Although outpatient treatment for depression in the United States has increased in the last decade, depression is underdiagnosed and undertreated in the primary care setting.^, Six to 15 percent of patients visiting a primary care physician for any reason have major depressive syndrome, and as many as 30 percent of primary care patients have depressive symptoms that do not meet criteria for major depression. A survey administered to 1007 patients at the Associates in Internal Medicine (AIM) practice found that the prevalence of major depression in our setting is 19 percent.

Why is one of the most common outpatient illnesses so frequently overlooked? There are multiple complex reasons intimately linked to the nature of the primary care doctor-patient encounter. Depressed patients may focus on the somatic complaints accompanying their affective disorder rather than their mood. Patients also tend to under-report personal distress to their physicians.⁴ In turn, physicians tend to focus on these somatic symptoms and often fail to detect the underlying mood disorder, missing the diagnosis in up to 50 percent of patients.⁴ Some physicians are reluctant to present a psychiatric diagnosis to patients for fear that they will become angry and seek medical attention elsewhere. There seems to be, as Eisenberg noted, "a covert agreement that physical symptoms are the only legitimate tickets of admission to a doctor’s office." ⁴

In addition to its effect on quality of life indices, unrecognized and untreated depression affects health care costs. One study found that patients with depressive and anxiety disorders in a HMO primary care setting incurred health care costs that were one and a half times greater than for patients without these disorders even when controlling for medical co-morbidity.

Major depression results from a combination of genetic predisposition and environmental factors, leading to changes in brain monoamine levels and altered hypothalamic-pituitary-adrenal axis function. Major depression It is not a normal reaction to life stress but rather a clinical syndrome consisting of a constellation of signs and symptoms. The goal of the clinician is to distinguish clinically significant depression, requiring intervention, from the sadness or distress that is a normal part of human existence. As depression is common, the clinical practice guidelines on depression in primary care published by the U.S. Department of Health and Human Services recommend that clinicians maintain a high index of suspicion and learn to evaluate patients for risk factors that predispose to depression. These risk factors include: prior history of depression, family history of major depressive or bipolar disorder, personal or family history of suicide attempts, concurrent general medical illness, concurrent substance abuse, symptoms of fatigue, malaise, irritability, or sadness, or history of recent stressful life events and lack of social support. Depression appears to be more prevalent in women than in men. Men, however, are at higher risk for successfully committing suicide.

The American Psychiatric Association has developed criteria for the diagnosis of major depressive disorder. The diagnosis is made when the patient has five of the following nine symptoms present during the same time period, most of the day, daily, for at least two weeks, and there is impairment of functioning:

• Depressed mood.
• Markedly diminished interest or pleasure in almost all activities (anhedonia).
• Significant weight loss/gain.
• Insomnia/hypersomnia.
• Psychomotor agitation/retardation.
• Fatigue or loss of energy.
• Feelings of worthlessness or excessive or inappropriate guilt.
• Impaired concentration or indecisiveness.
• Recurrent thoughts of death or suicide (suicidal ideation).

The first two symptoms, depressed mood and anhedonia, are in bold type as they are the hallmark symptoms of major depressive disorder. The diagnosis of major depressive disorder cannot be made without one of these two symptoms being present. The following two questions have a sensitivity of 96 percent and a specificity of 57 percent: "During the past month, have you often been bothered by feeling down, depressed, or hopeless?" and "During the past month, have you often been bothered by having little interest or pleasure in doing things?". If a patient answers yes to either one or both of these questions, further inquiry is needed to confirm a diagnosis of major depression. A simple mnemonic can be used to remember the above criteria is SPACE DIGS: S(leep); P(sychomotor retardation/agitation); A(ppetite); C(oncentration); E(nergy); D(epressed mood); I(nterest); G(uilt); and S(uicide). It is important to know the diagnostic criteria both to make an accurate diagnosis and to monitor a patient’s specific symptoms and response to therapy over time.

Major depression may be a primary psychiatric disorder, or it may present in the presence of - or as a complication of - other medical or psychiatric conditions. The clinician must establish that the depressive symptoms are not due to the direct physiological effects of a substance (Table 1) or a general medical condition (e.g. hypothyroidism). Secondary depressive symptoms may occur in patients with other psychiatric disorders, such as panic disorder, obsessive-compulsive disorder, and somatization disorder; in such cases it is important to diagnose and, if possible, treat the "primary" psychiatric disorder as well as the depression. Occurrence of major depression in a patient without prior history of depression after the age of forty warrants close consideration and exclusion of other contributing medical problems.

TABLE 1: Some of the medications that can cause depression

It is important to ask each patient about a history of manic or hypomanic episodes, and about a family history of bipolar disorder. Useful questions include whether they were ever told they had manic-depressive illness or if they have ever been treated with lithium. The treatment of bipolar depression is different from that of unipolar depression, and in such cases psychiatric consultation is appropriate. Patients presenting with major depression should also be screened for psychotic symptoms (e.g. auditory hallucinations, delusions of guilt, persecution), since their presence will change the treatment strategy.

Several subtypes of major depression have been identified, including depression with melancholic features, with atypical features, and with seasonal pattern. Depression with atypical features deserves comment here, since this subtype appears to respond better to treatment with the monoamine oxidase inhibitors or selective serotonin reuptake inhibitors than to the tricyclic antidepressants. The specifier of atypical features applies in cases of depression where there is mood reactivity (i.e.: mood brightens in response to actual or potential positive events), and two or more of the following features: significant weight gain or increase in appetite; hypersomnia; leaden paralysis; long-standing pattern of interpersonal rejection sensitivity that results in significant social or occupational impairment.

Some laboratory tests may be helpful in the initial evaluation of depressed patients to exclude the concurrence of other medical problems, particularly for patients who present with multiple somatic complaints or atypical symptoms or for patients over the age of forty. These include a complete blood count (CBC), thyroid function tests (TSH), calcium, and liver and kidney function tests. Urine toxicology screens are often requested for patients at high risk for substance abuse and in all patients presenting with new onset of psychotic symptoms. Other tests are not routinely requested but may be indicated in particular cases. If therapy with a tricyclic antidepressant (TCA) is being considered (see below) a baseline EKG is routinely obtained prior to instituting therapy. Brain imaging is not indicated unless there are focal neurologic findings or dementia on examination.

As with many medical and psychiatric conditions, the decision about whether or not to treat a major depressive episode is dependent on several factors, including the duration and severity of symptoms, the degree of impairment caused by the symptoms, and the relative risks and benefits of treatment. In planning treatment, the clinician must carefully evaluate the patient’s symptoms; past general medical and psychiatric history; psychological makeup and conflicts; life stressors; family, psychosocial and cultural environment; and patient preference for specific treatments or approaches.⁶ A range of psychotherapeutic and somatic treatments exist for the treatment of depression.

Although primary care physicians may not have received formal training in counseling or psychotherapy, an essential component of any treatment for depression is "psychotherapeutic management," which all physicians can deliver. This includes establishing and maintaining a supportive therapeutic relationship; being available to the patient in times of crisis; maintaining vigilance toward potential suicidal or homicidal impulses; providing education, knowledge and feedback; helping to motivate the patient and bolster morale; and enlisting the support of others in the patient’s social network.⁶ Physicians can help patients by identifying exaggerated negative thoughts and by suggesting ways of breaking life problems into smaller, more manageable components.

Psychotherapy is a general term for a variety of verbal treatments. Psychotherapy alone can be a first-line treatment in cases of mild to moderate depression, and in cases where the patient desires psychotherapy as an initial treatment. Several forms of psychotherapy have been found useful in the treatment of depression, including psychodynamic psychotherapy, brief therapy, interpersonal therapy, behavior therapy, cognitive therapy, marital and family therapy, and group therapy. A detailed discussion of these different interventions is beyond the scope of this chapter, but primary care physicians should be aware of the range of possible psychotherapeutic interventions for depression, particularly for patients who do not want medication, or in whom medication is contraindicated. Psychotherapy is often used in combination with medication, and the combination may be more effective than either treatment alone. For patients with mild depressive symptoms occurring in the context of a stressful life event, who do not meet criteria for major depression, referral to a social worker, psychologist, or community or religious support network for counseling might be considered.

Antidepressant medication is highly effective, with response rates as high as 60 to 70 percent.^6,7 There are at least 21 antidepressants available in the United States at present.^, Categories include cyclic antidepressants (including the tricyclic antidepressants and trazoadone); the selective serotonin reuptake inhibitors, or SSRIs (including citalopram, fluoxetine, sertraline, and paroxetine); and the monoamine oxidase inhibitors. The "atypical agents" include buproprion, mirtazapine, nefazodone and venlaxafine. One of the newer atypical agents, venlafaxine (Effexor™), is chemically unrelated to any other antidepressant, and is thought to inhibit the reuptake of both serotonin and norepinephrine. Venlafaxine and bupropion are available in sustained release preparations (Effexor XR™ and Wellbutrin SR™, respectively). Mirtazapine (Remeron™), also antagonizes enhances central serotonergicin and norepinephrine noradrenergic activity via both presynaptic and post-synaptic mechanisms (see Table 3).

SSRIs are the preferred first-line therapy for the treatment of depression in primary care. Factors to consider in choosing an antidepressant include the presence of concurrent medical or psychiatric disorders; the subtype of depression; a history of past response, good or bad, to an antidepressant; possible drug-drug interactions; cost; and the side-effect profiles of the anti-depressants.⁷ Common SSRI side effects include anxiety/restlessness, insomnia, sedation, nausea, headache, sweating, and sexual side effects (decreased libido, impotence, anorgasmia). SSRIs and venlafaxine are associated with a high incidence of sexual side effects, while bupropion, nefazodone and mirtazapine are rarely or not associated with sexual dysfunction. Tricyclic antidepressants and mirtazapine are more likely to cause weight gain and are thus best avoided in overweight or obese patients. In theory, antidepressants do not differ from one another in efficacy, although some antidepressants are more effective in certain subtypes of depression (e.g. MAO inhibitors and fluoxetine SSRIs in atypical depression), and a given individual may respond to one antidepressant, or class of antidepressant, preferentially.

Polypharmacy is a concern with all antidepressants; several of the newer drugs are potent inhibitors of the cytochrome P-450 enzymes of the liver and have potential serious drug-drug interactions. It is critical to know what medications your patient is taking, as well as whether or not s/he uses herbal supplements. St John’s wort (Hypericum perforatum), for example, has been found (in some studies) to be effective in mild to moderate depression,^, but has also been demonstrated to change drug levels of other medications, most notoriously that of indinavir. Care should be taken when prescribing SSRIs or the atypical agents with the medications listed in Table 2. In vitro data suggest that the two newest drugs, venlafaxine and mirtazapine, and one of the SSRIs, citalopram, may exert the least effect on P-450 metabolism and may be the safest to use in patients on multiple medications.⁹

Pharmacologic treatment of depression has three phases: the acute phase (4 to 12 weeks) in which medication type and dosage is adjusted until remission of symptoms is achieved; the continuation phase, in which medication is continued at full therapeutic dose for four to nine months after the remission of symptoms; and the maintenance phase, in which susceptible patients (e.g. patients with a history of three or more depressive episodes) may be kept on medication for longer periods of time to decrease the risk of recurrence. When initiating pharmacologic treatment for depression, the Agency for Health Care Policy and Research recommends weekly visits to the physician for the first 6 to 8 weeks of acute treatment, and every 4 to 12 weeks thereafter.⁶ Practically speaking, this frequency of visits may not be possible or necessary for each patient. However, patients should be seen for follow-up within one to two weeks after starting medication, and then every two to three weeks thereafter until stable. These contacts may be in the form of brief office visits or telephone calls, and are important for monitoring side-effects, adherence, and symptom response. Patients who have expressed suicidal ideation should be followed closely until suicidal thoughts have resolved.

It is important to remember that antidepressants are not immediately effective against depressive symptoms (though side-effects such as sedation or activation may occur immediately), and most patients will not respond fully to a given dose of an anti-depressant until 4 to 6 weeks after initiating treatment. If there has been no, or minimal, response to an antidepressant after 4 weeks, once patient adherence with medication has been assessed, the dose of medication should be increased (e.g. increase fluoxetine from 20 mg to 40 mg). For patients on an antidepressant with established therapeutic blood levels, such as amitriptyline, nortriptyline, imipramine and desipramine, it would be appropriate to draw a blood level. For patients who have failed to respond to an 8-week trial of a given antidepressant at the maximum therapeutic, or maximum tolerated dose, the next step would be to switch to a different class of antidepressant. A primary care physician should feel comfortable with the use of two to three antidepressant medications, for example two SSRIs and one atypical agent.

A standard approach to the treatment of patients with the diagnosis of major depressive disorder is outlined above. The approach to treatment of patients with other types of depression may vary according to sub-type of depressive disorder, presence of another concurrent psychiatric disorder, patient age, and severity of depressive symptoms. The following is a partial list of such subgroups:

Patients who do not meet full criteria for a major depressive episode may nonetheless benefit from treatment. In particular, patients with dysthymic disorder may benefit from either medication, psychotherapy, or a combination. Dysthymic disorder is a milder, more chronic form of depression characterized by depressed mood for most of the day, more days than not, for at least two years, and accompanied by two or more of the following symptoms: poor appetite or overeating; insomnia or hypersomnia; low energy or fatigue; low self-esteem; poor concentration or difficulty making decisions; and feelings of hopelessness. Current evidence suggests that psychotherapy alone is not effective for this condition and antidepressant medication is recommended.

In patients who present with depressive symptoms in the context of a significant loss (bereavement after death of a loved one, for example) or life stress, the decision whether or not to treat will depend largely on the duration and severity of symptoms, and degree of functional impairment. In cases where such a depressive syndrome is mild to moderate, a reasonable first strategy might be to observe and evaluate the patient over time. If symptoms persist for more than six months, treatment should be considered.

Depression often occurs in the setting of another psychiatric disorder that may pre-date the onset of depressive symptoms. It is commonly seen with anxiety disorders such as panic disorder, generalized anxiety disorder and obsessive-compulsive disorder (OCD). In such cases, it would be preferable to treat with a medication that has been shown to be effective for both disorders, for example to use imipramine or fluoxetine to treat a depressed patient with panic attacks. Particularly troublesome to internists are patients with somatoform disorders and hypochondriasis, discussed in greater detail in Chapter 35. Somatizing patients may present with depressive symptoms; conversely, depressed patients may be more likely to somatize psychological distress. Any patient who presents with somatization ought to be evaluated for depression; if such a patient has depressed mood or anhedonia, an anti-depressant medication should be considered even if full criteria for major depression are not met. In patients with alcoholism or other substance abuse or dependence who present with depressive symptoms, the substance abuse should be addressed first, before any treatment for depression is initiated, since depressive symptoms may clear once the patient has been detoxified. , depressive symptoms may be related to an underlying major depression or may be secondary to the substance use. It is key to address treatment of the substance abuse or dependence with the patient. In patients with alcoholism, treatment with an antidepressant may be started concurrently. However, especially if the patient continues to drink alcohol, this is best done in consultation with a psychiatrist, given the risks of prescribing medication for these patients.

Depressed mood and demoralization may accompany or be a reaction to medical illness. In such cases it may be difficult to determine which signs and symptoms are due to medical illness and which represent a major depressive disorder. The presence of symptoms which are commonly associated with depression, but not so commonly with medical illness, can aid in making a diagnosis. These include feelings of guilt or worthlessness, early morning awakening, low self-esteem, loss of insight (i.e. negatively distorted perception of self and events), and indecisiveness. In addition, a history of past episodes of major depression or a history of affective illness in a first degree relative may raise the suspicion of major depression. In treating depression in the medically ill with antidepressant medication, close attention should be given to side effects and drug interactions that may complicate the underlying medical condition and limit treatment.

When treating depression in the elderly, several factors should be considered. In geriatric patients, concurrent medical illness or use of non-psychiatric medications may cause or contribute to depression. The presence of depression may contribute to subsequent physical decline and early detection and treatment of depression may prevent loss of function in elders. Age, co-morbidity and polypharmacy may also affect the metabolism of antidepressant drugs, or present relative contraindications for the use of certain agents, e.g: tricyclics in patients with cardiac disease. Elderly patients often require lower dosages of psychiatric drugs, due to slower metabolism or diminished volume of distribution. Given the anti-cholinergic and anti-adrenergic properties of the TCAs such as orthostatic hypotension, constipation, and urinary retention, the SSRIs may beare preferable as first line agents and should be used at lower doses in the elderly. Of note, fluoxetine is more likely to cause side effects in the elderly than in younger patients.

Depressed elders should also be carefully evaluated for dementia, since mood and personality changes may be part of the presentation of dementia. Cost of antidepressant medications is an important consideration, since many elderly patients need to pay for medication out-of-pocket, and many of the newer antidepressants are quite expensive.

Depressed patients often have suicidal thoughts, and it is estimated that 15 percent of all patients with severe major depression will commit suicide. The clinician should always inquire about suicidal thoughts in all depressed patients, and assess the degree of suicidal risk. Suicidal ideation occurs along a spectrum of severity, ranging from passive thoughts of death (the feeling that life is not worth living), to a wish to be dead, to an actual plan to kill oneself. Risk factors for completed suicide include prior suicide attempt(s), hopelessness, substance abuse, concurrent general medical illness, presence of psychotic symptoms, and living alone.⁵ Active suicidal ideation is a psychiatric emergency, and such patients should be promptly evaluated by a psychiatrist.

Although primary care physicians should be comfortable with the diagnosis and treatment of uncomplicated depressive disorders, consultation with a psychiatrist is indicated in several situations. Indications for consultation or referral include severe depression; presence of suicidality or psychotic symptoms; failure to respond to treatment after one to two adequate anti-depressant trials (see above for definition of adequate trial); and in cases where the clinician does not feel certain about the diagnosis or treatment.^5,,