Pathophysiology

Our understanding of the chemistry behind depression has grown dramatically, but much of it is theoretical, and it remains a very controversial subject. The neurochemical basis of depression is complex and is not the result of any one specific deficit. The function of the hypothalamic-pituitary axis and the involvement of stress-related hormones are increasingly believed to play a role in the development of depression. In reality, researchers do not know exactly what causes depression, even though the norepinephrine system has been studied intensively. Changes occur in the α- and β-adrenergic receptors—receptors that norepinephrine acts upon within the brain. Upregulation of β-receptors is thought to be due to a relative deficiency of norepinephrine at certain critical synapses in the brain. In older studies, measurements of norepinephrine metabolites, such as 3-methoxy-4-hydroxyphenylglycol (MHPG), have been reported as well. A relative lack of serotonin and decreased density of the postsynaptic 5-HT₂ receptors have been noted to produce a relative deficiency of serotonin in the brain. A relative lack of dopamine in presynaptic neurons and dopamine transporters has also been observed. Pharmacologic research demonstrates improvement in depression when drugs are administered that increase relative amounts of these chemicals in at best 60% of cases, leaving 40% of patients with an unacceptable response, thereby highlighting the complex pathophysiology and response to pharmacology.

Disease Process

Significant depressive symptoms are seen in nearly 40% of primary care patients, and major depression occurs in up to 10%. In general antidepressants are ineffective in treating depressive symptoms solely and for the most part ineffective in treating mild to moderate depression. Major depression is a common, vastly undertreated, and potentially fatal disease, while mild to moderate depression is vastly overdiagnosed and extremely overtreated and with suboptimal efficacy. Depression is common in postpartum mothers, both young and old. It is a heterogeneous disorder with a wide variety of presentations.

Many mood disorders must be differentiated. See Box 47-1 for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR) diagnostic criteria for major depression. The patient with suspected major depression must have these symptoms on a daily basis for a minimum of 2 weeks. In addition, the severity of symptoms must significantly impair the patient’s quality of life and ability to perform activities of daily living (ADLs). Five types of depression or basic clusters of symptoms are known. Cognitive symptoms include memory loss, slowed thoughts, decreased attention, and inability to concentrate. Vegetative symptoms include increased or decreased sleep, altered appetite or weight, psychomotor movement, and decreased sexual function. Physical symptoms consist of fatigue, muscle tension, pain—especially head and stomach—decreased sexual drive, and weakness. Behavioral symptoms include social withdrawal, loss of interest in usual activities, crying, weeping, decreased frustration tolerance, agitation and irritability, phobias, and poor attention to self-care. Emotional symptoms occur as guilt, feelings of worthlessness, suicidal ideation or behavior, disappointment with self, hopelessness, helplessness, anxiety, and delusions or hallucinations.

Another depressive disorder commonly seen in the primary care patient is atypical or “minor” depression. Symptoms of minor depression occur at the same frequency (i.e., daily, or nearly daily for at least 2 weeks) as those of major depression. However, patients with minor depression will have only two to four depressive symptoms that often include weight gain and hypersomnia. This contrasts with major depression, in which weight loss and insomnia are typically seen.

Dysthymia is a depressive disorder in which symptoms are present for at least 2 consecutive years; these include lack of interest, low self-esteem, and low energy. It is present in approximately 3% to 5% of primary care patients and responds poorly if at all to pharmacotherapy.

Bereavement over the loss of a loved one may be associated with symptoms of depression. Despite the findings that 94% of these patients will meet the definition of major depression, only 17% will be treated with antidepressants. Treating bereavement is controversial, as it may also be both harmful and ineffective. During the normal course of grief, 94% of symptoms have been found to resolve in 13 months and often dramatically sooner.

Catatonic depression, comorbid anxiety disorder, and seasonal affective disorder (SAD) are other types of depressive disorder. Other diagnoses that should be considered include depression with alcohol or substance abuse or dependence, prenatal and postpartum depression, comorbid personality disorder, and the depressive phase of bipolar disorder.

The presence of bipolar disorder in the depressive stage always must be considered by the clinician. Treatment of a bipolar patient with antidepressants may induce rapid cycling to manic phase, so careful monitoring is required, particularly if bipolar disorder is suspected but has not yet been confirmed.

The natural history of untreated depression is that of recurrence. Untreated depression may resolve without treatment, but recurrences are common. Risks for recurrence include increased severity and duration of the depression, psychotic symptoms, incomplete recovery between episodes, and prior episodes of depression. If a patient has had three or more episodes of depression, the chance of a relapse is greater than 90%.

Assessment

A complete history and physical examination are essential for the differential diagnosis of depression and for selection of the best medication for the patient. The discussion below is a brief review. Medical illnesses and medications also can contribute to the development of depression (see Tables 47-3 and 47-4). The diagnosis must rule out other factors such as drug or alcohol abuse, use of other medications, and medical conditions. Medical conditions that increase the risk of depression are cancer, chronic lung disease, heart disease, stroke, diabetes, end-stage renal disease, dementia, hypothyroidism, chronic fatigue syndrome, fibromyalgia, systemic lupus erythematosus, anxiety, and panic disorder. Also ask about past episodes of depression and hypomania and a family history of bipolar disorder. See Box 47-2 for a list of risk factors for depression.

Formal screening tools for depression such as the Zung Self-Assessment Depression Scale, the Beck Depression Inventory, and the General Health Questionnaire (GHQ) are available to the provider. The choice of one tool overanother is a matter of preference. Two questions may elicit depression: “Over the past 2 weeks, have you felt down, depressed, or hopeless?” and “Over the past 2 weeks, have you felt little interest or pleasure in doing things?” Patients who test positive should undergo a complete diagnostic interview for a specific depressive disorder based on DSM-IV criteria.

It is crucial to assess the risk of suicide in the depressed patient. The provider should pay particular attention to the presence of the following:

Selective Serotonin Reuptake Inhibitors

All SSRIs work by increasing the amount of serotonin by blocking the presynaptic serotonin reuptake pump. At least 14 different postsynaptic serotonin receptors are present in humans. Each of these receptors controls a different physiologic and/or psychiatric function. The action of the SSRIs is related to which postsynaptic receptor is stimulated. It is believed that the 5-HT_1A receptors are primarily responsible for the antidepressant effect and that the other receptor subtypes may be responsible for some of the side effects of SSRIs.

Serotonin/Norepinephrine Reuptake Inhibitors

Venlafaxine (Effexor) and desvenlafaxine are non–tricyclic antidepressants with dual serotonin and norepinephrine reuptake inhibition and weak reuptake inhibition of dopamine that has demonstrated efficacy in the treatment of depression and produces fewer side effects than are produced by tricyclics. Thus, they act on all three of the monoamine neurotransmitters, as do the TCAs. Different from the TCAs and similar to the SSRIs, venlafaxine has virtually no affinity for muscarinic, histaminergic, or α₁-adrenergic receptors. The side effect profile is thus closer to that of the SSRIs than the TCAs. At higher doses, the risk of high blood pressure is increased. Another SNRI, duloxetine hydrochloride (Cymbalta), was approved for the treatment of major depressive disorder. Duloxetine is an inhibitor of serotonin and norepinephrine reuptake and a lesser inhibitor of dopamine reuptake. Milnacipran (a non–FDA-approved antidepressant) is an inhibitor of norepinephrine and serotonin reuptake.

Norepinephrine and Dopamine Reuptake Inhibitors

Bupropion is structurally similar to amphetamine and is considerably different from other antidepressants. Bupropion acts weakly as a norepinephrine and dopamine reuptake inhibitor (NDRI). It uniquely increases dopamine in the nucleus accumbens, which is known as the “reward area” of the brain in smokers. Therefore, bupropion is used for the treatment of smoking cessation.

Tricyclic Antidepressants

The TCAs were discovered in the 1950s and are named for their chemical structure, which contains three rings. They are subdivided further into the tertiary and secondary amines. The secondary amines (desipramine and nortriptyline) are metabolites of the tertiary amines (amitriptyline and imipramine). This results in significant differences in the pharmacokinetic and pharmacodynamic effects of each drug.

TCAs exert their therapeutic effects by blocking (inhibiting) reuptake of norepinephrine and serotonin at the presynaptic neurons. They block the reuptake of dopamine to a lesser degree. Some TCAs block 5-HT receptors—an added therapeutic action. In addition, they block cholinergic, histamine, and α₁-adrenergic receptors; this effect is associated with the many side effects of TCAs. TCAs also block sodium channels in the heart and brain, which can cause cardiac arrhythmias and seizures.

Noradrenergic Antagonists

Introduced in 1997, mirtazapine is a tetracyclic compound that is unrelated to the TCAs. It is an α₂-antagonist that blocks the α₂-receptors on the adrenergic neurons. The α₂-receptors are noradrenergic receptors that act as presynaptic autoreceptors. When they detect adequate levels of norepinephrine, they stop norepinephrine release. An α₂-antagonist will block the negative feedback loop, raising norepinephrine levels. This same mechanism also will stop norepinephrine from blocking serotonin release, thus raising serotonin levels. The drug blocks three serotonin receptors (i.e., 5-HT_2A, 5-HT_2C, and 5-HT₃) and has antihistaminergic properties.

Serotonin 2 Agonist/Serotonin Reuptake Inhibitors

These agents block 5-HT receptors and serotonin reuptake presynaptically and postsynaptically. Their most powerful action is to block 5-HT receptors. This is called 5-HT antagonism. They block serotonin reuptake, as do the SSRIs, but this is a less potent action. They are weak α₁-adrenergic blockers.

Nefazodone is a weak blocker of norepinephrine reuptake inhibitors. It has virtually no affinity for cholinergic, α₂-, or β-adrenergic, dopamine D₁, D₂, or histamine receptors.

Trazodone also blocks histamine₁ (H₁) receptors, and this causes sedation.

Monoamine Oxidase Inhibitors

The monoamine neurotransmitters dopamine, norepinephrine, and serotonin are broken down by the enzyme MAO. MAOIs are the medications that block this breakdown, causing increased levels of these three neurotransmitters. The first two MAOIs that blocked the MAO enzyme were irreversible, but very new ones are reversible inhibitors of MAO, known as reversible inhibitor monoamines (RIMAs).