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Evidence-Based Reviews

COPD: How to manage comorbid depression and anxiety

Psychiatrists can help oxygen-starved patients breathe more easily and get full benefit from medical treatments.

Vol. 2, No. 11 / November 2003

Mood disorders spell danger for patients with chronic obstructive pulmonary disease (COPD). Comorbid depression and anxiety often complicate or frustrate treatment of this debilitating—and ultimately fatal—respiratory disease (Box 1).

Managing COPD-related psychiatric disorders is crucial to improving patients’ quality of life. This article presents two cases to address:

  • common causes of psychiatric symptoms in patients with COPD
  • strategies for effectively treating these symptoms while avoiding adverse effects and drug-drug interactions.


Ms. H, age 59, a pack-a-day smoker since age 19, was diagnosed with COPD 3 years ago. Since then, dyspnea has rendered her unable to work, play with her grandchildren, or walk her dog. She has become increasingly apathetic and tired and is not complying with her prescribed pulmonary rehabilitation. Her primary care physician suspects she is depressed and refers her to a psychiatrist.

Box 1

COPD: debilitating and progressive

COPD is the fourth leading cause of death in the United States after heart disease, malignant neoplasms, and cerebrovascular disease. A total of 122,009 COPD-related deaths were reported in 2000.1

Cigarette smoking causes 80 to 90% of COPD cases.2 Occupational exposure to particles of silica, coal dust, and asbestos also can play a significant role. Alpha-1-antitrypsin deficiency—a rare, genetically transmitted enzyme deficiency—accounts for 0.1% of total cases.

Two disease processes are present in most COPD cases:

  • emphysema, resulting from destruction of air spaces and their associated pulmonary capillaries (Figure)
  • chronic bronchitis, causing airway hyperreactivity and increased mucus production.

The first symptom of COPD may be a chronic, productive cough. As the disease progresses, the patient becomes more prone to pulmonary infections, increasingly dyspneic, and unable to exercise. This results in occupational disability, social withdrawal, decreased mobility, and difficulty performing activities of daily living. Initially, an increased respiratory rate keeps oxygen saturation normal. Over time, however, the disease progresses to chronic hypoxia.

End-stage COPD is characterized by chronic hypoxia and retention of carbon dioxide due to inadequate gas exchange. Death results from respiratory failure or from complications such as infections.

During the psychiatrist’s initial interview, Ms. H exhibits anhedonia, feelings of worthlessness and hopelessness, and low energy. She also reports poor sleep and appetite. Her Beck Depression Inventory score of 30 indicates severe major depression.

She is taking inhaled albuterol and ipratropium, 2 puffs each every 6 hours, and has been taking oral prednisone, 10 mg/d, for 5 years. The psychiatrist adds sertraline, 50 mg/d. Her mood, anhedonia, and subjective energy level improve across 2 months. Her Beck Depression Inventory score improves to 6, but her positive responses indicate continued poor appetite, lack of sex drive, and low energy. She often becomes breathless when she tries to eat. Her body mass index is 18, indicating that she is underweight. Caloric nutritional supplements are initiated tid to increase her weight. Her sertraline dose is continued.

Approximately 1 month later, Ms. H is able to begin a pulmonary rehabilitation program, which includes:

  • prescribed exercise to increase her endurance during physical activity
  • breathing exercises to decrease her breathlessness.

Ms. H also begins attending a support group for patients with COPD.

After 12 weeks of pulmonary rehabilitation, Ms. H is once again able to walk her dog. The psychiatrist continues sertraline, 50 mg/d, because of her high risk of depression recurrence. She continues to smoke despite repeated counseling.

Discussion. This case illustrates how progressing COPD symptoms can compromise a patient’s ability to work, socialize, and enjoy life. The resulting social isolation and loss of independence and self-esteem can lead to depression.3

Forty to 50% of patients with COPD are believed to have comorbid depression compared with 13% of total patients.4 Small sample sizes have limited many prevalence studies, however.4-6

Long-term corticosteroid therapy may also have fueled Ms. H’s depression. Prednisone is associated with dose-related side effects, including depression, anxiety, mania, irritability, and delirium.7

Ms. H’s case also illustrates how depression can derail COPD treatment and predict poorer outcomes of medical treatment in COPD patients.8 Fatigue, apathy, and hopelessness kept her from following her pulmonary rehabilitation regimen.

Treatment. Selective serotonin reuptake inhibitors (SSRIs) are considered first-line treatment for comorbid depressive or anxiety disorders in patients with COPD. These agents are associated with a relatively low incidence of:

  • anticholinergic and other side effects
  • interactions with other drugs commonly used by COPD patients.

Sertraline, citalopram, and escitalopram have fewer side effects and affect the cytochrome P (CYP)-450 pathway to a lesser degree than do other SSRIs.

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, is another first-line option. This agent is associated with dose-dependent increases in blood pressure, so use it with caution in hypertensive patients.

Mirtazapine, which has been shown to stimulate appetite, can be considered for patients with prominent anorexia or if dyspnea frequently interferes with eating.

Tricyclic antidepressants and monoamine oxidase inhibitors are rarely considered first-line for COPD patients but may help in some clinical instances, such as in younger or middle-aged patients with chronic pain. Dosages for chronic pain generally are much lower than therapeutic dosages for depression. For example, amitriptyline is usually given at 25 mg/d for chronic pain and at 50 to 100 mg/dfor depression.

Table 1

Interactions between selected psychotropics and drugs used by COPD patients


Potential interactions


Itraconazole, fluconazole, cimetidine increase alprazolam levels


Lowers seizure threshold, so use with other drugs with seizure-causing potential (eg, theophylline) requires caution
May increase adverse effects of levodopa, amantadine


Erythromycin, itraconazole increase buspirone levels

Diazepam, lorazepam

Theophylline may decrease serum levels of these drugs


May increase prothrombin time and INR* in patients taking warfarin


May increase prothrombin time and INR in patients taking warfarin


Could increase atorvastatin, simvastatin levels


May interact with warfarin Cimetidine increases paroxetine levels Reports of increased theophylline levels


Metabolized by CYP-450 2D6 enzyme; potential exists for interactions, but none reported

INR: International normalized ratio, a standardized measurement of warfarin therapy effectiveness.

Tricyclics, however, may cause excessive sedation, orthostatic hypotension, confusion, constipation, and urinary retention. These effects can be debilitating in older patients.

Nefazodone is a potent inhibitor of the CYP-450 3A4 isoenzyme and may increase levels of triazolam and alprazolam. Levels of the lipid-lowering agents atorvastatin and simvastatin may increase threefold to fourfold when nefazodone is added. Use nefazodone with caution in patients taking digoxin, because nefazodone is 99% bound to serum proteins and may increase serum digoxin to a dangerous level. Nefazodone also carries a risk of hepatic failure, so hepatic enzyme levels should be monitored.9

Figure Destruction of air spaces and capillaries in emphysema

Many COPD patients have a mixture of emphysema and chronic bronchitis. Emphysema is characterized by damaged alveoli, loss of elasticity of airways (bronchioles and alveoli), alveoli compression and collapse, tearing of alveoli walls, and bullae formation. In chronic bronchitis, the bronchial walls are inflamed and thickened, with a narrowing and plugging of the bronchial airways.Table 1 lists selected psychotropics and their potential interactions with drugs commonly taken by COPD patients.


Ms. P, age 60, is hospitalized for an exacerbation of COPD, which was diagnosed 10 years ago. She is intubated and ventilated after developing pneumonia-related respiratory failure. After a 2-week hospitalization, her pulmonologist tries to wean her off the ventilator, but episodes of panic and dyspnea result in significant oxygen desaturations.

The patient is transferred to a rehabilitation facility. A psychiatrist is consulted and discovers a 10-year history of anxiety that had been managed with lorazepam, 1 mg tid, and sertraline, 50 mg/d.

On evaluation, Ms. P is sweating, tremulous, and hyperventilating. She cannot speak, mouth words, or nod because of her respiratory distress. During her hospitalization she has been receiving albuterol and ipratropium nebulized every 4 hours; intravenous methylprednisolone, weaned from 40 mg to 10 mg every 6 hours; sertraline, 50 mg/d; clonazepam, 1 mg qid; theophylline, 400 mg/d, and several intravenous antibiotics. Ciprofloxacin, 500 mg bid, was recently added for a urinary tract infection.

Table 2

Drugs commonly used to treat COPD and their potential psychiatric side effects



Possible psychiatric side effect


Short-acting bronchodilator



Long-acting bronchodilator

Anxiety, especially if used more than twice daily


Inhaled anticholinergic


Inhaled corticosteroid (eg, fluticasone, budesonide)



Oral corticosteroid (prednisone, methylprednisolone)


Depression, anxiety, mania, delirium

Montelukast tablets or chewable tablets

Possibly both anti-inflammatory and bronchodilator activity



Anti-inflammatory and respiratory stimulant

Anxiety, especially if blood level is >20 μg/mL

Ms. P’s mental status alternates between severe anxiety and obtundation. When her anxiety becomes acute, the attending physician prescribes intravenous lorazepam, 1 to 2 mg as needed. Her chart reveals that she has received 4 to 6 mg of lorazepam each day.

A blood test reveals a toxic theophylline level of 20 mg/mL. Acting on the psychiatrist’s suggestion, Ms. P’s physician decreases theophylline to 200 mg/d. Her anxiety improves slightly, but episodes of panic continue to block attempts to wean her from the ventilator. The psychiatrist increases sertraline to 100 mg/d and stops lorazepam. She adds gabapentin, 300 mg every 8 hours.

Within 3 days, Ms. P’s obtundation ceases and she is less tremulous and panicked. She can mouth words and answer questions by nodding. Within 1 week, her anxiety is improved. Five days later, she is weaned from the ventilator. The facility’s psychologist teaches her relaxation, visualization, and breathing exercises to counteract panic and anxiety.

Ms. P is discharged 2 weeks later, after beginning a pulmonary rehabilitation program. Her primary care physician weans her off clonazepam, and her gabapentin and sertraline dosages are continued.

Discussion. Although the estimated prevalence of anxiety among patients with COPD varies widely,10 anxiety is more prevalent in patients with severe lung disease.11

Panic attacks and anxiety in COPD have been linked to hypoxia, hypercapnia, and hypocapnia. Hyperventilation leads to a decrease in pCO2 , causing a respiratory alkalosis that leads to cerebral vasoconstriction. This ultimately results in anxiety symptoms.

Box 2

Psychiatric comorbidities and COPD: Keys to coordinating care

Communication with other care team members is crucial to psychiatric treatment of patients with COPD. To ensure proper coordination of care:

  • Medication history. Report changes in psychiatric medication to all doctors. Obtain from the primary care physician a complete list of the patient’s medications and medical problems to prevent drug-drug interactions.
  • Onset of depression, anxiety. Report warning signs of depression and anxiety to other care team members, and urge doctors to refer patients who exhibit these signs. Primary care physicians often miss these potential warning signs:
  • Suicidality. Alert other doctors to the warning signs of suicidality. Patients older than 65 and those with depression or chronic health problems are at increased risk of suicide. Many patients with COPD exhibit the following risk factors:

In patients with severe COPD, chronic hypoventilation increases pCO 2 levels. This has been shown in animals to activate a medullary chemoreceptor, which elicits a panic response by activating neurons in the locus ceruleus.

Lactic acid, formed because of hypoxia, is also linked to panic attacks. Investigators have postulated that persons with both panic disorder and COPD are hypersensitive to lactic acid and hyperventilation.12

In some patients, shortness of breath causes anticipatory anxiety that can further decrease activity and worsen deconditioning.

The crippling fear that comes with an anxiety or panic disorder can also complicate COPD therapy. Panic and anxiety often interfere with weaning from mechanical ventilation, despite treatment with high-dose benzodiazepines in some cases.13 The more frequent or protracted the use of ventilation, the greater the risk of ventilator-associated pneumonia.

COPD drugs that cause anxiety. A comprehensive review of the patient’s medications and lab readings is crucial to planning treatment. Ms. P was concomitantly taking several drugs for COPD that can cause anxiety or panic symptoms (Table 2):

  • Bronchodilators such as albuterol are agonists that can increase heart rate and cause anxiety associated with rapid heartbeat.
  • Theophylline, which may act as a bronchodilator and respiratory stimulant, can cause anxiety, especially at blood levels >20 mg/mL. In Ms. P’s case, the combination of ciprofloxacin and theophylline caused a CYP-450 interaction that increased her theophylline level. This is because ciprofloxacin and most other quinolone antibiotics are CYP 1A2 inducers, whereas theophylline is a CYP 1A2 substrate.9
  • High-dose corticosteroids (eg, methylprednisolone) also may contribute to anxiety.

Treatment. SSRIs are an accepted first-line therapy for COPD-related anxiety. Buspirone may also work in some COPD patients. Anticonvulsants such as gabapentin and divalproex are possible adjuncts to antidepressants.

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