using a randomised controlled trial in which patients with moderate depression and COPD receive either placebo or antidepressant medication. The outcomes chosen should reflect both observer-rated and patient-rated assessments for acute and medium-term outcomes for at least 6 months, and an assessment of the acceptability and burden of treatment. In addition to the assessment of symptoms of depression, the study should also assess the impact of antidepressant medication on symptoms of anxiety. The study should be large enough to determine the presence or absence of clinically important effects using a non-inferiority design together with robust health economic measures.

Here and elsewhere in the guideline, each study considered for review is referred to by a study ID in capital letters (primary author and date of study publication, except where a study is in press or only submitted for publication, then a date is not used).

Here and elsewhere in the guideline, each study considered for review is referred to by a study ID in capital letters (primary author and date of study publication, except where a study is in press or only submitted for publication, then a date is not used).

This recommendation also appears in NICE (2009) and has been taken from the previous NICE guideline (NICE, 2004a, 2007a). The evidence for this recommendation has not been updated and any wording changes have been made for clarification only.

This recommendation also appears in Section 7.4.1 where the psychosocial data is presented.

This recommendation also appears in Section 7.4.1 where the psychosocial data is presented.

This recommendation also appears in Section 7.4.1 where the psychosocial data is presented.

For additional considerations on the use of antidepressants and other medications (including the assessment of the relative risks and benefits) for women who may become pregnant, please refer to the BNF and individual drug SPCs. For women in the antenatal and postnatal periods, see also NICE (2007d).

Available from: www​.bnf.org.

This recommendation also appears in NICE (2009).

This recommendation also appears in NICE (2009).

This recommendation also appears in NICE (2009) and has been taken from the previous NICE guideline (NICE, 2004a, 2007a). The evidence for this recommendation has not been updated and any wording changes have been made for clarification only.

This recommendation also appears in NICE (2009) and has been taken from the previous NICE guideline (NICE, 2004a, 2007a). The evidence for this recommendation has not been updated and any wording changes have been made for clarification only.

This recommendation also appears in NICE (2009).

This recommendation also appears in NICE (2009).

This recommendation also appears in NICE (2009).

This recommendation also appears in NICE (2009).

This recommendation also appears in NICE (2009).

Features of serotonin syndrome include confusion, delirium, shivering, sweating, changes in blood pressure and myoclonus.

Discontinuation symptoms include increased mood change, restlessness, difficulty sleeping, unsteadiness, sweating, abdominal symptoms and altered sensations.

This recommendation also appears in NICE (2009).

This recommendation also appears in NICE (2009).

This recommendation also appears in NICE (2009).

Footnotes

48

Here and elsewhere in the guideline, each study considered for review is referred to by a study ID in capital letters (primary author and date of study publication, except where a study is in press or only submitted for publication, then a date is not used).

49

Here and elsewhere in the guideline, each study considered for review is referred to by a study ID in capital letters (primary author and date of study publication, except where a study is in press or only submitted for publication, then a date is not used).

50

This recommendation also appears in NICE (2009) and has been taken from the previous NICE guideline (NICE, 2004a, 2007a). The evidence for this recommendation has not been updated and any wording changes have been made for clarification only.

51

This recommendation also appears in Section 7.4.1 where the psychosocial data is presented.

52

This recommendation also appears in Section 7.4.1 where the psychosocial data is presented.

53

This recommendation also appears in Section 7.4.1 where the psychosocial data is presented.

54

For additional considerations on the use of antidepressants and other medications (including the assessment of the relative risks and benefits) for women who may become pregnant, please refer to the BNF and individual drug SPCs. For women in the antenatal and postnatal periods, see also NICE (2007d).

55

Available from: www​.bnf.org.

56

This recommendation also appears in NICE (2009).

57

This recommendation also appears in NICE (2009).

58

This recommendation also appears in NICE (2009) and has been taken from the previous NICE guideline (NICE, 2004a, 2007a). The evidence for this recommendation has not been updated and any wording changes have been made for clarification only.

59

This recommendation also appears in NICE (2009) and has been taken from the previous NICE guideline (NICE, 2004a, 2007a). The evidence for this recommendation has not been updated and any wording changes have been made for clarification only.

60

This recommendation also appears in NICE (2009).

61

This recommendation also appears in NICE (2009).

62

This recommendation also appears in NICE (2009).

63

NICE (2009).

64

This recommendation also appears in NICE (2009).

65

NICE (2009).

66

This recommendation also appears in NICE (2009).

67

Features of serotonin syndrome include confusion, delirium, shivering, sweating, changes in blood pressure and myoclonus.

68

Discontinuation symptoms include increased mood change, restlessness, difficulty sleeping, unsteadiness, sweating, abdominal symptoms and altered sensations.

69

This recommendation also appears in NICE (2009).

70

This recommendation also appears in NICE (2009).

71

This recommendation also appears in NICE (2009).

Copyright © 2010, The British Psychological Society & The Royal College of Psychiatrists.

All rights reserved. No part of this book may be reprinted or reproduced or utilised in any form or by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying and recording, or in any information storage or retrieval system, without permission in writing from the publishers. Enquiries in this regard should be directed to the British Psychological Society.

Cover of Depression in Adults with a Chronic Physical Health Problem
Depression in Adults with a Chronic Physical Health Problem: Treatment and Management.
NICE Clinical Guidelines, No. 91.
National Collaborating Centre for Mental Health (UK).
Leicester (UK): British Psychological Society; 2010.

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