There is a paucity of research of the effects regarding pharmacological and non-pharmacological therapies used to treat depression and anxiety in COPD, accounting for the absence of recommendations regarding the treatment of anxiety and depression in global and national COPD guidelines. Besides pulmonary rehabilitation, which is only available for a small percentage of patients,47 the updated Global Initiative for Chronic Obstructive Lung Disease guideline does not mention other treatment options for mental health issues.1 It is therefore not surprising that only a minority of patients with depression or anxiety are receiving appropriate treatment.48
Despite the lack of direct evidence in COPD populations, several effective and potentially effective treatment regimens for reduction of depression and/or anxiety symptoms in COPD can be proposed based on experiences in patients with other chronic diseases. These are considered later with descriptions of study results regarding the chronic disease population and COPD (if available).
Cognitive behavioural therapy
Cognitive Behavioural Therapy (CBT) is a structured, psychological intervention in which the patient works collaboratively with the therapist to identify the types and effects of thoughts, beliefs and interpretations on current symptoms, feelings states and/or problem areas.49 Its aim is to develop skills to enable the patient to control their symptoms and manage their disorder by utilizing a combination of behavioural and cognitive techniques to counteract problematic thoughts, beliefs and interpretations related to the target symptoms and problems.6,29
Given its strong evidence base, mental health guidelines recommend CBT as the treatment of choice for a range of mood and anxiety disorders and as an adjunct to others (e.g. National Institute for Health and Clinical Excellence (NICE)6,29). Low-intensity CBT-based psychosocial interventions (e.g. computerized CBT or a structured group physical activity programme using principles of CBT) are recommended for people with mild to moderate anxiety and/or depression.6 High-intensity psychological intervention using CBT in combination with medication is recommended for people with moderate to severe depression.6
The potential for CBT to ameliorate depression associated with chronic illness has recently been more widely recognized. Positive health outcomes from implementing CBT with chronic diseases and cancer have been reported.50–52 Positive effects have also been found in evaluating CBT for anxiety in clinical studies on a range of patient populations.53 It has been reported that the use of CBT either as a single-treatment modality or in combination with pharmacotherapy is well tolerated, cost-effective and produces substantial treatment gains for individuals with panic disorder over the short and long term.54
A recent review evaluated four small studies involving the use of CBT with COPD. It was concluded that when used with exercise and education, there is only limited evidence that CBT contributes to significant reductions in anxiety and depression among patients with COPD.55 Further, a recent large randomized controlled trial showed that CBT group treatment and COPD education can both achieve improvements in quality of life, anxiety and depression, with little difference between them.56 Another recent study indicated that a brief, specifically targeted CBT intervention can control panic attacks in patients and prevent the development and worsening of panic-spectrum psychopathology and anxiety symptoms.57 However, further randomized controlled trials studies are necessary to provide evidence on the effectiveness of CBT in COPD.55
A recent meta-analysis concluded that behavioural therapy, an approach that uses a conditioning formulation to develop a daily structured plan, may be as effective in ameliorating depression as the more comprehensive CBT model.58 This briefer approach may have potential benefits for people with co-morbid chronic disease and depression because it focuses on developing a short-term structure that could, for example, include organizing social activities into the daily plan to alleviate the isolation that is often a symptom of depression and illness.
Pharmacological interventions are commonly used to treat depression and anxiety in patients with COPD. Evidence for antidepressant therapy to overcome these mood disorders in COPD is limited.59–61 There is a lack of randomized controlled trials to assess the effects of pharmacological interventions in this population. In addition, most of the available studies have small sample sizes, large dropout rates or a short follow-up period.59
Despite the relative lack of scientifically rigorous evidence, pharmacotherapy appears to be as commonly used for anxiety and depression in patients with COPD as in other chronic disease groups. Medications used in standard clinical practice for depression include antidepressants, benzodiazepines, azapirones and less commonly, antipsychotic agents and anticonvulsants. The antidepressants are further classified into groups based on which chemicals in the brain they affect. The main classes of antidepressants include non-selective antidepressants (tricyclic antidepressants, e.g. nortriptyline, and monamine oxidase inhibitors, e.g. selegiline) and selective antidepressants (selective serotonin re-uptake inhibitors (SSRI, e.g. citalopram); serotonin and norepinephrine re-uptake inhibitors (e.g. venlafaxine) and norepinephrine and dopamine re-uptake inhibitors (e.g. bupropion).59
SSRIs are generally considered as preferred first-line agents for control of depressive symptoms in patients with COPD,29 with some evidence pointing to better depression scores and quality-of-life outcomes.62–64 A two-phase trial (6 weeks randomized and 6 weeks open labelled) has shown significant reductions in depression scores (Hospital Anxiety and Depression scale, Beck Depression Inventory), improved walking distance and health-related quality of life (the disease-specific St George's Respiratory Questionnaire) at 3 months follow-up.62 SSRIs are considered to be relatively selective in their pharmacological effects,65 although many inhibit cytochrome P450s (CYP). The CYP are members of a superfamily of oxidative enzymes, which represent the major system for oxidative metabolism of therapeutic substances, accounting for around 75% of the total.66,67 Human CYP are primarily membrane-associated proteins, located either in the inner membrane of mitochondria or in the endoplasmic reticulum of cells. They affect half-life, adverse effects and rates of clearance of other drugs.68,69
Either venlafaxine or mirtazapine are considered first-line drugs that are useful for patients who are not responsive to SSRI or with patients who previously had a good response to these drugs.70 Tricyclic antidepressants and monamine oxidase inhibitors can also be used with caution.71 One small, randomized, placebo-controlled trial of treatment in patients with major depression reported high efficacy for nortriptyline in improving short-term outcomes for depression, anxiety, panic attacks, cognitive function and overall disability.72 However, tricyclic antidepressants have significant adverse effects and are associated with clinically significant pharmacodynamic interactions with many medications frequently prescribed to elderly patients71 as well as those with chronic illnesses (Table 1).
Pharmacological interventions, in particular antidepressants and benzodiazepines, are commonly used to treat anxiety in patients with COPD. A recent systematic review shows a non-significant but clinically relevant benefit (minimum improvement of 1.5 points in Hospital Anxiety and Depression scale score or a change from baseline of 20% in patients with COPD73) with the use of SSRI to control anxiety symptoms in patients with COPD.59,62 Case reports have also reported an improvement in anxiety symptoms among patients treated with sertraline.74 However, little or no difference has been evident from trials for other classes of medications such as tricyclic antidepressants and azapirone.60,75 It is interesting to note that although benzodiazepines have been commonly used in clinical practice for control of anxiety in patients with COPD, no randomized controlled trails are available to asses the efficacy of benzodiapines in this population.
Current recommendations in anxiety management are for CBT to be used as a front-line treatment for generalized anxiety disorder and generalized social anxiety disorder,31 whilst adding SSRIs are recommended (notably escitalopram or paroxetine) if CBT is ineffective or unsuitable. If there is no improvement in the first 3 months, an alternative SSRI or imipramine or venlafaxine is recommended for generalized anxiety disorder and either sertraline, fluvoxamine or venlafaxine for generalized social anxiety disorder.29 Benzodiazepines are recommended only for short-term use for acute flare of anxiety symptoms.76
Numerous adverse effects from the use of antidepressant therapy have been reported70,77–82 (Table 3). Serotonin toxicity (symptoms such as, e.g. tremor, confusion, sweating, diarrhoea) may occur with a high dose of a single drug or when more than one serotonergic agents are used together or when changing antidepressants with an inadequate washout period between drugs.70 In the elderly, the commonly reported adverse effect of sedation may increase the risk of falls and fractures.83–85 Weight gain, which can occur with longer-term antidepressant therapy,70 may benefit those patients with more severe COPD in whom low body mass is frequent and contributes to a poorer prognosis.86 Caution should be taken while prescribing certain antidepressants (tricyclic antidepressants and mirtazapine) and benzodiazepines in patients with moderate to severe COPD, and especially for patients with COPD who are CO2 retainers, as there is an increased risk of respiratory centre depression and resulting respiratory failure. In addition, benzodiazepines have a high risk of tolerance and dependence and hence should only be used for short-term periods and/or for acute exacerbation of mood symptoms.76,87 Side-effects of various antidepressant medications used for treatment of anxiety and/or depression in COPD are summarized in Table 4.
Table 3. Important adverse effects from antidepressant therapy†
|Adverse effects||SSRI||Venlafaxine||Mirtazapine||Tricyclic antidepressants||Monoamine oxidase inhibitors|
|Elevated serum aminotrasferases||∼||∼||∼||∼||++|
|Myoclonus, twitching, tremor||++||++||∼||++||++|
|Sedation and/or drowsiness||++||+||++||++||++|
|Urine hesitancy or retention||∼||∼||∼||++||∼|
Table 4. Side-effects of antidepressant drug therapy in patients with COPD and co-morbid anxiety and/or depression as reported by various studies
|Study||Study type||Study size (n)||Medication||Side-effects reported†|
|Gordon et al.61||Cross-over trial||13||Desipramine (TCA)||Intolerable side-effects‡ (two), dry§ mouth§, fatigue§, tremor§|
|Light et al.60||Cross-over trial||12||Doxepin (TCA)||Blurred vision (five), drowsiness (three), dry mouth (two), headache (one).|
|Borson et al.72||Randomized controlled trial||36||Nortriptyline (TCA)||Dry mouth (one), sedation (one), orthostatic hypotension (one)|
|Singh et al.75||Randomized controlled trial||11||Buspirone (azapirone)||Nausea, diarrhoea and dyspnoea (two), dizziness and fatigue (one)|
|Lacasse et al.64||Randomized controlled trial||23||Paroxetine (SSRI)||Somnolence (five), tremor (two), constipation (two), nausea (two), headache (two), dry mouth (one), taste perversion (one)|
|Subbe et al.63||Randomized controlled trial||8||Citalopram (SSRI)||Insomnia, restlessness and worsening anxiety (one), minor side-effects† (six)|
|Eiser et al.62||Randomized controlled trial||28||Paroxetine (SSRI)||Nausea and vomiting (four)|
Pulmonary rehabilitation has extensive evidence supporting its benefits and is a highly recommended core component of treatment in COPD.88 Pulmonary rehabilitation programmes involve assessment of patient problems and goals, exercise training, education, nutritional intervention and psychosocial support.47 The aim is to restore the patient to the highest possible level of independent functioning.89 Documented benefits from pulmonary rehabilitation include improvements in quality of life and exercise tolerance, and a reduction in dyspnoea and fatigue.90 Over the last decade, evidence has also confirmed that pulmonary rehabilitation can reduce symptoms of anxiety and depression in patients with moderate to severe COPD.88,91 However, it is not clear which component(s) confer psychosocial benefits.92 Rehabilitation commencing soon after initial recovery from a severe exacerbation of COPD has been shown to have substantial benefits for patients’ exercise capacity, fatigue and emotional function.93 It is not established whether home-based exercise and nontraditional rehabilitation programmes (e.g. community-based rehabilitation) produce the same benefits for mental health. It is also not known whether combining CBT with pulmonary rehabilitation may provide even greater benefits in improving symptoms, self-confidence, quality of life and/or psychological symptomatology.
Relaxation is often a component of pulmonary rehabilitation, and it can be used as an adjunct to other forms of therapy (e.g. CBT and self-management programmes). Relaxation therapy encompasses a range of techniques such as autogenic training, breathing exercises, progressive muscle relaxation, isometric muscle relaxation, biofeedback, hypnosis and meditation. The purpose of these techniques is to facilitate the relaxation response by effectively managing the group of physiological changes accompanying anxiety. This allows regulation of the sympathetic nervous system and management of the stimulation of certain regions of the hypothalamus.94
A review of relaxation therapy concluded that it is effective in reducing hypertension, insomnia, anxiety, pain, and medication use across multiple populations, diagnostic categories and settings.95 A meta-analysis of trial with relaxation therapy in COPD found statistically significant beneficial effects on both dyspnoea and psychological well-being.96
Palliative care is delivered in a range of settings. A typical palliative-care team may include varying combinations of physician, mental health and palliative-care nurses, auxiliary staff, a pharmacist, bereavement counsellor, psychologist, chaplain, social worker and volunteers.44 The purpose is to maximize care, relieve suffering and improve quality of life for the patients and provide support for the family and carers.44
Successful approaches to the assessment and management of pain and some physical and psychological symptoms have been established in controlled trials.97 Promising improvements in mental health were also found for COPD in a study of an intensive home-based case management programme which included support for their psychological needs.98