Clinical, or major, depression is a major chronic disease worldwide. The World Health Organization predicts that, as it already is in the United States, unipolar depression (without mania or hypomania) will be surpassed only by heart disease as the leading cause of disability and premature death in developed countries by 2020.¹ Besides causing disability and loss of function, depression can be fatal, with a 15% mortality rate, primarily from suicide.² Depression’s frequent companion, anxiety, is the most prevalent mental disorder, occurring in 15% of the population each year.² Together, these two mental health conditions pose a key concern for primary care providers, including nurse practitioners. Undiagnosed and undertreated, they account for increased health care spending and repeated office visits, often for associated physical complaints.³

This article will focus on unipolar depression, particularly screening and accurate diagnosis; treatment and treatment compliance will be covered in less detail. Anxiety will be discussed in the context of its occurrence with depression.

Criteria for clinical depression

The diagnosis of major depression is made when five of the following symptoms have been present most of the time for two weeks and represent a change from usual functioning (one of the first two symptoms must be present): sad or empty mood, diminished interest or pleasure in activities, significant weight loss (when not dieting) or appetite changes, insomnia or hypersomnia, observable psychomotor agitation or retardation, fatigue or energy loss, feelings of worthlessness or excessive guilt, indecisiveness or trouble concentrating, recurrent thoughts of death or suicide.⁴

For purposes of screening, the following two questions about the first two symptoms will help determine whether a diagnosis of major depression needs to be pursued:⁵

1. During the past two weeks, have you ever felt down, depressed, or hopeless? (mood)
2. During the past two weeks, have you felt little interest or pleasure in doing things? (anhedonia)

A “yes” answer to either question requires additional inquiry about other symptoms and/or further screening.

Screening by asking about the first two primary symptoms of depression has been shown to increase the discovery of depression in primary care.⁵ Note that three of the symptoms involve emotion (mood, pleasure, worth), four are physical (weight, sleep, motor activity, and energy), and two are cognitive (concentration and thoughts). Depression is a whole-body illness; it is not “all in your head.”

Particularly among the elderly, the stigma of mental illness is strong, and practitioners must convey that physical symptoms are not mental creations, but are the depression: The body is depressed and is not functioning normally — chemistry, metabolism, pain reception, sleep, GI function, and the ability to think all may be affected. Asking, “Are you depressed?” in response to physical complaints is usually not helpful and likely will elicit a negative reply. Using the wording of the screening questions apart from inquiring about physical complaints may yield more accurate information.

Physical symptoms: People may present with GI disturbances ranging from changes in eating or appetite to constipation or diarrhea. Increased pain perception and sensitivity to pain are common; individuals may “ache all over” or experience vague pain that does not remit with usual treatment.

Fatigue is also common with depression. The depressed person is always tired, perhaps because of insomnia, but also may report sleeping all the time and still not feeling rested. Sleep EEGs of people with depression show that the majority have disrupted sleep cycles, frequently with inadequate deep and REM sleep,⁶ so although they appear to sleep, they are not getting needed restful sleep. Early morning waking (sleep cut short) is the most common type of insomnia.⁴ Psychomotor retardation may be consistent with lack of sleep, but so may agitation or restlessness; either slowing or agitation, or both at different times, may be present with depression.

Cognitive symptoms: Trouble with concentration or memory is also present with depression. PET scans of depressed brains show hypofrontality, or decreased metabolism and blood flow in the frontal lobes, where higher-level thinking takes place.⁶ Clinically depressed people may exhibit slowed speech or delayed response time to questions because of difficulty processing information. Thought content also changes with depression; the most obvious change is preoccupation with death or suicide. Preoccupation with past wrongdoings or failures is common. Perceptions change, as if everything is being viewed through a dirty window. Although this may be seen as an emotional symptom, practitioners should remember that information is constantly being exchanged in the brain between the cortex (thinking portion) and the limbic area (emotional center), so that emotion and thinking are never independent of each other.⁷

Affective or emotional symptoms: Depression is categorized by society as an emotional condition, and the two symptoms used for screening are in the affective domain: depressed mood and loss of interest or pleasure. An additional affective symptom is feelings of worthlessness. Associated emotions may include guilt, hopelessness, irritability, or anger. Although depression is commonly seen as a passive state, the dichotomy of emotions and physical symptoms reveal the confusion and complexity of this condition.⁷

Anxiety, the frequent companion: Two neurotransmitters (serotonin and norepinephrine) and two areas of the brain (amygdala and hippocampus) are known to be involved in both depression and anxiety.^2,6,7 It is not surprising that anxiety is comorbid with depression more often than not.² The term agitated depression has been used in the past to describe what was probably anxiety with depression. To be paralyzed by depressive symptoms and agitated by anxiety at the same time can create unbearable suffering. When panic disorder (a type of anxiety disorder with sudden onset of overwhelming dread, palpitations, diaphoresis, and possibly dyspnea and chest pain) is comorbid with depression, suicide risk is increased.⁴ The elderly are more likely to present with both anxiety and depressive symptoms.⁸

Other comorbidities

Symptoms sufficient to diagnose clinical depression are present 25% to 30% of the time with serious medical illnesses.⁶ The presence of depression with these illnesses negatively affects outcomes and increases mortality.⁹ The most pronounced example of medical comorbidity is cardiac disease. People with major depression are four times more likely to have a heart attack than the general population; those with a history of even mild depression have twice the chance.¹⁰ Depression increases mortality after myocardiol infarction (MI), so screening and monitoring are especially important in post-MI patients.¹⁰ People with diabetes are twice as likely to develop depression.¹¹ In primary care, those with depression and diabetes have more trouble with treatment adherence and functioning, and tend to have higher medical costs.¹² Therefore, it would be reasonable that accurately diagnosing and adequately treating depression comorbid with diabetes should improve outcomes.

Pain can make depression worse, and depression worsens pain. Those with chronic pain are at higher risk for depression, and those with depression suffer more physical pain.¹³ This is related to neurontransmitters involved in both pain and depression. Serotonin and norepinephrine, targeted neurontransmitters in depression, are thought to have a role in modulating pain.² With a diagnosis of chronic pain and depression, treating the depression may improve the pain as well because of the modulating effects of serotonin and norepinephrine on pain reception.

While about 12% of those with unipolar depression are alcohol dependent (alcoholic) and 5% abuse alcohol (compared to 7.4% and 3.4%, respectively, in the general population), 28% of alcoholics are likely to have depression.¹⁴ In other words, high alcohol use should alert the health care provider to look for depression, while depression in and of itself slightly increases the rate of alcohol dependence or abuse. With bipolar depression (including manic or hypomanic episodes), the substance abuse rate soars to 50% to 60%.⁶ As with all comorbid conditions, both the depression and the alcohol condition need to be treated.² The patient should be free of alcohol to start antidepressants and refrain from alcohol use for antidepressants to be most effective.^2,14

Differential diagnosis

The above comorbidities can complicate diagnosis of clinical depression. People most often present in primary care with physical complaints, and even in the presence of depression, medical causes must be ruled out and treated first. For instance, medication adverse effects or hypothyroidism may lead to depressive symptoms. Weight loss might be due to hyperthyroidism or diabetes. Depression in the elderly might look like dementia and often is a precursor to dementia.⁴ In the case of early dementia and depression, treating the depression improves cognitive function. In the elderly and in children and adolescents, somatic complaints may predominate,⁴ and changes in functioning, normal behavior, and outlook need to be considered.

Risk factors for depression and suicide

A family history or prior episodes of depression increase the risk of having clinical depression, as does a history of abuse or trauma, including domestic violence.^2,6 Females are twice as likely as males to be diagnosed with depression, and there is an increased chance of developing depression in the postpartum period.² As mentioned, medical illness increases the risk for depression. Stressful life events, substance abuse, and lack of social support also intensify risk. Suicide risk is increased by alcohol use, and suicide is a greater risk in elders and adolescents.⁴ Suicide risk is also greater if there has been a previous attempt.

When to refer: If a person voices suicidal thoughts, the practitioner needs to investigate further. Ask when and how often the thoughts occur. Ask whether the person has thought of a plan. Imminent thoughts and urges require immediate referral to emergency services. Less urgent or frequent thoughts need further assessment by a mental health professional. It is helpful for a primary care provider to identify a professional with whom to consult by phone if necessary. A psychiatric clinical nurse specialist, particularly one with prescriptive authority, may be one such possibility for a nurse practitioner in primary care.

Because of their increased risk and complexities, other cases that typically would require referral include a pattern of substance abuse or current intoxication. Patients with personality disorders, who have a chronic maladaptive pattern of dealing with stress and relationships, also may require consultation. Whenever depressive or anxiety symptoms are not managed with monotherapy with one antidepressant, consultation, if not referral, is warranted. One such instance would be in the case of bipolar depression, which responds better to mood stabilizers or combinations of medications.

Individuals with Bipolar I will have at least one intermittent episode of mania (extreme euphoria and/or irritation with little need for sleep); Bipolar II will have predominant depression with less noticeable episodes of hypomania (decreased need for sleep, with increased drive and energy). Screening for depression should include questioning about a history of decreased need for sleep or periods of elated mood; some antidepressants, primarily tricyclics, may trigger mania.¹⁵ Treatment-resistant depressions (which do not respond in 6 weeks to 12 weeks) or those with a bipolar component need referral or consultation.

Depression treatment

Depression is a serious and potentially fatal illness, but it is highly treatable.^2,6,10 Depression is most often discovered and first treated in primary care.³ Adequate screening, accurate diagnosis, and appropriate intervention and follow-up all are part of minimizing suffering, improving function, and saving health care dollars.

Mild depression may respond to referral to counseling alone; research has shown cognitive behavioral therapy to be one of the most effective types of counseling for depression.¹⁰ Moderate to severe depression requires medication in most cases. Both counseling and medication are more effective than either alone, although patients with significant cognitive impairment from the depression may benefit from medication initially to improve their response to psychotherapy. Since 25% of depressions become chronic,⁴ ongoing care and evaluation are important.

The goals of treatment extend over three phases. In the acute phase, lasting 6 to 12 weeks, the goal is to reduce or eliminate symptoms. This is followed by a continuation treatment phase of up to six months in which the goal is to restore function to a premorbid state. The maintenance phase, which may last a year to a lifetime (in chronic depression), aims to reduce relapse and recurrence.¹⁶ With a positive or partial response to medication in four to six weeks, an individual should be continued on the medication for another six weeks. Without a satisfactory response (symptom remission) with adequate dosing by 12 weeks, another medication or treatment modality should be considered, either to replace the current medication or treatment, or as an adjunct. Severe or chronic depressions require higher doses and a longer time to respond.¹⁶

Otherwise, treatment can be extended into a continuation period of six months. For people with recurrent depression, strong family or personal history, or multiple risk factors, maintenance therapy should be instituted with reevaluation at one year.

Antidepressants, when discontinued, should be tapered over at least two weeks; the shorter the half-life of the drug, the greater the chance of discontinuation symptoms. Helpful flow sheets and decision-making trees are available for practitioners from sources such as the Macarthur Initiative. Depression screening tools also can be used to monitor symptom reduction.

Because people may discontinue their medications when they begin to feel better, it is important to educate them about the various treatment phases and the usual course of depression.³ Helpful patient education materials are available from the National Institute of Mental Health, the American Psychiatric Association, or family practice websites.

However, taking time to give basic information and to answer questions in person may save time, money, and frustration in the long run. Remember that cognitive function can be slowed in depression, and repetition may be necessary. If anxiety is present with depression, learning may be more impaired. Follow-up by phone is also effective in maintaining compliance and adjusting therapy as needed.

Medication choices: Individual responses aside, older antidepressants (tricyclics) and newer antidepressants (selective serotonin reuptake inhibitors [SSRIs] and novel antidepressants) are equally efficacious.^2,3,16 Newer antidepressants have been favored because they have fewer side effects and require less titration. Side effects with older medications tend to be anticholinergic (dry mouth and eyes, constipation, sedation), and they also run the risk of causing potentially fatal cardiac arrhythmias in overdose. Older drugs are less expensive, a consideration for those who can tolerate their initial side effects and have no cardiac or suicide risk factors. Newer antidepressants are more likely to cause GI upset, such as diarrhea or nausea; agitation or nervousness are possible. Warning people to expect some side effects, and explaining that they are usually short-lived, may increase adherence to the medication regime. Adjustments such as taking a medication at bedtime to minimize nausea or sedation effects might be considered.

Most SSRIs are recommended to be taken with food. Both tricyclic antidepressants (e.g., Pamelor/nortriptyline, Norpramin/desipramine, Tofranil/imipramine) and SSRIs (Prozac/fluoxetine, Zoloft/sertraline, Paxil/paroxetine, Celexa/citalopram) are noted for their sexual side effects (decreased libido, inorgasmia). Paroxitine is one of the worst offenders for sexual side effects.¹⁷ It must be remembered that sexual dysfunction is a symptom found in 50% of depressions.¹⁷ People who report a change for the worse after being on an antidepressant for 8 to 12 weeks are more likely to be experiencing a medication side effect, rather than a symptom of depression.¹⁷ Lowering the dose after a therapeutic effect has been achieved may reduce sexual side effects; sometimes switching medications is necessary.

Bupropion (Wellbutrin) has fewer sexual side effects. Buspar (buspirone) or cyproheptadine (Periactin) can sometimes be added to an SSRI to address inorgasmia, and yohimbine (Yocon) is sometimes suggested for decreased libido.¹⁷ Sildenafil (Viagra) and vardenafil (Levitra) are available for treating erectile dysfunction. Some research on the use of sindenafil in women is being done, and prescribing patterns for women may need to be different than for men.¹⁷

Although weight gain is less of a problem with newer antidepressants, counseling on regular exercise and diet is warranted. Regular exercise itself is beneficial with depressive symptoms.

Medication cautions: SSRIs continue to be the antidepressants of choice in primary care because of a wider therapeutic index and fewer serious side effects.^3,10 Because of inducing or inhibiting drug-metabolizing liver enzymes (e.g., P450 enzymes), they do need to be checked against other drugs for interactions.¹⁸ For example, paroxetine can raise Coumadin levels.¹⁸

As mentioned, tricyclic antidepressants can cause cardiac arrhythmias in larger doses, a primary concern for those at risk for suicide — overdose can result in a fatal arrhythmia.¹⁸ SSRIs can potentiate tricyclics, so caution is warranted when switching from one to another; however, such potentiation can be used therapeutically when prescribing an SSRI and a tricyclic together.¹⁸

Depression may be present in one of five patients seen in primary care, but only one in 10 will identify depression as the reason for seeking care.⁶ With improved screening, primary care providers can diagnose and treat this disabling illness. With follow-up through acute, continuation, and, if necessary, maintenance therapy, relapse and disability can be reduced.