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

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.

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 Of these, one (SCT-MD-24) was unpublished and 60 were published in peer-reviewed journals between 1984 and 2008.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.

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 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.

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.

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.

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.

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 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).

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.

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.

8.3.1. 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.

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.

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.

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).

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.

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.

8.5.1. 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).

8.6.1. 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.

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.

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.

8.10.1. 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?