Depression

I. Co-morbid Depression in Patients with Chronic Heart Failure: What Every Physician Needs to Know

Why depression is important in patients with chronic heart failure

Depression is a common co-morbid condition in patients with coronary heart disease (CHD) and chronic heart failure (HF). We have found that 35% of 374 HF patients who were hospitalized because of cardiac problems were having mild or greater depressive symptoms via the self-administered Beck Depression Inventory scale (BDI – total score equal or greater than 10) and 14% of them met the criteria for major depressive disorder (MDD) via clinical psychiatric interview. A meta-analysis in 2006 found a 21% incidence of clinically significant depression in HF patients.

While depression is not only common, it adversely affects the prognosis of patients with HF. HF patients with depression, even mild, die earlier than those patients without depression. The more severe the depression is, the higher the mortality in HF patients. The negative impact of depression on the survival of HF patients may last for more than a decade. Depression is also associated with increased co-morbidity that requires hospitalizations in HF patients and reduces the quality of life of these patients. The negative impact of depression in patients with HF is independent of conventional cardiovascular risk factors.

Although there have been no results showing that treating depression improves outcomes, the above evidence clearly suggests that effective management of depression will be of substantial benefit for HF patients.

II. Diagnostic Confirmation: Are you sure your patient has depression?

As with all other mental conditions, diagnosis of depression is made by gathering information from talking with and/or observing the patients with/without obtaining collaterals. There is no laboratory test that may be used for the confirmation of the depression diagnosis. Psychiatric diagnostic interview is the gold standard for making the diagnosis. However, in “real life,” diagnosis of depression may be made via the following:

Having the patient provide answers on self-administered questionnaires, such as the BDI (Beck Depression Inventory) – 21 items – and the PHQ (Patient Health Questionnaire) – 9 (http://www.depression-primarycare.org/clinicians/toolkits/materials/forms/phq9/).

Asking two simple questions, i.e., are you feeling depressed, sad, down, or blue? And have you lost interest in doing things you used to enjoy?

A total BDI (21 items) score is equal to or greater than 10; the PHQ-9 score is equal to or greater than 10. “Yes” on either or both of the “are you feeling depressed, sad, down, or blue” and “have you lost interest in doing things you used to enjoy” questions are evidence indicating that the patient has depression. Another key element in making the diagnosis of major depressive disorder (MDD) is that the above symptoms have to be occurring most of the day, most days of the week, lasting for 2 or more weeks.

Should a patient fulfill the above criteria, clinical depression is indicated and intervention needs to be considered.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), clinical depression may be MDD, dysthymia or mild, chronic depression, seasonal affective disorder (SAD), or part of bipolar disorder. Diagnosis of MDD requires five or more of the following nine symptoms with least one of the A category symptoms occurring for 2 or more weeks. Diagnosis of dysthymia may not require five or more symptoms, but one has to have one of the A category symptoms and the duration of the depression needs to be 2 years or longer.

Nine symptoms of depression:

A:

Sadness or depressed mood most of the day or almost every day.

Loss of enjoyment in things that were once pleasurable.

B:

Major change in weight (gain or loss of more than 5% of weight within a month) or appetite

Insomnia or excessive sleep almost every day

Physically restless or rundown that is noticeable by others

Fatigue or loss of energy almost every day

Feelings of hopelessness or worthlessness or excessive guilt almost every day

Problems with concentration or making decisions almost every day

Recurring thoughts of death or suicide, suicide plan, or suicide attempt

The two items in the A category can be elicited via the PHQ-2 questionnaire as the following:(www.fpnotebook.com/Psych/Exam/PtntHlthQstnr2.htm):

In past 2 weeks, have you been bothered by:

Little interest or pleasure in doing things?

Feeling down, depressed or hopeless?

The rating of PHQ-2 can be used as “yes” or “no” to each of the two questions categorically, or scaled from 0-3 of each question to reflect the severity, as:

Not at all: 0

Several days: 1

More than half the days: 2

Nearly every day: 3

When the answer is positive (yes) to either question above, or the total score is 3 or greater, a detailed review of the 9 symptoms listed above or using the PHQ-9 is needed to ascertain the existence of depression.

A. History Part I: Pattern Recognition:

Symptoms of depression in HF patients may be mistaken as the symptoms of HF. Another common misconception is that because the patient has HF, therefore, he or she is depressed. Clinically we have observed many patients who have extremely low left ventricular ejection fraction (LVEF) but who maintain their exercise capacity and don’t fulfill the criteria for depression. On the other side, there have been patients whose LVEF has been relatively preserved, but they experience a lot of somatic symptoms that prevent them from participating in cardiac rehabilitation programs and routine daily activity. It is likely that many of these patients are suffering from depression, which has greatly accentuated the disability of their cardiac condition.

B. History Part 2: Prevalence:

Female patients with history of depression, anxiety (especially generalized anxiety disorder or panic disorder), and those who recently have had a significant loss, such as losing a loved one or a close friend, or their job, are more susceptible to developing depression. Susceptible patients may develop depression after learning they have heart failure or other medical illnesses.

C. History Part 3: Competing diagnoses that can mimic disease depression.

• Bipolar disorder: Question if the patient has had episodes (lasting for several days) of feeling euphoric, on top of the world, expansive, hyperenergetic with little sleep, and/or possessing nearly unlimited wealth, or if the patient has received comments from family members and/or close friends suggesting that he or she might have a manic/bipolar condition.

• Schizoaffective disorder: Question the patient if he or she has had experience of losing touch with reality, and/or hallucinations.

• Substance-induced or -related depression: Taking a careful history for drug or alcohol use is critical. When there are suspicions but the patient denies substance abuse, discussing it with the patient’s family may reveal significant problems that account for the depressive symptoms.

D. Physical Examination Findings.

One may say that there is no “physical examination” required for making the diagnosis of depression, but there are physical signs that patients with depression may reveal, such as constricted affect or sadness-appearing, psychomotor retardation, or slow movement, that cannot be fully explained by the underlying physical illnesses.

III. Management.

Figure 1 is a “Depression Care Algorithm for CHF Patients” based on the author’s clinical experience. While it walks through the care steps for clinicians or cardiologists who take care of these kinds of CHF patients, one needs to bear in mind the following:

Selective serotonin reuptake inhibitor (SSRI) antidepressants are believed to be efficacious in reducing depressive symptoms in patients with coronary heart disease (CHD) and safe from the cardiac standpoint relative to other kinds of antidepressants; however, there is no evidence suggesting antidepressants are effective for the treatment of depression in patients with HF. A well-conducted, randomized, double-blind, placebo-controlled clinical trial, i.e., the SADHART-CHF (Safety and Efficacy of Sertraline for Depression in Patients with CHF), failed to demonstrate sertraline is better than placebo for depression in 469 HF patients with MDD. The patients whose depression remitted had significant improvement in their quality of life measured by SF-36 and cardiac symptoms measured by the KCCQ. These findings suggest that effective treatment for depression can lead to important benefits for HF patients. The psychosocial support provided during the SADHART-CHF was believed to attribute to the depression remission of patients in the study. Of interest is the fact that a biomarker substudy of the SADHART-CHF study revealed that the majority of the SADHARD-CHF study participants had low omega 3 fatty acid in their blood. The low omega 3 might have contributed to the lack of antidepressant effect of sertraline.

Based on the SADHART-CHF findings, results of omega 3 supplementation in HF patients, and literature on omega 3 and depression, it may be necessary to start omega 3 supplementation with the EPA:DHA equal or greater than 2:1 for HF patients who have depression prior to the use of antidepressants, or to add the omega 3 supplement to the patients who have been taking antidepressants. A number of large scale clinical trials have shown that omega 3 supplementation improves the survival of patients with CHD and HF. Omega 3 supplementation has been associated with improved LVEF as well but this effect has not been confirmed.

Aerobic exercise has been shown to improve depression in the HD population and to be beneficial to outcomes of HF. HF patients with depression should be encouraged to engage in routine physical activities and/or aerobic exercise. The initiation of exercise may need to be monitored by cardiac rehabilitation services in selected patients.

Nurse-facilitated psychosocial supportive measures were believed to be contributory to the high rate of remission, i.e., disappearance of depression, in the SADHART-CHF trial, although there is also lack of evidence regarding non-pharmacologic intervention for HF patients with co-morbid depression. Psychosocial supportive intervention may be chosen as the first line of intervention for HF patients whose depression is mild.

When choosing an antidepressant, whether there are drug-drug interactions with the medications that the patients are currently taking needs to be carefully reviewed. Many cardiovascular medications may interact with the metabolization of antidepressants or vice versa. Therefore, (1) one may start an antidepressant at a lower dose than suggested; and (2) while monitoring the effects of the antidepressant, close monitoring of the effects of other medications and their side effects cannot be neglected. Please see Table I for commonly used antidepressants.

Figure 1.

Table 1.

A. Immediate management.

As indicated in the depression care algorithm for CHF patients (Figure 1), development of active suicidal ideation and/or psychosis will require immediate psychiatric care.

D. Long-term management.

In general, an episode of depression requires a 6-month continued intervention from the time the depression appears to be in remission prior to the taper of the intervention. For the patient who has had two or more episodes of depression in his or her life, the standard practice is to have the patient on effective antidepressants indefinitely. In addition, such patients should be under the care of psychiatric professionals.

There is no evidence at this time, however, that treatment of depressive symptoms results in longer survival or reductions in cardiovascular events.

E. Common Pitfalls and Side-Effects of Management

• The depression is not improving, or becomes worse: This usually indicates that either the patient is not on the appropriate treatment (medication or requires other interventions such as psychotherapy or electroconvulsive treatment) or the diagnosis is inaccurate. If you have attempted two trials of antidepressants, it is time to refer the patient to a psychiatrist or mental health provider.

• The patients are not compliant with the depression intervention: This may be due to patient lack of understanding of the treatment, or concern about the cost of medication. Psycho-education and/or finding low cost antidepressants from certain pharmacies are solutions.

• Common side effects of antidepressants disappear after 10-14 days of use, except the sexual dysfunction that stays until the antidepressant is terminated. For patients who cannot tolerate the sexual dysfunction side effects, remeron and wellbutrin may be the choice. While using these antidepressants, close monitoring of blood pressure is necessary.

• Serotonin syndrome: This is a life-threatening side effect that tends to happen in patients who take SSRIs or SNRIs (Selective Serotonin-Norepinephrine Reuptake Inhibitors) who are placed on other mediations that either have serotonergic effects or interact with the metabolization or clearance of SSRIs or SNRIs.

• Serotonin syndrome needs to be recognized rapidly. Immediate termination of the antidepressants and the exacerbating agent(s) usually abate the symptoms. Benzodiazepines are first-line medications to alleviate symptoms of serotonin syndrome. Patients with high fever, confusion or life-threatening vital signs need to be hospitalized.

Medications that may result in serotonin syndrome, especially when used in combination

SSRIs (See Table I)

SSNRIs

• Cymbalta (duloxetine)

• Effexor, Effexor XR (venlafaxine)

Triptans

Triptans are a class of drugs commonly used to treat migraine or cluster headaches. They act on serotonin receptors in the brain, thereby affecting serotonin levels. Examples of triptans include:

Amerge (naratriptan)

Axert (almotriptan)

Frova (frovatriptan)

Imitrex (sumatriptan)

Maxalt and Maxalt-MLT (rizatriptan)

Relpax (eletriptan)

Zomig and Zomig ZMT (zolmitriptan)

Tricyclic antidepressants

• Elavil (amitriptyline)

• Tofranil (imipramine)

• Sinequan (doxepin)

• Anafranil (clomipramine)

Monoamine oxidase inhibitors (MAOIs)

• Nardil (phenelzine)

• Parnate (tranylcypromine)

• Marplan (isocarboxazid)

• Emsam (selegiline)

Other antidepressants

• Desyrel (trazodone)

Other psychiatric medications

• BuSpar (buspirone)

• Eskalith (lithium)

Analgesics

• Codeine

• Fentanyl

• Tramadol

Antibiotic/antiretroviral medications

• Zyvox (linezolid)

• Norvir (ritonavir)

Herbal drugs/dietary supplements

• Hypericum perforatum (St. John’s Wort)

• Ginseng/Panax

Street drugs

• Amphetamines

• Cocaine

• LSD (lysergic acid diethylamide)

This list is not meant to be all-inclusive. To avoid an increased risk of patients developing serotonin syndrome, be certain to collect information about all drugs and dietary supplements they are taking or changing.

What's the evidence

Jiang, W, Krisnan, R, Kuchibhatla, M, Cuffe, MS, Martsberger, C. “for the SADHART-CHF Investigators. Characteristics of Depression Remission and Its Relation With Cardiovascular Outcome Among Patients With Chronic Heart Failure (from the SADHART-CHF Study)”. Am J Cardiol.. vol. 107. 2011. pp. 545-51. (The results of this study indicate that remission from depression may improve the cardiovascular outcome of patients with heart failure.)

O’Connor, CM, Jiang, W, Kuchibhatla, M, Silva, SG, Cuffe, MS. “for the SADHART-CHF Investigators. Safety and Efficacy of Sertraline for Depression in Patients With Heart Failure: Results of the SADHART-CHF Trial”. JACC. vol. 56. 2010. pp. 692-9. (This is the only existing study with randomization and double-blind control testing whether SSRIs are efficacious in improving depression and safe for patients with HF and co-morbid MDD.)

Adams, J, Kuchibhatla, M, Martsberger, C, Christopher, EJ, Alexander, JD. “Association of Depression and Survival in Patients with Chronic Heart Failure over 12 Years”. Psychosomatics. 2012 Jan 24. (The results of this study demonstrate that the impact of depression measured at one point of time on the survival of patients with HF lasts for decades.)

Hoffman, BM, Babyak, MA, Craighead, WE, Sherwood, A, Doraiswamy, PM. “Exercise and pharmacotherapy in patients with major depression: one-year follow-up of the SMILE study”. Psychosom Med. vol. 73. 2011. pp. 127-33. (This study suggests that improvement of depression resulting from exercise training lasted longer than the effects of SSRIs on depression improvement.)

Melvin R., Echols, Jiang, W. “Clinical Trials Evidence for Treatment of Depression in Heart Failure. HEART FAILURE CLINICS”. Heart Fail Clin. vol. 7. 2011. pp. 81-8. (This is a recently published study that summarizes the updated research findings in depression treatment in patients with HF.)

Barbour, KA, Edenfield, TM, Blumenthal, JA. “Exercise as a treatment for depression and other psychiatric disorders: a review”. J Cardiopulm Rehabil Prev. vol. 27. 2007. pp. 359-67. (This study summarizes the updated research results of exercise impact on depression.)

Rutledge, T, Reis, VA, Linke, SE, Greenberg, BH, Mills, PJ. “Depression in heart failure a meta-analytic review of prevalence, intervention effects, and associations with clinical outcomes”. J Am Coll Cardiol. vol. 48. 2006. pp. 1527-37. (This is a good reference in review of depression prevalence and impact on outcome of HF patients.)

Paraskevaidis, I, Parissis, JT, Fountoulaki, K, Filippatos, G, Kremastinos, D. “Selective serotonin re-uptake inhibitors for the treatment of depression in coronary artery disease and chronic heart failure: evidence for pleiotropic effects”. Cardiovasc Hematol Agents Med Chem. vol. 4. 2006. pp. 361-7. (This review helps readers to understand the use of SSRIs in patients with CHD and HF.)

Jiang, W, Alexander, J, Christopher, E, Kuchibhatla, M, Gaulden, LH. “Relationship of depression to increased risk of mortality and rehospitalization in patients with congestive heart failure”. Archives of Internal Medicine. vol. 161. 2001. pp. 1849-56. (The first systematically and prospectively conducted study examining the prevalence of depression and its impact on survival of patients with heart failure.)

Kroenke, K, Spitzer, RL, Williams, JB. “The Patient Health Questionnaire-2: validity of a two-item depression screener”. Med Care. vol. 41. 2003. pp. 1284-92. (This study discuss the use of the PHQ-2 in assessing depression at bedside and the sensitivity and specificity of the PHQ-2 for depression.)

“Validation of PHQ-2 and PHQ-9 to Screen for Major Depression in the Primary Care Population”. Ann Fam Med. vol. 8. 2010. pp. 348-53. (This study compares PHQ-2 and PHQ9 for diagnosing MDD.)

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