Chapter 2
Chronic Obstructive Pulmonary Disorder

CONTENTS

1. Introduction
   • Treatment of COPD
   • Mental illness in COPD
2. Antidepressants in COPD
   • Breathlessness
   • Smoking cessation
   • Summary
3. Anxiolytics in COPD
   • Benzodiazepines
   • Promethazine
   • Pregabalin
   • Summary
4. Antipsychotics in COPD
   • Acute respiratory failure
   • Infection
   • Summary
5. Addictions and substance use
   • Opiate substitute treatment
   • Benzodiazepines
   • Pregabalin
6. Drug interactions
   • Beta‐2 agonists
   • Muscarinic antagonists
   • Theophylline
   • Azithromycin
   • Roflumilast
7. Patient information
8. References

INTRODUCTION

Treatment of COPD

Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable disease characterised by persistent respiratory symptoms. These include breathlessness, chronic cough or sputum production, and frequent chest infections. Airflow limitation is progressive and not fully reversible. The aim of treatment is to reduce symptom burden, minimise the risk and severity of exacerbations, and reduce mortality. It must always include smoking cessation support. Drug treatment should include short‐acting beta‐2 agonists (SABAs – salbutamol, terbutaline) or short‐acting muscarinic antagonists (SAMAs – ipratropium), long‐acting beta‐2 agonists (LABAs – salmeterol, formoterol) and/or long‐acting muscarinic antagonists (LAMAs – tiotropium). Particular patients may require inhaled corticosteroids (ICS – beclomethasone, budesonide, fluticasone furoate), methylxanthines (theophylline), mucolytics, prophylactic antibiotics (azithromycin), oral phosphodiesterase‐4 inhibitors (roflumilast), or oral corticosteriods1.

Mental illness in COPD

Depression and anxiety are common comorbidities in patients with COPD. Reported prevalence varies widely (depression, 8–80%; anxiety, 6–74%2), and there is a link to severity of illness – patients with severe COPD are twice as likely to develop depression compared to patients with mild illness, and depression and anxiety worsen COPD outcomes (including hospitalisation rates3 and mortality4). Patients with depression and COPD who take antidepressants are more likely to adhere to their COPD treatment5,6. There are few high‐quality trials examining the efficacy and safety of pharmacological treatments for depression or anxiety in patients with COPD7,8, so medication choice is instead informed largely by data derived from the non‐COPD population. It is worth noting that some symptoms of COPD are similar to those in anxiety and depression – notably fatigue, altered sleep, and weight loss – and this might make decisions about treatment effectiveness more difficult.

Patients with schizophrenia or bipolar disorder are more likely than their counterparts in the general population to suffer with COPD (odds ratios from meta‐analyses of 1.573 and 1.551, respectively9), and proportions of undiagnosed illness may be high (1 in 4 smokers with serious mental illness (SMI) had undiagnosed COPD in one study10). The reason for this association is unlikely to be limited to the higher rates of smoking amongst patients with schizophrenia or bipolar disorder11; rather, poor self‐care, social deprivation, and the prevalence of other physical comorbidities in people with SMI are considered important9. Unfortunately, there is also evidence to suggest inequalities in the quality of care after diagnosis, and for increased mortality following acute exacerbations of COPD for patients with schizophrenia compared to those without12.

The concerns with treating mental illness in a person with COPD are primarily based on overlapping drug side‐effect profiles (e.g. anticholinergic effects, respiratory depression, or propensity to cause arrhythmias), or direct pharmacokinetic interactions. Most of these are theoretical, and there are few absolute contraindications. If psychotropic treatment is warranted but options are limited by the current airways prescription, each respiratory therapy should be reviewed by the patient’s lung clinician to determine its ongoing need and to consider alternatives that may pose less risk.

ANTIDEPRESSANTS IN COPD

As already noted, it is not clear whether antidepressant treatment for patients with depression and COPD is effective – data specifically relating to the COPD population are scarce and fraught with the confounders common to chronic medical illness. Even fewer data are available to compare drugs, or even just drug classes with each other. Small studies and case reports describe the use of selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) in patients with depression and COPD13,14. TCAs are not usually considered first‐line treatment for depression in the non‐COPD population, and for those with COPD, the potential for additive anticholinergic effects from muscarinic antagonist bronchodilators such as tiotropium and ipratropium will diminish their appeal further (although in practical terms, this is probably only theoretical; see section on drug interactions).

One large cohort study found a worsening of respiratory‐related morbidity and mortality in patients with COPD who were new users of SSRIs and serotonin‐ noradrenaline reuptake inhibitors (SNRIs)15. This appears alarming but should prompt close monitoring (adverse event rates remained small) rather than contraindicating use. Moreover, as beta‐2 agonists can lead to dose‐related QT interval prolongation and hypokalaemia, the risk of serious arrhythmia is theoretically increased if patients are also taking other agents that may prolong the QT interval or cause other cardiac arrhythmias. This makes TCAs, citalopram, and escitalopram less sensible choices (see section on drug interactions).

Breathlessness

There may be a relationship between depression, anxiety, and breathlessness, with symptoms of anxiety and depression being linked to the development of dyspnoea16; thus, treating the concurrent mood disorder may ease respiratory symptoms. In addition, some authors have suggested a role for antidepressants specifically in the direct treatment of breathlessness via inhibition of fear responses, altering the patient’s perception of, and emotional response to, unpleasant stimuli such as breathlessness17. Sertraline was not effective when examined in an RCT for this indication (although it did benefit quality of life)18. Mirtazapine appears theoretically promising but as yet unproven beyond case series17.

Smoking cessation

Smoking cessation is of vital importance in the management of COPD, and COPD patients who continue to smoke are more likely to suffer depression19. The antidepressants bupropion and nortriptyline have both been used in smoking cessation, although they are not considered the most effective options (for COPD patients this is varenicline and combined NRT20). Nortriptyline showed benefits to depression and anxiety symptoms in a single small study in patients with COPD21. The efficacy of bupropion for the treatment of depression or anxiety in patients with COPD is unproven. Although treating psychiatric symptoms and enabling smoking cessation with one single drug is an attractive prospect, given the importance of stopping smoking in this population it is probably preferable to try the most effective treatment (varenicline) for this indication first, and treat the depression or anxiety separately. If other smoking cessation strategies have failed, then it might be reasonable to consider bupropion earlier in the treatment cascade for depression. Note also that bupropion is unlicensed for the treatment of depression in some countries.

If patients are already prescribed bupropion for smoking cessation but depressive symptoms persist, then combining bupropion with other antidepressants is possible. Bupropion was used as an augmenting agent to citalopram in the STAR*D trial22, and is usually well tolerated, although it is known to lower the seizure threshold in a dose‐dependent manner and inhibit CYP2D6. Cautious dosing of the added antidepressant is recommended.

Summary

Choose an SSRI (avoid citalopram and escitalopram), or mirtazapine if sleep disturbance or poor appetite are particular problems. Consider bupropion (not first line), especially if other smoking cessation strategies have failed.

ANXIOLYTICS IN COPD

Antidepressants are generally recommended first line for anxiety, but other anxiolytics or sedatives (benzodiazepines, promethazine, pregabalin) may also be prescribed.

Benzodiazepines

Prescribers often worry about the risk of benzodiazepines causing respiratory depression. The reality is that benzodiazepines rarely cause respiratory depression in patients...